AUTH/3087/9/18 - Director v GlaxoSmithKline

Clinical trial disclosure

  • Received
    12 September 2019
  • Case number
    AUTH/3087/9/18
  • 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 GlaxoSmithKline 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 GlaxoSmithKline is given below.

General detailed comments from the Panel are given below.

The Panel noted the data in Goldacre et al in that the results of 33 of GlaxoSmithKline’s due trials had not been reported on EUCTR; the disclosure percentage was 88.7%.

The Panel noted GlaxoSmithKline’s submission that it found 34 rather than 33 trials that appeared to have results due but no results posted.

The Panel noted GlaxoSmithKline’s submission that of the 34 trials, 18 had no UK involvement, no UK centres, investigators or patients. The Panel considered that as there was no UK involvement, the matter did not come within the scope of the UK Code. No breach of the Code was ruled in relation to these 18 trials.

The Panel noted GlaxoSmithKline’s submission that of the 16 trials with UK involvement, 11 were cancelled prior to enrolling any subjects. There were no results to report. The Panel therefore ruled no breaches of the Code including Clause 2 in relation to these eleven trials.

The Panel noted GlaxoSmithKline’s submission that of the five trials with UK involvement and results, three trials were not clinical trials of a licensed medicine or a subsequently licensed medicine. Two (trial 2008-005288-33 and trial 2010-019832-11) of these three studies were exploratory studies of imaging methods (therefore not clinical trials of medicinal products, whether investigational or licensed). The Panel noted that according to Goldacre et al, which was the source of the complaint, any trial of any medicinal product conducted since 2004 in an EU country had already been required to register on the EUCTR, which was administered by the European Medicines Agency (EMA). Following the 2012 European Commission (EC) Guideline 2012/c302/03, sponsors must ensure that they disclosed the results of all trials registered on EUCTR since 2004 to the EMA within 12 months of trial completion. In the Panel’s view, there was no evidence before it that the results of the above two trials which were exploratory studies of imaging methods were required to be disclosed under EC Guidelines. The Panel therefore ruled no breaches of the Code including no breach of Clause 2 in relation to these two trials.

The Panel noted GlaxoSmithKline’s submission that trial 2011-005216-28 which completed on 22 August 2012 evaluated an investigational medicine, Vestipitant, that was not approved in any market. The Panel noted GlaxoSmithKline’s submission that summary results were disclosed on GlaxoSmithKline’s Clinical Study Register on 25 July 2013. The trial results were also published in the British Journal of Anaesthesia, 2015 March; 114(3):423-429. However, 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 GlaxoSmithKline. 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 was unsure whether or not the results were now disclosed on EUCTR but noted that they were published elsewhere as stated above. The Panel therefore did not consider that in the circumstances a breach of Clause 2 was warranted and ruled accordingly.

The Panel noted that trial 2011-005913-35 was a trial of umeclidinium and vilanterol in combination, compared to the individual component medicines. The product was first marketed on 18 December 2013 in the US and the trial completed on 11 June 2013. The Panel noted GlaxoSmithKline’s submission that summary results were posted on GlaxoSmithKline Clinical Study Register on 21 November 2013 and on Clinicaltrials.gov on 11 February 2014. However, 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 GlaxoSmithKline. 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 was unsure whether or not the results were now disclosed on EUCTR but noted that they were published elsewhere as stated above. The Panel therefore did not consider that in the circumstances a breach of Clause 2 was warranted and ruled accordingly.

The Panel noted that trial 2009-009885-15 involved a trial of lapatinib in combination with vinorelbine or capecitabine which received first market approval on 13 March 2007 in the US. The trial completed on 21 August 2012. The Panel noted GlaxoSmithKline’s submission that summary results were posted on GlaxoSmithKline Clinical Study Register on 18 April 2013 and on Clinicaltrials.gov on 18 July 2013. The Panel further noted GlaxoSmithKline’s submission that lapatinib was divested by GlaxoSmithKline to Novartis and responsibility of this trial was transferred to Novartis in 2015. 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 GlaxoSmithKline was not responsible for the disclosure of the results of trial 2009-009885-15, the matter did not come within the scope of the Code and it therefore ruled no breach in relation to trial 2009-009885-15.

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 EC 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 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 et al. 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 GlaxoSmithKline’s submission regarding the retrospective effort involved in posting older trials dating back to May 2004. The Appeal Board noted GlaxoSmithKline’s submission that it had to post 718 older trials (344 of which had UK trial sites) on the EUCTR. The Appeal Board noted the data in Goldacre et al in that the results of 33 of GlaxoSmithKline’s due trials had not been reported on EUCTR; the disclosure percentage was 88.7%. GlaxoSmithKline had submitted that it found 34 rather than 33 trials that appeared to have results due, but no results posted and that 18 had no UK involvement, no UK centres, investigators or patients. Of the remaining 16 with a UK nexus there were two trials at issue in the appeal.

The Appeal Board noted that the Panel had ruled breaches of the Code for GlaxoSmithKline’s failure to disclose results by 21 December 2016 or within the required timeframe in relation to two trials (trial 2011-005216-28 and trial 2011-005913-35) and these were the subject of the appeal.

The Appeal Board noted that for trial 2011-005216-28 posting on EUCTR was delayed because the trial was not tracked correctly as a GlaxoSmithKline-sponsored trial in internal systems and for trial 2011-005913-35, results posting on the EUCTR was delayed due to human error.

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 that both trials were published on GlaxoSmithKline’s Clinical Study Register within 12 months of completion and both trials were published in the scientific literature. According to GlaxoSmithKline, both trials were also published on the EUCTR in March 2018 before Goldacre et al was published and before the complaint in this case was received in September 2018.

The Appeal Board was concerned about the failure to disclose the summary results of the two trials on EUCTR within the timelines advised by the EC Guideline and other relevant advice. In the exceptional circumstances of this case, the Appeal Board did not consider that the late posting of the results of two trials on the EUCTR as part of a retrospective exercise involving 344 trials with a UK nexus warranted a breach of the Code, particularly as the two trials had already been publicly disclosed and prior to receipt of the complaint. 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 appeal in this case and in Cases AUTH/3079/9/18 (Pfizer), AUTH/3118/11/18 (Tesaro) and AUTH/3102/9/18 (Lilly) 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.