What happens when investigators are asked to hand over unblinded data from an ongoing clinical trial? In a Special Communication appearing in JAMA Internal Medicine, Walter N. Kernan, MD, and colleagues from Yale University School of Medicine reviewed a recent product liability litigation case involving pioglitazone, in which investigators were forced to weigh the importance of maintaining the integrity of a clinical trial against legal obligations.

Pioglitazone was evaluated in the Insulin Resistance Intervention after Stroke (IRIS) trial; in October 2012, after two epidemiologic studies described a possible increased risk for bladder cancer among patients with diabetes taking the drug, a subpoena was issued for IRIS documents, including unblinded adverse event reports of incident bladder cancer. Since the IRIS trial was ongoing during the litigation, and premature disclosure of unblinded data would have violated the study protocol and US Food and Drug Administration research guidelines, Yale University filed an objection. "Although Yale's litigation was successful, the case is a troubling demonstration of the potential for plaintiffs' attorneys and other outside parties to disrupt clinical research," Dr. Kernan and co-authors wrote. "Moreover, the case raised important issues about research integrity, academic freedom, and the role of researchers in court." 

Disclosing interim results of ongoing clinical trials in legal proceedings is problematic for numerous other reasons, the authors noted, including:

• Public release of interim data deprives researchers of the opportunity to fully interpret their findings.
• Public release effectively bypasses peer review, which is essential for maintaining credibility of the research process and ensuring data are appropriately vetted, analyzed, and interpreted before dissemination.
• Major medical journals may consider not publishing research that has already been publicized.
• Release of immature data may alter behavior by both research participants and investigators.
• Dissemination of unblinded findings could undermine review of data and emerging trends by the data and safety monitoring board.

In short, a little knowledge could be a dangerous thing.

In an invited commentary, lawyers Michelle M. Mello, JD, PhD, MPhil, and I. Glenn Cohen, JD, offer a broader context to this important issue, weighing the power of a subpoena against clinical researchers' obligations to protect their data. Drs. Mello and Cohen agree that a framework for equalizing risks and benefits is appropriate when it comes to lawyers' obligations in responding to subpoenas for clinical trial data. "The reaction of people who are not lawyers to Yale's predicament may be to ask ‘Why can third parties be burdened with subpoenas when they have nothing to do with a plaintiff's grievance?'" Drs. Mello and Cohen wrote. "Plaintiffs bear the burden of proof, yet defendants and others who have no incentive to share information typically have a considerable amount of the information that plaintiffs' attorneys need to build their case."

Can the various interests of the involved parties in these types of situations be balanced? Drs. Mello and Cohen offer various solutions, including:

• Judges should consider whether procedural safeguards could sufficiently minimize risks associated with the disclosure of data.
• Judges could issue protective orders that could substantially shift the risk-benefit balance.
• Judges could appoint a neutral third party to analyze unblinded data without releasing them to the plaintiff.

The most important factor to consider is the risk-benefit balance, questioning who stands to benefit from the release of unblinded data and who could be harmed by the clinical trial's interruption. "Data from clinical trials are arguably a public good," Kernan et al. write, "particularly when the government funds a trial." They admit secrecy (in this case, maintaining "the blind") is rarely in the public interest, but when a trial is ongoing, maintaining the blind stands at the heart of the scientific process. "Keeping data confidential is justified by the public's considerable interest in clinical research that is conducted properly and [in] science that may advance medical care."

Kernan WN, Viscoli CM, Varughese MC. JAMA Intern Med. 2014 July 21. [Epub ahead of print]
Mello MM, Cohen G. JAMA Intern Med. 2014 July 21. [Epub ahead of print]

Keywords: Financial Management, Motivation, Stroke, United States Food and Drug Administration, Epidemiologic Studies, Peer Review, Clinical Trials Data Monitoring Committees, Publishing, Risk Assessment, Insulin Resistance, Diabetes Mellitus, Lawyers

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