The following is a guest post by Marilyn Mann, who is an attorney at the U.S. Securities and Exchange Commission.* She first became interested in the issue of hidden clinical trial data when her teenage daughter, who has heterozygous familial hypercholesterolemia, was placed on ezetimibe (Zetia). Ezetimibe became controversial when the results of the ENHANCE trial were withheld by the sponsor for almost two years after the trial was completed.
*The U.S. Securities and Exchange Commission disclaims responsibility for any private publication or statement of any Commission employee or Commissioner. This blog post expresses Marilyn Mann’s views and does not necessarily reflect those of the Commission, the Commissioners, or other members of the Commission staff.
Why physicians and patients should support open data
“[S]cience, particularly medical science, is essentially an enterprise conducted for moral reasons. We need to do not just what is legal but what is right. As such, we must take into account the probable wishes of the patients who give us their blood, fill in our questionnaires and die on our trials. It is difficult to believe that any patient on my trial, who completed complex questionnaires so diligently over such a long period of time, would really have wanted me to keep the data for myself rather than share it with others for the benefit of medical science in general.” – Andrew Vickers (1)
“Every day, patients and their caregivers are faced with difficult decisions about treatment. They turn to physicians and other healthcare professionals to interpret the medical evidence and assist them in making individualized decisions. Unfortunately, we are learning that what is published in the medical literature represents only a portion of the evidence that is relevant to the risks and benefits of available treatments. In a profession that seeks to rely on evidence, it is ironic that we tolerate a system that enables evidence to be outside of public view.” – Harlan Krumholz (2)
We are all patients, and will all face questions about what medical treatments to pursue. Some questions are trivial and unimportant, while others can mean the difference between life and death. We rely on evidence-based medicine to give us reliable information about the risks and benefits associated with medical interventions, but a disturbing amount of evidence indicates that the medical literature is not always reliable. Many clinical trials are not published within a reasonable time after completion or are never published at all. (3-4) Missing data leads to systematic reviews that are based on only a portion of the trials that were conducted, which can affect the results in unknown and unpredictable ways.
Missing data may in some cases hold important information about risk, as in the case of Vioxx (rofecoxib). Merck had data several years before Vioxx was withdrawn from the market that showed the drug increased the risk of heart attacks, but most of the data was unpublished and out of public view. In other cases, clinical trials are published but the data are reported in a misleading and biased way, as when a negative trial is presented so as to appear positive, or analyses showing harm are omitted.
What can we do to make evidence-based medicine more evidence-based? Recently, a number of commentators have argued that making clinical research data available outside individual drug and device companies or research groups could greatly add to the depth and reliability of our knowledge. (1-2, 5-9) Currently, with certain exceptions, access to most clinical trial data is restricted to the investigators or the funders. Harlan Krumholz outlined some of the key concepts:
- Post, in the public domain, the study protocol for each published trial. The protocol should be comprehensive and include policies and procedures relevant to actions taken in the trial.
- Develop mechanisms for those who own trial data to share their raw data and individual patient data.
- Encourage industry to commit to place all its clinical research data relevant to approved products in the public domain. This action would acknowledge that the privilege of selling products is accompanied by a responsibility to share all the clinical research data relevant to the products’ benefits and harms.
- Develop a culture within academics that values data sharing and open science. After a period in which the original investigators can complete their funded studies, the data should be de-identified and made available for investigators globally.
- Identify, within all systematic reviews, trials that are not published, using sources such as clinicaltrials.gov and regulatory postings to determine what is missing.
- Share data. (2)
II. Recent developments
Several recent developments give hope that sharing clinical trial data will become a reality.
- In the wake of controversy over Infuse, a bone growth product, Medtronic agreed to turn over all of its Infuse data to a team at Yale for independent analysis.
- The European Medicines Agency has agreed to make clinical trial data sets available to interested parties and is holding a workshop on November 22, 2012 to discuss practical and policy issues with stakeholders.
- GlaxoSmithKline recently announced that it will share patient-level data from its clinical trials.
- Fiona Godlee, editor-in-chief of the BMJ, announced that starting in January 2013, the BMJ will publish clinical trials only where there is a commitment to make available patient-level data to independent researchers on reasonable request.
Physicians and patients deserve reliable information on the risks and benefits of medical treatments and the subjects of clinical trials deserve that their contributions be fully used to benefit other patients. Let us hope the new initiatives discussed above become part of a historic turning point in the availability of clinical trial data.
(1) Vickers AJ. Whose data set is it anyway? Sharing raw data from randomized trials. Trials. 2006;7:15.
(2) Krumholz HM. Open Science and Data Sharing in Clinical Research: Basing Informed Decisions on the Totality of the Evidence. Circulation: Cardiovascular Quality and Outcomes. 2012;5: 141-142.
(3) Eyding D, Lelgemann M, Grouven U, et al. 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.
(4) Ross JS, Mulvey GK, Hines EM, Nissen SE, Krumholz HM. Trial publication after registration in ClinicalTrials.Gov: a cross-sectional analysis. PLOS Med. 2009;6(9):e1000144.
(5) Ross JS, Lehman R, Gross CP. The Importance of Clinical Trial Data Sharing: Toward More Open Science. Circulation: Cardiovascular Quality and Outcomes. 2012;5;238-240.
(6) Gotzsche PC. Strengthening and Opening Up Health Research by Sharing Our Raw Data. Circulation: Cardiovascular Quality and Outcomes. 2012;5;236-237.
(7) Peter Doshi and Tom Jefferson, “Drug Data Shouldn’t Be Secret,” New York Times, April 10, 2012.
(8) Doshi P, Jefferson T, Del Mar C (2012) The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience. PLoS Med 9(4): e1001201. doi:10.1371/journal.pmed.1001201.
(9) Eichler H-G, Abadie E, Breckenridge A, Leufkens H, Rasi G (2012) Open Clinical Trial Data for All? A View from Regulators. PLoS Med 9(4): e1001202. doi:10.1371/journal.pmed.1001202.
Portions of this post were previously published on Marilyn Mann’s Blog.
Barbara Meier schreibt seit vielen Jahren für die NPAlliance Ratgeber und Testberichte. Dabei legt sie großen Wert auf die Ausführlichkeit sowie Richtigkeit ihrer Artikel. Sie zählt zu den wenigen Experten in ihrem Gebiet und hat sich über die letzten Jahren einen Namen in der Gesundheitsbranche gemacht.