CASE AUTH/3098/9/18 NO BREACH OF THE CODE
DIRECTOR v A MENARINI
Clinical trial disclosure
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 A Menarini 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 A Menarini 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 seven of A Menarini’s due trials had not been reported; the disclosure percentage was 69.6%.
The Panel noted from information provided by Menarini that six of the seven trials had no UK involvement. 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 six trials.
The Panel noted that trial 2011-000805-27 had one investigation site in the UK. The Panel noted that due to difficulties in screening and recruiting, only 4 of the planned 120 patients were randomized and the study was terminated early with the last patient out on 22 January 2014. The Panel noted A Menarini’s submission that posting on EUCTR was deemed not applicable in this case since a minimum efficacy and safety dataset was missing. Goldacre et al was silent on this point. An abbreviated clinical study report was finalised and sent to the competent Regulatory Authority and the Menarini Company posted the trial on the company website explaining why it was prematurely terminated. The Panel therefore ruled no breaches of the Code including no breach of Clause 2 in relation to this trial.
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. Results from trials with a commercial sponsor were substantially more likely to be posted than those from a non-commercial sponsor (68.1% v 11.0%, adjusted odds ratio 23.2, 95% confidence interval 19.2 to 28.2) as were trial results from a sponsor who conducted a large number of trials (77.9% v 18.4%, adjusted odds ratio 18.4, 15.3 to 22.1). More recent trials were more likely to report results (per year odds ratio 1.05, 95% confidence interval 1.03 to 1.07). Extensive evidence was found of errors, omissions, and contradictory entries in EUCTR data that prevented ascertainment of compliance for some trials.
The Director decided that the Goldacre et al article was such that she had received information from which it appeared that A Menarini 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.
COMPLAINT
The study concluded that compliance with the European Commission requirement for all trials to post results on to the EUCTR within 12 months of completion had been poor, with half of all trials non-compliant. EU registry data commonly contained inconsistencies that might prevent even regulators assessing compliance. Accessible and timely information on the compliance status of each individual trial and sponsor might help to improve reporting rates.
Goldacre et al noted that 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 their results of all trials registered on EUCTR since 2004 to the EMA within 12 months of trial completion; Phase I trials were exempt unless they were denoted as being part of a paediatric investigation plan. These trial reports were posted publicly on to the EUCTR within 15 working days of receipt by the EMA and were required to include salient features such as results for all pre-specified trial outcomes and statistical analyses, details of ‘serious’ and ‘non-serious’ adverse events, participants’ baseline characteristics, and protocol deviations, as well as discussion of design limitations and caveats. 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.
Goldacre et al assessed compliance with the EU requirement to post results on to EUCTR for all trials on the registry, explored factors associated with non-compliance, identified the individual trial sponsors that were best at complying, and created a live online service, driven by regular updates of the EUCTR data, to give ongoing and regularly updated performance statistics for compliance.
The publication listed a number of variables.
Goldacre et al stated that the EUCTR data underlying this study were updated regularly. An interactive online website presenting the overall reporting rate for all due trials, the reporting rates for each sponsor, ranks for these reporting rates, and details of each sponsor’s individual reported and unreported trials was developed. The data underlying this site was updated regularly following each new download of the EUCTR database: the results and ranks for each individual sponsor were therefore always current and changed as performance changed. All software underlying this service was shared as open source and available for open code review or for adaptation and re-use.
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. Ascertainment of the outcome – a results report on EUCTR – was therefore accurate and complete. 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. A manual search of academic journals and grey literature for a random sample of 100 trials unreported on EUCTR was conducted as requested as part of the peer review of the publication. Five were reported in the grey literature and 46 in a journal publication.
Goldacre et al listed sponsors with more than 50 trials on the EUCTR and did not mention products or specific clinical trials. The study publication listed the sponsors with the highest proportion of trials reported and those with the lowest proportion of trials reported.
Goldacre et al gave details of disclosure of clinical trial results for each sponsor. The data for A Menarini were as follows:
Sponsors with highest proportion of trials reported
|
Sponsor
|
Total trials on EUCTR
|
Due trials
|
Due trials with results
|
% reported
|
|
Menarini Group
|
64
|
23
|
16
|
69.6
|
When writing to A Menarini the Authority asked it to bear in mind the requirements of Clauses 2, 9.1, 1.11 and 13.1 of the Code. The Authority noted that previous editions of the Code might be relevant and provided details.
RESPONSE
A Menarini provided details of the seven relevant trials:
2011-000805-27 – This was an international, multicentre (4 investigation sites, 1 in UK, 2 in Italy and 1 in Spain) trial sponsored by Menarini International Operations Luxembourg (MIOL). The medicine at issue was ranolazine which was first licensed in January 2006 and commercially available in March 2006.
Due to difficulties in screening and recruiting, only 3 of the planned 120 patients were randomized and the trial was terminated early with the last patient out on 22/01/2014. An abbreviated clinical study report was finalised and sent to the competent Regulatory Authority. Furthermore, the Menarini Company posted the trial on the company website explaining why the trial was prematurely terminated. The matter related to the ERIPE study was covered by the Code as 1 UK site with 3 patients was involved but posting on EUCTR was deemed not applicable since even a minimum efficacy and safety dataset was missing. The publication in scientific literature of ERIPE study was not applicable since no efficacy and/or safety relevant results could be of such a scientific interest so as to be made public. The Menarini Company would reconsider this choice if deemed more appropriate and in line with applicable regulation.
2007-004438-18 was a Phase IV trial referred to as DIANECA investigating the effect of Carvedilol and Nebivolol on orthostatic hypotension in type 2 diabetic patients sponsored by Menarini International Operations Luxembourg. A Menarini submitted that this trial was not covered by the ABPI Code because no sites were opened in the UK, no UK patients were recruited and no UK investigators were engaged. A Menarini noted that the trial was withdrawn with no patients recruited and was posted on the company website with ‘withdrawn’ status updated. Posting on EUCTR was deemed not applicable since a minimum efficacy and safety dataset was missing. Publication in the scientific literature for the DIANECA trial was not applicable as no efficacy and/or safety results could be of scientific interest to be made public.
2009-018218-21 and 2010-022706-41 were part of the early clinical development of a treatment for infant colic. Both trials were phase IIa randomised, double-blind, placebo controlled, three parallel groups studies, with the aim to preliminarily evaluate the efficacy and safety of nepadutant given at two oral doses once daily for seven days in comparison to placebo for the treatment of infantile colic, sponsored by the Italian company Menarini Ricerche S.p.A.
- Trial 2009-018218-21 was conducted in 25 sites in Germany, Poland, Sweden, US and Russia. Ten centres from Europe, US and Russia completed the recruitment, with 94.8% of infants randomised in Russia. The study terminated on 28 December 2013. The clinical study report was finalised and sent to the competent Regulatory Authorities. Study results were posted on ClinicalTrials.gov (NCT01258153) and presented to international scientific congresses (ESPGHAN 2015 and DDW 2015) (references provided).
- Trial 2010-022706-41 was expected to be run in 3 sites in Italy, but due to enrolment difficulties, it was terminated early on 31 October 2012 with no patients enrolled.
Trial information was posted on ClinicalTrials.gov (NCT01258153) where the withdrawn status and actual enrolment of zero patients was reported.
The above-mentioned trials had not been submitted for publication in the Scientific Literature since their results lack of significant medical importance, in accordance with the Provisions of the Joint Position on the Publication of Clinical Trials of June 10, 2010.
The nepadutant project had been formally discontinued and the product was never licensed or commercially available.
2010-018300-85 – This trial was on ibodutant and was sponsored by Menarini Ricerche S.p.A. It was conducted in 78 European study sites in Bulgaria, the Czech Republic, Denmark, Germany, Italy, Poland, Spain and Sweden. The study terminated on 11 May 2012. The clinical study report was finalised and sent to the competent Regulatory Authorities.
Trial results were posted on ClinicalTrials.gov (NCT01303224), presented to international congresses (DDW 2013, DDW 2014 and UEGW 2015) and published in a scientific journal (Gut (2017) Aug;66(8):1403-1413 (references supplied)).
The ibodutant project had been formally discounted and the product was never licensed or commercially available.
2009-010971-26 – This trial was on brivudine and was sponsored by Menarini Ricerche S.p.A and conducted in 21 clinical sites in 3 European countries (9 sites in Germany, 6 sites in Italy, 6 sites in Spain). Due to the difficulties in patient enrolment, the study was discontinued with only 25 patients randomised out of the 50 planned on 26 October 2010. An abbreviated clinical study report was produced and sent to competent Regulatory Authorities.
Due to the paucity of available data results were not published on registers. In accordance with the Provision of the Joint Position on the Publication of Clinical Trials of June 10, 2010, the trial had not been submitted for publication in the scientific literature since the results lacked significant medical importance.
The brivudine project had been formally discontinued and the product was never licensed or commercially available.
2006-005556-32 – This trial compared the efficacy and safety of olmesartan medoxomil/hydrochlorothiazide 40/12.5mg combination vs olmesartan medoxomil 40mg monotherapy. The study was sponsored by Menarini Ricerche S.p.A and conducted in 86 clinical sites (8 in Croatia, 14 in the Czech Republic, 3 in Denmark, 19 in Germany, 11 in Israel, 8 in Italy, 11 in Poland, and 12 in Romania) and completed on 28 May 2008. The clinical trial report was finalised and sent to the competent Regulatory Authorities. Study information was posted on ClinicalTrials.gov (NCT00441350). Results were published in a scientific journal (Clin Drug Investig (2010);30(9):581-97) and this publication was automatically indexed to this trial by ClnicalTrials.gov Identifier.
Based on the above A Menarini denied a breach of the Code. The company and the group to which it belonged fully embraced the EFPIA principles and the EFPIA Data Sharing policy to enhance public access to clinical study information and clinical data sharing with qualified scientist and medical researchers.
GENERAL COMMENTS FROM THE PANEL
The Panel noted that Goldacre et al was not the subject of external complaint but was taken up under Paragraph 5.1 of the Constitution and Procedure.
The Panel noted that Goldacre et al was the basis of the complaint in relation to the allegation that sponsors with less than 100% reported trials were not meeting the requirements of the EC Guideline.
The Panel noted that all the cases would be considered under the Constitution and Procedure in the 2016 Code as this was in operation when Goldacre et al was published and the complaint proceedings commenced.
The Panel noted that there had been three previous studies looking at the disclosure of clinical trial data all published in Current Medical Research and Opinion (CMRO). The first study was the subject of an external complaint which gave rise to 27 cases in 2013 and 2014. The second study (Rawal and Deane 2015) was not the subject of external complaint but was taken up under Paragraph 5.1 of the Constitution and Procedure in 2015 and led to 15 cases. The third study (Deane and Sivarajah 2016) was not the subject of external complaint but was also taken up under Paragraph 5.1 in 2016 and led to 17 cases. Most of these cases were not in breach of the Code because they were not within the scope of the Code as there was no UK involvement and therefore only limited details were published on the PMCPA website.
The previous studies surveyed various publicly available information sources for clinical trial registration and disclosure of results searched between specific dates covering medicines (except vaccines) that were approved by the European Medicines Agency (EMA) in a particular year or years. The Panel noted that the previous cases had established a number of principles including deciding which Code applied.
Goldacre et al was different to the previous three studies which assessed compliance with the Joint Positions; it only assessed compliance with the EU requirement to post results on to the European Union Clinical Trial Register (EUCTR) for all trials listed on the registry. In that regard, trials involving investigational products that were not licensed for use anywhere in the world might be included. Companies had not made a detailed submission on this point.
The Panel noted that the European Clinical Trials Database (EudraCT) was a database hosted by the EMA in which clinical trial sponsors would upload summary results. These results would then be published on the EUCTR.
The Panel considered that in these circumstances the trial completion date would be the trigger for results disclosure on EUCTR. The Panel noted that the publicly available EudraCT and EUCTR Q&A document stated in response to the question ‘if the trial is prematurely ended/early terminated due to lack of subjects or lack of data to analyse, do I have to provide results?’, that in the case that no subjects were recruited, it was not appropriate to complete the full dataset. However, there was currently no functionality for sponsors to inform that recruitment never started or that the trial was prematurely ended in the results data model. In this specific case sponsors had to liaise directly with the National Competent Authority confirming that no results would be available for a specific trial due to ‘lack of subjects’ or that the trial was ‘prematurely ended’ so a statistical analysis could not be provided. The Panel noted that according to the Commission Guideline ‘Guidance on posting and publication of result-related information on clinical trials in relation to the implementation of Article 57(2) and Regulation No 726/2001 and Article 41(2) of Regulation No 1901/2006’, if the clinical trial ends prematurely, that date should be considered the end of trial date.
The Panel noted that according to Goldacre et al 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; Phase I trials were exempt unless they were denoted as being part of a paediatric investigation plan. These trial reports were posted publicly on to the EUCTR within 15 working days of receipt by the EMA and were required to include salient features. Goldacre et al noted that following 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 considered that the subject matter of the complaint was failure to publish results on EUCTR. It appeared to the Panel that under EUCTR for non-paediatric trials, at least one investigator site of the clinical trial should be located in Europe or in a contracting state of the European Economic Area (EEA). The Panel noted that it could only consider the matter with regard to the Code. In the Panel’s view, only those with a UK nexus would be considered to be within the scope of the Code.
The Panel noted that the Code did not explicitly refer to publication on the EUCTR. Clause 13.1 referred, inter alia, to disclosure of clinical trials in accordance with the Joint Positions on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases and the Publication of Clinical Trial Results in the Scientific Literature. According to the 2009 Joint Position, publication of clinical trial results in any free, publicly accessible internet-based clinical trials database should achieve the intended objectives.
The Panel noted the differences between the Joint Positions and the requirement to publish clinical trial results on the EUCTR; it was possible that results might not need to be published under the Joint Positions (for instance because the medicine was not licensed for use or commercially available) but might nonetheless be required to be published on the EUCTR. The Panel considered that companies would be well advised to ensure that all the clinical trial results were disclosed as required by the law, codes and Joint Positions. The Panel noted that Goldacre et al had not commented on whether the results disclosed met the requirements of the Joint Positions so this was not considered; in the Panel’s view the only matter for consideration was whether or not trial results had been disclosed within the required timeframe as required by the Commission Guideline 2012/C302/03 which came into operation in 2012, and by 21 December 2016 which was referred to by Goldacre et al as the final data for sponsor’s compliance. The Panel considered, therefore, that in this particular case it would make its rulings under the Code in operation on 21 December 2016, the 2016 Code. The Panel considered that its approach was a fair one.
The Panel noted that the companies had been asked to respond, inter alia, to Clause 13.1. Given that Goldacre et al did not refer to the Joint Positions and noting the differences between the requirements to disclose under the Joint Positions and under the Commission Guidelines the Panel considered, taking a pragmatic approach, that the matters raised by Goldacre et al would be considered under Clause 9.1, rather than Clause 13.1. The companies had been asked to respond to, inter alia, Clauses 9.1 and 1.11 at the outset and had been provided with a copy of Goldacre et al. The Panel noted that the publicly available EudraCT and EUCTR Q&A document referred to sponsors who were not fulfilling the legal requirements in providing results in EudraCT.
The Panel considered that the first issue to be determined was whether the matter was covered by the ABPI Code. If the clinical trial was conducted on behalf of a UK pharmaceutical company (whether directly or via a third party) then it would be covered by the ABPI Code. If a trial was run by a non-UK company but had UK involvement such as centres, investigators, patients etc it was likely that the Code would apply. The Panel appreciated the global nature of much pharmaceutical company sponsored clinical research and a company located in the UK might not be involved in research that came within the ABPI Code. It was a well-established principle that UK pharmaceutical companies were responsible for the activities of overseas affiliates if those activities came within the scope of the Code such as those related to UK health professionals or carried out in the UK.
The Panel noted that the Authority was not an investigative body as such and its consideration of these cases relied upon the information provided by the parties. The quantitative data published by Goldacre et al formed the basis of the complaint. The Panel noted that in that regard the case preparation manager had not used the live data web resource to identify the trials at issue.
PANEL RULING
The Panel noted its general comments above about the subject matter of the complaint as set out in Goldacre et al. The Panel had decided that the alleged failure to publish results in accordance with the Commission Guidelines was more appropriately covered by Clause 9.1 and potentially Clause 1.11. The Panel made no ruling in relation to Clause 13.1.
The Panel noted the data in Goldacre et al in that the results of seven of A Menarini’s due trials had not been reported; the disclosure percentage was 69.6%.
The Panel noted from information provided by Menarini that six of the seven trials had no UK involvement. 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 six trials.
The Panel noted that trial 2011-000805-27 had one investigation site in the UK. The medicine at issue was ranolazine which was first licensed in January 2006 and commercially available in March 2006. The Panel noted that due to difficulties in screening and recruiting, only 4 of the planned 120 patients were randomized and the study was terminated early with the Last Patient Out on 22 January 2014. The Panel noted A Menarini’s submission that posting on EUCTR was deemed not applicable in this case since a minimum efficacy and safety dataset was missing. Goldacre et al was silent on this point. An abbreviated clinical study report was finalised and sent to the competent Regulatory Authority and the Menarini Company posted the trial on the company website explaining why it was prematurely terminated. The Panel therefore ruled no breach of Clauses 1.11, 9.1 and 2 in relation to this trial.
Complaint received 12 September 2018
Case completed 16 May 2019
