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Tuesday, July 30, 2013
Sharing data from clinical trials: where we are and what lies ahead -BMJ
BMJ2013;347doi: http://dx.doi.org/10.1136/bmj.f4794(Published 30 July 2013)
The drive to make clinical trial data more accessible has garnered widespread international support, but rearguard actions by the drug industry could delay substantial change. Elizabeth Loder looks at international developments in the sharing of clinical trial data
Almost a decade ago an Italian scientist, Alessandro Liberati, wrote an impassioned Personal View in the BMJ. He had developed myeloma and needed to decide whether to have a second bone marrow transplant. Among the evidence pertinent to his decision were “four randomised controlled trials, whose results haven’t yet been fully published . . .” “Why,” he asked, “was I forced to make my decision knowing that information was somewhere but not available?” He concluded that “Research results should be easily accessible to people who need to make decisions about their own health.”1 His story put a human face on the harm that can occur when clinical research data are not available.
In 2003 the US National Institutes of Health (NIH) published a final statement on sharing of data from research activities it had funded. The statement reaffirmed support for the concept of data sharing, which NIH said was “essential for expedited translation of research results into knowledge, products, and procedures to improve human health.” Henceforth, NIH announced, investigators seeking NIH grants over $500 000 (£325 000; €377 000) or more would be “expected to include a plan for data sharing or state why data sharing is not possible.”2
It is difficult to identify exactly when the crusade began for better access to clinical trial data, but this action by NIH was certainly among the opening salvos in the struggle. Over the past decade, the movement for clinical trial data transparency has become global in scope, with European regulators, health research funders, and international coalitions of scientists taking a prominent role. Proponents of research data sharing say that increased access to clinical trial data will spur more efficient drug development and scientific innovation, increase trust in the clinical research enterprise by providing opportunities for close scrutiny of research results, and ultimately improve public health.3 They want wider access to the full spectrum of information gathered in clinical trials—not just aggregate data but also anonymised patient-level data and supporting information that would enable independent replication of trial results and facilitate individual patient data meta-analyses.4 These arguments have been met with sympathy by a diverse group of international organisations, and the movement towards the transparency of clinical trial data has gathered pace.
All aboard the bandwagon
Medical journals were among the first to endorse wider sharing of trial data, and to take steps to make it happen. In 2007 Annals of Internal Medicine began to require data sharing statements for research studies published in the journal, and in 2009 theBMJ introduced a similar policy.56 In 2013 the BMJ went further, requiring as a condition of publication that authors of drug and device studies agree to make relevant anonymised patient level data available on reasonable request.7 In mid-June of this year the BMJ and PLOS Medicine endorsed the RIAT (Restoring Invisible and Abandoned Trials) initiative, which provides a mechanism for the publication of unpublished studies and correction of those that were inaccurately reported—ideally by the original trial researchers or sponsors, but failing that by volunteer “restorative authors.”8 The effort is only possible because the authors of the RIAT proposal have access to detailed clinical trial data for a large number of drugs, most of it obtained in the course of legal proceedings.
Funders of Health Research
In 2011 an international group of private and governmental funders of medical research signed on to a joint statement that strongly endorsed “making research data sets available to investigators beyond the original research team in a timely and responsible manner, subject to appropriate safeguards.”9 Signatories included Inserm, the Wellcome Trust, and the UK Medical Research Council, along with the NIH, World Bank and others. The statement outlined both immediate and long-term goals, including a desire to change the culture of research so that data sharing will be “recognised as a professional achievement” and maintaining and sharing “well managed datasets” recognised as “an important professional indicator of success in research.”
Governmental bodies and regulators
In late 2010 the European Medicines Agency (EMA) began to release, on request, clinical trial documents and other reports that had been submitted by drug companies to support requests for drug authorisations. By April 2013, 1.9 million pages of information had been released.10 EMA has been explicit about its view that such data “should not be considered commercial confidential information.”11 In June of this year, a draft policy on publication and access to clinical trial data was released for public comment; the final policy will be published in the fall of 2013.12
Another project of note is the plan to revise current European Union (EU) clinical trial directives. The proposed EU clinical trial regulations, unlike the directives they would replace, would be binding and would not be subject to interpretation by EU member states. Among other things, they would require sharing of trial information in the form of clinical study reports (CSRs). The EU also aims to launch its own trial registry, similar to the US based ClinicalTrials.gov.13
The UK National Research Ethics Service, which is directed by the new UK Health Research Authority, will not only make trial registration a condition of ethical approval for research, but will also make sure that consent is sought from research participants in ways that will “not be a later barrier to data sharing . . .”14
January 2013 saw the launch of the AllTrials campaign, which unites a broad coalition of patient groups, private and public organisations, medical journals, researchers, medical professionals, and individuals. The group’s slogan is “All trials registered, all results reported” and it is petitioning “governments, regulators and research bodies to implement measures to achieve this.” AllTrials proposes that clinical study reports should be released or, in the case of academic or other non-industry funded trials, information equivalent to CSRs.15
Pledges of reform: companies say yes but do some mean no?
Meanwhile, in response to mounting criticism and the pressure of public opinion, some pharmaceutical companies have responded with initiatives to make more clinical trial information available. The most notable commitment has come from GlaxoSmithKline (GSK). The company has launched an online portal that provides a list of GSK studies for drugs that have received regulatory approval or, in the case of drugs for which approval will not be sought, those studies submitted for publication. The portal also lists studies that have not been published. More detailed data from these studies will be made available to investigators who submit analysis plans and commit to publication of their findings, subject to approval of an independent third party panel. GSK has also endorsed the AllTrials initiative.16
Roche, acknowledging the ongoing controversy about the accuracy and completeness of published trial information for the influenza drug oseltamavir, announced plans in February 2013 to make data for approved drugs available to researchers whose analysis plans are approved by an independent review body. Roche also plans to provide access to anonymised patient-level data from some studies.17
Device manufacturer Medtronic has pioneered a new model of clinical trial data release and scrutiny in partnership with a team of researchers from Yale Medical School. Medtronic’s commitment was motivated by falling sales of its bioengineered bone growth product rhBMP-2. This drop in sales came amid questions about the integrity of published clinical trial information for the drug, concerns that had been raised by the Spine Journal.18 Yale researchers selected two independent groups to analyse the data and Medtronic agreed that the findings, whatever they were, would be published. The two reviews, released in June 2013, concluded that the benefits of the product were small and that side effects and harms had been under-emphasised in original publications.1920
Although some companies seem to be genuinely struggling to adjust to a new world of shared data, others appear to be trying to hinder progress. Backed by the drug industry lobbying group Pharmaceutical Research and Manufacturers (PhRMA) in the US, the drug companies AbbVie and InterMune sued the EMA to prevent it from releasing information about their drugs in response to two requests for access. In May 2013 the General Court of the EU issued an interim ruling ordering the EMA not to provide any more documents, pending a final ruling from the court.21
PhRMA and its European counterpart EFPIA (European Federation of Pharmaceutical Industries and Associations) have emerged as key orchestrators of continued industry resistance to data transparency efforts. A memorandum from the two lobbying groups leaked to the Guardian had been sent to leaders of major pharmaceutical companies around the world. It outlined a strategy of “mobilising patient groups to express concern about the risk to public health by non-scientific re-use of data.”22
Several patient groups were quick to repudiate this strategy and reaffirm their commitment to data accessibility. They also took offence at the Guardian’s statement that an “army” of patient groups had been raised. The European Patients Forum was blunt, saying “we denounce the accusation that ‘an army of patients groups are being mobilised by pharma to lobby against plans to force companies to publish secret documents on drugs trials’ . . . We are not aware of any bona fide patient group that would advocate another stance . . . ”23 The European Aids Treatment Group acknowledged receiving substantial funding from drug companies but commented that “We believe that patients do a great service, willingly participating in clinical trials for the benefit of medical science and the greater good . . . It is a travesty of justice that this data is then considered to be ‘private.’ It should be in the public arena for all to see—easy to access and free for all.”24
In late July 2013 PhRMA and EFPIA released a set of principles for sharing data from clinical trials, which member organisations will adopt effective from January 2014. The principles outline mechanisms to make some clinical trial data available to approved researchers. They also affirm a commitment to the publication of all clinical trial results and to sharing summary trial results with the public. Critics, however, were quick to say that the principles do not go far enough, and derided them as an attempt to pre-empt alternative, more comprehensive plans for data sharing. 25
Adjusting to a new normal
While rearguard actions by the pharmaceutical industry may weaken or delay progress towards more complete access to clinical trial data, they are unlikely to be successful in the long run. The public is increasingly intolerant of the idea that commercial or other interests should be permitted to hoard information and have sole control over access to it. This cultural shift in attitudes about information sharing is based on a belief that clinical trial data are a valuable public good.26 There is strong, sustained support for data sharing from many sectors of society, well illustrated by the breadth and diversity of signatories to the AllTrials petition. All of this points to a future where sharing of research data is viewed as an essential characteristic of good science. The recent testimony of Roche director William Burns before the UK House of Commons Science and Technology Committee suggests that there is growing industry recognition of this new reality: “What we’ve seen is an increasing requirement over recent years for more stakeholders to have more access to the data, and if society wants that to happen, then we have to respond.”27
Cite this as:BMJ 2013;347:f4794
Competing interests: I have read and understood the BMJ Group policy on declaration of interests and have no relevant interests to declare.
Provenance and peer review: Commissioned; not externally peer reviewed.
Simmonds MC, Brown JV, Heirs MK, Higgins JP, Mannion RJ, Rodgers MA, et al. Safety and effectiveness of recombinant human bone morphogenetic protein-2 for spinal fusion. A meta-analysis of individual-participant data. Ann Intern Med2013;158:877-89.
Fu R, Selph S, McDonagh M, Peterson K, Tiwari A, Chou R, et al. Effectiveness and harms of recombinant human bone morphogenetic protein-2 in spine fusion. A systematic review and meta-analysis. Ann Intern Med2013;158:890-902.