FEDERAL COURT OF AUSTRALIA

AFT Pharmaceuticals (AU) Pty Ltd v Reckitt Benckiser (Australia) Pty Ltd [2020] FCA 672

ORDERS

THE COURT ORDERS THAT:

1.    On or before 26 May 2020, the parties file and serve submissions in support of any application for non-publication of information contained in the reasons for judgment.

2.    On or before 4 June 2020, the parties file and serve short minutes of orders to give effect to these reasons.

Note:    Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

REASONS FOR JUDGMENT

GLEESON J:

Introduction

1    The applicant (AFT) seeks a declaration that there is an adequate scientific foundation for statements which appear in an advertisement for its analgesic product, marketed and sold in Australia, called “Maxigesic” (new advertisement). Maxigesic is an ibuprofen/paracetamol combination medicine, which contains 150mg of ibuprofen and 500mg of paracetamol in a single tablet.

2    In summary, the advertisement makes claims to the effect that Maxigesic provides “better and faster” pain relief than paracetamol or ibuprofen alone. AFT contends that a 2018 study published in Daniels et al., “Analgesic Efficacy of an Acetaminophen/Ibuprofen Fixed-dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, Parallel-group, Placebo-controlled Trial” (2018) 40(10) Clinical Therapeutics 1765 (Daniels 2018 study), and a substantial body of scientific evidence consistent with the Daniels 2018 study, provide the scientific foundation for its claims.

3    The proceeding was commenced in February 2019, after a finding that AFT contravened the Australian Consumer Law, being Sch 2 to the Competition and Consumer Act 2010 (Cth), by publishing other different advertisements for Maxigesic: Reckitt Benckiser (Australia) Pty Limited v AFT Pharmaceuticals (AU) Pty Limited [2018] FCA 1552 (2018 judgment); decision upheld on appeal: AFT Pharmaceuticals (AU) Pty Limited v Reckitt Benckiser (Australia) Pty Limited [2020] FCAFC 45 (appeal judgment). The 2018 judgment was based on a conclusion that representations contained in those other advertisements lacked an adequate scientific foundation.

4    The 2018 judgment did not consider the Daniels 2018 study.

5    The 2018 judgment addressed claims which compared Maxigesic with paracetamol and ibuprofen as monotherapies (that is, in a product containing a single active ingredient, an example of which is an ibuprofen product marketed and sold by the respondent/cross-claimant (Reckitt) under the name “Nurofen”), as well as claims which compared Maxigesic with other combinations of paracetamol and ibuprofen (and, specifically, “Nuromol”, another product marketed and sold by Reckitt).

6    The 2018 judgment principally concerned representations directed to comparative performance of the relevant drugs when taken at their respective maximum daily doses. The representations involving a comparison of Maxigesic with paracetamol and ibuprofen as monotherapies were:

(1)    when taken at their respective maximum recommended daily doses, Maxigesic provides stronger and more effective relief from pain than over the counter (OTC) doses of either paracetamol or ibuprofen alone (representation (3) in the 2018 judgment); and

(2)    Maxigesic reduces pain by at least 32% more than a full daily OTC dose of either paracetamol or ibuprofen alone throughout the period of administration of either drug (representation (4) in the 2018 judgment).

7    By order 12 of orders made on 29 November 2018, the Court imposed a permanent injunction on AFT restraining it from making the representation (among others) that, when taken at their respective maximum recommended daily doses, Maxigesic provides stronger and more effective relief from pain than OTC doses of either paracetamol or ibuprofen alone without an adequate scientific foundation for doing so (restrained representation).

8    Reckitt disputes AFT’s entitlement to the declaration sought on the basis that the claims made in the new advertisement do not have an adequate scientific foundation. Further, by its cross-claim, Reckitt alleges that the new advertisement conveys the restrained representation. Reckitt also contends that the new advertisement, and other advertising materials making similar representations, contravene the Australian Consumer Law because those representations lack an adequate scientific foundation.

9    Accordingly, the principal issue for determination is whether or not there is an adequate scientific foundation for the claims now made and the representations conveyed by AFT’s advertising materials.

Advertising materials

10    The advertising materials the subject of this proceeding comprise:

(1)    the new advertisement, which was published in pharmacy and dental trade journals in February and March 2019;

(2)    a training aid used by AFT’s sales staff, but which is not in itself distributed within the trade; and

(3)    point of sale (POS) materials.

11    The new advertisement and training aid are directed to health professionals, whereas the POS materials are directed to a wider audience including consumers.

12    The new advertisement and the training aid contain the following statements, for which AFT contends that it has an adequate scientific basis:

(1)    “maxigesic GET BETTER1 & FASTER1 PAIN RELIEF THAN PARACETAMOL OR IBUPROFEN ALONE1”;

(2)    A new clinical study of moderate to severe dental pain shows that Maxigesic® provides better and faster pain relief than both paracetamol and ibuprofen alone, at maximum dosage1;

(3)    “Faster onset of meaningful pain relief than for Paracetamol or Ibuprofen alone1.”

(4)    “Maxigesic® is a unique Paracetamol+ Ibuprofen combination that provides superior analgesic efficacy for patients than either Paracetamol or Ibuprofen alone1.”

(5)    “PROVEN TO PROVIDE MORE EFFECTIVE PAIN RELIEF IN A NEW CLINICAL STUDY”; and

(6)    “36% MORE EFFECTIVE THAN IBUPROFEN1 & 78% MORE EFFECTIVE THAN PARACETAMOL1”.

Footnote

13    AFT pleads that the reference denoted by “1” in both the new advertisement and the training aid reads as follows:

(a)    (in the middle of the page) “Daniels study results assessed on the intent-to-treat (ITT) population with adjustment for the use of rescue medication. Sensitivity analysis confirms primary endpoint independent of rescue medication adjustment1.” (mid-page footnote); and

(b)    (at the foot of the page) “References: Daniels SE, Atkinson HC, Stanescu I, and Frampton C (2018), “Analgesic Efficacy of an Acetaminophen/Ibuprofen Fixed­ dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, Parallel-group, Placebo-controlled Trial”, Clinical Therapeutics 40 (10): 1765 – 1776. Result achieved in a trial of post-operative pain relief after removal of at least 2 impacted third molars using Maxigesic® fixed-dose combination (Paracetamol 975mg/Ibuprofen 292.5mg) compared with Paracetamol 975mg or Ibuprofen 292.5mg alone 4 times a day (Paracetamol 3900mg or Ibuprofen 1170mg per day). Maxigesic® 975/292.5mg combination is bioequivalent to Maxigesic® 1000/300mg Australian combination at full dose (Aitken et al, J Bioequiv Availab, 10:5). Research sponsored by AFT Pharmaceuticals…” (bottom page footnote)

14    For its part, Reckitt admits that the text set out above appears in “very small” font on the face of the new advertisement; and says that the text is so small of itself and/or by comparison to the surrounding text and/or is placed in such a position on the advertisement that it would not be read by a casual or reasonable observer of the advertisement and/or otherwise would not and does not operate to qualify the statements to which the reference denoted by “1” is affixed in the advertisement.

15    The font of the mid-page footnote is not so small as to be unreadable. The use of the reference denoted by “1” in connection with the descriptors “better”, “faster” and “superior” draws attention to the mid-page footnote. A reasonable reader of the new advertisement would be likely to read out the mid-page footnote when considering the footnoted statements in the advertisement.

16    The font of the bottom page footnote is smaller. AFT submitted that the Court should approach the matter on the basis that some readers, likely the majority, would not read the footnotes (although some would read the footnotes). On that basis, I have considered the meaning of the new advertisement on the footing that the information in the footnotes would not necessarily form part of the context in which statements in the new advertisement are to be understood.

17    For those readers who would read the footnotes, AFT noted that the footnotes to all of the advertising materials contain:

(a)    a statement that in the Daniels 2018 study, the participants took the fixed dose combination medicine four times a day;

(b)    a statement based on the Aitken Study that a fixed dose combination of 975mg of paracetamol and 292.5mg of ibuprofen (Daniels FDC) is bioequivalent to a fixed dose combination of 1000mg of paracetamol and 300mg of ibuprofen (i.e. Maxigesic) at full dose; and

(c)    in the context of product safety, a direction not to exceed the daily recommended dose.

18    However, AFT submitted the footnoted content was of “little relevance to the identification of the representations conveyed”, observing that the statements which convey the disputed representations are not found in the footnotes, but rather in the body of the various advertising materials.

POS materials

19    The POS materials all contain the following statement:

GET BETTER PAIN RELIEF than Paracetamol or Ibuprofen alone1

Immediately adjacent to that statement appears a round badge which reads:

Based on a new study.

20    The reference denoted by “1” directs the reader to footnotes which read as follows:

References: 1. Daniels et al (2018). Research sponsored by AFT Pharmaceuticals. Result achieved in a trial of post-operative pain relief after removal of at least 2 impacted third molars using Maxigesic fixed-dose combination (Paracetamol 975mg/Ibuprofen 292.5mg) compared with Paracetamol 975mg or Ibuprofen 292.5mg along 4 times a day (Paracetamol 3900mg or Ibuprofen 1170mg per day).

Maxigesic 975.292.5 combination is bioequivalent to Maxigesic 1000/300mg Australian combination full dose (Aitken et al., J Bioequiv Availab 2018, 1:5). Always read the label. Use only as directed. Incorrect use can be harmful. If symptoms persist consult your healthcare professional. WARNING: Do NOT combine with any other Paracetamol or Ibuprofen containing medicines. Do not exceed the daily recommended dose. AFT Pharmaceuticals Pty Ltd, Sydney. Patent No. 2005260243.

Interlocutory orders

21    On 5 March 2019, I made an interim injunction which restrained AFT from distributing materials comprising training aids and stickers identified at pages 15 to 23 of annexure DGF-4 of the affidavit of David Fixler made on 4 March 2019.

22    On 27 March 2019, I adjourned Reckitt’s application for an interlocutory injunction, noting that AFT had given an undertaking which was, in summary, to refrain from publishing or distributing the new advertisement and the training aid, and to refrain from making the six statements set out at [12] above until 7 May 2019. On 29 April 2019, I noted that AFT had agreed to extend the undertaking until the conclusion of the final hearing.

23    At the conclusion of the final hearing on 25 July 2019, I made an order, upon Reckitt giving the usual undertaking as to damages, to the effect that AFT be restrained from publishing the new advertisement and any matter substantially similar.

Legal framework

24    The relevant legal framework is set out in the 2018 judgment at [18] to [41], including the relevant provisions of the Australian Consumer Law and principles as to what is an adequate foundation for claims of a scientific nature. Of particular relevance is the following statement in Reckitt Benckiser (Australia) Pty Ltd v GlaxoSmithKline Australia Pty Ltd [2018] FCAFC 138 (GSK) at [41]:

When evaluating whether there was an adequate foundation in the body of scientific knowledge to support the representations that were made, the primary judge did not err by taking into account the totality of the scientific evidence available at the relevant time. Further, the primary judge did not err by concluding that it would be misleading or deceptive, or likely to mislead or deceive, to make the impugned representations on the basis of the Schachtel Study alone, when the balance of the scientific evidence demonstrated no clear-cut superiority of ibuprofen over paracetamol in terms of faster and more effective relief from pain caused by common headaches including [tension-type headaches]. The body of scientific evidence, which took into account the findings of the Schachtel Study, but balanced them against the findings of other studies, did not support the making of simplistic comparisons of the kind found in Reckitt’s comparative advertising material. It was misleading for Reckitt to make the representations it did-which carried with them an unqualified and definitive statement of scientific fact-when the overall conclusion to be drawn from the scientific evidence was that no authoritative comparisons between active treatments were possible in the then state of scientific knowledge.

25    AFT argues that in GSK, the Schachtel study (referred to in the passage above) was an outlier, in contrast to its case where, AFT contends, the Daniels 2018 study is consistent with a substantial body of scientific evidence.

26    In the appeal from the 2018 judgment, AFT accepted that the legal principles had been correctly stated but argued that they had been misapplied. In the appeal judgment, the Full Court summarised the case that Reckitt was required to make, on the basis of those principles, as follows (at [8]):

Reckitt bore the onus of establishing that there was no adequate scientific foundation for the impugned representations and thus that they were misleading or likely to mislead. That did not require Reckitt to positively establish that, at their respective recommended daily doses, Maxigesic does not provide stronger and more effective relief from all pain than Nuromol and other OTC paracetamol/ibuprofen combinations. It was enough for Reckitt to establish that, taking into account the totality of the scientific evidence available at the relevant time, which included evidence going both ways, the balance of the scientific evidence did not provide an adequate scientific foundation for AFT’s simplistic representation that Maxigesic provides stronger and more effective relief from all pain than Nuromol and other OTC paracetamol/ibuprofen combinations, carrying as it did a representation that was an unqualified statement of scientific fact.

How advertising material should be interpreted

27    Reckitt made the following submissions, which were not contentious:

(1)    When considering whether advertising is misleading or deceptive, or likely to mislead of deceive, “the ‘dominant message’ of the material will be of crucial importance”: Australian Competition and Consumer Commission v Coles Supermarkets Australia Pty Ltd [2014] FCA 634 (ACCC v Coles) at [42], citing Australian Competition and Consumer Commission v TPG Internet Pty Ltd [2013] HCA 54; (2013) 250 CLR 640 (TPG) at [45]. In ACCC v Coles at [160], Allsop CJ stated:

… the courts should be astute and careful not to permit consumers to be misled on available meanings or connotations of phrases deliberately chosen to sell products on the basis that everyone takes advertising with a pinch of salt. To place emphasis on advertising licence that bends the truth will not only degrade the language, but lead to a culture of deception in the market. These matters do not elevate this case to a question of principle, but they should be borne in mind when broad laudatory language, intended to affect the buying decisions of members of the public, is such as to lead consumers into error and so to mislead or deceive, and the justification for such involves an intellectual shrug and a knowing nod to the effect that the public is cynical enough to look after itself…

(2)    While “[t]here may be occasions upon which the effect of otherwise misleading or deceptive conduct may be neutralised by an appropriate disclaimer”, the general rule is that “a person engaging in misleading or deceptive conduct cannot use the device of a disclaimer to evade responsibility, unless that disclaimer erases the proscribed effect”: iNova Pharmaceuticals (Australia) Pty Ltd v Reckitt Benckiser (Australia) Pty Ltd [2018] FCA 1209 at [25(1)]-[25(2)]. See also Australian Competition and Consumer Commission v Signature Security Group Pty Ltd [2003] FCA 3 at [26] and [27]; Medical Benefits Fund of Australia Ltd v Cassidy (2003) 135 FCR 1 at [37] ff and National Exchange Pty Ltd v Australian Securities and Investments Commission [2004] FCAFC 90 at [50], [51] and [55].

(3)    In assessing whether “qualifying” or “additional” material is sufficiently prominent or conspicuous, “it is appropriate to consider not simply the words or images depicted but also their relative emphasis (whether by print size, location, colour or other manner of presentation)”: Australian Competition and Consumer Commission v Harris Scarfe Australia Pty Ltd [2009] FCA 54 at [53]. Important matters will include “the way the asterisk is placed, the size of the footnote relative to the text in the body of the advertisement, and the terms of the footnote”: ibid, citing Trade Practices Commission v QDSV Holdings Pty Ltd (t/as Bush Friends Australia) [1994] FCA 1562 at [37]-[40].

(4)    As pointed out by Hill J in Tobacco Institute of Australia Ltd v Australian Federation of Consumer Organisations Inc [1992] FCA 630; (1992) 38 FCR 1 at 50:

Where… the advertisement is capable of more than one meaning, the question of whether the conduct of placing the advertisement in a newspaper is misleading or deceptive conduct must be tested against each meaning which is reasonably open. This is perhaps but another way of saying that the advertisement will be misleading or likely to mislead or deceive if any reasonable interpretation of it would lead a member of the class, who can be expected to read it, into error. …

Res judicata/Issue estoppel

28    Reckitt contended that the 2018 judgment considered “the body of scientific evidence in the context of the alleged superiority of Maxigesic over the monotherapies and found that it did not support the claims made.” Reckitt submitted that AFT was bound by that finding and precluded from re-opening that question by the operation of the doctrine of res judicata and or issue estoppel.

29    I do not accept the premise of this argument because it mis-states the case that was determined in the earlier proceeding. Relevantly, that case was not simply the alleged superiority of Maxigesic over the monotherapies, but the narrower issue of whether there was an adequate scientific foundation for the restrained representation, which concerned the superiority of Maxigesic over the monotherapies “when taken at their respective maximum recommended daily doses”.

30    In contrast, as appears below, and although Reckitt does contend that the restrained representation is made by the advertising materials now in issue, AFT is bringing a case about claims that are different from the restrained representation. In turn, Reckitt’s cross-claim pleads representations apart from the restrained representation. For example, the agreed representation, that Maxigesic is more efficacious than paracetamol or ibuprofen alone, is broader than the restrained representation in that it is not confined by any dose or dosage period.

31    The concepts of res judicata and issue estoppel were explained by the High Court in Tomlinson v Ramsey Food Processing Pty Ltd [2015] HCA 28; (2015) 256 CLR 507 (Tomlinson) at [20]-[23].

32    In summary, the doctrine of res judicata provides that where judgment has been entered on a cause of action, no proceeding can thereafter be maintained on the same cause of action: Jackson v Goldsmith [1950] HCA 22; (1950) 81 CLR 446 at 466. The doctrine requires focus on the substance of the two proceedings: Trawl Industries of Australia Pty Ltd v Effem Food Pty Ltd [1992] FCA 272 at [51], [53]; that is, whether the controversy in the proceeding was determined in the first proceeding: Re Twenty-First Larena Pty Ltd; Maximova v Goodwin & Ors [2010] VSC 84 at [23].

33    In this case, having been unsuccessful in the 2018 judgment, AFT now seeks to argue that there is an adequate scientific foundation for claims made in a new and different advertisement that had not been published at the time of the 2018 judgment. AFT also seeks to argue that there is an adequate scientific foundation for new and different representations upon which Reckitt founds new claims for relief.

34    This proceeding can be characterised as a further iteration of a single controversy between AFT and Reckitt about whether AFT has an adequate scientific basis for its advertising of Maxigesic. However, once it is accepted that AFT’s disputed advertising materials contain materially different claims and representations, it is impossible to conclude that the 2018 judgment disposed of the issues raised by those materials or that the current proceeding involves a re-litigation of the earlier proceeding. In that sense, this proceeding concerns a new controversy.

35    Accordingly, AFT is not now seeking to rely on a cause of action that has merged in the 2018 judgment and is not precluded by the doctrine of res judicata from either bringing its primary claim or defending Reckitt’s cross-claim by reason of the earlier judgment.

36    Issue estoppel operates to preclude the raising in a subsequent proceeding of an ultimate issue of fact or law which was necessarily resolved as a step in reaching the determination made in an earlier judgment (Tomlinson at [22]). In Blair v Curran [1939] HCA 23; (1939) 62 CLR 464 at 532, Dixon J explained:

The distinction between res judicata and issue estoppel is that in the first the very right or cause of action claimed or put in suit has in the former proceedings passed into judgment, so that it is merged and has no longer an independent existence, while in the second, for the purpose of some other claim or cause of action, a state of fact or law is alleged or denied the existence of which is a matter necessarily decided by the prior judgment, decree or order.

Nothing but what is legally indispensable to the conclusion is thus finally closed or precluded. In matters of fact the issue estoppel is confined to those ultimate facts which form the ingredients in the cause of action, that is, the title to the right established.

37    The 2018 judgment resolved the factual issue of whether there was an adequate scientific foundation for, relevantly, the restrained representation. It did not resolve, for example, the factual question whether there is an adequate scientific foundation for the representation that Maxigesic is more efficacious than paracetamol or ibuprofen alone. Nor did it resolve the factual issue of whether there is now an adequate scientific foundation for the restrained representation because the science has evolved and, specifically, now includes the Daniels 2018 study.

38    In particular, I do not accept Reckitt’s argument that all of the representations the subject of this proceeding are relevantly identical to the restrained representation. If that were the case, Reckitt’s cross-claim would lack utility to the extent that it pleads other representations, to say the least. However, I do not consider that Reckitt’s cross-claim lacks utility because I accept that it pleads new causes of action based on new and different representations.

Representations

39    AFT accepted that the following representations were conveyed by the advertising materials:

40    Reckitt contended that the first representation is also conveyed by the POS materials.

41    Further, Reckitt contended that the following additional representations are conveyed:

(1)    by all advertising materials, the restrained representation, that is, that Maxigesic provides stronger and more effective relief from pain than OTC doses of either paracetamol or ibuprofen alone when taken at their respective maximum recommended daily doses; and

(2)    by the new advertisement and the training aid, that Maxigesic provides faster onset and more meaningful pain relief than for paracetamol and ibuprofen alone.

POS materials: more efficacious representation

42    Reckitt contends that in the context of the POS materials, “better” is synonymous with “more efficacious” and thus, the alleged representation of more efficacy is effectively the same as the conceded representation of better pain relief.

43    Reckitt noted that the 2018 judgment contains the following reasoning at [89], in relation to other advertising materials which included the statement “GET BETTER PAIN RELIEF than Paracetamol or Ibuprofen alone” (albeit footnoted by a reference to a study referred to as the “Merry study”):

... “better pain relief” could be understood by a reasonable member of the relevant class of readers to mean superior strength and efficacy, as the qualities of strength and effectiveness are qualities that are likely to make one form of pain relief better than another. In the absence of any qualifications, in my view, such a reasonable person could reasonably understand that this representation applies without any qualification ...

44    AFT contended that Reckitt’s argument “departs from the express wording of the POS materials, but does so without any evidentiary support or textual support” and submitted that the alleged representation “expands the meaning of the POS materials in a manner that has no support in the evidence”.

45    I do not agree. A pain relief product is purchased in most, if not all, cases for its efficacy as a remedy for pain. Accordingly, a reasonable consumer is likely to understand the claim “better pain relief” to amount to a representation that Maxigesic is more efficacious.

Restrained representation

46    Reckitt contended that the advertising material uses the same language as provided a basis for the finding that the restrained representation was made in the 2018 judgment (namely “GET BETTER PAIN RELIEF than Paracetamol or Ibuprofen alone”: see 2018 judgment at [85]). Reckitt noted that the words “and faster” are interposed between “better” and “pain relief” in the new advertisement and the training aid, but submitted that this makes no difference of substance.

47    It was not clear whether AFT disputed that a reasonable reader could understand the advertising materials to make a comparison between the relevant drugs “when taken at their respective maximum recommended daily doses”.

48    In my view, at least a reasonable reader who was able to read the bottom page footnote could understand the materials in that way because of the description of the trial dosages on a daily basis (that is “Maxigesic® fixed-dose combination (Paracetamol 975mg/Ibuprofen 292.5mg) compared with Paracetamol 975mg or Ibuprofen 292.5mg alone 4 times a day (Paracetamol 3900mg or Ibuprofen 1170mg per day)”.

49    Further, Professor Anthony Keech, an expert in relation to the conduct of clinical trials, gave uncontested evidence on behalf of Reckitt that the packaging of Maxigesic refers to dosage over a 24 hour period only. Dr Marc Russo, a specialist pain medicine physician who gave evidence on behalf of AFT, also said that there is “one concept of [sic] Maxigesic can be taken as a maximum of two tablets every six hours, not exceeding eight in a 24-hour period”. Accepting that at least some readers of the advertisement are likely to be familiar with the packaging or the concept described by Dr Russo, that provides another basis for a reasonable reader to understand the words “at maximum dosage” to refer to the maximum recommended daily doses.

50    In saying this, I note that Dr Russo’s evidence was that a reasonable pharmacist would not understand that the asserted benefits of Maxigesic would apply after taking the drug at its maximum dosage for 24 hours. Dr Russo said that such a reader would necessarily conclude that the maximum dosage would be related to the time periods specified in the study, because it is obvious from the advertising materials that they are to be understood in the context of the Daniels 2018 study.

51    Although I generally found Dr Russo to be a very impressive witness, I do not accept his evidence on this point which goes beyond his expertise as a pain physician. As his evidence revealed, maximum dosage of Maxigesic is generally measured on a six hourly basis and a daily basis. By not being more specific, AFT left it open to a reasonable reader of the relevant class of readers (noting that this class varies as between the different advertising materials) to conclude that “maximum dosage” referred to the maximum recommended doses.

52    AFT noted that, in contrast with the promotional materials addressed by the 2018 judgment, the word “stronger” is not used in the advertising materials under consideration in this proceeding. AFT submitted that the 2018 judgment was made on evidence that included evidence about the meaning of the word “stronger” in the context of the relevant promotional materials, and that no such evidence was adduced in this proceeding.

53    In my view, a reasonable interpretation of each of the advertising materials includes a claim in the terms of the restrained representation. In the cases of the new advertisement and the training aids, the interpretation arises from the references to “better” pain relief, “superior analgesic efficacy” and “more effective pain relief” because “stronger … pain relief” is one of the things that a reasonable reader might think would be entailed in those claims, since pain can be experienced in degrees of severity that might be thought to be alleviated by “stronger” pain relief. In the case of the POS materials, the interpretation arises from the reference to “better pain relief”.

Faster onset and more meaningful pain relief

54    Reckitt argued that the references to “faster” pain relief are not limited by the bullet point which refers to “faster onset of more meaningful pain relief”. I do not accept this submission, having regard to the relevant audience for the new advertisement and the training aid which I take to be relatively discerning and likely to understand the banner claim to be qualified by reference to the bullet-pointed claims, especially having regard to the repeated use of footnotes in the banner claim. Despite the fact that the footnotes do not refer the reader to the bullet points, the multiple footnotes in the banner claim signify that the claim is not unqualified. In my view, even without looking at the content of the footnotes, the repeated use of footnotes emphasised that the general claim of “better and faster pain relief” is to be understood by reference to a particular study or studies.

55    I also do not agree that the relevant reader would understand “meaningful pain relief” to be a subcategory of “pain relief”, distinct from “perceptible pain relief”. Rather, the reader would understand that the words “faster onset of meaningful pain relief” describe the results of a study and, equally, that the claims made in the advertisement generally reflect the results of a study so it would not be appropriate to draw an inference of “faster onset and more meaningful pain relief”.

56    Accordingly, I do not accept that the new advertisement and the training aid convey a representation that Maxigesic provides faster onset and more meaningful pain relief than for paracetamol and ibuprofen alone.

Scientific evidence

Witnesses

57    AFT relied upon the expert evidence of Dr Russo and Professor Ronald Aaron Thisted, Professor Emeritus at the Department of Statistics and Public Health Sciences, University of Chicago.

58    Reckitt relied upon the expert evidence of Professors Keech and Val Gebski, an expert biostatistician with a particular focus on the design of clinical trials.

59    The witnesses prepared a helpful joint report and gave evidence concurrently. Neither party suggested that any adverse credit finding should be made about any witness, although AFT submitted that the approach of Professors Keech and Gebski “warrants caution”, because of their tendencies to raise no more than “potential doubts around the margins of the case”. My impression, particularly from the concurrent evidence, was that all of the experts gave their evidence with due independence, and endeavoured to provide relevant and impartial evidence, within their respective areas of expertise. Accordingly, I have not treated the evidence of Professors Keech and Gebski with any greater caution or scepticism than the evidence of the other experts.

Daniels 2018 study

60    The Daniels 2018 study was a clinical trial which compared:

(a)    a fixed dose combination of 975mg paracetamol/ 292.5mg ibuprofen (comprising three tablets) (that is, the Daniels FDC);

(b)    paracetamol;

(c)    ibuprofen; and

(d)    placebo.

61    The study publication concludes (at p 1774) that the Daniels FDC:

...provided significantly superior analgesia over equivalent monotherapy doses of either ingredient alone in the treatment of moderate to severe pain in the 48 hour period after the extraction of at least 2 impacted third molars. Compared with both monotherapies and placebo, the fixed-dose combination provided a significantly shorter onset of meaningful pain relief, reduced the consumption of opioid rescue medication, and reduced maximum pain scores...

62    Under the heading “Discussion”, the study publication states:

Acetaminophen and ibuprofen are well-known, commonly used, and well-established analgesic agents for the treatment of mild to moderate pain, and they target pain through separate pathways. The present study adds to the existing literature that shows the additive analgesic effect of combined acetaminophen and ibuprofen over either monotherapy after third molar removal, over ibuprofen monotherapy after root canal, and over acetaminophen monotherapy in other pain models. Several of pain studies in emergency department patients have not shown the superiority of combined therapy over monotherapy, possibly due to differences in study populations, baseline pain levels, indications, study duration, and dosing regiments. This study is the first to show the superiority of a fixed-dose combination that provides doses of both active ingredients at the recommended OTC levels and adheres to the FDA [US Food and Drug Administration] request for the dose of acetaminophen to be limited to 325mg per unit. This study reinforces previous research by showing that when co-administered, acetaminophen and ibuprofen combine to deliver a superior analgesic effect over either active ingredient alone. This study reinforces previous research by showing that when co-administered, acetaminophen and ibuprofen combine to deliver a superior analgesic effect over either active ingredient alone. With comparisons versus equivalent doses of each drug, it is evident that both active ingredients contribute to the superior analgesic effect of the fixed-dose combination.

63    The study publication also states: “The findings of the present study are limited to adults and to a dental pain model.”

64    As appears from the study publication conclusion set out above, the primary end point of the Daniels 2018 study was the time-adjusted sum of pain intensity difference over 48 hours (SPID48). The authors of the Daniels 2018 study concluded (at p 1768) that analysis of the time-adjusted SPID48 “... showed that [Daniels] FDC 975/292.5 provided more effective pain relief than placebo, acetaminophen or ibuprofen”.

65    The abstract of the study publication sets out the following implications of the study:

Overall, the fixed-dose combination of acetaminophen and ibuprofen provided greater and more rapid analgesia than comparable doses of either agent alone or placebo in adults after removal of impacted third molars.

66    AFT also contended that it was important to note the post hoc additional analysis showing that over the first six hours of treatment (that, is, during the first dosing period), the Daniels 2018 study found that the SPID6 was 151% greater for Daniels FDC 975/292.5 than for paracetamol monotherapy (25.61 vs 10.20) and was 52% greater for FDC 975/292.5 than for ibuprofen monotherapy (25.61 vs 16.82) (at p 1771). In each case, these improvements were statistically significant.

67    The Daniels 2018 study also analysed several pre-determined secondary end points. The study publication identified the secondary end points as follows:

Secondary end points of the study included the following: time to perceptible and meaningful pain relief using the two-stopwatch method; maximum VAS [visual analogue scale] pain intensity score after the first dose of study medication; percentage of patients requiring rescue medication, time to first doses of rescue medication, and cumulative consumption (milligrams) of rescue medication; percentage of patients that achieved <50% reduction in baseline VAS pain before the consumption of rescue medication (response rate), time to peak response (time to maximum percentage reduction in VAS or time to first rescue medication use, whichever is shorter); and the categorical global pain relief rating.

68    The statistical analysis plan (SAP) for the study twice listed “secondary efficacy endpoints” which included “The time to onset of pain relief after the first dose of study drug defined as (i) perceptible and (ii) meaningful pain relief using the two stopwatch method”. It did not identify “median time to perceptible pain relief” and “median time to meaningful pain relief” as separate end points.

69    It also identified “the time to onset of pain relief after the first dose of study drug defined as (i) perceptible and (ii) meaningful pain relief” as the “key secondary endpoint”.

70    The study protocol is consistent with the SAP in that it identifies “[t]he time to onset of pain relief after the first dose of study drug defined as (i) perceptible and (ii) meaningful pain relief using the two stopwatch method” as a secondary end point and does not identify “median time to perceptible pain relief” and “median time to meaningful pain relief” as separate end points.

71    However, Table II in the study publication identified “median time to perceptible pain relief” and “median time to meaningful pain relief” as separate end points. Dr Russo’s evidence proceeded upon the basis that these were separate secondary end points.

72    On this basis, Dr Russo’s evidence was that the most clinically relevant secondary end points were:

(a)    median time to meaningful pain relief;

(b)    mean maximum VAS pain score; and

(c)    mean consumption of rescue medication (mg).

73    By reference to the language of the SAP and the study protocol, I would have doubted that time to meaningful pain relief was a separate secondary end point of the Daniels 2018 study. However, the joint expert report clearly identified time to meaningful pain relief as a secondary end point. In cross-examination both Dr Russo and Professor Thisted maintained that time to perceptible pain relief and time to meaningful pain relief were separate secondary end points. Dr Gebski’s report also identified them as separate secondary end points.

74    On the basis of the expert evidence, I accept that time to meaningful pain relief was a secondary end point of the Daniels 2018 study.

75    It was not disputed that the Daniels 2018 study publication reported:

(1)    the median time to meaningful pain relief was quicker for the Daniels FDC product (42.98 minutes) than any of the other study arms (ibuprofen, 61.86 minutes and paracetamol, 46.62 minutes) (Table II on p 1771);

(2)    the mean maximum VAS pain score was significantly lower for the Daniels FDC group (55.06mm) than the placebo group (72.05mm) and paracetamol group (64.46mm), and lower than the ibuprofen group (61.28mm);

(3)    the requirement for supplementary analgesia with oxycodone was lower in the Daniels FDC group compared with the other treatment groups (see p 1770). The mean amount of oxycodone consumed by participants in the Daniels FDC group was 3.7mg, compared with 7.1mg in the ibuprofen group, 11.0mg in the paracetamol group and 17.9mg in the placebo group.

76    Dr Russo also referred to the secondary end point of percentage of patients requiring rescue medication as providing clinically meaningful information regarding the comparative strength of analgesia of the Daniels FDC and the monotherapies. In respect of that secondary end point, significantly fewer patients in the Daniels FDC group required rescue medication (Daniels FDC, 23.9%, paracetamol, 53.2% and ibuprofen, 43.2%).

77    The experts agreed:

(1)    the study employs the Dental Impaction Pain Model (DIPM) which is “a validated method for evaluating efficacy of treatments for acute pain”;

(2)    the primary and secondary end points used in the Daniels 2018 study are commonly evaluated measures in the DIPM;

(3)    the primary end point “provides information about the extent of pain relief, but does not provide information concerning time to pain relief”;

(4)    “Each of the measures identified as primary or secondary end points in the Daniels 2018 study was identified as such in the protocol and in the statistical analysis plan, both of which were finalized prior to completion of the trial, locking of the database, and unblinding the resulting data”; and

(5)    for the primary end point and a range of secondary end points, including time to meaningful pain relief, “the reported p-value for comparing the Daniels FDC to each of the paracetamol, ibuprofen and placebo was less than 0.05, thereby meeting the stated criterion for superiority ...”.

78    Professor Thisted considered the Daniels 2018 study to be “well designed and executed” and “well documented”. Professor Thisted referred to the following features of the Daniels 2018 study as the basis for his opinion:

(a)    the approach to randomisation of patients;

(b)    the blinding of both investigators and patients;

(c)    the number of patients resulting in the study being sufficiently “powered”;

(d)    the treatment of data impacted by the use of rescue medication;

(e)    the appropriate selection of primary and secondary end points;

(f)    the statistical analysis methods used were appropriate;

(g)    the use of appropriate sensitivity analyses for the primary end point; and

(h)    the minimisation of any risk of sponsor-bias arising from AFT’s involvement in the study.

79    Dr Russo also considered the Daniels 2018 study to be “robust and reliable” because it:

(a)    was appropriately designed, using a standard model of acute pain;

(b)    had a sufficient number of participants in each study group to produce statistically and clinically significant results;

(c)    measured appropriately selected primary and secondary outcomes;

(d)    employed reasonable methods of statistical adjustment to take into account rescue medication; and

(e)    reached conclusions which were consonant with the results of the data.

80    The experts also agreed:

(1)    (Except Professor Gebski for whom DIPM is outside his sphere of expertise) DIPM does not assess effectiveness at controlling chronic pain, and one cannot extrapolate effectiveness in pain control from acute pain models such as DIPM to chronic pain settings.

(2)    The Daniels 2018 study is not directly informative concerning degree of pain relief or onset of pain relief in contexts other than the acute pain dental impaction setting.

(3)    The Daniels 2018 study does not evaluate the Maxigesic formulation being commercially marketed in Australia.

24 hours data?

81    Reckitt submitted that the Daniels 2018 study provides no support for any claim of efficacy over a 24 hour period. As appears above, the primary end point for the Daniels study was the SPID48.

82    Professor Keech’s evidence was:

The primary endpoint did not test the efficacy of the Daniels FDC over the monotherapies during a 24 hour period and no data is published in the Daniels study about the 24 hour time point, [and] nor did any secondary endpoints evaluate efficacy over 24 hours.

…

[There is] no data in the Daniels study … to make any conclusions about the various end points at the 24 hour time point.”

83    The experts agreed that the Daniels 2018 study “provides no information concerning pain relief specifically for the first 24 hour period of the study”, saying:

We disagree as to whether the statements in the Maxigesic Advertisement concerning pain relief imply that they refer to results at the 24-hour point in the Daniels Study. We agree that while the Daniels Study provides information concerning pain relief during the first 6 hours of the study (SPID6) and over the 48-hour study period SPID48), the Study provides no information concerning pain relief specifically for the first 24-hour period of the study. The SPID24 calculations reported in the Lambert Affidavit were not carried out at the time of the Maxigesic Advertisement, nor are they reported in the Daniels Study. Dr Lambert indicates that the same method of imputation for missing SPID24 values (for the ten patients who withdrew during the first 12 hours) was identical to that used for obtaining imputations for SPID48.

84    Even so, Dr Russo expressed the opinion that it is highly likely patients taking Maxigesic would experience better pain relief over a 24 hour period, saying:

... I consider that it is highly likely that patients would experience greater improved pain relief with the [Daniels] FDC (compared with the monotherapies) over the first 24 hours. The SPID48 is likely to be a more conservative figure to use for the following reason. The SPID48 findings include data collected from sampling periods in the first 24 hours after surgery, when the pain that patients were experiencing would have been highest. As it is more difficult to show statistically significant differences [in] reduction in pain levels in the second 24 hour period after surgery (as a patient’s pain will have naturally subsided to some extent), one can almost guarantee that if a statistically significant reduction in pain is observed over the entire 48 hour period, similar (if not greater) reduction would be observed over the first 24 hour period.

85    AFT submitted Dr Russo’s view is supported by the data reported in the Daniels 2018 study for the first six hours, which showed an even stronger comparison between the Daniels FDC and the monotherapies. Further, Professor Thisted observed:

[O]ver the first six hours of treatment, i.e., during the first dosing period, the SPID6 was 151 % greater for [Daniels] FDC 975/292.5 than for paracetamol monotherapy (25.61 vs. 10.20) and was 52% greater for FDC 975/292.5 than for ibuprofen monotherapy (25.61 vs 16.82). In each case, these improvements were statistically significant.

86    AFT argued that this evidence was reinforced by the following exchange during oral evidence:

MR MURRAY: Thank you. And I think you would agree that the SPID6 analysis was a post hoc analysis?

PROF THISTED: I would.

MR MURRAY: Yes. And you would agree that it’s not an adequate foundation for drawing conclusions about what the data would show at 24 hours?

PROF THISTED: In and of itself, no. However, the SPID calculation is a cumulative calculation, so that would imply that whatever SPID score one obtained at 24 hours, had one decided to measure it at the time, would be intermediate between the SPID6 and the SPID48, and so, in that respect, the SPID6 tells you something about what would be happening at 24 hours. So, for instance, the SPID6 for the fixed dose combination, so at six hours the SPID is greater for the fixed dose combination than either of the monotherapies achieved by 48 hours.

MR MURRAY: Yes.

PROF THISTED: And so that’s a something.

MR MURRAY: But it would not—I think you would agree with Dr Russo that you couldn’t place any faith on the percentage numbers shown in the advertisement as at the 24-hour period?

PROF THISTED: One would have no direct information about the percentage numbers at 24 hours. You would expect them to be intermediate between the 48 hour and the six-hour percentages. The percentages at six hours I think are actually more strongly favour the fixed dose combination at six hours than they do at 48, and so one would expect an attenuation of that at 24 hours before reaching the 48 hour cumulative percentages.

87    AFT also relied on the following exchange:

MR CRUTCHFIELD: ... You heard what Professor Thisted said about the 24-hour result. What’s your view about what you would expect at 24 hours when you’ve got this study in front of you?

DR RUSSO: More or less as what Professor Thisted said. We have to remember that the larger the amount of pain you have, the more likely an analgesic will show a reduction. The lower the amount of pain you have, the harder it is to ever show a reduction. To give a simple thing, if your pain is nine out of 10, it’s easier to pick up a reduction to 4.5, but if your pain is 1.1 out of 10, you might have a 30 or 40 per cent reduction, but that becomes difficult to detect, so that’s why clinical studies always pre-specify that you have to have a certain amount of pain to get into the study, and in this study you have to have pain that was at least four out of 10 on a pain scale to get into the study. Otherwise, you simply can’t find a difference, because no one has the problem. So the—as you—as the pain falls off over time, so at time zero, 100 per cent of people have pain. They’ve just had the operation, and then that falls off as people recover, and about 30 per cent of people have recovered by 24 hours, and about 95 per cent of people are recovered at 48 hours.

MR CRUTCHFIELD: Yes.

…

DR RUSSO: So—so the period of study should properly account for the totality of the pain experience, and that’s why 48 hours is taken, so we will see the best results at six, we will probably see intermediate results, as Professor Thisted said, at 24, and then we see the least impressive results at 48.

88    Having agreed that the Daniels 2018 study did not test for efficacy over a 24 hour period, the experts disagreed about whether the Daniels 2018 study provided a basis for a scientific opinion concerning efficacy over that period. I found the evidence of Professor Thisted and Dr Russo set out above to be persuasive. Accordingly, I accept that the Daniels 2018 study provides a rational basis for their respective opinions and expectations.

89    To that extent, Daniels 2018 study provides support for a claim of efficacy over a 24 hour period. Such a claim might be, as Dr Russo opined, that it is highly likely that patients would experience greater improved pain relief with the [Daniels] FDC (compared with the monotherapies) over the first 24 hours.

Is adjustment to statistical significance for multiple comparisons warranted?

90    This issue concerns the use that can be made of the secondary end point data in the Daniels 2018 study, and involves interpretation of the study protocol and the SAP, and the significance of statements in the study publication.

91    As AFT framed it, the particular question was whether the secondary end points were analysed on the basis that, in order to declare success, the Daniels FDC needed to be shown to be superior to all three comparators (that is, the same basis upon which it was agreed that the primary end point was analysed).

92    Reckitt put the issue differently. According to Reckitt, the question was whether the study was designed with the intent that the secondary end points would be analysed on that basis.

93    As Professor Thisted explained, “post hoc exploratory analyses are in general less reliable for forecasting what you would see in the future. Nonetheless, they remain very useful in rounding out the clinical picture, in describing what the data have to say about specific questions, and so they’re certainly very useful”.

94    The study publication includes the following statements:

(1)    “The onset of meaningful pain relief was significantly faster for the combination than for acetaminophen, ibuprofen, and placebo (all, P ˂0.05)”;

(2)    “The analgesic superiority of FDC 975/292.5 is reinforced by the results of the secondary end points, with FDC 975/292.5 exhibiting superior efficacy compared with all 3 comparators for time to onset of meaningful pain relief, maximum VAS pain scores, response rate, percentage of patients requiring rescue medication, time to first dose of rescue medication, cumulative consumption of rescue medication, and categorical pain relief score.”; and

(3)    “Compared with both monotherapies and placebo, the fixed-dose combination provided a significantly shorter onset of meaningful pain relief, reduced consumption of opioid rescue medication, and reduced maximum pain scores”.

95    The extracts from the study publication set out above show that there was at least post hoc analysis of whether the Daniels FDC was superior to all three comparators.

96    AFT submitted, referring to para 63 of the experts’ joint report, that the experts agreed no adjustment for multiple hypotheses was required, if the secondary end points were analysed on the basis that, in order to declare success, it was necessary for the Daniels FDC to be superior to all three comparators,. I do not read para 63 as contained such an agreement. Paragraph 63 states:

Professor Gebski notes that there is no statement in either the protocol or the statistical analysis plan requiring that, for each secondary endpoint, all three comparisons need to be < 0.05 to declare superiority for FDC. With respect to the secondary endpoints, the statistical analysis plan states “A two-tailed p-value < 0.05 will be taken to indicate statistical significance for all the secondary outcomes”. If, however, one assumes (without any evidence) that this requirement is implied for the two key secondary endpoints identified in the protocol, viz., (i) perceptible and (ii) meaningful pain relief, Professor Gebski agrees that no adjustment for multiplicity is necessary when interpreting these endpoints. However, for the remaining secondary and additional endpoints this requirement cannot be assumed and as such adjustments for multiple comparisons need to be performed.

97    Ultimately, as I understood AFT’s position, it accepted that more was required than post hoc analysis of the secondary end points showing superiority of the Daniels FDC to all three comparators. At least as between the experts, the issue was whether the Daniels 2018 study design included that analysis.

98    In their joint report, the experts agreed that the statement requiring that the Daniels FDC be superior to all three other comparators appeared in the section of the protocol entitled “Primary Endpoint” and that a similar statement was absent from the subsequent section entitled “Secondary Endpoint”.

99    In support of its position, AFT relied on the following matters, based principally on the expert evidence of Professor Thisted:

(1)    The study protocol identifies the study hypothesis as “that the analgesic effects of [the Daniels FDC] are greater than all three study comparators, paracetamol 325mg, ibuprofen 97.5mg and placebo”.

(2)    It would be at odds with the study hypothesis for the secondary end points to be analysed on a different basis, as Professor Thisted explained in this oral evidence. Professor Thisted said “[t]he only relevant comparison that I can envision is one in which one actually asks the question, is it better than each of its constituents”.

(3)    There is nothing in the SAP or the study protocol to suggest that the secondary end points would be assessed on a different basis to the primary end point, in the sense that no alternative methodology is specified.

(4)    The SAP states that the secondary end points would only be analysed if the primary end point was positive (i.e. against all comparators).

(5)    The study publication extracts set out above.

100    AFT contended that Professor Thisted’s approach is consistent with common sense in light of the purpose of the Daniels 2018 study. In contrast, AFT argued, Reckitt’s interpretation (based on the evidence of Professors Gebski and Keech) would conflict with that purpose and would result in the study reporting commercially irrelevant findings.

101    AFT also referred to the following passage of his oral evidence of Professor Gebski, based on the extracts from the study publication:

MR CRUTCHFIELD: So you agree with me, don’t you, that the Daniels study did – what was happening in the Daniels study was an analysis of superiority of the FDC over all three comparators. Do you agree with that?

PROF GEBSKI: It – it was an analysis comparing of FDC to the – each of the comparators. I agree with that.

102    I do not agree that this passage reveals an acceptance by Professor Gebski that the Daniels study design included analysis of the secondary end points over all three comparators. Rather, Professor Gebski was commenting on the actual analysis, including post hoc analysis, as revealed by the study publication. In this regard, I note that the experts agreed, in their joint report that “[f]or the fixed-dose combination to be considered as a superior treatment it needed to be statistically significantly superior to each of the three other study treatments, for the primary endpoint”. I understand Professor Gebski’s evidence to be reiterating this agreement.

103    Reckitt argued that AFT’s case assumes, without textual foundation, that the designers of the Daniels 2018 study prospectively intended the better than all three rule to apply to the statistical analysis of the secondary end points. To the contrary, Reckitt noted that both the study protocol and the SAP:

(a)    expressly declare that “[t]here will be no correction for multiple comparisons for the analyses of the secondary endpoints”;

(b)    expressly state that the better than all three rule applied for the statistical analyses of the primary end point, saying “[a] two tailed p-value < 0.05 will be taken to indicate statistical significance and for [the Daniels FDC] to be considered a superior treatment it needs to be statistically superior to all three other study treatments”; and

(c)    notably omit the better than all three rule for the statistical analyses of the secondary end points, saying “[a] two tailed p-value < 0.05 will be taken to indicate statistical significance for all the secondary outcomes”.

104    Reckitt contended, based on the expert evidence of Professor Gebski and Professor Keech, that the better than all three rule was clearly not intended to be applied to each of the secondary end points and that is not appropriate to use the study publication to inform the interpretation of the SAP and the study protocol.

105    Reckitt also discounted the significance of the study hypothesis for the secondary end points, on the basis that it is the result of the primary end point that dictates the success or failure of the study.

106    Ultimately, the study protocol and the SAP do not clearly reveal that the study methodology for the secondary end points was as claimed by AFT, and the contrast between the description of the methodology for the primary and secondary end points arguably points against AFT’s claim.

107    Thus, it is not clear whether adjustment is warranted. If the adjustment were to be made in accordance with the approach advocated by Professors Keech and Gebski, the results for the secondary end points would lack statistical significance. This raises a doubt about the reliability of the Daniels secondary end points as an adequate scientific foundation for AFT’s claims.

Testing for faster pain relief

108    The experts agreed that the two-stopwatch method for measuring time to perceptible pain relief and time to meaningful pain relief is a validated procedure.

109    Concerning the use of median times, the joint expert report states:

Although the median time to pain relief (for both perceptible and meaningful relief) favour the FDC over each monotherapy, Professors Gebski and Thisted agree that the median provides only limited information, and the shorter times for the FDC compared to the monotherapies are insufficient by themselves to conclude that relief times are actually shorter. They agree that another comparative measure, the hazard ratio, would have provided more information about how the treatments compare with respect to onset times. However, the log-rank statistical tests for time to perceptible/meaningful pain relief do test the hazard ratios and are a sufficient basis on which to assess whether the FDC affords shorter times to perceptible or meaningful pain relief.

110    The experts’ disagreements centred primarily around whether time to “perceptible pain relief” as opposed to “meaningful pain relief” is relevant to the “faster pain relief” statements in the new advertisement.

111    The experts agreed that a superiority claim could not be made unless an end point reaches statistical significance, and that a claim of faster onset of perceptible pain relief would not be supported by the Daniels 2018 study.

Bioequivalence

How the issue arises

112    The bottom page footnote on the new advertisement and the training aid states relevantly:

Maxigesic® 975/292.5mg combination is bioequivalent to Maxigesic® 1000/300mg Australian combination at full dose (Aitken et al, J Bioequiv Availab, 10:5).

113    This statement reflects the fact that AFT’s statements and representations are predicated on the proposition that the Daniels FDC and Maxigesic are “bioequivalent”.

114    The Daniels FDC contained approximately 2.6% less of each active ingredient than Maxigesic.

115    AFT contended that its claim of bioequivalence should be understood as referring to the Daniels FDC and Maxigesic achieving essentially the same outcome clinically. I do not agree. To the extent that it is relevant to consider how the footnote may be interpreted, in my view, the words “(Aitken et al, J Bioequiv Availab, 10:5)” signify that the claim of bioequivalence is based on the Aitken study.

116    However, the larger issue is whether the findings of the Daniels 2018 study can be extrapolated to Maxigesic since AFT extrapolates from those findings about the Daniels FDC to make its claims. The legitimacy of that reasoning depends on it being possible to say that the Daniels FDC and the Maxigesic combinations are relevantly similar.

117    Reckitt did not allege that AFT’s claims of bioequivalence in the new advertisement and the training aid involve any contravention of the Australian Consumer Law.

What is bioequivalence?

118    Dr Russo agreed that bioequivalence, as understood by Australian pharmacists and physicians, is a scientific and technical concept. Similarly, Professor Thisted explained:

I think that an Australian pharmacist would be like a European pharmacist or a US pharmacist, that the standards in bioequivalence studies are the same across all of those and they entail the 90 per cent confidence interval of – or the particular blood parameter being measured to lie completely within the 80 to 125 per cent limits.

119    The experts also agreed that:

(1)    In assessing whether two drugs are bioequivalent in this scientific or technical sense, a “standard” or “typical” bioequivalence study will examine two pharmacokinetic parameters in respect of the relevant active ingredient(s): peak serum concentration (Cmax) and 12-hour total serum concentration or “area under the curve” (AUC). Cmax is an indicator of how rapidly a drug is absorbed and AUC is an indicator of the average amount of the drug available over a 12 hour period.

(2)    Bioequivalence in respect of Cmax or AUC is established when the 90% confidence interval for the ratio of means lies completely between 80% and 125% for each active ingredient.

(3)    While a bioequivalence study may measure Cmax and AUC in either fed or fasting conditions (or both), a bioequivalence study conducted under fasting conditions is generally more sensitive to potential differences between formulations than a study conducted under fed conditions.

120    Dr Russo’s evidence contemplated the possibility that there could be a “variation in one minor aspect of bioequivalence”, which would then lead to a question about whether that “alteration” had any clinical meaning. He said:

If that is of a trivial nature where there is a small deviation in one graph line to another, that would not in and of itself destroy the concept of essential bioequivalence of the product.

121    Reckitt relied on the European Medicines Agency Guideline on the Investigation of Bioequivalence which states:

For products where the SMPC recommends intake of a reference medicinal product on an empty stomach or irrespective of food intake, the bioequivalence study should hence be conducted under fasting conditions.

122    Dr Russo agreed that this guideline suggests that a fasting study would be appropriate for testing bioequivalence in this case, because Maxigesic is a product that may be taken “irrespective of food intake”.

123    The experts agreed that bioequivalence between two formulations does not imply that their therapeutic effects are exactly the same, but rather that their therapeutic effects can be expected to be substantially similar.

Aitken study

124    The experts agreed that the Aitken study reported on eight tests of bioequivalence between the Daniels FDC and Maxigesic, being each of two measures of drug levels in the blood after a single dose (Cmax and AUC) for each of ibuprofen and paracetamol, under both fed and fasting conditions.

125    The experts also agreed that the Aitken study demonstrated bioequivalence for seven of the eight tests, failing to do so for one of them, saying:

29.    … Aitken demonstrated full bioequivalence (under both conditions, for both blood-level measures) for the ibuprofen components of the two FDCs. It also demonstrated full bioequivalence for both monotherapies under fed conditions.

30.     The one test for which the Aitken Study did not establish bioequivalence indicated that the peak blood level (Cmax) for paracetamol shortly after dosing was about 19% higher for the US formulation than for the Australian formulation under fasting conditions only. We agree that a bioequivalence study conducted under fasting conditions is generally more sensitive to potential differences between formulations than a study conducted under fed conditions.

31.    When a drug is administered, it is absorbed and enters the blood stream. The concentration of the drug in the blood varies over time. In the case of paracetamol, it rapidly achieves a peak serum level within about an hour of dosing. This peak concentration is referred to as Cmax. The concentration then declines over time as the drug is metabolised and eliminated from the body. The average amount of drug in the blood over a dosing period is proportional to the area under this concentration curve over time (AUC). Thus the difference in Cmax levels for paracetamol in the fasting study would be most relevant to the onset of perceptible pain relief.

Are the Daniels FDC and Maxigesic bioequivalent?

126    AFT contended that the Aitken study demonstrates that the Daniels FDC and Maxigesic are bioequivalent in the clinically relevant condition and in any event likely to result in sufficiently similar clinical outcomes, such that the findings of the Daniels 2018 study may be read directly on to Maxigesic.

127    Ultimately, the experts were not in agreement as to whether it is appropriate to describe Daniels FDC and Maxigesic as bioequivalent where the products satisfied seven of the eight tests for bioequivalence set in the Aitken study. Whatever the better position, the Aitken study does not provide unqualified support for a conclusion that the two combination products are bioequivalent because the study included a test for bioequivalence of Cmax in fasting conditions, which test was not passed.

Can the findings of the Daniels 2018 study be extrapolated to Maxigesic?

128    I accept that the Aitken study shows that the two combination products are bioequivalent in clinically relevant conditions and, on that basis, the Daniels 2018 study be extrapolated to Maxigesic, at least to some extent. Specifically, I accept that:

(1)    The AUC is the key measure for assessing analgesic efficacy, because it demonstrates the amount of the active ingredients available on average over a 12 hour period. The Aitken study found that the combination products were bioequivalent in all respects in relation to the AUC.

(2)    Cmax is not determinative of analgesic response, which is a combination of both pharmacokinetic parameters (including Cmax and AUC) and pharmacodynamic factors. In this regard, Cmax relates to the rate of absorption but Dr Russo’s evidence was that the drug provides no analgesia from the bloodstream.

(3)    Maxigesic is not, in Dr Russo’s clinical experience, typically taken in fasted circumstances and certainly not under the fasted conditions of the Aitken study.

(4)    While Professor Keech did not agree that the percentage improvements in the Daniels 2018 study can be directly extrapolated to Maxigesic, he expected that the true figures would be “very similar”.

129    As already noted, the experts agreed that the difference in Cmax for paracetamol under fasted conditions is relevant to perceptible pain relief. Specifically, the experts agreed that this difference would be “most relevant to the onset of perceptible pain relief”. I accept that perceptible pain relief is a much less clinically significant parameter because of the risk of placebo effect, but also because, as Dr Russo explained, perceptible pain relief may be far from meaningful pain relief and may not be a clinically important degree of relief for the patient.

130    Dr Russo agreed that a more rapid absorption of paracetamol in the Daniels FDC than for Maxigesic opens up the possibility of a quicker time to meaningful pain relief by reason of the quicker absorption of the paracetamol. In that way, the question of bioequivalence between the two drugs with respect to paracetamol has the potential to bear upon what Dr Russo considered to be a clinically significant parameter, namely, time to meaningful pain relief. However, this qualification to Dr Russo’s evidence does not detract from the doctor’s overall opinion.

Wider body of scientific evidence

131    AFT submitted that there is a “wider body of scientific literature” in support of its statements that Maxigesic provides better pain relief and faster pain relief.

132    Based on his survey of the literature, Dr Russo expressed the following opinions:

106.    In my view, the conclusions in the PaPaS Cochrane Reviews referred to above, recommendations in the Acute Pain Book, and results of other systematic reviews and individual studies, indicate to me that it is likely that:

(a)    an incremental analgesic response will be achieved by using sub-maximal, but reasonable, doses of ibuprofen (being greater than 100mg per tablet) and paracetamol (being greater than 250mg per tablet);

(b)    administering combination analgesic products containing between 200mg and 400mg ibuprofen and between 500mg to 1000mg paracetamol (ie, where the paracetamol:ibuprofen ratio is at least 2.5:1) would provide superior analgesia to ibuprofen or paracetamol alone, at equivalent doses; and

(c)    administering combination analgesic products containing between 200mg and 400mg ibuprofen and between 500mg to 1000mg paracetamol, is likely to result in faster onset of meaningful pain relief to ibuprofen or paracetamol alone, at equivalent doses.

107.    Accordingly, I consider the results of the Daniels Study are consistent with, and to be anticipated based on, the results of the wider body of literature concerning the comparative analgesic efficacy of combination analgesics against monotherapies. Thus…I consider that any pain medicine specialist would have expected that 975mg paracetamol/292.5mg ibuprofen (as tested in the Daniels Study) delivers superior analgesia than 975mg paracetamol, 292.5mg ibuprofen and placebo.

108.    I also consider that the results of the Daniels Study in relation to speed of onset of analgesia are consistent with the results reported in three prior studies of combination ibuprofen/paracetamol products. Notably, each of the Daniels 2011 Study, Mehlisch 2010a Study and the Mehlisch 2010b Study demonstrated that faster onset of meaningful pain relief is more likely to be achieved with the combination as against the monotherapies, as determined using the two-stopwatch method to measure time to meaningful pain relief.

133    For its part, Reckitt submitted:

(1)    there is not a single clinical study that supports any representation of comparative superiority between Maxigesic and the monotherapies, noting that the Daniels study tested the Daniels FDC;

(2)    even assuming bioequivalence, there is no support in the Daniels study for any claim of superiority of Maxigesic over the monotherapies at the 24 hour period;

(3)    no meta-analysis (Cochrane review or otherwise) has assessed the comparative efficacy of Maxigesic over the monotherapies;

(4)    no meta-analysis (Cochrane review or otherwise) has assessed the comparative efficacy of a combination analgesic over the monotherapies other than at six to eight hours. There is no meta-analysis to support any claim of comparative efficacy at 24 hours or 48 hours; and

(5)    accordingly, the Cochrane meta-analyses do not support any representation of comparative superiority of Maxigesic over the monotherapies as made in the advertising material.

134    I have addressed below the materials, studies and reviews relied upon by AFT, from most recent to oldest.

Acute Pain Management: Scientific Evidence (4th ed. 2015)

135    Dr Russo’s evidence was that this book is a pre-eminent publication in relation to pain medicine and is regarded in Australia as the “gold standard” in evidence-based management of acute pain. The authors state in sections entitled “Efficacy” concerning each of paracetamol and “Nonselective NSAIDs and coxibs”:

The combination of paracetamol and NSAIDs is more effective than paracetamol or NSAID alone (Ong 2010 Level I, 21 RCTs, n=1,909). This is particularly well documented for the combination of paracetamol and ibuprofen in the setting of wisdom tooth removal (Bailey 2013 Level I [Cochrane], 7 RCTs, n=2,241).

136    Reckitt noted that the authors rely only on two Cochrane reviews in support of this conclusion: the Bailey review (2013) and the Ong review (2010), both of which are considered below. Accordingly, the weight of the statement above depends on an analysis of those two reviews.

137    In a section called “Summary of Key Messages”, section 8 is entitled “Specific Clinical Situations”. In that section, there is a further sub-section, entitled “Postoperative pain”. The third sub-category within that sub-section is “Orofacial pain”. Within that sub-category are acute dental pain, dental extraction, tonsillectomy, pharyngitis, sinusitis and oral mucositis. Under the heading “Dental extraction”, point 4 is:

Combinations of paracetamol with ibuprofen (N) (Level I [Cochrane Review]) and other nonselective NSAIDs (N) (Level I) provide superior analgesia to either drug alone after dental extraction.

138    This illustrates that the text treats “dental extraction” as one of several kinds of “orofacial pain” which is itself treats as one of several kinds of “postoperative pain”, and tends to suggest that conclusions about pain management in cases of dental extraction cannot be readily extrapolated onto other kinds of pain.

Moore review (2015)

139    The Moore Cochrane review was a “Cochrane review of Cochrane reviews”, which considered 39 separate Cochrane reviews investigating 41 analgesics or combination analgesics given as single doses in acute postoperative pain conditions from around 460 studies, including around 50,000 patients.

140    The review produced an updated version of the “Oxford League Table of Analgesic Efficacy”. AFT contended that it was notable that the combinations of ibuprofen / paracetamol sit close to the top of the table, whereas equivalent doses of the monotherapies sit close to the bottom of the table. Dr Russo considered that the table “provides strong evidence of the superior analgesic efficacy of combination paracetamol/ibuprofen over paracetamol or ibuprofen alone at the same dosages”.

141    In the 2018 judgment, I made the following findings concerning this review, of potential relevance in this proceeding:

[152]    The Moore review examined the results of Cochrane reviews looking at the efficacy of different oral analgesics in the treatment of acute postoperative pain. The authors concluded:

There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses.

142    So far as the comparison of Maxigesic with paracetamol or ibuprofen is concerned, the Moore review had no obvious relevance to the disputed representations because it concerns studies of single doses of the relevant drugs. Accordingly, the findings in the 2018 judgment about the Moore review were otherwise generally concerned with results for different combinations of paracetamol and ibuprofen, or with the dose responses of analgesics that are not presently relevant.

143    AFT noted and Reckitt did not dispute the following findings of the Moore review:

(1)    A combination of 200mg ibuprofen/500mg paracetamol was more effective than both 200mg ibuprofen and 500mg of paracetamol as monotherapies (with NNTs [Number Needed to Treat] of 1.6, 2.9 and 3.5).

(2)    A combination of 400mg ibuprofen/1000mg paracetamol was more effective than both 400mg ibuprofen and 1000mg of paracetamol as monotherapies (with respective NNTs of 1.5, 2.5 and 3.6).

144    For its part, Reckitt noted that:

(1)    All of the Cochrane reviews considered by the review “had as their primary outcome the number of participants with at least 50% pain relief over four to six hours compared with placebo”.

(2)    The review did not analyse time to onset of pain relief.

Bailey review (2013)

145    The Bailey review was a Cochrane review of seven studies designed to compare the beneficial and harmful effects of paracetamol, ibuprofen and a combination of both for pain relief following surgical removal of lower wisdom teeth, at different doses, administered postoperatively.

146    AFT relied on Dr Russo’s conclusion that the Bailey review concluded (on p 21) that “a greater proportion of patients receiving 1000mg paracetamol/400mg ibuprofen achieved >50% maximum pain relief over six hours post-surgery, than those receiving 400mg ibuprofen or 1000mg paracetamol”. That finding is not recorded on p 21 of the study publication.

147    Reckitt noted the following matters concerning the review:

(1)    The review analysed the “proportion of patients with at least 50% pain relief (based on total pain relief (TOTPAR) and summed pain intensity difference (SPID) data) … at both two and six hours postdosing”.

(2)    Insofar as the combination analgesic was concerned, the review analysed the results of only one study: the Mehlisch No. 1 Study, as Dr Russo agreed in cross-examination.

(3)    Concerning the quality of the evidence review, the Bailey review notes that “when comparing the combined versus single drugs, the body of evidence for the proportion of patients with >50% maximum pain relief ... over two and six hours was assessed as of moderate quality due to imprecise estimates based on single studies. This means that further research is likely to have an important impact on our confidence in the estimate of the effect”.

(4)    One of the stated “key results” was that “[o]n limited evidence, the combination of ibuprofen and paracetamol appeared to be no more effective than the single drugs when measured two hours after surgery. However, again on limited evidence, it was found to be more effective than the drugs taken singly when measured at six hours after surgery. Participants taking the combined drug also had a smaller chance of requiring rescue medication”.

(5)    The review did not analyse time to onset of pain relief.

Derry review (2013)

148    The Derry review, entitled “Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain (Review)” was a Cochrane review of the three studies addressed below: the Daniels 2011 study, the Mehlisch No. 1 study and the Mehlisch No. 2 study. The review assessed the efficacy and safety of a single dose of a paracetamol/ibuprofen combination analgesic (with varying amounts of paracetamol and ibuprofen) as against either the same amount of ibuprofen or placebo.

149    The authors concluded (at p 2):

Ibuprofen plus paracetamol combinations provided better analgesia than either drug alone (at the same dose), with a smaller chance of needing additional analgesia over about eight hours, and with a smaller chance of experiencing an adverse event.

150    Dr Russo stated that the following findings of this review are particularly relevant:

(1)    1000 mg paracetamol/400 mg ibuprofen provided better pain relief over six hours than 400mg ibuprofen with the combination giving an NNT of 1.6 (1.5 to 1.8 with confidence intervals), and NNT of 5.4 (3.5 to 12 with confidence intervals) for 400mg ibuprofen compared with the combination.

(2)    The relative benefit of the combination treatment compared with ibuprofen alone was 1.3 (1.1 to 1.3).

151    Reckitt noted the following matters concerning this review:

(1)    The study tested combination analgesics that contained different amounts of paracetamol and ibuprofen as compared to Maxigesic. The three combination analgesics in question contained: (a) ibuprofen 200mg and paracetamol 500mg (compared against placebo); (b) ibuprofen 400mg and paracetamol 1000mg (compared against placebo); and (c) ibuprofen 400mg and paracetamol 1000mg (compared against ibuprofen 400mg).

(2)    The “primary outcome” for the review was “[p]articipants achieving at least 50% of maximum pain relief over 4 to 6 hours”.

(3)    The review did not analyse time to onset of pain relief.

152    Reckitt relied on Dr Russo’s acceptance in cross-examination that the Derry review “is not a review that includes data for paracetamol as a monotherapy” and that the “focus there is on ibuprofen monotherapy but not paracetamol” to submit that the conclusion reached in the Derry review, that “ibuprofen plus paracetamol combinations provided better analgesia than either drug alone (at the same dose)” must be understood as a conclusion relating only to ibuprofen, and not paracetamol.

153    AFT contended that the fact that there was no single study in the Derry Review comparing the combination to paracetamol misunderstands the methods employed to prepare a Cochrane review such as the Derry review. AFT noted that Dr Russo was not asked whether this impacted on his ability to rely on the Derry review.

Daniels 2011 study

154    In the 2018 judgment, I made the following findings concerning the study:

[116]    The Daniels study assessed the efficacy of single doses of 1000mg paracetamol/400mg ibuprofen and 500mg paracetamol/200mg ibuprofen against 400mg ibuprofen/25.6mg codeine, 1000mg paracetamol/30mg codeine and placebo in a dental pain model of removal of at least three impacted teeth.

[117]    Under the heading “Discussion”, the authors concluded:

In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200mg/paracetamol 500mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics marketed for strong pain. Paracetamol combined with ibuprofen, at the dose range studied, is a more effective analgesic than codeine combined with ibuprofen. The novel single-tablet combination of ibuprofen/paracetamol would provide a useful alternative analgesic option for people not wishing to take codeine.

[118]    As AFT contended, the Daniels Study concluded that:

(1)    1000mg paracetamol/400mg ibuprofen was significantly more efficacious than 500mg paracetamol/200mg ibuprofen. The precise finding was that “[t]wo tablets of the single-tablet combination of ibuprofen 200mg/paracetamol 500mg were statistically significantly more efficacious than 1 tablet of the single-tablet combination”.

(2)    “The pain relief scores over time curves ... illustrate that the peak pain relief was higher and sustained for longer with 2 tablets of the single tablet combination of ibuprofen/paracetamol compared with all other treatments”.

[119]    Reckitt contended that the Daniels study made no comparative finding as to a statistically significant difference between 500mg paracetamol/200mg ibuprofen and 1000mg paracetamol/400mg ibuprofen over a single 8 hour dose. Under the heading “primary efficacy endpoint’, the authors states:

The results of all 5 planned primary comparisons were positive for both 1 and 2 tablets of the single-tablet combination of ibuprofen 200mg/paracetamol 500mg compared with the other treatments.

[120]    However, the statements identified by AFT do appear to me to be comparative findings. There is also a finding that “2 tablets of the single-tablet combination of ibuprofen 200mg/paracetamol 500mg provided significantly more pain relief than 1 tablet from 5 hours onwards”.

[121]    Thus, in my view, the Daniels study provides scientific evidence that a combination of 1000mg paracetamol/400mg ibuprofen is a more effective dose than 500mg paracetamol/200mg ibuprofen. It does not provide scientific evidence that a combination of 1000mg paracetamol/300mg ibuprofen (that is, a combination containing less ibuprofen) is a more effective dose than 500mg paracetamol/200mg ibuprofen, because it did not test that comparison.

155    AFT submitted that the Daniels 2011 study concluded that:

(1)    1000mg paracetamol/400mg ibuprofen was significantly more efficacious than 500mg paracetamol/200mg ibuprofen and the monotherapies in combination with codeine;

(2)    a combination of 1000mg paracetamol/400mg ibuprofen provided faster onset of pain relief than a combination of 500mg paracetamol/200mg ibuprofen and the monotherapies in combination with codeine.

156    As Reckitt noted, this study compared two paracetamol/ibuprofen combinations as against other combination analgesics, rather than against paracetamol or ibuprofen alone.

157    AFT’s written submissions did not explain how this study supported the statements and representations at issue in this proceeding, which involve comparisons between Maxigesic and two monotherapies.

158    Dr Russo expressed the view that the Daniels 2011 study demonstrated that:

[I]n the 12 hour study period the combination of 1000mg paracetamol/400mg ibuprofen provides:

…

(c)    faster onset of pain relief (measured by the secondary endpoint of median time to pain half gone of 30 minutes), compared to:

(i)    44 minutes for 500mg paracetamol/200mg ibuprofen;

(ii)    45 minutes for two tablets of 200mg ibuprofen/12.8mg codeine;

(iii)    45 minutes for two tablets of 500mg paracetamol/15mg codeine; and

(iv)    300 minutes for placebo.

159    I do not accept Dr Russo’s evidence, set out at [132] above, that the Daniels 2011 study “demonstrated that faster onset of meaningful pain relief is more likely to be achieved with the combination as against the monotherapies, as determined using the two-stopwatch method to measure time to meaningful pain relief” without more explanation, for the following two reasons:

(1)    the study did not test the performance of either paracetamol or ibuprofen as a monotherapy; and

(2)    the study publication’s description of the study does not refer to testing for meaningful pain relief using the two-stopwatch method.

160    However, I do accept Dr Russo’s evidence that the Daniels 2011 study was one of several studies that “contribute to the wider body of scientific literature relating to combination analgesics”.

Mehlisch studies (2010)

161    Reckitt noted that the Mehlisch studies are the only studies referred to by AFT which report any measurements of time to onset of pain relief. As for the Daniels 2018 study, these measurements are secondary end points. Therefore, Reckitt argued, at best the results of these studies and the Daniels 2018 study can be used to generate a hypothesis for a subsequent clinical trial that is designed specifically to compare the time to onset of pain relief for ibuprofen/paracetamol combinations against the monotherapies. There is no study relied on by AFT which considers this hypothesis as the primary end point.

Mehlisch No. 1 study

162    In the 2018 judgment, I made the following findings concerning the study:

[128]    The Mehlisch No. 1 study compared the pain relief provided to patients undergoing the removal of three to four impacted molars by a single dose of paracetamol (1000mg and 500mg), a single dose of ibuprofen (400mg and 200mg) and combinations of the two monotherapies (1000mg paracetamol/400mg ibuprofen and 500mg paracetamol/200mg ibuprofen).

[129]    The authors noted:

One of the main objectives of this proof-of-concept study was to test the hypothesis that combination therapy with ibuprofen and paracetamol would be more effective than either agent alone when used at their maximum licensed over-the-counter doses, as stipulated by regulatory authorities in the United States.

[130]    The authors also referred to the study as a “pilot study”. There were 234 patients in the intent-to-treat population.

[131]    The authors noted that “doses of ibuprofen and paracetamol were selected to be at or near their analgesic ceiling in relation to their respective dose-response curves”.

[132]    The study’s conclusions included that:

(1)    1000mg paracetamol/400mg ibuprofen provided significantly better mean pain relief than 500mg paracetamol/200mg ibuprofen, with the authors noting that “[a] dose-response effect for SPRID8 [Sum of Pain Relief and pain Intensity Differences from base line (0 hour) to 8 hours after dosing] was observed with combination therapy;

(2)    ibuprofen 400mg/paracetamol 1000mg was ~30% more effective than ibuprofen 200mg/paracetamol 500mg”;

(3)    1000mg paracetamol/400mg ibuprofen provided a higher peak mean pain relief score than 500mg paracetamol/200mg ibuprofen, which was significant at 4 hours;“[at] most time points, patients in the ibuprofen 400mg/paracetamol 1000mg group achieved significantly better mean PID [Pain Intensity Difference] scores than ibuprofen alone, paracetamol alone, and ibuprofen 200mg/paracetamol 500mg”; and

(4)    1000mg paracetamol/400mg ibuprofen provided superior pain relief to 400mg ibuprofen whereas 500mg paracetamol/200mg ibuprofen did not.

[133]    Reckitt noted that 1000mg paracetamol/400mg ibuprofen was found to be no different in efficacy between zero and four hours, compared to the 200mg/500mg combination. Accordingly, Reckitt submitted, there was no better pain relief, at all, over that four hours, between 500mg paracetamol/200mg ibuprofen and 1000mg paracetamol/400mg ibuprofen. As such, Reckitt argued, the Mehlisch No. 1 study provides no basis for any comparison between Maxigesic and any other combination analgesic and furthermore provides no basis for any assertion of superiority of Maxigesic (single dose duration six hours) over one tablet of Nuromol (single dose duration eight hours) in circumstances where there was no difference in efficacy between 500mg paracetamol/200mg ibuprofen and 1000mg paracetamol/400mg ibuprofen over the first four hours.

[134]    Accepting Reckitt’s qualifications set out above, the Mehlisch No. 1 study provides scientific evidence that a combination of 1000mg paracetamol/400mg ibuprofen is a more effective dose than 500mg paracetamol/200mg ibuprofen.

163    AFT noted the observation, in the discussion of the Mehlisch No. 1 study, that:

The results indicated that of the 4 active treatment arms, ibuprofen 400 mg/paracetamol 1000 mg provided significantly better analgesic efficacy than ibuprofen 400 mg alone and paracetamol 1000 mg alone on virtually every outcome measure, including the primary end point. Although ibuprofen 400 mg/paracetamol 1000 mg was also significantly better than ibuprofen 200 mg/paracetamol 500 mg on a number of efficacy end points, the lower-dose combination was nonetheless often more effective than both ibuprofen 400 mg alone and paracetamol 1000 mg alone.

164    Dr Russo expressed his own opinion as to what was demonstrated by the study “in the eight hour study period”, including that:

(1)    500mg paracetamol/200mg ibuprofen provided superior analgesic efficacy than 1000mg paracetamol alone and possible superior analgesic efficacy than 400mg ibuprofen alone; and

(2)    1000mg paracetamol/400mg ibuprofen likely provided superior analgesic efficacy than 500mg paracetamol/200mg ibuprofen.

165    Dr Russo also expressed the following opinion based on his review of a summary table of the secondary end points used in the study to test comparative speed of onset:

Based on my review of these results, I consider that the secondary endpoints of “time to first meaningful pain relief’ and “time to pain half gone” are most relevant to assessing speed of analgesia. In this regard, I note that participants in both 1000mg paracetamol/400mg ibuprofen and 500mg paracetamol/200mg ibuprofen arms achieved faster times to first meaningful pain relief and pain half gone than ibuprofen 400mg, paracetamol 1000mg and placebo. Accordingly, I consider that the combination treatments will likely provide faster pain relief than either paracetamol or ibuprofen.

166    Reckitt made the following observations concerning the study:

The Mehlisch No 1 Study was a “proof of concept” study for the Mehlisch No 2 Study. A proof of concept study is conducted to test whether the next cycle of investment is justified. Thus the Mehlisch No 1 Study had only 234 patients, whereas the later Mehlisch No 2 Study had 735 patients. Neither study analysed Maxigesic or a combination analgesic with the same formulation as Maxigesic. Neither study analysed any comparison between a combination analgesic and the monotherapies beyond eight hours. Neither study provides any data about Maxigesic or any data about analgesic efficacy after eight hours.

… AFT claim that Mehlisch No 1 concluded that 1000mg paracetamol/400mg ibuprofen and 500mg paracetamol/200mg ibuprofen achieved faster times to meaningful pain relief than ibuprofen and paracetamol alone. However they failed to mention the results for the 1000mg paracetamol/400mg ibuprofen comparison to the monotherapies were not statistically significant and neither was the 500mg paracetamol/200mg ibuprofen comparison for ibuprofen alone.

Mehlisch No. 2 study

167    In the 2018 judgment, I made the following relevant findings:

[135]    The Mehlisch No. 2 study was two stage clinical trial that was designed to confirm and extend the findings of the Mehlisch No. 1 study and to generate data for regulatory purposes. A total of 735 patients were randomly assigned in stage one and 715 entered and 678 completed stage two.

[136]    The report of the study described its objectives as follows:

This study was a 2-stage clinical trial that was designed to confirm and extend the findings of the earlier study in the same dental plain model and to generate data for regulatory purposes. The objective of stage 1 was to compare the efficacy and tolerability of 3 doses of a single-tablet fixed-dose combination (FDC) of ibuprofen and paracetamol (ibuprofen 100 mg/paracetamol 250 mg, ibuprofen 200 mg/paracetamol 500 mg, and ibuprofen 400 mg/paracetamol 10000 mg) with comparable doses of ibuprofen monotherapy, paracetamol monotherapy, and placebo. In addition, and from a clinical dosing standpoint, it was of interest to compare results for the FDC ibuprofen 200 mg/paracetamol 500 mg with ibuprofen 400 mg alone and paracetamol 1000 mg alone. The objective of stage 2 was to compare the efficacy and tolerability of the same 3 doses of the FDC with each other and with placebo over the 72 hour postoperative period following stage 1.

[137]    The stated conclusion of the report was:

FDC ibuprofen 200 mg/paracetamol 500mg and ibuprofen 400 mg/paracetamol 1000 mg were significantly more effective in this population than were comparable doses of ibuprofen or paracetamol alone in moderate to severe acute dental pain and were significantly more effective than placebo in providing sustained pain relief.

[138]    The Mehlisch No. 2 study (a) did not find a statistically significant difference between 1000mg paracetamol/400mg ibuprofen and 500mg paracetamol/200mg ibuprofen, and (b) found that 1000mg paracetamol/400mg ibuprofen was superior to 400mg ibuprofen but that 500mg paracetamol/200mg ibuprofen was not.

[139]    AFT noted the following observations of the report’s authors:

The dental pain model is widely used to evaluate the efficacy of analgesic agents such as NSAIDs [Nonsteroidal Anti-inflammatory Drugs] and paracetamol ... The dental pain model has a proven record of assay sensitivity in separating active drugs from each other and from placebo and has the potential to demonstrate additional pain relief with combination therapy (ie, upside model sensitivity).

168    AFT referred to the conclusion set out at [137] of the 2018 judgment. AFT also referred to the following statement in the study:

Overall, analgesia had a faster onset, was more effective, and had a longer duration with the FDC regimens than with monotherapy or placebo in the immediate post-operative period (stage 1).

169    Based on his review of the secondary end points result in the study, and relevant discussion in the study publication, Dr Russo’s opinion was as follows:

I consider that the study provides evidence that 500mg paracetamol/200mg ibuprofen provides faster pain relief than 250mg paracetamol/100mg ibuprofen, 1000mg paracetamol, 400mg ibuprofen and 200mg ibuprofen. This is because the time to meaningful pain relief (based on a Kaplan-Meier median) was the lowest for the 500mg paracetamol/200mg ibuprofen (39.3 minutes) compared with the lower dose combination (45.9 minutes), ibuprofen (70.5 minutes for 400mg and 80.0 minutes for 200mg) and 1000mg paracetamol (45.6 minutes).

170    Reckitt submitted that AFT did not dispute that of the six time to pain relief measurements reported, none of the results were statistically significant in respect of the combination versus paracetamol except for time to meaningful pain relief.

Ong review (2010)

171    The Ong review, entitled “Combining paracetamol (Acetaminophen) with Nonsteroidal Antiinflammatory Drugs: A Qualitative Systematic Review of Analgesic Efficacy for Acute Postoperative Pain”, was a systematic review of literature from 1988 to 2009 of 32 randomised controlled trials that compared combinations of paracetamol with various NSAIDs versus at least one of these constituent drugs. The review states the following conclusion: “Current evidence suggests that a combination of paracetamol and an NSAID may offer superior analgesic compared with either drug alone.”

172    Dr Russo stated that the Ong review reported the following:

(a)     In 17 out of 20 studies (~85%) comparing NSAIDs / paracetamol combinations against paracetamol alone, the combination “was more effective than paracetamol alone in terms of lower pain scores, lower supplemental analgesic requirements, or better globally assessed pain relief (positive studies).” (see page 1171 ).

(b)    NSAID / paracetamol combinations were more effective than paracetamol in 4 out of 5 studies involving the dental pain model (see page 1171).

(c)    In 9 out of 14 studies (~64%) comparing NSAIDs / paracetamol combinations against NSAID alone, the combination “more effective than an NSAID alone in terms of lower pain scores, lower supplemental analgesic requirements, or better globally assessed pain relief for the combination group" (see page 1174).

(d)    NSAID / paracetamol combinations were more effective than NSAID alone in 3 out of 4 studies involving the dental pain model (see page 1171).

173    Dr Russo expressed the view that the Ong review “indicates … that there is highly likely a “class response” in terms of the superior analgesic efficacy of NSAIDs (as a class of drugs) when combined with paracetamol, over their individual constituents.

174    Reckitt noted the following concerning the review:

(1)    The review was a literature review and the authors noted that its “limitations” included: (a) its “qualitative approach”; (b) “the wide range of acute pain models included in the studies reviewed”; and (c) the fact that “[a] quantitative meta-analysis” was not possible for the studies reviewed “because of heterogeneity of study design”. Dr Russo acknowledged these matters in cross-examination.

(2)    Only three of three trials considered by the review compared a paracetamol/ibuprofen combination to ibuprofen alone: the Dahl, Menhinick and Viitanen studies. Of these:

(a)    the Dahl Study showed “no difference in outcome measures” (i.e. pain scores and supplemental analgesic requirements) as between the combination analgesic and ibuprofen alone;

(b)    the Menhinick study is not relied upon by AFT except as “early research” indicating that combination analgesics are likely to provide better analgesia than individual drugs; and

(c)    the Viitanen study considered single rectal doses of the study drugs in relation to paediatric tonsillectomy.

Doherty study

175    The Doherty study was tendered by Reckitt in cross-examination. It illustrates the distinction made by the experts between acute and chronic pain models. The Doherty study utilised a chronic pain model, with participants aged over 40 years, experiencing osteoarthritic pain for more than three months. AFT did not dispute Reckitt’s submissions about the findings of the study, including that the study showed no superiority of two fixed-dose combination tablets over ibuprofen at ten days.

Adequate scientific foundation for claims and representations?

Maxigesic provides better pain relief

176    AFT argued that there is an adequate scientific foundation for its claims about better pain relief for the following three reasons:

(1)    The primary end point of the Daniels 2018 study (SPID48) provides a foundation for these claims. Ultimately, there appeared to be little dispute about this among the experts. The SPID6 results reported in the Daniels 2018 study also provide support these claims. Further, several of the secondary end points of the Daniels 2018 study, including mean consumption of rescue medication (mg) and percentage of patients requiring rescue medication, provide further support for the claims. The results of the Daniels 2018 study can be read directly on to Maxigesic. There is common ground between the experts that, to the extent that the fasted Cmax difference is of any relevance, its relevance would bear upon to the time to perceptible pain relief, rather than the extent of relief. That does not concern the primary end point or AFT’s claims in the new advertisement insofar as they claim “better” relief.

(2)    The wider body of scientific literature provides strong support for the conclusion that the combination of 400mg ibuprofen/1000mg paracetamol will provide better pain relief than 400mg ibuprofen or 1000mg paracetamol as monotherapies.

(3)    Insofar as the claims refer to Maxigesic being 36% more effective than ibuprofen and 78% more effective than paracetamol, those claims are based on the primary end point of the Daniels 2018 study and the derivation of the percentages is a matter of mathematics. The percentages are not to be understood as absolute figures, but rather the percentages achieved in the Daniels 2018 study itself. It can be recognised that a different study may achieve different percentages, but that is not the point.

177    As to the first point, the experts’ agreement is more specific than AFT acknowledges. The agreed statement was:

45.    We agree that the Daniels Study demonstrated better pain relief, as measured by the SPID48, for the Daniels FDC as compared to equivalent amounts of each of the monotherapies, each delivered as three tablets every 6 hours. The Daniels FDC produced greater cumulative pain relief by 6 hours (SPID6) than either paracetamol or ibuprofen produced by 48 hours (SPID48).

178    The new advertisement can be read as a set of claims about the results of the Daniels 2018 study. As I understood the evidence of Dr Russo and Professor Thisted, each of them read the advertisement in that manner. I accept that a reasonable reader may read the new advertisement in that way, particularly because of the extensive use of footnotes and the reference, in the body of the advertisement, to a “new clinical study of moderate to severe dental pain” which “shows that Maxigesic provides better and faster pain relief …”. On that reading of the new advertisement, I accept, for example, that the primary end point of the Daniels 2018 study (SPID48) provides a foundation for the claim that Maxigesic provides better pain relief than paracetamol or ibuprofen alone. On that reading, it is implicit that the claim of better pain relief is limited to better pain relief as measured by the Daniels 2018 study, extrapolated onto Maxigesic on the basis of the Aitken study.

179    However, the case proceeded on the basis that the advertising materials conveyed much broader representations. For example, the first agreed representation, that Maxigesic is more efficacious than paracetamol or ibuprofen alone, is unrestricted as to the nature of the pain treated, the dosage of the drugs taken and the duration of treatment. There was no expert evidence that the results of the Daniels 2018 study could be extrapolated to an unqualified statement that Maxigesic is more efficacious than paracetamol or ibuprofen alone in all contexts. To the contrary, the experts agreed that the Daniels 2018 study is not directly informative concerning degree of pain relief in contexts other than the acute pain dental impaction setting. The experts also agreed that one cannot extrapolate effectiveness in pain control from acute pain models, such as was used in the Daniels 2018 study, to chronic pain settings.

180    Similarly, neither the experts collectively, nor Dr Russo individually, gave evidence that the implications of the wider body of scientific literature are as far reaching as AFT now contends. The broadest statement is in the Acute Pain Management text but, on closer examination, that does not support an unqualified claim that Maxigesic provides better pain relief than either paracetamol or ibuprofen alone.

181    As to the claims referring to Maxigesic being 36% more effective than ibuprofen and 78% more effective than paracetamol, I accept that those claims are based on the primary end point of the Daniels 2018 study and the derivation of the percentages is a matter of mathematics.

182    However, since the Daniels FDC contained different quantities of paracetamol and ibuprofen from Maxigesic, the relative effectiveness of Maxigesic to corresponding treatment with ibuprofen and paracetamol separately cannot be assumed to match the figures for the Daniels FDC. Professor Keech’s view that the true numbers would be different by an unknown amount, even though we would expect them to be very similar. Professor Thisted agreed that the results would not be identical if the Daniels 2018 study was replicated using Maxigesic, but held “that the percentage differences in pain relief should be substantially similar and the 36% and 78% figures would not misrepresent them”.

Maxigesic provides faster pain relief

183    AFT relied on the following two matters to support its contention that there is an adequate scientific foundation for its claims about faster pain relief:

(1)    the secondary end point of the Daniels 2018 study of median time to meaningful pain relief; and

(2)    the wider body of scientific literature, in particular, the Mehlisch studies and the Daniels 2011 study.

184    AFT relied on Dr Russo’s evidence that, from a clinical perspective, time to meaningful pain relief is relevant rather than time to perceptible pain relief. The significance of this observation was that the Daniels 2018 study did not report statistically significant results in favour of the Daniels FDC for the following end points:

(a)    time to perceptible pain relief;

(b)    time to peak response;

(c)    time to perceptible pain relief confirmed by meaningful pain relief; and

(d)    time to requirement of rescue medication in the first dosing interval.

185    In particular, Dr Russo said:

… I disagree that time to perceptible pain relief is the appropriate measure for determining “better and faster”' analgesia. In my view, as I stated above, from a clinical perspective, I am more interested in faster onset of analgesia, meaning that a patient’s pain has decreased by a meaningful (and not trivial) amount. This is measured in the Daniels Study by “median time to meaningful pain relief”, where [Daniels] FDC outperformed the monotherapies. By contrast, time to perceptible pain relief is merely marking the point at which any differences in the patient’s perceptible pain was reported. In my view, this does not provide an accurate picture of the onset or degree of analgesia, and is less clinically significant.

186    AFT also relied upon the following passage of the oral evidence of Dr Russo:

MR MURRAY: No. And do you agree that quicker perceptible relief is likely to be desirable?

DR RUSSO: Not really, no.

MR MURRAY: And that’s because in your opinion, it’s meaningful relief that’s the relevant measure.

DR RUSSO: Yes. I mean, when you talk about perceptible pain relief, the instructions – how that’s defined is press this button on the stopwatch as soon as you think you can detect any sort of change downwards in your pain at all.

MR MURRAY: Yes.

DR RUSSO: So typically we’ve seen in studies that that represents a three per cent to a five per cent reduction that people typically will press the button at.

MR MURRAY: Yes.

DR RUSSO: So if your pain is eight out of 10 and it then goes to 7.84 out of 10, that is not a meaningful difference that makes any difference to the patient’s suffering, for example. You’re still in severe pain. So there’s a concept of minimum clinically important difference and that is typically defined by a .5 or more reduction on a VAS scale or – or a 30 per cent reduction global pain levels and that is what appears to be significant to patients when you ask their opinion. Doctors typically use 50 per cent, but that turns out to be a conservative measure. And you won’t find that with perceptible; you will find that with – when asking people to record their meaningful pain relief or their maximum pain relief.

187    Reckitt submitted that, even without adjustment for multiple hypotheses testing, four of the six secondary end points in the Daniels study that measured the speed of efficacy of the Daniels FDC did not reach statistical significance for one or both of the monotherapies. These secondary end points were:

(a)    median time to perceptible pain relief;

(b)    median time to peak response;

(c)    median time to perceptible pain relief confirmed by meaningful pain relief; and

(d)    median time to the requirement of rescue medication within the first dosing interval.

188    Reckitt also argued that, having regard to the identification in the Daniels 2018 study of the “key secondary endpoint” which included time to perceptible pain relief, and the references to the testing of time to perceptible pain relief in the SAP and the study protocol, it is not tenable to dismiss the results on that end point as irrelevant. As Professor Keech put it:

… [T]o the extent that a patient is given an analgesic product after a wisdom tooth extraction and asks the question, “When is this going to work”, then it’s obviously relevant as the designers of the study indicated themselves in designing it as a secondary [end point].

189    I am satisfied that the Daniels 2018 study secondary end point of median time to meaningful pain relief provides an adequate scientific foundation for the statement that Maxigesic provides “Faster onset of meaningful pain relief than for paracetamol or ibuprofen alone”, where it is implicit that the statement is limited to speed of onset as measured by the Daniels 2018 study, extrapolated onto Maxigesic on the basis of the Aitken study.

190    Otherwise, I am not satisfied that the single secondary end point provides an adequate scientific foundation for a claim of faster pain relief because the Daniels FDC results did not achieve statistical significance for all secondary end points related to time to pain relief.

191    As to the wider body of scientific literature, I am not satisfied that the Daniels 2011 study supports a claim that Maxigesic provides faster pain relief than either paracetamol or ibuprofen because that study did not assess the comparative efficacy of either paracetamol or ibuprofen as a monotherapy.

192    I am not satisfied that the Mehlisch No. 1 study supports a claim to this effect for the reasons identified by Reckitt, that is, it studies different formulations of the combination analgesic (1000mg paracetamol/400mg ibuprofen and 500mg paracetamol/200mg ibuprofen) and the results for time to pain relief included results that lacked statistical significance.

193    I am also not satisfied that the Mehlisch No. 2 study supports a claim to this effect because it studies different formulations of the combination analgesic and again because the results for time to pain relief included results that lacked statistical significance.

Conclusions about statements in new advertisement

194    I accept that AFT has an adequate scientific foundation, in the Daniels 2018 study, read with the Aitken study, for the statements which appear in the new advertisement, to the extent to which they are read as reporting the results of the Daniels 2018 study:

(1)    “Faster onset of meaningful pain relief than for Paracetamol or Ibuprofen alone1”;

(2)    “Maxigesic® is a unique Paracetamol+Ibuprofen combination that provides superior analgesic efficacy for patients than either Paracetamol or Ibuprofen alone1.”

(3)    “PROVEN TO PROVIDE MORE EFFECTIVE PAIN RELIEF IN A NEW CLINICAL STUDY” ; and

(4)    “36% MORE EFFECTIVE THAN IBUPROFEN1 & 78% MORE EFFECTIVE THAN PARACETAMOL1”.

195    As presented in the new advertisement, the statements are referrable to the study results. For example, the advertisement read with its footnotes indicates that the claim to provide “faster onset of meaningful pain relief” is supported by the result for that secondary end point in the Daniels 2018 study.

196    However, even reading the new advertisement as making statements that can only be understood by reference to the Daniels 2018 study, I am not persuaded that the statements which claim “faster pain relief” have an adequate scientific foundation because the Daniels FDC did not meet the stated “key secondary endpoint”, which concerned time to pain relief, to a statistically significant degree or, alternatively, because it did not meet the stated end point of time to perceptible pain relief to a statistically significant degree.

Conclusions about representations

197    On the basis of the findings set out above, the following unqualified representations do not have an adequate scientific foundation:

(1)    Maxigesic is more efficacious than paracetamol or ibuprofen alone;

(2)    Maxigesic provides better and faster pain relief than both paracetamol or ibuprofen alone;

(3)    Maxigesic provides better and faster pain relief than both paracetamol or ibuprofen alone at maximum dosage;

(4)    Maxigesic provides 36% more effective pain relief than ibuprofen and 78% more effective pain relief than paracetamol; and

(5)    Maxigesic provides better pain relief than paracetamol and ibuprofen alone.

198    The reason for these conclusions is that each of the representations is unlimited as to nature of pain, dosage and treatment duration. As explained above, the scientific evidence is addressed to much more specific comparisons and the expert evidence does not support a conclusion that there is an adequate scientific basis for extrapolating from the Daniels 2018 study and the wider body of scientific evidence to the unqualified representations. Even the evidence of Dr Russo and Professor Thisted, that the Daniels 2018 study provides an adequate scientific foundation for the statements in the new advertisement, must be understood in the context of their agreement that the study is not directly informative concerning degree of pain relief in contexts other than the acute pain dental impaction setting. As I understood their evidence on this point, it was predicated upon an assumption that the claims in the advertisement are addressed to the treatment of acute pain.

199    Further, there is no adequate scientific foundation for making the restrained representation.

200    It follows that the five representations listed above are misleading or deceptive or likely to mislead or deceive. By making those representations in the new advertisement, and to the extent that there has been any publication of the training aid or the POS materials, AFT has engaged in conduct in contravention of ss 18, 29(1)(g) and 33 of the Australian Consumer Law.

201    By making the restrained representation in the new advertisement, AFT has breached order 12 of the orders made on 29 November 2018.

Conclusion

202    I will direct the parties to file and serve short minutes of orders to give effect to these reasons.

Associate:

Dated:    21 May 2020