Tom Jefferson and Peter Doshi are two of the guys who battled for four years to access clinical study reports on antivirals for influenza for their Cochrane review. Here they muse on the possible arrival of look-but-don’t-touch research. Trudo Lemmens is a law professor. He has been working on the promotion of data transparency for the last decade. Here he looks at some of the possible legal ramifications of the story.

In 2010 the world changed for those who, like us, do Cochrane reviews (TJ, PD) and try to promote public health oriented science (TJ, PD, TL). The European regulator, the European Medicines Agency (EMA), changed its policy on the public disclosure of clinical study reports of clinical trials and other documents in its holdings. This occurred in response to criticism by the European Ombudsman who had accepted the strong case made by the Nordic Cochrane Centre.

EMA was widely praised for its apparently uncompromising stance and newly found openness. Researchers were delighted that open access to regulatory documents could address the ravages of reporting bias (1, 2). A body of evidence has grown over the past two decades showing how selective publication and distortion of trial evidence risked derailing the evidence based medicine movement. Extreme critics have even claimed that because of reporting bias the very foundations of evidence based medicine (like our reviews) were based on little more than synthesis of commercial messages dressed as clinical trials (3).

Because of availability of clinical study reports and the relative ease of discourse with the EMA our group produced the first Cochrane review based on regulatory material, principally clinical study reports, in 2012 (4). The results confirmed the difference in wealth of detail and reliability of reviews based on publications and those based on complete trial datasets. A new era had dawned and the paradigm of evidence based medicine appeared on the right path once again thanks to the openness of the European system. This had been enhanced even further by the 2 April announcement that all clinical study reports submitted to EMA from 2016 would be made public. All we needed was an infrastructure that could change gear and transition from publication based to clinical study report based systematic reviews.

We had been part of EMA’s clinical trials advisory groups responsible for advising EMA on its proactive release policy: how, going forward, EMA is to share clinical trial data from trials of pharmaceuticals that had been through the regulatory process. Everything seemed to proceed smoothly.

Then Trudo, on 24 April, and Tom on 8 May, received warning of a “meeting with academics” to discuss the finalization of the EMA policy. The meeting was scheduled for 10 am GMT, a time that was very awkward for the North-Americans who were included. Peter never received an invitation despite serving on two of the EMA advisory groups. Because of the short notice Tom and Trudo could not reschedule to be at the EMA meeting in London. Tom relied on phone attendance, very much second best, to follow what was going on.

When Tom and Trudo opened the background documents (admittedly two days before the meeting) they got a shock. No clinical study reports would be proactively released. The companies are apparently being put in the driver’s seat: they will prepare special redacted reports for public use and negotiate their content with the EMA. But no one will be allowed to download even these redacted reports. Screen-only viewing will be allowed without screen capture. The Terms of Use document also contains a list of further transparency exceptions. A noticeable exception is that “novel statistical or other analytical methods and exploratory endpoint results about potential new uses of a medicine” could be commercially confidential. Safety and efficacy data about off-label prescribed drugs could thus be kept out of third party view.

The Terms of Use contract also contains highly contested clauses and strengthens companies’ control over the process. “The User acknowledges that the Information is protected by copyright and proprietary rights of the Information Owner and can be considered commercially valuable when used for commercial and regulatory purposes.” Researchers thus will have to contractually affirm companies’ legal rights in data, even if these rights are still not clearly established in law and are currently still debated in court cases, including in a case in which EMA is involved (5, 6). “The User acknowledges that the Information will be made available to the User in a “view-on-screen-only” mode, after completing the registration process. The User agrees that the User is not permitted to download, save, edit, photograph print, distribute or transfer the Information. The User agrees not to access the Information using a method other than the interface provided by the EMA, or remove, bypass, circumvent, neutralise or modify any technological protection measures which apply to the Information.” Most surprisingly, the draft documents indicate that EMA will ask data users (i.e. researchers) to contractually agree that third parties (i.e. pharmaceutical companies) will have direct legal claims under UK law against them for possible violations of the Terms of Use. Infractions to the cumbersome procedural limits could thus not only be punished by withdrawal of access. Should the EMA’s draft policy be adopted as presently proposed, it appears to open up the possibility of spurious lawsuits over “misuse of data” that essentially silence critics.

When Tom and Peter finally completed their Cochrane review on neuraminidase inhibitors (7, 8), they needed to continually cross check different parts of the clinical study reports they were working on, mark and annotate the text. This is very important especially if the documents are thousands of pages long, are complicated and contain appendices, tables, and figures which are part of a whole narrative of a trial and its inception. Data extraction from a screen is not advisable in complicated datasets. One of the proudest moments for our team was the posting of all 107 clinical study reports available on the Dryad repository for anyone to reproduce our analysis.

It seems that the European Ombudsman shares most of the concerns of those who attended the 16 May meeting. Emily O’Reilly wrote to EMA’s Guido Rasi on 13 May enquiring why the EMA has apparently shifted to a more restrictive policy.

The current draft policy and the way it has been presented to those who have been supporting EMA, the European Parliament, and the push for transparency makes any kind of meaningful evidence synthesis impossible and risks taking us back to the dark days of 15 page publications or even worse, to a kind of peeping tom based medicine, with threats of lawsuits hanging as a sword of Damocles above their heads if reviewers make a mistake.

That really can’t be part of EMA’s public mandate.

Tom Jefferson, Reviewer, Cochrane Acute Respiratory Infections Group, 00187, Roma, Italy.

Peter Doshi, assistant professor, Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA.

Trudo Lemmens, Associate Professor, Scholl Chair in Health Law and Policy, University of Toronto Faculty of Law, Toronto, Ontario.

Disclosures:

TJ and PD are co-recipients of a UK National Institute for Health Research grant (HTA – 10/80/01 Update and amalgamation of two Cochrane Reviews: neuraminidase inhibitors for preventing and treating influenza in healthy adults and children – http://www.nets.nihr.ac.uk/projects/hta/108001).

In addition:
PD received €1500 from the European Respiratory Society in support of his travel to the society’s September 2012 annual congress in Vienna, where he gave an invited talk on oseltamivir. Dr Doshi is an Associate Editor of The BMJ.

TJ receives royalties from his books published by Blackwells and Il Pensiero Scientifico Editore, Rome. TJ is occasionally interviewed by market research companies for anonymous interviews about Phase 1 or 2 pharmaceutical products. In 2011-2013 TJ acted as an expert witness in a litigation case related to oseltamivir phosphate; Tamiflu [Roche] and in a labour case on influenza vaccines in health care workers in Canada. In 1997-99 TJ acted as consultant for Roche, in 2001-2 for GSK and in 2003 for Sanofi-Synthelabo for pleconaril (an anti-rhinoviral which did not get approval from FDA). TJ was a consultant for IMS Health in 2013 and is currently retained as a scientific adviser to a legal team acting on the drug Tamiflu (oseltamivir, Roche).

TL receives royalties for books published with University of Toronto Press and Themis (University of Montreal). He has no other relevant financial interests. He has written about data access issues in the past.

References:
1.    Doshi P, Jefferson T. The first 2 years of the European Medicines Agency’s policy on access to documents: secret no longer. JAMA Intern Med. 2013 Mar 11;173(5):380–2.

2.   Doshi P. Transparency interrupted: The curtailment of the European Medicines Agency’s policy on access to documents. JAMA Intern Med [Internet]. 2013 Aug 19 [cited 2013 Aug 20]; Available from: http://dx.doi.org/10.1001/jamainternmed.2013.9989

3. Every-Palmer S, Howick J. How evidence-based medicine is failing due to biased trials and selective publication Journal of Evaluation in Clinical Practice 2014; doi:10.1111/jep.12147

4. Jefferson T, Jones MA, Doshi P, Del Mar CB, Heneghan CJ, Hama R, Thompson MJ. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD008965. DOI: 10.1002/14651858.CD008965.pub3.

5. Lemmens T “Access to pharmaceutical data, not data secrecy, is an Essential Component of Human Rights” 8 April 2014. http://www.law.utoronto.ca/blog/faculty/access-pharmaceutical-data-should-be-framed-human-right-not-data-secrecy : 3 pages.

6.Lemmens T, Telfer C. Access to information and the right to health: the human rights case for clinical trials transparency. Am J Law & Med 2012; 38: 112. (online: http://ssrn.com/abstract=1932436)

7.    Jefferson T, Doshi P. Multisystem failure: the story of anti-­‐influenza drugs. BMJ 2014;348:g2263.

8. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD008965 DOI: 10.1002/14651858.CD008965.pub4