Narrative of Facts
12 The narrative of the facts which follows is largely drawn from the chronologies prepared by the parties and much of it is not controversial. Some of it is reflected in the extracts from the specification of the patent in suit already set out.
13 Bisphosphonates have been known since the 1970s to be inhibitors of bone resorption. The clinical application of bisphosphonates including their use, effectiveness and side effects in the treatment and prevention of osteoporosis was well known. Gastrointestinal (GI) side effects were well known. Etidronate and clodronate were each bisphosphonates developed for clinical use. Pamidronate followed. It was the first aminobisphosphonate compound developed for clinical use in the treatment of osteoporosis. Clinical trials were organised by Ciba-Geigy in 1989-1990. The trials of oral administration of pamidronate were discontinued because of GI side effects. The trial experience was published in November 1994 in Vol 4 of the periodical Osteoporosis International in an article by Lufkin et al entitled 'Pamidronate: An Unrecognised Problem in Gastrointestinal Tolerability'. The 1995 edition of Bisphosphonates in Bone Disease by Professor Fleisch reported (at p 152) that:
'Oral pamidronate as well as other aminobisphosphonates can give rise to dose-related gastrointestinal disturbances that may be severe'.
That report related to oral doses of 300 mg or more daily.
14 In about 1987 or 1988, Merck acquired the rights to the base Gentili patents for alendronate and set about exploiting them. It was necessary to satisfy the Food and Drug Administration (FDA) of the United States of efficacy and safety pursuant to the US regulatory regime concerning drugs for the treatment of humans. Phase II clinical trials commenced in 1991 with the Harris study of six weeks on 65 healthy post-menopausal women. It was followed by the two year Chesnut study in 1992-1993 as to 5, 10, 20, and 40 mg orally daily on 188 post-menopausal women with osteoporosis. That study was reported in September 1995 in the periodical American Journal of Medicine, Vol 99 in an article by Chesnut et al 'Alendronate Treatment of the Postmenopausal Osteoporotic Woman: Effect of Multiple Dosages on Bone Mass and Bone Remodeling' (the Chesnut article).
15 The Phase III clinical trials were conducted over three years between 1993 and 1995 in the so-called Liberman study. That was an international trial on 994 women with post-menopausal osteoporosis treated with 5 or 10 mg daily for three years or 20 mg daily for two years followed by 5 mg daily for one year. The results of that trial were reported in December 1995 in the periodical New England Journal of Medicine, Vol 333, No 22 in an article by Liberman et al entitled 'Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis' (the Liberman article).
16 Lunar Corporation was a US company with a business that specialised in bone densitometry. The principal was Dr Mazess (whose qualifications and experience were in the fields of radiology and medical physics). It did business with Merck from time to time. Several times a year it published a magazine entitled 'Lunar News' which contained articles on topics of interest related to its business. The articles footnoted relevant journal references. It will be necessary to examine the question of the publication of Lunar News in more detail later. The December 1995 issue included an article headed 'Update: Bisphosphonates' and commenced as follows:
'Bisphosphonates are the preferred agents among researchers today for treating osteoporosis, although they are not yet part of routine clinical management. This will change in the near future because alendronate (Fosamax by Merck) gained FDA approval in the U.S. in October 1995.'
(original emphasis)
The article proceeded to review developments in relation to alendronate and other bisphosphonates including risedronate. The Chesnut article was footnoted amongst others.
17 By October 1995 alendronate was approved for sale and was on sale by Merck in the United States under the trade name 'Fosamax' on the basis of a dosage of 10 mg per day for the treatment of osteoporosis and 40 mg per day for the treatment of Paget's disease.
18 In March 1996 the Clinical Development Oversight Committee (CDOC) of Merck considered adverse GI events (AE) which had occurred with the use of Foxamax after marketing commenced. One of the consultants involved was Dr Piet de Groen from the Mayo Clinic. The observations were summarised as follows:
'… that the incidence and severity of esophageal AEs appear to be greater than observed in clinical trials, that improper dosing is likely to be common in the marketed use of alendronate (especially in patents with post-marketed reports of esophageal AEs), and that only rare cases (n=6) exist of severe esophageal AEs in patients who appear to have taken alendronate correctly. The Team concluded that alendronate appears to cause chemical esophagitis in a small number of patients, which may be severe, improper dosing may be a factor, and the role of concomitant therapies and prior UGI disorders are not established with existing data.'
19 It was agreed that action should be taken and the assignments included the following:
'FOSAMAX - Project Team/Pharm R&D - Discuss the possibility of new formulations of alendronate which may alleviate some of the dosing difficulties.'
20 On 15 March 1996 a letter was sent to physicians (known internally as the 'Dear Doctor letter') as follows:
'We would like to call your attention to esophageal side effects in patients taking FOSAMAX Since market introduction of the product, some of these side effects have been of greater severity than we observed in our controlled clinical trials. It is clear from the case reports received by Merck & Co., Inc. that FOSAMAX can be irritating to the esophagus but that careful adherence to the dosing instructions can reduce the potential for these side effects. In a large proportion of cases reported, there is evidence that FOSAMAX was not dosed in the manner recommended in the Product Circular. We have therefore made modifications to the Product Circular (and Patient Package Insert) that we believe will further reduce the risk of adverse reactions such as esophagitis, esophageal erosion or ulceration. Merck & Co., Inc. is writing to you directly as the most rapid way to bring this important information to your attention.
FOSAMAX is an aminobisphosphonate, a selective inhibitor of bone resorption that is the first nonhormonal therapy indicated for the treatment of osteoporosis in postmenopausal women (the daily oral dosage is 10 mg). FOSAMAX is also indicated for the treatment of Paget's disease of bone (the daily oral dosage is 40 mg for six months). In controlled clinical trials of three years' duration in postmenopausal women with osteoporosis, FOSAMAX was generally well tolerated. Like other bisphosphonates, however, FOSAMAX was recognized to have the potential to cause local irritation of the upper gastrointestinal mucosa. In ongoing, carefully-monitored studies of over 12,000 patients, esophageal irritation has been no different in incidence or severity than observed in the completed three-year trials. (As you know, esophageal ulcers, considered to be drug related, were reported in 1.5% of the patients taking FOSAMAX 10 mg in three-year trials.)
As part of our customary postmarketing surveillance, we have become aware of a number of case reports of esophagitis and esophageal ulceration in which patients have presented with difficulty or pain on swallowing, and/or retrosternal pain. When endoscopy has been performed, the findings have been consistent with a chemical irritation of the esophagus.
Although infrequent, the reports of esophagitis/ulceration have generally been of a more severe nature than observed in either previous clinical trials, or in ongoing studies of FOSAMAX (alendronate sodium tablets). In a large majority of the postmarketing reports, it appears patients were not compliant with our recommended dosing instructions (for example, patients were taking FOSAMAX with little or no water, taking it at bedtime and/or lying down within minutes after taking it, etc.). Several patients continued taking FOSAMAX after the occurrence of symptoms suggestive of esophageal irritation. In a few cases, patients have been found to have previously undiagnosed esophageal disorders.
We therefore strongly advise strict compliance with the dosing instructions, which have been updated in the Product Circular, and are summarized in the attachment. Please read them carefully, and in the case of any question contact the Merck National Service Center at (800) 672-6372. Enclosed is a copy of the revised Product Circular. Merck has been taking, and is continuing to take, a number of steps to ensure that physicians, pharmacists, and patients understand the importance of proper dosing of FOSAMAX. We believe that the risk of esophageal irritation can be substantially decreased with adherence to these recommendations.
At Merck, our primary concern remains the safety and well-being of the patients who use our products. We appreciate the continuing efforts of doctors, pharmacists and other healthcare professionals in communicating dosing information to patients. We truly value your trust in us and thank you very much for your time and attention to this matter.'
21 A comprehensive report followed. That report included the following:
'II. PRECLINICAL DEVELOPMENT OF ALENDRONATE
Alendronate was licensed by Merck & Co., Inc. from Gentili S.p.A. for treatment of disorders associated with increased bone resorption. The formulation that had been developed by Gentili was the free acid, which had low solubility and had been shown to be associated with esophageal ulceration in two patients treated with an oral formulation. In recognition of the potential for mucosal irritation of this formulation, alendronate was reformulated by Merck as the sodium salt. Alendronate sodium has a more neutral pH and greatly improved solubility characteristics relative to the original acid formulation, and was very well tolerated in animal studies. Gastric ulceration was observed in rats treated with alendronate at a dose of 10 mg/kg (equivalent to approximately 50 times the human osteoporosis treatment dose of 10 mg per patient per day). Ulceration was not observed at 5 mg/kg, although some gaseous distention was seen at that dose, presumably due to effects on the GI flora. Furthermore, no GI ulceration was observed in dogs treated with doses of up to 8 mg/kg/day over one year. Both in the rat and dog studies, alendronate was given by gavage, and therefore exposure of the esophagus to alendronate was limited to reflux that occurred upon removal of the gavage tube.
Based upon the experience in preclinical studies, it was considered that the alendronate sodium formulation would be acceptable for clinical use, although irritation of the upper gastrointestinal mucosa was clearly considered to be a potential side effect of alendronate treatment. For this reason, the dosing instructions utilized in the clinical trials were developed to reduce the potential for sticking of the alendronate tablets within the esophagus. Specifically, patients were instructed to take alendronate with a full glass (six to eight ounces) of water and to take study medication while upright and not to lie down for at least 30 minutes thereafter. Several published studies identify upright position and volume of water as critical for ensuring rapid delivery of tablets to the stomach. The amount of water most commonly referred to as adequate for this purpose is at least 100 mL, which is approximately 4 oz (Channer and Virjee, 1986; Hey et al., 1982).'
22 The report summarised the clinical trial experience as follows:
'… this review of all studies included in the current osteoporosis treatment database has found no evidence of increase in either all, serious, or clinically severe esophageal adverse reactions with alendronate 10mg. There may be a slight increase in such events at the 20 or 40mg dose. The labeling adopted in the prescribing information therefore remains an accurate description of the clinical trial experience with alendronate.'
(emphasis added)
23 Another relevant part of the report was:
'IV. PAGET'S DISEASE OF BONE
The studies in Paget's Disease of bone (N = 235) include four protocols with either 3 or 6 months of alendronate therapy at higher doses (20, 40 and 80 mg) of alendronate. As in the osteoporosis treatment studies, patient with active upper GI disease or NSAID use were prohibited from entering these studies. There was only one serious and/or clinically severe case of esophagitis reported (Study 059001 AN 1226). This patient is interesting in that she initially would lie down after taking alendronate, but once her improper dosing was corrected, the esophagitis cleared, and she was able to go back onstudy therapy (alendronate 40 mg) without further adverse experiences. A table of the incidence of all upper GI AEs in the studies of Paget's disease of bone is provided in Appendix 3.'
(emphasis added)
Interestingly, the experience in a Fracture Intervention Trial (ie prevention) at 5 mg of alendronate or placebo, with the dose for the active treatment group increased to 10 mg at month 24, was consistent with the osteoporosis treatment clinical studies at the higher dose in relation to GI effects ie no dose response was observed.