On June 5, the University of Minnesota announced it had hired the Association for the Accreditation of Human Research Protection Programs (AAHRPP) to manage a review of the university’s “human protections programs.” The three individuals AAHRPP selected as reviewers are Dr. Melissa Frumin, Dr. Jeremy Sugarman, and Ms. Joan Rachlin. The announcement failed to note that at the time of her selection Dr. Frumin was being sued for negligence in a medical malpractice lawsuit brought by an alleged victim of research misconduct.
With many other faculty members and concerned citizens, I am concerned that the AAHRPP-managed review will by design fail to address longstanding allegations of psychiatric research misconduct at the University of Minnesota. Before her organization signed a contract with the university, AAHRPP’s president, Elyse Summers, stated, “AAHRPP is not an investigative body.” Of even greater concern, the inquiry is restricted to review of current research practices and policies. This focus on contemporary protections for research subjects means the AAHRPP review will not investigate the Department of Psychiatry’s troubled history of research misconduct and questionable research practices.
“The best outside experts from across the country”
According to a press release issued by the University of Minnesota, “AAHRPP submitted the strongest proposal and found the best outside experts from across the country to conduct the inquiry.” The proposal AAHRPP submitted describes the selected reviewers as “world-renowned experts.”
In future posts I will examine AAHRPP’s selection of Dr. Sugarman and Ms. Rachlin as expert reviewers. Dr. Sugarman has served as a consultant for Quintiles, a contract research organization with financial ties to the University of Minnesota Department of Psychiatry. Dr. Sugarman has also served as a member of Genentech’s Strategic Council. Genentech is another company with financial links to the Department of Psychiatry. I plan to explore why AAHRPP selected a reviewer with what appears to be an obvious conflict-of-interest. I also intend to address Ms. Rachlin’s qualifications as a reviewer. In addition, I plan to scrutinize hiring of AAHRPP to manage the review. Since AAHRPP accredits the university’s research protections programs, AAHRPP is now in the conflicted position of conducting a review that ought to examine not only the university’s research protections but also its own repeated accreditation of those programs. Here, however, I want to narrow scope of inquiry and examine the selection of Dr. Melissa Frumin as an “expert” reviewer.
Examining Dr. Frumin’s Status as an “Expert Reviewer”
The press release announcing the selection of AAHRPP as contractor fails to explain what makes Dr. Frumin a “world-renewed expert.” Dr. Frumin has a clinical position in the Department of Neurology at Brigham and Women’s Hospital in Boston. She is also an Assistant Professor in the Department of Psychiatry at Harvard Medical School and Chair of the Partners HealthCare Institutional Review Board. Acknowledging these appointments, her résumé does not support the claim that she is a “national expert” or “world-renowned expert” qualified to review the university’s research protections programs.
According to her curriculum vitae, Dr. Frumin has no publications or research grants related to such topics as research ethics, governance of human subjects research, ethics of psychiatric clinical trials, responsible conduct of research, and institutional review boards. She obtained her medical degree over twenty years ago and has had at least two decades to contribute to these areas of scholarship. Dr. Frumin’s current CV lists eleven “local” or “national” presentations addressing such topics as teaching medical students human subject protection, advanced directives for research, ethical considerations and IRB issues, and the roles and responsibilities of the unaffiliated/non-scientific member of the IRB. These talks fall into the category of scholarship in research ethics. However, Dr. Frumin cannot be characterized as a “national expert” or “world-renowned expert” on the basis of these eleven talks.
It is possible that AAHRPP and the University of Minnesota want to claim that Dr. Frumin is a nationally or internationally recognized expert in psychiatry. Dr. Frumin is co-author on a total of 28 publications inclusive of peer-reviewed articles and book chapters. However, her most recent publication in psychiatry dates to 2007 and her last funded project ended in 2005. While Dr. Frumin has made credible contributions to psychiatric research, seven years have passed since she was an active scholar in this field.
Dr. Frumin’s main claims to being qualified to review the University of Minnesota’s research protection programs appear to be that she completed a one year fellowship in medical ethics at Harvard Medical School, served as a member of Partners HealthCare IRB from 2003 to 2005, and since 2005 has served as Chairperson of Partners HealthCare IRB. However, Dr. Frumin’s tenure as Partners HealthCare IRB Chair has been marked by controversy. At the time AAHRPP appointed Dr. Frumin as a reviewer of the University of Minnesota’s research protections programs she was being sued for negligence along with other IRB members. Dr. Frumin and the other IRB members have since been dismissed from the suit because the judge assigned to the case concluded IRB members do not have legal duties to research subjects. Nonetheless, her status as a defendant in a lawsuit, the manner in which she and other IRB members were dismissed from the lawsuit, the numerous ethical issues related to the approval of an informed consent form that allegedly failed to disclose numerous risks, and her limited record of accomplishments in research ethics and psychiatry prompt serious questions about why AAHRPP selected her to review the University of Minnesota’s research protections.
Zeman et al v. Williams et al
Zeman et al v. Williams et al, filed in the United States District Court for the District of Massachusetts, alleged that Dr. Frumin and other IRB members were negligent in their review of informed consent forms used in clinical trial testing gene transfer in individuals suffering from early-onset Parkinson’s disease. Judge George O’Toole, Jr. dismissed the claims against all IRB members on the basis that they did not have legal duties to research subjects “with respect to the obtaining of informed consent.” The dismissal of the negligence claim brought against Dr. Frumin and other IRB members has unsettling similarities to the outcome of the lawsuit Mary Weiss brought against the University of Minnesota after her son, Dan Markingson, committed suicide while he was a research subject in a psychiatric clinical trial. The university’s failure to conduct a credible investigation of Dan Markingson’s death played an important role in prompting the Faculty Senate to pass a resolution requesting an investigation of human subjects research.
According to Zeman et al v. Williams et al, in 1996, Robert Zeman was diagnosed with Young Onset Parkinson’s disease. By late 2008, the therapeutic effects of the medications Mr. Zeman was using had diminished and his Parkinson’s disease-related symptoms had increased. Mr. Zeman subsequently decided to participate in a randomized controlled gene transfer trial conducted at Massachusetts General Hospital. The study was designed to transfer genes into both sides of Mr. Zeman’s brain. Dr. Frumin and other IRB members allegedly approved the informed consent form for this clinical trial.
On December 4, 2008, Mr. Zeman was the first subject in the clinical trial, “Safety and Efficacy Study Evaluating Glutamic Acid Decarboxylase Gene Transfer of Subthalamic Nuclei in Subjects with Advanced Parkinson’s Disease.” Dr. Ziv Williams performed the surgical procedure enabling gene transfer. A medical device manufactured by Medtronic, the Acute Brain Infusion Delivery System (ABID system), was supposed to be used to deliver the genes into both sides of Mr. Zeman’s brain. However, the catheter components of the ABID System were allegedly not correctly placed into each side of Mr. Zeman’s brain. Instead, the lawsuit claims that the end points of the catheters were both placed on the left side of Mr. Zeman’s brain. As a result, Mr. Zeman allegedly received a double dose of the study agent on the left side of his brain and no dose on the right side of his brain. This error can cause what the lawsuit describes as a “handicapping” effect.
The lawsuit further alleges that following the surgical procedure Mr. Zeman was not informed that he had received a double dose on one side of his brain. Indeed, according to the lawsuit, there was reportedly no mention that his care had allegedly included a serious adverse event. Instead, at first he was reportedly told, “the surgery went well.” He was later allegedly not informed of post-operative bleeding in his brain. According to the complaint, Mr. Zeman was unaware a serious adverse event had occurred until one of the physicians involved in the trial remarked, “So you’re the guy who got the double dose of the gene on one side?”
The lawsuit claims that following the alleged double dose Mr. Zeman was asked to sign a second informed consent form. This document reportedly asked Mr. Zeman to provide “consent”—after the surgical procedure had already occurred—to the previously undisclosed risk that he could receive a double dose or no dose of the study agent.
Dr. Williams, the neurosurgeon who performed the gene transfer, is being sued for negligence, lack of informed consent, battery, intentional infliction of emotional distress, and deceit/intentional misrepresentation/fraud in the inducement/breach of fiduciary duty. Another physician reportedly involved in the trial, Dr. Emad Eskandar, is being sued for lack of informed consent, negligence, intentional infliction of emotional distress, and deceit/intentional misrepresentation/fraud in the inducement/breach of fiduciary duty. A third physician, Dr. Michael Kaplitt, an employee of the study sponsor, Neurologix, is being sued for negligence. Neurologix, a company that declared bankruptcy two years ago, is also a defendant in the lawsuit and is being sued for negligence and breach of warranty. Medtronic, originally named as a defendant, has since been dropped from the lawsuit.
Mr. Zeman sued for negligence Dr. Frumin and the other IRB members that allegedly approved the study’s informed consent form. According to the lawsuit, the informed consent document reviewed and approved by Dr. Frumin and other IRB members failed to disclose more than ten study-related risks and protocol details that should have been described to prospective research subjects. The list of undisclosed risks allegedly includes the failure to disclose that the catheters might be misplaced and research subjects could receive a double dose of the study agent on one side of the brain.
Unless plaintiffs’ lawsuit against remaining defendants is unsuccessful and plaintiffs’ counsel files an appeal, Dr. Frumin and the other IRB members will not have to address particulars of Mr. Zeman’s claim that they approved an informed consent document missing important information related to risk of participating in gene transfer trial. (However, organizations such as the FDA, Harvard University, Partners HealthCare, and Massachusetts General Hospital could choose to investigate whether the IRB should have approved the study protocol and informed consent document.) On July 7, a judge dismissed the claims brought against all IRB members. In his Opinion and Order Judge O’Toole wrote,
The IRB members argue that they do not stand in such a relationship to a subject in a clinical trial such as Mr. Zeman as to give rise to a duty of care with respect to the obtaining of informed consent, and that consequently the complaint fails to state a claim against them. I agree.
The judge added,
The doctrine of informed consent has been developed in actions for malpractice by medical professionals who are treating a patient…. The IRB members stand outside any treatment relationship with Mr. Zeman. Under the Massachusetts cases, they do not have any duty to him (or any other specific patient) with respect to the obtaining of informed consent.
In reaching this conclusion, Judge O’Toole’s decision-making appears to have been informed by the “Memorandum of Law” submitted by the IRB members’ attorneys. The memorandum states,
Plaintiffs have failed to state a claim upon which relief can be granted because, as a matter of law, there is no private cause of action under the applicable statutes and regulations and even assuming a cause of action exists, the IRB has no duty to individual plaintiffs.
Similarities Between the Claims Against IRB Members in the Zeman Case and the IRB in the Markingson Case
What is particularly noteworthy about Zeman et al v. Williams et al is the similarity between the negligence claim brought against IRB members named in the case and claims made against the University of Minnesota’s IRB in the Markingson case.
First, before the claim against IRB members was dismissed, Dr. Frumin and other IRB members were alleged to have approved an informed consent form that failed to fully disclose all risks associated with participating in the gene transfer clinical trial. This allegation resembles the failure to disclose all study-related risks to Dan Markingson.
Second, Dr. Frumin and other IRB members were alleged to have approved an informed consent form that failed to fully disclose all financial conflicts-of-interest. In the Markingson case, one of the claims made against the University of Minnesota was that researchers had failed to disclose all financial conflicts-of-interest.
Third, before being dismissed from the suit, Dr Frumin and other IRB members were accused of approving an informed consent form that failed to follow federal regulations governing human subjects research. The failure to comply with all applicable federal regulations was another claim made against psychiatrists and the university’s IRB in the Markingson lawsuit.
Fourth, in their defense, Dr. Frumin and the other IRB members named as defendants in the lawsuit claimed they were “immune from liability” and “had no duty to individual plaintiffs.” These claims are identical to claims made by the University of Minnesota’s lawyers in the Markingson case.
For individuals who assume institutional review boards have ethical and legal duties to research subjects on the basis of responsibilities of IRBs as defined by federal regulations (See 45 CFR 46 and 21 CFR 56), it can be a shock to discover that in cases where IRBs and individual IRB members are sued they appear to be quite successful at arguing they are immune from litigation and have no legal duties to research subjects. This line of defense prompts serious questions about why IRBs exist. It also generates questions concerning whether IRBs play a meaningful and accountable role in protecting human research participants from harm or operate as litigation-defeating Trojan horses.
Will There Ever Be a Legitimate Independent Investigation of Psychiatric Research at the University of Minnesota?
Given the persistent failure of senior university officials to investigate allegations of psychiatric research misconduct, perhaps managing to be dismissed as a defendant from a lawsuit brought by an alleged victim of research misconduct is just the sort of accomplishment one might expect to find in the résumé of a reviewer selected to examine the University of Minnesota’s research policies and practices. Recognizing the university’s troubled history of overseeing psychiatric clinical trials, maybe this is what “expert peer review” means in the context of examining the university’s research protections programs. But can anyone who is not an AAHRPP executive or senior university official actually believe that the most qualified individuals for the task are conducting the review of research protections at the University of Minnesota? What is the point of initiating and funding such a review if it is not conducted by qualified experts and given a mandate to investigate both current research protections and particular allegations of research misconduct?
What appears to be underway is a carefully managed “review” that is designed to ignore the elephant-in-the-room. This faux inquiry is conducted by one reviewer who is unqualified for the task, another reviewer with a conflict-of-interest, and an organization that has an obvious financial conflict-of-interest as it reviews a research protection program that it already accredits. Once again, senior university officials have eliminated the possibility of a meaningful independent inquiry. Perhaps the investigation by Jim Nobles, Minnesota’s legislative auditor, will examine the allegations of research misconduct that AAHRPP’s reviewers have not been asked to investigate.