LUNDBECK AUSTRALIA PTY LIMITED and MINISTER FOR HEALTH AND AGEING

[2009] AATA 445

Administrative Appeals Tribunal

DECISION AND REASONS FOR DECISION [2009] AATA 445 

ADMINISTRATIVE APPEALS TRIBUNAL      )

)          No 2008/5840

GENERAL ADMINISTRATIVE DIVISION		)
Re		LUNDBECK AUSTRALIA PTY LIMITED

Applicant

And MINISTER FOR HEALTH AND AGEING

Respondent

DECISION

Tribunal Mrs Josephine Kelly, Senior Member
Dr T M Schafer (formerly Baker), Member

Date19 June 2009

PlaceSydney

Decision We are not satisfied that it is reasonable in all the circumstances of this case to extend the time for the making of the application for review of the decision of the Minister's delegate dated 12 May 2006.  The application is refused.

...................[sgd]...........................

Presiding Member
  Mrs Josephine Kelly, Senior Member

CATCHWORDS

PRACTICE AND PROCEDURE – Extension of time application - Therapeutic Goods Administration – Application for registration of Azilect (rasagiline) – Rejected – Whether Tribunal satisfied reasonable in all circumstances to grant extension to review – Held no acceptable explanation for two and a half year delay – Prospects of success of substantive application not reasonable  - Application refused

Administrative Appeals Tribunal Act 1975, ss, 25, 29

Therapeutic Goods Administration Act 1989, ss 3, 4, 16, 23, 29, 60, 60A

Comcare v A’Hearn (1993) 45 FCR 44

Hunter Valley Developments Pty Ltd v Cohen (1984) 3 FCR 344

Minister for Health and Aged Care v Pharmacia and Upjohn Pty Ltd (2001) 65 ALD 76

Re Eli Lilly Australia Pty Ltd and Minister for Health and Family Services (1999) 56 ALD 541

Re Pharmacia & Upjohn Pty Ltd and Minister for Health and Aged Care (2000) 58 ALD 285

Re Roussel Uclaf Australia Pty Ltd and Minister for Family Services (1994) 35 ALD 645

REASONS FOR DECISION

19 June 2009 Mrs Josephine Kelly, Senior Member
Dr T M Schafer, Member   

SUMMARY

1.          The Applicant in these proceedings, Lundbeck Australia Pty Ltd, (Lundbeck) is the Australian sponsor of the drug Azilect (rasagiline mesylate) 1 mg tablet (rasagiline), a new chemical entity for the treatment of idiopathic Parkinson's disease, both as monotherapy and as an adjunct therapy to levodopa.

2.          On 31 March 2004, Lundbeck applied to the Therapeutic Goods Administration (TGA) to register rasagiline for the treatment of idiopathic Parkinson's disease, both as monotherapy and as an adjunct therapy to levodopa, at a dose of 1 mg once daily.

3.          The Delegate of the Secretary, Department of Health and Ageing (the Delegate) rejected Lundbeck's application on 16 December 2005 (the initial decision).  On review, the Delegate of the Minister for Health and Ageing (the Minister's Delegate) affirmed that decision, on 12 May 2006.

4. On 8 December 2008, more than two and a half years later, Lundbeck applied to this Tribunal, pursuant to s 29(7) of the Administrative Appeals Tribunal Act 1975 (the AAT Act), to extend the time for making an application for a review of the decision made by the Minister's Delegate.

5.          For the reasons that follow, we have decided not to grant Lundbeck's application for an extension of time.

ISSUE

6.          The issue is whether we are satisfied that it is reasonable in all the circumstances of the case to grant Lundbeck's application for an extension of time for making an application to the Tribunal for a review of the decision of the Minister's Delegate dated 12 May 2006.

THE CASE FOR LUNDBECK

7.          Mr Anforth, counsel appearing for Lundbeck, provided written and oral submissions for our consideration.  In summary, the matters he relied upon are: 

1.There is a reasonable explanation for Lundbeck's delay in making an application for review to this Tribunal.  It was hesitant to press its application on the basis of the evidence available in May 2006 and needed to await the outcome of the "ADAGIO study". It  was also monitoring developments in Canada, the United States (US) and the European Union (EU).   A further matter which Mr Anforth  emphasised in his initial written submissions but which we did not understand him to press strongly in his further submissions or orally, was Lundbeck's lack of awareness until it recently obtained legal advice that it could seek an extension of time in which to make the application for review to this Tribunal.

2.The outcome of the ADAGIO study now demonstrates that rasagiline is even more efficacious than previously thought.  Concerns about the safety of rasagiline , specifically in relation to melanoma, lack merit.  This is  supported by the registration of the drug in other jurisdictions.  Therefore, the  prospects of success of the substantive application are reasonable.

3.If this application for extension of time is rejected, Lundbeck and Parkinson’s disease sufferers will suffer the following detriment.   First, Lundbeck will have to pay another application fee of about $175,000.   Secondly, if a new application has to be made to the TGA, Lundbeck and Parkinson’s disease sufferers will have to wait at least another two years before this efficacious drug is available.  If this application is granted, the Tribunal will  be able to finalise the matter in a shorter time frame which would be consistent with  the objective of timeliness in the Therapeutic Goods Act 1989 (the Act).  Mr Anforth argued that the Respondent would suffer no prejudice if the application is granted.  

4.The Respondent's submission that Lundbeck is now seeking registration for a different "indication" from that for which registration was originally sought, is incorrect.

CONSIDERATION

8.          We have taken into account all the evidence before us and the written and oral submissions made on behalf of the parties. We set out below the regulatory history and legal framework, and then address each of the matters relied upon in support of the case put on behalf of Lundbeck.

The Regulatory History

9.          Following is a summary of the relevant regulatory history of Lundbeck's application to register rasagiline:

(a)On 22 November 2004, the TGA issued a clinical evaluation report in relation to the application to register rasagiline.  The clinical evaluator recommended rejection of the application because of deficits in the efficacy data provided in the dossier and the statistically significant adverse results for two of the pre-defined safety variables in one of the clinical studies supporting registration.

(b)The Delegate's Overview in relation to the application was issued on 24 June 2005.  Despite the clinical evaluator's concerns, the Delegate considered that the efficacy of rasagiline had been satisfactorily established, and proposed to approve rasagiline at a dose of 1 mg per day for the symptomatic treatment of idiopathic Parkinson's disease as monotherapy (without concomitant levodopa/decarboxylase inhibitor therapy) or as adjunct therapy (with concomitant levodopa/decarboxylase inhibitor therapy).

(c)At its meeting held on 4-5 August 2005, the Australian Drug Evaluation Committee (ADEC) resolved that there should be no objection to the approval of Lundbeck's submission to register rasagiline for:

"the symptomatic treatment of idiopathic Parkinson's disease as monotherapy (without concomitant monotherapy) or as adjunct therapy (with concomitant levodopa/decarboxylase inhibitor therapy)".

(d)On 22 August 2005, the Delegate wrote to Lundbeck and stated that he had decided to accept ADEC's recommendation for approval, but noted that before approving registration of the product it was necessary for the content of the product information to be finalised.  However, the Delegate also stated that the application raised a number of other regulatory matters, which it asked Lundbeck to provide comments to by 2 September 2005.

(e)Lundbeck wrote to the TGA on 1 September 2005 and 2 September 2005 addressing the Delegate's letter of 22 August 2005 and providing a revised product information.

(f)On 8 September 2005, the Delegate again wrote to Lundbeck requesting further changes to the product information and commenting on Lundbeck's responses to the other regulatory matters.

(g)On 24 October 2005, the Delegate wrote to Lundbeck advising them that following further consideration of the available data on the association between rasagiline and melanoma, he was proposing to reject the application, even though he had initially proposed to register the drug and subsequently indicated to Lundbeck that he had decided to accept the positive recommendation of ADEC.  The Delegate advised that, as this was an unexpected development, Lundbeck was invited to comment on the proposed action and provide any additional information which Lundbeck considered might address the TGA's concerns.

(h)On 16 December 2005, the Delegate wrote to Lundbeck and decided, pursuant to section 25 of the Act, not to approve the registration of rasagiline on the grounds that the evaluation had failed to satisfactorily establish the drug's safety for the proposed indication.  In particular, the Delegate was concerned about the increased incidence in melanoma associated with Azilect treatment.

(i)On 14 March 2006, Lundbeck submitted an appeal to the Minister for Health and Ageing (the Minister) pursuant to section 60 of the Act appealing the Delegate’s initial decision. Lundbeck disagreed with the Delegate’s opinion regarding rasagiline’s safety for the proposed indication and submitted evidence in support of rasagiline. 

(j)On 12 May 2006, the Minister's Delegate decided to uphold the initial decision of the Delegate not to register rasagiline.  The Minister's Delegate remained unconvinced of the safety of rasagiline for the treatment of idiopathic Parkinson’s disease, in particular in relation to the possible increased incidence of melanoma in patients treated with rasagiline. At the end of the decision letter was written:

“Your rights of appeal

Should you be dissatisfied with the results of this appeal you may, subject to the Administrative Appeals Act 1975, appeal to the Tribunal for review of the Minister's/Delegate's decision.”

The legal framework

10. The effect of ss 29(1)(d) and 29(2)(a) of the AAT Act was that Lundbeck was required to lodge an application for review in this Tribunal within 28 days of the date Lundbeck was given a copy of the Minister’s Delegate’s decision and reasons dated 12 May 2006. As already stated, the application for an extension of time was lodged on 8 December 2008.

11. Section 29(7) of the AAT Act confers a discretion on this Tribunal to extend the time for making an application. The parties accept that the applicable principles to be followed are those set out by Wilcox J in Hunter Valley Developments Pty Ltd v Cohen (1984) 3 FCR 344, as qualified by the Full Federal Court in Comcare v A'Hearn (1993) 45 FCR 441.

Explanation for the delay

12.        We find, on the evidence, that the reason Lundbeck did not make an application until the end of 2008 was that it did not have any additional data to support its case until some preliminary results from the ADAGIO study became available in late 2008, which it maintains supports its application.

13.        We do not accept that the monitoring of regulatory developments in other countries was a material reason for the delay. Rasagiline was approved in the EU on 21 February 2005, before the initial decision was made, and in the US on 17 May 2006, five days after the decision of the Minister's Delegate, and within the 28 day time frame for application for review to this Tribunal.  Lundbeck had informed the Minister's Delegate of the EU approval in its section 60 appeal, but that did not cause the Minister's Delegate to decide that the drug should be registered.  In Canada, Azilect was approved on 21 August 2006.  We infer that Lundbeck did not consider that the approvals in the EU and the US were of such weight as to justify an application for review in May/June 2006.   Such a view would be consistent with this Tribunal's decision in Re Roussel Uclaf Australia Pty Ltd and Minister for Family Services (1994) 35 ALD 645 that the fact that a drug is registered in other countries does not assist the Tribunal in determining whether or not a drug should be registered in Australia.

14.        We also do not accept that a lack of knowledge that it could seek an extension of time was a factor in the delay. Lundbeck relied on three documents apparently the property of Teva Pharmaceutical Industries (Teva) which came into existence from late 2008 onwards in support of this application.  The earliest in time is entitled: "Rasagiline Mesylate Synposis TVP-1012500 (ADAGIO) DRAFT December 17, 2008" (the draft synopsis)”.  We infer that Lundbeck acted as soon as it found out that preliminary results of that trial supported its application.

15.        We accept Mr Anforth's submission that it is not a precondition for success in the present application that an acceptable explanation for the delay must be given “although it is to be expected that such an explanation will normally be given, as a relevant matter to be considered” (Comcare v A’Hearn at 444).

16.        We do not consider the explanation given in this case is acceptable.  As Wilcox J said in Hunter Valley Developments Pty Ltd at 348, the 28 day time frame is not to be ignored, and we need to be positively satisfied that it is proper to grant the application.   Further, there is no evidence that Lundbeck has made the Respondent aware that it was contesting the finality of the decision.  Indeed, we find that Lundbeck had no such intention until the preliminary results of the ADAGIO study became available in late 2008.   

17.        The circumstances in this case are not analogous to those in Re Pharmacia & Upjohn Pty Ltd and Minister for Health and Aged Care (2000) 58 ALD 285. In that case the application was not lodged due to expectations that the application would be unsuccessful. It was only after the Tribunal approved a similar product with identical properties to that produced by the applicant for the same therapeutic purpose, that the application was lodged. There has been no such proceeding or decision by the Tribunal in this case. Further, for the reasons that follow, we do not agree with Lundbeck's assertion that its substantive application has reasonable prospects of success.

The merit of the substantive application

18.        Mr Anforth's emphasis on the ADAGIO study requires us to scrutinise carefully the documents Lundbeck relies upon.

19.        When a sponsor submits an application for registration, it is required to provide sufficient data to demonstrate that the quality, safety and efficacy of the drug for the purposes for which it is to be used have been satisfactorily established (section 25(1)(d) of the Act).

20.        The Delegate rejected the application for registration for rasagiline because he was not satisfied on the evidence submitted by Lundbeck that the safety of rasagiline had been established.  In particular, the Delegate was concerned that there was an increased incidence of melanoma associated with rasagiline treatment.

21.        Although the clinical evaluator had expressed concerns about the efficacy of rasagiline and proposed rejection on efficacy grounds during the TGA's evaluation of rasagiline, the Delegate did not share those concerns and was satisfied that the efficacy of rasagiline in the treatment of idiopathic Parkinson's disease had been satisfactorily established.  The initial decision by the Delegate to reject the application to register rasagiline was on the basis that its safety had not been satisfactorily established.

22.        However, the Applicant has contended that "new, important evidence" from the ADAGIO study demonstrates that the drug has important disease-modifying properties in addition to merely treating symptoms, as is the case with most other drugs for the indication of Parkinson's disease. This trial, Lundbeck contends, demonstrates that rasagiline slows the progression of Parkinson's disease, which is considered the most important un-met need in the management of the disease.

23.        That is, the results of the ADAGIO study, which Lundbeck refers to as "new, important evidence", relate to the efficacy of rasagiline, not to its safety.

24.        As stated earlier, the statutory framework that underpins the requirements for registration of rasagiline provides that, for an application to be approved, the sponsor must demonstrate that the quality, safety and efficacy of the goods for the purposes for which they are be used have been satisfactorily established.  In relation to the application for registration of rasagiline, in the view of the Minister's Delegate, the quality and efficacy of rasagiline had been established, but there was insufficient data to support its safety.

25.        Even if we accept that the ADAGIO study demonstrated additional efficacy benefits associated with rasagiline treatment, it is the safety concerns that were the reason for rejection of the application.  In Re Eli Lilly Australia Pty Ltd and Minister for Health and Family Services (1999) 56 ALD 541 at 553, this Tribunal said:

"In matters of this kind, we consider that we should be guided by the evidence given by those qualified to offer opinions on technical matters......the test would still be whether the changes effected by the proposed therapy are efficacious in serving the intended indication. They may serve it well or they may serve it indifferently. Some products are 'wonder drugs', others have a more common place effect. So long as they produce what they claim to do, then we do not see it as part of our function to give marks in accordance with the excellence of results... There must be at all times a level of safety appropriate to the intended therapy".

26.        We now consider the three documents, apparently from Teva, which were relied on by Lundbeck in relation to its argument that the substantive application has reasonable prospects of success.  The first in time was the draft synopsis dated  December 17, 2008. The first page appears to be letterhead for TEVA Pharmaceutical Industries Ltd.  The details included: 

TEVA
            TEVA PHARMACEUTICAL INDUSTRIES LTD

Global Innovative P & D, PO Box 8077, Sapir Ind. Zone, Netanya 42504, Israel, Tel: + 972-9-863-9715 Fax: [phone]

27.        The objective of the study was: “To assess rasagiline as a disease modifying therapy in Parkinson’s disease”. There is no reference in this draft synopsis to melanoma, including in the section addressing “safety”. The conclusion stated in the document in relation to safety was: "Overall the data of this study does raise any new safety issues”. On the material before us, it is clear that the possible relationship between an increased incidence of melanoma with rasagiline treatment of Parkinson’s disease sufferers was not a "new safety issue".

28.        The second document is entitled “Rasagiline Mesylate Melanoma Safety Update” dated “January 2009" (the Safety Update). It is a review of data about the reported incidence of melanoma related to treatment with rasagiline. On its face it states:

“This confidential document is the property of Teva Pharmaceutical Industries Ltd. No information contained herein may be disclosed without the prior written approval of Teva Pharmaceutical Industries Ltd”.  

29.        That document did not have the letterhead details that appear on the first page of the draft synopsis.

30.        The Safety Update refers to three sources of data: from the Adagio trial; 15 clinical trials that comprised the original clinical development program of rasagiline as a symptomatic anti-Parkinson’s disease drug; and two clinical trials to assess rasagiline in Alzheimer’s disease patients. The stated conclusion is that the sponsor does not believe that the data presented in that document indicates a causal relationship between melanoma and rasagiline treatment.

31.        In relation to the Adagio trial, the Safety Update states that the screening for that trial excluded subjects diagnosed with melanoma based on a skin examination by a dermatologist, subjects with a history of melanoma, and subjects with suspicious lesions at baseline who did not undergo a biopsy that examination. Randomized subjects were required to undergo a repeat skin examination at Weeks 36 and 72 or at an early termination visit. Subjects diagnosed with malignant melanoma during the trial were to be discontinued. The result was that only one rasagiline-treated subject was diagnosed with melanoma. No placebo subjects were diagnosed with melanoma during 361.5 patient years of placebo follow up.

32.        The third document relied on was on TEVA letterhead and was entitled "Regulatory Background" and dated "February 2009".  It set out information about the regulatory approvals of rasagiline in the EU, the US and Canada, information about labelling changes required by the Food and Drug Administration (FDA) in the US as of 27 March 2007, and an alteration as of 15 June 2007 to the kind of study the FDA required TEVA to undertake in relation to comparing the incidence rate of melanoma in Parkinson’s disease patients versus the general population, and of rasagiline treated patients versus non-rasagiline treated Parkinson’s disease patients.

33.        Contrary to Mr Anforth's submission, we find that this material suggests that no significant new data about the incidence of melanoma and rasagiline treatment for Parkinson’s disease patients has come into existence since the decision was made by the Minister's Delegate.

34.        The ADAGIO study was directed to the efficacy of rasagiline, not its safety, and in particular that study was not directed to any relationship between rasagiline treatment and the incidence of melanoma.  The objective of the study was to assess rasagiline as a disease-modifying therapy in the treatment of Parkinson's disease.  The study was not designed to assess the difference in the incidence of melanoma between rasigiline-treated and placebo-treated subjects and was not powered for that purpose. 

35.        Although safety and tolerability data were generally collected as part of the study, safety data relating to the incidence of melanoma were not referred to in the draft Synopsis, but were provided in the Safety Update. We infer, therefore, that the Safety Update and the Regulatory Background documents were created for the purpose of these proceedings. 

36.        The study required by the US FDA is directed to looking at the possible relationship between rasagiline treatment and melanoma. Notably, no material has been put before us as to the progress of that study or of any results from it.

37.        On its face, we do not consider that the material Lundbeck relied upon would go in any way to satisfy the concern of the Minister's Delegate that:

Any future registration applications for this medicine would need to demonstrate conclusively that there is not an increased rate of melanoma formation amongst patients utilising rasagiline in the Australian context. The Sponsor may be able to support their theory that the increased rate of melanoma development among patients  taking rasagiline in the clinical trials to date is due to detection bias though the completion of large-scale Australian and international trials, and/or registries of paitents taking rasagiline. At this stage the data presented does not satisfactorily demonstrate that this is the case and therefore the safety of rasagiline has not been adequately demonstrated.  (Emphasis added)

38.        We don’t accept Mr Anforth’s assertions, variously phrased that we could conclude that the substantive application is almost certain to succeed, or has strong, or even reasonable, prospects of success on any full hearing on its merits because of the results of the ADAGIO study, and taking into the account what has happened in relation to regulation in other jurisdictions.  We find that that the results of the ADAGIO study, as they appear in the draft synopsis, do not support a critical finding that rasagaline is safe in relation to the incidence of melanoma in patients treated with the drug.  It was not directed to that relationship

Prejudice/Detriment to Lundbeck

39.        We also take into account the matters put by Mr Anforth in relation to the prejudice or detriment to Lundbeck of having to pay another new application fee of about $175,000 and a possible two years delay caused to it, and to Parkinson’s disease sufferers being denied better treatment, if Lundbeck had to go through the approval process again.   We do not find these arguments persuasive because they were based on the assertion that the substantive application would almost certainly succeed, which we do not accept for the reasons given above. 

Other arguments

40.        Mr Anforth argued that the Respondent's contention that the results from the ADAGIO study will only be available at some unspecified time in the future, such that reliance on that data will constitute "an open-ended timeframe" for the appeal was incorrect.  As is apparent from the discussion above, on the material before us, it does not appear that the results of the ADAGIO study will assist Lundbeck in relation to the critical issue of safety, whenever they become available.

41.        We do not accept that refusal of this application is inconsistent with the statutory objective of s 4(1)(a) of the TGA Act to provide for: "the timely availability of therapeutic goods".  That is only part of the objective, which also states to: "provide for the establishment and maintenance of a national system of controls relating to the quality, safety, efficacy and timely availability of therapeutic goods" that are used or exported from Australia.  In our view our decision is consistent with that objective.

42.        Mr Anforth also sought to cast some responsibility on the Respondent to have obtained the results from its European counterpart.  We do not accept this argument.

43.        Finally, the Respondent argued that Lundbeck's case was for the registration of a different "indication" or "specific therapeutic uses of the goods" (s 3 and 16 of the TG Act).   We do not need to address this matter as we have decided to refuse Lundbeck's application.

44.        For the reasons set out above, we are not persuaded to exercise the discretion conferred on this Tribunal in favour of Lundbeck.

DECISION

45.        We are not satisfied that it is reasonable in all the circumstances of this case to extend the time for the making of the application for review of the decision of the Minister's delegate dated 12 May 2006.  The application is refused.

I certify that the 45 preceding paragraphs are a true copy of the reasons for the decision herein of Mrs Josephine Kelly, Senior Member and Dr T M Schafer, Member.

Signed: ………[sgd]..…….

Steven Mulipola, Associate

Date of interlocutory hearing:                   26 March 2009

Date of decision:  19 June 2009

Counsel for the Applicant:  Mr A Anforth

Solicitors for the Applicant:  Corrs Chambers Westgarth

Counsel for the Respondent:  Ms M Allars

Solicitors for the Respondent:                  DLA Phillips Fox