Clinical trial data for all drugs in current use

BMJ 2012; 345 doi: https://doi.org/10.1136/bmj.e7304 (Published 29 October 2012) Cite this as: BMJ 2012;345:e7304

Re: Clinical trial data for all drugs in current use

The BMJ’s initiative requiring sponsors to make relevant anonymised individual patient data (IPD) available as a precondition for publication is highly commendable, as is GlaxoSmithKline’s announcement to grant access to such data under certain conditions. However, in our view this would at best solve the issue of reporting bias for individual trials or individual drugs, but not for clinical research as a whole. Conclusions of systematic reviews regarding a drug’s benefits and harms, especially compared to treatment alternatives, could thus still be incorrect.

In our opinion, comprehensive access to trial data on drugs marketed in Europe (at least to data submitted to the European Medicines Agency, EMA) can only be ensured by the routine release of all clinical study reports (CSRs) by EMA once a drug has been approved. EMA previously denied access to clinical trial documents to systematic reviewers [1, 2]. But the agency has since changed its position: In 2010 it introduced a new policy, including the release of documents submitted as part of marketing authorization applications (e.g. CSRs) after procedures concerning a drug had been finalized [3], and has since published an update and accompanying guidance on the handling of commercially confidential information and personal data [4, 5]. However, the format of the data to be released is still under discussion (“conventional” CSRs following the International Conference on Harmonisation E3 guideline [6] and generally including anonymised IPD listings as PDF files or CSRs supplemented by anonymised IPD stored in electronic databases [2, 7]). In addition, EMA plans to make the data available only on request.

We suggest the following approach:

Firstly, CSRs of new drugs should be made routinely available on the EMA website after marketing authorization. This could be done by including a link to the CSRs of studies considered in the authorization process and listed in the European Public Assessment Reports (EPAR). Further CSRs submitted to EMA later in the drug’s life cycle could be added consecutively.

Secondly, as biased evidence is not only a problem of new drugs, but also of older ones still widely used in clinical practice, CSRs of older drugs submitted during previous approval processes should also be made available in a central repository at EMA to complete the evidence base. Pharmaceutical companies could also release these documents, thus underlining their commitment to transparency.

Thirdly, anonymised IPD stored in electronic databases could be provided for the above CSRs. As implementation of this step could be time consuming, this should not be merged with the issue of releasing CSRs, but should instead be discussed in parallel [2].

The first two steps could be taken quickly, providing systematic reviewers with invaluable information: CSRs represent the most comprehensive source for the evaluation of a clinical trial [8], and the addition of data from CSRs potentially changes the conclusions of systematic reviews based solely on journal publications and trial registry entries [9, 10]. Speedy access to CSRs is therefore required and would be a milestone for transparency in clinical research.

Of course the above comments do not only apply to Europe, which has been lagging behind the United States in terms of data transparency. The US Food and Drug Administration (FDA) Amendments Act of 2007 [11], which among other things, prescribes the online posting of methods and results of trials of drugs subject to FDA regulation, is currently the most comprehensive mandatory provision on access to clinical trials. The FDA itself has also taken substantial steps to increase data transparency (e.g.[12]). Several researchers have used clinical trial documents available on the FDA website or unpublished data provided by the FDA to assess the effects of reporting bias [13-17]. EMA and the FDA already cooperate on a regular basis; a joint initiative on the issue of access to CSRs, possibly also involving other regulatory agencies, suggests itself and would ensure access to a substantial amount of the worldwide evidence on clinical trials.

1. Gotzsche PC, Jorgensen AW: Opening up data at the European Medicines Agency. Bmj 2011, 342:d2686.
2. Wieseler B, McGauran N, Kerekes MF, Kaiser T: Access to regulatory data from the European Medicines Agency: the times they are a-changing. Systematic reviews 2012, 1(1):50.
3. European Medicines Agency widens public access to documents. Press release, 30 Nov 2010 [www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2010/11/...
4. Principles to be applied for the implementation of the HMA/EMA Guidance on the identification of CCI and PPD in MA Applications [http://www.ema.europa.eu/docs/en_GB/document_library/Other/2012/03/WC500...
5. HMA/EMA Guidance document on the identification of commercially confidential information and personal data within the structure of the Marketing Authorisation (MA) Application - Release of information after the granting of a Marketing Authorisation [http://www.hma.eu/fileadmin/dateien/HMA_joint/02-_HMA_Topics/07-Transpar...
6. Guideline for Industry - Structure and Content of Clinical Study Reports [http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm129456.pdf]
7. Eichler HG., Abadie E, Breckenridge A, Leufkens H, Rasi H: Open Clinical Trial Data for All? A View from Regulators. PloS Medicine 2012, 9 (4) e1001202(4 e1001202).
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9. Eyding D, Lelgemann M, Grouven U, Harter M, Kromp M, Kaiser T, Kerekes MF, Gerken M, Wieseler B: Reboxetine for acute treatment of major depression: systematic review and meta-analysis of published and unpublished placebo and selective serotonin reuptake inhibitor controlled trials. Bmj 2010, 341:c4737.
10. Doshi P, Jefferson T, Del Mar C: The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience PloS Medicine 2012, 9 (4) e1001201(4 e1001201).
11. FDA Amendments Act (FDAAA) of 2007, public law no. 110-85 § 801 [http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=110_cong_publi...
12. Asamoah AK, Sharfstein JM: Transparency at the Food and Drug Administration. N Engl J Med 2010, 362(25):2341-2343.
13. Turner EH, Knoepflmacher D, Shapley L: Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. PLoS Med 2012, 9(3):e1001189.
14. Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R: Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008, 358(3):252-260.
15. Rising K, Bacchetti P, Bero L: Reporting bias in drug trials submitted to the Food and Drug Administration: review of publication and presentation. PLoS Med 2008, 5(11):e217.
16. Lee K, Bacchetti P, Sim I: Publication of clinical trials supporting successful new drug applications: a literature analysis. PLoS Med 2008, 5(9):e191.
17. Hart B, Lundh A, Bero L: Effect of reporting bias on meta-analyses of drug trials: reanalysis of meta-analyses. Bmj 2012, 344:d7202.

Competing interests: Non-financial competing interests: All authors are employees of the Institute for Quality and Efficiency in Health Care, Cologne, Germany. In order to produce unbiased health technology assessment reports, the Institute depends on access to all of the relevant data on the topic under investigation. The authors therefore support public access to clinical study reports.

09 November 2012
Beate Wieseler
Head, Drug Assessment Department
Natalie McGauran, Thomas Kaiser
Institute for Quality and Efficiency in Health Care
Im Mediapark 8, 50670 Cologne, Germany