In the May 2012 issue of The Scientist, Data Diving: What lies untapped beneath the surface of published clinical trial analyses could rock the world of independent review. Discusses the problem of missing data and how it affects the reliability of systematic reviews.
On the Scientific American website, a guest post by cardiologist and researcher Jalees Rehman, Open Science and Access to Medical Research. Rehman discusses the special challenges of sharing clinical research, including the need to maintain patient confidentiality and the need for independent institutions to interpret the data in an unbiased manner so that vulnerable patients are not misled or given false hope.
In the November 21, 2011 issue of the Medical Journal of Australia, Time to mandate data release and independent audits for all clinical trials, by Ian Haines and George Gabor Miklos. Here are the last two paragraphs:
Medical journals and their editors have a choice — to be viewed as “an extension of the marketing arm of pharmaceutical companies,” or to be beacons of transparent data processes that inform clinicians, improve patient treatment, and provide high standards on which governments, health care providers and patients can have confidence.
Medical journals should demonstrate strong leadership by mandating open access to detailed clinical trial protocols and de-identified raw study data. They should insist on independent audits of data, concomitant publication of an “accompanying abstract,” and lodgement of the data in independent databases; these three actions should be a precondition for publication. (citations omitted)
Finally, in Science Translational Medicine, Learning from Hackers: Open-Source Clinical Trials, by Adam Dunn, Richard Day, Kenneth Mandl and Enrico Coiera. Behind a paywall, but here’s a news article in Australian Life Scientist and a post on Dunn’s blog.
In the USA at least, the data legally belong to trialists on the grounds that it requires work to create knowledge from data. But science, 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. Vickers AJ. Whose data set is it anyway? Sharing raw data from randomized trials. Trials. 2006;7:15.
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. 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
We are all patients, and will all face questions about what medical treatments to pursue. Some questions are trivial and unimportant, 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. 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 is to be done? What can we do to make evidence-based medicine more evidence-based? Four commentaries in the March 2012 issue of Circulation: Cardiovascular Quality and Outcomes discuss how 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. Currently, with certain exceptions, access to most clinical trial data is restricted to the investigators or the funders. Harlan Krumholz, in an editor’s perspective, outlines the key concepts:
Now is the time to bring data sharing and open science into the mainstream of clinical research, particularly with respect to trials that contain information about the risks and benefits of treatments in current use. This could be accomplished through the following steps:
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.
It must be acknowledged that there are many obstacles — political, cultural, financial — to accomplishing these goals. Some of these obstacles are discussed in the other three commentaries, which are open access and which I urge you to read:
Spertus, JA. The Double-Edged Sword of Open Access to Research Data. Circulation: Cardiovascular Quality and Outcomes. 2012;5;143-144.
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.
Gotzsche PC. Strengthening and Opening Up Health Research by Sharing Our Raw Data. Circulation: Cardiovascular Quality and Outcomes. 2012;5;236-237.
Whatever the difficulties, the current situation is clearly intolerable. 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.
Section 6002 of the Patient Protection and Affordable Care Act requires disclosure of payments by the drug and device industry to physicians and teaching hospitals. On December 14, 2011, the Centers for Medicare and Medicaid Services proposed regulations that would implement these “sunshine” provisions. See this Pharmalot post for background. I also recommend this commentary by Robert Steinbrook and Joseph Ross. The comment period closed on February 17, and I submitted a comment, excerpted below. You can access the proposed regulations and comments by going to www.regulations.gov and searching on “CMS-5060-P.”
Re: Transparency Reports and Reporting of Physician Ownership or Investment Interests; CMS-5060-P
Dear Ms. Tavenner:
I am writing to support the adoption of the above-referenced proposed rules implementing section 6002 of the Patient Protection and Affordable Care Act of 2010 (PPACA). As you know, this section of the PPACA requires drug, device, biological, or medical supply manufacturers to report certain payments and transfers of value to covered recipients, entities, individuals and teaching hospitals. The reported information would be available on a public website.
I believe the rules should be adopted substantially as proposed. In particular, I believe it is essential for the rules to require disclosure of both direct and indirect payments. Indirect payments include those a company makes to a third party, such as a medical society, contract research organization, or medical education and communication company, but that are ultimately intended for a physician or other covered recipient. The reporting of indirect payments is essential to meet the goals of transparency and completeness and to prevent the institution or continuation of arrangements that impede full disclosure of the financial relationships between industry and the medical profession.
In addition, I urge you to give careful consideration to the design of the proposed website. It should be designed to make possible it easy for members of the general public to find all payments to a particular provider or entity in one search regardless multiple addresses or variations in names (e.g., with or without a middle initial). I urge CMS to provide an opportunity for public discussion and comment on the proposed website design, such as through a public forum and/or focus groups.
Finally, I urge CMS to provide greater detail on specific enforcement mechanisms to ensure that manufacturers comply promptly and completely with the reporting requirements.
Thank you for the opportunity to comment on this important proposed regulation.