(a) Professor Pouton, a Professor of Pharmaceutical Science, at the Monash Institute of Pharmaceutical Sciences; > > (b) Dr Scott, a veterinary consultant of over 50 years' experience, including over 20 years practice in the field of veterinary medicine in connection with the treatment of horses; > > (c) Professor Mills, a Professor of Veterinary Pharmacology at the School of Veterinary Science of the University of Queensland; and > > (d) Dr Margerison, the Director of Chemistry and Manufacture, of the respondent authority's Risk Assessment Capability Program.

3. Additionally, there was a considerable volume of documentary material that was collated in a Joint Tender Bundle ("JTB"). The JTB included confidential material.

1. On 3 February 2022, the applicant lodged with the respondent Authority an application for registration of a chemical product, which is known as Trimidine Paste.[2] Whilst the contents of the application are referred to in their entirety, it should be observed that the application was accompanied by a vast array of information. The application is divided into several parts including "Data and Information List", "Formulation", "Manufacturers Details", "Container and Net Content Details", "Storage Stability Details", "Label Details", "Reference Product", "Chemistry and Manufacture", "Toxicology" and "Efficacy". The section entitled "Data and Information List" was accompanied by 50 data items.
2. Following the receipt of the application, the respondent's case manager requested that Professor Mills conduct a review of the efficacy and safety of Trimidine Paste. Professor Mills conducted the review as requested. In a letter addressed to the case manager, dated 12 May 2022, Professor Mills expressed the opinion that - based upon the data provided with the application - the respondent could not be satisfied that the use of Trimidine Paste would be effective if used according to label instructions, as was claimed on such label.[3]
3. Also included in this May 2022 letter were Professor Mills' further recommendations to the respondent. He stated that in order for the respondent to further consider the applicant's submission, the applicant should provide answers to two questions as follows:

(a) Demonstrate that the removal of Brohexine (and Vanilin crystals and a Polar Brilliant Blue) does not affect the bioavailability of Sulfadimidine Trimethoprim, compared to Bromotrimidine Paste; and > > (b) Demonstrate that the removal of bromhexine does not reduce the efficacy of Trimidine paste (compared to Bromotrimidine paste) for respiratory infections.

4. Further, Professor Mills also expressed the opinion that the use of Trimidine Paste according to the label instructions would be unlikely to have harmful unintended effects upon target animals. Much was made by the applicant of this opinion, in cross examination of Professor Mills and in submissions. More will be said about that later.
5. On 13 September 2022, a delegate of the respondent served on the applicant a notice under s 159(1)(a) of the Agvet Code ("the 159 notice"), as it was entitled to do, seeking further information on several topics pertaining to what was described as "Chemistry and Manufacture Requirements".[4] The notice required a response by 11 October 2022.
6. A response to the s 159 notice was provided by the applicant's Research & Development Manager on 11 October 2022.
7. The following further interactions between them, 24 February 2023 the respondent gave a notice purportedly under s 8S of the Agvet Code that it proposed to refuse the application to register Trimidine Paste.[5]
8. Further correspondence passed between the applicant and the respondent for some time after the service of the notice purportedly under s 8S of the Agvet Code. Eventually, on 30 March 2023 another notice under s 159 of the Agvet Code was served by the respondent on the applicant seeking further information and data. The applicant responded to this additional s 159 notice on 6 April 2023. The reviewable decision was then made on 18 April 2023.
9. The reasons given by the respondent in the reviewable decision for refusing the application under s 14 (2) of the Agvet Code were because the respondent was not satisfied that:

(a) The chemical product, the subject of the application, meets the efficacy criteria in accordance with the requirements of s 14(1)(c)(i) of the Agvet Code; and > > (b) The chemical product meets these safety criteria in accordance with the requirements of s 14(2) of the Agvet Code.

10. A Statement of Reasons was attached to the reviewable decision which contained material findings of fact and the reasons relied upon.

1. In considering the legislative framework contained in the Agvet Code it is useful to briefly identify some of its objects which are enumerated in s 1. Those objects are:

(a) The evaluation, approval, and control of the supply, of active constituents for proposed or existing agricultural chemical products or veterinary chemical products; and > > (b) The evaluation, registration, and control of the manufacture and supply, of agricultural chemical products and veterinary chemical products.

2. Further, s 1A(2) provides that the Agvet Code is to be implemented in a manner that:

(a) Recognises that the health and safety of human beings, animals and the environment is the first priority of the system for regulating chemical products and their constituents, in part to ensure that the use of chemical products at the present time will not impair the prospects of future generations; and > > (b) Reflects established best-practice principles for the assessment and management of risk, based on science; and > > (c) Balances regulatory effort and any burden imposed by the system of regulation on: > > > (i) Holders of approvals, registrations, permits and licenses; and > > > > (ii) The domestic industry for manufacturing and formulating chemical products and their constituents; and > > > > (iii) The users of chemical products;

with the risk of the use of the products and constituents to the health and safety of human beings, animals and the environment; and

....

(d) Promotes community confidence in the regulation of chemical products and their constituents, is open and accountable, and gives opportunity for public involvement and participation; and

(e) Secures compliance with the Agvet Code through appropriate, proportionate, consistent and effective compliance and enforcement measures.

1. Section 10 of the Agvet Code enables a person to apply to the respondent for:
   • approval of an active constituent for a proposed or existing chemical product; and
   • registration of a chemical product; and
   • approval of a label for containers of a chemical product.
2. Such applications must meet the application requirements which are contained in s 8A and, for an active constituent or chemical product, must include proposed instructions for use of the constituent or product.
3. Under s 14 (1)(c)(i) of the Agvet Code, the respondent must approve the active constituent or label or register the chemical product if it is satisfied that the product meets the "safety criteria", "the trade criteria" and the "efficacy criteria".
4. The definition of the "safety criteria" of the Agvet Code concerning a chemical product is contained in s 5A. It is worthwhile reproducing some parts of that section:

5A Definition of meets the safety criteria

(1) An active constituent or chemical product meets the safety criteria if use of the constituent or product, in accordance with any instructions approved, or to be approved, by the APVMA for the constituent or product or contained in an established standard:

(a) is not, or would not be, an undue hazard to the safety of people exposed to it during its handling or people using anything containing its residues; and

(b) is not, or would not be, likely to have an effect that is harmful to human beings; and

(c) is not, or would not be, likely to have an unintended effect that is harmful to animals, plants or things or to the environment.

(3) For the purposes of being satisfied as to whether a chemical product meets the safety criteria, the APVMA:

(i) the toxicity of the product and its residues, including metabolites and degradation products, in relation to relevant organisms and ecosystems, including human beings;

(ii) the relevant poison classification of the product under the law in force in this jurisdiction;

(iv) the composition and form of the constituents of the product;

(v) any conditions to which its registration is, or would be, subject;

(vi) any relevant particulars that are, or would be, entered in the Register for the product;

(via) whether the product conforms, or would conform, to any standard made for the product under section 6E to the extent that the standard relates to matters covered by subsection (1);

(vii) any matters prescribed by the regulations; and

(b) may have regard to one or more of the following:

(i) the acceptable daily intake of each constituent contained in the product;

(ii) any dietary exposure assessment prepared under subsection 82(4) of the Food Standards Australia New Zealand Act 1991 as a result of any proposed variation notified under subsection 82(3) of that Act in relation to the product, and any comments on the assessment given to the APVMA under subsection 82(4) of that Act;

(iii) whether any trials or laboratory experiments have been carried out to determine the residues of the product and, if so, the results of those trials or experiments and whether those results show that the residues of the product will not be greater than limits that the APVMA has approved or approves;

(v) the specifications for containers for the product;

1. The definition of the "efficacy criteria" of the Agvet Code concerning a chemical product is contained in s 5B. It is also worthwhile reproducing some parts of that section.

5B Definition of meets the efficacy criteria

(1) A chemical product meets the efficacy criteria if use of the product, in accordance with instructions approved, or to be approved, by the APVMA for the product or contained in an established standard, is, or would be, effective according to criteria determined by the APVMA by legislative instrument.

(2) For the purposes of being satisfied as to whether a chemical product meets the efficacy criteria, the APVMA must have regard to the following:

(a) whether any trials or laboratory experiments have been carried out to determine the efficacy of the product and, if so, the results of those trials or experiments;

(b) any conditions to which its registration is, or would be, subject;

(c) any relevant particulars that are, or would be, entered in the Register for the product;

(ca) whether the product conforms, or would conform, to any standard made for the product under section 6E to the extent that the standard relates to matters covered by subsection (1);

(3) For the purposes of the operation of this Code in relation to a particular chemical product, the APVMA is required to have regard to the matters set out in subsections (1) and (2) only:

(a) to the extent prescribed by the regulations; or

(b) if there are no such regulations--to the extent that the APVMA thinks the matters are relevant.

1. As is apparent from the language used in 5B(1) of the Agvet Code, for the Tribunal as decision-maker to be satisfied as to whether a chemical product meets the Efficacy Criteria it must have regard to the matters articulated in s 5B(2).
2. Section 5B(1) of the Agvet Code provides that a chemical product meets the efficacy criteria if the use of the product is, or would be, effective according to criteria established by the respondent by legislative instrument. Such legislative instrument is the Agricultural and Veterinary Chemicals Code (Efficacy Criteria) Determination 2014 (Cth) ("the Efficacy Determination").
3. Paragraph 6 of the Efficacy Determination identifies applicable criteria based on demonstrated effectiveness. That paragraph provides as follows:

6. Criteria based on demonstrated effectiveness

The use of a veterinary chemical product, in accordance with instructions approved, or to be approved, by the APVMA for the product, is also taken to be effective if:

(a) it would, to a reasonable degree, achieve one of the effects listed in paragraphs 5 (2) (a) to (d) of the Agvet Code; and

(b) this is evidenced or demonstrated by:

1. target animal efficacy studies, including dose determination studies, dose confirmation studies or confirmatory clinical or field studies; or
2. pharmacological studies, such as in vivo or in vitro bioequivalence studies in target animals, pharmacokinetic studies or pharmacodynamic studies; or
3. other relevant studies or data, such as clinical case studies, compatibility studies or palatability studies; or
4. full results from overseas efficacy trials or experiments and the associated assessment reports by an overseas regulator that are relevant to the proposed product and use; or
5. valid scientific argument; or
6. a combination of 2 or more of the above.

Note; The APVMA will consider, on a case-by-case basis, which of the above matters are necessary to demonstrate effectiveness in a particular case. The APVMA also takes into account other relevant matters: 5B (2) of the Code. The APVMA's data guidelines and regulatory guidelines made under section 6A of the Code, published on the APVMA's website, set out information about the kind of data considered sufficient to demonstrate effectiveness in particular cases."

1. Reference should also be made to the respondent's "Efficacy and target animal safety general guideline" (Part 8) ("Efficacy Guideline").[6] That document does address the question of what constitutes "valid scientific argument." Paragraph 1.6.3 of the Efficacy Guideline "Scientific references or extrapolated scientific argument", provides as follows:

"Scientific argument is one that is supported by science/data. When submitting published scientific papers, you should explain their role in the summary so that the relevance of such additional data is explained to the reviewer..

Scientific papers should be critically evaluated to ensure that they are relevant to the data requirements of the product to be registered or varied. The statistical analysis should be appropriate for the intended purpose.

Literature using the proposed final formulation manufactured by or for the sponsor provides the best, most relevant evaluation and the highest evidentiary weight. Unless appropriate justification is provided, literature that does not use the final formulation of the proposed new animal drug product provides less weight in the evidentiary support scheme.

Other factors to consider when submitting valid scientific arguments are:

• the effects that the excipients in a formulation may have on the bioavailability of the active constituent;
• the effects that the excipients may have on the solubility or permeability of the active constituent;
• the effects that the excipients may have on gastric motility and gastric emptying;
• the physicochemical properties of the excipients (for example, excipients that adjust pH may affect the biological activity of active constituents that are pH -dependent, and excipients that adjust viscosity may affect the distribution of a pour-on product;
• discussions based on pharmacokinetic and pharmacodynamic principles, comparisons of pharmacokinetic parameters, comparisons of pharmacodynamic indices and a literature supporting comparable bioavailability of inactive constituent when administered by the oral or parenteral route;
• the change in the drug: excipient ratio when excipients are substituted, deleted or added to a formulation.

1. There are certain matters in terms of the requirements of the Agvet Code which are not in dispute between the parties. Insofar as s 14(1) is concerned it is conceded that an application was made to the respondent for the registration of a chemical product in accordance with s 10(1)(b). It is also conceded by the respondent that such application meets most of the application requirements as specified in s 8A for the purposes of s 14 (1) (a). Therefore, for the purposes of this application that provision is not in issue.
2. Further, it is also not in dispute between the parties that there is no "established standard for the product" for the purposes of s 14(1)(c)(ii).
3. The issues that arise for consideration by the Tribunal in this matter are whether Trimidine Paste meets, for the purposes of s 14(1)(c)(i) of the Agvet Code:

(a) the "safety criteria" in s 5A; and

(b) the "efficacy criteria" in s 5B.

A preliminary observation concerning the expert evidence

1. It is appropriate to make a preliminary observation concerning the expert evidence given at the hearing of this application.
2. Each of those expert witnesses were highly qualified and vastly experienced. The opinions they expressed when giving their evidence were genuinely held expert opinions based upon their unquestionable extensive qualifications, vast experience and store of professional knowledge acquired throughout their careers. They were extremely impressive witnesses.
3. Their evidence bore the hallmarks of a good expert witness. They understood that their overarching obligation was to assist the Tribunal and not fulfil the role as an advocate for the party who called them. Their evidence was candidly given by way of accurate responses to the questions asked of them without gloss or exaggeration. They readily made appropriate concessions when called upon.

1. There were two principal expert reports in evidence from Professor Pouton dated 30 September 2024[7] ("the first Pouton report") and 20 February 2025[8] ("the second Pouton report").[9]

1. The first Pouton report was prepared following a letter of instruction from the applicant's lawyers. Professor Pouton was briefed with an array of documents. He also requested to respond to specific questions in relation to the Trimidine Paste formulation. As is common with expert reports of this type, the first Pouton was broken up into several subject headings being "Background", "Documents considered", "Technical considerations" and a "Conclusion". His responses to the specific questions asked of him in the letter of instruction from the applicant's lawyers followed the Conclusion. The contents of the first Pouton report have been read and considered by the Tribunal. It is useful to refer to some aspects of it.
2. Under "Technical considerations", Professor Puton referred to a number of matters:

(a) He stated that there are several sulphonamide/trimidine combination ("TMPS") products approved in Australia for use in horses. Such products are, he stated all antibiotics for treatment of respiratory infections. Some are a combination of sulfadiazine and trimethoprim, and others are combinations of sulfadimidine and trimethoprim. > > (b) Eight of eleven approved products, including the applicant's Trimidine Powder, do not contain bromhexine. Three approved products, including the applicant's Bromotrimidine Paste and Bromotrimidine Powder, include bromhexine as a mucolytic agent. Several of the approved products are in the form of a paste, which would be expected to assist in oral administration to a horse. The appropriate dose of a paste can be administered into the mouth using a syringe or similar device. > > (c) The product to which approval is sought, Trimidine Paste (in common with three approved products - Trimidine Powder, Calesulpha-T Paste and Ilium Sulprim Oral Powder) contains the combination of sulfadimidine and trimethoprim. These products are all to be used twice daily, each providing a dose of 12.5g/55kg bw sulfadimidine and 2.5g/500kg bw trimethoprim in each administration. > > (d) Five of the approved TMPS products use the combination of sulfadiazine and trimethoprim. These products are less consistent in terms of dose of antibiotics per 500kg bw, but given that the sulfonamide used is different, these products cannot be easily compared with Trimidine Paste. > > (e) The respondent's Statement of Reasons document suggests that oral absorption and pharmacokinetics of the antibiotics in Trimidine Paste may differ in absorption from the approved product Bromotrimidine Paste, due to the inclusion of 9mg/g bromhexine, 0.14g/kg Vanillin or 0.08g/kg Polar Brilliant Blue in the latter product. While this is conceivable, although unlikely in the case of bromhexine content, it is highly unlikely that the low concentrations of flavouring or colouring agent could affect the bioavailability of the 450g/kg sulfadimidine or 90g/kg trimethoprim in the product. > > (f) Professor Pouton further stated more importantly that there is no need to consider whether Trimidine Paste and Bromotrimidine Paste are bioequivalent in relation to the availability of the antibiotics, since there are three approved products (Trimidine Powder, Calesulpha-T Paste and Ilium Sulprim Oral Powder) that contain the same dose of the two antibiotics in the absence of bromhexine. > > (g) Both sulfadimidine and trimethoprim are readily absorbed from a powdered form. The Trimidine Paste formulation of these drugs in propylene glycol and glycerol, which are both water soluble excipients would be expected to aid dispersion of the drugs after administration, leading to a more consistent dissolution rate, and reduced variability in bioavailability. Accordingly, he expected that Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprim Oral Powder. > > (h) The formulation of Calesulpha-T Paste is an oily formulation containing the same doses of the two antibiotics as Trimidine Paste, Trimidine Powder and Ilium Sulprim Oral Powder. Given that the oily formulation could potentially affect the rate of absorption, it would be necessary to run a bioequivalence study to know whether this product would be bioequivalent to the other three products. Of the seven approved TMPS products presented in paste form, like Trimidine Paste, six are presented in pastes that would be soluble in aqueous media, suggesting that this type of formulation is preferred for TMPS products.

3. Having considered the above-named Technical Considerations, Professor Pouton concluded that he would expect Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprim Oral Powder. Given that these approved products have been shown to be efficacious and safe, in his opinion, it is reasonable to conclude that Trimidine Paste would to a reasonable degree, achieve the antibiotic effect sought, to prevent, cure or alleviate an appropriate disease or condition in a horse.
4. The first specific question that Professor Pouton was requested to respond to in preparing the first Pouton report was whether in his opinion Trimidine Paste would to a reasonable degree, achieve the effect of preventing, curing or alleviating a disease or condition a horse, or cure or alleviate an injury suffered by horse.
5. Professor Pouton responded that based on the data provided, and the knowledge that Trimidine Powder and Ilium Sulprim Oral Powder have been approved for use, in his opinion Trimidine Paste would, to a reasonable degree, achieve the desired efficacy. He stated that the dosage of the two antibiotics is identical for the three products, in terms of the ratio of masses of drugs, the intended dose, and frequency of dose. The approved formulations have, he also noted, been determined to be efficacious in prior decisions of the respondent. Much was made of this by the applicant in cross examination of the respondent's witnesses and in submissions.
6. In Professor Pouton's opinion, the formulation of Trimidine Paste with the two commonly used water-soluble (and generally regarded as safe-GRAS status) pharmaceutical excipients, glycerol and propylene glycol, would present the drug products in a suitable form for dissolution and absorption. There is, he also stated, no reason to expect that Trimidine Paste would compromise the bioavailability of the two drugs since the evidence provided by approved products suggests that they are readily absorbed after oral administration in a powdered form. Based on the known performance of the two approved products, Trimidine Powder and Ilium Sulprim Oral Powder, in his opinion Trimidine Paste would be expected to a reasonable degree to achieve the desired efficacy.
7. It was further observed by Professor Pouton in the first Pouton report that the data provided in the study provided by SCEC Pty Ltd (report for Caledonian Holdings - report 108SCECCALST April 2009), compares Trimidine Powder with a paste formulation from a competitor. The report suggests that sulfonamide/trimethoprim are likely to be efficacious in either powdered or paste formulations. Absorption is consistent from both formulations. Whilst the paste used in the SCEC report is an oily product, Professor Pouton considered it provides evidence that the two drugs are readily absorbed from either powder or paste formulations.
8. Professor Pouton also stated in the first Pouton report that he had been provided with documentation from the respondent describing an analogous powder-to-paste reformulation exercise by Troy Laboratories. The company sought to register the paste to improve the accuracy of the oral dose. He recorded that Ilium Sulprim Paste is now an approved paste formulation of sulfadimidine and trimethoprim in water-soluble excipients (substantially golden syrup thickened with xanthan gum). This product was compared prior to approval with Sulprim Oral Powder, also from Troy Laboratories. The respondent's document concluded that, "The results indicated equivalence in the amount of sulphadimidine absorbed between the paste and powder, and a higher bioavailability of trimethoprim from the paste". This he considered provided further support for his opinion that Trimidine Paste would be expected to a reasonable degree to achieve the desired efficacy.
9. The other specific question that Professor Pouton was asked to respond to was whether in his opinion he would agree that Trimidine Paste would not be, an undue hazard to the safety of people exposed to it during its handling or people using anything containing its residues and, that it is not, or would not be likely to, have an unintended effect that is harmful to animals, plants or things or to the environment.
10. Professor Pouton stated that based on the data provided, there are five approved products containing the combination of sulfadimidine and trimethoprim. Three products contain identical proportions of the two drugs and are used at the same dose. The excipients included are commonly used in many pharmaceutical products and are classed as GRAS ingredients. In his opinion he agreed that Trimidine Paste would satisfy the safety criteria as previously stated by him.

1. The second Pouton report was produced following a request from the applicant's lawyers that he provide comments on Professor Mills' report of 20 November 2024, which was lodged in the application on behalf of the respondent.[10] In preparing his second report, Professor Pouton considered Professor Mills' November 2024 report and reconsidered documents that he had previously reviewed.
2. Professor Pouton held that it is not necessary to consider whether the removal of bromhexine, Vanillin crystals and Polar Brilliant Blue from the existing product Bromotrimidine Paste (APVMA is 46084 approved 12 December 1997) would affect its efficacy_._ Instead, attention should be focused on the application for approval of Trimidine Paste.
3. He then reiterated the opinion contained in his first report that he would expect Trimidine Paste would be bioequivalent to the approved products Trimidine Powder and Ilium Sulprin Oral Powder. Professor Pouton repeated that this opinion was based on a consideration of the similarity between the specifications of Trimidine Paste and the approved products, Trimidine Powder and Ilium Sulprin Oral Powder. His opinion had not changed.
4. A passage from Professor Mills' report was then reproduced in full where Professor Mills stated that Professor Pouton had provided no evidence to support his comment of bioequivalence (BE), yet determining BE is the cornerstone of generic medications.[11] It was also repeated that Professor Mills observed there are very clear and scientific guidelines to demonstrate BE (e.g Martinez, 2010), which are clearly defined regulatory authorities' websites, including the FDA and APVMA. Assessment of BE should therefore not be an opinion, but a consideration of pharmacokinetic (PK) parameters, as per the guidelines.
5. Professor Pouton, by way of response, agreed that he had not provided data specifically comparing the rate and extent of absorption of sufadimidine and trimethoprim from Trimidine Paste in comparison with an approved product. However, he referred to s 4 of the Agricultural and Veterinary Chemicals Code (Efficacy Criteria) Determination 2014. He then emphasised that s 4(b)(ii) of that Code makes specific provision for scientific argument, and s 4(b)(iii) of that code, a history of sale and effective use in equivalent uses.
6. He then stated that his understanding of "valid scientific argument" in this context is that data available regarding efficacy of closely related approved products, combined with general knowledge of the factors that influence bioavailability, efficacy and safety of pharmaceutical products, may be used to make a judgement as to whether Trimidine Paste is likely to prevent, cure or alleviate an appropriate disease or condition in a horse. Critically, for the purposes of this matter he then stated that "valid scientific argument" in this context he opined does not necessarily require the definitive evidence of bioequivalence to which Professor Mills had referred. One should observe that Professor Mills did not say, in his report or oral evidence, that a requirement for approval (or more accurately, the "valid scientific argument") was the definitive evidence of bioequivalence that Professor Pouton discussed in this section of his report. What Professor Mills did say on this question will be referred to in more detail later in these reasons.
7. Professor Pouton then expressed the opinion that he would expect Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprin Oral Powder for the following reasons:

(a) Trimidine Paste, in common with Trimidine Powder and Ilium Sulprin Oral Powder, contains the combination of sulfadimidine and trimethoprim. These products are all to be used twice daily, each providing a dose of 12.5g/500kg bw sulfadimidine and 2.5g/500 kg trimethoprim in each administration. > > (b) The two drugs, sulfadimidine and trimethoprim, are presented in powdered form in Trimidine Powder, and Ilium Sulprin Oral Powder. The paste formulation of Trimidine Paste is a water-soluble formulation (including propylene glycol and glycerol) that is likely to present the drug in a form more easily and consistently absorbed than the powdered formulations. > > (c) For practical reasons the dosage of Trimidine Paste is likely to be more precise than the doses of the powdered products, since the paste can be administered by syringe to the mouth of the horse. > > (d) Sulfadimidine and trimethoprim are well-established antibiotics which have a high therapeutic index. As such, the efficacy or toxicity of the two drugs would not be expected to be sensitive to small changes in the rate of drug absorption. The efficacy of the product would be a function of the absolute bioavailability. It is reasonable to expect that Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprin Oral Powder. > > (e) Finally, he observed that Professor Mills suggested that the efficacy for generic formulations such as Trimidine Paste, must be determined using a BE study, which he describes as definitive science. Further, he observed Professor Mills suggesting or that without a definitive BE study, it was not possible to determine if efficacy or safety would be the same between the Trimidine Paste (or "investigatory product) and the existing approved products (the "reference formulations"). However, Professor Pouton observed that the Agricultural and Veterinary Chemicals Code appeared to allow for a judgement to be made on scientific opinion, which he believed did not necessarily require a definitive BE study.

8. Some comments should be made about the observations made by Professor Pouton concerning Professor Mills' conclusions concerning the need for a definitive BE study as expressed in his report. He did not say, as Professor Pouton suggests, that efficacy must be determined using a BE study. Further, he did not say that that without a definitive BE study, it was not possible to determine if efficacy or safety would be the same between the investigatory and reference formulations. What he did say was that efficacy and safety can be demonstrated using a BE study, comparing the investigatory drug to a currently registered formulation. He said the same thing in cross examination.[12] He also said he would judge the data presented to him.
9. Also, both in his report and in oral evidence, Professor Mills - having said that efficacy and safety can be demonstrated by means of a BE study - consistently reiterated the need for what he described as "definitive science", "good scientific support", "rigorous science" and "valid scientific argument to show that the literature is showing for these particular products and demonstrating that the new formulation for Trimidine is the same as the reference product". The nature of this science included a range of studies and clinical trials. Presumably, such data or scientific evidence could have included that of the type referred to by Professor Pouton in paragraph 47 above, being data specifically comparing the rate and extent of absorption of sulfadimidie and trimethoprim from Trimidine Paste in comparison with an approved product. The absence of such data, or any other clinical trials, was a point of much contention between the parties. Such data would clearly it seems be highly relevant in determining whether the efficacy criteria had been satisfied.
10. One should observe at this juncture, that it is surprising that Professor Pouton's observations in his second report concerning the opinions expressed by Professor Mills that "valid scientific argument" required the definitive evidence of a BE study, as just described, were not correct.
11. Therefore, the second Pouton report concludes that Professor Pouton would expect Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprin Moral Powder. Given that these approved products have been shown to be efficacious and safe, in his opinion it is reasonable to conclude that Trimidine Paste would to a reasonable degree, achieve the antibiotic effect sought, to prevent, cure or alleviate an appropriate disease or condition in a horse.
12. He contended that Trimidine Paste, in common with three approved products Trimidine Powder, Calesulpha-T Paste and Ilium Sulprim Oral powder, contains a combination of sulfadimidine and trimethoprim. Such products are all to be used twice daily, each providing a dose of 12.5g/55kg bw sulfadimidine and 2.5g/kg trimethoprim bw in each administration. However, when pressed in cross examination on this question it should be observed that Professor Pouton accepted that none of the other products which he described in various ways such as "related products" or "similar products" have the exact formulation of the product for which the applicant seeks registration under the Agvet Code.[13]
13. Another key point of difference between the opinions expressed by Professor Pouton and the respondent's experts were that he considered that there was no need to consider whether Trimidine Paste and Bromotrimidine Paste are bioequivalent in relation to the availability of the antibiotics, since there are three approved products (Trimidine Powder, Calesulpha -T Paste and Ilium Smlprim Boral Powder) that contain the same dose of the two antibiotics in the absence of brohexine. Therefore, as already noted he would "expect" that Trimidine Paste would be bioequivalent to the approved products.
14. On the question of bioequivalence, it is important to record oral the evidence of the experts on this topic. Professor Pouton readily conceded in cross-examination that bioequivalence is the cornerstone of generic medications.[14] Dr Scott in his evidence conceded that he accepted the proposition from Professor Mills' report that determining bioequivalence is the cornerstone of generic medications. His response was as a general term he did accept that proposition. At one point in cross examination, he even said, "...bioequivalence trial is for me the gold standard. I accept that".[15]
15. In his oral evidence, Professor Mills briefly explained how a bioequivalence study is undertaken, which would record, amongst other things, plasma concentration over times, limits and percentage confidence intervals. So, within anywhere in that range enable a determination of whether two drugs are the same or bioequivalent. He also stressed that, when determining to a reasonable degree how an effect can be achieved, defined scientific evidence is required. One would observe that this explanation from Professor Mills about how a bioequivalence study is undertaken was not address by the applicant's expert witnesses - save for the reference by Professor Pouton referred to above at paragraph 48, concerning data specifically comparing the rate and extent of absorption of sulfadimidine and trimethoprim from Trimidine Paste in comparison with an approved product.
16. In a passage of cross-examination, Professor Pouton was taken into the specific provisions contained in Clause 6 of the Efficacy Determination. Mr Liu specifically put to him each of the subparagraphs contained in paragraph 4(b)(i) to (v) of that Determination. He readily conceded the following:

(a) There were no target animal efficacy studies within the meaning of subparagraph 4(b)(i); > > (b) There were no pharmacological studies within the meaning of subparagraph 4(b)(ii); > > (c) There were no other relevant studies or data within the meaning of subparagraph 4(b)(iii); > > (d) There were not full results from overseas efficacy trials or experiments and the associated assessment reports from an overseas regulator that are relevant to the proposed product and use within the meaning of subparagraph 4(b)(iv).[16]

17. Given these concessions by Professor Pouton in cross examination, the only category of evidence that could rationally be available to satisfy the criteria prescribed in s 6 of the Efficacy Determination is that contained in s 6(b)(v), being "valid scientific argument". More will be said about this later, but it clearly comes down to effectively a "battle of the experts" as to that the meaning or application of this term.
18. Professor Pouton then conceded that he was relying on his expertise and understanding of the two active antibiotic ingredients in this specific product for which registration was sought to draw the inference that it was efficacious. He also emphasised that he was relying on the fact that the applicant already had three approved products, all of which are very similar to the Trimidine Paste. It was reiterated by him that he was making a judgement based upon the fact that this company has three very closely related products, to the one they are trying to get approval for. Further, he relied upon the fact that there are many other generic products of this type which are obviously efficacious. He also emphasised that these generic products had been used for some time. Additional emphasis was placed by him upon the fact that there were two other closely related products to Trimidine Paste which had already been approved, as well as Bromotrimidine Paste. Professor Pouton stated that, in reaching his conclusions, he relied upon a combination of all these factors that it is extremely unlikely that Trimidine Paste would not be efficacious. Professor Pouton could not think of a reason why it wouldn't be so.
19. Additionally, Professor Pouton, in his oral evidence, relied upon his understanding of the formulations. He emphasised that the excipients were unlikely to affect the drug being absorbed adequately.[17]
20. It was then acknowledged by Professor Pouton that none of the other products that had been registered, which he variously called "related products", or "similar products", have the exact same formulation as Trimidine paste.[18]
21. In another passage of cross-examination, it was further put to Professor Pouton that he could not know as a matter of scientific certainty whether the particular formulation for Trimidine Paste would be bioequivalent to the products he had mentioned. His response was that certainty is something which is not necessarily demonstrated in a bioequivalence study. He explained that a bioequivalence study is a surrogate of an efficacy study. An efficacy study requires one to compare several products in a clinical setting. He then contended that efficacy studies are not something that is typically undertaken. In his opinion, "an efficacy study for a product like this requires you to show that you have actually cured the infection". However, he did concede that, "...yes of course, we don't have a lot of certainty that this product is going to be efficacious. .... I think what we have is a lot of confidence".[19]
22. Another question was asked of Professor Pouton in cross-examination whether one would have more certainty if there had been a bioequivalent study demonstrating, for example, the same therapeutic plasma concentrations with the oral administration of Trimidine Paste compared to the other products identified in his evidence. His response was that it would be a form of data that would be helpful, but he did not think it was necessary. Further in response he stated he wouldn't be any less certain or any more certain about the question. He went on to explain that if one wishes to prove efficacy then it is necessary to conduct a study which is based on sick horses, to see if the infection can be cured. He stated that is something that really not something that is ever done. Further, he observed that he did not believe such a study had been undertaken for any of the products, other than probably the very first one. His opinion was the subsequent generic products probably were partial studies of plasma profiled, as suggested. However, they are not necessarily efficacy studies. They are studies of plasma profile. Accordingly, scientific judgement is not used in all of these cases.
23. When pressed, Professor Pouton repeated that in his opinion, it was extremely likely that Trimidine paste would be bioequivalent to the other three products that the applicant already produced. Professor Pouton emphasised that the other products were approved at approximately the same time almost 30 years ago. The other products include two powder products and one paste product. The paste product, he observed, contains bromhexine, and one of the powdered products also contains bromhexine. He noted that other powdered products do not contain bromhexine. He summarised that the applicant is seeking to produce a paste product that also does not contain bromhexine. Professor Pouton presumes that the other products are efficacious as they have been in use for 30 years. Therefore, he was very confident that Trimidine paste would be efficacious. He stated, "That's really my position
24. Further, Professor Pouton also opined that there were five approved products containing the combination of sulfadimidine and trimethoprim. Such products contained identical proportions of the two drugs and are used the same dose. He further opined that the excipients included are commonly used in many pharmaceutical products. Therefore, he expressed a professional opinion that the product Trimidine paste would satisfy the safety criteria.
25. Professor Pouton stated that sulfadimidine and trimethoprim are well-established antibiotics which have a high therapeutic index. As such, the efficacy or toxicity of the drugs would not be expected to be sensitive to small changes in the rate of drug absorption. The efficacy of the product would also be a function of the absolute bioavailability. It is reasonable to expect that Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprim Oral Powder.
26. Therefore, he concluded that he expected that Trimidine Paste would be bioequivalent to the approved products, namely Trimidine Powder and Ilium Sulprim Boral Powder. Given that these approved products have been shown to be efficacious and safe, in his opinion it is reasonable to conclude that Trimidine Paste would to a reasonable degree, achieve the antibiotic effect sought, to prevent, cure or alleviate an appropriate disease or condition in a horse.

1. Dr Scott is a vastly experienced veterinarian. He has particular expertise in the field of veterinary pharmacology. Amongst other things, he has been a Member of the Australian and New Zealand College of Veterinary Scientists - Pharmacology Chapter for many years. He was previously the president of that Chapter. I also note his Curriculum Vitae for his specific qualifications, experience, roles and publications.[20]
2. The primary statement (or, as he entitled it, the "Declaration") made by Dr Scott is dated 1 October 2024.[21] It has a significant number of annexures to it.[22]
3. Dr Scott in his report of 1 October 2024, his subsequent declaration of 21 February 2025, and in oral evidence - expressed the opinion that, based upon his consideration of the various information and material before him, Trimidine paste meets the safety criteria.
4. In the analysis contained in his report of 1 October 2024, Dr Scott commenced by addressing each of the matters that the decision-maker must have regard to for the purposes of being satisfied as to whether a chemical product meets the safety criteria, as enumerated in s 5A(3)(a) of the Agvet Code.
5. Commencing with the question of the toxicity, Dr Scott identified the constituent components or parts of Trimidine paste. He explained that they were known substances each of which had been the subject of prior approvals, copies of which were in evidence. It was also recorded by Dr Scott that Propylene Glycol and Glycerol are both on the FDA "Generally Regarded as Safe" and on the Food Standards of Australia and New Zealand Food Additives list. Copies of that list were also in evidence.
6. Additionally, he referred to a product registered by the applicant called Bromotrimidine Paste, which included several components including those from which Trimidine paste as constituted. By reason of that analysis, Dr Scott concluded that the toxicity of the product and its residues, including metabolites and degradation products, in relation to relevant organisms (including human beings) and ecosystems are satisfactory from the perspective of safety.
7. Dr Scott then addressed the relevant poison classification of Trimidine paste. He concluded that the poison classification of Trimidine paste under the law in force in Australia would not prevent Trimidine paste product from being registered.
8. The next question addressed by Dr Scott was how the product was formulated. He observed that the respondent did not make any objection based on any considerations concerning the manner in which the product was formulated. Accordingly, he made no further observations concerning this question
9. Next, Dr Scott considered the composition of the form of the constituents of the product, any conditions to which the product's registration is, or would be, subject to, matters prescribed by applicable regulations, and concerns regarding safety. As the respondent's only objection raised in connection with these issues with the shelf-life data for a 1.2L pack size, Dr Scott offered no comment or objection regarding these issues.
10. Dr Scott then considered any conditions to which the product's registration is, or would be, subject to. It was recorded by him that the only objection concerning safety raised was in connection with the self-life data for the 1.2l pack size, and accordingly the respondent did not make any objection on the basis of any considerations on the proposed registration of the product, and he offered no further comment understandably.
11. Any relevant particulars that are, or would be, entered into the Register for the product were then addressed by Dr Scott. Apart from the objection raised as to safety concerning the shelf-life data of the 1.2l pack size, he noted no other objections were raised based on any considerations of the relevant particulars that are, or would be, entered in the Register for the product
12. In addressing whether the product conforms, would conform, to any standard made for the product under s 6E to the extent that the standard relates to matters covered by ss (1), Dr Scott observed that there was no established standard for Trimidine Paste.
13. With regard to any matters prescribed by the regulations, Dr Scott reiterated that the only objection raised was in connection with the shelf-life data for the 1.2l pack size. There were no other matters, or matters prescribed by applicable regulations concerning this product
14. Dr Scott then considered each of the matters that the decision-maker may have regard to for the purposes of being satisfied as to whether a chemical product meets the safety criteria, as enumerated in s 5A(3)(a) of the Agvet Code.
15. Concerning the acceptable daily intake of each constituent contained in the product, Dr Scott observed there had been no objection by the respondent relying upon this ground. He further stated that this is consistent with the position in Australia where there are several prior registrations for sulfadimidine/trimethoprim formulations where the ratio of 5:1 (sulfadimidine/trimethoprim) in the dosage of 30 MG of actives per KG of body weight per day being 25 MG/KG sulfadimidine and 5 MG/KG trimethoprim is used.
16. He then addressed any dietary exposure assessment prepared under s 82(4) of the Food Standards Australia New Zealand Act 1991 (Cth) because of any proposed variation notified under s 82(3) of that Act in relation to the product, and any comments on the assessment given to the respondent under s 82(4) of that Act. He noted that the only objection raised as to safety was, as already noted, concerning the shelf-life data for the 1.2L pack size. He also observed, which is hardly controversial, that in Australia horses are not kept for meat production for human consumption.
17. The next matter addressed by Dr Scott was whether any trials or laboratory experiments have been carried out to determine the residues of the product and, if so, the results of those trials or experiments, and whether those results show that the residues of the product will not be greater than limits that the respondent has approved or approves. Dr Scott repeated that the only objection raised as to safety was in connection with the shelf-life data for the 1.2L pack size. Accordingly, the respondent did not make any objection on the basis of residues. Further, he repeated that horses in Australia are not kept for human consumption so drug residue issues would not therefore have safety implications that would concern humans.
18. The stability of the product was the next mattered to be considered and addressed by Dr Scott. He repeated the objection concerning the shelf-life data for the 1.2L pack size. He also noted that no objection was raised in connection with the 32ml syringe, 60 ml syringe and 100g cartridges.
19. The specifications for the containers for the product was the next matter to be addressed by Dr Scott. Apart from repeating the objection concerning the stability data for the 1.2L pack size, he recorded that no objection was raised in connection with specifications for the containers for the product. Additionally, he recorded that the Final Chemistry Report based on the storage stability results provided concluded that the product was not expected to have an adverse effect on the packaging (30mg, 60g and 100g) and the packaging was not expected to have an adverse effect on the product.
20. Dr Scott then addressed such other matters as the decision-maker thinks relevant. Once again, he referred to the objection raised as to the stability data for the 1.2L pack size. He noted that the Final Chemistry Report at page 206, of Annexure DS-9, concluded that other than the shelf-life issue previously referred to, the draft label correctly stated the names and concentrations of the active constituents. It was further observed in that report that the label correctly states that the product is to be stored below 30°C (Room Temperature) and to protect from light. It also concluded the draft label was acceptable from a chemistry perspective.
21. A summary regarding safety was then included in that report. The matters referred to in that summary warrant repeating and are as follows:

(a) For the proposed pack sizes 30g, 60g, and 100g, in-use stability is satisfied. > > (b) There was no issue raised in relation to toxicity and the ingredients are well-known and safe for animal consumption in the proposed dosage amounts. > > (c) There appears to be no issue to resolve in relation to the safety criteria in relation to Trimidine paste. > > (d) This conclusion that the formulation for Trimidine Paste would be safe is consistent with the safety findings discussed in relation to other Australian registered TMPS formulations at paragraphs 19, 20, 24, 27, 28, 36, 37, 40, 41, 43 and 44 of Confidential Annexure DS-6. > > (e) Therefore, Dr Scott expressed the opinion and based upon his consideration of the materials referred to earlier in his report that Trimidine paste meets the safety criteria of the Agvet Code.

22. Dr Scott then turned to the Efficacy Criteria. In introducing this section of his report, he referred to the provisions of s 5B of the Agvet Code and of course s 6 of the Efficacy Criteria Determination. Each of the matters then referred to in s 6(b) of the Efficacy Criteria Determination were then addressed by him.
23. Dr Scott stated that s 6(b) of the Efficacy Criteria Determination allows for the efficacy of the veterinary chemical product to be demonstrated in several ways. He opined that there is more than one way that efficacy may be demonstrated, including by means of long clinical practice and scientific argument. Critically, and unlike Professor Mills, he expressed the opinion that there is a reason for not completing a bioequivalence study when what is being considered is a well-known generic formulation with widespread data showing its effectiveness. This is because the bioequivalence study would subject animals to stress and pain.
24. Dr Scott then expressed the opinion that in connection with the Trimidine Paste application the applicant had submitted:

(a) Valid scientific argument; and > > (b) Other relevant studies or data (including in respect of comparable products such as Bromotrimidine paste as well as referencing other registered sulfadimidine/trimethoprim registrations in Australia).

25. Dr Scott then canvassed a number of other matters in subsequent sections of his report. In a section entitled "Australian Registrations", he opined that the respondent did not give sufficient consideration to what he described as a well-known use of the active ingredients sulfadimidine and trimethoprim to treat infections in animals over many decades. He further observed that there are few formulations that have had such widespread and continuous effective use as trimethoprim/sulfadimidine formulations. In support of these contentions and opinions, he referred to a table that had been prepared summarising details of 12 Australian registered trimethoprim/sulfadimidine products and their active ingredients, the ratio of the active ingredients, the excipients used, the dosage and frequency of dose.[23]
26. Dr Scott then observed that prior registrations of similar veterinary products by the respondent reflected the tasks, and presumably investigations, it had undertaken in assessing other trimethoprim/sulfadimidine formulations. In his opinion therefore, the efficacy and safety of these formulations is a matter more easily established where there is such a long history of registration and use of such formulations. He then stated that it was worthwhile summarising such information in the present application for approval of Trimidine Paste as the same quantity of sulfadimidine and trimethoprim are included, in the same ratio and the same daily dosage, with both formulations sharing the excipients from Trimidine Paste which are Propylene Glycol and Glycerol and with both formulations in paste form. The information that he referred to in that section of his report comprised the subject headings "Pharmokinetics", "Minimum Inhibitory Concentration or MIC", "Bioavailability" and "Dosage Frequency".
27. With respect to Pharmokinetics, Dr Scott referred to paragraphs 1 to 19 of Annexure DS-5, being a "Primer on relevant scientific terms and concepts". These paragraphs explain the characteristics and history of use of sulphonamides and trimethoprim together. It was a most helpful document to someone not trained in pharmacology or related disciplines and the Tribunal would like to acknowledge the considerable assistance it gained from a consideration of it. In these paragraphs, Dr Scott referred to learned texts and articles. Dr Scott reported that combinations of trimethoprim and sulphonamides are typically used together in animal medicine and explained that they interfere with the synthesis of folate in bacteria. This process was explained in a process diagram in paragraph 12 of that primer.[24]
28. Dr Scott further observed that there are several scientific studies relating to the use, safety and efficacy of sulphonamides and trimethoprim formulations containing the same ingredients as Trimidine paste. Once again, in making this observation he referred to several publications.[25] These studies explain the long history of such formulations to treat infections in horses. They also demonstrated a high bioavailability of sulfadimidine and trimethoprim. Therefore, he concluded that they are efficacious. To further reinforce this opinion, Dr Scott compiled a table derived from publicly available information. He contended that the data contained in the table supports the finding of efficacy with respect to sulphonamides with trimethoprim in a ratio of 5:1 sulphonamide to trimethoprim and a daily dosage 25mg/kg for the sulphonamide and 5mg/kg trimethoprim. He also noted that in some studies a lower dose[26] was found efficacious and a higher daily dose was found to be safe.[27]
29. Dr Scott also opined that it is common to treat sulphonamides as a class of active ingredient for combinations of trimethoprim and sulphonamides formulations as they can usually be used interchangeably in the horse. He gave several examples derived from various sources is supported this contention. The details of those sources are referred to.[28]
30. Finally, concerning pharmokinetics Dr Scott explained the significance of the 1:5 ratio (trimethoprim to sulphonamide). When given together, trimethoprim and sulphonamides are combined in a fixed ratio of 1:5, regardless of the sulphonamide used, to maximise the synergistic effect of the two antibiotics.
31. With respect to Minimum Inhibitory Concentration ("MIC"), Dr Scott referred again to a table contained at Tab 1 of Annexure DS-7 of Australian registered trimethoprim and sulphonamides formulations, which was referred to earlier.[29] This table is derived from publicly available information. The products identified in that table all have a ratio of 5:1 of sulphonamide to trimethoprim. He also noted that the efficacy of such a formulation had been shown by a University of Sydney study (referenced on the Brotrimidine Paste label) to exceed the MIC required to treat a number of types of bacteria.[30]
32. Dr Scott then considered the question of bioavailability. He stated that the available evidence as to bioavailability of the active ingredients in sulfadimidine/trimethoprim formulations which had already been addressed in paragraphs 12 to 21 of Annexure DS-5 (referred to above) was supplemented by specific information that he had applied to the assessment of Trimidine paste. He referred to the contents of several paragraphs of Annexure DS-8 to that statement or declaration.[31]
33. In paragraph 15 of Annexure DS-8, Dr Scott observed when looking at the formulations of Trimidine paste and the reference product Trimidine powder, the active ingredients are exactly the same dose rate.[32] He explained the major formulation differences are the excipients. Thus, Trimidine paste has the active ingredients in a water-based solution whereas Trimidine powder is a solid powder with its excipients primarily giving bulk to the powder formulation. This, he stated, is relevant to bioavailability; release of active ingredients from the pharmaceutical form of an oral preparation depends first of all upon dissolution. With Trimidine paste, the ingredients are already in solution and so are readily available for absorption, but in Trimidine powder, they still must dissolve in the gastrointestinal tract before they become available. Therefore, Dr Scott opined that it stands to reason that the active ingredients in Trimidine paste are actually more readily available than those in Trimidine Powder.
34. On the question of dosage frequency, Dr Scott referred to the table containing the other Australian registered products, sub-joined to paragraph 20 of Annexure DS-5.[33] Other than the product Illium Sulprim Paste, the quantity of actives in the recommended daily dose was the same - being 30mg of active ingredients per kg of body weight, per day, and specifically 25mg/kg sulfadimidine and 5mg/kg trimethoprim. Bromotrimidine paste and Trimidine paste also share this dosage quantity and frequency. Referring to his observations in paragraphs 2 to 23 of Annexure DS-5, such trimethoprim/sulfadimidine formulations deliver a more powerful formulation than is needed to combat the kind of infections that usually respond to the medication. He considered that the respondent ought to have given such information significant weight when assessing whether the formulation "would to a reasonable degree alleviate an infection in a horse."
35. After addressing Australian Registrations, Dr Scott then assessed and gave opinions on several other matters which should briefly be referred to.[34]
36. Dr Scott commented on the letter from Professor Mills to the respondent dated 12 May 2022, which has already been disused. Dr Scott observed, as is self-evident from reading the letter itself, that Professor Mills did not explain the reasons for his conclusions in relation to the likely effect of the removal of Bromhexine (and Vanillin crystals and Polar Brilliant Blue.) The Tribunal took this as an implicit criticism of Professor Mills on this question. It was also noted by Dr Scott that where Bromotrimidine paste is used to treat infections, it was not proposed that Trimidine Paste be specifically stated to be used for respiratory infections. Showing an equivalent efficacy in relation to respiratory infections was, he stated, an incorrect assumption on the part of Professor Mills in the assessment of the efficacy of Trimidine paste. Dr Scott referred to the labels for the two formulations which specify precisely for what treatment they applied to. The Trimidine paste label states that is for the treatment of infections in horses, whereas the Bromotrimidine paste label states that it is for the treatment of respiratory infections in horses.[35] He also contended that it is clear from an examination of the information contained in the label for Bromotrimidine paste than it is the additional active ingredient Bromhexine Hydrochloride that provides the additional properties to target respiratory infections.
37. Dr Scott made some comments in his statement of 1 October 2024 concerning the "Efficacy and Target Animal Safety of Veterinary Medicines Risk Assessment" document, which was prepared by the respondent. Dr Scott took issue with the document recording that since bromhexine is a mucolytic, it could be expected to enhance the treatment of respiratory diseases, particularly when excessive mucus is being produced. He repeated, as he had with respect to the letter of 12 May 2022 from Professor Mills, that such a statement concerning the mucolytic effect of bromhexine disregards what the indications of the Trimidine Paste product actually are as described on the labels. It should be repeated that the labels for that product were contained in their entirety earlier in Dr Scott's statement. As he explained, Trimidine paste does not specifically refer to respiratory infections, and of course the applicant, as he noted, still markets Bromotrimidine paste for respiratory infections. On the other hand, Dr Scott explained that Trimidine paste is aimed at infections in other parts of the body that do not require a mucolytic and the addition of bromhexine is a superfluous for these applications. He further noted that the presence or absence of bromhexine is not relevant to the efficacy of Trimidine paste the non-respiratory infections. A prescriber, he stated will be aware of what Bromotrimidine paste does and whether the additional effect of bromhexine is required in any given case.
38. He was also critical of the concern in the Efficacy and Target Animal Safety of Veterinary Medicines Risk Assessment that the effect of any interplays between drugs on the bioavailability of Trimidine paste had not been addressed, despite food presence in the gastrointestinal tract having an effect on oral absorption. Dr Scott considered that this again missed the point that a paste is designed to be administered orally on an empty stomach. He considered that the paste would still have efficacy if given with food, though potentially less efficacy. Dr Scott went on to explain the effects of food on drug absorption. Firstly, there is the mass of the ingesta which can delay gut emptying, thus delaying drug absorption into the body, and secondly, the fact that some level of the chemicals can potentially absorb into the food, making them less available for absorption into the body.
39. Dr Scott then considered each of the studies referred to in the Efficacy and Target Animal Safety of Veterinary Medicines Risk Assessment. He identified five of those studies which he described as bearing "low or no weight for various reasons". He explained by reference to several matters including learned scientific literature why he disagreed with these conclusions. Other than to acknowledge this for the purposes of these reasons, it is not necessary to refer any further detail to this portion of Dr Stott's declaration of 1 October 2024. However, the details have of course been considered by the Tribunal.
40. Dr Scott then turned to what he described as evidence that was available in the included references that should have been given weight in the efficacy and safety of Trimidine paste. In this part of his declaration, he identified three such references.[36] The contents of that section of Dr Scott's first declaration are referred to and have been considered. He was critical of several statements in the Efficacy and Target Animal Safety of Veterinary Medicines Risk Assessment concerning the references. He described some comments as "flawed" or being a "flawed analysis". He also observed with respect to the article from the author Van Duijkeren (1994) et al J Vet App Pharmacol. Therap. 17, which concluded that when considering different formulations with different excipients, the specific formulation did not affect bioavailability. He considered this was a highly relevant point that was not observed by the assessor. It is fair to say that this observation by Dr Scott on this question, whether expressed in the learned article by Van Duijkeren or otherwise, was a significant point of difference between the professional opinions expressed by Dr Scott and Professor Pouton on the one hand and of course Professor Mills on the other.
41. The subject of the removal of bromhexine was then considered by Dr Scott.[37] For the reasons articulated in particular in paragraphs 24 to 26 of Annexure DS-5, amongst other things, he concluded the absence of bromhexine from Trimidine Paste would not have any impact on the efficacy of it with respect to the indication being "the treatment of infections in horses due to organisms susceptible to the combination of sulfadimidine and trimethoprim." He also stated that for reasons explained in Annexure DS-5, bromhexine does not have an antibiotic effect. He also repeated that as explained in paragraphs 24 to 26 of Annexure DS-5, bromhexine is readily absorbed into tissue and thus is unlikely to be present to impair bioavailability of trimethoprim and sulfadimidine.
42. With respect to vanillin crystals, Dr Scott relying upon his analysis contained in paragraphs 39-40 of Annexure DS-5, which need not be repeated for the purposes of these reasons but have been considered, concluded that their absence from Trimidine paste will not have an impact on its efficacy in respect of the indication "the treatment of infections in horses due to organisms susceptible to the combination of sulfadimidine and trimethoprim".[38] He also recorded that, as it would seem is self-evident, vanillin crystal is an excipient and does not have an antibiotic effect. He noted that the quantity of excipient is also too small for its removal to have any effect on efficacy or safety of Trimidine paste. Also, he noted the presence or absence of vanillin crystal will have no impact on either gastric emptying or absorption.
43. Finally, in his declaration, of 1 October 2024 Dr Scott addressed the absence of Polar Brilliant Blue.[39] For the reasons explained in paragraphs 41 to 44 of Annexure DS-5, which need not be repeated, he concluded that the absence of Polar Brilliant Blue from Trimidine paste will not have any impact on the efficacy of that product in respect of the indication of "the treatment of infections in horses due to organisms susceptible to the combination of sulfadimidine and trimethoprim." Like vanillin crystals, he observed that Polar Brilliant Blue is an excipient and does not have an antibiotic effect. Similarly, he observed that this quantity of excipient is also too small for its removal to have any effect on the efficacy or safety of Trimidine paste. Once again, he observed that the presence or absence of Polar Brilliant Blue will have no impact on either gastric emptying or absorption.
44. A further declaration or statement was made by Dr Scott on 21 February 2025.[40] It was made in response to the report of Professor Mills of 20 November 2024. In addition to being furnished with a copy of Professor Mills' report, Dr Scott was also provided with a collated bundle of documents which had been briefed or provided to the respondent's experts, together with the references in that report, and additionally the report of Dr Margerison.
45. Dr Scott's declaration of 21 February 2025 addressed two questions. Firstly, the removal of Bromhexine, and secondly the excipients.
46. On the question of the removal of bromhexine, Dr Scott summarised the conclusions of Professor Mills at paragraph 27 of his report of 20 November 2024. It is useful to reproduce the summary referred to by Dr Scott in that paragraph of his second declaration.[41] He recorded in paragraph 27 of Professor Mills' report he referred to the effects of Bromhexine "in isolation" (not words used by Professor Mills in that paragraph of his report) and made the following statements:

(a) Bromhexine can also cause gastrointestinal intolerance and impair the mucus barrier in the stomach; and what this means is that; > > (b) The presence or absence of bromhexine in a formulation will have a direct effect on the gastrointestinal system; > > (c) Which therefore directly impacts on the absorption of active drug when administered orally, i.e. will directly affect the PK of the other components in the formulation.

47. Dr Scott stated he did not agree that the second and third statements in the previous paragraph follow from the first statement for the reasons he then explained.
48. It was emphasised by Dr Scott that the first statement concerning bromhexine alone refers to gastrointestinal intolerance as something that can but does not necessarily occur. He then opined that if significant or problematic gastrointestinal intolerance typically occurred from oral ingestion of bromhexine, then it would be surprising for this substance to be an approved product on the Australian Register of Therapeutic Goods. He referred to Annexure DS-6 to his first declaration which contained product information for a product which included bromhexine hydrochloride and referred to its effects. Such effects he observed had not been an obstacle for registration of drugs such as Bromotrimidine Paste, Sulfa-B Paste or Bromotrimidine Powder. Relying on this analysis or this consideration, he concluded there is no reason why the exclusion of Bromhexine would have an adverse effect on gastrointestinal intolerance.
49. Then, in what seemed to be more a matter of argument or submission, rather than expert opinion, he observed that the first statement derived from paragraph 27 of Professor Mills' report referred to something that can happen (significant/problematic gastrointestinal intolerance), however the second statement then claims it because of this, the presence or absence of bromhexine in a formulation will have a direct effect on the gastrointestinal system. He stated that as a matter of logic, this does not follow.
50. It was emphasised by Dr Scott that for completeness, the stimulation of a vagal reflex because of "gastrointestinal irritation" is in his opinion speculative and for the reasons articulated previously in that section of his second declaration, if correct, is unlikely to cause significant/problematic gastrointestinal intolerance.
51. Therefore, Dr Scott concluded in the light of this analysis by him, the assertion by Professor Mills in the second part of paragraph 27 of this statement, as paraphrased, "the presence or absence of bromhexine in a formulation will have a direct effect on the gastrointestinal system", in the context of gastrointestinal absorption of a drug is unsupported.
52. Dr Scott then referred to paragraph 31(b) of Professor Mills' report and reproduced the paragraph in full. That paragraph referred to bromhexine as having specific activity in treating respiratory diseases and facilitating the penetration of antibiotics into lung tissues, so removing that active ingredient from a formulation would have a direct effect on efficacy for respiratory infections.
53. In response to that paragraph of Professor Mills' report Dr Scott referred to and repeated the contents of paragraph 75 of his first declaration which emphasised that it was not proposed that Trimidine paste be specifically labelled as to be used for respiratory infections. Further, showing an equivalent efficacy in relation to respiratory infections was an incorrect assumption in the assessment of the efficacy of that product. Further to this reference Dr Scott made two further points as follows:

(a) Combinations of trimethoprim and sulphonamides are useful for a wide range of infections for horses other than respiratory infections. There is no benefit to include bromhexine in a formulation that is used to treat these infections; > > (b) Combinations of trimethoprim and sulphonamides are prescribed by veterinarians, who will understand what conditions it should be prescribed for, and who will understand the label (which provide only general directions). By way of example, Dr Scott referred to the label for "Equibactin", which is a paste for horses that comprises sulphonamide and trimethoprim. Its label states that it is "For the treatment of bacterial infections in horses caused by organisms sensitive to the combination of sulfadimidine and trimethoprim." There is no additional note with respect to the treatment of respiratory infections. A copy of that label was annexed to his second declaration as Annexure DS-16.[42]

54. Dr Scott then, in his second declaration, addressed some aspects of Professor Mills' report concerning excipients.
55. Reference was made to paragraphs 33 to 40 of Professor Mills' report concerning excipients, and it was observed by Dr Scott that most of the contents of those paragraphs related to the function of excipients in solid dosage forms, including tablets, rather than liquid dosage forms which includes pastes.
56. Dr Scott then noted that the two excipients concerned namely Polar Brilliant Blue (0.008%), is a colouring and Vanillin (0.01%), is a flavouring. He then further noted that neither of those two excipients have the function of:

(a) Dissolution of a solid drug form (the drug form in this case is not solid); > > (b) Increasing or decreasing solubility in the gastrointestinal tract or elsewhere (the drug form is liquid, with or without these excipients, and the amount of the excipients is very small); > > (c) Degradation, reduction or increase in bioavailability of the drug (the very small amount of the excipients can also be noted in this regard); > > (d) Stabilising the drug (the very small amount of the excipients can also be noted in this regard); > > (e) Assisting in the manufacture and preserving of the drug (the very small amount of the excipients can also be noted in this regard).

57. Dr Scott then referred to paragraphs 35 and 36 of Professor Mills' report, in which Professor Mills addresses various commonly used pharmaceutical excipients, thought to be pharmacologically inert, showed effects on drug transporters and/or metabolic enzymes. Thus, Professor Mills, stated that the pharmacokinetics (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients are possibly altered by excipients which modulate the transport and metabolism of the drugs (Patel et al. 2020).
58. With respect to these observations by Professor Mills, Dr Scott stated that whilst the report references the possible effect of inhibition or activation of transport systems and enzymes, there is no reference either to Polar Brilliant Blue or Vanillin doing either of those things. Further, he stated that the Patel paper Professor Mills referred to, and which discusses problems connected with poorly absorbed drugs does not refer to flavourings or colourings, or for that matter Polar Brilliant Blue or Vanillin. Further combinations of trimethoprim and sulphonamides were not discussed as being poorly absorbed.
59. Several aspects of Dr Scott's oral evidence should be outlined. During one passage in cross examination, he was probed about his opinion that bioequivalence studies were not necessary because other similar products had been approved. It was put to him that those other products did not have the exact same formulation as Trimidine paste. Dr Scott reluctantly conceded they do not. He qualified this response by saying that he was really contending that there are other products on the market with and without bromhexine. He said they were bioequivalent to each other. He contended the evidence showed that bromhexine has little effect on the pharmacokinetics of the other active ingredients.[43]
60. It was put to Dr Scott that he did not have "hard data" to demonstrate that Trimidine paste is bioequivalent to the products he had referenced. He stated that was correct. However, he stated that the products would be bioequivalent because it had been shown time and again with other products. He referred to a learned article, which was in evidence before the Tribunal, to contend that the formulation concerned has little bearing on the bioequivalence of the availability of active ingredients on trimethoprim or sulphonamides drugs.[44]
61. Later in cross-examination, it was suggested to Dr Scott that there was scarce data concerning, for example, pharmacokinetics and bioavailability of this specific formulation of Trimidine paste. The next passage of cross-examination is worthwhile reproducing in full.

"And on this topic of scarce data, do you accept that there is also scarce data for-for example, pharmacokinetics, and the bioavailability of this specific formulation? Of this-you're talking about the ---

The Trimidine Paste-the specific formulation of the Trimidine Paste, alone. Not compared to anything else-just this specific formulation? Yes, I think, when you're looking at the specific compilation, reason why there is not a load of data in this formulation, is because it's a new formulation."[45]

1. However, he later qualified this response by pointing out that this line of questioning involves what he described as the "bromhexine argument". That argument the effects of the presence or absence of bromhexine. The formulation itself without bromhexine, for which he considered that there was enough data for the respondent to register the Bromotrimidine paste, with the excipients that it had in it.[46]
2. In another passage in cross-examination Dr Scott again conceded that there was no bioequivalence data. Then he contended that the argument is that there is enough bioequivalence data derived from all the other products on the market, to show that bromhexine has little effect. Therefore, the removal of bromhexine from this formulation, in his opinion, should have little effect on the kinetics. Further, he stated that the other active excipients in the product which are glycerol, in the propylene glycol are the major excipients. He pointed out that they are the same in this formulation and data had already been accepted by the respondent for previously registered products.[47]
3. Dr Scott accepted that for the product for which registration is sought, there is no data, for example, about whether the oral administration Trimidine paste would result in therapeutic plasma concentrations. He accepted there was no trial data to show that. He stated that it came down to scientific argument.[48] Reference was made to a confidential part of his report referring to several studies that dealt with the efficacy of the two antibiotic ingredients. That part of his report has been mentioned earlier.
4. Critically, it was then conceded by Dr Scott that in all the studies he had referred to that dealt with the efficacy of the two antibiotic ingredients, none of the subjects of those studies bore the specific formulations as the new formulation for Trimidine paste.[49]
5. Dr Scott further conceded that he accepted that there was no hard data to demonstrate that the oral administration of the Trimidine paste would result in the same therapeutic plasma concentrations as all the other registered products. Having accepted that fact that there was no hard data, he then stated that the whole crux of the matter is scientific argument. Then, acknowledging that there had not been a bioequivalence study, Dr Scott agreed that he is asking the Tribunal to accept his opinion as the scientific argument in this case.
6. Dr Scott repeated his concession that a bioequivalence study could possibly be done. However, Dr Scott feels a bioequivalence study was not necessary. However, he considered that this was not really a question for him, but a decision for the Tribunal. Further, he acknowledged that if a bioequivalence study was undertaken it would establish the relevant therapeutic plasma concentration. However, he repeated that in his opinion such a study was not necessary.
7. Dr Scott was asked, by reference to Professor Mills' report, whether he accepted that he was also providing a scientific argument. Dr Scott's response was that he had looked at Professor Mills' report quite closely, and Professor Mills had taken the position that everything needed to be done by trial work and testing, which in Dr Scott's opinion was not totally scientific. He further said that one can prove everything by science, but he did not believe that Professor Mills was using scientific argument itself. He contended that Professor Mills was using suppositions when he referred to the gastrointestinal intolerance, which he did not consider was the argument.[50]
8. To Dr Scott's credit he readily accepted that his opinion could be wrong, although he did not believe it was.[51]

1. Professor Mills, as noted above, is a Professor of Veterinary Pharmacology, and Head of Pathobiology in the School of Veterinary Science at the University of Queensland. He prepared a witness statement dated 20 November 2024.
2. Initially, as also previously observed, Professor Mills was retained by the respondent to review material provided by the applicant to change the formulation of Bromotrimidine paste (APVMA#: 46084) by removing bromhexine hydrochloride HCI (mucolytic agent 0.9%; 9mg/g), Vanillin crystals (for flavour; 0.01%) and Polar Brilliant Blue (for colour; 0.008%).
3. Upon completion of that review Professor Mills provided a report to the respondent agency on 12 May 2022 ("the review"). The review was of course in evidence before the Tribunal. Several matters referred to in the review were reiterated by Professor Mills in his November 2024 statement.
4. In the review, Professor Mills referred to a Pre-application Assistance ("PAA") report that had the respondent had given to the applicant. In the review, he reiterated that the PAA report stated that a major point of contention was that there was no information in the literature to demonstrate if and how the removal of the bromhexine would affect efficacy and safety. He further recorded that it was recommended that the applicant consider obtaining scientific evidence and/or an expert pharmacologist stating that the removal of bromhexine in the formulation of the proposed product would have no effect on the efficacy and target animal safety. Alternatively, a bioequivalence study could be performed.
5. Professor Mills also stated in the review that no clinical trial data was provided, and the application consisted of scientific papers and reports, plus two expert opinions from Dr Page and Dr Scott. However, the scientific information provided was inconclusive, and often non-specific. He acknowledged that although both expert opinions stated that the removal of bromhexine from the formulation would not affect efficacy or safety, he considered these opinions were not based on suitable scientific evidence. Consequently, Professor Mills stated that the application was denied since the information provided did not conclusively or scientifically demonstrate that the efficacy of the new formulation (Trimidine paste) would be the same as the currently registered formulation (Bromotrimidne paste). It is fair to say that this opinion is, to a significant degree, the fulcrum of this dispute between the parties.
6. It is appropriate to also reproduce some other opinions expressed by Professor Mills in the review. He further stated that while it could be expected that the removal of an active and two excipients may not affect safety, it certainly cannot be expected that efficacy will be unaffected. Efficacy, he opined will depend on absorption via the oral route (bioavailability) and oral absorption can certainly be affected by the presence or absence of bromhexine and two excipients. Bioavailability may not only be affected by drug interactions but may also be directly affected by gastrointestinal activity and secondarily affecting absorption. In effect, he opined that the applicant is stating that the pharmacokinetics, particularly oral absorption, will be unchanged with the removal of bromhexine (and Vanillin crystals and Polar Brilliant Blue), but have provided no evidence to support this claim. Furthermore, since bromhexine is a mucolytic, it could be expected to enhance the treatment of respiratory diseases, particularly when excessive mucus is being produced, while removal of this active raises concerns that a similar efficacy could be expected.
7. In summary, Professor Mills considered in the review that insufficient information had been presented to support the efficacy of Trimidine paste for registration in Australia.
8. The first two paragraphs of Professor Mills' report, or witness statement of 20 November 2024, reiterated the findings that he had expressed in the review. He then noted that the applicant had disputed his findings and the decision of the respondent to deny registration of the Trimidine paste.
9. He then made reference was to the letter of instruction that he received from the respondent's lawyers and the specific matters that he was requested to address in his statement.[52] The contents of that letter need not be reproduced, though it suffices to say that Professor Mills was requested to advise whether he agreed or disagreed with the conclusions of Professor Scott and Professor Pouton. Several issues or questions for his consideration referred to in the letter of instruction to him were highlighted by Professor Mills. The first question was:

"Would the chemical product Trimidine Paste, to a reasonable degree, achieve the effect of preventing, diagnosing, curing or alleviating a disease or condition in a horse, or curing or alleviating an injury suffered by a horse? ("the first issue")[53]

1. Reproduced by Professor Mills was a section of Professor Pouton's report that concluded as follows:

"I would expect that Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprim Oral Powder. Given that these approved products have been shown to be efficacious and safe, in my opinion it is reasonable to conclude that Trimidine Paste would to a reasonable degree, achieve the antibiotic effect sought, to prevent, cure or alleviate an appropriate disease or condition in a horse".

1. Further, Professor Mills considered that the question posed was too broad and non-specific, with an obvious difference between "alleviating" and "curing". However, he observed that when Professor Pouton addressed this question, he had made two comments that were unsupported and unscientific:

(i) That Trimidine Paste would be bioequivalent to the approved products, Trimidine Powder and Ilium Sulprim Oral Powder."

1. Professor Mills took issue with this opinion expressed by Professor Pouton. He did so because he contended that Professor Pouton had provided no evidence to support his stance regarding bioequivalence (BE), yet in Professor Mills' opinion bioequivalence is the cornerstone of generic medications. Further, he stated there are very clear and scientific guidelines to demonstrate bioequivalence (e.g. Martinez, 2010), which are clearly defined on websites for regulatory authorities, including the FDA and APVMA. Assessment of bioequivalence should therefore not be an opinion, but a consideration of pharmacokinetic ("PK") parameters, as contained in the applicable guidelines.
2. It was then explained by Professor Mills that a good example of why scientific guidelines must be followed can be seen from the review of Sulfatrim Oral Paste by the APVMA. The formulation was compared against a reference formulation, Airway TMPS Powder, and the results indicated equivalents in the amount of sulphadimidine absorbed between the paste and powder, but a higher bioavailability of trimethoprim from the paste. In short, he concluded the paste, and the powder were not bioequivalent, yet Professor Pouton suggested that Trimidine paste would be bioequivalent to the two approved products, Trimidine Powder and Hium Sulprim Oral Powder, following what he considered to be a cursory review of their respective formulations.
3. The next opinion of Professor Pouton addressed by Professor Mills in his witness statement was where Professor Pouton stated:

"(ii) It is reasonable to conclude that Trimidine Paste would to a reasonable degree, achieve the antibiotic effect sought, to prevent, cure or alleviate and appropriate disease or condition in a horse".

1. Professor Mills then emphasised that when he was reviewing Trimidine paste, he was working under the Agvet Code. Within that (as he described it) "general directive" he then assessed what was efficacious and safe.
2. He expressed the opinion that to determine efficacy and safety, a range of studies are performed, commencing with dose determination then dose confirmation. A series of laboratory/pen-based studies are then performed to determine PK parameters (for dosing intervals, etc) and preliminary efficacy and safety, particularly a Target Animal Safety study (guidelines for which can be found on the APVMA website). A series of clinical trials are then performed to confirm efficacy and safety. Alternatively, if a formulation is similar (generic) or undergoes minor alterations (such as some actives or excipients added or removed), efficacy and safety can be determined using a BE study, comparing the investigatory drug to a currently registered formulation (the reference formulation, which has already been assessed for efficacy and safety). This approach was recommended by the APVMA in the PAA provided to the respondent. It seems that seeking such data, information or evidence, however it may be described, certainly accords with what one would expect amounts to "valid scientific argument", as contemplated by s 6(b)(v) of the Efficacy Determination. He noted that such advice was not followed by the applicants, which presented scientific opinion that the removal of an active and two excipients would not affect the efficacy or safety of Trimidine paste as compared to Bromotrimidine paste (which was nominated as the reference formulation). Since this scientific opinion did not appear to be supported by definitive science, it was not possible to determine if efficacy or safety would be the same between the investigatory and reference formulations.
3. Professor Mills then addressed the question of the effects of bromhexine. In terms of the uptake of orally administered drugs' BE, he observed that bromhexine has a secretagogic effect on submucosal glands that occurs biphasically. The first phase results from the vagal reflux probably through a gastrointestinal irritation, and the second phase results from a direct action on the glands (Takeda et al, 1984). Brohexine in a formulation will have a direct effect on the gastrointestinal system, which therefore directly impacts on the absorption of active drug when administered orally - i.e. will directly affect the PK of the other components in the formulation.
4. He then undertook a review of the efficacy of bromhexine. He summarised his opinions on this question as follows:

(a) Bromhexine will affect the gastrointestinal system, which may affect the absorption honorary administered formulation. This will directly affect the PK parameters of other actives within a formulation also containing bromhexine. > > (b) Bromhexine has specific activity in treating respiratory diseases and facilitating the penetration of antibiotics into lung tissues, so removing this active from a formulation will have a direct effect on efficacy for respiratory infections.

5. Professor Mills then addressed the effect of excipients and changing formulation on PK. He stated that it is generally well accepted in the literature that changing a formulation, particularly by adding or removing excipients, can change the bioavailability of an orally administered formulation. He observed, however, that this appeared to have been refuted or disregarded by the applicant and its experts. He then proceeded to summarise in his report recent literature to support his contention that changing excipients in a formulation has a high potential to change the oral bioavailability of the active/s.
6. He noted that conclusions derived from previously reported articles have revealed that many commonly used pharmaceutical excipients, known to be pharmacologically inert, show effects on drug transporters and/or metabolic enzymes. Thus, the pharmacokinetics (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients are possibly altered because of the excipients' modulation to transport and metabolism (Patel et. Al. 2020).
7. Additionally, he recorded that excipients are generally pharmacologically inert but can interact with drugs in the dosage form and the physiological factors at the site of absorption to affect the bioavailability of a drug product (Panakanti & Narang, 2012).
8. Professor Mills concluded that several scientific studies (those he had listed above being a small example) have reported that many commonly used pharmaceutical excipients, known to be pharmacologically inert, may affect drug transporters and/or metabolic enzymes. Thus, the PK (absorption, distribution, metabolism and elimination) of active pharmaceutical ingredients within a formulation are possibly altered by the presence (or absence) of these excipients. This will have a direct effect on the efficacy and/or safety of the formulation since any changes in PK directly affects plasma drug concentrations of the actives.
9. Professor Mills was extensively cross-examined. It is appropriate to record some aspects of cross examination.
10. He was probed on several occasions as to his definition or understanding of the term "scientific evidence". He explained that his understanding of the term could include something that is very well accepted in academic or scientific literature or accepted, good scientific evidence. In response to another question, he stated that scientific arguments could include a bioequivalence study or other information. Additionally, Professor Mills stated that from his understanding, if an expert opinion were being presented, such as those presented by the applicant, it must be backed up by either science or something else that demonstrates such an opinion is valid, causing him to return to the concept of scientific argument.
11. Professor Mills was questioned about the initial refusal of the application by the respondent. He concurred that the reason for this was that there was no clinical trial data, scientific papers and reports tp support the application, and it was rather backed as expert opinions which he considered were inconclusive and non-specific. The material what was then lodged did not conclusively or scientifically demonstrate the efficacy of the new formulation would be the same as the currently registered formulation.
12. Some considerable time in Professor Mills' cross-examination, understandably, was devoted to the question of bioequivalence studies in the context of assessing whether the product concerned, to a reasonable degree, achieved the effect sought. He stated that if a bioequivalence study is undertaken it produces information regarding plasma concentrations over time. There are, he explained, limits of 90 to 120% confidence intervals. Therefore, within that range one can say whether the two drugs are the same or bioequivalent. He reiterated that it would not say that such drugs will be exactly the same because that is what is being interpreted within the context of the term "to a reasonable degree" however when one addresses several different ways of showing what a reasonable degree does, in his view include very defined scientific evidence.
13. Professor Mills also noted in response to another line of questioning that when one looks at pharmacokinetic parameters, one would expect both compared drugs to have the same cure rate. He also stated that information derived from overseas trials, even clinical case studies could amount to what is technically a bioequivalent study. Overseas trials could include all sorts of information.
14. An important passage in cross examination of Professor Mills commenced with the proposition being put to him that valid scientific argument, in the context of this application, does not necessarily require the definitive evidence of bioequivalence which he had referred to or contended in his several reports and earlier evidence. A detailed response followed.
15. He stated that it is comparatively easy for an applicant to get someone to write an expert opinion. He explained that anyone could have been paid to write an expert opinion. If regulatory agencies simply relied upon an expert's opinion, there would be a lot of generic drugs registered with no idea if they're actually safe or efficacious.[54]
16. Professor Mills emphasised that he had concerns anybody would think that an opinion was sufficient to justify registering a product. What he considered necessary, and wanted in support of that opinion, was what he described as rigorous science to support that opinion. He reiterated that the applicant's expert's opinions were that changes to Trimidine Paste compared to existing approved drugs would or should not affect bioavailability. He emphasised that bioavailability is a very big term. He explained that it means oral absorption. With any drugs administered orally, variability increases, and so anything that can affect efficacy and safety will affect it, because how the drug enters the body is meaningful. Professor Mills described bioavailability as a big term to consider.
17. Finally, Professor Mills stated that he had never required a bioequivalence test to be done. He stated he would be judging the data presented to him. He pointed out that a bioequivalence study was not done but, noted that Professor Pouton's expressed the opinion that he thought that Trimidine paste would be bioequivalent. Professor Mills emphasised that that, in his opinion, Professor Pouton's opinion was scientifically inappropriate. What he was looking for was valid scientific argument to show what the literature establishes that the new formulation of Trimidine is the same as the reference product. This had not been demonstrated with respect to the application presently before the respondent.[55]
18. Another part of the cross-examination of Professor Mills concerned the contrast between powdered and water-soluble products. He highlighted that even if you have the exact same products in a formulation that are a powder versus a paste, there is a potential, which he considered Professor Pouton confirmed, that there may be a difference in the uptake of the drug, which then directly affects its efficacy and potentially safety.[56]
19. Professor Mills was also asked about efficacy or toxicity, and it was suggested to him that the drug "would not be expected to be sensitive to small changes in the rate of drug absorption." Professor Mills disagreed with that proposition. He stated that there was a big "would not be expected" as soon as one talks about oral drug absorption, which is part of the bioavailability factor, and anything can change that. Therefore, he stated for him to express an opinion, which he observed that Professor Pouton was willing to do, that it wouldn't have such an effect, he as a reviewer could not take that opinion on face value. He explained he needed some demonstrative proof that it would not. If that was provided, he stated he would then be happy.[57]
20. Further, Professor Mills agreed in cross examination with the opinion expressed by Professor Pouton that the two drugs sulfadimidine and trimethoprim are well-established antibiotics with a high therapeutic index.[58] In this matter one should observe that such a conclusion is not controversial.
21. Professor Mills was briefly taken to the question of a reference product, and comparisons to, for example Trimidine powder and Illium Sulprim Oral Powder. He was asked what role the comparison had in his report. Professor Mills stated that the easiest way to explain this, probably for the benefit of all, would be as he described to give an example or anecdote. He referred to a drug on the market called "cyclosporine", which is an autoimmune drug. He described it as lowering the immune state for inflamed conditions. Apparently, there are more than five products of that type available on the market. Professor Mills explained that each of those products have the same amount of cyclosporine in them. However, they all have different amounts of drug coming through, so they're all different dose rates. So, despite being for the same indication, the same active drug, slight differences in formulation mean big differences in bioavailability, and therefore efficacy, so the dose rates are different. Professor Mills stated that he could say the same for all the matters presently before the Tribunal. If the formulation is not the same as per the guidelines for generic drug applications (which could include the excipients or the formulation form itself - i.e., powder versus paste) then there is some reasonable doubt that bioavailability will be the same. This was his point in his first report, which he made by looking through all the other literature provided.[59]

1. Dr Margerison is the Director of Chemistry and Manufacture, which falls under the respondent's Risk Assessment Capability Program. He worked for the respondent in various scientific assessment roles for more than 20 years. His specific experience relates to evaluating the chemical aspects of agricultural and veterinary products, including the chemical composition, analysis, manufacture and stability.
2. Dr Margerison prepared a report for the Tribunal dated 27 November 2024.[60] His report was divided into several sections. Of particular relevance to this application are the sections entitled "Stability considerations based on packaging type (syringes versus pails)," "Potential extrapolation of shelf life from powder products" and "Potential extrapolation of shelf life from Brotimidine Paste".
3. Dr Margerison's report considered the stability of packaging and shelf-life for Trimidine paste when stored in syringes or what was described as "pails". He noted that there were other important differences besides syringes and pails. The difference in headspace (the space between the top surface of the paste and the top of the container) between the 32ml, 60ml and 100g syringes and the 1.2L/1kg pale was considered significant. Whereas the syringes had negligible headspace, the pail does have headspace, and such headspace volume will grow with repeated opening and closing of the pail and withdrawal of the product over the shelf life. Therefore, because of the greater headspace and repeated opening and closing of the lid, the product stored in the pail will have greater exposure to the atmosphere than the product in syringes, which would be expected to increase the degradation of the product in the pail through oxidation (reaction of the product with atmospheric oxygen) and interaction with atmospheric moisture. Therefore, due to the differences in the headspace for paste products packed in syringes and in pails, he could not support extrapolation of a shelf life for Trimidine Paste stored in 1 kg pails from the shelf life supported for Trimidine paste stored in syringes.
4. Dr Margerison noted in the section of his report dealing with potential extrapolation of shelf life from powder products that the applicant considered the respondent had not placed enough weight on comparing Trimidine paste against two powder products Bromotrimidine Powder and Trimindine Powder, two products that have featured extensively in the evidence before the Tribunal.
5. Dr Margerison also reported that although the two powder products and Trimidine Placed all contain sulphadimidine and trimethoprim as active ingredients, (with Bromotrimidine paste additionally containing bromhexine hydrochloride), the non-active ingredients in Trimidine paste, he stated are "different from those in the two powder products."
6. He further stated that because of containing two different ingredients, the paste product and the powder products are expected to have different properties, for example different capacities to absorb atmospheric moisture, leading in turn to different rates of degradation due to hydrolysis (reaction of formulation ingredients, including the active ingredients, with water absorbed from the air).
7. Dr Margerison stated that given the different physical forms of the powder products compared with the paste products (a finely divided solid versus a finely divided solid suspended in liquid ingredients), means that the degree of exposure to the atmosphere is different. The different ingredients have been the capacity to absorb oxygen from the air would differ for powders and posts. Therefore, the rate of degradation due to oxidation would differ for powders and pastes.
8. For these resaons, Dr Margerison did not support an extrapolation from the stability of Bromotrimidine powder and Trimidine powder to determine the stability and shelf life of Trimidine Paste.
9. Finally, in his report, Dr Margerison considered the question of potential extrapolation of shelf life from Bromotrimidine paste. He noted that Bromotrimidine paste contains the same concentrations of the active constituents as Trimidine paste. Additionally, he recorded that the two products have a similar, but not identical, formulation base (the mix of non-active ingredients). Therefore, he considered that a shelf life could be extrapolated from Bromotrimidine paste to Trimidine paste when those products are packaged in the same sizes and types of containers.
10. Dr Margerison stated that given there is no stability data for Trimidine paste when stored in a 1 kg (or any other size) pails, a shelf life extrapolated from Bromotrimidine paste when stored in pails could not exceed the shelf life for Bromotrimidine Paste.
11. Dr Margerison also noted that the 1 kg pail is double the size of a 500 g pail. He observed that there are several consequences of a doubling of the pack size for a paste which can affect the stability of the product. These include:

(a) The ratio of surface area to fill volume; > > (b) The ratio of headspace to fill volume; > > (c) The ratio of contact area to fill volume; and > > (d) An increased number of broachings (openings) of the larger pack size over time, causing greater exposure to moisture and oxygen.

12. The changes in these parameters mean that the stability behaviour of Trimidine Paste in a 1 kg pail could differ from a 500gm pail (bucket).
13. Dr Margerison repeated that no stability data was provided for either Trimidine paste or Bromotrimidine paste in a 1 kg pack size. He also noted that the only available verified shelf life relevant to Trimidine paste when stored in pails is for a somewhat different product, for a shorter period of time than the shelf life proposed for Trimidne paste, when stored in a smaller pail.
14. Therefore, Dr Margerison did not support a 1 kg pack size for Trimidine paste based on the available information for Trimidine paste and Bromotrimidine paste, with either a 24- or 36-month shelf life.
15. In conclusion, Dr Margerison decided that he did not consider there was sufficient data or information to support the proposed 1 kg pail pack size for Trimidine Paste. On the other hand, he concluded that consistent with the chemistry assessment report for Trimidine paste he supported a shelf life of up to 24 months, with storage below 30c, for Trimidine paste in pails containing up to 500 gm of product.
16. Dr Margerison gave evidence at hearing. He adopted the contents of his report. He was probed on several issues in cross examination.
17. He was probed about statutory criteria, or "the governing legislation". He stated that there are several ways in which the statutory criteria could be satisfied. He stated it could be achieved by scientific data, or it could be done by scientific argument with reference to existing registered products. He also noted that a bioequivalence study between the proposed product in the reference products could be conducted. That is where a study is conducted to demonstrate that the two products would perform in the same way to the same standard.[61]
18. It was put to Dr Margerison that expert analysis could be sufficient in an appropriate case. He conceded that that could be correct. He reiterated in response to another question whether scientific evidence could be enough depending on what it is, that he agreed.[62]
19. In response to questions put to him concerning extrapolation of the products as described in his report, Dr Margerison gave explanations which amplify the conclusions contained in his report. He explained that Trimidine paste and Bromotrimidine paste, while share strong similarities in their formulations, are not identical. The effect of changing the formulation was not expected to have very significant effects on the stability, but in moving from a syringe to a pail or a tub, there are significant changes in the product's interaction with the environment. Dr Margerison also referred to factors such as humidity and light. Such products all have a different light permeability. He reiterated that the method closure of the packaging will be different. A syringe has a much smaller orifice where the paste is pushed through a little hole, so there is less exposure to the atmosphere when compared with a pail or a tub.[63]
20. When probed about the statutory test with respect to a 1 kg pail, Dr Margerison explained that the packaging would have relevance to both the safety and efficacy criteria for the decision-maker. If a product is not stable, it may lose potency. The active ingredient may degrade to a level where the product might have reduced efficacy. In those circumstances, the product may not then meet the statutory criteria.
21. Dr Margerison also emphasised that the product concerned is an antimicrobial or an antibiotic, so that if the levels of the product that are being administered to a horse are significantly below what the label says, the product then may not effectively treat the disease. So, the animal may not recover from whatever infection it is suffering from. Therefore, that could ultimately lead to a non-satisfaction with respect to the safety criteria because in giving understrength antimicrobials, antibacterials, and antibiotics to animals one could potentially be inducing antibiotic resistance or facilitating the growth of resistant microbes. That can have wider implications, not just for the animal being dosed, but also for other animals, and indeed humans, if these microbes are also pathogenic in humans.[64] This extremely important evidence given by Dr Margerison, a highly qualified and vastly experienced expert in chemistry, was not challenged and it is accepted by the Tribunal.
22. Dr Margerison was probed in cross examination about the probability of a 1 kg pail degrading as he described. It was suggested to him that degradation was more an outside risk that he couldn't discount, rather than the likelihood. He stated that it was probably somewhere in between the two. He stated he wasn't thinking in percentage terms when he made his recommendation. He then commented that adverse effects would happen, and he would put it more in the roles of a possibility than a likelihood.[65]
23. There were several other passages of cross examination that should be referred to. It was suggested to him in one line of questioning that nothing stood out in the excipients as a cause for concern. Dr Margerison replied that, as a chemist and as someone with some knowledge of pharmaceutical ingredients, there was nothing particularly out of the ordinary there in terms of an oral paste. He observed that it looked to be a functional product containing antimicrobial actives, that would certainly treat bacterial infections in horses. However, he said there were some questions that would need to be resolved by experts in other areas.[66]
24. Dr Margerison readily conceded that when conducting the exercise in question that the respondent was assessing a data dossier, and he acknowledged in this case that the respondent has such a dossier. He acknowledged that the respondent did have some data.[67]
25. In another passage of cross examination, it was suggested to Dr Margerison that if it was thought that the product for which registration was sought was identical or closely similar to a reference product the applicant would have fewer obligations to submit data upfront. He responded that was correct and explained that the respondent oversees a category of products called re-packs under the regulations. He explained that literally means the same factory is making the same product, on the same line, with the same ingredients putting it in the same container, with the same label. That label will then be placed on the container with brand X rather than brand Y and the different name, but other than that it is identical. He further acknowledged that the further one strays from that position the respondent would require more and more scientific argument, and/or data and advice.[68]
26. When probed on the excipients, Dr Margerison acknowledged that part of his assessment, and the skills that the respondent applies when conducting such assessments, he understood what the excipients are, what they do, and what they contributed. He also acknowledged that they understood their impact on the active ingredients. Further, he stated that it helps to have data on the formulation as a whole, because there are any number of combinations of ingredients and excipients that could be conceived.[69] In another passage of cross examination on this topic, Dr Margerison conceded that with respect to the excipients it was quite a simple formulation. He further stated the product looked to be able to be manufactured and reproduced to specification. He observed there was nothing out of the ordinary in the formulation for an oral paste for use in horses.[70]

1. The applicant contends that the safety criteria contained in s 5 of the Agvet code have been satisfied. In inviting the Tribunal to reach this conclusion it relies on several grounds.
2. There was the evidence of Professor Pouton in his several reports referred to above which was reiterated in oral evidence. Much of his oral evidence was derived from, or consistent with, his reports in evidence.
3. A reference in a letter initially sent by Professor Mills to the respondent on 12 May 2022, together with a response to a question in cross examination, was advanced to contend that the safety criteria had been satisfied with respect to Trimidine paste. It is appropriate to refer to the entire paragraph of the letter from Professor Mills to the respondent for contextual accuracy. He stated, "In my opinion the use of Trimidine Paste (92053-134286) according to the label instructions.... Would not be likely to have an unintended effect that is harmful to target animals."[71]
4. In cross examination, Professor Mills acknowledged that he had seen s 5 of the Agvet Code. He also acknowledged what he was asked to do in the letter of instruction to him from the respondent's lawyers. He also conceded that the necessary test was whether the product concerned is likely to have an unintended effect that is harmful to animals. Reference to the earlier report or letter from him to the respondent was made. It was put to him that in that report he observed that the use of Trimidine paste, according to the label instructions, would not be likely to have an unintended effect that was harmful to the target animals. He stated that he had already clarified that and observed that when undertaking the task, he assesses efficacy first and then safety. He reiterated he saw no reason for safety to be affected.[72]
5. Similarly, reliance was also placed by the applicant on the responses of Dr Margerison to several questions in cross examination. They emerged from a consideration of the statutory test in the context of a 1 kg pail and a 500 mg tub. The entire passage in cross examination should be referred to. The paragraph relied upon by the applicant at the end of that passage from Dr Margerison was that as for adverse effects he would put it more in the realms of possibility than a likelihood. The Tribunal notes that he certainly did not go so far as to say that the safety criteria were met in any part of the answers he gave in response to that passage of cross examination.
6. The Tribunal is not persuaded that this passage of cross examination of Dr Margerison relied on by the applicant enables the Tribunal to conclude that Dr Margerison considered the safety criteria had been met. It is also persuaded that Dr Margerison's evidence concerning the significant changes in a product that can occur when it interacts with the environment including such factors as outside temperature, humidity and light. It will be recalled that Dr Margerison felt that these factors potentially affect both the safety and efficacy criteria for the decision-maker. His emphasis on the fact that a product if not stable may lose its potency is important. He explained how, in such circumstances, an animal may not recover from whatever infection it is suffering from. This potentially could lead to a violation of the safety criteria. This is, as he said, because in giving understrength antimicrobials, antibacterials and antibiotics to animals one could potentially be inducing antibiotic resistance or facilitating the growth of resistant microbes. As he then stated, that can have wider implications, not just for the animal being dosed, but also for other animals, and indeed, humans. This evidence was not challenged. It is accepted by the Tribunal. Further, it is also considered by the Tribunal that this approach accords with the provisions of s 1A(2)(a) of the Agvet Code which provides that it is to be implemented in a manner that recognises that the health and safety of human beings, animals and the environment is the first priority of the system. This should not be overlooked.
7. With respect to both the safety criteria and the efficacy criteria, in various ways the applicant relied upon products previously registered by the respondent or products, described as "reference products" that had already been registered without evidence that such products were bioequivalent.
8. In its submissions it referred to "Regulatory Precedent" for five reference products being Bromotrimidine paste (46084), Trimidine powder (37721), Ilium Sulprim paste (62878), Ilium Sulprim powder (51718 and CaleSulpha-T paste (62149). It contended the only differences between these products and Trimidine paste related to what was described as the physical form and/or excipients. A table was produced in the applicant's closing submissions identifying the products and registration numbers, with the respondent describing whether registration was based on a bioequivalence study, together with notes concerning the registration details.[73] Of these reference products, Ilium Sulprim paste, and CaleSulpha-T paste were registered based on bioequivalence studies. These studies compared those drugs' paste formulations to powder formulations. It was noted that CaleSulpha-T paste was registered notwithstanding what was described as differences in Trimethoprim. Such difference was not readily identified. However, no point was taken about this in the application. It was noted that Bromotrimidine paste, and Ilium Sulprim powder were registered without requiring bioequivalence studies. Instead, what was relied upon was said to be established actives together with published and other data. Such data was not identified. Relying upon this evidence, the applicant submits that the existence of other formulations of potentiated sulphonamide products is relevant to both the respondent and the Tribunal as decision-maker in undertaking its assessment of the application for registration Trimidine paste. It was submitted that by reason of the prior registration such products are all presumed safe and efficacious.
9. Relying on evidence from several sources, the applicant provided what it described as a "Comparative Formulation Analysis" of a variety of approved products containing the combination of sulfadimidine and trimethoprim. The Comparative Formulation Analysis was distilled into tabular format according to several considerations. It was contended that from that analysis, that Trimidine paste is, at worst, closer to its reference products than the pastes that the respondent authority has already registered without evidence that the products are bioequivalent. Therefore, it was submitted this provides a further foundation for its contention that the refusal to register Trimidine paste is inconsistent with prior approval of similar products.
10. It is useful to refer to each of the tables referred to in the applicant's closing submissions lodged on its behalf.[74] Firstly, there was "Table 1-Actives, Ratios and Label Dose", (Applicant's closing submissions paragraph 35).[75] Relying on the evidence of Dr Scott and Professor Pouton, who opined that identical actives and ratio render Trimidine paste equivalent to TPw and Ilium Sulprim Powder and at least as effective as the pastes approved otherwise by the respondent. "Table 2-Excipients, Physical State", (Applicant's closing submissions paragraph 36). Relying upon the evidence of Professor Pouton, which was not challenged, it was said by Professor Mills the water-miscible excipients in Trimidine paste favour faster dissolution and less variable absorption and powders are royal suspensions. "Table 3-Regulatory Treatment", (Applicant's closing submissions paragraph 37). By reference to this table, it was contended on behalf of the applicant that the refusal to register Trimidine paste was inconsistent, having accepted what is described as a greater formulation divergence with respect to a product known as Randlab paste and Calesulpha-T paste. "Table 4-overall Comparative Assessment", based on above information (Applicant's closing submissions paragraph 38) contented that the contents of this table establishes that Trimidine paste is, at worst, closer to its reference product than the pastes already registered by the respondent without any evidence of bioequivalence.
11. In various ways, the applicant mounted a significant attack on Professor Mills' evidence based on his reports and oral evidence on the question of the safety criteria. It was contended that concessions made by him in cross-examination were such as to cause the Tribunal to reach the conclusion that his opinions carry very little, if any weight.
12. The Tribunal is unable to accept this contention. True it is that he was extensively cross-examined, and did time from time make certain concessions. These are the hallmarks of a good witness.
13. The Tribunal was persuaded that it should prefer the evidence of Professor Mills over Professor Pouton and Dr Scott on the question of whether Trimidine paste meets the safety criteria. It does so several reasons.
14. Reference has already been made to the evidence of Dr Margerison on the question of the safety criteria in the context of the potential for inducing antibiotic resistance or facilitating the growth of resistant microbes which was accepted as explained.[76] The potential for wider implications, not just for the animal being dosed, but also for other animals, and indeed humans, if these microbes are also pathogenic in humans is a significant safety issue within the meaning of s 5A of the Agvet Code.
15. There was evidence given by the other experts concerning the potential for outcomes such as antimicrobial resistance, that to a significant degree was in conformity with respect to the application of the safety criteria. This was highlighted by the respondent's closing submissions.[77]
16. Professor Pouton, in a passage in cross-examination, was asked whether he would accept that if the chemical product as administered to a horse were subtherapeutic it could result in outcomes such as anti-microbial resistance. He agreed. He accepted that this was an undesirable outcome. However, he qualified this response by stating he didn't think it was likely to happen because such antibiotics are given in a relatively high dose to guard against such an.[78] His acknowledgement of an outcome such as antimicrobial resistance was very similar to that of Dr Margerison.
17. Professor Mills, in an exchange during cross-examination concerning the question of either curing or alleviating a condition in a horse, disagreed with the proposition put to him. He further stated (quite emphatically) that when one talks about antibiotics, one must cure the infection. He stated curing the infection may alleviate some of the symptoms, but if one is not curing the disease, it has failed as an antibiotic. Further, and if one is not fully treating the disease, there is a risk of antimicrobial resistance developing.[79] This evidence, which was not challenged, largely conforms with the evidence given by Dr Margerison and Professor Pouton.
18. Dr Scott was asked in cross-examination that if he were wrong, for example, about the therapeutic impact of Trimidine paste, whether he accepted that one of the difficulties that might be caused with subclinical medication such as this, is that it could result in antimicrobial resistance. He responded candidly that there was a possibility of antimicrobial resistance. That answer was qualified by his further statement that it depends on one's understanding of microbial resistance. If the drug was not inhibiting the bacteria, it is not causing what he described as "selection pressure". So, one is, as he explained, opening up another massive argument currently prevailing in the "medical world".[80] Notwithstanding the subsequent qualification in his response, Dr Scott did not fundamentally retract his admission there was a possibility of antimicrobial resistance.
19. On the question of antimicrobial activity, reference should be made to some of the expert literature that was before the Tribunal. More is said about this later in these reasons when addressing the efficacy criteria.[81] However, in the article from Papich and Riviere, and Van Duijkeren, Vulto, Van Miert, it is noted that there is limited information about the antimicrobial activity of different sulphonamides and pyrimidines and their combinations against equine pathogens. As they acknowledge, there are still many questions to be answered. These observations accord with the evidence of the experts on this topic of the potential for antimicrobial resistance to develop referred to above. It does highlight the level of scrutiny that must be applied to an application such as this for Trimidine paste when determining whether the safety criteria contained in s 5A of the Agvet Code have been satisfied or met.
20. The Tribunal considers that in the material before it, the possibility of antimicrobial resistance which was explained in the evidence from each of the experts, has not been adequately addressed by the applicant with respect to Trimidine paste under the provisions of the Agvet Code. As was noted by Dr Margerison in his evidence, this may have wider implications, not just for the animal being dosed, but also for other animals and indeed humans, if these microbes are also pathogenic in humans. This is clearly a significant safety issue as contemplated by the definition of meeting the safety criteria enumerated in s 5A of the AGvet Code. It should be repeated that in section 1A(2) of the Agvet Code is to be implemented in a manner that recognises that health and safety and human beings, animals and the environment which is described in that section as a first priority of the system for regulating chemical products and their constituents.
21. Notwithstanding the significant and various attacks on Professor Mills', his contention that a major point was that there was no information in the literature or other technical or scientific data such as from clinical trials, to demonstrate if and how the removal of bromhexine would affect efficacy and safety was not effectively addressed by the applicant. True it is that opinions were expressed, and the Tribunal considers they were genuinely held professional opinions, by both Professor Pouton and Dr Scott, that it would not have any effect on the efficacy and target animal safety, but there was simply no, or insufficient scientific evidence or data, or for that matter a bioequivalence study, that verified these opinions. Put another way, there was not a sufficient scientifically based evidentiary platform or foundation to support such a conclusion or opinion. It therefore prefers the opinions on this topic expressed by Professor Mills.
22. Professor Mills also highlighted that there was no clinical trial data provided. He further observed that the scientific information provided was inconclusive and non-specific. The opinions initially from Dr Paige and Dr Scott he considered were not based on suitable scientific evidence. This difference of opinion, as noted earlier is still to a large degree the fulcrum of this dispute between the parties.
23. The Tribunal was also persuaded by the evidence of Professor Mills (which it does not believe was displaced by any of the evidence of the experts called by the applicant) that in order to determine efficacy and safety a range of studies are performed, commencing with dose determination then dose confirmation.[82] He explained in detail what those studies comprise of, as outlined above. Alternatively, it will be recalled, he stated that if a formulation is similar (generic) or undergoes minor alterations (such as some actives or excipients added or removed), efficacy and safety can be determined using a bioequivalence study, comparing the investigated drug to a currently registered formulation.
24. There was another feature of Professor Mills' evidence which the Tribunal considers significant in terms of preferring his evidence over that of the experts called by the respondent concerning the safety criteria. It will be recalled that he stated that it is generally well accepted in the literature that changing a formulation, particularly by adding or removing excipients, can change the bioavailability of an orally administered formulation. Whilst this conclusion was particularly challenged by the evidence of Dr Scott in his second declaration (where he explained the functions of the two excipients and took exception to the interpretation by Professor Mills of the Patel reference) he did not advance evidence, or perhaps more accurately other scientific literature, which provided an alternate conclusion, that ultimately enables the Tribunal to not accept this aspect of Professor Mills' evidence.[83] In expressing his opinion on this topic, Professor Mills also referred to six other learned publications which were not challenged by Dr Scott. It should also be observed that with respect to the "recent literature" referred to and summarised by Professor Mills in the section of his report concerning the "Effect of excipients and changing formulation on PK," he stated that the scientific studies he referred was but a "small example" of what must presumably be a significant volume of work on the topic supporting his conclusions.[84] Therefore, to a large degree this question was, as contended for by Professor Mills, not readily conceded or acknowledged by the applicant's experts and appeared to have been refuted or disregarded by them. Having accepted Professor Mills' evidence on this question concerning the effect of excipients and changing formulation on PK, the Tribunal considers that the applicant has not satisfied it that the chemical product for which registration is sought namely Trimidine paste has satisfied the safety criteria.
25. Having accepted this evidence from Professor Mills, it must be repeated that both Professor Pouton and Dr Scott in cross-examination conceded that none of the related products or similar products have the exact same formulation as the new formulation of Trimidine paste. This evidence also conforms with that given by Professor Mills and Dr Margerison on the question. Professor Pouton, it will be recalled, conceded in cross-examination that he had not provided data specifically comparing the rate and extent of absorption of sulfadimidine and trimethoprim from Trimidine paste in comparison with an approved product. Therefore, because there is a change of formulation which can affect the bioavailability of an orally administered formulation, the Tribunal (without more valid scientific data or information, as explained by Professor Mills, and as admitted by Professor Pouton was not provided) cannot be satisfied that both the safety and efficacy criteria have been met.
26. On the question of safety, it will be recalled that Professor Pouton concluded that he would expect Trimidine paste would be bioequivalent to the approved products, Trimidine powder and Illium Sulprim Oral powder. He opined that, given such approved products have been shown to be efficacious and safe, it was reasonable to conclude that Trimidine paste would to a reasonable degree achieve the antibiotic effect sought, to prevent, cure, or alleviate an appropriate disease or condition in a horse. There is much force in the submission of the respondent that in reaching this conclusory opinion, as he does, Professor Pouton does not identify and refer to any specific scientific literature, data surveys and the like derived from any recognised studies.
27. It will be recalled that each of Professor Pouton, Dr Scott and Professor Mills agreed that bioequivalence is the cornerstone of generic medications. It was even referred to on one occasion as the "gold standard". The Tribunal finds it difficult to accept Professor Pouton's conclusion that Trimidine paste would be bioequivalent to the approved products without an actual bioequivalence study being undertaken which would record, amongst other things, specific drug plasma concentration over times and the limits of percentage confidence intervals. Alternatively, if not a bioequivalence study, data obtained from conducting such investigations as clinical evaluations, clinical trials, or controlled or similar tests or surveys. These investigations would enable a determination to be made of whether the two drugs are the same or bioequivalent.
28. The applicant's contentions concerning "Regulatory Precedent" and its "Comparative Formulation Analysis", whilst at one level perhaps having some attraction in terms of addressing whether or not the safety criteria have been met, ultimately does not withstand scrutiny. Such contentions do draw some support from the evidence of the applicant's experts Professor Pouton and Dr Scott. In particular, Dr Scott engaged in a significant level of detail on these questions. However, the concessions made by both of those witnesses, which were in conformity with the evidence of Professor Mills and Dr Margerison, that none of those comparative reference chemical products had the exact same formula, persuade the Tribunal that such evidence should not be relied upon to reach the required state of satisfaction that the safety criteria have been met. It is persuaded by the evidence of Professor Mills on the effects of bromhexine and excipients of the changing formulation on pharmacokinetic parameters. As for bromhexine, Professor Mills concluded that the presence or absence of it in a formulation will have a direct effect on the gastrointestinal system, which therefore directly impacts on the absorption of the active drug when administered orally. I.e., it will directly affect the pharmacokinetic parameters of the other components in the formulation. It will be recalled that he concluded that changes in formulation will have a direct effect on the efficacy and/or safety of the formulation, since any changes in pharmacokinetic parameters directly affects plasma drug concentrations of the actives. There is simply no data, results of clinical trials, surveys or test results that might in some way address whether Trimidine paste meets the safety criteria of the same way as the previously registered chemical products referred to and relied upon by the applicant.
29. The language of s 5B(3) of the Agvet Code requires the Tribunal as decision-maker to be "satisfied" as to whether a chemical product meets the safety criteria. The term "satisfied" is well-known and construed in administrative law and decision-making. The Tribunal was referred to a recent decision of the Full Court of the Federal Court of Australia in National Disability Insurance Agency v Lampard which addressed how a decision-maker will be "satisfied" in various circumstances or situations.[85]
30. It was observed by the Full Court that to be "satisfied" there must be a state positive satisfaction or relative certainty which must be obtained in relation to each criterion specifically. Whilst there is not a formal onus of proof, an applicant does bear the practical onus of placing before the Tribunal as decision-maker or pointing to material before it, that can persuade it that each of the applicable criteria are met. The Tribunal considers in this matter the applicant has not done so for the reasons explained.
31. By reason of the foregoing matters, Tribunal is not satisfied that the chemical product known as "Trimidine Paste for which the applicant seeks registration, meets the Safety Criteria in 5A of the Agvet Code.

1. In contending that Trimidine Paste satisfied the efficacy criteria as prescribed by s 6 of the Agvet Code the applicant relied on several grounds.
2. The expert evidence of Professor Pouton and Dr Scott has been canvassed in some detail above. That evidence as summarised earlier in these reasons is referred to in its entirety. In summary, it will be recalled that Professor Pouton stated that he would expect Trimidine paste to be bioequivalent to other approved products, Trimidine powder and Ilium Sulprin Oral powder. In any event he said that there was no need to consider whether they are bioequivalent in relation to the availability of the antibiotics since there were three approved products that contain the same dose of the two antibiotics in the absence of bromhexine. Also, of course, there was his evidence that he was relying on his expertise and understanding of the two antibiotic ingredients in this specific product Trimidine paste to draw the inference that it was efficacious. Dr Scott gave similar and extensive evidence on the topic, both from his own knowledge and expertise, and by reference to scientific literature in which he identified several scientific studies relating to the use, safety and efficacy of sulphonamides and trimethoprim formulations. He emphasised the high bioavailability and concluded that they are efficacious.
3. However, there was a passage of Professor Pouton's evidence in cross examination, earlier referred to and which should be repeated, which causes concern with respect to whether the Tribunal can be satisfied from his evidence that the applicant has met the efficacy criteria for Trimidine Paste. He stated that, "...yes of course, we don't have a lot of certainty that this product is going to be efficacious. ... I think what we have is a lot of confidence". Whilst the Tribunal accepts that this evidence from Professor Pouton is a genuinely held professional belief, it does not fit hand in glove with the statutory test necessary to establish that the applicant has satisfied the requirements of the efficacy criteria as specified in s 5B of the Agvet Code. Confidence, which may well be legitimately held by a highly qualified and experienced expert witness, does not necessarily equal a valid scientific argument as required by the statutory mechanism.
4. Additionally, in the materials contained in the JTB there were a series of learned texts and articles on various aspects of the efficacy of the active ingredients contained in Trimidine paste.
5. The first of these publications was the text Veterinary Pharmacology and Therapeutics, (9th ed), Papich & Riviere. That text observes that potentiated sulphonamides at a 5:1 ratio of sulphonamide to trimethoprim are highly effective and have a high therapeutic index in horses. It is contended that this finding was supported by the following publications:

(a) Sulphonamides and Sulphonamide Combinations, MSD Veterinary Manual, 2015;[86] > > (b) Sulphonamides, Diaminopyrimidines, and their Combinations in Antimicrobial Therapy in Veterinary Medicine (5th ed) (2013) eds S. Giguere, J. F. Prescott and P. M. Dowling;[87] > > (c) Plumbs Veterinary Drug Handbook (6th ed) D. C. Plumb;[88] > > (d) Overview of the use of antimicrobials for the treatment of bacterial infections in horses. Equine Veterinary Education, E. F. Haggett and W. D. Wilson;[89] > > (e) Antimicrobial chemotherapy in the horse, P. B. English;[90]

6. It should be observed that the material contained in these publications did not, and it was not submitted on behalf of the applicant to that effect, contain any specific analysis of the exact same formulation of the chemical product for which registration was sought. This fact must, to some extent limit what support the applicant can draw from these articles in support of its application.
7. Otherwise, it is not necessary for the purposes of these reasons to engage in any detailed summary of contents of these publications. They observe, amongst other things, that sulphonamides are one of the oldest groups of antimicrobial compounds still in use today. Frequently, when used in horses, they are combined with other drugs including, relevantly for this matter, trimethoprim. They have been clinical use for well over 50 years. This is consistent with the evidence of Professor Pouton and Dr Scott, which was also acknowledged by Professor Mills, both in their reports and in their oral evidence. They have been commonly used for the treatment of susceptible microbial infections in horses, including the respiratory tract, urogenital tract, elementary tract, skin joints and wounds. These texts and articles also address the pharmacokinetics of sulphonamides. These include oral absorption, distribution, metabolism and excretion. Side effects of such drugs, including the combination of sulphonamides and trimethoprim were also described and considered. On the question of side-effects Papich and Riviere in the chapter of their publication that was before the Tribunal observed sulphonamides can produce a variety of adverse effects in animals.[91] They also noted that when trimethoprim-or ormetoprim-sulphonamide combinations are administered, the adverse effects are primarily attributed to the sulphonamide component. They identified a series of adverse effects.
8. Several observations warrant mention in the article by Van Duijkeren, Vulto, Van Miert, "Trimethoprim/sulfonamide combinations in the horse: a review". In the section reviewing "Phrmacokinetics" they record that there have been few studies published on the bioavailability of trimethoprim/sulphonamide combinations in horses. The Tribunal considers that such studies as referred to by those authors would fall within the definition of "valid scientific argument" within the meaning of s 6(b)(v) of the Efficacy Determination. One should observe that there was no expert evidence before the Tribunal that challenged that observation by Papich and Riviere and Van Duijkeren, Vulto, Van Miert in that article. It also highlights the need for a significant level of scrutiny to be applied by the respondent to an application such as this for registration of a chemical product under the provisions of the Agvet Code - in particular whether the efficacy criteria contained in s 5B of Agvet Code have been met.
9. In the section entitled "Discussion", Papich and Riviere and Van Duijkeren, Vulto, Van Miert reviewed the indications for use, side-effects, and pharmacokinetic parameters of trimethoprim, sulphonamide's and their combinations in the horse. They concluded from the papers they had reviewed that, although trimethoprim/sulphonamide combinations had been used extensively in equine medicine for more than 20 years, there are still many questions to be answered. They gave as an example, that in equine therapy many different sulphonamide's are used in combination with trimethoprim, although supporting information is mainly available for sulfadiazine and sulfamethoxazole. In addition, they noted that there is limited information about the antimicrobial activity of different sulphonamide's and pyrimidines and their combinations against equine pathogens. The sulphonamide's differ in their antibacterial potency and pharmacokinetic properties, and as a consequence their clinical efficacy will be influenced by the choice of the sulphonamide and its dosage regimen. They also identified another complicated factor as being the difference in pharmacokinetic distribution of the components.
10. Van Duijkeren, Vulto, Van Miert relevantly observed that there are few well documented efficacy studies of trimethoprim/sulphonamides combinations in the horse, and such studies are indispensable for rational therapy. Regarding the fixed combination of trimethoprim/sulphonamides and sulphonamide, the in vitro synergistic effect of the combination has not been confirmed in viro in the horse. In the clinical situation, the advantages of using the combination over the single components are not easily demonstrated, because when one of the components reaches its effective concentration at the site of the infection, the presence of the other component does not contribute to the beneficial effect (Bushby, 1980). Finally, they conclude trimethoprim/sulphonamides combinations are of great importance in the antimicrobial therapy of horses, but more research is necessary to establish optimum trimethoprim/sulphonamides combinations, improved drug formulations, routes of administration and dosing regimens.
11. The matters identified by Papich and Riviere and Van Duijkeren, Vulto, Van Miert and referred to in the previous two paragraphs concerning trimethoprim/sulphonamides combinations are highly relevant considerations in assessing the efficacy of Trimidine paste. The Tribunal considers they do bear upon the task it has to undertake in determining whether the efficacy criteria contained in s 5B of Agvet.
12. Of the learned texts, journals and articles that were before the Tribunal, including those of Papich and Riviere and Van Duijkeren, Vulto, Van Miert, another observation should be made. The articles concerned contain a vast array of scientific data derived from the authors' review and analysis of a wide variety of sources contained in academic and expert literature. Those sources include such things as the results of clinical evaluations, both controlled and non-controlled, clinical trial data, and a detailed statistical analysis in a table of the pharmacokinetics of sulphonamides derived from a wide variety of studies undertaken by eminent experts in the field of veterinary pharmacology[92] (Professor Mills stated that an assessment of bioequivalence involves a consideration of pharmacokinetic parameters). Data provided included percentages of the rate and extent of drug absorption (bioavailability) of, for instance, the drug trimethoprim, when orally administered to a horse on both empty and full stomachs. By way of example, Van Duijkeren, Vulto, Van Miert in the subsection "Absorption following oral administration" of the section in their article "PHARMACOKINETICS", provide details of a controlled protocol undertaken with six ponies, which found the bioavailability of sulfamethazine to be 84% when the drug was given in solution (160mg/kg) by nasogastric tube. They observed that this was consistent with earlier findings of a study that estimated 75% bioavailability after the administration of sulfamethazine mixed with speed at a dose of 6.5mg/kg to 10 horses. Their estimate was calculated by comparing pharmacokinetic data with previously reported i.v. data.
13. The point is that the degree of specialist data provided as a result of many intensive studies, surveys and various clinical trials do, in the view of the Tribunal, give some indication of the type of data and comparatively detailed information needed to underpin a contention that there is "valid scientific argument" (within the meaning of s 6(b)(v) of the Efficacy Determination) that the veterinary chemical product for which registration is sought therefore satisfies the efficacy criteria. This was stressed by Professor Mills both in his report and in his oral evidence, where it will be recalled he used such terms as the requirement for "clearly defined scientific evidence," "rigorous science", "demonstrative proof", "definitive science" and "I'm looking for valid scientific argument to show the literature is showing for these particular products and demonstrating that the new formulation Trimidine is the same as the reference product from Trimidine, and that wasn't there". This approach to the information or data required to satisfy the requirement to furnish valid scientific argument by Professor Mills is accepted by the Tribunal for several reasons. His evidence on this topic conforms with the matters identified in the Efficacy Guideline concerning scientific argument supported by science/data, the critical evaluation required of scientific papers and literature using the proposed final formulation manufactured (emphasis added) and the several other factors contained therein.[93] It is a comprehensive prescription. Also, such an approach the Tribunal considers conforms with the provisions of s 1A(2)(b) of the Agvet Code which provides that it is to be implemented in a manner that reflects established best-practice principles for the assessment and management of risk, based on science. Additionally, it is accepted because of the range of data articulated in detail in the literature before it, identifying what studies, clinical trials and other investigations can be undertaken, but also because Professor Mills explained why such data or information was required. The Tribunal considers that Professor Pouton and Dr Scott did not explain, or adequately explain, why such information or data was not required. To this extent, the Tribunal accepts the contentions of the respondent that a "valid scientific argument" is more than simply one expert's opinion based on subjective assumptions about the efficacy of a product. The applicant has not provided either to the respondent, or the Tribunal, scientific data, information or other evidence of the classes, categories or types recorded in the several articles and literature that was in evidence before it. Certainly, not of the breadth and detail, by way of example as recorded in the publications from Papich and Riviere and Van Duijkeren, Vulto, Van Miert as discussed above. Further, it has not provided information, data, results of clinical trials and like information as described by Professor Mills.
14. Selected aspects of answers that Professor Mills gave to questions in cross-examination were also targeted by the applicant as effectively corroborating or supporting the scientific platform or foundation relied upon by it. It is appropriate to briefly record those responses from Professor Mills relied upon as follows:

(a) He agreed that sulphonamides can be "rapidly absorbed from the gastrointestinal tract when administered orally"; > > (b) Although he did not accept that sulfamethazine and sulphadimidine were the same, he stated that, "the very slight differences will not change the efficacy overall"; > > (c) He agreed that the use of trimethoprim and a sulphonamide drug in combination, "is well established" and a large number of products have been "safely used for many years"; > > (d) He accepted that the antibacterials spectrum of the combination is broad and includes a high proportion of anaerobic bacteria; > > (e) He further accepted that the usual compounding ratio was five parts sulphonamide drug to one part trimethoprim; > > (f) He also accepted the validity of Professor Pouton's opinion that water-soluble TP paste is "likely to present the drug in a form more easily and consistently absorbed than the powdered formulations"; > > (g) He also accepted that sulphadimidine and trimethoprim are well-established antibiotics with a "high therapeutic index".

15. These answers provided by Professor Mills in cross examination are acknowledged. Such responses are consistent with evidence also given by Professor Pouton and Dr Scott. They also conform with the expert opinions and results that are reviewed in the literature that was in evidence before Tribunal, much of which has been addressed above. However, it does not, and cannot be construed in any way as meeting the requirement of "valid scientific argument" within the meaning of s 6(b)(v) of the Efficacy Determination which it will be recalled from the cross-examination of Professor Pouton is the only subclause of that statutory instrument which the applicant is relying on to advance an argument in its favour that it has met the efficacy criteria in s 5B of the Agvet Code with respect to Trimidine paste.[94]
16. Additional reliance was placed upon several passages of the cross examination of Professor Pouton, which have been referred to above. Those passages reiterated that he considered it was extremely unlikely that Trimidine paste would not be efficacious, and he could not really think of a reason why it would not be efficacious. Reference was also made to a response that he gave to a question in cross examination where he conceded that a bioequivalence study demonstrating, for example, the same therapeutic plasma concentrations with the oral administration of Trimidine paste compared to other products would be a form of data that would be helpful, but as noted earlier, he did not consider it necessary. Finally, in that passage of questioning he responded that he wouldn't be any less certain, or any more certain. With respect to the applicant's reliance upon this aspect of Professor Pouton's evidence the Tribunal cannot accept that it is the equivalent of "valid scientific argument" within the meaning of s 6(b)(v) of the Efficacy Determination.
17. As the respondent contended, from the perspective of the drafting formulation or textual context of that section, if as the applicant contends, "expert opinion", such as that expressed by Professor Pouton or Dr Scott, were sufficient for an applicant to satisfy the efficacy criteria, such language or words could have been incorporated in the text and applied according to their ordinary meaning or proper construction. However, this is not the case. The statutory instrument has identified a requirement to provide "valid scientific argument", as supplemented by Part 8, of the Efficacy Guideline, referred to previously. The obligation to implement the provisions of the Agvet Code as specified in s 1A(2)(b) in a manner that reflects established best-practice principles for the assessment and management of risk, based on science, also assumes significance in this context. One should observe that the intentional use of such language in the drafting of the clause of the Efficacy Determination creates a higher threshold to cross than one of merely an "expert opinion". For these reasons the Tribunal cannot accept this contention on the part of the applicant with respect to Professor Pouton's evidence on this question.
18. The applicant then further buttressed its contentions that Trimidine paste satisfied the efficacy criteria by relying on what it described as "Regulatory Precedent". Five reference products were identified which utilise identical actives and daily doses. It emphasised that the only differences between these products and Trimidine paste related to physical form and/or excipients. Of those five reference products, it was stressed that only Ilium Sulprimpaste and CaleSulpha-T paste were registered based on bioequivalence studies comparing their paste formulations to powder formulations. It was noted that Calesulpha-T paste was registered in spite of differences in the level of Trimethoprim. Bromotrimidine paste and Illium Sulprim powder were registered without requiring bioequivalence studies, relying instead on established actives and other published data.
19. It was submitted that the existence of other approved formulations of potentiated sulphonamides products is relevant to the assessment of Trimidine paste, because those products are all presumed safe and efficacious.
20. Another passage of cross examination of Professor Mills was emphasised by the applicant. It involved a review of a paste versus a powder approach used by the respondent leading to approval of a new formulation. This was relied upon to contend that the refusal of respondent to register the product Trimidne paste was inconsistent with its acceptance of what was described as "a greater formulation divergence" in Randlab paste and Calesulpha-T paste. It was contended that such precedents were contrary to, or did not support what was described as Professor Mills' "rigid interpretation".
21. On the question of "Regulatory Precedent" the Tribunal does not accept the applicant's contentions that this is an appropriate evidentiary platform or basis for finding that Trimidne paste satisfies the efficacy criteria. It considers that such matters are irrelevant, do not accord with the statutory scheme concerning the efficacy criteria created by the Agvet Code and are contrary to established principles of administrative law. As the respondent contends, the applicant's reliance on the fact that there are other approved products, as previously described, being Bromotrimidine Paste, Timidine Powder and Ilium Sulprim Oral Powder does not, and cannot establish that the requirements of paragraph 6 (b) of the Efficacy Determination have been satisfied. The respondent's submission that the mere fact that there are other chemical products with the same antibiotics does not mean that the efficacy of Trimidine Paste is "evidenced or demonstrated by", the classes or categories of data, studies, evidence or information as enumerated in paragraph 6 (b) of that determination, as supplemented by the provisions of the Efficacy Guideline previously referred to. The Tribunal also accepts the respondent's contentions that identifying, in written submissions, to earlier applications or processes that may have resulted in another product being registered several years previously cannot, on any view, let alone on the true and proper construction of paragraph 6 (b) of the Efficacy Determination, amount to "valid scientific argument".
22. The respondent in closing submissions referred to two authorities concerning the principles to be applied by the Tribunal as a decision-maker when addressing the questions for determination in an application such as this.[95] The first of those authorities being, Australian Postal Corporation v Oudyn, although it was applied in a different statutory context, does contain an accurate statement of the guiding principles to be applied by the Tribunal as follows:

(a) A decision-maker muster terminal for each distinct application whether "under one of more sections of the Act..... That section has been satisfied". Each decision "is a determination under that section and "it operates in respect of the claim then in existence ..... Under that section." "It does not operate as a bar to future claims." > > (b) The decision-maker "cannot bind itself in advance to reject [or approve] any future application on the basis of" and earlier determination "under a particular section of the Act".

23. The guiding principles as articulated in Australian Postal Corporation v Oudyn do conform with more recent observations in the High Court of Australia in Khalil v Minister for Immigration, Citizenship, Margaret Services and Multicultural Affairs.[96] That decision emphasised a well settled principle that an administrative decision-maker is required to make their decision on the basis of material available to them at the time the decision is made. The court further explained that such a principle is a reflection of the fact that there may be found in the subject matter, scope and purpose of nearly every statute conferring power to make an administrative decision, an implication that the decision is to be made on the basis of the most current material available to the decision-maker. Clearly, as was contended for by the respondent, this involves making a decision on the available contemporaneous material and law applicable at the time of such a decision. There is no authority to support a contention, as submitted by the applicant, that a notion of "regulatory consistency" or "regulatory precedent" can be determinative, or otherwise relied on to decide whether the efficacy criteria created by the statutory scheme under the Agvet Code has been satisfied with respect to Trimidine Paste.
24. For these reasons, insofar as the applicant relies on "regulatory consistency" or "regulatory precedent" as an appropriate evidentiary platform or basis for finding that Trimidne paste satisfies the efficacy criteria, it is rejected.
25. As is apparent from a review of the applicant's contentions outlined above, as submitted by the respondent, the applicant relies on two grounds to establish that it satisfies the efficacy criteria.
26. The first ground is that Professor Pouton and Dr Scott, in their reports, which include a review of learned literature, and of course their evidence at the hearing of the application before the Tribunal, establishes "valid scientific argument" as contemplated by all within the meaning of subsection 6(b)(v) of the Efficacy Determination.
27. The second ground relied upon is that of the "Regulatory Precedent" or as it was sometimes referred to throughout the evidence and submissions, "regulatory consistency". Therefore, the respondent, or in this instance the Tribunal as decision maker should register Trimidine paste, as has happened in the past with respect to reference products utilised actives and daily dose with the only difference being the physical form and/or excipients. In doing so such registration should be permitted relying on the applicant's contentions concerning what constitutes "valid scientific argument" and without requiring a bioequivalent study to be undertaken or not otherwise requiring bioequivalence. This ground has been addressed above, and rejected.
28. It is acknowledged that the term "valid scientific argument" is not defined in the Efficacy Determination. In addressing whether the applicant has provided "valid scientific argument" that supports the application for registration of Trimidine Paste reference should be made to paragraph 1.6.3 of the Efficacy Guideline. The language used in that paragraph of the Guideline is not difficult to construe or apply, and certainly not difficult to construe or apply to the material that has been produced by the applicant to the respondent, and this Tribunal when prosecuting this application. In the first paragraph of the Efficacy Guideline, it specifies that scientific argument is one supported by science/data. Additionally, it should be repeated that it states that when submitting published scientific papers an explanation of their role in the summary, so that the relevance of such additional data is explained to the reviewer.
29. The Tribunal does not, as it has explained above, accept that the opinions expressed by Professor Pouton and Dr Scott, which it acknowledges are genuinely held expert opinions based upon their unquestionable qualifications and vast experience. However, they did not produce science or data of the type contemplated by paragraph 1.6.3 of the Efficacy Guideline. The Tribunal has explained why it prefers the evidence of Professor Mills concerning the meaning of a valid scientific argument. Neither insofar as scientific papers or learned journals are produced, and referred to, is there an appropriate explanation of their role in such a way that the relevance of such additional data in reaching a conclusion that the efficacy criteria have been satisfied by the applicant with respect to Trimidine paste is explained to the reviewer or, as in this case, the Tribunal. Critically, and ultimately fatal to this application, any literature produced does not fit within the description of "literature using the proposed final formulation manufactured by or for sponsor".
30. In this context, it should be emphasised that Professor Pouton in his evidence before the Tribunal accepted that none of the other products - the "related products" or "similar products" - have the exact same formulation.[97]
31. Dr Scott, in his oral evidence, in answer to a question in cross examination, that in all of the studies dealing with the efficacy of the two antibiotic ingredients concerned, none of the specific product formulations, that are the subject of all of those studies, is the same as the new formulation for this product, for which the applicant is seeking registration.[98]
32. Dr Scott also conceded that he did not have any hard data to demonstrate that the oral administration of Trimidine Paste would result in the same therapeutic plasma concentrations, as for all of the other products that had been registered. Having accepted that there was no hard data he repeated that the whole crux of the matter is scientific argument.[99]
33. These concessions from Professor Pouton and Dr Scott (that the Trimidine paste does not have the exact or same specific product formulations as the related or similar products) the Tribunal considers are caught by the language of paragraph 1.6.3 of the Efficacy Guideline, meaning that its requirements to establish a "valid scientific argument" have not been satisfied. To this extent, it also accepts the respondent's contention that this conclusion or approach is in in accordance with the provisions of s 5(2) of the Agvet code which provides a veterinary chemical product is a substance or mixture of substances that is represented as being suitable for, or is manufactured, supplied or used for, administration or application to an animal. In this case the product for which registration is sought by the applicant comprises a "mixture of substances said to be suitable for administration to an animal".
34. Apart from the assistance provided in paragraph 1.6.3 of the Efficacy Guideline concerning the question of "scientific argument", the Tribunal accepts the contention of the respondent that the evidence of Professor Mills on this question during cross-examination should be accepted. A passage of his evidence should be reproduced as it is both self-explanatory and quite compelling.[100]

A passage from Professor Pouton's second report concerning his understanding of the term "valid scientific argument" in that context was read to him.

Mr Vincent then asked Professor Mills after reading that passage to him, "Valid scientific argument in this context does not necessarily require the definitive evidence of bioequivalence to which Professor Mills refers?

Well, there's quite a few things that probably need to be discussed when you're looking at all that. First and foremost, we've got the same point about prevention, cure, alleviate, so I won't go there again. Then wev'e got to look at what is valid. How do you determine valid? Now, as a regulatory agency, which the APVMA is, and as one of the reviewers for them, it's very easy for anybody to get anybody to write an expert opinion. Anybody could have been paid to write an expert opinion and they will provide their opinion. If a regulatory agency ever just relied on expert's opinion, we'd have a lot of generic drugs registered and no idea they're actually safe or efficacious."

"So I have concerns if anybody would think that an opinion is sufficient to justify registering a product, and what I would want for that opinion is good scientific support-rigorous science to support that opinion. So we are looking at that for valid scientific argument, and prevention, cure, alleviate we've covered, then what he's basically saying here is that they think their opinion is that it might not or shouldn't affect bioavailability, and bioavailability is a very term. It means oral absorption. Any drugs given orally, you can have much greater variability of everything, so anything that can affect that, will affect efficacy and safety because it affects how this drug goes into the body. That's a very big term to consider, and then finally, I never required a bioequivalence test to be done. I'm going to be judging the data presented to me. I pointed out that it was not done, but in several of Professor Pouton's comments, he thinks-he says, "I think it would be bioequivalent". That is scientifically inappropriate. I am looking for valid scientific argument to show how the literature is showing for these particular products and demonstrating that the new formulation Trimidine is the same as the reference product from Trimidine, and that wasn't there."

He was then asked_, "And don't you see room for an opinion to be the natural in point of a scientific argument?"._ His response was_:_

"Opinion can always be the natural end point that if the scientific argument is there in the first place, but for anybody to just write, "I don't think", or, "I believe they are bioequivalent", to be less totally inappropriate and very unscientific.

1. Whilst that passage from the cross-examination of Professor Mills speaks for itself, it does however highlight that any contention on the part of the applicant that the respondent exclusively requires the provision of a bioequivalence study is not correct. As was submitted by counsel for the respondent in closing submissions, he is saying that, in effect, far better data is required then just a conclusory opinion from two experts, as has been advanced by the applicant.
2. There is another reason advanced by the respondent, which the Tribunal agrees with, that concerns the difficulty facing the applicant in relying solely on expert opinions of Professor Pouton and Dr Scott, if they can be characterised indeed as "valid scientific argument". There is course that one opinion, or even several expert opinions obtained by the applicant can be contradicted by equally genuinely held valid expert opinions of others. The evidence of Professor Mills about obtaining expert opinions not being sufficient to justify registering a veterinary product referred to above has much attraction and is accepted by the Tribunal.[101] That evidence from Professor Mills was not addressed, or adequately addressed, and rebutted in any of the evidence given by either Professor Pouton or Dr Scott.
3. To reinforce this contention the respondent referred to a passage in cross examination of Dr Scott. It is worthwhile reproducing that passage from the transcript is the respondent did in its closing submissions. The passage is as follows:

"You accept that he has expertise, to offer an opinion about these matters, don't you? Absolutely, I do. Yes.

And you accept that if he has expertise, to offer an opinion about these matters, your opinion, to the contrary, could be wrong. Do you accept that? I accept that if we differ-if anyone has a different opinion, one of them has got to be wrong, yes.

I just want to be more precise about this. In circumstances where you accept that Professor Mills has sufficient expertise, to offer the opinions that he offers, with his expertise, and having given these opinions, you accept that your opinion to the contrary, it could be wrong? Yes, but I don't think it is, personally.

1. This concession, properly made by Dr Scott, that he could be wrong, does highlight that there can be an equally valid opposite or different opinion and, the blueprint or pre-requisites contained in the Efficacy Determination in adopting the language that it does in s 6(b) as supplemented by the Efficacy Guideline therefore does not mandate the provision of an expert opinion as a prerequisite to registration, but rather technical, scientific and to some degree statistical categories or classes of evidence, knowledge or information.
2. By reason of the foregoing matters, Tribunal is not satisfied that the chemical product known as "Trimidine Paste" for which the applicant seeks registration meets the Efficacy Criteria in s 5B of the Agvet Code.

1. Having concluded that the applicant has not satisfied the Tribunal that either the safety criteria in section 5A or the efficacy criteria in section 5B of the Agvet Code have been met, the reviewable decision is affirmed.

[1] A letter to the Chief Executive Officer of the applicant from the acting Chief Executive Officer of the respondent advising of the reviewable decision is at page 238 of the Joint Tender Bundle ("JTB"). The Statement of Reasons for the Decision is at JTB, 8.

[5] The notice referred to this section of the Agvet Code. There appears to be no such section. In any event nothing turns on it for the purposes of this application.

[9] There was in evidence a third report from Professor Pouton of 5 August 2025. Its purpose was to correct a reference in the second Pouton report to the Agricultural and Veterinary Chemicals Code (Efficacy Criteria) Determination 2014. In the view of the Tribunal nothing turns on the contents of this document.

[15] In fairness to Dr Scott further stated in that passage in cross-examination that the applicant had not done a bioequivalence trial because in his words it was, "almost like reinventing the wheel."

[23] Confidential Annexure "DS-7", JTB, 312.

[26] Detwiler, Straub, Heitman, & Gysin (1987)

[27] Wilson, Hammond, Clark & Ravis (1989)

[28] Paragraph 16 (a) to (e) of Annexure DS-5, JTB 152. Those sources are:

b) Antibiotic judicious use guidelines for the New Zealand veterinary profession-Equine 2018; (Dr Scott was the author of this document)

c) European agency for the evaluation of the distal products, veterinary medicines evaluation unit 2007.

d) Distribution of orally administered Trimethoprim and sulfadiazine into non-infected subcutaneous tissue chambers in adult ponies. Van Djurken et al (2002); and

e) Trimethoprim/sulphonamide combinations in the horses: a review by Van Duijkeren and Miet (page 2 to 5-234 of Annexure DS-10).

Each of them was in evidence before the Tribunal in the JTB.

[31] Specifically, to paragraphs 15, 28, 32, 33, and 45 of Annexure DS-8.

[32] Annexure DS-8 is at JTB 16. Paragraph 15 is JTB 168.

[34] Paragraphs 75 to 94 of Dr Scott's declaration of 1 October 2024. (JTB-1780-1786).

[35] Those labels were reproduced in paragraphs 27 and 28 of Dr Scott's declaration of 1 October 2024. The exact contents of those labels, which are quite extensive, are referred to for their full force and effect. (JTB 1762-1765).

[36] Paragraph 82 of his declaration of 1 October 2024. (JTB 143).

[37] Paragraphs 83 to 87 of his declaration of 1 October 2024. (JTB 144).

[38] Paragraphs 88 to 90 of his declaration of 1 October 2024. (JTB 144).

[39] Paragraphs 91 to 93 of his declaration of 1 October 2024. (JTB 145).

[41] Paragraph 8 of his declaration of 21 February 2025. (JTB 225)

[44] T 81, L25-37. 0The article was Van Duijkeren, Vulto, Van Miert, "Trimethoprim/sulfonamide combinations in the horse: a review". This article will be referred to in more detail later in these reasons.

[52] The questions were repeated in paragraph 4 of his report. They need not be reproduced for the purposes of these reasons.

[53] This question is of course derived from s 6 (a) of the Efficacy Determination.

[73] Paragraph 21 of the applicant's Closing Submissions of 29 August 2025.

[74] Applicant's Closing Submissions paragraphs 35, 36, 37 and 38.

[75] JTB, 24, Confidential Annexure DS-7-Tab 1.

[77] Paragraphs 45 48 of the respondent's closing submissions of 19 September 2025.

[82] At paragraphs 241 and 242 below when considering the application of the efficacy criteria, details of some of the scientific data derived from studies of the type identified by Professor Mills in his evidence, referred to in several learned publications in evidence before the Tribunal and authored by several experts including Papich and Riviere and Van Duijkeren, Vulto, Van Miert is considered. That analysis is referred to and repeated for the purposes of this aspect of these reasons with respect to the safety criteria and data or scientific evidence that could be produced to the respondent or the Tribunal as decision maker.

[83] Paragraphs 16 to 25 of the second declaration of Dr Scott of 21 February 2025 is referred to. (JTB, 226-228.)

[84] Paragraph 40 of Professor Mills' report of 20 November 2024.

[85] [2025] FCAFC 139 at [31].

[91] Veterinary Pharmacology and Therapeutics, (9th ed), Papich & Riviere, Chapter 33, Sulfonamides and Potentiated Sulfonomides.

[92] For instance, see Papich and Riviere, Table 3.3, JTB, 248 and Van Duijkeren, Vulto, Van Miert, Table 2, JTB, 276 which provide extensive details of the pharmacokinetic parameters or values concerned. Such data includes the species, dose (mg/kg), route, Vd (L/kg), t1/2 (hr), clearance (mL/hr/kg), protein binding and the reference, being the citation of the source contained in the literature from which such information was derived.

[93] It is appropriate on this question to reproduce in full that paragraph of the Efficacy Guideline concerning the provision of literature. It provides as follows:

"Literature using the proposed final formulation manufactured by or for the sponsor provides the best, most relevant evaluation and the highest evidentiary weight. Unless appropriate justification is provided, literature that does not use the final formulation of the proposed new animal drug product provides less weight in the evidentiary support scheme."

The Tribunal considers that there was no literature before it using the proposed final formulation (as admitted by the applicant's experts) of the chemical product for which registration was sought.

[94] Details of that cross examination of Professor Pouton are at paragraph 57 above.

[95] Paragraphs 62 to 64 of the respondent's closing submissions of 19 September 2025 are referred to.

[101] See paragraphs 166 and 167 above.