Clinical Data Transparency Considered by Group of European Regulators

by Howard E. Rosenberg, Ph.D.

people-in-line.jpg Doshi et. al. (“Doshi”) in a recent publication in PLoS Medicine highlighted their difficulties in obtaining full clinical trial data surrounding the approval of the influenza antiviral Tamiflu® (oseltamivir). Their interest in the drug was aroused when they began examining claims for the utility of drug and the differing ways that the World Health Organization (“WHO”), FDA and other health authorities around the globe interpreted the effectiveness and thus the recommended method of treatment plans for the drug. The information that was freely available to Doshi came from published trial data and meta-analyses but this proved to be unsatisfactory, as it did not allow them to really examine how the differing understandings of the drug’s effectiveness and treatment patterns were decided upon by the world health authorities.

Widening their research into clinical trial reports and published data provided for other drugs that had subsequently been withdrawn or turned out to be unsatisfactory (e.g., rosiglitazone, rofecoxib, etc.), when it became clear to them that what they needed to see original clinical trial data without any “spin” attached. They pointed out that although published randomized clinical trials (“RCTs”) are considered the “gold standard” source of synthesized evidence, their conclusions are vulnerable to distortion when the trial sponsors have strong interests that might benefit from suppressing or promoting selected data. From their point of view, a better method to independently assess drugs would be to enable the access and review of the clinical trial documentation and reports sent to the government drug regulators. However, these reports are historically treated as commercial confidential documents, impeding additional scrutiny by independent researchers. As a result, Doshi was unable to get all the data they required for their Tamiflu® project, despite putting in a great effort trying to get key documents released by government regulators.

A group of European regulators have replied to the Doshi article, agreeing that clinical trial data should not be considered commercial confidential information, particularly as most patients enrolling in clinical trials do so with an assumption of contributing to general medical knowledge, and that non-disclosure of complete trial results undermines this. They see many potential advantages in having public disclosure, for example, in enabling the development of predictive models for patient selection to appropriate treatments and the potential for better individualized therapeutic decisions.

The European Regulators take issue with Doshi’s comment regarding financial conflicts of interest and sponsorship “spin” by pointing out that academics too are potentially just as likely to have conflicts of interest, e.g., personal academic advancement, or potential bias in the confirmation of previously-defended positions. In addition, there is a concern that unrestricted availability of full datasets may in some cases facilitate the publication of papers containing misleading results, which in turn lead to urgent calls for regulatory action. In a worst case, this would give rise to unfounded health scares with negative public health consequences such as patients refusing vaccinations or discontinuing drug treatment.

The European Regulators, however, do put forward several proposals to move the debate forward.

1) Develop and agree upon adequate standards for protection of personal data when publicizing RCT datasets.

2) Ensure general adoption of established quality standards of meta-analyses and other types of (confirmatory) data reanalysis that may warrant regulatory action.

3) Make use of the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP) guidance for raw data sharing, which follow the principle of maximum transparency while respecting the need to guarantee data privacy and to avert the potential for misuse.

The European Regulators emphasize that they believe the same standard of openness should apply to everyone (irrespective of sponsor) and that any and all studies carried out should be open to the same levels of inspection. The Regulators said, “We welcome debate on these issues, and remain confident that satisfactory solutions can be found to make complete trials data available in a way that will be in the best interest of public health.”