AUTH/3102/9/18: Director v Lilly – Clinical trial disclosure

Clinical trial disclosure

  • Received
    12 September 2018
  • Case number
    AUTH/3102/9/18
  • Applicable Code year
    2016
  • Completed
    18 September 2019
  • No breach Clause(s)
  • Additional sanctions
  • Appeal
    Appeal by respondent
  • Review
    To be published in the Code of Practice Review

Case Summary

A study published online in the British Medical Journal (12 September 2018) was entitled ‘Compliance with requirement to report results on the EU Clinical Trials Register: cohort study and web resource’ (Goldacre et al 2018).

The study objectives included assessing compliance rates with the European Commission’s requirement that all trials on the EU Clinical Trials Register (EUCTR) posted results to the registry within 12 months of completion (final compliance date 21 December 2016). The study objectives also included identifying features associated with non-compliance, ranking sponsors by compliance and building a tool for live ongoing audit of compliance. The published paper listed the trial sponsors with the highest proportion of trials reported and the trial sponsors with the highest proportion of trials unreported. The results were that of 7,274 trials where results were due, 49.5% (95% confidence interval 48.4% to 50.7%) reported results.

Goldacre et al stated that the European Commission (EC) Guideline required the results of all trials to be reported in structured form on to the register itself. It was possible that some trials that did not report results to EUCTR reported results elsewhere eg in a conference presentation, an academic journal article, as part of a meta-analysis after data were requested by systematic reviewers, or in the grey literature. Such publications did not meet the reporting requirements of the EC Guideline and were therefore outside the scope of the study.

Goldacre et al listed sponsors with more than 50 trials on the EUCTR and did not mention products or specific clinical trials. Goldacre et al gave details of disclosure of clinical trial results for each sponsor.

The Director decided that the Goldacre et al article was such that she had received information from which it appeared that Lilly might have breached the Code and decided in accordance with Paragraph 5.1 of the Constitution and Procedure to take the matter up as a complaint.

The detailed response from Lilly is given below.

General detailed comments from the Panel are given below.

The Panel noted the data in Goldacre et al in that results of forty-five of Eli Lilly’s due trials had not been reported on EUCTR; the disclosure percentage was 47.7 %.

The Panel considered that as there was no UK involvement in 41 trials, the matter did not come within the scope of the UK Code. No breach of the Code was ruled in relation to those trials.

The Panel noted Lilly’ submission with regard to the four trials that were conducted in the UK.

Trial 2012-005477-31 started in August 2013 and ended in March 2016 and involved emibetuzumab. The development of emibetuzumab had been terminated and the product was not licensed or commercially available anywhere in the world.

The Panel noted Lilly’s submission that it had published the results on EudraCT in April 2018. The Panel noted that the results did not appear to be published on EUCTR within the required timeframe. The Panel therefore ruled a breach of the Code which was appealed by Lilly. The Panel noted from the evidence before it that there did not appear to have been any formal finding by any judicial authority or appropriate body charged with determining matters in relation to the Commission Guidelines that the company had not complied with the relevant laws and regulations. The Panel therefore ruled no breach of the Code in relation to this trial. The Panel noted that the results were now disclosed on EUCTR. The Panel therefore did not consider that in the circumstances a breach of Clause 2 was warranted and ruled accordingly.

Trial 2010-022101-18 started in May 2012 and finished in October 2015 and involved tabalumub. Tabalumab was not licensed or commercially available anywhere in the world. The Panel noted Lilly’s submission that it had published the results on EudraCT in April 2018. The Panel noted that the results did not appear to be published on EUCTR within the required timeframe. The Panel therefore ruled a breach of the Code which was appealed by Lilly. The Panel noted from the evidence before it that there did not appear to have been any formal finding by any judicial authority or appropriate body charged with determining matters in relation to the Commission Guidelines that the company had not complied with the relevant laws and regulations. The Panel therefore ruled no breach of the Code in relation to this trial. The Panel noted that the results were now disclosed on EUCTR. The Panel therefore did not consider that in the circumstances a breach of Clause 2 was warranted and ruled accordingly.

Trial 2006-004486-34 started in October 2006 and finished in July 2009 and involved enzastaurin. Enzastaurin was currently in development and was not licensed or commercially available anywhere in the world. The Panel noted Lilly’s submission that it had published the results on EudraCT in January 2018. The Panel noted that the results did not appear to be published on EUCTR within the required timeframe. The Panel therefore ruled a breach of the Code which was appealed by Lilly. The Panel noted from the evidence before it that there did not appear to have been any formal finding by any judicial authority or appropriate body charged with determining matters in relation to the Commission Guidelines that the company had not complied with the relevant laws and regulations. The Panel therefore ruled no breach of the Code in relation to this trial. The Panel noted that the results were now disclosed on EUCTR. The Panel therefore did not consider that in the circumstances a breach of Clause 2 was warranted and ruled accordingly.

Trial 2008-003843-36 started in September 2008 and finished in January 2010 and involved exenatide (Byetta), which received its first licence in the US in April 2005 and was made commercially available there in June 2005. The Panel noted Lilly’s submission that the trial was published in December 2010 in Annals of Internal Medicine and hence met the disclosure requirement. Lilly noted that AstraZeneca acquired exenatide in August 2012.

The Panel noted Goldacre et al which stated that following the 2012 European Commission (EC) Guideline 2012/c302/03, sponsors must ensure that they disclosed their results of all trials registered on EUCTR since 2004 to the EMA within 12 months of trial completion. Following various delays in the EMA’s implementation of the software platform for results posting, the final date for sponsors’ compliance was 21 December 2016.

The Panel noted that it appeared from the information provided that the circumstances were such that on 21 December 2016 Eli Lilly was not responsible for the disclosure of the trial results of Trial 2008-003843-36.

The Panel considered that in the particular circumstances of this case as far as Eli Lilly was concerned the matter did not come within the scope of the Code and it therefore ruled no breach in relation to Trial 2008-003843-36.

The Appeal Board noted that Article 57(2) of Regulation (EC) No 726/2004 and Article 41(2) of Regulation (EC) No 1901/2006 required that clinical trial data be published on EUCTR. European Commission (EC) Guideline 2012/c302/03 gave guidance as to when the clinical trial results data should be published. According to the guideline posting of results of clinical trials which ended one year or more prior to finalisation of the programming of the relevant database, should be done within 24 months of finalisation of that programming. According to the ‘What’s New’ section of the EudraCT public website (post-dated 13 January 2016), the deadline for submission of these results was 21 December 2016. This date was referred to in Goldacre el al. In this regard, it appeared to the Appeal Board that whilst the regulation mandated disclosure of results on EUCTR, the EC Guideline and other material advised companies how to comply with the regulation including in relation to the timing of such disclosures. The Appeal Board considered that it was within the spirit of the Code and good practice to comply with the guideline in question.

The Appeal Board noted Lilly had stated that it had 86 trials with results and 41 were due to be published on the EUCTR. The Appeal Board noted the data in Goldacre et al in that the disclosure percentage was 47.7%. Lilly submitted that four of the trials at issue were conducted in UK and were, therefore, subject to the Code. Of the remaining four trials with a UK nexus there were three trials at issue in the appeal (trials 2012-005477-31, 2010-022101-18 and 2006-004486-34).

The Appeal Board considered that there would be a difference between action to deliberately hide clinical trial data or systematic failure resulting in non or late disclosure and late disclosure of results as part of a retrospective exercise contrary to non-mandatory timelines due to mitigating factors. The Appeal Board, nonetheless, noted its view above about good practice and disclosure in accordance with the EC Guideline.

The Appeal Board noted Lilly’s submission at the appeal that it had noted the non-mandatory EC Guideline and other relevant advice when it was introduced, and it had taken a cautious approach by waiting to see what other pharmaceutical companies would do before it decided what to do. Lilly subsequently decided to follow the EC Guideline and it published the data from the three trials in question on EUCTR in January and April 2018 which was prior to receipt of the complaint.

Whilst the Appeal Board was concerned about the failure to disclose the summary results of the three trials on EUCTR within the timelines advised by the EC Guideline and other relevant advice and queried whether Lilly’s ‘wait and see’ approach was appropriate. In the exceptional circumstances of this case, the Appeal Board did not consider that the late posting of the results of three trials on the EUCTR as part of a retrospective exercise warranted a breach of the Code. The Appeal Board ruled no breach of the Code in relation to each trial. The appeal was successful.

Following its completion of the consideration of the appeals in this case and in Cases AUTH/3079/9/18 (Pfizer), AUTH/3087/9/18 (GlaxoSmithKline) and AUTH/3118/11/18 (Tesaro) the Appeal Board noted that the respondent companies in Case AUTH/3084/9/18 (Boehringer Ingelheim), Case AUTH/3091/9/18 (UCB), Case AUTH/3097/9/18 (Teva), and Case AUTH/3099/9/18 (Allergan), accepted the Panel’s rulings of breaches of the Code and had not appealed.

The Appeal Board agreed that Boehringer Ingelheim, UCB, Teva and Allergan should be contacted and informed of the outcome of the appeals in Cases AUTH/3079/9/18, AUTH/3087/9/18, AUTH/3118/11/18 and AUTH/3102/9/18. The PMCPA Constitution and Procedure did not cover this unusual situation where more than one company was involved in a similar set of circumstances and the Appeal Board had taken a different view to the Panel. Boehringer Ingelheim, UCB, Teva and Allergan should each be offered the opportunity to appeal out of time and the appeal process would operate in the usual way. The Appeal Board noted that each cases’ circumstances might differ, and the result of any appeal could not be guaranteed. The reports for Case AUTH/3084/9/18 (Boehringer Ingelheim), Case AUTH/3091/9/18 (UCB), Case AUTH/3097/9/18 (Teva) and Case AUTH/3099/9/18 (Allergan), should be updated to reflect the situation and to cross refer to the cases which were successfully appealed. Allergan and UCB declined the opportunity to appeal. Boehringer Ingelheim and Teva successfully appealed the Panel’s rulings of breaches of the Code.