Plaintiff v Defendants

CONSUMER LAW - Whether devices not of 'merchantable quality' within the meaning of s 74D of the Trade Practices Act 1974 (Cth) or 'acceptable quality' within the meaning of s 54 of the Australian Consumer Law - Expectations of reasonable consumer of medical device - Medtel Pty Ltd v Courtney [2003] FCAFC 151; (2003) 130 FCR 182 - Lack of merchantable quality not established.

CONSUMER LAW - Where goods manufactured by foreign defendants in same corporate group and supplied by local corporations - Where foreign defendants had no place of business in Australia but impugned conduct took place in Australia - Whether foreign defendants can be found liable for contraventions of the Trade Practices Act 1974 (Cth) and the Australian Consumer Law - Whether certain conduct of foreign defendants was 'in trade or commerce' - Whether foreign defendants were carrying on business in Australia.

NEGLIGENCE - Duty of care - Content of duty owed by manufacturers and suppliers to end users of medical devices - Whether defendants were negligent in development, design and marketing of device - Extent of obligation to warn where products supplied through 'learned intermediaries' - Whether product information and warnings insufficient to inform consumers of potential risks - Wrongs Act 1958 (Vic), s 48 - Gill v Ethicon Sàrl (No 5) [2019] FCA 1905 - Merck Sharp & Dohme (Australia) Pty Ltd v Peterson [2011] FCAFC 128; (2011) 196 FCR 145 - Plaintiff failed to establish breach of duty owed by defendants.

LIMITATION OF ACTIONS - Whether certain actions statute-barred - Effect of long-stop provisions - Trade Practices Act 1974 (Cth), ss 74J, 75AO - Trade Practices Amendment (Personal Injuries and Death) Act (No 2) 2004 (Cth) ss 87F, 87G, 87H - Statutory claims of group members in respect of supply of devices before 13 July 2004 statute-barred - Statutory claims of group members in respect of devices supplied between 13 July 2004 and 28 June 2007 expired.

D Collins KC and B Walker SC with K Brazenor, D Wong and J Teng

French National Agency for Medicines and Health Products Safety

Trade Practices Act 1974 (Cth)

Therapeutic Goods Act 1989 (Cth)

Wrongs Act

Wrongs Act 1958 (Vic)

Competition and Consumer Act 2010 (Cth)

Evidence Act 2008 (Vic)

Trade Practices Amendment (Personal Injuries and Death) Act (No 2) 2004 (Cth)

1 This proceeding concerns Essure, a permanent contraceptive device that was commercially supplied to women in Australia between 2001 and August 2017 as an alternative to laparoscopic tubal sterilisation.

2 Essure is a spring-like device that consists of inner and outer metal coils with PET fibres located in between. During the implantation procedure, it is hysteroscopically inserted into a woman's fallopian tube. The outer coil is released and expands to press against the inner walls of the fallopian tube, holding the device in place. Features of the device including the PET fibres and expanded outer coil incited a localised inflammatory foreign body response in the fallopian tube in order to cause fibrosis resulting in tubal occlusion and sterilisation.

3 After the birth of her third child, the plaintiff Patrice Turner sought out options for permanent contraception. Essure was one of the options she discussed with her gynaecologist. Turner understood that Essure implantation was a day procedure, was less intrusive and had a faster recovery time than tubal ligation. She chose to proceed with Essure.

4 Turner returned to normal health a few days after the procedure was performed. However, within a few years she began to experience abnormal uterine bleeding ('AUB') and pelvic pain. Turner's menstrual bleeding became much heavier and lasted for longer. She also began to suffer sharp and debilitating pelvic pain, and constant heavy and dull pain in a band around her lower abdomen and back. Turner's symptoms worsened over time.

5 Almost five years after having Essure implanted, Turner consulted a gynaecologist who advised her to have a hysterectomy. By that time Turner was suffering severe pelvic pain and regular heavy menstrual bleeding. After Turner's hysterectomy, the debilitating symptoms she had been experiencing resolved. Turner was 32 years old when she had hysterectomy surgery.

6 Turner brings this representative proceeding on her own behalf and on behalf of all women who had Essure implanted and allegedly suffered harm as a result. She relies on three causes of action. First, Turner alleges that Essure had a defect within the meaning of s 75AC of the TPA and/or a safety defect within the meaning of s 9 of the ACL, giving rise to a cause of action under s 138 of the ACL ('Defect claim'). The defendants raised the statutory 'state of scientific knowledge' defence to the Defect claim. Second, she alleges that Essure was not of merchantable quality within the meaning of s 74D of the TPA and/or not of acceptable quality within the meaning of s 54 of the ACL, giving rise to a cause of action under s 271 of the ACL ('Merchantable Quality claim'). Third, Turner alleges that the third defendant, Bayer HealthCare LLC ('Bayer HealthCare') and the fourth defendant, Bayer Essure Inc ('Bayer Essure') were each negligent in the design, development, manufacture, supply and distribution of Essure in Australia. Further, Turner alleges that all of the defendants apart from the second defendant Bayer Aktiengesellschaft ('Bayer AG'), were negligent in failing to provide adequate warnings about the device defects and associated risks to women's health, and in failing to ensure that information disclosing the defects and risks was made available to women who already had Essure implanted ('negligence claims').

7 There were three important features of the case that were critical to the determination of the claims Turner made.

8 Turner alleged, as the first and principal limb of her case, that in a not insignificant number of women Essure caused ongoing chronic inflammation that resulted in chronic pelvic pain ('CPP') and AUB ('inherent defects'). Turner argued that unlike other implanted biomedical devices, Essure was designed to promote an inflammatory response in order to create scar tissue. She alleged there was an inherent risk that Essure would cause ongoing chronic inflammation in some women because of its fundamentally problematic design, and because of certain features of the fallopian tube environment and adjacent uterus. Turner alleged that in some cases, the corrosion of metal ions and particles from the device would likely cause or contribute to the chronic inflammatory response. Turner relied on expert evidence that ongoing chronic inflammation caused by Essure could result in women experiencing CPP, dysmenorrhea and/or AUB. She said this meant that many healthy young women who chose Essure as a permanent contraceptive option suffered severe symptoms that could only be resolved by major surgery involving removal of the fallopian tubes or uterus ('removal limitation'). The defendants argued that the foreign body response to Essure devices resolved normally and that there was no evidence that Essure could cause ongoing chronic inflammation resulting in CPP, dysmenorrhea or AUB.

9 The following categories of evidence were critical to the determination of whether, as a question of general causation, Essure can cause ongoing chronic inflammation resulting in CPP, dysmenorrhea or AUB. The first is clinical studies which report histologic assessment of fallopian tube tissue from women who had Essure devices surgically removed. Turner argued that the histologic assessments showed ongoing chronic inflammation that would be associated with adverse health outcomes in fallopian tube tissue caused by Essure devices in a not insignificant proportion of women. The defendants argued that the histologic assessments were evidence of a normal foreign body response to Essure, and that in most or all cases the assessments reported the mere presence of certain types of immune cells. The defendants argued the histological studies were not evidence that Essure can cause ongoing chronic inflammation that is pathologic and injurious to health.

10 The second category is corrosion studies. Turner argued that the studies showed that the Essure device corroded in vivo, resulting in significant accumulation of metal ions and particles in adjacent fallopian tube tissue. She argued that the accumulated metal ions and particles were likely to be a cause of ongoing chronic inflammation in some women. The defendants argued that the rate of Essure corrosion in vivo decreased over time. They accepted there was a risk that metal ions from a device could cause an allergic hypersensitivity reaction in some women, which could be associated with an ongoing inflammatory response. They argued that hypersensitivity reactions were extremely rare, the subject of an adequate warning, and amenable to treatment. The defendants argued that Turner had not established that corrosion occurred at a rate or to a degree that was unsafe, or that corrosion was a likely cause of ongoing chronic inflammation.

11 The third category is evidence of the biological plausibility of mechanisms that Turner argued explained how Essure could cause ongoing chronic inflammation leading to CPP, dysmenorrhea and AUB. Turner relied on what she submitted was compelling scientific opinion evidence of biological causal mechanisms provided by the expert witnesses she called. The defendants submitted that the expert evidence of causal mechanisms relied on by Turner amounted to no more than 'brainstormed' hypotheses which were hotly contested by their own expert witnesses. Further, the defendants argued that even if the biological explanations advanced by Turner were found to be plausible, they were not sufficient to establish that Essure was a cause of CPP and AUB, in the face of contrary evidence including epidemiological studies and the results of extensive testing conducted before and after Essure was placed on the market.

12 The fourth category is epidemiological studies examining the possibility of a relationship between Essure and adverse events including CPP and AUB, using laparoscopic tubal sterilisation as a comparator ('comparative studies'). The outcomes of these comparative studies do not show any increase in the rate of CPP and AUB for women who underwent hysteroscopic sterilisation (principally by use of Essure) compared to women who underwent laparoscopic sterilisation. Turner argued that high quality biostatistical studies of Essure should have but had not been undertaken and that the comparative studies were of inferior design and poor quality, meaning very little weight could be attributed to the available epidemiological evidence.

13 The defendants made two points in response. First, the defendants argued that consistent with the approach taken in legal authority and in scientific analysis, epidemiological evidence was critical to consideration of the possible causal connection between an exposure such as by implantation of Essure and the adverse outcomes under consideration. The defendants submitted that Turner's attempt to prove general causation without relying on epidemiological evidence was novel. Second, the defendants argued that the comparative studies, which examine the experiences of over 100,000 women, show that Essure is not associated with an increase in the incidence of CPP or AUB. The defendants submitted that the most probable explanation is that the rates of CPP and AUB identified in those studies reflect the background rates of those conditions experienced by women of reproductive age. The defendants argued that it logically follows from the outcomes of the comparative studies that Turner had not established an association, let alone a causal relationship, between Essure and CPP or AUB.

14 The fifth category is clinical evidence. The evidence of gynaecologists who had treated women for CPP, dysmenorrhea and AUB did not support a causal connection between Essure and these conditions. There is no evidence that laboratory tests for the presence of pathological chronic inflammation in women who had Essure devices implanted had been administered. The histological assessment in Turner's case did not report the presence of chronic inflammation in her fallopian tubes. Turner's medical records do not indicate that her treaters had a clinical suspicion of pathologic chronic inflammation. Turner's treating surgeon, who was not called to give evidence, diagnosed adenomyosis as the cause of her gynaecological symptoms.

15 The final category is evidence of the prevalence and range of causes of CPP and AUB in women. CPP and AUB commonly affect women of reproductive age. There is a broad range of potential causes of both disorders. Diagnosis is complex and causation is often multifactorial. It is not uncommon that no causal pathology is identified. This context is relevant to Turner's attempt to attribute causation of CPP and AUB to Essure.

16 For the detailed reasons that follow I have largely accepted the defendants' submissions. I have concluded that the biostatistical evidence weighs heavily against causation, and represents a very significant barrier to Turner proving general causation. The evidence supporting general causation in the histological and corrosion studies, and the expert evidence of biologically plausible causal mechanisms is far from compelling. The clinical evidence does not support general causation. In relation to the first limb of Turner's case, I am not satisfied that she has established that Essure can cause ongoing chronic inflammation in some women resulting in CPP, dysmenorrhea and/or AUB.

17 The second feature of Turner's case was her allegation that, following implantation, there were risks that an Essure device would migrate into the peritoneal cavity; be expulsed from the fallopian tube; break or fragment; corrode; fatigue; perforate the fallopian tube, uterus or other organs such as the bowel; and/or leach nickel or other metals into the body of the recipient ('failure defects'). Turner alleged that eventuation of one or more of these risks could result in new pain or increased pain including dysmenorrhea, new or increased menorrhagia and/or damage to internal organs.

18 The defendants accepted that there were risks of migration, expulsion, perforation and metal leaching that may be associated with adverse health outcomes. They argued that these risks were associated with many biomedical devices and surgical procedures, that the degree of risk was low, that the magnitude of an adverse health outcome if a risk eventuated was likely to be small, and that the risks were the subject of adequate warnings. The defendants argued that the only evidence of the devices breaking or fragmenting was in the process of surgical implantation or removal, and that Turner had not proven a risk that Essure devices could corrode or fatigue resulting in them breaking or fragmenting in vivo.

19 The third feature of Turner's case was her allegation that the defendants distributed patient information brochures ('PIBs') and published webpages about Essure which did not adequately disclose the risks of adverse events and outcomes Essure could cause. The defendants accepted they did not provide a warning that Essure could cause ongoing chronic inflammation resulting in CPP, dysmenorrhea or AUB because they said that risk did not exist. They argued that the warnings and information they provided about Essure included the content of training programs for gynaecologists who performed the Essure procedure, physician training manuals ('PTMs') provided to gynaecologists, and Instructions For Use ('IFUs') supplied with Essure devices. They argued that this material adequately disclosed risks that were associated with Essure, and that Turner had not demonstrated any relevant deficiency in the information provided about the device.

20 There was a risk that an Essure device could migrate, be expulsed from the fallopian tube, perforate organs, corrode, and leach nickel or other metals into the body. I conclude that in most cases, the degree and magnitude of these risks were small and that they were often associated with placement or removal of the device. I do not accept that there was a risk that Essure could break, fragment or fatigue once implanted in the body.

21 I have again largely accepted the defendants arguments. I have concluded that the defendants provided adequate warnings of the established Essure risks in the PTMs and IFUs. It was reasonable to expect that treating gynaecologists would provide information and warnings about the established risks to their patients based upon their own specialist skill, expertise and experience and the information provided by the defendants. The PIBs and webpages relied on by Turner did not represent the entirety of the information and warnings about the Essure risks provided by the defendants and available to women considering undergoing the Essure procedure.

22 For the reasons that follow, I have concluded that the three claims made by Turner have failed.

23 The uterus is an inverted pear-shaped muscular organ of the female reproductive system, located in the middle of the pelvis in the space between the bladder and the rectum.[1] A circular narrowing in the inferior portion of the uterus divides it in two. The upper part is called the uterine corpus (body of the uterus). The lower part is called the uterine cervix (cervix), and is a tubular structure that connects the endometrial cavity and the vagina. The cervix, uterine corpus, fallopian tubes and ovaries together form the female upper genital tract (shown in the following diagram).[2]

24 The uterus has three main layers. The outer layer that forms the surface of the organ facing the peritoneal cavity is the serosa or perimetrium. The thick muscular wall of the uterus is the myometrium. The inner layer of the uterus is the endometrium, where embryos normally implant and develop when a pregnancy occurs.[3] The endometrium itself is divided into three layers: the thin surface layer called the epithelium; the functionalis or 'functional' layer, which contains glands that are most responsive to the hormones estrogen and progesterone during the menstrual cycle and is completely shed during menstruation; and the less responsive basalis or 'basal' layer located between the functionalis and myometrium.[4]

25 The epithelium consists of a single layer of epithelial cells. It provides a degree of protection from infectious organisms but is soft, easily damaged and does not protect against chemical agents or trauma.[5]

26 The hormonal response of the functionalis results in transient changes to its physical structure, cellular composition and function over the course of the menstrual cycle. Each month, estrogen stimulates the dynamic growth and proliferation of the functionalis, followed by degeneration and shedding in response to progesterone. The cycle of menstruation then regeneration, represented in the following diagram, is unique to the uterus.[6]

Glands in the functionalis become progressively more secretory in the second half of the menstrual cycle, delivering fluids into the endometrial cavity to support an embryo that may have formed in the event of conception. If conception has not occurred the endometrial layer will undergo a phase of senescence, with cells beginning to die and be progressively lost as menstrual fluid.[7]

27 The myometrium has robust contractile action that is most important for labour and birth, but also promotes shedding and expulsion of endometrial tissue during menstruation. This can cause menstrual cramping and pain that should not occur to the level that interferes with normal daily functions.[8]

28 The two fallopian tubes arise from the body of the uterus and provide the connection between the uterus and each ovary.

29 The fallopian tube has four segments. The funnel-shaped infundibulum is the distal end of the tube that opens into the peritoneal cavity adjacent to the ovary. Attached to the distal end of the infundibulum are fimbria, which are finger-like mucosal projections which project over the medial surface of the ovary. The ampulla is the longest segment of the fallopian tube. Fertilisation usually takes place within the lumen of the ampulla.[9] The final two segments of the fallopian tube are the isthmus which is about 2-3 cm long, followed by the intramural region (also known as interstitial region or SUTJ) which is approximately 1 cm long and connects the fallopian tube and the uterus.[10]

30 The fallopian tube has three layers: an outer serosa layer, a middle smooth muscle layer and an inner mucosal layer comprised of lamina propria (a thin layer of connective tissue) covered by a single columnar epithelial lining.

31 The features and dimensions of different segments of the tube vary relative to the role played in transporting ova, sperm and early embryos; conception; and early embryo development.[11] A diagrammatic illustration of conception in the fallopian tube and implantation of the embryo in the uterus follows:[12]

32 The external diameter of the fallopian tube and the internal diameter of the lumen progressively reduce along its length as it approaches the uterus. The ampulla has large numbers of branching folds that appear in cross-section as a labyrinth of finger-like projections with little space between them. The folds are less highly branched and numerous in the isthmus, and less again in the intramural region.[13] These features are demonstrated in the following figure:[14]

Figure 2. Normal fallopian tube anatomy and the microscopic findings at each segment. All histologic images are at 10x, low magnification except the second isthmus image, which is at 20x, medium magnification. The intramural cross section demonstrates a fallopian tube lumen with surrounding uterine smooth muscle (myometrium). The first cross section of isthmus is surrounded by the fallopian tube muscular wall (myosalpinx), which is composed of 3 layers 1) an inner longitudinal layer, 2) a circular layer 3) an outer longitudinal layer. The second cross section of isthmus shows a thick-walled muscle layer. Note the expanded lumen with more plica (longitudinal branching folds) compared to the first cross section of isthmus. The ampulla has a thin-walled muscular area and an expanded lumen with normal plicae. The fimbriated end has numerous finger-like projections, each covered with a single layer of epithelium.

The narrowing of the lumen of the fallopian tube is necessary to allow the inner walls to form contact with the embryo and propel it towards the uterus.[15]

33 The transport of ova and embryos in the direction of the uterus is mediated by delicate cilia (fine hair-like structures) on the surface of the fimbriae in specialised cells of the tubal epithelium. These cilia cells beat in the direction of the uterus, creating a current that transports the ovum towards the site of fertilisation.[16] Peristaltic activity in the tubal muscular layer propels sperm against the current of the cilia from the uterine end of the fallopian tube into the ampulla, where fertilisation of the ovum takes place.[17]

34 Any surgical procedure that prevents transport of the ovum, sperm and/or early embryo along the fallopian tube by occluding, interrupting or removing a segment or the entirety of both tubes is a method of permanent sterilisation.[18]

35 Essure was developed as an alternative to tubal ligation. Each Essure device is comprised of:

(a) a 316L stainless steel inner coil;

(b) a chromium doped nitinol (nickel/titanium) dynamically expanding outer coil;

(c) PET fibres attached to the inner coil;

(d) a ball tip at the distal end of the inner coil, composed of either silver-tin solder or remelted 316L stainless steel;[19]

(e) a platinum/iridium half band at the proximal end of the outer coil; and

(f) a platinum/iridium positioning marker attached to the inner coil.[20]

36 Each device was delivered hysteroscopically into the fallopian tube in a wound down configuration, attached to a delivery wire, constrained by a release catheter and sheathed by a flexible, hydrophilically coated delivery catheter. In the wound down configuration, an Essure device was approximately 4 cm in length and 0.8 mm in diameter. The delivery catheter extended only to the joint between the inner and outer coil. The unsheathed ball tip acted as a guidewire to cannulate the fallopian tube. The platinum/iridium half band and positioning marker acted as a visual guide for the physician to determine the correct depth of insertion into the fallopian tube. Once released, the device expanded to an approximate diameter of 2.0 mm to acutely anchor itself into the fallopian tube, with a number of outer coils trailing into the uterus. A drawing of the Essure device and the internal delivery components is shown below:

37 The Essure insertion procedure was designed to be performed without the need for incisions. In Australia, the Essure procedure was performed under anaesthetic in an operating theatre setting by a gynaecologist.[21]

38 The intended placement of the Essure insert in the fallopian tube and uterine cavity is shown in the following diagram:[22]

39 The PET fibres were intended to promote an inflammatory response resulting in fibrotic tissue ingrowth that secured the device in place and occluded the fallopian tube lumen, resulting in permanent sterilisation.

40 Turner was born in 1986. She has three children. In September 2013 after the birth of her youngest child, Turner underwent hysteroscopic implantation of Essure into each of her fallopian tubes. Turner had hysterectomy surgery resulting in explantation of the devices on 25 June 2018.

41 Turner brings this proceeding on behalf of all women who had Essure devices implanted at any time on or before 31 December 2018, and who have suffered harm as a result.

42 Essure was at all times manufactured overseas and imported into Australia. From the late 1990s, some Essure devices were supplied for clinical trials conducted in Australia that involved implantation into participating women. The defendants admitted that Essure devices were commercially supplied in Australia from about 2001 to 28 August 2017 ('commercial supply period').

First defendant - Bayer Australia Ltd ('Bayer Australia')

43 Bayer Australia is an Australian corporation in the Bayer group of companies which was the registered sponsor of Essure on the ARTG under the TG Act from 29 January 2018 to 9 February 2018. Bayer Australia admitted that its name was included on some material published in Australia regarding Essure between 1 July 2013 and August 2017.[23] What further role, if any, Bayer Australia played in relation to Essure was in issue. Turner alleged that Bayer Australia was a 'manufacturer' of Essure within the meaning of s 7 of the ACL. Bayer Australia submitted that it did not supply Essure in Australia and was not a manufacturer of Essure for the purposes of the ACL.

44 Bayer AG is a corporation registered in Germany. It has no place of business or registered office in Australia.

45 Bayer AG is the owner of the following trademarks numbered 1950359, 242139, 242143 and 1188965:

From around 1 July 2013 to August 2017, one or more of these trademarks appeared on some material published in Australia regarding Essure. Turner submitted the evidence established that Bayer AG was a manufacturer of Essure under the ACL from 5 June 2013. Bayer AG submitted that because of the extra-territorial provisions of the ACL, the legislation did not apply to it; and that in any event, it was not a manufacturer of Essure within the meaning of the ACL and did not supply the device in Australia.

46 Bayer HealthCare is an indirect subsidiary of Bayer AG and is a limited liability company registered in Delaware in the US.

(a) it was responsible for the design and development of Essure from around 5 June 2013 to 1 January 2016;

(b) it was responsible for limited manufacturing and assembly of Essure from around 1 July 2013 to 1 January 2016;

(c) it supplied Essure for importation into, and distribution in, Australia from around 1 July 2013 to 31 May 2017;

(d) from around 1 July 2013 to August 2017, some material published in Australia regarding Essure included the name of Bayer HealthCare; and

(e) it was the registered manufacturer of Essure on the ARTG from around May 2014 to 9 February 2018.[24]

Bayer HealthCare admitted that it was a manufacturer of Essure in accordance with the TPA and ACL from 5 June 2013 until about 9 February 2018.[25] However, it denied that it came within the extra-territorial jurisdiction of the TPA and ACL and argued that the statutory provisions Turner relied on did not apply to it.

48 Bayer Essure is a company registered in Delaware in the US.

49 From 1992 to 25 October 2013, Bayer Essure was named Conceptus Inc ('Conceptus'). On 5 June 2013, Conceptus was acquired by a wholly owned subsidiary of Bayer HealthCare. On 25 October 2013, Conceptus changed its name to Bayer Essure Inc.

50 During the period from December 1999 to around 1 July 2013, Bayer Essure (as Conceptus) designed, developed and manufactured Essure and supplied the device for importation to Australia.[26] Bayer Essure admitted that from about 1999 to about 2014 it:

(a) owned the trademark 'Conceptus' and the Conceptus logo; and

(b) was listed on the ARTG as the manufacturer of Essure.[27]

51 Bayer Essure admitted that it was a manufacturer of Essure from about 1999 to about 1 May 2014 within the meaning of s 74A of the TPA and s 7 of the ACL.[28] Bayer Essure denied that it was a manufacturer of Essure under the ACL at any time from 1 May 2014. Further, Bayer Essure denied that it came within the extra-territorial jurisdiction of the TPA or ACL.

52 Gytech was the importer and the exclusive distributor of Essure in Australia, and the registered sponsor of the device on the ARTG, from 19 August 2010 to 31 December 2014. Gytech admitted it was a manufacturer of Essure for the purposes of the TPA and ACL during this period.[29]

Sixth defendant - Australian Medical & Scientific Ltd ('AMSL')

53 AMSL is incorporated in New Zealand and registered in Australia as a foreign company. From around 23 January 2015 to 28 January 2018, AMSL was the registered sponsor of Essure on the ARTG. From 1 January 2015 to around 31 May 2017, AMSL was the importer and sole distributor of Essure in Australia. From 2015 to 2017, AMSL promoted and marketed Essure in Australia and the AMSL name appeared on material relating to Essure during this time. AMSL admitted it was a manufacturer of Essure within the meaning of s 7 of the ACL from 1 January 2015 to 1 August 2017.[30]

54 Turner alleged that Essure was defective, and that this resulted in the risk of women who had the devices implanted suffering from adverse events and injuries. She alleged that the defendants failed to disclose the existence of the defects and the risk of adverse events in the marketing material they published. These allegations were the foundation of each of the claims advanced by Turner.

55 In paragraph [18] of her amended statement of claim ('ASOC'), Turner alleged that by reason of its design and method of operation, Essure:

1. disrupted the inner layers of the uterine horn and/or the fallopian tubes;
2. caused initial acute inflammation in the fallopian tubes and/or endometrium;
3. caused ongoing chronic inflammation in the fallopian tubes and/or endometrium; and/or
4. incited a foreign body response to the Essure Insert in the fallopian tubes and/or endometrium and/or uterine cavity.[31]

In her final submissions, Turner clarified that the matters alleged in sub-paragraphs (a), (b) and (d) above were not relied on as separate defects, but were part of the explanation for why Essure caused chronic inflammation in some women. A central issue at trial was whether Turner had established the allegation in (c) above.

56 Turner alleged that an ongoing chronic inflammatory response to Essure occurred in some women implanted with the device by reason of:

(i) the acute inflammatory response not resolving;

(ii) limited biocompatibility in the constituent materials of the Essure Insert hindering the physiological healing process following acute inflammation;

(iii) lack of surface functionalisation of the Essure Insert;

(iv) the metal and synthetic components of the Essure Insert including the mixing of metals of different electrochemical potential;

(v) corrosion and metal ion release;

(vi) micromovements causing ongoing mechanical injury in the tissue of the fallopian tube;

(vii) the Essure Insert not resorbing in the body;

(viii) the Essure Insert not promoting a functional integration with host tissues;

(ix) the propensity of female reproductive tissue and organs towards a pro-inflammatory response; and/or

(x) the interaction of the female reproductive tissue with the Essure Insert as a foreign body and the elicitation of the foreign body response.[32]

57 The defendants agreed that Essure was designed to disrupt the inner layers of the fallopian tube upon insertion, cause acute inflammation and incite a foreign body response. They said that this was a necessary part of the process leading to development of fibrotic scar tissue to occlude the fallopian tube. However, the defendants denied that Essure caused an ongoing chronic inflammatory response as alleged.

58 In paragraph [19] of the ASOC, Turner pleaded that there was a risk that following implantation, an Essure device:

1. would:
   1. migrate, including into the abdominal cavity;
   2. be expulsed from the fallopian tube and/or uterus;
   3. break or fragment;
   4. corrode;
   5. fatigue; and/or
2. would perforate the fallopian tube, uterus or other organs such as the bowel; and/or
3. would:
   1. leach nickel or other metals into the body of the recipient; ...[33]

59 The defendants agreed that unsatisfactory location of the device during implantation could be associated with migration, expulsion or perforation of the fallopian tube, uterus or bowel in some patients. They said that nickel alloys were commonly used in medical devices, and that nickel may be released at low levels from an Essure device following implantation. They said that during the commercial supply period, publications were made available to doctors and patients in Australia regarding Essure that contained information and risk warnings about matters including the following:

(i) the fact that all medical procedures and implantable devices carry risks and that there were risks associated with implantation and use of the Essure Device; and

(ii) risks that may be associated with implantation, use and/or removal of the Essure Device included:

1. movement of the Essure Insert such as migration or expulsion from the fallopian tube;

2. breakage or fragmentation of the Essure Insert during removal;

3. perforation of or damage to internal organs such as the uterus during implantation or as a result of unsatisfactory location of the Essure Insert during the implantation process;

4. an allergic reaction to nickel-titanium;

5. pain; and

6. bleeding.[34]

60 The defendants accepted that an Essure device may corrode in vivo. However, they denied that there was a risk that a device might break or fragment because of corrosion or fatigue, or that this could result in migration, expulsion, perforation or injury.

61 The defendants argued that the degree and magnitude of the admitted risks were small.

62 Turner alleged in paragraph [20] of the ASOC that, by reason of any one or more of the inherent defects and/or the failure defects, there was a risk that an Essure insert would cause:

1. pain or increased pain, including serious, chronic and/or recurring pain;
2. new, increased or worsened menorrhagia (heavy menstrual bleeding);
3. new, increased or worsened dysmenorrhoea (intense uterine cramping and pain); and/or
4. damage to internal organs.[35]

63 Turner principally relied on ongoing chronic inflammation as the cause of the adverse events in (a), (b) and (c) above. At trial, those adverse events were described broadly as CPP, dysmenorrhea and AUB. The risk of the adverse event in (d) was alleged to arise from perforation, migration, breakage or fragmentation of the device and to result in pain and bleeding.

64 The defendants denied there was a risk that Essure could cause ongoing pathologic chronic inflammation resulting in CPP or AUB.

65 The defendants relied on the information and warnings they had made available to doctors and patients in Australia regarding the risk of adverse events associated with Essure.

66 It was not in dispute that Essure was designed to anchor in a woman's fallopian tube after insertion and quickly become embedded in fibrotic tissue.

67 Turner alleged that a woman who experienced an adverse event associated with Essure would be unable to resolve the adverse event without abdominal surgery to remove the insert. This removal surgery would likely involve a salpingectomy or hysterectomy. Turner relied on the removal limitation as being relevant to the magnitude of the risk of an adverse event.

68 The defendants admitted that Essure was designed to promote tissue ingrowth and long-term anchoring, and might require salpingectomy or hysterectomy to effect its removal if a patient experienced an adverse event. They alleged that information and risk warnings made available to doctors and patients regarding Essure included:

1. the fact that all medical procedures and implantable devices carry risks and that there were risks associated with implantation and use of the Essure Device;
2. the Essure Device procedure was permanent and not reversible;

1. removal of the Essure Insert may require surgery; and

1. if surgical removal of the Essure Insert was required, a salpingectomy or hysterectomy might be required[.][36]

...[b]y reason of one or more of the Inherent Defects, the Failure Defects and/or the Removal Limitation and/or the occurrence of one or more of the Adverse Events, the Plaintiff and group members suffered injuries as a result of implantation of the Essure Insert.[37]

70 The particulars of injuries allegedly resulting from the inherent defects include:

(iv) By reason of the Inherent Defects and/or the Removal Limitation, some Group Members suffered the following injuries (GM Implantation Injuries):

...

1. the development of acute and then chronic or persistent chronic inflammation in the fallopian tubes and/or endometrium; and

   1. associated symptoms or conditions of pain (including pelvic or abdominal pain o[r] cramping) and/or abnormal uterine bleeding, and/or menstrual abnormalities, (including exacerbation of any of the above), some with resulting sexual dysfunction, and/or psychological conditions or symptoms;

   2. in some cases requiring:

      1. hysterectomy (with or without bilateral or unilateral salpingectomy and with or without oophorectomy);
      2. salpingectomy (bilateral or unilateral, with or without oophorectomy and/or corneal resection)[.] [38]

71 Turner particularised injuries resulting from the failure defects as follows:

(vii) By reason of the Failure Defects, in some Group Members the Essure Device migrated, was expulsed from the fallopian tube or uterus, broke or fragmented, corroded, fatigued and/or leached nickel or other metals into the body of the recipient.

(viii) By reason of the matters in the previous subparagraph, some Group Members suffered:

1. disruption of tissue;

2. acute inflammation;

   1. chronic or persistent chronic inflammation; and/or

   2. damage to internal organs; and/or

   3. associated symptoms or conditions of pain (including abdominal, pelvic pain and cramping) and/or bleeding (including menstrual abnormalities) (including exacerbation of any of the above), some with resulting sexual dysfunction, and/or psychological conditions or symptoms;

   4. in some cases requiring:

      1. hysterectomy (with or without bilateral or unilateral salpingectomy and with or without oophorectomy)
      2. salpingectomy (bilateral or unilateral, with or without oophorectomy and/or corneal resection);
      3. surgery to investigate the cause of symptoms or conditions;
      4. other surgery to excise the device from the body; and/or
      5. removal of other organs or part of an organ.[39]

72 The defendants' case was that there were known or expected risks associated with implantation of a biomedical device such as Essure; that they communicated information and warnings about those risks in published material made available to doctors and potential recipients of Essure; and that the degree and magnitude of the risks were small.

73 Turner alleged that between 1999 and 2018, the defendants published PIBs and webpages about Essure which were directed to potential recipients of the device ('marketing material'). Turner alleged:

The Marketing Material did not or did not adequately disclose the existence of the Inherent Defects, the Failure Defects, the risk of Adverse Events, and/or the Removal Limitation (the Marketing Conduct).

Particulars

(i) The Marketing Material did not contain express references to the Inherent Defects, the Failure Defects, the risk Adverse Events and/or the Removal Limitation.

(ii) To the extent that the Marketing Material made any references to any one or more of the Inherent Defects, the Failure Defects, the Adverse Events and/or the Removal Limitation, any risks were downplayed and/or were represented as rare and/or temporary.

(iii) The general impression given by the Marketing Material was that the Essure Device was safe, gentle and had a low impact on the body.

(iv) There was no or no adequate reference to the Essure Insert operating as an intrauterine device nor to any increased risks associated with the Essure Device and any pain or bleeding conditions. [40]

...

74 The defendants responded that Essure was supplied to women via their treating gynaecologist, and that publications they made available to gynaecologists and women regarding Essure disclosed the risks associated with implantation of the device. The publications relied on by the defendants were the PIBs, IFUs contained in the boxes in which Essure was supplied, and PTMs provided to doctors as part of training for the Essure procedure. The defendants alleged that prior to performing the Essure procedure the gynaecologist would, as a matter of course, have consulted with the patient, synthesised information relevant to the patient's needs, provided information and advice about Essure, and made recommendations as to the most appropriate contraceptive option for the patient. The defendants alleged that in those circumstances, it was reasonable for them to expect that a patient undergoing the Essure procedure would be informed by their doctor of the risks and benefits associated with alternative contraceptive options, including Essure.

75 The defendants' response to the risks associated with Essure alleged by Turner dictated the central matters in issue at trial. As stated above, the defendants accepted that some of the alleged risks existed. The defendants argued that context relevant to consideration of the accepted risks included the following: every contraceptive option carries risks; all medical procedures and implantable devices carry risks; information and warnings were made available to doctors and patients in Australia regarding the risks; it was reasonable to expect that doctors would inform their patients about the comparative risks and benefits of Essure; and the magnitude and degree of the accepted risks was small.

76 The defendants understandably took a different approach to the pleaded risks which they argued did not exist. The defendants accepted that they did not provide information or warnings to doctors or patients about the risk that Essure could cause ongoing pathologic chronic inflammation resulting in CPP or AUB, because they denied that risk existed. The most significant issue at trial was whether Turner had established the existence, degree and magnitude of this alleged risk.

77 Turner alleged that by reason of the inherent defects, failure defects, adverse events and removal limitation, the Essure devices acquired by her and group members were not sufficiently fit for purpose, free from defects or as safe as would be expected by a reasonable consumer. Turner alleged on this basis that Essure was not of merchantable quality within the meaning of ss 74D(1) and 74D(3) of the TPA and/or was not of acceptable quality within the meaning of s 54 of the ACL.

78 Turner alleged that by reason of the inherent defects, failure defects, adverse events and the removal limitation, along with the marketing conduct, the safety of Essure was not such as persons generally were entitled to expect. Turner alleged on this basis that Essure had a defect within the meaning of s 75AC of the TPA and/or a safety defect within the meaning of s 9 of the ACL.

79 Turner alleged that she and group members had suffered loss and damage by reason of Essure not being of merchantable/acceptable quality and/or having a defect/safety defect. She claimed that group members were entitled to damages under the TPA against Bayer Essure in respect of the period to 31 December 2010, and under the ACL against all defendants for the period from 1 January 2011.

80 Turner made a claim in negligence against Bayer Essure as manufacturer for the whole period that Essure was supplied in Australia. Turner alleged that the inherent defects, failure defects, adverse events and removal limitation gave rise to risks of harm that were foreseeable and not insignificant. She alleged that a reasonable person in the position of Bayer Essure would have:

(a) not designed, developed or manufactured Essure; and/or

(b) not distributed or supplied the device for sale in Australia.

81 Turner alleged in the alternative that a reasonable person in the position of Bayer Essure would have taken reasonable care to ensure that:

(a) Essure was promoted or marketed to potential recipients with adequate warnings about the inherent defects, the failure defects, the risk of adverse events and the removal limitation; and

(b) information disclosing the inherent defects, failure defects and risk of adverse events was made available to persons who had already received Essure.

82 Turner alleged that Bayer Essure breached its duty of care to her and group members by:

(a) designing, developing and manufacturing Essure;

(b) distributing or supplying Essure for sale in Australia;

(c) promoting or marketing Essure without adequate warnings about the inherent defects, failure defects, risk of adverse events and removal limitation;

(d) failing to make available to the plaintiff and group members who had already received Essure, information disclosing the inherent defects, failure defects, and/or risk of adverse events.

83 Turner made a claim in the same terms against Bayer HealthCare from 1 July 2013.

84 Turner made claims against Gytech and AMSL for the period that each was the importer and exclusive distributor of Essure in Australia. She alleged that each of those companies knew or ought to have known that Essure had the inherent defects, failure defects, risk of adverse events and removal limitation. She alleged that Gytech and AMSL breached the duties they owed by failing to warn group members about those matters.

85 Turner also made a 'failure to warn' claim against Bayer Australia for the period from 2014.

86 The defendants raised a number of defences in relation to Turner's pleaded claims. Some of the defences are relevant to the consideration of the individual claims of group members and are unnecessary to discuss further in these reasons.

87 The defendants pleaded reliance on State-based limitations statutes in relation to the negligence claim: ss 74J, 75AO, 82 and div 2 of Part VIB of the TPA; div 2 of Part VIB of the CCA; and ss 143 and 236 of the ACL.

88 The defendants do not allege that Turner's case is statute-barred.

89 I will return to the issue of limitations in Chapter XXII of these reasons.

90 The defendants alleged that should the Court find some of the defects alleged by Turner were caused by Essure, that the state of scientific and technical knowledge during the relevant period was not such as to enable those defects to be discovered.[41] The defendants relied on s 75AK(1)(c) of the TPA and s 142(c) of the ACL.

91 The defence is invoked in respect of the following alleged defects:

(a) 'ongoing chronic inflammation', insofar as that term refers to persistent, pathologic chronic inflammation;

(b) the inherent defects insofar as they are alleged to have operated outside of the fallopian tubes (namely, in the endometrium and/or uterine cavity and/or uterine horn);

(c) a number of the alleged failure defects, being the risks of:

(i) corrosion (other than in relation to the silver-tin solder component of the device, and beyond the ordinary low-level rate at which all implanted medical devices release metal ions in situ);

(ii) fatigue;

(iii) leaching of nickel or other metals (other than in respect of hypersensitivity reactions, and beyond the ordinary low-level rate at which all implanted medical devices release metal ions in situ); and

(iv) the alleged 'adverse events' other than the pain, bleeding and damage to internal organs specifically warned of during the relevant period.[42]

92 The defence is not invoked in respect of those risks associated with Essure which the defendants accept exist.[43]

Safety defects did not exist at the time of supply

94 The defendants also relied on s 75AK(1)(a) of the TPA and s 142(a) of the ACL in relation to the Defect claim. Section 142(a) of the ACL relevantly provides:

In a defective goods action, it is a defence if it is established that:

(a) the safety defect in the goods that is alleged to have caused the loss or damage did not exist:

...

(ii) in any other case - at the time when the goods were supplied by their actual manufacturer[.]

95 This defence requires the manufacturer to prove that the defect did not exist at the time that the goods 'passed from the manufacturer's control'.[44]

96 The defendants relied on this defence to the extent any safety defects that are found came into existence by reason of the acts or omissions of gynaecologists who consulted with women and performed Essure procedures, where those gynaecologists:

(a) did not provide advice and warnings to women about matters contained in information made available to them regarding Essure;

(b) did not carry out the Essure procedure properly.

97 Consideration of this defence does not arise in Turner's own case or on the common questions. The defence may arise for consideration on the circumstances of an individual group member's claim. It does not need to be further addressed in these reasons.

98 To the extent that Turner's pleaded claims are subject to the Wrongs Act, the defendants submitted that in the event the Court accepts that the personal injuries alleged to have been suffered by Turner are the result of Essure and but for Essure would not have been suffered, they accept that Turner satisfies the 'significant injury' threshold, and is therefore entitled to recover damages for non-economic loss.

99 I return to the application of the Wrongs Act to the assessment of Turner's claim in Chapter XIX.

100 The defendants further rely on the applicable State and federal civil liability legislation in respect of the determination of individual group members' claims. This does not need to be further addressed in these reasons.

101 Lorraine Shields is Turner's mother. She lives in Mount Gambier and is a registered nurse. Turner lived with Shields for brief periods of time in late 2015 and late 2016.

102 Jason Smith is Turner's partner. They began dating in November 2015 and he lived with her in Ballarat between around March 2018 and June 2019.

103 Ulrike Bodesheim is the current head of regulatory affairs, strategy, cardiology and nephrology for the second defendant, Bayer AG. Bodesheim worked within the Global Regulatory Affairs team at Bayer AG from about June 2006, and was head of the Regulatory Affairs Strategy Women's Health Care team from about July 2015 until about March 2021. The latter team is part of the Global Regulatory Affairs team, which is broadly responsible for developing and implementing integrated global regulatory strategies.

104 Christian Schalk is a lawyer and the senior trademark counsel at Bayer Intellectual Property GmbH, a fully owned affiliate of Bayer AG. He has been in this role since 2007. He oversees all trademark matters related to the pharmaceutical division of Bayer AG.

105 Patricia Carney is a trained doctor who was employed by Bayer HealthCare from 2009 to 2012 and 2013 to 2020. She was the Essure medical lead from 2013 to 2017 and the Essure global safety lead from 2018 to 2020. Carney ceased full-time employment with Bayer in 2020 but continued to provide consulting services in relation to clinical trials, regulatory affairs, benefit/risk management, pharmacovigilance and litigation until about April 2022. This included giving two depositions about Essure in related legal proceedings in the US.

106 Janet Padgham is the managing director and co-founder of the fifth defendant, Gytech. Padgham is a trained nurse.

107 Christine Merrell is a trained nurse and midwife, and the current corporate development manager of the sixth defendant, AMSL. She was also the national Essure product expert at AMSL during the period of its distributorship of Essure in Australia. She commenced employment with AMSL in about September 2005 and has held a number of roles within the company since then.

108 Samy Saad is a trained doctor and the general manager of AMSL. He began working for AMSL in about June 2011. Saad was the corporate development manager from February 2012 and the medical division manager from July 2013 until March 2016. He then worked as the division manager (diabetes and medical) from March 2016 to August 2021, before taking up his current role.

109 Suhayl Khan is a trained pharmacist who began working for AMSL as a corporate development associate in January 2014. In early 2015, Khan transitioned into a quality assurance and regulatory affairs role.

110 The expert witnesses gave evidence under the following topic headings:

(a) Gynaecology specific to Turner: Dr Bernadette White and Associate Professor Alan Lam;

(b) Gynaecology: Professor Andrew Korda and Dr Sawsan As-Sanie;

(c) Pathology: Professor Sarah Robertson and Dr Tricia Murdock;

(d) Immunology: Professor Sarah Robertson and Associate Professor Caroline Sokol;

(e) Biomaterials: Professor Sarah Robertson, Professor Wojciech Chrzanowski, Dr Stephen Badylak and Dr Lawrence Eiselstein;

(f) Epidemiology: Professor Ian Gordon, Professor Val Gebski and Dr Arthur Brandwood; and

(g) Regulatory: Kea Dent and Dr Arthur Brandwood.

111 Each of the experts prepared primary reports, and in some cases reply and supplementary reports. Conclaves were held, joint expert reports ('JERs') were prepared, and the experts gave concurrent evidence under each of the above topic headings.

112 Two further experts gave evidence. Dr David Weissman prepared a medico-legal psychiatric report in relation to Turner that was tendered. Weissman did not give oral evidence.

113 Dr David Rosen is a gynaecologist who gave evidence about Essure training, performing the Essure procedure and contraception generally.

114 Bernadette White has worked in Melbourne as an obstetrician and gynaecologist since 1988. She was appointed as the clinical director of obstetrics at the Mercy Hospital for Women in 2003. She is included on the Royal Australian and New Zealand College of Obstetricians and Gynaecologists ('RANZCOG') register of expert witnesses qualified to give an opinion in the area of general obstetrics and gynaecology.

115 Alan Lam is a gynaecologist and clinical associate professor at Northern Sydney Medical School where he teaches about pelvic pain and endometriosis. He is the director of the Centre for Advanced Reproductive Endosurgery. Lam was previously the chair of the RANZCOG Endometriosis Online e-Learning Resources Steering Committee and the president of the Australian Gynecological Endoscopy and Surgical Society. He was also on the editorial board of the Journal of Minimally Invasive Gynecology from 2005 to 2007.

116 I do not accept Turner's criticism that Lam acted as an advocate rather than an independent expert. In his comprehensive primary report, Lam set out in a detailed and even-handed fashion the relevant clinical history, reported scans and surgical outcomes. Lam gave a fulsome explanation of gynaecological conditions to be considered as part of a differential diagnosis. His report contains a great deal of information about current standards and diagnostic processes. Lam did seem relatively determined to settle on a diagnosis for Turner's symptoms. However, I conclude that this was a matter of enthusiastic scientific enquiry and not advocacy for the defendants' case.

117 Andrew Korda has practised in Sydney as a gynaecologist and urogynaecologist since 1969. He has held university and teaching appointments in obstetrics, gynaecology and urology in Australia and overseas since the mid-1970s. His experience includes the management of reversible and permanent contraception, and hysteroscopic and laparoscopic procedures. He has performed six hysterectomies to remove Essure devices over a period of 10 to 15 years. He has not personally implanted an Essure device.

118 Sawsan As-Sanie is an associate professor, co-chief of gynaecology, and director of minimally invasive gynaecological surgery in the department of obstetrics and gynaecology at the University of Michigan. She is director of the University of Michigan Chronic Pelvic Pain and Endometriosis Consultative Clinic. In addition to her specialist training in obstetrics and gynaecology, As-Sanie completed a further two years to obtain additional sub-speciality training in complex gynaecologic surgery with a large focus on CPP and endometriosis, together with an additional year in order to obtain a masters in public health and epidemiology. As-Sanie devotes half her work time to clinical practice that involves receiving referrals from other physicians of patients who have complex gynaecological conditions including CPP, endometriosis, uterine fibroids, abnormal bleeding and/or ovarian masses. The balance of As-Sanie's work is taken up with teaching and training other physicians, supervising a team of clinicians and in her leadership positions, which included presidency of the International Pelvic Pain Society in 2018. She has given over 100 scientific lectures at national and international meetings on the topics of pelvic pain, dysmenorrhea, endometriosis, and AUB.

119 As-Sanie routinely treats women who have undergone Essure sterilisation, including evaluation of CPP and AUB.

120 As-Sanie has impressive research and clinical expertise and experience addressing complex gynaecologic disorders, particularly pelvic pain, dysmenorrhea and CPP. Her evidence about the presentation, causes and treatment of pelvic pain and AUB was comprehensive and clear.

121 As-Sanie's qualifications and expertise in epidemiology and biostatistics do not match those of Gordon (at [148]-[149] below). However, her analysis of relevant studies was informed by her unchallenged expertise in research and treatment of the gynaecological disorders of interest, and her unmatched clinical experience in the treatment of women with Essure devices implanted.

122 Sarah Robertson is a professor in the faculty of health science and biomedical researcher at the University of Adelaide with a PhD in reproductive immunology. She has specialised knowledge in reproductive biology, reproductive biomedicine, reproductive endocrinology, the immune causes and consequences of disease and injury, and the immunopathology of the female reproductive tract. She is the author or co-author of around 230 publications related to her areas of research and was editor of the Journal of Reproductive Immunology for four years from 2009. She is experienced in the development and commercialisation of interventions in reproductive medicine, and has worked as an adviser and consultant to commercial organisations and government on this topic.

(a) Robertson is a highly credentialled biomedical scientist with specialised knowledge in reproductive physiology and immunology whose career spans 30 years.

(b) Robertson has extensive experience and training in reviewing reproductive tissue histopathology and interpreting those results by reference to the body's immunological response.

(c) Robertson is involved in specialised research centres around reproductive immunology and the immune response of the fallopian tube, uterus, ovaries and female reproductive tract. She is a leading researcher and her knowledge and experience in this area is unmatched by any other expert in this proceeding. Her training and experience in immunological responses of the female reproductive system to stimuli put her in a unique position to opine and assist the Court with respect to the scientific issues in dispute.

(d) Robertson gave evidence in three separate concurrent evidence sessions in this proceeding, spanning twelve sitting days. Her opinions remained consistent and were clearly expressed. Robertson's independence as an expert witness was never challenged.[45]

124 The defendants submitted that Robertson's evidence should be considered in light of the following:

(a) Robertson gave evidence that she approached her task of giving expert evidence in this proceeding as a 'brainstorm'. Rather than confining her evidence to hypotheses for which she could identify direct (or even indirect) evidence in support, her written evidence extends to hypotheses that are apparently without any evidentiary support, and are more accurately characterised (by Robertson herself) as possibilities or mere 'biological plausibilities'. The chief consequence of this is that her evidence is voluminous, ranges far beyond the scope of Turner's pleaded case, and makes it difficult for the Court to distinguish between:

(i) opinions without scientific support;

(ii) extrapolations from different circumstances to Essure; and

(iii) opinions for which there is actual, direct evidence of their application to Essure.

This is a significant problem because the probative weight of each category of evidence is not equal.

(b) She was prepared to venture opinions that she was unqualified to give.

(c) During the course of her oral evidence, there were occasions where it was revealed that certain studies Robertson cited in her written evidence did not, in fact, stand for the propositions for which they were cited.

(d) During oral evidence, she not infrequently sought to defend unreasonable or extreme contentions and/or failed to make reasonable concessions during cross-examination.[46]

125 Robertson's primary report is 203 pages.[47] Her reference list of scientific studies and articles runs to a further 18 pages. Robertson also prepared a 177-page reply report,[48] a 16-page supplementary report,[49] and made significant contributions to the pathology, immunology and biomaterials JERs. Robertson's written evidence is replete with interrelated theories and hypotheses. She was asked in cross-examination the following question about her approach to preparing her evidence in chief:

... Your report on one level represents a little bit of a brainstorm, doesn't it, an educated one but one where you are sitting down and identifying all of the ways in which you possibly can, that you think this device might contribute to either a failed wound healing response or other adverse effects on patients?---Yes, I have tried to give a full response and I think that I've used appropriate language to discriminate and to ... indicate very clearly ... how strong I consider the evidence to be and what is the sort of biological rationale ... [T]here's a big distinction between a hypothesis, a theory, and a fact... and then there is a huge space in the middle. A lot of what scientists do is find the right words and terms to discuss that space in the middle and to provide the right weighting to and use language appropriately to ensure that a qualified person reading that information will understand the weight of evidence. In this case I've used the word 'could' ... to indicate that this is a possibility in my mind ... I have used appropriate language to distinguish things that are based in strong evidence from things that are more at the theoretical end.[50]

Robertson's approach to giving evidence made it necessary to carefully examine the language she used when espousing a hypothesis or theory, or giving an opinion about its relevance, and whether there was evidence in scientific studies or articles, or from other sources, to support it.

126 The broad and complex evidence given by Robertson in the proceeding, and her participation in the pathology, immunology and biomaterials conclaves and concurrent evidence sessions, meant that it was important to keep the boundaries and limits of her expertise in mind. Relevant concessions made by Robertson in oral evidence included:

(a) acknowledging that while she has some understanding of 'epidemiological studies', an epidemiologist was better placed than her to comment on the epidemiological studies;[51]

(b) accepting that while she works closely with gynaecologists and obstetricians, she is not a qualified or practising gynaecologist or clinician;[52]

(c) agreeing that she did not have the benefit of a gynaecologist's clinical experience and consultation with real patients;[53]

(d) accepting that she is 'not an expert in how metal devices break down in the body'[54] or 'corrosion of devices in salt baths in laboratories and the physics of that';[55]

(e) saying, when asked about the histology studies:

... I'm not a biostatistician and I'm not a clinician and, as I've indicated in my reports, I'm aware of these studies and I'm aware that they align with and are consistent with my biological interpretations and synthesis of facts, but I'm going to be cautious about being drawn on inferring information from them given the boundaries of my expertise.[56]

127 Robertson said that while she was not a qualified pathologist, she had trained in immunology, a key component of which involved histological evaluation of tissues. She said she uses histological and pathological approaches to understand the component parts of the female reproductive tract.[57] Robertson said she had evaluated fallopian tube and uterine tissue on many occasions over the course of her career.

128 I give further consideration to Robertson's evidence throughout these reasons.

129 Tricia Murdock is a clinical faculty member of the gynaecologic pathology division at John Hopkins Hospital in the US. She has a bachelor of science in biochemistry and a degree in medicine. She completed an obstetrics and gynaecology residency in 2012 and in that time became familiar with Essure and implanted devices in several patients. She has also completed pathology residencies at the University of Vermont and John Hopkins Hospital. Murdock's daily clinical work involves reviewing specimens from the fallopian tube, broad ligaments, ovaries, uterus, endometrium, vulva and vagina. Murdock is also involved in research projects focused on discovering the different genes that cause gynaecologic cancer, and is the author or editor of pathology textbooks.

130 Turner submitted that unlike Robertson, Murdock is in the early stages of her career; is not a leader in her field; has only authored a small number of publications; and has not held any editorial positions. I reject this criticism. Murdock trained as a gynaecologist and obstetrician, and is a qualified clinical pathologist who specialises in gynaecologic pathology. In her work as a clinical pathologist Murdock examines an average of between 30 and 40 fallopian tube tissue samples per day, as well as other tissue samples from the female reproductive tract.[58] While Robertson has undertaken some training in pathology, she is not formally qualified as a clinical pathologist. I conclude that in the specialist field of clinical pathology Murdock's expertise and experience is superior to that of Robertson. For reasons I will come to, I reject Turner's criticism that Murdock took extreme positions in her evidence that were unsupported by authorities she cited or other evidence.

131 Caroline Sokol is an Assistant Professor in Medicine at Harvard Medical School and an Assistant Physician in Medicine at Massachusetts General Hospital, with a speciality in allergy and immunology. She has a bachelor in biochemistry and masters of chemistry from the University of Pennsylvania, and a medical degree and PhD in immunology from Yale University School of Medicine. Sokol is a diplomate of the American Board of Internal Medicine and the American Board of Allergy and Immunology. She is also a fellow of the American Academy of Allergy, Asthma and Immunology. Sokol's research focuses on the mechanisms which drive immune cell recognition of and activation to allergens; by which peripheral neurons affect immune cell function; by which immune cells initiate allergic immune responses; and by which immune cells move in response to allergens. She has authored multiple peer-reviewed research articles and reviews and presented internationally on these topics.

132 Turner made a number of criticisms of Sokol's evidence. First, she submitted that Sokol was fairly junior in her speciality compared to Robertson. Turner noted Sokol's evidence where she accepted she had no immunology specialty in the reproductive biologic context, and had not published any papers on that topic. These matters do not devalue Sokol's evidence. She is obviously a very well-qualified immunologist with the advantage of a clinical practice. I generally found her opinions to be logical, clearly explained and well supported by her cited articles and studies.

133 Second, Turner criticised Sokol for acting as a paid consultant for Bayer since 2020. Sokol properly disclosed this matter in her primary report. Sokol was not retained by Bayer. She has consulted on and off since 2020, giving opinions on hypersensitivity reactions to metals and systemic hypersensitivity reactions to biomedical implants. Neither Sokol's consultancy work nor the manner in which she gave her evidence demonstrated any lack of independence as an expert.

134 Third, Turner criticised Sokol for resiling from positions of agreement taken in the immunology conclave. I deal with this issue at [783] of these reasons. I accept Sokol's evidence that there is no inconsistency between the agreed positions in the immunology conclave and her evidence in the concurrent session.

135 Wojciech Chrzanowski is a professor of nanomedicine at the University of Sydney with a PhD in biomedical engineering. His specialty is biomaterials and biomedical engineering. A focus of his work has been the characterisation and assessment of interactions between biomaterials and biological systems. He has lead the Nanomedicine and Nano-Bio-Characterisation laboratory in the faculty of medicine and health at the University of Sydney since 2010, and in 2017 became the health and medicine team leader at the University of Sydney 'Nano Institute'. He has published over 200 peer-reviewed articles, edited three books and has five patents. He has advised the World Health Organisation on methods to assess risks of nanomaterials.

136 Turner submitted that Chrzanowski's experience as a biomedical engineer was unmatched by any other expert called in the proceeding. The defendants submitted that the weight attributed to Chrzanowski's evidence should be reduced because he not infrequently sought to defend unreasonable or extreme contentions, and was prepared to venture opinions that he was not qualified to give.

137 I accept that Chrzanowski's evidence about what he and Robertson described as the 'fundamental tenets' of biocompatibility can be criticised.[59]

138 The occasions when Chrzanowski strayed into giving evidence outside his field of expertise did not substantially undermine his biomaterials evidence.

139 Lawrence Eiselstein is a metallurgist, corrosion engineer and the principal engineer at Exponent, the largest engineering firm in the US. He has consulted on design analysis and testing for FDA approval of numerous types of implantable devices manufactured from plastics, ceramics, stainless steel, superelastic Nitinol, cobalt-chromium alloys and other materials. Eiselstein is also a licensed professional engineer in the fields of metallurgical engineering and corrosion engineering in California.

140 The defendants emphasised Eiselstein's 40 plus years' experience as a metallurgist and corrosion engineer, specialising in material science as applied to product design and material testing and evaluation. They submitted that Eiselstein has extensive medical device consulting experience for FDA approval design analysis and testing, including but not limited to devices manufactured from stainless steel and super elastic nitinol, and has conducted numerous corrosion resistance, metal leaching and fretting quantification tests for FDA submissions. They submitted that Eiselstein has published extensively on corrosion, durability and metal testing, and has been part of American Society for Testing and Materials ('ASTM') committees for implantable medical devices which focus on developing appropriate test standards.

141 Turner criticised Eiselstein for adopting a selective approach when commenting on the published studies on device corrosion and metal leaching. I reject this criticism.

142 While both Chrzanowski and Eiselstein are very well qualified, I considered Eiselstein's lengthy experience more pertinent to the biomaterials issues in this case. Eiselstein's experience related more directly to design analysis and testing of biomedical devices relevant to the process of FDA approval. Eiselstein comprehensively analysed the biomaterials issues and the relevant evidence. His reasoning from that foundation was clear and considered, and based on his considerable expertise. He comprehensively analysed the corrosion testing undertaken on Essure, relevant testing standards, and the outcomes of corrosion studies relating to the device.

143 Stephen Badylak is the deputy director of the McGowan Institute for Regenerative Medicine and the director of the Centre for Preclinical Studies at the University of Pittsburgh. Badylak has trained as a veterinarian, a clinical pathologist, an anatomic pathologist (PhD), a medical doctor, and a biomaterials scientist. He practiced clinical medicine from 1985 to 2001 and has conducted research since 1985 in the field of biomaterials related to tissue engineering and regenerative medicine, and the design of implantable surgical mesh devices including polypropylene. Badylak has authored more than 400 peer-reviewed articles in this area of study. Badylak has served on advisory committees for the FDA and has participated in the preparation of applications to the FDA for approvals, clearances, and labelling of new medical devices. He is a member of the immunology devices panel of the medical devices advisory committee at the FDA.

144 The defendants emphasised Badylak's qualifications as a medical doctor, clinical pathologist, anatomic pathologist and biomaterials scientist with 38 years' research experience.

145 Turner submitted that despite Badylak's experience and credentials, he presented as an advocate who was unwilling to accept any evidence of active inflammation. Turner submitted that Badylak actively sought to explain every case report of chronic inflammation associated with Essure as 'normal' and 'expected', despite a contradictory position in his own expert report concerning the hallmarks of inflammation. She submitted that Badylak's evidence about chronic inflammation strained logic and could not be accepted. I accept that Badylak sometimes delivered his evidence in a lecture-like manner. While the strength with which Badylak expressed his opinions may not have always been justified, I do not accept that he presented as an advocate.

146 Turner also criticised Badylak as being untruthful when he said repeatedly in cross-examination that he had not seen the acute and chronic inflammation graphs and some histologic section assessments from the pre-hysterectomy study,[60] which had in fact been previously shown to him in a conference with counsel. Badylak explained that he did not recall having previously seen the documents, that he had been shown many documents, and that he had recently arrived from the US before the conference and was tired. I do not conclude that Badylak was being untruthful when giving his evidence about these documents in cross-examination. As Badylak said, there was no reason for him to deny having seen the documents.

147 When he was challenged on these matters, Badylak said that his credibility had never been questioned before. A decision of the United States District Court for the Eastern District of Virginia which contained comments on him as an expert witness was put to Badylak. He said that he had not seen the document before. In the circumstances, that aspect of cross-examination went nowhere.

148 Ian Gordon is a professor of statistics and director of the Statistical Consulting Centre at the University of Melbourne. He has worked as an applied statistician for approximately 40 years and is accredited by the Statistical Society of Australia. He has a PhD in statistics from the University of Melbourne and has worked on research projects for government, business, industry and academia, including published work on randomised trials in the field of medical statistics.

149 Gordon has unquestioned expertise in biostatistics and epidemiology. His evidence was clear and precise. The reasoning to his expressed conclusions was transparent and logical. My only reservation is that in his evidence in chief, Gordon focused on the weaknesses and limitations of the available biostatistical evidence. It was only in cross-examination that Gordon agreed that some of the studies comparing adverse outcomes from Essure and laparoscopic sterilisation were of some value in assessing the safety of Essure. Further, I have rejected Gordon's criticism of the approach taken by As-Sanie to analysis of the comparative studies.

150 Val Gebski is a professor of biostatistics and research methodology at the University of Sydney. He is involved in curriculum development and teaching in public health, clinical epidemiology and medicine at the university. He is a senior biostatistician at the Crown Princess Mary Cancer Care Centre based at Westmead Hospital, Sydney and an honorary fellow of the Royal Australian and New Zealand College of Radiologists. He is the group statistician for several national collaborative clinical trials groups in oncology including Breast Cancer Australia, the Australian Gastro-Intestinal Trial Group and ANZ Gynaecological Oncology. He is also a member of a number of editorial committees including the statistical editor at the ANZ Journal of Surgery, associate editor of Pharmaceutical Statistics, and the American Journal of Clinical Oncology.

151 Turner submitted that on contentious matters, Gebski's written and oral evidence was unreliable and should be rejected. She submitted that Gebski's evidence was contaminated by undisclosed interactions with the defendants' lawyers, that he was unwilling to bring an independent mind to the questions on which he was briefed, and was unwilling to give responsive answers or make obvious concessions in oral evidence.[61]

152 I reject Turner's criticisms. Little turns on the fact that Gebski did not disclose in his reports that the outcomes he attempted to measure using his pooled analysis were suggested by the defendants' lawyers. There was nothing inappropriate about the outcomes that Gebski analysed. While Gebski's evidence at times lacked the clarity achieved by Gordon, I do not agree that he was an unresponsive witness.

153 Kea Dent is the managing director of KD&A Pty Ltd, an Australian based company established in 2005 which provides regulatory and quality management system advice to medical device companies selling on Australian and international markets. Dent founded and was the managing director of Dentsleeve Pty Ltd, a medical device (gastrointestinal catheter) manufacturing business from 1993 to 2003. During that time, Dent said she obtained the regulatory approvals required for supply of the device in 44 countries.

154 Arthur Brandwood is a medical device and biomaterials development and regulation expert. He has experience in applied research teaching, the manufacturing industry, as a senior officer for the TGA, and as an advisor to government regulatory agencies and industry bodies. He holds a PhD in biomechanics and is a chartered engineer through the UK Institute of Materials, Minerals & Mining and the UK Council of Engineering. He founded medical devices regulatory consultancy firm Brandwood Biomedical in 2000 and clinical research organisation DevDx Clinical in 2012. He is the chair of Standards Australia He-30, the Australian committee responsible for preparation of technical standards on biological safety of medical devices.

155 David Weissman is a consultant psychiatrist engaged by Turner for the purposes of providing a medico-legal psychiatric review and report. He obtained a bachelors of medicine and surgery and a masters in psychological medicine from Monash University, and is a fellow of the Royal Australian and New Zealand College of Psychiatrists. Weissman has completed Impairment Assessment Training, sat on medical panels and performed over 14,000 medico-legal assessments.

156 David Rosen is a gynaecologist with a special interest in minimally invasive (laparoscopic) gynaecological surgery. He is the director of the Sydney Women's Endosurgery Centre and the Centre of Excellence programme for that group. Rosen has performed over 150 Essure procedures and was engaged by Conceptus as a contractor from 2000 to 2005 to train fellow gynaecologists in the procedure. He has also lectured widely and published in Australian and international journals on the Essure procedure.

157 Turner alleges that Essure caused adverse events that are broadly described as CPP, dysmenorrhea and AUB. It is relevant to describe those conditions and to say something about their prevalence and aetiology.

158 Pelvic pain is any pain that occurs in the lowest part of the abdomen and pelvis,[62] which can sometimes radiate to the lower back, buttocks or thighs. Pelvic pain can be acute, lasting less than three to six months, or chronic, lasting three to six months or longer.

159 As-Sanie said the patterns of persistent pelvic pain that can occur over time:

... include chronic non-menstrual pain (often referred to as "chronic pelvic pain"), dysmenorrhea, dyspareunia, dysuria, and dyschezia. While some women experience only one type or pattern of pain, most women with persistent pelvic pain experience a combination of two or more of these patterns of pain. Each pattern of pain symptoms can occur as a consequence of many different underlying conditions and any given condition can have a variety of pain patterns. This means that while the pattern of symptoms can help narrow the differential diagnosis, diagnosing the cause (or causes) of pelvic pain cannot be done solely based on the pattern of pain.[63]

160 CPP occurs on most days of the month and is severe enough to cause functional disability or lead to medical care. As-Sanie said that:

CPP affects approximately 15% of women in the United States and contributes substantially to direct and indirect healthcare spending as it is the primary indication for up to 20% of gynecologic office visits, 40% of hysterectomies performed by laparotomy or laparoscopy for benign indications, and 40% of gynecologic diagnostic laparoscopies.[64]

161 Dysmenorrhea, which is painful menstruation or pelvic pain during menstrual periods, is further sub-classified as 'primary' or 'secondary':

Primary dysmenorrhea is painful menstruation in the absence of anatomic pathology, whereas secondary dysmenorrhea is painful menstruation in the presence of anatomic pathology, such as endometriosis or adenomyosis.[65]

Dysmenorrhea is the most common pain disorder among women, estimated to affect approximately 40-90% of women in their reproductive years. Up to 20% of women report pain severe enough to interfere with usual activities. ... While the mechanism of pain is not fully understood, an overproduction of uterine prostaglandins has been shown to contribute to myometrial hypercontractility, arteriolar vasoconstriction, and endometrial ischemia.[66]

162 Dyspareunia is defined as pain with sexual intercourse.

164 Dyschezia is defined as pain with bowel movements.[67]

165 As-Sanie explained that because there are so many conditions within the pelvis that can contribute to symptoms, the evaluation and management of CPP is usually complex. She said that most often '[CPP] is associated with several diagnoses arising from multiple conditions and treatment is multimodal but not curative'.[68]

166 As-Sanie explained that there are no standard clinical tests or radiological studies for women with CPP. Rather, the tests and studies that are applied are guided by clinical history and physical examination. There are a large range of conditions that can cause or contribute to CPP. The following table, taken from As-Sanie's expert report, summarises the conditions in each organ system which can be associated with dysmenorrhea and CPP.[69]

Endometriosis*, leiomyomata (uterine fibroids)*, adenomyosis*, ovarian remnant syndrome*, pelvic inflammatory disease*, pelvic adhesions, adnexal/ovarian cysts, chronic post-ablation tubal sterilization syndrome

Irritable bowel syndrome (IBS)*, inflammatory bowel disease*, celiac disease, abdominal/pelvic hernias

Interstitial cystitis/painful bladder syndrome*, radiation cystitis*, recurrent urinary tract infections, urethral syndrome, recurrent/chronic urolithiasis

Abdominal wall myofascial pain (including trigger points)*, coccygodynia*, degenerative disk/joint disease, fibromyalgia*, pelvic floor tension myalgia*, stress fractures

Central sensitization of pain*, pudendal neuralgia, abdominal wall nerve entrapment (ilioinguinal and iliohypogastric)*

* Conditions excluding cancer associated with to chronic pelvic pain. The condition marked with an asterisk (*) are those that there is high-level evidence for a causal relationship with CPP.

... the presence of any of these conditions does not always cause pain and even when one or more of these conditions is present, they [are] not necessarily the cause of pain or the only cause of pain in an individual patient.[70]

Similarly, White said that pelvic pain is a very complex condition which is not well understood, and that in some women there will be no detectable pathology to explain their pain.[71] White said that the fact that hysterectomy surgery does not relieve CPP for some women indicates that in those cases, the underlying mechanism of pain is not understood.[72]

167 As-Sanie said that the most common gynaecological causes of pelvic pain and dysmenorrhea are endometriosis, adenomyosis, leiomyomas, intra-abdominal adhesions, pelvic inflammatory disease ('PID'), pelvic congestion syndrome, ovarian remnant and residual ovarian syndrome and gynaecologic malignancy.

168 As-Sanie described endometriosis as 'a systemic, chronic inflammatory disease characterised by the growth of endometrial-like tissue outside of the uterus'. She said that endometriosis was the most common gynaecological cause of CPP and dysmenorrhea.[73] She said that 10% of reproductive-age women suffer endometriosis, but that the condition may not cause dysmenorrhea or CPP and 'the presence and severity of endometriosis does not correlate with symptom severity'.[74]

169 Adenomyosis is characterised by the presence of endometrial glands and stroma within the myometrium. It is a common disorder in reproductive-age women but its relationship to CPP is not fully understood. Symptoms are variable and a significant proportion of cases are asymptomatic.[75]

170 Most women are affected by leiomyomas (uterine fibroids) during their lifetime. As-Sanie said that peritoneal adhesions develop following most abdominal surgeries, though in varying severity. However, As-Sanie said that the relationships between these disorders and CPP is poorly defined.[76]

171 As-Sanie said that PID 'refers to acute (fevers, pain, elevated white blood cell count, and tenderness on exam) or subclinical infection (no symptoms of fever or tenderness, but infection is still present and causes sequela) of the upper genital tract in women'.[77] She said that the self-reported lifetime prevalence rates of PID range from approximately 3% to 10%, and that up to 30% of women with PID subsequently develop CPP.

172 As-Sanie said that the non-gynaecological causes of pelvic pain included irritable bowel syndrome ('IBS'), interstitial cystitis/bladder pain syndrome ('IC/BPS'), myofascial pelvic pain syndrome ('MPPS') and fibromyalgia.

173 Approximately 10% of the population has symptoms compatible with IBS. Women are diagnosed more often than men. As-Sanie said that CPP has been reported as occurring in up to 35% of women diagnosed with IBS, but that 'in many women with CPP and IBS, the IBS has not been diagnosed or treated'.[78]

174 A diagnosis of IC/BPS is applied to patients with chronic bladder pain and urinary urgency and frequency in the absence of other etiologies. It is a common cause of CPP.[79]

175 As-Sanie described myofascial pelvic pain as 'pain that arises from dysfunction, spasticity, and/or hypersensitivity of the muscle, fascia, or joints in the abdominal wall, pelvic floor, and/or low back'.[80] She said that MPPS 'is an extremely common but under-recognized source of pain in women with CPP'.[81]

176 Fibromyalgia is a chronic pain syndrome characterised by sensitisation of the central nervous system. CPP is sometimes identified as the primary symptom in women with fibromyalgia.

177 As-Sanie said that the evaluation of women with CPP must also take into account the correlation with psychosocial disorders, opioid dependency, any history of physical or sexual abuse, depression and other mood disorders.[82]

178 AUB is any uterine bleeding that is abnormal in quantity, duration or schedule in reproductive-age, non-pregnant women.[83] Menorrhagia or 'heavy menstrual bleeding' is defined as 'excessive menstrual blood loss that interferes with a woman's physical, social, emotional or material quality of life'.[84]

179 In the gynaecology JER, Korda and As-Sanie agreed:

[A]bnormal bleeding is a less challenging issue when associated with a sterilization because it can be treated by medical therapy (such as hormonal contraceptive medications), can be cured by a hysterectomy and is a very common condition in any event.[85]The acronym 'PALM-COEIN' refers to the causes of AUB and is widely used to guide the evaluation and management of the condition. 'PALM' refers to the structural causes of AUB, being polyps, adenomyosis, leiomyoma and malignancy. 'COEIN' refers to non-structural causes - coagulopathy, ovulatory, endometrial, iatrogenic and 'not-yet-classified'.

180 Endometrial polyps are common, but women with this condition are often asymptomatic. Among patients with symptoms of endometrial polyps, intermenstrual bleeding is the most frequent symptom.[86]

181 As-Sanie said that 'many patients with adenomyosis do not have symptoms of AUB, and others describe heavy, prolonged or painful menstrual periods'.[87]

182 Approximately 25% of patients with leiomyomas experience bothersome symptoms, most commonly AUB and pelvic pain.[88]

183 As-Sanie said that 15% to 29% of women presenting with heavy menstrual bleeding have some type of predisposition to a bleeding disorder.[89]

184 Ovulatory dysfunction is one of the most common causes of AUB. The '[p]ossible causes of ovulatory dysfunction include postmenarche and menopausal transition, polycystic ovarian syndrome ('PCOS'), thyroid disease, liver and kidney disease, and stress or poor nutrition'.[90]

185 Endometrial dysfunction refers to the disturbance of molecular and cellular mechanisms responsible for regulation of the volume of blood lost at menstruation. Relevant conditions 'include local endometrial hemostasis disorders, endometritis and pelvic inflammatory disease'.[91]

186 Iatrogenic causes of AUB include hormonal contraceptives and anticoagulants.

187 White said that in many women who have hysterectomy surgery because of heavy and painful periods, pathological examination does not reveal a specific pathological cause such as uterine fibroids, infection or adenomyosis. In those cases, it is assumed that the symptoms relate to some unidentified dysfunction or pathology in the endometrium.[92]

188 Pregnancy and childbirth carry risks of morbidity and mortality.[93] All forms of female contraception carry risks and benefits.[94] Access to contraception and the opportunity to choose a form of contraception that is appropriate to individual needs are important health issues.

189 Female tubal sterilisation is the most commonly used form of contraception worldwide.[95] Other common methods include oral contraception, condoms, intrauterine devices ('IUD') and injectables.

190 Female tubal sterilisation 'prevents conception by blocking transporter sperm from the lower genital tract to an ovulated oocyte'.[96] Laparoscopic sterilisation is the main method for permanent contraception. A common method involves placement of Filshie clips, which are made of silastic with a titanium coating, across the lumen of the fallopian tubes. The surgery is performed under general anaesthetic and involves inserting a laparoscope into the abdomen through the umbilicus via a trocar. Risks of the procedure include damage to pelvic organs and blood vessels with insertion of the trocar, incorrect placement of the Filshie clip and subsequent pregnancy, and post-operative pain associated with the abdominal incisions, the procedure itself and placement of the Filshie clip. Patients often require one to three days' rest to recover from surgery.[97]

191 The risks and benefits of other contraceptive options were discussed by Rosen. In summary he said:

(a) While condoms are universally available and have spontaneous application, they have a high failure rate and are generally rejected by long-term couples who do not wish to conceive again.[98]

(b) Diaphragms are not commonly used in Australia and lack the benefit of spontaneity, requiring insertion with appropriate spermicide applied 1-2 hours before and 6 hours after sexual intercourse.[99]

(c) Copper IUDs are an effective, long-acting, immediately reversible contraceptive device with no hormonal effect on the user. However, a copper IUD requires removal and replacement every five years; insertion may cause significant discomfort and may not be feasible in the outpatient setting; and may cause an increase in menstrual loss, dysmenorrhea and an increased risk of PID in the user.[100]

(d) The hormonal oral contraceptive pill ('OCP') is the most commonly prescribed and used form of contraception in Australia. Advantages include reduction in menstrual loss and discomfort, accessibility, and that no medical procedure is required. Disadvantages include that the user must remember to take the pill daily, it may compete with other medication, and it carries an increased risk of cardiovascular complications.[101]

(e) Long-acting reversible contraceptives such as the Depo-Provera injection, the Implanon implant and the Mirena IUD are highly effective, reversible on removal and user independent. The disadvantages of these contraceptives include issues or discomfort with insertion, mood changes, acne, spot bleeding and weight gain.[102]

192 Permanent sterilisation can be achieved by hysterectomy or salpingectomy. The risks of salpingectomy include infection, bleeding, trauma to vessels or viscera (pelvic organs) and the risks of laparoscopic entry.[103] I will deal with risks associated with hysterectomy later in these reasons.

193 Conceptus began to develop Essure in 1995. The device was developed to provide women seeking permanent contraception a non-incisional alternative to surgical tubal ligation, which at that time was the most common form of permanent birth control worldwide.

194 Essure was developed in five design concept phases between 1995 to 2001: the 'Alpha' design; 'Beta' design; 'Pre-Gamma' design; 'Gamma' design; and copper/faux cooper[104] versions of the Beta and Gamma designs. Each design concept was clinically evaluated. The Gamma design, with its dynamic outer coil, was ultimately adopted and branded as the Selective Tubal Occlusion Procedural ('STOP') device. The device name changed to 'Essure' in around 2001.[105] The other four designs were not pursued due to issues with either device placement or device retention.

195 Between approximately 1995 and 2002, the early device designs underwent non-clinical laboratory testing[106] which consisted of:

(a) evaluation of navigation and deployment in pig fallopian tubes; tensile testing of raw materials; initial tip fatigue evaluation; release mechanism testing; delivery wire release testing; handle process evaluation; initial corrosion analysis and fibering evaluation (concept testing);

(b) positioning marker evaluation; catheter tip integrity testing; new fibre configuration testing; tracking and retraction evaluation; initial handle functional testing and initial corrosion/leaching evaluation (feasibility testing); and

(c) tensile testing to show design and process repeatability; functional testing; environmental cycle testing of the final Essure device to show material and component stability; chemical analysis of the etched nitinol material and corrosion analysis (verification testing).

196 The performance categories tested in the non-clinical laboratory testing were flexibility; navigation (tracking); retraction, deployment; disengagement, anchoring/expansive forces; chemistry (including corrosion and other chemical analysis); and magnetic resonance, safety and compatibility.

197 Between 1995 and 1997 Conceptus conducted three studies on rabbits to provide early proof of concept and effectiveness data, and one study on rats to assess the effect of varying amounts of PET fibre and different fibre configurations on the tissue reaction to the device. [107] The conclusion of two of the rabbit studies was that 'the rabbit animal model was a potential viable model in which to conduct effectiveness studies'.[108] The other rabbit study of device effectiveness concluded that an early Essure design iteration prevented conception in 100% of cases in which the inserts were correctly placed. The rat study concluded that a greater amount of PET fibre in the device could possibly result in a more robust tissue reaction, with potential improvement of device retention and effectiveness.[109]

198 Conceptus also planned biocompatibility testing of Essure components with feedback from the FDA. This included studies on cytotoxicity, sensitisation, genotoxicity, muscle implantation, vaginal irritation, mutagenicity, sub-chronic toxicity and acute systemic toxicity.

199 Specific tests included a 12-week muscle implantation study of Essure inserts in rabbits, conducted in 2000 ('12-week rabbit study'). The findings of the pathologist who initially undertook histopathological tissue analysis and reported on the inflammatory tissue response to PET fibres were subsequently reviewed by a second pathologist at Conceptus' request, who reached different conclusions. The outcome and relevance of the 12-week rabbit study was the subject of expert evidence at trial. I will return to this study and that evidence later in these reasons.

200 The biocompatibility tests were reported as showing that Essure did not exhibit toxicity or elicit any evidence of acute or sub-chronic toxicity, and that the results were consistent with the long history of the safe use of the constituent materials in the insert and the well-characterised in vivo response to PET fibre. The biocompatibility studies conducted by Conceptus are summarised in the tables in Schedule 1 to these reasons.[110]

201 Following the completion of non-clinical testing, Essure entered the clinical testing phase of development. Four clinical studies were conducted in this phase to measure:

(a) placement feasibility in patients immediately prior to hysterectomy ('peri-hysterectomy study');

(b) placement, safety and the mechanism of action in patients scheduled for hysterectomy ('pre-hysterectomy study');

(c) preliminary long-term safety and effectiveness ('Phase II study'); and

(d) long-term safety and effectiveness to inform the PMA application to the FDA ('Pivotal trial').

202 The peri-hysterectomy study was conducted from September 1995 to late 2000. The study was designed to evaluate the feasibility of the five Essure design iterations in terms of device placement and initial safety.[111] Participants enrolled in the study were already scheduled to undergo a hysterectomy, and had Essure inserted after anaesthesia and immediately prior to the start of the hysterectomy procedure. While the study allowed for device placement by either hysteroscopy, ultrasonography or fluoroscopy, the vast majority of evaluations were performed using the hysteroscopic placement method. All data collected on the Gamma design (which eventually became Essure) was gathered from cases performed using hysteroscopic placement.[112]

203 Success in the study was measured by the ability to cannulate and place Essure in the proximal portion of the fallopian tube, either bilaterally or unilaterally.[113] The study was performed using the Gamma device on 99 participants. The procedures were performed by 23 investigators, all of whom were physicians experienced in hysteroscopy. Four of the 99 participants implanted with the Gamma model were excluded from the final data analysis due to the untimely death of one of the investigators.

204 Three percent (3/99) of participants experienced a perforation during the procedure. No other adverse events were reported during the study. Bilateral cannulation was achieved in 80% (76/95) of participants, and unilateral cannulation was achieved in 6.3% (6/95) of participants. Cannulation was not possible in 13.7% (13/95) of participants. Bilateral placement was achieved in 72.6% (69/95) of participants, and unilateral placement was achieved in 12.6% (12/95) of participants. Devices could not be placed in 14.8% (14/95) of participants. Reasons for failure to place the device included thick endometrium, fibroids, prior tubal ligation, and device and cannulation related issues.[114]

205 Overall, the device could be placed in 96% of tubes accessed (either bilaterally or unilaterally), and 95% of inserts tested were acutely anchored. Immediate occlusion of the fallopian tube was seen in 82% of tubes tested. The study authors concluded that Essure could be reliably and safely placed at a reasonably high rate in the patient population, and was considered feasible and safe for evaluation in subsequent studies.[115] The peri-hysterectomy study was subsequently used as Essure placement training for clinical investigators who participated in the Pivotal trial.[116]

206 The pre-hysterectomy study commenced in October 1998 and was completed in December 2001.[117] The study was conducted by two investigators on 63 participants, all of whom were scheduled for hysterectomy.[118] The objectives of the study were to evaluate:

(a) placement of Essure in the proximal portion of the fallopian tube;

(b) detachment of Essure from the delivery wire;

(c) patient tolerance of and recovery from the placement procedure;

(d) device stability within the fallopian tube until hysterectomy;

(e) occlusion of the fallopian tube within the study period (24 hours to 12 weeks following placement);

(f) local tissue response to the device;

(g) the effect of PET fibre on the ability of Essure to create a local tissue response; and

(h) the ability to retrieve Essure transcervically in a subset of the patient population pre-hysterectomy.[119]

207 The participants rated their tolerance of the placement procedure as 'good' to 'excellent' in all cases.[120] The device was successfully placed in 84.7% (100/118) of tubes visualised, with bilateral placement achieved in 73% (46/63) of participants and unilateral placement achieved in 12.7% (8/63) of participants. Devices could not be placed in 14.3% (9/63) of participants.[121] Reasons for failed placements included tube blockages, issues with the catheter release, tubal and uterine pathology, and difficult angles during placement.[122]

208 Participants completed a questionnaire one week post-Essure placement to assess post-procedural pain, bleeding and general satisfaction. Results were available from 52 participants. Fifty-four percent of participants reported pain post-procedure, which resolved in 8 hours or less in 63% of participants and within three days for 96% of participants. Eleven of the participants described the pain as moderately or significantly more than period pain, and 14 participants reported taking medication for the pain. Post-procedure bleeding or spotting was reported in 50% of participants; all bleeding was resolved within seven days.[123]

209 Participants in the study were followed until their hysterectomy. There were no reports of pain subsequent to the post-procedure pain described above. Participants wore the device for 24 hours up to 14+ weeks, as shown below:[124]

Table III. 7: Length of Micro-insert Wearing by Woman

210 Tubal occlusion was evaluated in 94.2% of participants by hysterosalpingography scans prior to hysterectomy. The study authors stated that 100% of the 92 tubes that contained a properly placed device were occluded, including in those participants who wore Essure for less than 12 weeks.[125]

211 Gross examination of the uteruses showed no evidence of inflammation, ulceration, or haemorrhage except in one participant with adenomyosis.[126] Following examination and x-ray the uterine specimens were bivalved and examined further to evaluate inflammation, haemorrhage and ulceration in the area of the uterine cornua (the points in the upper uterus where the fallopian tubes exit to meet the ovaries) which was in contact with the trailing length of the Essure insert. Mild gross inflammation was noted in two cornuas, as well as a slight haemorrhage in one cornua. There was no evidence of ulceration in any of the specimens.[127]

212 Following gross examination, the fallopian tube specimens were sent for microscopic evaluation. The pathologists were blinded to the wear times of each participant until the histological evaluation was completed.[128] The histological responses for each characteristic presented (acute and chronic inflammation, granulation tissue, loose and dense fibrosis, neovascularisation, disruption of epithelium and level of obliteration) were rated on a scale of '0-3', with '0' meaning 'absent' and '3' meaning 'severe.'

213 The histology findings from the pre-hysterectomy study were the subject of considerable expert evidence at trial, particularly in relation to the issue of chronic inflammation. The study authors concluded that the Essure implantation procedure was 'safe with minimal post procedure discomfort and sequalae and minimal adverse events'. They found that the occlusive, benign tissue response demonstrated by the histological evaluation of the specimens supported the theorised mechanism of action, and that the acute inflammatory response and 'low level' chronic inflammatory response was consistent with other medical devices that used PET fibres. I will return to the histopathology from the pre-hysterectomy study and the related expert evidence later in these reasons.

214 The Phase II study of the Gamma model commenced in November 1998. Two hundred and sixty-nine women, all of whom were seeking permanent contraception, had been enrolled by June 2000 and 227 women ultimately underwent an Essure placement procedure. Bilateral device placement was achieved in 200 women and unilateral placement in six women.

215 The study followed the participants for up to 36 months and was conducted by five investigators across the US, Australia, Belgium and Spain.[129] The objectives of the study were to evaluate:

(a) tolerance of, and recovery from, the Essure placement procedure;

(b) safety of the Essure placement procedure;

(c) tolerance of the implanted device;

(d) long-term safety and stability of the implanted device; and

(e) effectiveness of Essure in preventing pregnancy.[130]

216 Participants completed a questionnaire at one week post-placement to document any symptoms they experienced following the procedure. They were also asked to keep a diary for six months following the placement procedure detailing menstruation, sexual activity and any associated symptoms.[131] Participants underwent a hysterosalpingogram ('HSG') (and in some cases, ultrasound) at three months post-procedure to review the position and retention of Essure, and occlusion of the fallopian tubes.[132] The participants were then followed up at six, 12- and 18-months post-procedure, and at 24 months following discontinuation of alternative contraception.[133]

217 HSG scans performed on 200 participants at the three-month point showed satisfactory placement and bilateral occlusion in 187 women. Repeat scans of seven women after three months showed they also had satisfactory placement and occlusion.[134]

218 Participant tolerance to wearing Essure was ascertained at various points post-procedure:[135]

219 Reports of pelvic pain were also recorded at follow-up visits:[136]

Table II.12: Pain reported at follow-up visits

2/203 ( > Table II.13: Unusual bleeding reported at follow-up visits

222 Adverse events that occurred after the day of the Essure implantation procedure were recorded in the following table:[140]

Preexisting tubal occlusion (2); perforation with use of the Support Catheter (4)

Laparoscopic sterilization (5) with device retrieval in 3; cornual resection and device removal (1)

1 ( > The Essure Micro-insert placement procedure was found to be safe and acceptable to women. The procedure-related adverse events were within an expected and acceptable range for a hysteroscopic procedure, with less than 1% of women experiencing an adverse event on the day of the procedure. Adverse events experienced after the day of the procedure occurred in less than 4% of women.

The primary adverse event experienced was perforation. Of the perforations, 4/6 (67%) utilized the Support Catheter, which was associated with a high rate of perforation. The Support Catheter was discontinued prior to commencement of the Pivotal Trial, and the perforation rate in the Pivotal Trial was less than 1%.

The long-term acceptability of wearing the Essure Micro-inserts was found to be "good" to "excellent" in 99% of women who have been followed for l-3 years.

The observed one-year effectiveness rate of 99.5% (98.1%-100%) and the two-year effectiveness rate of 99.4% are comparable to other methods of sterilization currently available.

Thus, although the Phase II trial was initially designed to serve as a preliminary study of safety and effectiveness for purposes of supporting commencement of a Pivotal Trial, the data from this study support the safety, effectiveness, and patient satisfaction with the Essure placement procedure and the implanted Micro-insert.[141]

224 The Pivotal trial was conducted from May 2000 to December 2007. [142] The trial was designed as a multi-centre, non-randomized international study of women seeking permanent contraception. It was designed to capture five years of follow-up data, with the first year of data intended to inform a PMA application to the FDA. Participants were instructed to continue using alternative contraception during the first three months of Essure wear, with an HSG conducted at the three-month mark to evaluate insert location and tubal occlusion. Assuming both were satisfactory, participants were then instructed to discontinue alternative contraception (thus relying solely on Essure for contraception) and followed up at the six and 12-month points.[143]

225 The study endpoints were summarised as follows:

The primary endpoints for this study were:

• Prevention of pregnancy;

• Safety of the Micro-insert placement procedure; and

• Safety of the Micro-insert wearing.

The secondary endpoints for this study were as follows:

• Participant satisfaction with the Micro-insert placement procedure;
• Participant satisfaction with Micro-insert wearing;
• Bilateral Micro-insert placement rate; and
• Development of a profile for an appropriate candidate for the Essure procedure.[144]

226 Of the 507 women enrolled in the study, bilateral placement was achieved in 464 women and single insert placement was achieved in two women with unicornuate uteruses.

227 Of the 456 women with bilateral placement who completed the three-month visit, 446 were ultimately found to have Essure inserts in satisfactory locations with bilateral occlusion.

228 In relation to pain, the study authors recorded:

During the 3-month PDP and 3, 6, and 12-month PAC follow-up visits, women were asked about unusual pain they experienced since the last contact... Of the women who reported pain, only one woman reported "persistent" pelvic pain. Ten women (2.1 %) had "recurrent" dysmenorrhea, 8 women (1.7%) reported "recurrent" dyspareunia, 2 women (0.4%) reported "recurrent" ovulatory pain, and 15 (3.2%) recorded "recurrent" other pelvic pain that could not clearly be classified into a different category.[145]

229 In relation to changes in menstrual pattern, the authors recorded for the one year follow-up data:

... women reported episodes of both heavier than normal and lighter than normal menstrual flow. "Recurrent" changes in menstrual pattern were noted infrequently and "persistent" changes were reported rarely, with almost equal percentages of women reporting persistent increase or decrease in menstrual flow, for no significant net change overall.[146]

230 Adverse events reported during the first year of reliance and rated by investigators as at least 'possibly' related to Essure are recorded in the following table:[147]

Table 46. Adverse Events by Body System

Rated by Investigator as at least possibly related: For the First Year of Reliance*

N=6885 women months of follow-up for 476 patients with at least 1 Micro-insert

Probability of an AE is expressed as number of reports/number of woman months of follow-up (6885)

* Only events occurring in > 2.5/1000 women-months are reported

** Eight women reported persistent decrease in menstrual flow.

231 After one year of follow-up, the study authors made the following finding in relation to patient satisfaction and comfort:

Women in the study consistently rated their overall satisfaction and comfort in wearing the Micro-inserts as very high. One-week post-device placement, >95% of women rated their comfort as 'good' to 'excellent' and their satisfaction as 'somewhat satisfied' to 'very satisfied'. At all subsequent study visits, 99% of women rated their comfort with wearing Essure as 'good' to 'excellent'. At all study visits, at least 98% of women rated their overall satisfaction as somewhat to very satisfied (this included women who were not able to rely on Essure).[148]

232 In relation to the first year of data, the study authors summarised their conclusions as follows:

In summary, we believe that the data contained in this Pivotal Trial Report, together with the data provided elsewhere in the PMA, provide a reasonable assurance of the safety and effectiveness of the Essure System based on valid scientific evidence.[149]

233 Bayer also conducted a bench test in a simulated corrosive environment to assess the risk of corrosion of the metallic components of the Essure insert (resulting in loss of mechanical integrity of the insert) and the release of ions during the corrosion process ('corrosion bench test').

234 The corrosion bench test was performed over 180 days on two sample groups of inserts. 'Group A' samples were placed in saline in a heated water bath for periods of time ranging from seven to 180 days. 'Group B' samples were placed in similar solution, with the saline removed for analysis at specified points and replaced with fresh saline.

235 The corrosion bench test acceptance criteria were:

The leaching rate of nickel ions from the samples must be lower than the average levels of human intake of nickel from diet and the environment.

The Micro-inserts must maintain mechanical integrity for at least three months. That is, each Micro-insert must still be in one piece after exposure to a corrosive saline environment for three months. In particular, the fibered inner coil must remain attached to the outer coil.[150]

236 The study authors concluded that the test passed both acceptance criteria.

237 Corrosion of the solder on the inserts was described as follows:

As expected, the solder showed signs of corrosion resulting in pitting and increasing porosity with the worst corrosion damage on the ball tip. At the three-month time point, approximately 25-50% of the solder had corroded. At the six-month time point, the ball tips of some of the samples were almost completely corroded, but all of the solder bonds continued to hold together. In all cases, the outer coil remained attached to the fibered inner coil. This is an acceptable level of solder corrosion, because it did not result in the loss of mechanical integrity. No other components showed signs of corrosion.[151]

238 The study authors noted the following conclusions:

• The Essure Micro-insert passes the corrosion susceptibility bench test.
• The daily leaching rate of nickel and tin ions released are at least 2000 times less than everyday intake of food and water and exposure to environment.
• The daily leaching rate of chromium is below the detection limit.
• The Essure Micro-insert maintained mechanical integrity during the six months of exposure to a bench top corrosive saline environment.
• The corrosion rate of the solder is acceptably low.
• Besides the solder, no other signs of corrosion were visible in the SEM images.[152]

239 The outcomes and adequacy of the corrosion bench test were the subject of expert evidence. I will return to this test and that evidence later in these reasons.

240 Conceptus submitted its PMA application to the FDA for approval of Essure as a Class III device (the highest risk classification for a medical device) in the following stages:

(a) Module I was submitted on 21 November 2001. It provided general information about Essure, a description of the device, and a summary of the animal studies and peri-hysterectomy study.[153]

(b) A further submission was provided on 24 January 2002 which responded to FDA questions and included a revised version of Module I with changes to the device description.[154]

(c) Module II was submitted on 14 February 2002. It provided a hazard analysis and non-clinical laboratory studies for physical and chemical performance which addressed bench testing of the inserts and delivery system, corrosion and MRI compatibility.[155]

(d) A further submission was provided on 5 April 2002 which responded to FDA questions and provided updated summary tables and test data.[156]

(e) Module III was submitted on 8 April 2002, and contained the results of non-clinical biocompatibility studies and the pre-hysterectomy study.[157]

(f) Volume 5 of Module III, which was missing from the original submission, was submitted on 17 June 2002.[158]

(g) Module IV was submitted on 15 April 2002. It included information on the methods used in, and the facilities and controls used for, the manufacture, processing, packing and storage of Essure.[159]

(h) An amendment to Module IV was submitted on 15 May 2002 regarding the expiration date of Essure, along with supporting documents.[160]

(i) Module V was submitted on 9 April 2002. It included the results of the Phase II study, marketing studies and information about marketing in countries outside of the US.[161]

241 On 22 May 2002, the FDA notified Conceptus that the PMA application was sufficiently complete to begin the substantive review process. The FDA Obstetric and Gynecology Devices Advisory Panel ('OGDAP') was convened on 22-23 July 2002 to review the PMA application.[162] Conceptus submitted a package of documents with key information from the PMA application for distribution to the OGDAP prior to the meeting.[163]

242 At a public hearing on 22 July 2002, the OGDAP considered questions about device effectiveness, safety, labelling, training, and post-approval studies based on the key information package provided by Conceptus.[164]

243 Dr Thomas Wright, who was engaged as a consultant by Conceptus to perform the histopathological analysis of specimens from the pre-hysterectomy study, gave evidence at the hearing.[165] Wright summarised his findings as follows:

... Key histological features observed in the sections were graded in a blinded fashion. Over time, we observed an increase in the amount of dense fibrosis which is shown in the yellow line and a reduction in the amount of acute inflammation which is shown in the white line. Both chronic inflammation and loose fibrosis appeared relatively stable up to a 15-week period of looking at these devices.

In conclusion, the prehysterectomy study has shown total tubal occlusion by hysterosalpingograms in all of the participants at all of the time points, including even those women who wore the device for less than four weeks. The histological studies have shown that the tissue response to the device is predictable and is progressive. It is occlusive in nature and it produces a dense fibrosis.

Finally, the tissue response is quite localized. Sections from the tubes taken approximately five millimeters distal to where the device was showed a normal tubal architecture and there was no evidence that the reaction to the device extended out to the serosal surfaces of the tube. So the reaction was confined to the area around the device.[166]

During the hearing, the OGDAP discussed the long-term efficacy of Essure in occluding the fallopian tubes and achieving sterilisation. The following exchange took place between Wright and OGDAP member Dr Gerald Shirk in relation to the mechanism of action of the PET fibres:

[WRIGHT:] ... If you have a loose weave, such as what we are seeing here, in the space between the inner and the outer coil, you've got a lot of inflammatory infiltrate, then you will get a dense fibrosis.

In systems that this event looked at over time, this response appears to be very durable in that it does not diminish, it remains as it is, and you maintain a chronic inflammatory infiltrate at the site of the fibers which is the way it remains as a durable fibrotic response.

Does that answer your question?

SHIRK: Yes. I just wanted some information what the fibers were made out of and obviously it creates a chronic kind of inflammatory response?

WRIGHT: An acute initially and then a chronic.

SHIRK: During the patient's entire lifespan?

WRIGHT: That's right, and with vascular grafts, we have long histories of patients who wear these for very long periods of time, showing that it does not cause adverse effects.[167]

244 OGDAP member Dr Subir Roy then raised a related concern that long-term placement of PET fibres may be associated with abnormal growth of cells in that part of the body:

ROY: The last concern would be, is there any reason for us to be wondering whether these giant cells that infiltrate this area or are produced are in any way precursors for a neoplastic process?

WRIGHT: Right, and I didn't answer to that. It's the same sort. The pictures I showed you with giant cells could be from any vascular graft in the body, and we have a very long history of use of devices using PET fibers for long-term implants and they have been shown to be neoplastic.

ROY: But those vascular grafts are typically in much older individuals and for reasonably shorter periods of time than what we're envisioning here. If we're anticipating the use of this as a sterilization process in women in their twenties who presumably and hopefully would live to their eighties, so is that differential time span a concern to someone such as yourself who's been involved in these investigations and processes?

WRIGHT: That is not a concern to me, because I know of no data to suggest or to implicate PET for producing neoplasms long term, and in fact many of the implantable devices, such as cardiac valves which have PET as a dense mass around the valve rings which it's there in order to suture into, are put into quite young, you know, children get cardiac valves which contain PET.[168]

Turner relied on this exchange as putting the defendants on notice of the need to consider possible adverse consequences from long-term placement of Essure related to an inflammatory process stimulated by the PET fibres.

245 Wright told the OGDAP that he knew of no analogous situation where an implantable medical device containing PET fibres had been used to occlude an epithelial line structure such as the fallopian tube.[169] He added that histopathology from the pre-hysterectomy study showed ingrowth of dense fibrosis together with some smooth muscle tissue, which was typical of the histopathological response to PET at a variety of different body sites.

246 Dr Charles Carignan, Vice-President of Clinical Research and Medical Affairs at Conceptus, gave evidence about the Pivotal trial to the OGDAP. In relation to adverse events, he said:

This table shows the number of events reported and the number that you can see here, the most frequent were low back pain, abdominal pain or cramps, and dyspareunia. Only eight events were rated as definitely related to the Essure device. The reports of pain, bleeding and adverse events are kept in perspective when looking at satisfaction with Essure. From the three-month post-device placement visit onward, more than 90 percent of women rated their satisfaction with Essure as very satisfied.[170]

247 Conceptus advised that it had conducted all biocompatibility testing required by FDA guidelines, and that the results demonstrated that Essure was not chronically toxic or mutagenic. The FDA lead reviewer advised the OGDAP that 'the appropriate testing [had been] conducted for this implant device' and that Conceptus had '[chosen] a material that has a long history as an implant material.'[171]

248 Ultimately, the OGDAP voted in favour of approving the PMA application with the following conditions:

(a) that an HSG be performed three months' after implantation;[172]

(b) that physician training occur and that it be a training requisite that the physician be knowledgeable in hysteroscopy;[173]

(c) that Essure labelling address success/failure rate, age of patient, young age, potential sequelae, metal sensitivity, electrocautery, and pregnancy subsequent to the procedure;[174]

(d) that physicians be given recommendations regarding procedure time length and a 1,500 millilitre saline limit for use in the patient;[175]

(e) that the procedure be performed at the proliferative phase of the menstrual cycle;

(f) that written informed consent be obtained from patients (with Conceptus to provide the FDA an example of the consent form);[176]

(g) that recommendations be included in the patient pamphlet about what to do if the patient misses a period and a fallback plan if Essure insertion is unsuccessful;[177] and

(h) that Conceptus continue observation of current Essure patients for five years to better assess insertion rate failure for the purpose of patient counselling and labelling.[178]

249 On 4 November 2002, the FDA approved the PMA application subject to the following conditions:[179]

(a) Conceptus was to follow Phase II study and Pivotal trial participants to assess safety and effectiveness at two, three, four and five years after implantation or discontinuation of alternative contraception. The data collected was to be reported to the FDA each year.[180]

(b) Conceptus was to conduct a post-approval study in the US intended to document the bilateral placement rate for newly trained physicians.[181]

(c) Before making any change affecting the safety or effectiveness of Essure, Conceptus was to submit a PMA supplement for review and approval by the FDA (subject to certain exceptions). A PMA supplement was to be submitted if and when unanticipated adverse effects, increases in the incidence of anticipated adverse effects, or device failures necessitated a labelling, manufacturing or device modification.[182]

(d) Conceptus was to submit annual post-approval reports ('annual PMA reports') which included, along with follow up data from existing studies:[183]

(i) identification of, among other things, new indications for use of the device; labelling changes; changes in the performance or design specifications, circuits, components, ingredients, principles of operation, or physical layout of the device; and

(ii) a summary of any information not previously submitted which is known or should reasonably be known to Conceptus, including unpublished reports of data from any clinical investigations or non-clinical laboratory studies involving the device or reports in the scientific literature concerning the device or related devices.[184]

(e) Conceptus was to provide a report to the FDA after receiving or becoming aware of any information:

(iii) concerning a mix-up of the device or its labelling with another article; or

(iv) about any adverse reaction, side effect, injury, toxicity, or sensitivity reaction attributable to the device which had not been addressed on the device labelling, or that had occurred with unexpected severity or frequency.[185]

Essure was commercially available in the US from the date of FDA approval.

250 Neither Australia nor Europe recognise the regulatory status of medical devices under FDA regulations. The FDA PMA processes for Essure therefore had no bearing on the determination of regulatory approval in those jurisdictions. However, at the time of the Essure PMA application, the FDA PMA process was recognised globally as the most rigorous regulatory process for high risk devices.[186]

251 In 1997, the TGA acknowledged Conceptus' notification of importation of the STOP device (as Essure was then known) for the purpose of conducting clinical trials.[187]

252 Conceptus was first registered with the TGA as manufacturer of Essure in 1999. Essure was listed on the ARTG that same year, which was a necessary precondition for sale of the device in Australia.[188] At that time, approval for the sale of medical devices like Essure in Australia did not involve a formal evaluation process. Instead, TGA approval required:

(a) information which reasonably demonstrated the safety and quality of the device for its intended use;

(b) contact and address details of the device sponsor and manufacturer;

(c) a copy of the manufacturing quality management systems certificate; and

(d) copies of product manuals and labelling.

The TGA did not require that risk management files, safety testing, design data or clinical evidence be supplied for devices such as Essure.

253 Bayer Essure and/or Bayer HealthCare supplied Essure to the following companies, for importation into and distribution in Australia:

(a) Bepen Pty Ltd between about 1 December 1999 and about 6 November 2000;

(b) Conceptus (Australia) Pty Ltd between about 6 November 2000 and about January 2005;

(c) N Stenning & Co Pty Ltd between about January 2005 and August 2010;

(d) Gytech between about August 2010 and January 2015; and

(e) AMSL between about January 2015 and August 2017.[189]

254 Module V of the PMA application dated 9 April 2002 stated, in relation to commercial supply of Essure outside of the US:

The Essure System is currently commercially available in the following countries: Australia, certain European countries, Singapore and Canada. Registration of the product for commercial sale in Australia and Singapore was made with the appropriate regulatory authorities. CE Mark approval was granted by TUV and a Medical Device License was granted by Health Canada.

...

The first commercial shipments of Essure began in the second quarter of 2001 to both Australia and Singapore, followed by the first commercial shipment to Europe in the third quarter of 2001, and the first commercial shipment to Canada in the first quarter of 2002. As of March, 2002, over 1,200 commercial units have been shipped, with an estimated number of Essure procedures conducted at over 750. In addition, over 175 physicians have undergone the Essure Physician Training Program.[190]

255 In the EU, devices which meet regulatory requirements for commercial supply are granted a CE Mark. Conceptus was granted a CE Mark of certification for Essure in 2001.

256 As outlined at [194] above, Conceptus evaluated several Essure designs before adopting the Gamma model. The first commercial shipments of Essure model number 'ESS004' to Australia began in the second quarter of 2001. The ESS004 model was approved by the FDA on 4 November 2002. It underwent several design changes during the period in which it was commercially available, but those changes related primarily to the disposal delivery system.

257 A subsequent device model, 'ESS205', was approved by the FDA in March 2003. Around this time, Conceptus sought a revision to the anchoring of the longitudinal PET fibres in the ESS205 model. The changes were to mitigate the risk of the proximal anchoring loops of the fibres becoming wrapped around the delivery wire, which made it difficult to remove the wire from the insert. The change was approved by the FDA on 1 July 2003 and made commercially available in Australia.

258 A subsequent iteration of Essure, the 'ESS305' model, was approved by the FDA in June 2007. The only difference between this model and the ESS205 related to the delivery catheter.

259 I will return to the post-market clinical evaluations undertaken by Conceptus of the ESS205 and ESS305 models later in these reasons.

260 Conceptus submitted the final Phase II study in its annual PMA report to the FDA on 19 June 2006. The final reporting period was between 8 October 2002 and 6 January 2006.[191] As required by the FDA, the reporting period captured data in relation to the contraceptive efficacy and safety of Essure at two, three, four, and five years post-insertion (for participants using the device for safety only), or from discontinuation of alternative contraception (for participants using the device for contraception).[192] Of the 206 subjects in whom bilateral or unilateral placement of the device was initially achieved, 171 completed the five year study.[193]

261 The tolerance to wearing Essure reported by participants is recorded in the following table:[194]

262 Pain reported by participants at follow-up visits is recorded in the following table:[195]

2/203 ( > Table II.14: Unusual bleeding reported at follow-up visits

1/194 ( > *No data reported for some women that indicated unusual bleeding (N=2 at 24 months; N=1 at 36, 48 and 60 months)

There were a further 13 reports by participants of unusual bleeding made at unscheduled meetings. Fifteen participants (7.5%) reported recurrent menstrual changes. One participant (0.5%) reported recurrent post-coital bleeding.[199]

264 Investigators assessed and rated adverse events[200] according to their likely relationship to Essure as 'highly probable', 'probable', 'possible', or 'unlikely'.[201] No adverse events were rated as 'highly probable' or 'probable', and only three were rated as 'possible' during the reporting period. Fifty-five adverse events were assessed as having an 'unlikely' relationship to the device.[202] It is not clear what criteria investigators applied to determine the relationship, if any, between adverse events and Essure. The table extracted below lists all 'possibly related' adverse events during the period 8 October 2002 to 6 January 2006. [203]

Table II.19: AE's that began or ended from 10/08/2002 to 01/06/2006 that are at least "Possibly Related" to Essure

This table is sorted by 'Start Date'

Relationship to study Device = HIGHLY PROBABLE

Pt is continuing in study with no adverse effects as of 3-yr visit. X-rays are OK.

S10-201

No problems with periods at 3-year visit February 2003

Resolved with medication as of 4-year visit August 2003

Patient had a hysterectomy and was termed from study 12/13/02 per protocol

S10-119

S10-403

265 Five participants underwent a hysterectomy after Essure placement. Conceptus obtained the uteruses and/or fallopian tubes for histological analysis from two of these procedures, and the surgical pathology report from a third. The results of these histological analyses are recorded later in these reasons.[204]

266 The final report concluded that the data from the Phase II study supported the overall safety profile of Essure.[205] It stated (original emphasis):

The Essure micro-insert placement procedure was found to be safe and acceptable to women. The procedure-related adverse events were within an expected and acceptable range for a hysteroscopic procedure, with less than 1% of women experiencing an adverse event on the day of the procedure. Adverse events experienced after the day of the procedure that prevented reliance on Essure occurred in less than 4% of women. There were no adverse events between October 8, 2002 and January 6, 2006 that were rated by the Investigator as having a high probability of relating to the Essure device. Furthermore, only three adverse events were reported during the same period that were rated as "possibly" related to Essure.

...

A woman's tolerance to wearing Essure was ascertained at the 3, 6, 12, 18, 24, 36 48, and 60-month follow-up, and has been rated as "good" to "excellent" in 99% of women at all visits.

...

Persistent pain and bleeding were not reported. Recurrent pain and bleeding were rarely reported. Thirteen women (13/199 = 6.5%) reported recurrent pain (reported on 2 or more visits that may or may not be consecutive) while persistent pain (reported at every visit) was not reported by any woman. Fifteen women (15/199 = 7.5%) reported recurrent menstrual changes, one woman (1/199 = 0.5%) reported recurrent post-coital bleeding and no women reported persistent menstrual changes.

...

In conclusion, the data from this study (in conjunction with the Pivotal Trial data) support the safety, effectiveness, and patient satisfaction with the Essure placement procedure and the implanted micro-insert. Five-year follow-up of patients in this study is complete.[206]

267 Conceptus submitted the final Pivotal trial follow-up data to the FDA in its annual PMA report on 31 March 2008.[207] The data from both the Pivotal trial and Phase II study final annual PMA reports were not made publicly available until 2015.[208]

268 As outlined previously, participants in the Pivotal trial were instructed to rely on alternative contraception for the first three months following Essure placement. Those participants with satisfactory device placement and tubal occlusion at the three-month mark were then instructed to rely solely on Essure for contraception, thus entering the post-alternative contraception ('PAC') phase. The study followed up participants in the PAC phase after 18, 24, 36, 48 and 60 months.[209] The follow-ups included a pelvic exam; x-ray verification of insert retention at one, two and five years; and questions relating to adverse events, comfort, overall satisfaction, and plans for intrauterine procedures or extirpative surgery of reproductive organs.[210]

269 The study initially targeted a population of 400 women with the FDA later approving a population of 350 women during the follow-up period.[211] Of the 453 participants who relied on Essure for contraception, 364 completed the study with the remaining terminated or lost to follow-up.[212] The primary endpoints of the follow-up study were pregnancy prevention and safety.[213]

270 Bilateral placement was achieved in 92% of participants who had Essure devices implanted. Ninety-eight percent of the participants who completed the three month post-device placement visit successfully relied on Essure for contraception.[214]

271 Participants were asked to rate their comfort and overall satisfaction with Essure at each of their follow-up visits. At least 99% of women rated their comfort between 'good' and 'excellent' at all visits, while at least 95% rated their satisfaction between 'somewhat' and 'very satisfied' at all visits during the follow-up period.[215]

272 The following data were captured in relation to recurrent[216] changes in menstrual function:

(a) 14.8% of participants reported irregular menses;

(b) 18.8% of participants reported bleeding between menses;

(c) 37.5% of participants reported heavier than usual menstrual flow; and

(d) 23.3% of participants reported less than usual menstrual flow.[217]

The report noted that 46% of participants reported using oral contraceptives before entering the PAC phase, and said:

Since discontinuation of oral contraceptives is known to cause menstrual changes in some women, and has been reported as a potential confounding variable in the literature on post-tubal ligation menstrual changes, the reported changes in menstrual function after the 3-month PDP visit could be influenced by the discontinuation of oral contraceptives.[218]

273 The proportion of participants reporting some pelvic pain at each visit is shown in the following table:[219]

* Recurrent: symptom reported at more than one visit.

** Persistent: symptom reported at all prior visits.

*** Other: defined as pelvic pain that was not reported to be dysmenorrhea, dyspareunia or ovulatory pain.

274 Adverse events assessed as preventing reliance on Essure for contraception are recorded in the following table:[220]

Table 45. Adverse Events Preventing Reliance Among Bilateral Placements

Proximal placement (13); placement into endometrial tissue (1).

9 successfully underwent second Micro-insert placement procedure; 4 underwent laparoscopic sterilization; 1 required laparotomy due to preexisting Crohn's disease

Pre-existing tubal occlusion (2); poorly identified ostium (2);

3 underwent laparoscopic sterilization; one requesting repeat Micro-insert placement procedure

Proximal placement on one side (0 mm trailing) and difficulty placing on the perforated side

Proximal Micro-insert removed hysteroscopically during lap sterilization, perforated side was suspicious on x-ray and confirmed during lap sterilization

Awaiting women's decision to undergo lap sterilization (2)

Two participants whose expelled devices were initially retained in the uterus complained of mild spotting and intermittent cramping, which ceased upon device removal. There were no reports of symptoms by the remaining participants. All expulsions were found to have occurred in cases where the device was not placed in accordance with the placement criteria.[221]

275 Investigators assigned ratings to adverse events according to their severity and likely relationship to Essure. Investigators determined that 16 adverse events were at least 'possibly' related to Essure during the follow-up period.[222] This data is captured in the table below:[223]

Table 47. Adverse Events Reported from 10/15/02 to 12/05/07

(Rated at least "possibly" relating to Essure according to the Investigator)

The only adverse event rated by investigators as 'definitely' related to Essure concerned a participant who desired fertility. Bilateral salpingectomy was performed to remove the devices in preparation for IVF implantation. No adverse events were rated as having a 'probable' relationship to Essure.

276 The report concluded in relation to safety, participant comfort and satisfaction with device wearing:

There were 21 women (4.5%) who experienced an adverse event that initially prevented them from relying on the Micro-inserts for contraception. The vast majority of these events were Micro-insert expulsions, all of which occurred in cases where the Micro-insert was not placed in the tube or was placed too proximally, not in accordance with the placement criteria for trailing lengths. The majority of the women who experienced an expulsion (9/14, 64%) underwent a second Micro-insert placement procedure, and 9/9 (100%) achieved successful bilateral placement with subsequent finding of bilateral occlusion and satisfactorily located Micro-inserts on HSG. Therefore, overall, only 12/464 (2.6%) women who had bilateral placement were unable to rely on the Micro-insert for contraception due to an adverse event.

None of the women who experienced these adverse events reported symptoms, other than two women whose expelled Micro-insert was retained in the uterus. They complained only of mild spotting and intermittent cramping, and these symptoms ceased when the Micro-inserts were removed from the uterus. It should also be noted that none of the adverse events initially preventing reliance occurred in women with properly placed Micro-inserts.

...

In conclusion, the data from this study (in conjunction with the Phase II study data) support the safety, effectiveness, and patient satisfaction with the Essure placement procedure and the implanted micro-insert. Five-year follow-up of patients in this study is complete.[224]

277 The FDA PMA approval required Conceptus to conduct a study which documented bilateral placement rates for newly trained physicians for the purpose of evaluating training procedures and updating labelling.[225] Conceptus conducted two newly trained physician studies, the 'ESS205 Post- Approval Study' and the 'ESS305 Post-Approval Study'.[226]

278 Conceptus provided the results of the ESS205 Post-Approval Study to the FDA on 22 November 2005. The report contained data in relation to the 585 participants enrolled as of 3 October 2005.[227] Forty-one physicians at 39 sites in the US participated in the study to evaluate placement rates using the Gamma delivery device and coil catheter.[228]

279 The purpose of the study was stated as follows:

... to document the bilateral placement rate for newly trained physicians. These data will be used to evaluate the training procedures and to update labeling. Data collected will include the following:

a. rates of successful bilateral placement of the Essure System at first attempt; and

b. identification of factors predictive of failure to achieve bilateral placement [of] the Essure system at first attempt.[229]

280 In relation to the study design, the report stated:

This study was designed to collect demographic and micro-insert placement data on a total of 800 women from 40 physicians in the commercial setting in whom an Essure System is placed through an operating channel of the hysteroscope. Data were also collected on women in whom the procedure was begun, but in whom an Essure System was not placed through the operating channel of the hysteroscope ("non-attempts").[230]

Adverse events that occurred during and after the Essure placement procedure have been reported in 15/585 women (2.6%). All reported events were minor with the exception of Patient 32-013. One micro-insert perforated the left uterine fundus and embedded in omentum causing pain. The peritoneal portion of the micro-insert was laparoscopically removed and each tube was banded with Falope rings. The patient reported increased pain of unknown etiology and was to be scheduled for diagnostic studies and became lost to follow-up. None of these events represent unanticipated adverse effects...[231]

282 Conceptus submitted the results of the ESS305 Post-Approval Study to the FDA on 11 June 2009.[232]

283 The purpose of the study was stated as follows:

... this study is intended to document the bilateral placement rate for the ESS305. These data will be used to evaluate the training procedures and to update labelling. Data collected include the following:

a. bilateral placement of the ESS305 micro-insert at first attempt;

b. identification of factors predictive of failure to achieve bilateral placement of the ESS305 at first attempt;

c. comparison of bilateral placement success between newly trained physicians and experienced physicians;

d. evaluation of aspects of the ESS305 design that may impact bilateral placement rate;

e. hysteroscopy time to perform the procedure;

f. adverse device effects; and

g. adverse procedure events.[233]

284 The study was initially designed to collect data on a minimum of 800 women from 80 physicians implanting the ESS305 model. The FDA later approved a request to terminate the study early with 584 subjects enrolled, with no requirement for a hypothesis test comparing placement rates between experienced and newly trained physicians.[234] Seventy-six physicians performed placement procedures at 76 sites in the US.[235]

285 Bilateral placement was achieved in 562 participants. Unilateral insert placement failed in 10 participants, and bilateral insert placement failed in six participants.[236]

286 Device issues were reported in 14 procedures, and six adverse events were reported during and after the procedure.[237] The final report concluded in relation to adverse events:

All reported events were minor with the exception of Patient 80-04. The patient was hospitalized after hysteroscopy resulted in a uterine perforation by the hysteroscope. The Essure device did not cause the injury to the patient. None of these events represent unanticipated adverse device effects.[238]

287 The SUCCES II clinical trial was initiated by Conceptus France in 2008, with the final report delivered on 27 January 2017.[239] SUCCES II was a prospective, multi-centre, non-interventional observational study. The study collected data using questionnaires and assessed satisfaction, effectiveness and complications of the Essure procedure in the short (three months), middle (12 and 24 months) and long-term (five years).[240]

Primary

To assess patient satisfaction with the Essure® procedure at 5 years. Patients with complications (Essure® migration, Essure® expulsion, upper genital tract infection) or pregnancy during the follow-up are considered as not satisfied by convention.

Secondary

To assess:

- dissatisfaction and its causes at all time points;

- pain experienced during and after Essure® placement and the potential risk factors for pain;

- methods used and the interpretation of the 3-month control test; - effectiveness, complications and satisfaction of the Essure® procedure in the short and middle tern;

- long term regret of patients to have undergone an Essure® procedure;

Safety

To collect adverse events (AEs), with a specific focus on removal and perforation.[241]

289 The primary objective was evaluated by the number of patients who reported being 'very satisfied' or 'satisfied' at five years. Patients were considered 'not satisfied' by default when any of the following outcomes occurred:

(a) a complication or unintended pregnancy;

(b) placement or procedure failure;

(c) hysterectomy related to Essure;

(d) Essure removal related to the device; or

(e) dissatisfaction at the last observation (in the case of premature discontinuation not related to the procedure).

290 The study results captured data from 2,593 patients from 13 centres.[242] These patients comprised the 'intention to treat set' ('ITTS'). Of those, 2,218 patients (85.5%) had a successful Essure placement, meaning they could rely on Essure for contraception.[243] These patients comprised the 'per protocol set' ('PPS'). Nine hundred and seventy patients, or 37.4% of the ITTS, were lost to follow-up.

(a) Of 1,392 assessable patients in the PPS, the satisfaction rate at five years was 94%. Sixty out of 1,385 patients (4.3%) reported they were 'not satisfied' after five years, independent of whether or not they experienced complication/s or pregnancy. The rate of patients who experienced at least one complication (upper genital tract infection, expulsion or migration) or pregnancy during the follow-up period was between 1.4% to 2.2%.[244]

(b) At each interim time point (three, 12 and 24 months), between 1.9% and 2.9% of patients reported that they were 'not satisfied'. At the same time points, the rate of patients who experienced at least one complication ranged from 0.5% to 1.9%. One unintended pregnancy was reported at the three month follow-up visit; five were reported at the 12 month follow-up; four at the 24 month follow-up; and one at the five year follow-up.[245]

(c) Pain was a frequently reported symptom. Overall, pain was reported by 2,168 (83.6%) patients with 81.5% of the reports related to the placement procedure. Post-operative pain and cramping was reported by 590 patients (approximately 25%). In addition, post-operative bleeding was reported by 403 patients (17.3%). A total of 600 patients (23.1%) reported abdominal pain (which included post-operative pain/cramps and other pain events reported during the entire course of the study) and 49 patients (1.9%) reported pain related to their reproductive organs (e.g. pelvic pain).[246]

292 The results of the study were reported as follows:

The patient satisfaction rate 5 years after a successful Essure® procedure (primary outcome) was 94.0%. This rate highlights a high level of satisfaction towards Essure®, but it should be noted that a final assessment of satisfaction could not be obtained in many patients due to their loss to follow up.

Complications (migration, expulsion, infection) were in line with the rates observed in the clinical trials and reported in the literature. During the whole follow-up, abdominal migration of the device, expulsion and upper genital tract infection was observed in 1.6%, 0.9% and 0.6% of patients, respectively, while fallopian tube and uterine perforation were reported in 0.5% and 0.4% respectively. 165 patients (6.4%) underwent a subsequent surgical intervention on genital organs during the follow-up which entailed Essure® removal. This included 87 hysterectomies (3.4%), of which only one hysterectomy was considered related to Essure®, as well as for 78 removals other than hysterectomy (73 related to Essure®). Laparoscopic tubal sterilization was offered to 40 patients following placement failure while in a further 13 patients an incidental device removal was entailed after unilateral placement failure.

Five patients became pregnant unintendedly after a satisfactory confirmation test indicating an efficacy rate of 99.8%. Six other unintended pregnancies were reported in patients told not to rely.

The majority of adverse events were elicited through structured polar questions (Y / N) without further precision, at the 3-month visit, pertaining to the post-operative period. The reported rates are not unexpected in the context of post-operative complaints after hysteroscopy and Essure® insertion. The majority of patients who complained about pain or bleeding in the post-procedural period did not complain about such disturbances at any later time point. While the occurrence of some pain or vaginal bleeding is well known in the post-procedural period, the high satisfaction rate elicited at the 3-month follow-up and beyond provides evidence that these post-procedural bleeding and pain events had a low clinical impact. In conclusion, the final analysis of the SUCCES II study shows a high level of patient satisfaction, a high efficacy rate, and confirms the positive benefit/risk profile of Essure® without raising any new and unexpected safety concern.[247]

293 On 29 June 2015, the FDA approved a prospective clinical study to evaluate the effectiveness of use of transvaginal ultrasound ('TVU') to confirm Essure placement in patients ('TVU study').[248]

294 Prior to June 2015, an HSG was required to evaluate Essure location and tubal occlusion in the US.[249] Outside the US, TVU and/or pelvic x-ray were used to evaluate Essure location.[250] In those countries, an HSG was performed only for those patients whose pelvic x-ray or TVU findings showed suspicious or unsatisfactory Essure location.[251]

295 The primary purpose of the TVU study was to gain approval of a TVU/HSG 'confirmation test' algorithm in the US.[252] The study followed 620 patients for 10 years following discontinuation of alternative contraception.[253] Of these patients, 597 underwent the Essure procedure and 547 were told to rely on Essure for contraception.[254] At the time of trial, the study remained ongoing.[255]

296 A condition of approval was that the TVU study further evaluate pregnancies and adverse events, with reports including this information to be submitted to the FDA each year.[256]

297 The 2019 TVU study in the annual PMA report set out the following information about the study:

2.1 Study Co-Primary Endpoints

• Occurrence of confirmed pregnancy at 1 year among subjects relying on Essure inserts for birth control on the basis of the TVU/HSG confirmation test.

• Intent-to-treat (ITT) reliance rate 3 months following TVU/HSG confirmation test protocol.

2.2 Study Secondary Endpoints

• Subject satisfaction with TVU
• Occurrence of confirmed pregnancy at 10 years among subjects relying on Essure inserts for birth control on the basis of the TVU/HSG confirmation test.[257]

298 The report sets out the following results in relation to reliance on the device:

3.2.4 Reliance time to date

All calculations are based on the current data cut-off. The calculation summarizes the total number of women-months observed up to the data cut-off. As of the data cut-off date for this report, 291 subjects had a 6-year follow-up visit and 21 subjects had a 7-year follow-up visit. To date, 4 pregnancies occurred in a total of 33,189 women-months of follow-up.[258]

As of the data cut-off date, 1560 AEs were reported in 383 (64.2%) subjects. Note that a subject may have reported more than one AE. AEs reported in >5% of subjects were menorrhagia (13.6%), pelvic pain (9.0%), dysmenorrhoea (7.9%), and abdominal pain (5.4%).[259]

...

Serious adverse events (SAEs) and pregnancies are presented in Table 3-1 l; there are 116 SAEs/pregnancies in 66 subjects listed.[260]

300 Finally, in relation to Essure removals it reports:

Of the 548 subjects who were told to rely, 59 subjects (10.8%) had at least one device removed[.]

...

The mean number of days from the last insert procedure to the removal procedure was 1585 days. There were two instances of unintended removal (24-007 and 21-013) and 58 intended removal procedures. Among the primary reasons for intentional device removals (n=58), the most common was "Adverse events" 26 (43.3%), followed by "Removals in conjunction with other gynecologic surgery" 19 (31.7%), "Removal per subject request" 12 (20.0%), and "Other" 1 (1.7%). When possible, subjects who reported removal for reasons other than AE but reported concomitant Essure related AEs are being queried to clarify the primary reason for device removal.[261]

301 Endometrial ablation ('EA') is a treatment for pre-menopausal women with menorrhagia and dysfunctional uterine bleeding, and can be an alternative to hysterectomy in appropriate patients. The 'NovaSure' EA procedure delivers radio frequency into the uterine cavity via a bipolar electrode array in order to ablate the endometrium and decrease uterine bleeding.[262]

302 The NovaSure EA clinical trial was a prospective, multi-centre, single-arm observational study to monitor the effectiveness and safety of Essure when the NovaSure radiofrequency EA procedure is performed, following a successful Essure confirmation test.[263]

... evaluate the effectiveness and safety of the Essure system when a NovaSure EA procedure was performed following a successful Essure Confirmation Test.[264]

304 Bayer sent an interim report to the FDA on 22 February 2019.[265] The final report, dated 27 October 2021, was provided to the FDA on 7 January 2022.[266]

305 The objectives and endpoints of the study are listed in the interim report as follows:

Objectives

• Evaluate the contraceptive failure rate of Essure when NovaSure is performed following a successful Confirmation Test, and

• Monitor the incidence of adverse events (AEs) and/or complications associated with the performance of NovaSure in the presence of Essure inserts.

Post-approval Study Endpoints

• Occurrence of confirmed pregnancy at 1 and 3 years after NovaSure EA among subjects relying on Essure inserts for permanent birth control when NovaSure is performed following a successful Confirmation Test.

306 The study population consisted of adult women between 21 and 50 years of age with menorrhagia who had completed a successful Essure confirmation test. The NovaSure EA procedure was performed on a total of 209 participants, of which 174 (83.3%) completed the study.[267]

307 The final report found, in relation to adverse events:

The frequency of AEs was reported as an event count. A total of 398 events were reported in 116 subjects (55.0%) in the SAF population. The intensity of most of the AEs (240 events in 92 subjects [43.6%]) was considered mild. There were 123 moderate-intensity events reported in 55 subjects (26.1%) and 35 severe-intensity events reported in 19 subjects (9.0%).[268]

308 Four adverse events in three subjects were reportedly related to Essure.[269]

309 The final report found, in relation to serious adverse events:

A total of 28 SAEs were reported in 18 subjects (8.5%). The intensity of most (22 events) of the SAEs was considered severe (15 subjects, 7.1%). There were 4 moderate-intensity events reported in 3 subjects (1.4%) and 2 mild-intensity events in 2 subjects (0.9%). There were 2 SAEs in 2 subjects (0.9%) that were related to Essure device...[270]

310 In February 2016 the FDA directed Bayer to conduct a post-market surveillance ('PMS') study to gather more data about the benefits and risks, and the effectiveness, of Essure ('522 study').[271]

311 The 522 study is an open label, non-randomised, prospective observational cohort study of two cohorts of subjects who chose to undergo either the Essure procedure or laparoscopic tubal sterilisation.

312 The primary safety end points of the 522 study are:

(a) new onset or worsening chronic lower abdominal and/or pelvic pain;

(b) new onset or worsening AUB;

(c) new onset or worsening hypersensitivity and allergic reactions, and autoimmune disorders (new onset) or autoimmune-like reactions; and

(d) invasive gynaecologic surgery including Essure removal.

313 The 522 study is ongoing. From time to time the FDA has published interim data from the study.

314 Further consideration of the 522 study is undertaken in Chapter XV of these reasons.

315 Carney gave evidence that Bayer had a number of processes and procedures in place for PMS and risk management in relation to Essure.[272] These included:

(a) the preparation of [the annual PMA reports];

(b) the preparation of Clinical Evaluation Reports (or similar documents such as Clinical Evaluation Update Reports);

(c) the preparation of various risk management file materials;

(d) the preparation of periodic post-market surveillance reports;

(e) the preparation of pharmacovigilance trend reports;

(f) the preparation of risk analysis reports; and

(g) discussion of issues and risks related to post-market surveillance activities relating to the Essure Device at Bayer Management Review Meetings.[273]

316 Carney said that because the US was considered the 'lead market' for Essure, many of the processes and procedures focused on matters concerning the US. However, she said that regulatory affairs matters related to Essure which arose in or relating to the US had implications for sales and distribution in other jurisdictions.[274] Some of Bayer's specific regulatory functions included:

(a) performing a weekly review of all complaints arising from clinical trials;

(b) conducting a weekly and monthly review of other complaints to identify new areas of concern;

(c) conducting the verification process for potential safety signals and escalating verified safety signals to the Product Quality and Safety Committee (PQSC);

(d) preparing and maintaining policies and procedures for complaint trending, data systems used for signal analysis and global complaint databases; and

(e) preparing weekly literature reports related to Essure and permanent contraception more generally.[275]

317 FDA regulations required Bayer to submit annual reports regarding the safety of Essure which addressed certain matters and reporting criteria. These included:

(a) a summary of changes affecting the safety of Essure during the reporting period;

(b) a summary and analysis of pregnancies associated with Essure;

(c) a summary and analysis of unsatisfactory device location incidents; and

(d) a summary and analysis of device removal cases.[276]

318 Bayer prepared a number of clinical evaluation reports in relation to Essure. The clinical evaluation reports typically included a description of Essure and its intended application; the context for the clinical evaluation and choice of clinical data types; and a summary of the clinical data.[277]

319 Carney gave evidence that she had direct responsibility for the preparation of two of these reports: the Clinical Evaluation Update Report dated 28 September 2018 and the Clinical Evaluation Update Report dated 19 September 2019.[278]

320 Bayer prepared quarterly risk management reports for Essure (from 2013 to 2015), which were subsequently called 'Post Market Surveillance Review Reports' (from 2015 to 2017). The reports were prepared by the Bayer pharmacovigilance team and covered, amongst other things, any new hazards associated with Essure.[279]

321 Bayer also prepared monthly 'Essure Post Market Surveillance Reports' from 2013 to 2015, which addressed the worldwide commercial distribution of Essure and noted key product technical complaints.[280]

322 Bayer prepared a number of other risk analysis reports, later called 'Device Risk Management Reports'. These included the general characteristics and intended purpose of Essure, an evaluation and summary of possible hazards, the risk-to-benefit ratio, and details on specific device risk characteristics.[281]

323 Bayer also prepared, from time to time, a number of complaint trend reports for Essure.[282]

324 Between 2014 and January 2018, Bayer held quarterly PMS and risk management meetings relating to Essure.[283] Matters discussed at these meetings included updates about regulatory affairs; ongoing clinical studies and other medical affairs; pharmacovigilance; product supply and quality; sales and marketing; and risk assessment.[284]

Increased medical reporting and concerns about Essure

325 In November 2013, Carney commenced her role as director of the 'US Medical Affairs, Women's Healthcare' team at Bayer HealthCare. She said that from that time, her practice was to keep apprised of publications (including news articles) concerning Essure. This included reviewing alerts sent to her by the Bayer library team, some of which contained references to social media activism relating to Essure.[285] Carney said that around the time she commenced her role, it became apparent to her that the primary social media commentary about Essure was generated from a private Facebook group called 'Essure Problems'. Carney said that she was involved in formulating Bayer's response to the concerns raised by the 'Essure Problems' group and other social media activity.[286]

326 It appears that from around this time, a social media monitoring report was circulated internally within Bayer Healthcare each week.[287] A report for the period 27 January 2015 to 2 February 2015 recorded the daily volume of Essure 'mentions' on Facebook, Twitter and other online forums.[288] These mentions were categorised by sentiment (positive, negative, neutral or mixed) and theme (side effects, removal, efficacy, news sharing, seeking information). The report also recorded the 'notable drivers' of Essure-related online conversation.

327 Medical device reports ('MDRs') comprised one of the FDA PMS data sources. MDRs were submitted to the FDA Manufacturer and User Facility Device Experience ('MAUDE') database by mandatory reporters (manufacturers, importers and device user facilities) and voluntary reporters (healthcare professionals, patients and consumers). The FDA used MDRs to monitor Essure performance, detect potential device-related safety issues and contribute to benefit-risk assessments of the product. MDRs were also used to establish a 'qualitative snapshot of adverse events' and detect actual or potential device problems in a 'real world' setting.[289]

328 Carney said that Bayer reviewed and analysed MDRs related to Essure, including those from patients and implanting physicians. She said that in 2013, she learned there had been a sudden increase in the number of MDRs voluntarily submitted to the FDA compared to previous year-on-year figures, and that this trend continued into 2014 and beyond. Carney attributed the increased reporting rates in part to a shift in policies and procedures used to capture customer feedback, but said she was otherwise confused by the trend.[290]

329 Bayer HealthCare conducted a global pharmacovigilance PMS review of Essure for the period 1 October 2013 to 30 June 2014.[291] The review reported the following trend analysis:

Total numbers of medically confirmed and non-medically confirmed case reports independently of reported events are rendered in Table 5 and show that the number of medically confirmed case reports has only gone up slightly (26% increase over previous period) whereas the number of non-medically confirmed reports has increased disproportionally (310% increase over previous period). The increase in non-medically confirmed cases is mirrored in a disproportionate increase of case reporting for events which have a greater propensity to be described in consumer reports, such as hypersensitivity type of events, pain, infections and device complications which constitutes of a broad range of unspecific terms.[292]

330 The review concluded that the observed increase in case and event reports after 1 October 2013 was not related to any safety or quality issue or any change in the known safety profile of Essure, but could be attributed to company procedure and external factors. Such factors included stimulated reporting due to media attention; active collection of adverse events from healthcare professionals within targeted markets; reimbursement programs; and changes to the processing and classification of adverse event case reports. Activities including 'online listening' were also said to have generated case reports which were not medically confirmed.[293]

331 In July 2014, Bayer HealthCare reported a major procedural and policy shift in customer feedback processes following Bayer's acquisition of Conceptus. It was reported that these procedural and policy changes also resulted in an increased capture rate of adverse events associated with Essure. Changes included an increase in sales force; the launch of the active 'online listening' program; responses to customer service inquiries as to the occurrence of an adverse event; and proactive literature searches.[294]

332 Bayer maintained the 'ARGUS' database as part of its internal pharmacovigilance system. The database recorded all reports of adverse events including, but not limited to, those concerning Essure.

333 The Bayer defendants produced spreadsheets of data from the ARGUS database relevant to Essure between 2000 and 2019. Turner prepared a summary of the data in a table which is reproduced below:[295]

Cumulative cases recorded in ARGUS by 'Company causality (event assessment)', 'Medically confirmed' = 'MC' only

'device dislocation : related' or 'device expulsion : related'

334 Turner does not rely on this data as proof of causation of relevant adverse events, but as being relevant to the Bayer defendants' knowledge of the risk of adverse events, and therefore to foreseeability relevant to her negligence claim.

335 The defendants' spreadsheets contain a 'company causality (event assessment)' column and a 'case medically confirmed' column. With respect to data in the latter column, according to the user manual for ARGUS:

A report is medically confirmed if it was initially received from a Health Care Professional (HCP) or reported on behalf of a HCP (e.g. if reported by the physician's office manager who is not a HCP), or at least one adverse event in a non-HCP report is subsequently suspected to be causally related to a BHC product by a HCP. It is important to distinguish between verification of the facts by the HCP (things did or did not happen as described by the patient) and the HCP's confirmation that a drug related adverse event occurred.[296]

336 Carney was asked in re-examination about what was meant by the descriptor 'medically confirmed':

What does medically confirmed mean to you?---Medically confirmed means that either the initial reporter was a doctor, a nurse, someone with a medical background, or if it had been reported by, let's say, the patient, that we were able to get additional information about that patient's medical history.

And what does not medically confirmed mean?---Not medically confirmed means whatever the complaint was we take it at face value but we have no other way of verifying any of the information.

What, if any, relationship do those two terms bear in relation to whether something was caused by the relevant fact, in this case the device?---Causality is difficult and MDRs in and of themselves and, yes, I predominantly worked with the US and even the FDA says MDRs, it's extremely difficult to assess causality because you don't have the information. You don't have a medical history. You don't have what medication she's on. You don't have operative reports. Now, if you have a medically confirmed case you are more likely to be able to assess that information. But even then MDRs are not the easiest information to assess causality. Again, never ignored, they are - you can find out a whole lot of other things, but MDRs are really not designed to assess causality.

Let me ask it this way. What is being confirmed in the phrase medically confirmed in your experience?---The complaint.[297]

337 With respect to the 'company causality' column, the database recorded data using the following descriptors:

Related: There is a reasonable suspicion that the event was caused by the drug. Indicators for this may be but are not limited to: the timely sequence of the onset of the event to the administration of the drug and the unlikelihood that the event is attributed to concomitant, intercurrent or underlying diseases/conditions or other drugs or chemicals. In addition, the clinically reasonable response on withdrawal of the drug (de-challenge) can be used to suspect a causal relationship.

Unrelated: There is [no] reasonable suspicion that the event was caused by the drug. Indicators for this may be but are not limited to: suspect medication has not been used before the onset of the event, a clear alternative explanation exists which excludes any causality by the drug (e.g. mechanical bleeding at a surgical site). Alliteratively, a causal relationship might not be plausible, examples: the patient is struck by an automobile and there is no indication that the drug caused disorientation that may have led to the event, or patient developed cancer a few days after drug administration.

Not assessable: An adverse event cannot be assessed because information is insufficient or contradictory and which cannot be supplemented or verified. Any efforts to obtain more information and/or to clarify the contradiction must be performed (Follow-up requests).[298]

338 In 2015, the FDA conducted a review of Essure in advance of a meeting of the OGDAP held on 24 September of that year ('2015 OGDAP meeting').[299] The introduction to the FDA review report began:

Sterilization for permanent birth control may be accomplished in a variety of ways. One method, hysteroscopic sterilization, began to be widely used in the United States after the 2002 FDA approval of the Essure System (P020014; original applicant, Conceptus, Inc.). Since initial approval, FDA has continued to monitor the safety and effectiveness of the Essure System and the, safety concerns that have been raised within the patient and healthcare provider community. FDA believes that, in keeping with its public health mission, it is appropriate to do the following:

• have an open and transparent dialogue among FDA and its stakeholders, including the device manufacturer, health care providers, researchers, patients, and the public,

• review and discuss available data regarding the benefits and risks associated with the use of the Essure System, and

• obtain FDA Advisory Committee and public input on the safety and effectiveness of the Essure System.

As such, FDA's Obstetrics and Gynecology Devices Advisory Panel is being convened to review and discuss current information related to the effectiveness of the Essure System, adverse events associated with, or suggested to be associated with, the Essure device, and the overall benefitrisk profile of the device. The Committee will be asked to provide input regarding the need for product labeling changes, the collection of additional post-market safety data, or other mitigation steps, and the overall benefit-risk profile of the device based on current available information[.][300]

Beginning in late 2013, FDA has received a significant increase in the number of adverse event reports related to Essure; in particular, from patients who have received the device. The Agency has also been cognizant of complaints related to the device being conveyed in traditional and social media outlets. Accordingly, FDA has recently conducted an additional review of data related to the Essure system and determined that the information should be vetted and discussed in an open forum, i.e., this panel meeting.[301]

339 The FDA noted that limitations of MDRs included the potential submission of incomplete, inaccurate, untimely, unverified, or biased data, particularly in circumstances where the device in question had not been directly evaluated.[302] The review report stated that 'the incidence or prevalence of an event cannot be determined from this reporting system alone due to potential under-reporting of events and lack of information about frequency of device use.' The report also stated:

Other limitations of MDRs include, but are not limited to:

• MDR data alone cannot be used to establish rates of events, evaluate a change in event rates over time, or compare event rates between devices. The number of reports cannot be interpreted or used in isolation to reach conclusions about the existence, severity, or frequency of problems associated with devices.

• Confirming whether a device actually caused a specific event can be difficult based solely on information provided in a given report. Establishing a cause-and-effect relationship is especially difficult if circumstances surrounding the event have not been verified or if the device in question has not been directly evaluated.

• MAUDE data is subjected to reporting bias, attributable to potential causes such as reporting practice, increased media attention, and/or other agency regulatory actions.

• MAUDE data does not represent all known safety information for a reported medical device and should be interpreted in the context of other available information when making device-related or treatment decisions.[303]

340 The report also noted that the FDA sent copies of voluntary reports to the device manufacturer, who evaluated the data and submitted MDRs for those it considered met the mandatory reporting criteria. This meant there were 'many instances in which multiple MDR reports [were] submitted for the same event'.[304]

341 The review reported a 'sharp increase' in the number of MDRs received between 2013 and 2015, primarily due to a significant increase in voluntary reports.[305] It concluded that MDR data could not be used to establish rates of adverse events, or to confirm whether a device actually caused or worsened a specific event.[306] The report said:

Because rates of events cannot be determined by MDR data, it is not possible to determine whether the numbers of reports represent a true increase in rates of particular known or expected events, or rather represents an increase in the reporting of adverse events or increase in the number of devices in clinical use.[307]

The figure below was included in the report and presented an overview of the number of MDRs received per year:[308]

342 The MDRs included a broad range of reported symptoms. The FDA focused on the more commonly discussed or reported adverse events which included:

• Pain and cramping (abdominal, pelvic) - with a focus on chronic/persistent pain

• Abnormal bleeding or menstrual irregularities

• Headache

• Metal allergy/sensitivity.[309]

343 The review report said that the majority of MDRs received by the FDA noted the presence of abdominal or pelvic pain and/or cramping.[310]

344 On 30 May 2017, an independent committee convened by the French National Agency for Medicines and Health Products Safety ('ANSM') prepared a report assessing concerns about Essure.[311] The committee was tasked with providing an opinion on the benefit-to-risk ratio of Essure and putting forward new recommendations if necessary, in the context of increasing regulatory concerns in the US, Canada, France and the Netherlands.

345 Following a meeting held on 19 April 2017, the committee unanimously concluded that:

(a) the data from the literature, medical device vigilance and the findings of the epidemiological study conducted by ANSM did not alter the favourable benefit-to-risk ratio of Essure;

(b) no new regulatory measures were required in view of ANSM's scientific knowledge at that time; and

(c) patients who were considering permanent contraception should be provided with independent information on all of the contraceptive methods available and, in particular, on the advantages and risks of the two methods of permanent female contraception to allow them to make an informed decision.[312]

346 The increase in adverse event reporting coincided with increased concerns about Essure from international regulators, including in the US, Canada, the EU and Australia.

347 On 22 July 2015, the FDA announced it would convene the 2015 OGDAP meeting in order to:

... seek expert scientific and clinical opinion on the risks and benefits of the Essure System. The committee will be asked to evaluate currently available scientific data pertaining to the safety and effectiveness of the Essure System, such as events related to implant perforation/migration, device removal, chronic pain, allergic reactions, and unintended pregnancy. The committee will be asked to provide recommendations regarding appropriate device use, product labeling, and potential need for additional postmarket clinical studies.[313]

348 The panel for the 2015 OGDAP meeting included medical professionals with speciality in gynaecology; reproductive epidemiology; biostatistics; pelvic medicine and reproductive surgery; allergy and immunology; biomedical engineering; reproductive endocrinology; dermatology and toxicology; an industry representative (external to Bayer); and consumer and patient representatives. Representatives of the FDA and Bayer and members of the public including patients, medical practitioners, non-profit organisations and medical professional societies, also attended.[314]

349 Carney said that the 2015 OGDAP meeting was broadly structured into four parts:

(a) First, a presentation by the representatives of Bayer (including Dr Zampaglione, Dr Basinksi and [Carney]).

(b) Secondly, a presentation by the representatives of the FDA.

(c) Thirdly, submissions by members of the public in the "open public hearing".

(d) Finally, after the 'open' portion of the meeting had concluded, the Panel considered six questions prepared by the FDA relating to the safety and effectiveness of the Essure Device.[315]

350 Bayer prepared two documents for the meeting: an Executive Summary dated 3 September 2015 which provided an overview of Essure including in relation to research, development and post-market monitoring; and a presentation based on the executive summary.[316] The presentation consisted of an introductory section, a 'clinical interest' section, and a risk-benefit section.[317]

351 The FDA presentation addressed the historical perspective and current landscape of female sterilisation, the FDA review of effectiveness and safety data concerning Essure, and an epidemiological review of this data.[318]

352 Carney said that 43 members of the public addressed the OGDAP during the open public hearings. Many identified themselves as members of the 'Essure Problems' Facebook group or as others advocating for the removal of Essure from the market.[319]

353 Finally, the OGDAP was directed to discuss and comment on the following six topics prepared by the FDA:

(a) the degree of association between adverse events and Essure;

(b) the clinical implications and possible risk mitigation strategies for each adverse event;

(c) general recommendations for modifications to the physician and/or patient labelling to address concerns;

(d) the need for any additional post-market bench and/or clinical data related to adverse events and risk mitigation;

(e) recommendations regarding the decision to pursue hysteroscopic or laparoscopic Essure removal; and

(f) the overall benefit-risk profile of Essure.[320]

The OGDAP discussion was not binding but provided guidance for the FDA and Bayer to consider.[321]

354 On 26 September 2015, Bayer received the following summary of the OGDAP's discussion of the FDA topics:

Question 1

Regarding the topics of interest identified by FDA:

• There is insufficient information in all instances to connect pelvic pain and bleeding to Essure

• All events should be evaluated for relation to the device

Question 2

Regarding physician training, pre-operative evaluation / selection and post-operative monitoring, the panel discussed:

• Consent Form

• Patient Card

• Improved compliance with confirmation test

• Post procedural protocol to assist in providing guidance on potential complications

• Device removal advice and identification of qualified physicians

• Early imaging / TVU at the time of placement

• Hypersensitivity for nickel and other components; potential testing

• Consider pre-procedure checklist / screening to determine history of autoimmune or inflammatory disorder or any chronic pain, obtain data to assess, not clear on methods or targets

Question 3

Suggested modifications to the labeling included:

• Permanent surgical procedure that requires hysteroscopy

• More prominence of materials contained in the device

• Device removal

Question 4

Regarding additional data:

• Study patients who had device removed, obtaining medical history and pathology reports of tissue

• Analyze existing preclinical testing on biocompatibility

• Collect additional safety information from TVU long term study

• Consider registry, registry vs RCT - RCT low feasibility

Question 5

Regarding device removal:

• Persistent abdominal pain without evidence of incorrect placement, look at other causes

• Pain with incorrect positioning, consider near term removal

• Asymptomatic with suspected incorrect placement, consider removal and alternate contraception

• Hypersensitivity- more data needed on whether to remove device

Question 6

Regarding the Benefit / Risk:

• Favorable benefit / risk profile for patients; ideal Essure patient
• Patient specific considerations noted: hypersensitivity, autoimmune disorders, pelvic inflammatory disease, dysfunctional uterine bleeding, prior uterine surgery, chronic pelvic pain and those with complications at time of placement, however, Essure may still be the best option for some of these patients.[322]

355 In October 2015, Bayer and FDA representatives met to discuss Bayer's proposals for addressing the matters raised by the OGDAP. On 4 November 2015, Bayer provided a written submission to the FDA in relation to these matters. Actions included in the submission related to:

(a) physician training and patient counselling;

(b) data generation activities from ongoing clinical trials and database studies;

(c) Essure insert removal; and

(d) hypersensitivity / nickel allergy.[323]

356 Negotiations between Bayer and the FDA to prepare updated US product labelling and patient information followed throughout 2016. The proposed updates involved the addition of a 'boxed warning' which would appear at the top of an IFU or PIB and contain key information and warnings for the reader's immediate attention. Bayer provided a number of written submissions to the FDA outlining its proposed updates.

357 In March 2016, the FDA published a draft guidance document on labelling for hysteroscopically-placed tubal implants intended for sterilisation, which was followed by a 60-day feedback period ('draft guidance').[324] The draft guidance included the following:

FDA believes that a boxed warning should be part of physician and patient labeling materials for a permanent, hysteroscopically-placed tubal implant for sterilization and should:

• Note the types of significant and/or common adverse events that may be associated with the device and its insertion and/or removal procedures, including those noted in clinical trials, as well as those reported in device use experience.
• Include a statement noting that these risks should be conveyed to the patient during the woman's decision-making process.[325]

The draft guidance also suggested introducing a patient decision checklist with key information about Essure, and proposed text for the boxed warning. Carney said that she and others within Bayer treated the draft guidance document as being, in effect, binding from this time.[326]

358 On 31 October 2016, the FDA issued the final version of the guidance document ('guidance document').[327] Although the guidance document related to all permanent, hysteroscopically-placed tubal implant devices intended to achieve sterilisation, Essure was the only such device supplied in the US at the time of publication.[328] The guidance document addressed new labelling components such as the boxed warning and patient decision checklist, and stated:

This guidance identifies the content and format for certain labeling components for permanent, hysteroscopically-placed tubal implant devices intended for female sterilization. FDA believes this guidance will help to ensure that a woman receives and understands information regarding the benefits and risks of this type of device prior to undergoing implantation.

FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe FDA's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.[329]

359 On 15 November 2016, the FDA approved the negotiated changes to the IFU and PIB labelling.[330] The final boxed warning in use from this time read:

WARNING: Some patients implanted with the Essure System for Permanent Birth Control have experienced and/or reported adverse events, including perforation of the uterus and/or fallopian tubes, identification of inserts in the abdominal or pelvic cavity, persistent pain, and suspected allergic or hypersensitivity reactions. If the device needs to be removed to address such an adverse event, a surgical procedure will be required. This information should be shared with patients considering sterilization with the Essure System for Permanent Birth Control during discussion of the benefits and risks of the device.[331]

360 On 9 April 2018, the FDA announced that the sale and distribution of Essure would be legally restricted to healthcare providers and facilities that adhered to the new labelling requirements. The FDA said it required this restriction:

... after becoming aware that some women were not being adequately informed of Essure's risks before getting the device implanted, despite previous significant efforts to educate patients and doctors about the risks associated with this device.[332]

361 On 19 April 2018, Bayer submitted a plan for implementing new labelling language to alleviate the FDA's concerns, which included monitoring the use of the patient decision checklist. [333]

362 Around the same time that Bayer and the FDA were corresponding about the 2015 OGDAP meeting outcomes, Bayer was also corresponding with Health Canada about whether the Canadian IFU should include a boxed warning.

363 On 10 May 2016, Health Canada requested that, inter alia, Bayer:

(a) expand warnings (including by providing a boxed warning) and revise the 'Possible Adverse Effects' statement in the Canadian IFU;

(b) revise patient labelling to explain the expanded warnings and revisions;

(c) provide a 'safety information sheet' with similar content to the proposed US FDA Essure patient decision checklist;

(d) issue a risk communication which included a general discussion of Essure, types of adverse events, and reported patient outcomes; and

(e) provide an update on the 522 study and submit the results to Health Canada when available.[334]

364 On 31 May 2016, Health Canada posted a communication on its website informing healthcare professionals of the reported complications with Essure use.[335]

365 On 6 December 2016, Bayer submitted its proposed updated IFU, PIB and patient decision checklist (including amendments to the boxed warning) to Health Canada.[336] The changes were approved on 10 January 2017. [337] Health Canada announced the labelling changes the following month, summarising them as follows:

1. The addition of a Boxed Warning listing information on the Essure Confirmation test, adverse events that have been reported either in clinical studies or through post market surveillance and situations where device removal may be indicated.

2. The IFU has also been updated with additional information. This includes a new section on patient counseling in addition to revisions in the sections discussing safety, clinical studies, instructions for use and patient management.

3. The introduction of a PIB including a Checklist. The PIB, along with the Checklist, is intended to be reviewed by the physician and patient to facilitate the patient's understanding of birth control options, benefits and potential risks associated with the use of Essure, as well as what to expect during and after the Essure procedure.[338]

366 The NSAI, the relevant EU regulatory authority, also raised regulatory concerns about Essure between 2014 and 2017.

367 The NSAI suspended the Essure CE mark for a period of 90 days in July 2014 while investigations into device safety and performance were carried out following an audit.[339]

368 From around June 2016 until mid-2017, the NSAI carried out the Essure CE mark re-certification process.[340] In October 2016, the NSAI informed Bayer of several new re-certification requirements including that a statistically robust EU post-market clinical follow-up study of Essure be conducted.[341]

369 On 14 February 2017, ANSM informed Bayer that Essure promotion in France had been suspended while the regulator conducted a reassessment of Essure data.[342]

370 On 3 August 2017, Bayer received an NSAI 'query report' which identified a number of the NSAI and ANSM's concerns.[343] Among other matters, the query report stated:

Bayer states the post market data is not consistent with other clinical data and that stimulated reporting is the reason for this in relation to allergy, pain and bleeding patterns. Bayer states that the PMCF study is being conducted because of the increased rate of pain, bleeding and allergy reported in PMS but this is due to stimulated reporting. Bayer will need to be open to the consideration that the need for this study is not just based on stimulated reporting and that there may be a problem in relation to pain, allergy and bleeding pattern[s].[344]

371 The query report also raised concerns about the Essure biocompatibility data and the limitations of the PMA testing that had been carried out. In particular, the report raised concern that there was no data addressing the inflammatory effect of Essure beyond three months, and that corrosion phenomena in vitro had not been assessed from a safety point of view.[345]

372 Accordingly, also on 3 August 2017, the NSAI notified Bayer of its decision to again suspend the Essure CE mark for 90 days. The notification letter stated (original emphasis):

Pursuant to discussions held between NSAI and Bayer Pharma AG on June 7th 2017 and clarified by e mail on June 14th by NSAI to Bayer Pharma AG indicating that if the queries are not closed out prior to the expiration date, 3rd August 2017, NSAI will not be in a position to provide an extension to the certificates.

The responses received by NSAI pursuant to the outstanding queries were available and reviewed by the NSAI team on Tues Aug 1st to Thursday August 3rd 2017, the responses were deemed inadequate to address the queries.

[...]

NSAI's Technical Review Committee have made the decision to suspend the product family certificates 252.618, Fallopian Tube Occlusion Insert (Essure System), Annex II.3 and II.4, for a period of 90 days effective 3rd August 2017, until 2 Nov 2017[.]

The decision has been made based on inadequate clinical data coupled with outstanding biocompatibility data, as identified in report form 252.618.33.

[...]

Bayer Pharma AG must immediately refrain from the use of any NSAI registration marks, advertising or labelling that makes use of or reference[s] the NSAI name, identification number, or trademark. Please confirm receipt of this communication and your cessation of placing these devices on the Market carrying CE Marking with NSAI's Notified Body Number until this issue is resolved[.][346]

373 Around this time, it appears that Bayer internally discussed its options in relation to the CE mark suspension, including not seeking CE mark renewal. On 6 September 2017, Bayer sought internal legal advice with respect to the CE mark withdrawal proposal.[347]

374 The TGA raised the issue of a boxed warning with Bayer and AMSL shortly after the FDA announced the proposed US warning.[348] On 2 March 2016, AMSL advised the TGA that it was aware of the draft guidance and that 'once the changes [had] been approved [AMSL expected] this to flow to any Essure devices sold in Australia'.[349]

375 The TGA followed up with AMSL on 15 April 2016 requesting confirmation of whether the Australian IFU would incorporate the boxed warning and whether the patient decision checklist would be provided as a risk mitigation.[350] AMSL replied on behalf of itself and Bayer on 29 April 2016:

The discussions on the IFU which would include FDA's proposed boxed warning and the PIB with the proposed decision checklist are ongoing with FDA. We are in the process of revising the labelling based on FDA's feedback and a planned submission is scheduled for mid-May. FDA will review Bayer's proposed revisions and in parallel review the public comments to the draft labelling guidance document. Once we have received FDA approval for the final labelling (IFU/PIB), we will work with TGA to implement the changes locally.[351]

376 On 5 May 2016, the TGA issued AMSL with a notice requiring provision of adverse event reports within a shorter timeframe, and annual reports for a further five years. The reasons included an 'increase in adverse event reports' and 'safety concerns' surrounding Essure.[352]

377 In June 2016, AMSL notified the TGA of Health Canada's risk communication. In July-August 2016, the TGA requested further updates from AMSL about the inclusion of a boxed warning, patient information sheet and patient decision checklist 'given the recent decisions made internationally including by the FDA and Health Canada'.[353] AMSL maintained that the changes were under review by the FDA, Health Canada and the NSAI, and that the proposed amendments would be submitted to the TGA for evaluation once approved.[354]

378 Following FDA approval of the US boxed warning in November 2016, the TGA again requested an update as to when the changes would be implemented in the Australian market.[355]

379 In February 2017, AMSL sent the TGA a draft IFU which included a boxed warning.[356] AMSL noted that the NSAI was yet to finalise the document and that a final version of the changes would be provided in due course.[357] Further TGA requests for timeline updates were met with the same response from AMSL.

380 In March 2017, AMSL notified the TGA that Health Canada had introduced the boxed warning in Canadian IFUs and PIBs, and that Essure had been suspended in France.[358]

381 On 9 May 2017, the TGA proposed suspending Essure ARTG registration. The TGA advised that it was undertaking a review 'in response to international regulatory action taken against this device as well as an increase in the number of adverse event reports being received by the TGA'.[359] The TGA correspondence set out a timeline of AMSL's failure to engage in relation to the boxed warning update, and stated:

To demonstrate compliance with subsection 41GN(1)(b) [of the TG Act] you as the person in relation to whom the goods are included in the ARTG must be able to provide sufficient evidence to substantiate compliance with Essential Principles 2 and 13 as set out in the Act and/or the Regulations.

Essential Principle 2 refers to "Design and construction of medical devices to conform with safety principles". Design and construction includes packaging, labelling and Instructions for Use. Essential Principle 2 requires the manufacturer to identify hazards and associated risks and foreseeable misuse of the device and if unable to mitigate these risks by design or other means, ensure that adequate protection measures are taken, including alarms if necessary, and inform the users of the residual risks that may arise due to any shortcomings of the protection measures adopted. You have identified a risk and developed a strategy to inform clinicians and patients of the risk; however you have not implemented this in Australia within a reason [sic] time frame. Therefore, I find that you are not compliant with Essential Principle 2.

Essential Principle 13 refers to the information that must be provided with the device. This includes information about the intended performance of the device and any adverse events and contraindications. You have identified a risk and have not adequately informed the user of the device in the information that is provided with the device. Therefore, I find that your device does not comply with Essential Principle 13.[360]

382 In a meeting between Bayer, AMSL and TGA representatives on 19 May 2017, the TGA indicated that Bayer would need to submit a response package for TGA consideration within a matter of weeks to have the proposed suspension lifted.[361]

383 Bayer submitted a response package to the TGA on 24 May 2017. It proposed a black box warning to be included in IFUs and PIBs in the following terms:

• An Essure Confirmation Test should be performed three months after insert placement to evaluate insert retention and location. The patient must use alternative contraception until an Essure Confirmation Test demonstrates satisfactory results (see section XII 'Essure Confirmation Test').
• There have been reports of perforation of the uterus and/or fallopian tubes, inserts located in the intra-abdominal or pelvic cavity, persistent pain, and allergy or hypersensitivity reactions in some patients. Some of these reported events resulted in insert removal that required abdominal surgery. Device removal may lead to improvement or resolution of symptoms when: the onset is shortly after placement, imaging indicates an unsatisfactory insert location, and other etiologies for these symptoms have been considered. This information should be shared with patients consider[ing] sterilization with Essure during discussion of the benefits and risks of the device.[362]

384 I accept Turner's submission that there was an inordinate delay by AMSL and Bayer HealthCare in responding to the TGA in relation to the black box warning. However, for reasons set out in Chapter XX, the information and warnings in the IFUs that were in use about the risks addressed in the black box warning were not inadequate.

385 On 31 May 2017, Bayer informed the TGA that it intended to discontinue the sale of Essure in Australia, Canada, Belgium, Czech Republic, Denmark, Finland, Italy, the Netherlands, Norway, Portugal, Slovenia, Sweden, United Kingdon, Chile, Columbia, Costa Rica, Mexico and New Zealand.[363]

386 On 30 August 2017, AMSL in consultation with the TGA issued a hazard alert referring to symptoms including chronic bleeding, perforation, migration and the requirement for abdominal surgery or hysterectomy for device removal.[364] Shortly after issuing the warning, AMSL recalled unused Essure stock in Australia and withdrew the device from the Australian market.[365] Around this time, Bayer noted in an internal communication that it had also agreed to recalls with Spanish and French health authorities.[366]

387 On 31 August 2017, Bayer discontinued the sale of Essure in Canada.[367]

388 On 18 September 2017, Bayer sent a letter to the NSAI confirming its decision to withdraw its application for re-certification of the CE mark, and undertaking not to place any Essure products bearing the NSAI number or mark on the market.[368]

389 On 18 July 2018, Bayer notified the FDA of its decision to discontinue sales of Essure in the US market by the end of the year.[369]

390 In its communications with relevant regulatory bodies, Bayer maintained that the decision to discontinue sales of Essure internationally was commercial in nature and not based on safety or effectiveness concerns. Carney said decommercialisation was the result of a decline in sales of Essure globally that began in 2013. However, Turner submitted that at least a substantial reason for the decision to remove Essure from international markets from about mid-2017 was the growing regulatory and public concerns about the safety of the device and 'Bayer's ensuing fear of final adverse regulatory findings' (particularly from the NSAI, which had not yet completed its re-certification process).[370] In cross-examination, Carney agreed that the decline in Essure sales coincided with increased regulatory intervention and that the public's underlying safety concerns had directly impacted sales.[371]

391 Turner submitted that Jones v Dunkel[372] ('Jones v Dunkel') inferences should be drawn because of the defendants' unexplained failure to call a number of witnesses in relation to the decision to discontinue Essure in the context of the growing regulatory concerns from 2014 to 2017.

Manal Morcos, Alicia Lowery and Declan McGuinness

392 From January 2014, Manal Morcos was Director Group Head Essure and Device at Bayer HealthCare. From April 2016, Morcos' formal title was Director, Regulatory Affairs; Global Head, Essure and Devices.[373] Morcos ceased her employment with Bayer HealthCare in around October 2017.

393 Alicia Lowery was employed by Conceptus in Regulatory Affairs from 2008. She became Assistant Director Global Regulatory Affairs and remains employed by the Bayer defendants.

394 McGuinness was the Global Brand Manager, Essure, from November 2013, and was still employed by the Bayer defendants at the time of trial. McGuinness led an internal Bayer group known as the 'Women's Health Taskforce' from 2015, and was involved in the response to regulatory concerns raised about Essure.

395 Turner submitted that the failure to call Morcos and Lowery meant the following substantive inferences could be drawn with greater confidence:

(a) that the NSAI Essure suspension in 2014 did raise safety implications;

(b) that any 'compromise' by Bayer defendants in interactions with regulators involved a calculated consideration on the part of Bayer as to what commercial and regulatory consequences would flow if 'compromise' did not occur;

(c) that it was Bayer that was dilatory in not implementing warnings in Australia in 2016 equivalent to the FDA boxed warning, not the NSAI;

(d) that the failure by Bayer to appeal any of the adverse regulatory decisions of the NSAI and FDA is explained by at least a concern about wanting to control the 'narrative', which would not be available if appeals were lost; and

(e) that the decision to discontinue Essure was not entirely a commercial decision.

Turner relies on the failure to call Declan McGuinness only in respect of the fifth inference.

396 The rule in Jones v Dunkel does not require a party to call evidence that is merely cumulative or corroborative.[374] A very considerable volume of documentary and witness evidence was called by the defendants in this proceeding to explain the regulatory and commercial history of Essure. Each inference identified by Turner has been the subject of evidence. Turner did not bring a regulatory case. The inferences are peripheral to the case that was brought. In the circumstances, the failure to call Morcos, Lowery and McGuiness adds little if anything to consideration of the issues relevant to the inferences identified by Turner.

397 Christina Dixon was apparently the author of an internal Bayer note shown to Carney in cross-examination concerning the Bayer defendants' interactions with the NSAI in 2017. Turner did not identify any inference that should be drawn as a result of Dixon's absence. The note, and Carney's response to it, are in evidence. No matter was raised requiring some further explanation by Dixon.

Any current or former employee of Bayer Australia

398 Turner identified Prisca Drysdale and Teresa Lai, who were successively in the position of Regulatory Affairs Manager at Bayer Australia from December 2013 to March 2018. Turner relies on the failure to call Lai and Drysdale as being relevant to the substantive inference that the Bayer defendants delayed introduction of the enhanced boxed warnings in 2016. Chloe Perot was the National Sales Manager for Women's Health at Bayer Australia. Turner submitted that her failure to give evidence was relevant to inferences that should be drawn about discontinuation of Essure.

399 As explained above, the history of regulatory concerns and discontinuation of Essure was the subject of extensive evidence at trial. Bayer Australia had a relatively limited role in relation to Essure. The failure to call any witness from Bayer Australia is of limited weight in relation to the inferences Turner identified.

400 In the period 2013 to 2017 Bayer faced significant public concern about the safety of Essure driven at least in part by social media, an associated substantial decline in sales, and the costs of responding to the concerns of regulators in multiple jurisdictions. Bayer's decision to discontinue sales of Essure is understandable in those circumstances. I accept Carney's evidence on this issue.

401 Bayer continued to prepare clinical evaluation reports in relation to Essure after decommercialisation. Carney prepared a report dated 28 September 2018 which annexed a biological risk assessment report prepared for Bayer by medical scientists from research organisation North American Science Associates ('NAMSA').[375] The report summary included:

Based upon examination of the device materials, use of the Essure Insert would not be expected to result in an adverse biological response in patients. This risk assessment indicates that the likelihood of a toxic effect from the Essure Insert is negligible and that the device can be considered safe for use as intended. No further biocompatibility testing is recommended.

The Essure Insert meets the requirements of ISO 10993-1:2009, EN ISO 14971:2012, FDA General Guidance on the Use of International Standard ISO 10993-1:2016, and the European Union Medical Device Directive 93/42/EEC for a permanent (>30 days) implant in contact with tissue and can be considered safe for use as a contraceptive when used as intended.[376]

After an analysis of the materials used to construct the Essure Insert, it was apparent that all materials used are well characterized with a long history of clinical use in and of clinical use in similar or closely related, approved and marketed medical devices.[377]

The report stated, in relation to risk assessment and risk control:

Based upon the risk analysis, use of the Essure Insert would not be expected to result in an adverse biological response in patients. This risk assessment indicates that the likelihood of a toxic effect from the Essure Insert is negligible and that the device can be considered safe for use as intended. Consideration has been given to all potential biological hazards for the materials and final product, and testing for each hazard is not necessary.[378]

402 In November 2019, the FDA Center for Devices and Radiological Health ('CDRH') held a meeting of the Medical Devices Advisory Committee Immunology Devices Panel ('Metals Advisory Committee'). The panel included 22 experts from a variety of specialties including metallurgy, clinical practice and biomaterials science, including Badylak.

403 The FDA published a briefing paper in advance of the meeting. The purpose of the paper was described as follows:

This paper presents FDA's review of currently available scientific information related to metals and their uses in medical implants, with focus on how metal materials are impacted by a physiological environment, expected and potential immune system responses to the metal associated with an implant, as well as subsequent clinical manifestations. It is the result of a collaborative effort amongst subject matter experts (SMEs) gathered from across the Center for Devices and Radiological Health (CDRH), the organization within the FDA that is charged with regulating medical devices. Just as importantly, this paper identifies where gaps exist in the scientific evidence related to immunological responses to metal-containing implants, and where opportunities for further research exist and will serve as a starting point for a public discussion on November 13 and 14, 2019 as part of an advisory panel meeting.[379]

404 In relation to inflammation, the paper identified that no FDA standards at that time provided:

... all-inclusive guidance for comprehensive assessment of the overall inflammatory response that would incorporate nonclinical and clinical testing... because certain types of inflammatory responses to metals, and other select materials, in medical devices resulting in clinical manifestations (particularly systemic effects) had not been well-recognized in the past and are still the subject of debate, as described in this paper.[380]

405 On 28 October 2019, Bayer submitted a briefing document to the Metals Advisory Committee. Carney said that she 'considered [the document] to contain the most up-to-date information known to Bayer with regard to the Essure device and metal hypersensitivity issues,'[381] including:

(a) Essure metal release rate;

(b) clinical data of any nickel hypersensitivity that might be associated with Essure;

(c) the available epidemiological data/studies on matters such as pain and hysterectomy rates; and

(d) issues with relying on adverse event reports during post-marketing reporting.

406 Carney said that the Metals Advisory Committee did not publish any conclusions related to Essure.[382]

1. PHYSIOLOGICAL RESPONSE TO ESSURE IMPLANTATION

407 An understanding of the physiological response to Essure implantation is critical to determination of Turner's claims.

408 Essure was designed to promote an inflammatory response intended to cause development of fibrosis and tubal occlusion. Insertion of the device disrupted the inner layers of the fallopian tube, causing a wound. The inflammatory response to this wound was promoted by the continued presence of the device as a foreign body in the fallopian tube, and by features including the PET fibres located between the outer and inner coils of the device.

409 Turner argued that biomedical devices should be designed to minimise the inflammation that occurs as part of the foreign body response to a device and the development of dysfunctional tissue. She argued that because Essure was designed to have the opposite effect, there was an inherent risk that in a significant number of women, implantation would cause ongoing chronic inflammation that was pathological and inconsistent with optimal health.

410 The defendants submitted that there was no evidence on which the Court could find that insertion of Essure caused ongoing, pathological chronic inflammation.

411 It is necessary to say something about the immune system, foreign body responses to biomedical devices, biocompatibility and chronic inflammation before turning to consider the histological evidence relevant to Essure.

412 The immune system plays a central role in wound healing and the foreign body response that follows implantation of a biomedical device.

413 The immune system consists of 'a diverse collection of cell types that patrol the body and reside in tissue to provide protection from threats including microbial infection, damage (e.g. a wound response), altered self (e.g. cancer, which derives from mutations altering the proteins expressed by a tissue), while at the same time preventing inappropriate activation against self-proteins, and regulating aspects of normal tissue turnover and remodelling (termed 'homeostasis')'.[383]

414 Immune cells may be pro-inflammatory or anti-inflammatory, depending on cell type and the processes occurring where they are located in the body.

415 The following table describes the major immune cells:[384]

Cytokine* production targeted against viruses and intracellular bacteria

Cytokine* production targeted against allergens and helminth parasites

Cytokine* production targeted against extracellular bacteria and fungi

Suppresses the activity of other CD4* T cells and CD8* T cells; produces anti-inflammatory cytokines*

Blood resident cell; involved in acute inflammation

Blood resident cell; involved in acute inflammation

Blood or tissue resident cell; kills infected or cancerous cells

Tissue resident cell in immature state; activates CD4* and/or CD8* T cells

Blood resident cell; involved in acute inflammation

Long-lived tissue resident cell; either present from birth or generated from monocytes

Long-lived cell that forms by the fusion of macrophages in the tissue

* Cytokines are secreted factors that modulate immune cell phenotype or function.

416 The innate immune system monitors the body for evidence of infection or damage. When activated by pathogens or foreign materials, it will attempt to remove the substance and heal any damage. If a foreign material cannot be removed from the body, the innate immune system will attempt to wall off the substance through fibrosis.[385]

417 The adaptive immune system, once activated, is able to provide long-term memory and protection against pathogens. It can produce both pro-inflammatory T-cells which cause inflammation and damage to pathogens, and anti-inflammatory (regulatory) T-cells which prevent inflammation and protect tissue.[386]

(a) leukocytes: white blood / immune cells that emigrate to and accumulate in tissue as part of the inflammatory response, for example to a wound.[387] Leukocytes include the following cell types:

• Neutrophil (polymorphonuclear leukocyte, PMN): A type of white blood cell that is an important part of the immune system and helps the body fight infection. When microorganisms, such as bacteria or viruses, enter the body, neutrophils are one of the first immune cells to respond. They travel to the site of infection, where they destroy the microorganisms by ingesting them and releasing enzymes that kill them. Neutrophils also boost the response of other immune cells.

• Eosinophil: A type of immune cell that has granules (small particles) with enzymes that are released during infections, allergic reactions, and asthma.

• Basophil: A type of immune cell that has granules (small particles) with enzymes that are released during allergic reactions, and asthma.

• Macrophages: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells.

• Lymphocytes: A type of immune cell that is made in the bone marrow and is found in the blood and tissue. The two main types of lymphocytes are B lymphocytes and T lymphocytes. T lymphocytes (more common in fallopian tubes than B lymphocytes... ) help control immune responses. A lymphocyte is a type of white blood cell.

• Plasma cells: A type of immune cell that makes large amounts of a specific antibody. Plasma cells develop from B cells that have been activated.

• Mast cells: Found in connective tissues all through the body. They play an important role in how the immune system responds to bacteria and parasites.

• Natural killer (NK) cell: A type of immune cell that contains enzymes that kill tumor cells or cells infected with a virus.

• Dendritic cell: A type of phagocyte and antigen presenting cell that act as a communicator by presenting the antigen to other cells of the immune system[.][388]

(b) fibroblasts: a type of cell which contributes to the formation of connective tissue (a fibrous cellular material that supports and connects other tissues or organs in the body). Fibroblasts secrete collagen proteins that help maintain the structural framework of tissues and play an important role in healing wounds.[389]

(c) neovascularisation: the development of new blood vessels that can be a feature of wound healing and an inflammatory response in tissue.[390]

(d) granulation tissue: the new blood vessels and connective tissue that form as part of the wound healing process.[391] Granulation tissue is generated by the deposition of extra cellular matrix of fibroblasts and neovascularisation by proliferating endothelial cells.[392]

(e) fibrosis: connective tissue created by the proliferation of fibroblast cells.[393]

(f) foreign body giant cell: giant cells that may be found around the site of a foreign body that are the result of fusion of macrophages.[394]

(g) phagocytes: immune cells capable of phagocytosis (process of engulfing), which include monocytes, macrophages, dendritic cells, and neutrophils.[395]

419 The physiological process of wound healing involves a predictable sequence of four stages: first, haemostasis or blood clotting; second, an inflammatory response; third, fibroblast proliferation and scar formation; and fourth, tissue remodelling. A completely healed wound is characterised by the resolution of inflammation and then by fibrotic tissue and scar formation.[396]

420 In their expert reports, Sokol and Robertson each gave greater detail describing the wound healing response. Sokol said:

Tissue damage leads to the release of pro-inflammatory cytokines from damaged cells that act alone or in concert with locally activated tissue resident innate immune cells (e.g., macrophages, mast cells), to induce immune cell entry to the site of the wound. This second phase is characterized by the influx of large numbers of innate immune effector cells (e.g., neutrophils, eosinophils, monocytes that can differentiate in the tissue into more macrophages). These innate immune effector cells share a common goal of removing damaged tissue and debris, while at the same time activating local structural cells (e.g., fibroblasts and myofibroblasts) to divide, differentiate, regenerate damaged vessels and supports, and heal the wound[.] This initial healing resolves the acute insult of tissue breakdown, but is often marked by a scar and disordered fibroblasts and other structural cells[.] The second phase of wound healing then occurs, with local tissue resident macrophages (some descending from the monocytes that originally entered the tissue) secreting cytokines to promote the remodeling of myofibroblasts and supporting cells, with the goal of ultimately reducing or eliminating the scar and optimizing tissue strength[.][397]

421 Robertson described the four stages of wound healing as follows:

1. Haemostasis ( > Figure 9. Diagrammatic representation of the phases and cellular processes involved in a healthy wound response. The four phases and approximate time course for a healthy wound response.

423 The experts agreed that the kinetics and final form of wound repair can vary depending on body location and individual characteristics, including genetics and other biological and health factors.[400] However, they disagreed about the timeframe for completion of the first three stages of wound healing. Robertson said that if wound healing up to the maturation or remodelling phase was not complete by three months, the wound would meet the definition of a 'chronic wound'.[401] Sokol said that there was no consensus in the medical literature on a precise timeframe by which a wound would be considered 'chronic'.[402] I will return to the issue of wound healing timing and kinetics later in these reasons.

424 The pattern of leukocyte infiltration during the wound healing stages is depicted in the following figure, taken from Robertson's primary report:[403]

Figure 11. Pattern of leukocyte infiltration into wounds. Inflammatory cells are present during each of the phases of wound repair, represented here as haemostasis (yellow panel), acute (early) inflammation (light pink panel), chronic (late) inflammation (dark pink panel) and resolution/remodelling (blue panel). The relative density of the four most prominent types of leukocytes in wounds (mast cells, neutrophils, macrophages and T cells) is depicted. Whereas neutrophils and lymphocytes disappear, low numbers of resident mast cells and macrophages are present during the lengthy remodelling phase. T cells usually do not persist once inflammation has resolved.

425 The phenotype of a population of macrophages exists on a spectrum from pro-inflammatory macrophages ('M1' phenotype) to anti-inflammatory macrophages ('M2' phenotype). The average or net phenotype of a macrophage population may change over time depending on the function that the cells are engaged in. As Sokol explained:

The process of wound healing is dependent on the function of macrophages, which generally act to first promote inflammation in the early stages of wound healing and then to resolve that inflammation in later stages.[404]

426 It is not in dispute that insertion of Essure caused damage and injury to the fallopian tube and surrounding tissue. In the biomaterials JER, the participating experts agreed that deployment of Essure caused 'tissue injury, focal bleeding and damage to the internal lining of the isthmus and the SUTJ regions of the fallopian tube and uterus.'[405] The experts said:

We agree that insertion of the Essure Device into a fallopian tube causes localised mechanical injury to the surrounding tissue. This is because the isthmus segment of the fallopian tube is a thin-walled, soft and fragile tissue. The SUTJ is also soft but has a thicker wall. Both parts have a very narrow internal diameter that is substantially less than the diameter of the Essure Device. At the time of insertion, in order to fit into the intended site and exert the desired effect, the Essure Device causes injury to the cells and tissue structures of the fallopian tube. This would happen to varying degrees in all women who receive it, because the tube is narrower than the device and has a limited ability to stretch without tissue[.]

Once the Device is positioned in the isthmus and SUTJ regions of the fallopian tube, it is then deployed so that a spring-like action causes its external nitinol coil to be unwound, expand in diameter, and engage with the inner layers of the fallopian tube.[406]

In the days after insertion, the tissue injury caused by Device placement would begin a typical wound healing program[.] The ability of the Device to cause tubal occlusion and deliver its intended contraceptive effect depends on it provoking the surrounding tissues to undergo a typical wound healing response including fibrosis (the deposition of scar tissue). In most women the device placement causes short-lived inflammation followed by fibrosis and scar formation.[407]

427 Robertson and Sokol agreed that a 'chronic wound' is a wound with ongoing inflammation and immune response activity which fails to heal.[408]

428 Robertson said that 'a chronic wound is a wound that has not proceeded through orderly and timely reparation to produce anatomic and functional integrity after three months'.[409] She said that a chronic wound will exhibit ongoing inflammation and immune response activity.[410]

429 Murdock said that a chronic wound 'stalls' in the acute phase of the wound response without significant progression to granulation tissue formation and fibrosis. She said that microscopically, a chronic wound is comprised of extensive acute and some chronic inflammatory cells, lacks any fibrosis, and is basically an abscess cavity. She said:

Chronic wounds can be classified as vascular ulcers, diabetic ulcers, and pressure ulcers. Common features shared by each of these wounds include prolonged excessive inflammation, persistent infections, formation of drug resistant microbial biofilms, and the inability of dermal and/or epidermal cells to respond to reparative stimuli. Importantly, these features were not observed in relevant published literature of tissues adjacent to the Essure Device (Valle, 2001 and Banet, 2020)[.][411]

The literature Murdock referred to is discussed later in these reasons.

430 Robertson disagreed with Murdock's definition of a chronic wound for three reasons. First, Robertson said that a chronic wound may exhibit spatial heterogeneity in the degree of wound healing and fibrosis, with some parts of the wound showing more progress towards healing (including patches of fibrosis and granulation tissue) than others.[412] Second, she said that while vascular ulcers, diabetic ulcers and pressure ulcers are common types of chronic wounds, the term also incorporates surgical wounds, radiation wounds and ulcers that arise in response to infectious or sterile injuries.[413] Third, Robertson said that it was not necessary for a wound to exhibit all of the features referred to by Murdock in order to be classified as 'chronic'.[414] Robertson said that the critical feature of a chronic wound is inflammation, and that other features included neovascularisation, haemorrhage and tissue disruption.[415]

431 Murdock disagreed with Robertson's evidence about patchy fibrosis. She said she had not seen fibrosis or attempts at wound healing when examining chronic wounds under the microscope.[416] Murdock did not agree that haemorrhage was necessarily a concerning feature. I will return to this debate later in these reasons.

432 A 'foreign body' relevantly includes an implanted biomedical device or prosthesis. A 'foreign body response' to a biomedical device is a form of wound response complicated by the ongoing presence of the device.

433 Robertson and Sokol agreed that the foreign body response is the immune system's response to 'a foreign (non-self) substance, material or medical device embedded or implanted in the body'.[417] They agreed that 'the function of the foreign body response is to eliminate or physically segregate the foreign body and defend the body from the perceived or real threat it poses'.[418]

The foreign body response involves a cascade of molecular and cellular steps triggered when a foreign body causes tissue injury. This provokes inflammation - an altered tissue state characterized by immune cell accumulation and activation - that in turn causes activation of local fibroblasts. These cells proliferate to surround the foreign body, creating a barrier that when successfully completed, ultimately acts to 'wall-off' or cover the foreign body to prevent it from further provoking the immune response. When not successful - that is, when the foreign body is not walled-off - the unresolved foreign body response may cause the affected tissue to remain in a state of active inflammation.

The foreign body response can be viewed as a form of wound response that is complicated by the ongoing presence of the non-self entity that cannot be removed by the usual process of engulfment by immune cells. The foreign body response has a comparable sequence of steps or phases to those of a standard wound healing response, but is modified and specialized by the presence of the foreign body and its effect on the immune response. Like a wound response, the foreign body response to medical implants includes four stages, which can be summarized as haemostasis, inflammation, fibroblast proliferation and scar formation, and finally scar maturation[.]

We agree that this broad definition would be agreed upon by immunologists, pathologists and clinicians.

We agree that when a foreign body response is elicited by a medical device, many host factors (the tissue site, host immune status, age, comorbidities) and device features (size, surface area, material and composition of the device) can affect the kinetics of the foreign body response.[419]

Badylak, Chrzanowski and Robertson expressed agreement in the same terms in the biomaterials JER.[420]

435 However, the experts did not agree on the expected timeline of this response.

436 Robertson said that the kinetics of a foreign body response should follow a similar timeframe to completion as the wound healing response.[421] She said that 'the wound response to a metal device is often never fully "healed" or "completed" in the same way as a standard wound usually is'.[422] She said this was because of the continued presence of the device, the resulting disruption of normal tissue architecture, and the ongoing engagement with (and effects on) the immune response caused by the device. She said that if wound healing in response to a medical device is not complete within three months and chronic inflammation is present, the wound around the foreign body would share features with a chronic wound.[423]

437 Robertson said that when inflammation associated with a wound or foreign body response does not resolve within a limited time, there is a high chance of persistent chronic inflammation that is damaging to ongoing health.[424]

438 In the biomaterials JER, Robertson and Chrzanowski said that resolution of inflammation associated with a foreign body response is crucial for wound healing, and echoed Robertson's view that inflammation which does not resolve within a limited time carries a high chance of becoming persistent and chronic.[425]

439 Sokol said that the foreign body response is different to the wound healing response because it includes the complication of a foreign body. She said that a foreign body response can fully resolve, but that the foreign body may alter the timeline for complete resolution.[426] Sokol said that the goal of an acute inflammatory response during the foreign body response is to ultimately 'wall off' the device to separate it from the immune system and prevent chronic activation of the immune system, which would be indicated by the presence of continued neutrophils in the site. She said that with most foreign body responses this process takes time, and while acute inflammation can often transition into chronic inflammation at the six-week stage it is not a foregone conclusion that inflammation will always be active.[427] Sokol said that host and device factors can lead to widely disparate 'normal' kinetics that should be considered before speculating on whether a foreign body response has failed or stalled.[428] Sokol said there was no consensus in the medical literature on the precise timeframe for a chronic wound, and that chronicity could only be determined by comparison to the expected wound healing kinetics for the host and wound type.[429]

440 Badylak did not agree with the precise timelines specified by Robertson for resolution of the foreign body response. He agreed with Sokol that the timeline will vary with host and device factors.[430] In his expert report, Badylak said that the overall response to a foreign body transitions from an 'active pro-inflammatory' response to a 'pro-remodelling steady' state within a two to three month period after implantation, which is characterised by an abundance of fibrous tissue deposited by the recruited fibroblasts.[431] He said that the fibroblasts deposit collagen, which is the core substance of fibrous/scar tissue. He said:

The end result of these cellular and tissue remodeling events is a dense fibrous (scar) tissue response with associated relatively small number of pro-remodeling mononuclear inflammatory cells adjacent to the metal materials and PET fibers. This foreign body response reaches a steady state in which the tissue ingrowth process is essentially complete over a period of several months. The small number of mononuclear or multinucleate cells that are present after 3-4 months will likely persist for the life of the patient. It is inaccurate and misleading to characterize the presence of these cells as a persistent and active inflammatory reaction that causes continuous tissue damage.[432]

441 Murdock said that the foreign body response, or 'foreign body giant cell reaction' is a response to a foreign material in biological tissue.[433] Murdock said:

Professor Robertson's argument that there must be a resolution of inflammation for "wound healing" (incorrect use of the term "wound," see my response to 2i), or scar formation and scar maturation, is incorrect. The response to the Essure Device was orderly and predictable and resulted in dense fibrosis (scar formation) and occlusion of the fallopian tube lumen in 100% of patients (Valle, 2001).[434]

She said that in the field of pathology she 'would not use the term "chronic wound" to describe the tissue response to a medical device'. She described the response as follows:

The tissue response to implanted medical devices is a predictable tissue reaction that begins within minutes to hours and is characterized by an acute inflammatory cell infiltrate including polymorphonuclear leukocytes (neutrophils) and some mononuclear cells (monocytes and macrophages). Over time (variable for each patient), the tissue reaction develops into a chronic inflammatory response with granulation tissue formation, and eventually fibrosis... Regarding the Essure Device, the PMA data, as well as Rubin (2020), Banet (2020), and Valle (2001) all demonstrated at least loose, and most cases showing dense fibrosis and obliteration of the fallopian tube lumen ([scar formation] in 100% of patients, Valle) a normal tissue healing response (scar formation), and therefore, the term "chronic wound" does not apply and is misapplication of the term.[435]

442 Robertson, Sokol and Murdock agreed that the presence of foreign body giant cells adjacent to an implanted device, without other immune cells, was not sufficient to indicate active inflammation or an abnormal response to the foreign body.[436]

443 Robertson, Chrzanowski, Badylak and Eiselstein agreed in the biomaterials JER to the following definition of biocompatibility:

Biocompatibility refers to the ability of a biomaterial to perform its desired function with respect to a medical therapy, and to generate the most appropriate beneficial cellular or tissue response in that specific anatomic location, while mitigating any undesirable local or systemic effects in the recipient.[437]

We agree that an "ideal" biomaterial involves the overlapping properties of biocompatibility, safety and efficacy. "Inert" and "non-inflammatory" characteristics in biomaterials were identified as desirable and considered key features of biocompatibility several decades ago. However, it is now recognized that no biomaterial is absolutely inert or non-inflammatory.

We agree that the act of introducing a biomaterial into the body, including the disruption to tissues of the implantation procedure, and the subsequent presence of the foreign material, will always elicit at least some degree of host tissue response. The response manifests as an inflammatory reaction and the associated subsequent formation of variable amounts of fibrous connective tissue. This fibrous connective tissue may be identified as dense collagenous connective tissue, scar tissue, or fibrous tissue, among other monikers, and is a consequence of the body's innate immune system response. The nature of this inflammatory response, with respect to both its temporal and spatial characteristics, is a determinant of the clinical outcome.[438]

444 Chrzanowski and Robertson said that over and above the issue of biocompatibility, a biomedical device should meet the following fundamental 'tenets':

(1) an intention to repair a damaged tissue and/or treat a state of tissue pathology, and (2) an intention to not cause or increase dysfunction in the tissue. ... [I]n the event of meeting neither of these fundamental tenets, the value proposition of a Device or intended Device is likely to be unreasonable. In their opinion, the Essure Device does not meet either of these fundamental tenets - that is, it does not (a) act to repair a tissue or repair a state of tissue pathology, and (b) it operates to cause tissue dysfunction, by virtue of its eliciting damage to otherwise healthy fallopian tube tissue.[439]

445 Chrzanowski further explained his opinion in relation to biocompatibility in oral evidence:

... biocompatibility is the characteristic or property of the material which we frequently refer to as the biomaterial, to enable [it] to perform a desired function in respect to the medical therapy. I would like to highlight the word 'therapy' here. Also biocompatibility refers to generating appropriate and beneficial cellular and tissue responses in the specific anatomic location, while mitigating any undesired localised or systemic effects in the recipient. So what it means, is that the material that is considered biocompatible will be the material which supports our body to regenerate its function. It is therapy. Therapy means regenerating, regaining the function or supporting the function. It is not about creating pathological tissue which does not have any function, what is a biological function, in the body. So biocompatibility means material which will support the organs or our body in regaining the actual physiological functions and supporting us in living and our longevity.[440]

446 Badylak did not agree with the 'fundamental tenets' described by Chrzanowski and Robertson. He said that the tenets were not found in any textbook or peer-reviewed publication of biomaterials or biocompatibility. He said:

... the function of any particular biomaterial depends upon the choice of anatomic placement and the desired outcome which in the case of the Essure device is to cause permanent sterilization by occlusion of the fallopian tube with fibrous tissue. He further considers that integration of surrounding tissues with the biomaterial of choice, access of the biomaterial to the host vascular network, the presence of pores (holes) within certain biomaterials ..., and the occurrence of a transient proinflammatory tissue response phase by the recipient are not only acceptable characteristics ..., but in fact desirable and required characteristics.[441]

447 The cross-examination of Chrzanowski and the defendants' submissions on this issue proceeded on the basis that the tenets needed to be separately considered, and that both must be satisfied. Chrzanowski repeatedly said in oral evidence that the tenets were to be considered together. Further, Chrzanowski and Robertson expressly stated that the value proposition of a device was likely to be considered 'unreasonable' if it met 'neither of these fundamental tenets'. Robertson said that while there may be a 'serious problem' if a device fails to meet either tenet, there may be occasions where breaking the tenets is justified.[442]

448 The defendants also criticised the 'fundamental tenets' on the basis that their application would lead to the following absurd consequences:

(a) devices implanted for purely cosmetic purposes would be considered 'not biocompatible' or otherwise inappropriate to be implanted in the human body;

(b) nitinol coils, wires and stents delivered to the sites of cerebral aneurysms for the purpose of causing blood coagulation and occluding blood flow would not satisfy the fundamental tenets;

(c) devices used in tubal ligation to facilitate permanent contraception by interfering with the normal function of the fallopian tubes, such as Filshie and Hulka clips, would never satisfy either of the asserted tenets.

Further, the defendants criticised Chrzanowski and Robertson for proposing the tenets in the absence of any textbook or other authoritative support and, particularly in the case of Chrzanowski, for his adherence to and defence of the fundamental tenets in oral evidence.[443]

449 Chrzanowski and Robertson appear to have made a distinction between a biomedical device that is to be used for a medical purpose and a cosmetic device for an aesthetic purpose relevant to application of the tenets. It is not clear why this distinction should be made. It is not clear why tenets of biocompatibility would not apply to a cosmetic device that may have a therapeutic psychological purpose.

450 Chrzanowski rejected the defendants' proposition that nitinol coils and stents designed to treat cerebral aneurysms did not satisfy the tenets because they caused blood coagulation and occluded blood flow. Chrzanowski explained that the pathology the coils are intended to treat is altered blood flow associated with an aneurysm.[444] He said:

I'm sorry, it does repair the damage because the tissue is damaged, it's a pathological state when your blood vessels are pathologically altered, they are completely changed. That's why the blood flow is circulating the completely wrong way and you are correcting pathology, the same way as you correct pathology in your heart when you have the arrythmia.

It's changed by creating dysfunctional tissue, isn't it?---Yeah, it is the dysfunctional tissue which allows you to restore the function, regain the proper blood flow and save lives.[445]

Chrzanowski explained that the vast majority of biomedical devices create a certain level of pathology in order to achieve the therapeutic purpose of restoring function. He said that blood coagulation caused by the nitinol coil results in a substantial plaque that acts as the plug to prevent dysfunctional blood flow.[446] Chrzanowski said that while the nitinol coils do cause a small amount of dysfunction, they do so in order to allow the entire tissue to overcome pathology and regain function.[447] I do not accept this aspect of the defendants' criticism.

451 There is merit in the defendants' submission that Filshie and Hulka clips used to achieve permanent contraception do not satisfy the fundamental tenets. Chrzanowski and Robertson's tenets were directed to treatment of tissue damage or pathology by medical therapy. Contraceptive choice does not involve the treatment of an illness, disease, tissue damage or pathology. Contraception may be better understood as an interference with biological function, rather than therapy directed to regaining or supporting that function. It is surprising that Chrzanowski and Robertson proposed as the main principles against which biocompatibility should be assessed tenets which could not be satisfied by tubal ligation, which is the obvious comparator to Essure when considering permanent sterilisation.

452 Chrzanowski and Robertson can also be criticised for proposing what they described as 'fundamental tenets' of biocompatibility without making any attempt to identify reputable and authoritative scientific literature that supported their proposition. Chrzanowski and Robertson did not even refer to other publications of their own in which they identified the tenets and argued in their support. I accept Badylak's evidence that the tenets could not be found in any textbook or peer-reviewed publication. Save in the one respect referred to above, the defendants' criticisms of Chrzanowski and Robertson were warranted.

453 The defendants submitted that 'the extremity of the views expressed by Professor Chrzanowski is well demonstrated by the fact that, in all of the circumstances, he describes contraception as "a non-essential clinical outcome".'[448] This submission is a reference to the following statement by Chrzanowski in his first report:

In my opinion it is an unorthodox strategy to achieve a nonessential clinical outcome - contraception - by forming a fibrotic tissue which does not perform any physiological function.[449]

The above sentence appears in the summary section of Chrzanowski's report in a paragraph dealing with the risks associated with the design approach to Essure, which he said intentionally maximised the foreign body response and promoted chronic inflammation contrary to accepted practice in biomedical engineering. Chrzanowski was not given an opportunity to further explain the context in which the sentence was made in cross-examination. It may be the case that Chrzanowski used the term 'non-essential' to distinguish Essure from a biomedical insert which is 'essential' in the sense of being necessary to maintain life. In the circumstances I make nothing of this criticism.

454 Robertson and Chrzanowski said that there is an inverse relationship between biocompatibility and the degree and duration of the inflammatory or immune response elicited by a device.[450] They said that:

... any inflammatory response after placement of a medical device is undesirable, and should be time-limited and rapidly resolved ... [A]n ongoing inflammatory response or immune response in the vicinity of an implanted medical device is not an acceptable characteristic of a medical device.[451]

Badylak disagreed that an inflammatory response to a biomedical device was undesirable. He said that without an inflammatory response and fibrous tissue deposition, there would be no subsequent healing. He noted that inflammation and fibrous tissue deposition occur as part of all wound healing even in the absence of biomaterial.[452] I accept Badylak's evidence. However, the real issue is whether there was a risk that the immune response to implantation of a biomedical device such as Essure would fail to resolve and cause ongoing chronic inflammation.

455 Pathologist James Anderson, who authored a number of articles tendered into evidence, was cited by the experts as an authority in relation to the foreign body response to implanted biomedical devices.[453] In a 2013 text chapter titled 'Inflammation, Wound Healing, and the Foreign-Body Response' ('Anderson 2013'), Anderson described biocompatibility and implantation in the following terms:

Implantation of a biomaterial, medical device, or prosthesis results in tissue injury that initiates host defense systems, e.g., inflammatory, wound healing, and foreign-body responses. The extent and time-dependent nature of these responses, in the context of the characteristics and properties of the biomaterial, form the basis for determining the biocompatibility or safety of the biomaterial. In addition to defining the biocompatibility of a biomaterial, a fundamental understanding of these responses permits their use as biological design criteria.[454]

456 Anderson described the temporal sequence of events following implantation of a biomaterial using the figure included below:[455]

FIGURE II.2.2.1 The temporal variation in the acute inflammatory response, chronic inflammatory response, granulation tissue development, and foreign-body reaction to implanted biomaterials. The intensity and time variables are dependent upon the extent of injury created in the implantation and the size, shape, topography, and chemical and physical properties of the biomaterial.

The size, shape, and chemical and physical properties of the biomaterial may be responsible for variations in the intensity and duration of the inflammatory or wound-healing process. Thus, intensity and/or time duration of the inflammatory reaction may characterize the biocompatibility of a biomaterial.[456]

457 Anderson used the figure reproduced below to demonstrate the sequence of events involved in inflammation and wound healing when medical devices are implanted:[457]

He said that, generally, the end-stage healing response to biomaterials is fibrosis or fibrosis encapsulation.[458]

458 Anderson 2013 described the foreign body reaction to a biomaterial as follows:

The foreign-body reaction to biomaterials is composed of foreign-body giant cells and the components of granulation tissue (e.g., macrophages, fibroblasts, and capillaries in varying amounts), depending upon the form and topography of the implanted material.

...

The foreign-body reaction consisting mainly of macrophages and/or foreign-body giant cells may persist at the tissue-implant interface for the lifetime of the implant ... Generally, fibrosis (i.e., fibrous encapsulation) surrounds the biomaterial or implant with its interfacial foreign-body reaction, isolating the implant and foreign-body reaction from the local tissue environment.[459]

459 In an earlier article published in 2001, Anderson defined biocompatibility as follows:

Biocompatibility is generally defined as the ability of a biomaterial, prosthesis, or medical device to perform with an appropriate host response in a specific application, and biocompatibility assessment, i.e. evaluation of biological responses, is a measure of the magnitude and duration of the adverse alterations in homeostatic mechanisms that determine the host response. Practically speaking, the evaluation of biological responses to a medical device is carried out to determine that the medical device performs as intended and presents no significant harm to the patient or user. Thus the goal of biological response evaluation is to predict whether a biomaterial, medical device, or prosthesis presents potential harm to the patient or user by evaluating conditions that simulate clinical use.[460]

460 There were significant differences of opinion between the experts about the meaning of terms including 'inflammatory cells', 'acute inflammatory cells', 'acute inflammation', 'chronic inflammatory cells' and 'chronic inflammation'. The experts also differed in their views on how those terms were used in scientific literature by immunologists and pathologists, and in studies involving histological analysis of tissue following explantation of Essure inserts.

461 In the immunology JER, Robertson and Sokol agreed:

We agree that acute inflammation is an immune response characterized by the infiltration or accumulation (entry out of the blood vessels and into tissues) of predominantly granulocytes (neutrophils and eosinophils), as well as lesser numbers of monocytes and macrophages. We also agree that this term is sometimes used to describe a chronic inflammatory response where neutrophils or eosinophils are the predominant infiltrating cells.

We agree that this broad definition would be agreed upon by immunologists, pathologists and clinicians.[461]

In the biomaterials JER, Badylak, Chrzanowski and Robertson agreed to the same definition of acute inflammation.[462] Murdock agreed to the first sentence of this definition in the pathology JER.[463]

462 Robertson said that the acute inflammatory response in wound healing should be short‑lived and progress rapidly with a characteristic sequence of different immune cell types passing into the wound. She said that this progression could be broken into 'early inflammation' and 'late inflammation' stages. By four weeks (or three months at the latest), the inflammatory response should be resolved and the immune cells should disappear by dying or exiting the wound.[464]

463 Sokol said that the standard meaning of 'acute inflammation' was any inflammation lasting up to six weeks after onset.[465]

464 In the biomaterials JER, Robertson, Chrzanowski and Badylak agreed:

... that in all women, the wound healing response to placement of an Essure Device involves an acute inflammatory response phase. In most women, this phase will be short-lived and will be completely resolved within hours or days of Device placement, at which time it transitions to a chronic inflammatory response. We agree that in some women where the Device continues to elicit a chronic inflammatory response that is dominated by immune cells of the granulocytic type (neutrophils or eosinophils), the inflammatory response has been termed an 'acute inflammatory response', even though the Device was placed many weeks or months earlier (eg. Valle et al 2001).[466]

465 In the immunology JER, Robertson and Sokol agreed:

... that the presence of a predominant neutrophil infiltrate surrounding the Essure device in the fallopian tube at 3 months or more after placement is consistent with active inflammation and not expected of the normal wound healing response.[467]

466 Robertson said that acute inflammation 'only occurs after it is elicited by a pro-inflammatory stimulus, and is not a feature of healthy quiescent tissue'.[468] She said that acute inflammation can be 'low grade' or 'high grade', and that low grade inflammation may not be readily detectable using standard clinical tests but can still adversely affect health if not rapidly resolved.[469] Sokol considered the 'low grade' and 'high grade' nomenclature to be descriptive without clear definition.[470]

467 Murdock said that in the clinical practice of pathology, 'acute inflammation' is a collective term that can mean the presence of one or more types of acute inflammatory cells, including neutrophils, eosinophils and/or basophils. She said that the presence of one or more of these cell types would usually be reported as 'acute inflammation'. She said that 'in general terms, acute inflammation is of relatively short duration, lasting from minutes to days, depending on the extent of injury'.[471] Murdock said:

In clinical practice, when examining tissues adjacent to a medical device, the clinician responsible for the patient will request for us (pathologists) to specify in the pathology report if the inflammatory response to the medical device is composed of acute or chronic types. This is important information to the clinician taking care of the patient because if "acute inflammation" is present (i.e., neutrophils), then the patient may need clinical intervention (i.e., antibiotics). However, if "chronic inflammation" is present, this is an expected response to a medical device and no further clinical intervention is needed. This is why we (pathologists) specify acute versus chronic in the pathology reports of tissues adjacent to medical devices, but "chronic inflammation" is not meant as a systemic abnormal process, this is simply to communicate to the clinician that the inflammatory cell population is not comprised of acute inflammatory cells.[472]

468 This evidence demonstrates that the term 'acute inflammation' is used by immunologists and pathologists in a number of different but related ways. First, it describes an inflammatory response in which neutrophils, and sometimes eosinophils and basophils, predominate. This acute response occurs in the minutes, hours and days following injury.

469 Second, it may describe circumstances where neutrophils or eosinophils predominate in an inflammatory infiltrate that is present at a later point in time. This may also be described as a chronic inflammatory response.

470 Third, 'acute inflammation' may be used to describe inflammation that occurs in wound healing or as part of the foreign body response. The inflammatory response can be broken into 'early inflammation' and 'late inflammation' stages. Anderson described the early stage as 'acute inflammation' because neutrophils predominate. The later stage of the inflammatory response as part of normal wound healing can be called 'chronic inflammation' because macrophages predominate.

471 In the immunology JER, Robertson and Sokol agreed:

... that "chronic inflammation" in tissues is an inflammatory state usually characterized by an accumulation of leukocytes, predominantly macrophages and lymphocytes, in substantial excess of the numbers usually present in the tissue. Inflammation can be considered chronic when present for 6 weeks or longer since the initiating insult[.]

We agree that the term chronic inflammation can apply to a specific tissue site, for example in the proximity of a foreign body response, and/or to a systemic state where many tissues of the body may be affected.

We agree that the term "chronic inflammation" generally implies a pathological state of abnormal immune activation, as chronic inflammation is inconsistent with optimal health[.]

We agree that this broad definition would be agreed upon by immunologists, pathologists and clinicians.[473]

Robertson, Chrzanowski and Badylak agreed on a definition of chronic inflammation in almost identical terms in the biomaterials JER.[474]

472 Sokol said that in the absence of activating stimuli, macrophages exist in tissues in a non-inflammatory quiescent state. Their simple presence in tissue does not indicate whether they are producing pro-inflammatory cytokines.[475] She said that the presence of other inflammatory cells that are consistent with an acute inflammatory reaction, including granulocytes such as neutrophils or eosinophils, can be used as a surrogate to indicate whether inflammation is occurring.[476] She said that 'since these granulocytes may also be present in normal uterine or fallopian tube tissue, it is essential to compare the numbers and proportion of these cells to those seen in normal tissue at the same locations'.[477]

473 Robertson and Sokol agreed that there were 'circumstances where the presence of inflammatory cells immediately adjacent to an Essure [d]evice means that "acute inflammation" or "chronic inflammation" are present.'[478] In the immunology JER, they said:

... that the presence of immune cells, the number of immune cells, and the interval since Device placement, are relevant factors in designation of one or the other types of inflammation... [T]he presence of a predominant infiltrate of neutrophils immediately adjacent to an Essure Device would be consistent with active inflammation... [I]n the event that a neutrophil infiltrate immediately adjacent to an Essure Device was detected less than 6 weeks after placement, this would be considered "acute inflammation", and would be considered consistent with a normal foreign body response. In the event that neutrophils were identified immediately adjacent to an Essure Device 6 weeks or more after placement this would indicate active inflammation that could be termed "acute inflammation" or could be termed "chronic inflammation" as it is beyond the usual time frame for resolution of an acute inflammatory response... [W]hether the term "acute" or "chronic" is used in this circumstance and the precise time points for assigning these terms varies between investigators.[479]

474 During the immunology concurrent evidence session, I asked Sokol about this evidence and the agreed definition of 'chronic inflammation':

So in the context of the Essure Device if there is a circumstance where neutrophils are identified immediately adjacent to the device six weeks or more after, placement, that would be indicative of active inflammation?---Yes.

And could be termed chronic inflammation?---Depending on how the investigator is defining their terms. They could either refer to it as acute inflammatory cells or acute inflammation because of the presence of neutrophils, or they could refer to it as chronic inflammation because it is ostensibly going on for more than six weeks.

Chronic inflammation, in the way that you have used that term in this report from line 380 onwards - so if we go to line 380 - in the four paragraphs under the heading 'Chronic inflammation' [see agreed definition at [471] above] ---Yes.[480]

475 In the biomaterials JER, Robertson, Chrzanowski and Badylak explained the chronic inflammatory response phase of the foreign body response to Essure as follows:

We agree that in all women, the wound healing response to placement of an Essure Device involves formation of fibrotic tissue around the Essure Device. The formation of fibrotic tissue occurs as a consequence of the infiltration of immune cells (specifically macrophages) and fibroblasts into the vicinity of the device, as part of the chronic inflammatory response phase of the foreign body response. This formation of fibrotic tissue is an intended and desired component of the response to an Essure Device; it is what the Device is intended to elicit, in order to completely occlude the fallopian tube and cause a contraceptive effect. In most women, the fibrotic response will be extensive and will result in complete occlusion of the fallopian tube. In this event the laying down of fibrotic tissue may cease and become quiescent. We agree that there are many individual factors that affect the extent and duration of the fibrotic response, so these parameters will vary between women.

...

We agree that in all women, the wound healing response to placement of an Essure Device involves a chronic inflammatory response phase. In most women, this phase will be short-lived and will be completely resolved within 6 weeks, and at most 3 months of Device placement. We agree that in many women, the Device undergoes complete healing with resolution of inflammation and extensive fibrotic tissue/scar formation[.][481]

476 Badylak said that the acute inflammatory response is short lived - three to seven days - after which it transitions to a chronic phase that is dominated by macrophages and a small but variable number of foreign body giant cells. He said:

This chronic phase is also accompanied by a progressive infiltration of fibroblasts that deposit collagen and contribute to the fibrous connective tissue component of the healing response. These events reach a "steady state" within 2-3 months. There is no scientific evidence that the cells remaining in the remodelled tissue that surrounds the Essure device are actively participating in an adverse "proinflammatory" process.[482]

477 The experts did not agree on the designation of chronic inflammation in clinical and scientific practice. This was an extension of their disagreement about the term 'inflammatory cells' (at [481]-[483] below). Robertson considered that when designating a state of chronic inflammation in tissue using histological analysis, immunologists and pathologists take into account other features of the tissue sample in addition to the number of immune cells. Those features include evidence of phagocytic activity, the presence of a pro-inflammatory stimulus, and the spatial proximity of immune cells to the stimulus.[483]

478 Sokol and Robertson agreed that the presence of immune cells in tissue does not, without more, indicate an active inflammatory response.

479 Sokol said it is necessary to know the numbers and types of infiltrating immune cells to determine whether there is active inflammation. She said that since evidence of phagocytic uptake can be seen in quiescent or active immune cells, there must be standard evidence of inflammation (that is, abnormal numbers of immune cells infiltrating into tissue) to conclude that inflammation is present. She considered that because there are different types of immune responses which lead to chronic inflammation, it is necessary to provide details of the cellular influx or markers used to diagnose chronic inflammation in histological analyses, instead of relying simply on the use of the term 'chronic inflammation'.[484]

480 The features of chronic active inflammation may include accumulation of leukocytes, swelling, heat, redness, fluid discharge, neovascularisation and pain.[485] Badylak said that a:

chronic active inflammatory state does not occur as part of the foreign body response that accompanies permanently implanted devices such as the Essure device. If such a phenomenon did indeed occur, one would expect to see the hallmarks of an active, self-perpetuating process such as continued neovascularisation, foci of tissue necrosis with focal accumulations of neutrophils, and a robust fibroblast presence.[486]

481 Murdock said that in practice pathologists use the term 'chronic inflammation' as a collective term to describe 'the presence of one or more types of chronic inflammatory cells, including macrophages, lymphocytes, plasma cells, mast cells, natural killer (NK) cells and dendritic cells'. She said that chronic inflammatory cells can be found in normal fallopian tubes and that the term 'chronic inflammation' can also be applied to normal tissue if necessary. She said that when examining tissue adjacent to a medical device in clinical practice, pathologists will specify whether the inflammatory response to the device is composed of acute or chronic inflammatory cells.

It is clear from Professor Robertson's reports that she lacks the clinical training and experience in pathology, has misinterpreted the pathology literature, and misconstrues the presence of chronic inflammatory cells (chronic inflammation) adjacent to the Essure Device as a systemic chronic inflammatory process or causing a systemic changes in the immune response. When in fact, we know that chronic inflammatory cells (chronic inflammation) are present in normal fallopian tubes... and are expected to be in the tissue adjacent to the Device, in addition, normal fallopian tube histology was observed within 5 mm from the Device (Valle 2001).[487]

...disagrees with Dr Murdock that inflammatory cells present in tissues adjacent to a medical device do not signify an abnormal tissue response. [Robertson] considers that existence of chronic inflammation associated with a medical device implies an abnormal state of immune activation and that ongoing chronic inflammation is inconsistent with optimal health[.] In her opinion, the persistence or duration of chronic inflammation associated with a medical device is a factor in the risk of adverse health impact[.][488]

484 Anderson 2013 described chronic inflammation in the following terms:

Chronic inflammation is less uniform histologically than acute inflammation. In general, chronic inflammation is characterized by the presence of macrophages, monocytes, and lymphocytes, with the proliferation of blood vessels and connective tissue. Many factors can modify the course and histologic appearance of chronic inflammation.

Persistent inflammatory stimuli lead to chronic inflammation. While the chemical and physical properties of the biomaterial in themselves may lead to chronic inflammation, motion in the implant site by the biomaterial or infection may also produce chronic inflammation. The chronic inflammatory response to biomaterials is usually of short duration, and is confined to the implant site. The presence of mononuclear cells, including lymphocytes and plasma cells, is considered chronic inflammation, whereas the foreign-body reaction with the development of granulation tissue is considered the normal wound healing response to implanted biomaterials (i.e., the normal foreign-body reaction). Chronic inflammation with the presence of collections of lymphocytes and monocytes at extended implant times (weeks, months, years) may also suggest the presence of a long-standing infection... The prolonged presence of acute and/or chronic inflammation also may be due to toxic leachables from a biomaterial.[489]

485 This extract was put to Murdock. She did not agree that the chronic inflammatory response to biomaterials is usually of short duration, because it may last for 'the lifetime of the device'.[490] Murdock agreed that chronic inflammation with the presence of collections of lymphocytes and monocytes for extended periods after implantation may suggest longstanding infection, but added that she would want to examine the tissue in such circumstances.[491]

486 Sokol expressed general agreement with the passages from Anderson 2013 extracted above. She agreed that the passages suggested that the prolonged presence of lymphocytes and monocytes indicated something 'out of the ordinary' or inconsistent with a normal foreign body response, but noted that a 'normal' response to one foreign body could differ from the 'normal' response to another and that data would be necessary to determine what was truly 'abnormal'.[492]

487 Again, the evidence demonstrates that 'chronic inflammation' is used by immunologists and pathologists in a number of ways. First, it can be used to describe the late inflammatory stage of wound healing or the foreign body response where the numbers of neutrophils have decreased and macrophages predominate.

488 Second, Murdock said that 'chronic inflammation' can be used as a collective term to simply describe the presence of certain types of immune cells, including macrophages, in tissue.

489 Third, it may describe an active inflammatory state that is present after the time when wound healing or the foreign body response should have resolved. In those circumstances, 'chronic inflammation' may be characterised by a predominance of macrophages and lymphocytes in substantial excess of the numbers usually present in tissue, or by a predominating neutrophil infiltrate. Other hallmarks or features would be expected in cases of active, self-perpetuating chronic inflammation.

490 Sokol said the presence of active chronic inflammation can be detected by standard laboratory tests including high sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR), and fibrinogen levels.[493] She said elevation in any one of these markers is indicative of inflammation, but that the results do not reveal the cause. Sokol said that if she suspected inflammation in a patient, she would request that these tests be performed. There is no evidence that these tests have been performed on Essure patients. Sokol said that this meant inflammation was not 'on the mind of the physician' as a differential diagnosis.[494]

491 Robertson said that like acute inflammation, chronic inflammation can be 'low grade' (and not readily detectable using standard clinical tests) or 'high grade'.[495] In her reply report, Robertson said that '[w]hile a positive score for one of these tests may be considered indicative of inflammation (high grade or low grade), absence of a positive result does not exclude low grade inflammation'.[496]

492 Robertson gave the following further explanation in her oral evidence:

And the key element is inflammation, and I think that I have said that and, you know, I think that there are examples of inflammation that might not necessarily meet the grade at which a pathologist would diagnosis chronic salpingitis or chronic endometritis, but where there is change in the phenotype function pro-inflammatory disposition and inflammatory activation of immune cells in a tissue that are occurring to a level that causes injury and harm without necessarily changing the pattern of tissue that histologists or pathologists see in a microscope. There are many examples emerging. I was talking about inflammation earlier where a low grade or low level inflammation alters the immune cells in such a way as to have a considerable impact on the tissue and to elicit harm and injury. So I think I've made it clear that in my view, you know, it's not necessary to have chronic salpingitis or chronic endometritis for chronic inflammation to be there and to be a pathology and to be causing harm. Even if it's common or expected or usual, or perhaps normal even as part of a certain kind of response, that isn't inconsistent with it causing harm.[497]

493 Badylak said that while there can be degrees of intensity of the inflammatory response the terms 'low grade' and 'high grade' are not conventional in the field of pathology.[498] He said that a number of reliable laboratory tests are available to determine whether an active inflammatory process is occurring, but that these had not been done in the case of Essure.

494 In the immunology JER, Robertson and Sokol agreed:

We agree that laboratory blood tests such as ferritin, fibrinogen, hsCRP, CRP, and ESR are methods used to diagnose the presence of either chronic inflammation or persistent chronic inflammation (Sokol report, lines 717-718). We also agree that it has not been proven whether or not scoring within normal ranges for these indicators rules out the presence of any inflammation causing an adverse health impact, although elevations in these indicators correlate with increased health risks.[499]

495 Despite this agreement, in her oral evidence Robertson said that her understanding was 'that there are examples of ... where even the high sensitivity test wouldn't detect the presence of the low grade inflammation'.[500] It was put to Robertson:

I suggest, Professor Robertson, that if there's a sufficient level of inflammatory process occurring in the human body so as to cause an adverse effect to a person's health, it would be capable of being detected by one or more of these tests?---I think you're wrong. I could quote to you from Harvard Health publishing if you like, 'Low-grade inflammation may continually simmer below the surface'. It's a type of persistent inflammation and I would say that 'simmer below the surface' implies unable to be readily detected, subclinical.

What are you reading from, Professor Robertson?---One of the first definitions of low-grade inflammation that comes up when you look it up on - it's one of the pieces of information about a definition of low-grade inflammation.

And where is that referred to in your report?---It's not in my report but I have in my report talked about low-grade inflammation as being subclinical. It's consistent with the statements I've made. It's part of my response to your question because you're persisting with the point that it should be able to be detected and I'm saying to you that it's common knowledge that it's not always possible to detect a low-grade inflammation, especially with those tests.[501]

496 In evidence the following day Sokol questioned Robertson's reliance upon the Harvard Health publishing website. She said the website did not mention CRP testing. It did mention low grade inflammation that can simmer below the surface in conditions including rheumatoid arthritis, lupus, ulcerative colitis, multiple sclerosis, cancer and cardiovascular disease. Sokol said CRP is elevated for all of those diseases.[502]

497 Robertson did not identify any other scientific literature to support her proposition that low-grade inflammation may not be detected by clinical tests. I accept Sokol's evidence that the Harvard Health website does not support Robertson's contention. I accept the evidence of Sokol and Badylak that standard and reliable laboratory tests are available to diagnose the presence of active chronic inflammation, and that there is no evidence that these tests have been performed in the case of Essure. I reject Robertson's evidence, which seemed imprecise and unscientific.

498 Robertson and Sokol agreed that 'persistent', when used in conjunction with 'chronic inflammation', is a descriptive term.[503] Robertson said that 'persistent' was an appropriate descriptor to specify chronic inflammation that persists for greater than three months and does not show indications of resolving. She said that the phrase 'persistent chronic inflammation' is commonly used in immunology literature. Sokol did not agree that use of the phrase was common or that it referred to a precise clinical entity.

The term persistent in the context of a medical device is misleading. We know that chronic inflammatory cells (chronic inflammation) may be present in the adjacent tissues for the lifetime of the device and does not signify an abnormal tissue response[.] In addition, chronic inflammatory cells are present in normal fallopian tubes.[504]

... that the term 'pro-inflammatory response' describes a type of immune response that provokes, facilitates, amplifies, or propagates an acute or chronic inflammatory response. A pro-inflammatory response involves certain types of immune cells or their molecular mediators after they are triggered by an activating stimulus. This is in contrast to the term 'anti-inflammatory response', which describes a type of immune response that suppresses, constrains and/or resolves an inflammatory response.[505]

501 Robertson said that 'inflammatory cell infiltrate':

... is a term that is used to describe a distinctive pattern of immune cell accumulation or localisation in a tissue under circumstances where inflammation is occurring or inferred to be occurring, and infiltration of immune cells from the peripheral blood is indicated ... The immune cells in an inflammatory infiltrate are usually but not always detected by histology, and may show other features indicative of an inflammatory activation state, such as phagocytic activity ...

In the context of an infiltrate, the term "inflammatory cell" may encompass a range of immune cell types including granulocytes (neutrophils, eosinophils), monocytes and macrophages, mast cells and lymphocytes. However, ... [the] term "inflammatory cell" is not interchangeable with "immune cell" or "leukocyte" or any other term for immune cell subsets, as it only applies to immune cells located in a tissue site in which active inflammation is occurring or inferred to be occurring.[506]

502 Sokol said that the presence of chronic inflammatory infiltrate does not mean that the cells are active. She said that she would want to know whether there were neutrophils in the tissue or any other evidence of activation before reaching that conclusion.[507]

In pathology, "Inflammatory cell infiltrate" is used to describe a pattern of inflammatory cell localization in normal or abnormal tissue, where the inflammatory cells have infiltrated the tissue layers. This inflammatory cell infiltrate can be "acute" or "chronic" and would be specified and reported as such (e.g., "x tissue with acute inflammatory cell infiltrate"). It is important to note that the number of inflammatory cells is not quantified.[508]

504 In the immunology JER, Robertson and Sokol agreed:

... that the presence of a predominant neutrophil infiltrate surrounding the Essure device in the fallopian tube at 3 months or more after placement is consistent with active inflammation and not expected of the normal wound healing response.[509]

505 In the immunology JER, Sokol and Robertson agreed that 'inflammatory cells' is a non-specific term referring to immune cells that can promote inflammation. It can be used to describe a wide range of cells including granulocytes (neutrophils, eosinophils), monocytes and macrophages, mast cells and lymphocytes.[510]

506 Sokol and Robertson disagreed on whether the term 'inflammatory cells' necessarily indicates that the cells are actively engaged in or are promoting inflammation. [511] Sokol said that the term 'inflammatory cells' was:

often used interchangeably with 'immune cells' in the medical literature. Because immune cells can have both pro-inflammatory and anti-inflammatory functions, she considers the presence of 'inflammatory cells' to not necessarily indicate active inflammation ...[512]

507 Murdock agreed with Sokol. She said that in pathology, 'inflammatory cells' is a collective term and can refer to acute or chronic inflammatory cells.[513]

508 Robertson disagreed. She said that 'there is an important distinction between the term "immune cells" (which encompasses a wide range of functional states) and the term "inflammatory cells" which specifically relates to immune cells with pro-inflammatory activity.'[514] Robertson said that experienced immunologists and pathologists would not call immune cells in healthy tissue 'inflammatory cells', and that the term would only be used in the event of strong suspicion that the immune cells were engaged in inflammatory activity.[515] She explained:

Unlike the term 'inflammatory cell', the term 'immune cell' is commonly used to describe leukocytes regularly found in most tissues of the body as part of normal tissue homeostasis, or 'house-keeping'. The housekeeping activities that immune cells undertake in healthy tissues (especially in mucosal tissues such as the uterus and fallopian tube) include (1) modulation of the behaviour of other cells, such as epithelial and decidual cells; (2) regulation of tissue turnover (removal of dead and dying cells); (3) remodelling of the extracellular matrix; and (4) surveillance for new foreign invaders (microbes, tumor cells, spermatozoa).

...

In histological analyses, a judgement on the likelihood of inflammatory activity would be made based on the pattern of tissue location of the cells - their numbers, identity, physical characteristics, and other indicators of their likely function in the tissue - for example their proximity to other types of cells that have specific biological functions in the tissue, such as epithelial surfaces or blood vessels. They would also take into account whether there was reason to suspect an inflammatory response - that is, whether there is evidence of tissue injury, destruction, disease or dysfunction.[516]

509 It is worth noting that Sokol is an experienced practising clinical immunologist and Murdock is an experienced practising clinical pathologist. Robertson has not practised as an immunologist or a pathologist.

Acute inflammatory cells and chronic inflammatory cells

510 Robertson said that 'acute inflammatory cells' and 'chronic inflammatory cells' are not scientific terms, nor are they commonly used in scientific literature to describe immune cells in a healthy quiescent uterus or fallopian tube.[517] She said that immune cells cannot have 'chronic' or 'acute' properties.[518] She said that when the terms are used, they are intended to connote the presence of immune cells in tissue in which active inflammation is occurring or inferred to be occurring. [519]

511 Murdock said that 'acute inflammatory cells' is a scientific term frequently used in pathology as a collective term to describe the presence of one or more types of acute inflammatory cells including neutrophils, eosinophils and/or basophils. She said that there are numerous examples in pathology literature describing 'acute inflammatory cells' in tissue, including in normal tissue.[520] Similarly, Murdock said that 'chronic inflammatory cells' is a collective term used to describe the presence of types of cells including lymphocytes, macrophages, plasma cells, mast cells, natural killer cells and dendritic cells. She said that the term was used to describe the presence of those types of cells, whether in normal or abnormal tissue.[521]

512 Murdock gave the following examples of texts and studies in support of her contention that 'chronic inflammatory cells' and 'chronic inflammation' are simply used to describe the presence of certain immune cells in tissue, including in normal tissue: the 1994 study by Wollen et al ('Wollen 1994');[522] extracts from the textbook Blaustein's Pathology of the Female Genital Tract ('Blaustein');[523] Ardighieri et al ('Ardighieri 2014');[524] and Hunt and Lynn ('Hunt 2002').[525]

513 Wollen 1994 involved histological examination of the fallopian tubes removed by laparoscopy from 60 healthy non-pregnant women without any history of salpingitis. Thirty-one of the women had used a copper IUD for a period of two to 10 years. The remaining 29 women, who were the control group for the purposes of the study, had not used an IUD for the last 12 months.

514 Histological analysis of fallopian tissue revealed the presence of various types of immune cells in all of the tubes. The authors relevantly described the results as follows:

In sections from the control group a moderate and variable number of mononuclear cells, interpreted as lymphocytes, were found both in the tubal epithelium, subepithelially, in the lamina propria, myosalpinx and the serosa. Granulocytes and plasma cells were also present, but in lower numbers and mainly localized in the center of the mucosal folds. Mast cells were present, but scarce, in the lamina propria and myosalpinx (Fig. I).

When compared to the normal presence of leukocytes in the fallopian tube, biopsies with a subjectively increased infiltration of granulocytes, lymphocytes and/or plasma cells in the endosalpinx, were characterized as inflamed (Fig. 1). An inflammatory reaction was apparently present in 14% of the biopsies in the control group and in 68% the [IUD] users, a difference which was statistically highly significant (Table II). In both groups, the majority was of the chronic type of inflammation, with a predominance of mononuclear cells (Table II).[526]

Table II referenced above follows:[527]

Table II. Distribution of the morphological changes according to the histological evaluation

515 The authors only used the terms 'acute' and 'chronic' when describing the presence or type of inflammatory reaction. Where immune cells were seen, but not in increased numbers, they were identified by type and not by use of the collective terms 'acute inflammatory cells' or 'chronic inflammatory cells'. Murdock agreed that Wollen 1994 did not use 'chronic inflammation' to describe the normal presence of immune cells in the fallopian tube.

516 In a chapter of Blaustein referred to by Murdock, 'chronic inflammation' and 'chronic inflammatory cells' are used in the context of a description of acute salpingitis.[528] However, the authors refer to 'a small number of acute or mixed acute and chronic inflammatory cells' being found in association with an asymptomatic form of acute salpingitis where attempts to culture for bacteria were unsuccessful.[529] Further, the authors note that where certain clinical information raises for consideration diagnosis of early tuberculosis salpingitis 'the mere finding of acute and chronic inflammatory cells should lead to consideration of staining for acid fast organisms'.[530] These extracts provide some support for Murdock's contention.

517 Another chapter of Blaustein used 'inflammatory cells' when discussing specific tumour types:

Another pattern of necrosis that may be seen in ulcerated submucous leiomyomas features acute inflammatory cells and an associated zonal reparative process.[531]

...

Submucous leiomyomas, particularly if they protrude into the endometrial cavity, may display extensive necrosis, often with acute inflammatory cells, unlike the necrosis common in leiomyosarcoma.[532]

IMT is an uncommon uterine spindle cell tumor that typically has a prominent myxoid stroma that contains variable numbers of chronic inflammatory cells.[533]

518 Ardighieri 2014 describes the normal immune cell population in the fallopian tube. The study does not assist the consideration of this issue.

519 The purpose of Hunt 2002 was to document the frequency of histologic changes in fallopian tubes removed for all reasons or associations with clinical history. Two hundred and eighty-seven fallopian tube specimens were reviewed. In the summary of results, the authors said:

Inflammatory cells were relatively common; 69% of specimens contained intramuscular mast cells, 19.9% had stromal plasma cells, 10.5% had neutrophils, and 2.1% had lymphoid follicles.[534]

In a more detailed description of results, the authors said:

Beyond the ubiquitous intraepithelial lymphocytes, inflammatory infiltrates were not uncommon in our specimens. Inflammatory infiltrates were only included if they were composed of clusters of inflammatory cells occurring in significant numbers. Marginated neutrophils around vessels were specifically excluded; they were thought to be procedure- or pregnancy-related findings... Infiltration of neutrophils (acute salpingitis) in the epithelium was seen in 10.5% of specimens and was associated with a younger age. In addition, 69% of specimens demonstrated a minimum of 1 intramuscular mast cell per high-power field.[535]

Hunt 2002 used the term 'inflammatory cell' in a manner consistent with Murdock's evidence. Both authors are pathologists.

520 Robertson was cross-examined on the text 'Histology for Pathologists' by Stacey Mills ('Mills 2012') during her evidence. [536] She said that in the total of approximately 1,500 pages of the text, there were only one or two occasions when the term 'chronic inflammatory cells' was used in the context of normal tissue.[537]

521 Only 95 pages of Mills 2012 were tendered. My review of those pages shows that in most cases, the use of 'chronic inflammatory cells' was related to specific pathologies. This is hardly surprising as the text is directed to the identification of pathological processes. However, the portion of the text I reviewed also included the following:

Microscopic periductal aggregates of chronic inflammatory cells and duct dilatation are not uncommon findings in the normal esophagus.

...

The superficial gastric lamina propria normally contains some chronic inflammatory cells. It is often a [matter] of judgment whether these are considered normal or increased in number because there is no simple satisfactory method of objective measurement.[538]

522 This limited review of pathology literature did reveal some examples where 'inflammatory cells' and 'chronic inflammatory cells' were used in a manner consistent with Murdock's evidence. I accept that pathologists may use those terms in a similar way when reporting histological analysis of tissue.

523 In the immunology JER, Robertson and Sokol said:

We agree that the human non-pregnant uterus normally contains a wide variety of immune cells including, but not limited to, monocytes/macrophages, mast cells, dendritic cells, innate lymphoid cells including uterine natural killer cells (uNK), and lymphocytes (B cells, CD4+ T cells and CD8+ T cells). The uterus and the fallopian tubes are mucosal tissues with immune cells similar to other mucosal sites, but with three key distinctive features relating to their function: (1) the numbers, composition, and functional properties of these immune cell populations vary in their composition over the course of the menstrual cycle, (2) they play a critical role in the remodeling of the uterine lining over the course of the menstrual cycle, and (3) they play a critical role in permitting and regulating embryo implantation.[539]

Each of these immune cell subsets has a remarkable capacity to undergo a range of programmed functions (so-called 'phenotype flexibility'). Different phenotypes confer different effects on wound healing, on promoting and resolving inflammation, in generating immune tolerance or immune defence, and in regulating hemostasis and remodelling of blood vessels.[540]

She said that immune cell populations are spatially and temporally regulated by molecular cues in the functionalis tissue microenvironment that respond to sex hormones and other signals. She said that '[fertility] and healthy pregnancy depend on a remarkable ability of the uterine immune response to cycle between pro-inflammatory (estrogen dominated) and anti-inflammatory (progesterone dominated) states'.[541] She said that sophisticated discriminatory capabilities allow the uterus 'to sense and respond selectively to gametes, embryos, microbes and foreign entities or noxious stimuli' at appropriate stages of the menstrual cycle, thus conferring what she described as a 'hypervigilant immune capacity'.[542]

In the proliferative phase and at ovulation, when under the predominant influence of estrogen, the uterus is generally disposed towards activating inflammatory and effector responses, and will only elicit tolerance in the context of strong permissive signals. In the luteal phase after ovulation, when progesterone is the dominant sex hormone, the uterine immune response becomes disposed towards immune tolerance and tissue remodelling, and requires a stronger degree of stimulation to sustain an inflammatory response. When pregnancy occurs, this pro-tolerogenic and anti-inflammatory state continues, to support maternal tolerance of the fetus and its placenta. This is state is not the absence of inflammation, but rather the presence of a controlled inflammatory response that is kept in check by anti-inflammatory checks and balances.[543]

526 Robertson said that the uterine immune response is highly sensitive to environmental disturbances, and that:

In women with a chronic wound response and persistent chronic inflammatory response to the Essure Device, the ongoing pro-inflammatory stimulus would be expected to change the behaviour (phenotypes) of immune cells not just in the immediate vicinity, but also more broadly in the tissue. This happens because the pro-inflammatory mediators affect the proliferation and function of immune cells in the lymph nodes draining the fallopian tube and uterus, and the cells produced in this site then recirculate to become disseminated in nearby tissue sites in the female reproductive tract (elsewhere in the uterus, fallopian tubes and ovaries) and elsewhere in the body.[544]

527 Robertson said that uterine immune cells modulate the uterine vasculature to ensure bleeding associated with menstruation is time-limited and resolves rapidly, allowing the blood vessels to close over and repair once bleeding is complete.[545]

In some aspects the events of menstruation resemble a tightly-controlled, self-limited inflammatory response. Just prior to menstruation, immune cells infiltrating into the decidualized endometrium to facilitate tissue breakdown, and allow it to be followed by vasoconstriction and an efficient hemostatic response (to allow bleeding to cease). The predominant infiltrating cells are macrophages and uNK cells.

Macrophages recruited into the endometrium prior to and during menstruation initially acquire a pro-inflammatory phenotype, but a finely controlled modulation of their function and progression to an anti-inflammatory phenotype must occur in a timely manner so that tissue breakdown rapidly gives way to tissue repair, with cessation of bleeding followed by endometrial proliferation.

Macrophages present in the tissue at menstruation play a key role in initiation of endometrial shedding by secreting matrix metalloproteinases (MMPs). Specifically, secretion of MMP-12, MMP-9, and MMP-14 are required for the breakdown of the functionalis layer. If the phenotype of uterine macrophages is incorrectly controlled or not correctly synchronised over the entire endometrial surface of the uterus (for example due to an excessive inflammatory activation (M1 phenotype) in regions adjacent to the SUTJ), this would be expected to contribute to bleeding at inappropriate stages of the cycle, or heavy bleeding in menstruation.

Both uNK cells and macrophages are essential to allow menstrual bleeding to occur in a temporally- and spatially-controlled manner. uNK cells are critical for menstruation, through their ability to actively promote cell death of uterine decidual cells when progesterone withdrawal occurs. If uNK cells are insufficient in number, decidual breakdown may be compromised. If uNK cells are dysregulated in their phenotype or functional behaviour, this could contribute to bleeding at inappropriate stages of the cycle, or heavy bleeding in menstruation.

These observations imply that sufficient numbers and precise functions in uterine immune cells are required to prevent uterine bleeding disorders such as menorrhagia (abnormally heavy or prolonged bleeding at menstruation), dysmenorrhoea (intense uterine cramping and pain), amenorrhea (abnormal absence of menstruation), and irregular bleeding.[546]

529 Murdock said that acute and chronic inflammatory cells may be identified in the normal endometrial stroma depending on the phase of the menstrual cycle.[547] She said:

In menstrual endometrium, where the endometrium is breaking down and sloughing away, numerous acute inflammatory cells including neutrophils are present, as well as a lesser degree of lymphocytes. In proliferative endometrium, (when the endometrial glands and stroma are building back up again), there are scattered stromal lymphocytes (chronic inflammatory cells) and during the late secretory phase, the predominant chronic inflammatory cell within the stroma is the lymphocyte.[548]

530 Sokol said that the uterine immune cells play different functions during the menstrual cycle, 'with macrophages dominating during menses, neutrophils infiltrating during the proliferative phase, and uNK cells proliferating during the secretory phase'.[549] She said that monocytes and monocyte-derived macrophages that enter endometrial tissue during breakdown and menstruation have been shown to be largely anti-inflammatory 'based on surface marker expression and the constitutive production of reparative cytokines'. She said that expression of low levels of antigen presentation molecules indicates that uterine macrophages are not only anti-inflammatory, but are likely deficient in their ability to initiate an adaptive immune response.[550] Sokol made further observations about the roles of neutrophils and uterine Natural Killer ('uNK') cells in the uterus that she said supported the concept that the uterine immune response was reparative and anti-inflammatory in nature.[551]

531 Robertson disagreed. She said that there is considerable evidence that uterine macrophages can be involved in initiation of an adaptive immune response.[552] She said there was compelling data in studies showing that uterine macrophages express elevated levels of pro-inflammatory cytokines and regulators during the peri-ovulatory phase and late luteal phase, compared to the time of receptivity to embryo implantation in the mid luteal phase.[553]

532 Sokol and Robertson agreed that the uterus had the capacity to develop a chronic inflammatory response, but disagreed on the nature of such a response in the context of Essure. Robertson said:

there is a strong biological rationale for the uterus to respond with a pro-inflammatory response to an Essure Device, especially considering the Device is designed to provoke an inflammatory response.[554]

while pre-clinical studies indicate that the human uterus can mount a proinflammatory response, there are no data to suggest that the human reproductive tract is primed to specifically mount an inflammatory response to the Essure device.[555]

533 Robertson said that under normal circumstances, the fallopian tube would not have anywhere near the number of immune cells that are found in the uterus, and that the types of immune cells are different. She said that there are some macrophages in the fallopian tubes but not as many as in the uterus. She said there are predominately lymphocytes located just below the epithelium in the inner mucosal lining of the fallopian tube and lamina propria.[556] She said that PMNs (neutrophils, eosinophils and basophils) are rare in the fallopian tube, and when present engage in 'housekeeping' functions under normal circumstances. She said that depending on the identity and nature of specific triggers, the epithelial and immune cells in the fallopian tube secrete a wide array of both pro-inflammatory and anti-inflammatory cytokines.

534 Robertson said that the 'dynamic and selective' immune response of the fallopian tube, which is similar to the uterus, 'is relevant to the Essure device as it will promote the likelihood of a robust pro-inflammatory immune response to the presence of the device and noxious materials leached from it'.[557]

535 Murdock said that a normal fallopian tube contains 'a heterogeneous population of innate (first line of defence in the immune response) and adaptive immune cells (activated when the innate immune response is insufficient) including lymphocytes, macrophages, NK cells and dendritic cells'.[558] She said:

Lymphocytes, macrophages, dendritic cells, and NK cells are types of chronic inflammatory cells. The most common cell type identified in the normal fallopian tube is the T cell, which is a lymphocyte and type of chronic inflammatory cell. When chronic inflammatory cells are present in an abnormally increased amount, this is termed chronic salpingitis. Importantly, when the cells described in [Ardighieri 2014] (lymphocytes, macrophages, etc.) are observed in the fallopian tube, they would be described by pathologists as "chronic inflammation," if necessary.

... One of the most important points in my report is that chronic inflammatory cells may be identified in normal fallopian tubes, this includes innate and adaptive types (see previous paragraph). From my clinical practice and everyday microscopic examination of human fallopian tubes, there are chronic inflammatory cells including lymphocytes, which can be found in the muscular wall (MW), lamina propria (LP) and intraepithelial (IE) parts of the normal fallopian tube. In addition, it is worth stressing that in [Ardighieri 2014] they examined normal fallopian tubes and found chronic inflammatory cells (including those involved in both the innate and adaptive immune response) including CD8+ T cells (lymphocyte), CD4+T cells (lymphocyte), [natural killer] cells, and macrophages in all three parts (IE, LP and MW) of the fallopian tube[.]CD8+ T cells (lymphocytes that participate in adaptive immunity) would be just one cell type expected to be in the tissues adjacent to a medical device and are also the dominant lymphoid subset in the normal fallopian tube tissues.[559]

Murdock gave similar evidence in relation to the uterus.

536 Robertson said that like the uterus, the SUTJ region of the fallopian tube is primed towards a pro-inflammatory immune response at the periovulatory and late secretory phases of the menstrual cycle.[560] She said that this is by virtue of its responsiveness to fluctuating ovarian sex hormones, particularly estrogen. She said that this responsiveness enabled a selective regulation of embryo implantation and menstruation.

537 Sokol considered that there was no convincing human data to suggest such a state of priming in the fallopian tubes under homeostatic conditions or conditions of tissue injury.[561] In cross-examination, Sokol agreed that the fallopian tube has a highly functional immune response.[562] She agreed that the uterus and fallopian tubes are not always anti-inflammatory and that they are capable of eliciting a strong inflammatory response.

538 Robertson and Murdock agreed that very few neutrophils were found in a healthy fallopian tube, and that most cells that were present were found in blood vessels, not in tissue.[563]

539 I deal with Robertson's contention that the fallopian tubes and uterus are primed towards a pro-inflammatory response, and the relevance of that evidence to ongoing chronic inflammation and Essure, in Chapter XIV.

540 The relevant experts considered six primary histological studies which each involved analysis of fallopian tube tissue following explantation of Essure inserts. These studies are:

(a) the pre-hysterectomy study together with a report on that study by Rafael Valle et al ('Valle 2001');[564]

(b) 'Removal of Essure sterilization devices: a retrospective cohort study in the Netherlands' by Maassen et al ('Maassen 2018');[565]

(c) 'Pathologic findings in fallopian tubes of woman with chronic pelvic pain after Essure placement' by Rubin et al ('Rubin 2020');[566]

(d) 'Clinical and histopathologic characteristics of patients undergoing surgical excision with Essure coils: Longitudinal experience at a women's speciality hospital' by Natalie Banet ('Banet 2020');[567]

(e) 'Symptomatic Bilateral Granulomas after Essure Sterilization' by Hoogendam et al ('Hoogendam 2020');[568] and

(f) 'Confirmation of the systematic presence of tin particles in fallopian tubes or uterine horns of Essure implant explanted patients: A study of 18 cases with the same pathological process' by Catinon et al ('Catinon 2022').[569]

I have also included in this section the 12-week rabbit study and a 24-week rabbit study conducted for Conceptus; histological analysis of post-hysterectomy tissue from four women published in the annual PMA reports; and a 2012 Conceptus study of a proposed new Essure model ('Essure 505 study').

541 Turner relied heavily on the histopathological evidence reported in the studies to establish that Essure was a cause of ongoing chronic inflammation in the fallopian tubes of a not insignificant number of women. She submitted that while the defendants' experts initially disputed that the studies contained findings of active chronic inflammation caused by Essure, Murdock and Sokol accepted that proposition after cross-examination, leaving Badylak isolated on this issue.

542 In her expert reports, Robertson said that the histological studies showed compelling evidence of a chronic inflammatory response which extended beyond three months from the date of implantation in women with Essure. Robertson's evidence is summarised in the following statement taken from the pathology JER:

Individually and collectively these studies demonstrate a high incidence of chronic inflammation in fallopian tubes of women with Essure Devices of more than 3 months duration. Importantly, each of these studies clearly uses the term "inflammation" or "chronic inflammation" (not just "presence of immune cells"). We can therefore infer that in the judgement of the investigators, the features of the tissue - including the abundance, types, and locations of immune cells - met the common understanding of constituting inflammation. Designating chronic inflammation requires more than the simple presence of immune cells. If it were simply the presence of a few immune cells, to a degree that was not different to healthy tissue, this would be expected in all the examined tissues.[570]

Robertson said that it was implicit in the conclusions of the investigators in each study that the observed patterns of leukocyte abundance and composition were different to those seen in healthy fallopian tubes.[571]

Robertson raises [Banet 2020], which supposedly showed types of inflammation in the fallopian tubes caused by the Essure Device. As I previously discussed..., since the fallopian tubes normally contain immune cells, it is essential to not only quantify the number of immune cells seen in these pathological samples, but to compare them to normal control tissue. If there were more or less immune cells as compared to healthy controls, it could indicate that Essure was associated with that difference. Unfortunately [Banet 2020] neither quantified the immune cell infiltrate nor did it include a normal control comparison, making it impossible to interpret in any meaningful manner. Furthermore, [Banet 2020] did not show any correlation of supposed inflammation with patient symptoms, making any clinical correlation impossible. Although it also did not quantify the immune cell infiltrate, [Rubin 2020] did compare the fallopian tubes of women who had Essure with those who did not. Acute inflammation, as indicated by the presence of neutrophils, was only seen in one of the control patients and was not associated with active disease since it did not correspond with any symptoms in that patient. Macrophages and giant cells were detected in two of the three Essure patients, but there was no evidence of acute inflammation indicating that these cells were not active[.] [Rubin 2020] underscores the importance of including controls in any study, but both [Rubin 2020 and Banet 2020] are limited in the number of samples evaluated. Thus, it remains to be determined whether the Essure Device is associated with chronic inflammation in the fallopian tubes.[572]

Sokol disagreed with Robertson's evidence that the studies demonstrated a high incidence of chronic inflammation in response to Essure. She said that it was normal and expected to see increased numbers of macrophages and foreign body giant cells at the site of a foreign body response.[573] She said that the simple presence of immune cells at the site did not indicate an active inflammatory response. In the immunology JER Sokol said:

Furthermore, in these same studies Dr. Sokol considers there to be a lack of quantitative data on the immune cell infiltrates and a lack of criteria provided to define the inflammatory state. None of the studies cited by Prof. Robertson define or provide the criteria by which investigators determined the presence of "inflammation". Furthermore, each study uses different terms to describe "inflammation", indicating that the investigators are not using a shared and standard nomenclature. Based on this, Dr. Sokol considers it absolutely necessary for the investigators to then define or provide quantitative data on the immune cell infiltrate so that their data can be properly interpreted, and their conclusions on the presence of "inflammation" verified.

Finally, Dr. Sokol considers there to be a lack of evidence suggesting active inflammation. [T]he presence of foreign body giant cells alone does not indicate acute or chronic inflammation. However, the presence of foreign body giant cells was considered to be indicative of "inflammation" in [Banet 2020 and Rubin 2020]. For these reasons, Dr. Sokol considers these studies to be flawed, fundamentally limiting their generalizability to patients.[574]

544 Robertson disagreed with Sokol's opinion in her reports. She said that healthy control tissue was often difficult to access in histological studies and it was common for such studies to designate chronic inflammation in its absence. She said further that studies often use a qualitative or semi-quantitative analytical approach to reporting immune cell prevalence and designating chronic inflammation.[575] Robertson said that the reported findings of chronic and acute inflammation in the vicinity of the device, photomicrographs from several studies which indicated a clear spatial relationship between the surface of a device and immune cell infiltrates, and a statement in Valle 2001 that PET fibres elicited a strong fibrotic inflammatory tissue response supported a causal connection between the observed inflammation and Essure. She said that the numbers of women studied and the similarities in the reported findings across the studies indicated that chronic inflammation was not an uncommon event in women with Essure.[576]

545 Murdock said that it was incorrect to say that the findings of chronic inflammatory cells in tissue adjacent to the Essure device reported in Banet 2020, Rubin 2020 and Valle 2001 equated to an abnormal process. She said Robertson's interpretation of the histological studies was incorrect because:

... 1) chronic inflammatory cells are present in the normal fallopian tubes, 2) the chronic inflammatory cells were not present in an excessive amount to warrant a diagnosis of chronic salpingitis, and 3) [the] conclusion statement [in Rubin 2020] is **"**Given the minimal and bland inflammation in the Essure cases, symptoms may more plausibly be ascribed to confounding gynecologic conditions or other mechanisms." The Essure Device causes a predictable and orderly tissue response and chronic inflammatory cells may be present for the lifetime of the device.[577]

...

A pathological (abnormal) tissue response to the Essure Device does not occur. The Essure Device followed a normal and localized tissue response confined to the inner layers of the fallopian tube and normal histology was observed within 5 mm of the distal end of the Device. The Device causes a tissue response that is similar to other medically implanted devices. The response begins with an acute inflammatory cell infiltrate, followed by a chronic inflammatory cell infiltrate and fibrosis. This tissue response to the Device is appropriate and should not be considered pathological. This opinion is based on the [pre-hysterectomy study], the Annual [PMA] Reports (2003-2007), PMDA studies, and the peer reviewed medical literature including [Valle 2001, Banet 2020 and Rubin 2020]. In addition, chronic salpingitis (abnormal chronic inflammatory response in the fallopian tube was not identified in any study.[578]

546 In his primary report, Badylak said Valle 2001 concluded that Essure appeared to be 'feasible, safe and well accepted by patients'.[579] He said that the Banet 2020 findings were 'consistent with the expected foreign body response', with inflammation characterised as acute in patients with a shorter implant time and chronic in patients with a longer implant time.[580] Badylak noted that Rubin 2020:

... concluded that "changes in the Essure patients were bland and showed only minimal chronic inflammation, in the form of foreign-body reaction, and no acute inflammation, suggesting that pain is unlikely to be due to an ongoing localized inflammatory process".[581]

547 Badylak said that it was inaccurate and misleading to characterise the presence of macrophages and foreign body giant cells as a persistent and active inflammatory reaction that causes continuous tissue damage in the context of a foreign body response.[582]

548 As referred to earlier in these reasons, the 12-week rabbit study was conducted in 2000 by NAMSA. The purpose of the study was to evaluate the potential for a local irritant or toxic response to Essure materials implanted in direct contact with muscle tissue.

549 A minimum of four sections of the Essure insert ('test articles') were implanted in three male rabbits. Control articles made from USP negative control plastic were placed in three control male rabbits. Histopathology results were recorded at one, four and 12 weeks. The microscopic irritant response to the articles was graded as 'non-irritant', 'slight', 'moderate' or 'severe'.

550 The table of scores following histopathological examination by a pathologist at 12 weeks is as follows:[583]

*Used to determine Irritant Ranking Score shown below as the Conclusion. A negative difference was recorded as zero.

On the basis of this data, the NAMSA pathologist rated the Essure test articles as a 'severe irritant' compared to the control articles.

551 After receiving the NAMSA results, Conceptus sought a second opinion on the histology from a pathologist at a different organisation.[584] The second pathologist observed two types of changes in rabbit muscle, the first associated with the PET fibres and the second associated with the coil. In relation to the PET fibres, the pathologist stated (original emphasis):

Overall the test article appears well tolerated after 12 weeks in rabbit skeletal muscle and does not elicit any host reaction considered to be adverse. There is a low severity grade foreign body reaction to the [PET fibre] without evidence of encapsulation or necrosis.

The foreign body reaction is spatially limited to the areas where [PET fibre] is present and does not extend in adjacent tissues. In my experience, the severity of the foreign body response to the [PET fibre] observed in this study is at the lower end of the range of severity typically observed with this type of material when placed in animal tissues (across species, including the rabbit). I have seen other devices causing marked irritation characterized by dense inflammatory infiltrate encroaching upon adjacent tissues with formation of a thick wall of granulation tissue and sometimes necrosis of the host tissue within and around the device. These features are clearly absent from the sections examined for the "STOP Device".[585]

In all samples there is a focal nodular accumulation of acellular amorphous and partially mineralized material. This material appears well tolerated and stable, and is not associated with significant inflammation. This material is probably derived from sequestered proteinaceous body fluid and inflammatory cells that accumulated inside the device coil and was prevented from organization by the presence of the coil around it. I do not regard this feature as evidence of necrosis. This interpretation is supported by the near absence of inflammation at the interface between this material and host tissue. In addition, these accumulations have a diameter comparable or slightly smaller to that of the outer coil of the device and would fit entirely within their inner compartment.[586]

552 The pathologist said that changes elicited by the test articles extended less than 0.5 mm in all three animals. The pathologist concluded that the tissue response to the test articles was minimal to mild, and irritation associated with the device was low.

553 Badylak said that the second pathologist's description of the test results as showing an accumulation of inflammatory cells around the PET fibre, but not extending further, was consistent with the expected findings.

554 Covance Laboratories Inc conducted a 26-week rabbit intramuscular implant study for Conceptus in 2002 ('26-week rabbit study').[587] The purpose of the study was to evaluate the subchronic toxicity of Essure. Two devices and two control strips were implanted in the muscle tissues of 20 female rabbits. The study pathologist found minimal or mild granulomatous inflammation in more sites containing the device than in sites containing the control strip. The pathologist noted that the inflammation was largely associated with the small fibres within the device and was characterised by the presence of macrophages and multinucleated giant cells.[588] There was no adverse effect on the rabbits associated with the inflammation.

555 Badylak said that rabbits were used in the muscle implantation studies because they are hypersensitive.[589]

556 Badylak agreed that the 26-week rabbit study showed granulomatous inflammation. He was asked:

In those circumstances where the device was to be permanently implanted into the body of a woman for her lifetime, would you agree that it would have been reasonable to study the consequences of this inflammatory effect beyond the 26 week timeframe that was studied?---That's not a simple answer. It would depend upon the type of inflammation that was present. By type what I mean is was there an active component to it, were there other signs of a systemic inflammation? So it would depend upon the device. I think in some cases you're right, it would be. In others you have to look at the whole story.

In this case?---I don't believe so. I'm trying to put myself in the position of the people who, you know, came to this conclusion. It's hard, though, when you know the rest of the story. As I mentioned just a few minutes ago, you will always see an accumulation of inflammatory cells, macrophages, around the device. If that is called granulomatous inflammation, like it may be in this report, then that's not surprising, it's expected, and I'm not sure anything further is needed.[590]

557 As outlined at [206] above, Conceptus conducted the pre-hysterectomy study of Essure on 63 women scheduled for a hysterectomy from 1998 to 2001.[591] Forty-six women had bilateral placement and eight women had unilateral placement.[592] There was a failure to implant any device in the remaining women. Participants wore inserts for up to 16 weeks (and in the case of one woman for 30 weeks) prior to explantation by hysterectomy.

558 Forty-nine women were enrolled through investigator Rafael Valle in Mexico and 14 through a second investigator in the US.[593] Valle 2001 is based on the histology findings for 27 of the study participants.

559 Care was taken at the time of hysterectomy to remove the uterus and fallopian tubes en bloc whenever possible, without cutting into the Essure insert. The uterus and fallopian tubes were x-rayed to determine the position of the insert. The uterine cornuae and fallopian tubes were then excised for histological examination.

560 After x-ray, the fallopian tubes were divided into three blocks according to the insert position:

1. Block A included the uterine cornua up to the utero-tubal junction (UTJ),
2. Block B included the UTJ to the proximal isthmic portion of the tube, and
3. Block C included the proximal isthmic portion to a point within 5 mm distal to the end of the Micro-insert.[594]

The following figure illustrates the three blocks:[595]

561 Two cross-sections were then taken from the uterine end of each block (indicated by 'AU', 'BU' and 'CU' on the figure above), and from the fimbrial end of Block C ('CF' on the figure above).[596]

562 Below is an example of how microscopic assessment of histological sections was reported by the pathologists, in this case for the participant identified as '826' who had a wearing time of 13.86 weeks before hysterectomy.[597] The assessing pathologists were blinded to participant wear time. The histological response for each assessed characteristic was rated on a scale of 0-3, with '0' meaning absent, '1' mild, '2' moderate and '3' severe.[598] No further information or guidance was provided about the grading system. In most cases the assessing pathologist was Dr Thomas Wright.

563 The cell types recorded by the examining pathologist on the right and left B-U cross-sections were PMNs (neutrophils), lymphocytes, plasma cells, macrophages and fibroblasts. Similar findings were made at other cross-sections.

564 The following graphs from the pre-hysterectomy study provide some of the information derived from the histology slides of the study participants. The histological response for each assessed characteristic on the '0-3' grading scale is represented on the Y-axis. The X-axis shows the wearing time in weeks. For each characteristic, the histological rating for each fallopian tube within the same timeframe was averaged to develop a mean score which was plotted.[599]

565 The study authors summarised the findings in the graphs as follows:

The histological response to the Essure Micro-insert is characteristic of the histological response observed with the use of PET fibers in other anatomical sites. Specifically, the PET fibers appear to elicit a strong fibrous and inflammatory tissue response that extends into the space between the inner and outer coils of the Essure Micro-insert. The tissue response consists predominantly of macrophages and lymphocytes, with some foreign-body type giant cells seen in women who wore the devices for longer periods of time (12 weeks or longer), and larger numbers of polymorphonuclear cells (PMNs) seen in shorter wearing times (less than 12 weeks). The fibrous response consists of both loose and dense fibrous tissue, with moderate loose fibrosis apparent as soon as one week after implantation, and dense fibrosis becoming moderate to severe after four weeks of wearing. In some specimens, smooth muscle cells are also observed migrating from the fallopian tube wall into the space between the inner and outer coils, more commonly in women who wore the devices for longer periods of time, 12 weeks or longer.

...

Normal tubal architecture was present within 5mm distal to the end of the Micro-insert. The histological analysis of slides taken past the ball tip of the Essure Micro-insert, revealed normal tubal segments that were absent of inflammatory cells.[600]

The procedure was found to be safe with minimal post-procedure discomfort and sequelae and minimal adverse events. The short-term wearing of the Micro-insert, from one to 30 weeks was also found to be acceptable, with no side effects reported in the participant diaries.

...

The local, occlusive, benign tissue response demonstrated by histological evaluation of the specimens supports the theorized mechanism of action. The acute inflammatory response and low level chronic inflammatory response is consistent with other devices that have used PET fibers. The reaction is confined, however, to the area immediately adjacent to the Micro-insert and does not extend beyond the tubal wall. Also, immediately distal to the Micro-insert, the tube resumes its normal appearance.

Based on the histological observations from this study, it is apparent that the response to the Essure™ Micro-insert is occlusive in nature and should provide for long-term Micro-insert retention as well as pregnancy prevention. This study demonstrated that the tissue in-growth reaction is predictable, occurred in all fibered specimens collected, was localized to the Micro-insert, and did not result in adverse clinical sequelae.[601]

567 Valle 2001 evaluated patient tolerance and recovery from device placement; patient safety and comfort during device wearing; occlusion of the fallopian tube up to 12 weeks after device placement; and fallopian tube histologic information in order to confirm the theorised mechanism of action.[602]

568 The authors commented on the histology findings as follows:

The PET fibers appear to elicit a strong fibrotic and inflammatory tissue response that extends into the space between the inner and outer coils of the STOP device. The reaction is localized to the inner portion of the fallopian tube wall, with normal tubal architecture present within 5 mm of the distal end of the device. There is no evidence that fibrosis induced by the device extends into the wall of the fallopian tube or causes peritubal adhesions or serositis.

The tissue response consisted predominantly of macrophages and mononuclear cells, with some foreign-body-type giant cells and acute inflammatory cells. The fibrous response consisted of both loose and dense fibrous tissue. In some specimens, smooth muscle cells were also observed migrating from the fallopian tube wall into the space between the inner and outer coils. This is clearly demonstrated in Figure 4.

The tissue response varied according to the elapsed time after placement. Acute inflammation was predominant in early specimens whereas chronic inflammation and fibrosis was more extensive in the fallopian tubes of patients who had worn the device for 8 to 30 weeks. The overall reaction to the device and fibers was more pronounced over time.[603]

The histologic evaluation of the specimens supported the hypothesized mechanism of action, namely that long-term anchoring and occlusion are achieved with fibrosis into the device. The acute inflammatory response and low-level chronic inflammatory response were consistent with other devices that have used PET fibers. The reaction was confined to the area immediately adjacent to the device and did not extend into the tube wall. Immediately distal to the device, the tube maintained its normal appearance.[604]

569 The histology results were summarised in the following table:[605]

570 Figure 4 in Valle 2001 contained four tubal cross-section images with the following description:

Microscopic view of cross section of tube containing the STOP device. (A), One week: fibrosis and acute inflammation cells migrating into device. (B), Four weeks: fibrosis replacing tube, acute and chronic inflammatory cells present. (C), Eight weeks: dense fibrosis filling the tube. Epithelium destroyed. Tubal lumen occluded. (D), Thirty weeks: dense fibrosis replacing tubal lumen; scant acute inflammatory cells present.[606]

The STOP transcervical approach to tubal sterilization, evaluated in this prehysterectomy study, appears to be feasible, safe, and well-accepted by patients. It holds promise as a new female sterilization procedure that offers a transcervical alternative to incisional methods of tubal sterilization.

Based on the histologic observations from this study, it is apparent that the tissue response to the STOP device is occlusive in nature, providing long-term anchoring of the device. This study demonstrates that the tissue in-growth reaction was predictable, occurred in all fibered specimens collected, and was localized to the device.

This demonstration of the feasibility of this approach prepares the way for clinical trials to evaluate long-term safety and effectiveness of the STOP device for tubal sterilization.[607]