Research Participant Suicide

On March 26, 2024, the FDA sent a warning letter to a psychiatrist clinical investigator. He was informed "of objectionable conditions observed during the U.S. Food and Drug Administration inspection conducted at your clinical site between December 19, 2022, and January 10, 2023." The warning letter had a long history.

The story was reported in the New York Times on August 10, 2023:

Federal regulators have suspended research on human subjects at the Columbia-affiliated New York State Psychiatric Institute, one of the country’s oldest research centers, as they investigate safety protocols across the institute after the suicide of a research participant....
It is unusual for the U.S. regulatory office to suspend research, and this suggests that investigators are concerned that potential violations of safety protocols occurred more broadly within the institute. Almost 500 studies, with combined budgets totaling $86 million, are underway at the institute, according to its website.
The inquiry followed the death by suicide of a person enrolled in a study led by Dr. Bret R. Rutherford, an associate professor of psychiatry at Columbia University who was testing a drug for Parkinson’s disease, levodopa, as a treatment for depression and reduced mobility in older people.

As a former Institutional Review Board Chair, this triggered thoughts I'd like to share on:

• Unethical Protocols & IRB Role
• Meticulously Follow the Protocol
• Clinical Investigator Responsibility is 100%
• Sponsor Responsibility
• Clinical Research Coordinator Responsibility
• Institutional Responsibility
• Deaths in Medical Research

Unethical Protocols; IRB Role

Protocols are research designs that answer a question, such as whether drug A significantly reduces depression compared to placebo.

The Institutional Review Board (IRB) is the ethics committee that reviews the study and must approve it before it starts. Traditionally, the IRB was within the institution conducting the research, though central IRBs outside the institution have been more commonly used in the past few decades.

The IRB's role is focused on minimizing risks and ensuring that risks to participants are reasonable in relation to anticipated benefits. In the study discussed in the New York Times, the suicide was in the placebo group. Some of the ethical issues to consider include:

• For the depressed person who enters the study, is it reasonable to have a placebo arm? Many would say no, it is not. Why not have a study looking at drug A (experimental) vs drug B (a standard of care drug for depression)? This would change the study hypothesis to whether drug A is non-inferior to standard of care drug B. While there may be a scientific reason to prefer a placebo controlled trial, is it worth the risk to the participants in the placebo arm? During my 17 years as IRB Chair, I spoke to some of the FDA headquarters drug division specialists about sponsors that said the FDA required a placebo controlled trial only, and each time, they made clear they do not mandate placebo controlled trials.
• Are there rigorous enough methods in the study to exclude participants who are at higher risk for suicide? There was an exclusion criteria for this in the protocol, which appeared to be sufficient. If it was sufficient on paper, was it strictly enforced even as enrollment proved difficult?
• Was adequate non-drug support provided to research participants in this depression trial to proactively avert self-harm, whether in the experimental or placebo arm? E.g., would regular therapist visits to monitor participants' self harming trends and determine who should be removed from the study have been prudent? Some would say such removal from the study might harm scientific validity. Yet it is the right thing to terminate a research participant from a study if it appears to be significantly harming them. We must also acknowledge that this would not have guaranteed the participant would not have committed suicide.

There is an FDA Guidance document about placebo use in cancer studies that states:

Given that using a placebo in randomized controlled clinical trials of therapies to treat hematologic malignancy and oncologic disease for which there is known effective therapy is ethically unacceptable, sponsors should consider using a placebo-controlled design only in selected circumstances (e.g., when surveillance is standard of care) or with certain trial design features (e.g., when the trial uses an add-on design).

FDA regulations at 21 CFR 314.126(b)(2) review study designs with valid controls that "provide a quantitative assessment of drug effect." While a placebo controlled trial is one method, it is not the only method. Placebo controlled studies make ethical sense when there is no standard of care drug treatment (e.g., no FDA approved drug for that indication), or when harms are minimal. An example of the latter might be a minoxidil competitor drug in a study for hair growth, where a placebo controlled trial with the new drug is acceptable since the potential harm is minimal (and most people with the condition are not on any treatment for it).

The code of federal regulation at 21 CFR 56.111 says that before approving a study, the IRB must determine in part that:

Risks to subjects are minimized:
(i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and
(ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.

(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies that subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.

Meticulously Follow the Protocol

Study protocols are carefully designed to (1) answer the proposed scientific hypothesis and (2) protect participants' safety. They must be carefully followed, or these goals can be jeopardized.

For example, at the end of the study, one goal may be to determine if drug A significantly reduces depression compared to placebo. However, if the drug wash out periods were shortened to make enrollment easier (apparently the case in the study above), then this protocol violation could compromise scientific validity and participant safety. The hypothesis being tested is aimed at a specific population, so the inclusion and exclusion criteria must be followed for results to be valid in the population of interest.

Some protocol elements are focused on subject safety. Perhaps the drug being studied is known to be more dangerous in those with severe renal disease, so the criteria for enrollment might be a blood test showing an eGFR>=60 (meaning the kidneys are normal). If this is violated, the risk to the research participant is higher than was approved.

Clinical Investigator Responsibility is 100%

As the FDA stated in its warning letter:

We emphasize that as the sponsor-investigator and clinical investigator, it was ultimately your responsibility to ensure that these studies were conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the integrity of study data. Your failure to ensure subjects met protocol-required eligibility criteria by not following the protocol-required tapering and medication washout requirements, raises significant concerns about the safety of the study subjects enrolled at your site and raises concerns about the reliability of the data collected at your site. Multiple subjects were randomized and received the investigational product at your site that were ineligible for enrollment in the study.

A clinical investigator may be too busy with their clinical work, other research studies, the process of seeking funding, writing papers, etc., to pay proper attention to this particular study. When problems are found in an FDA audit, the first response is often, "I depended on the clinical research coordinator, it is their fault." However, clinical investigators are 100% responsible for everything in the study. When they delegate tasks, they are responsible for ensuring the clinical research coordinator is trained on the study, competent to perform their duties, and monitored effectively to ensure the study protocol is properly carried out. It is like the captain of a ship being 100% responsible for what happens to their ship and the safety of the passengers.

Rarely, a clinical research coordinator or other person working on a study has criminally falsified data or harmed participants. FDA has occasionally referred cases to the Department of Justice, and individuals have been prosecuted. But even in these rare cases, the clinical investigator is responsible and should have had audits and double-checks along the way to ensure the protocol was being carried out properly.

Sponsor Responsibility

A research drug study often has a pharmaceutical company as the sponsor. The pharmaceutical company has teams of scientists who design the study protocol. The sponsor then finds clinical investigators at various institutions to open and supervise the study at their institution.

As the study progresses, sponsors are responsible for monitoring the study site and double-checking that the study is being conducted properly. They review regularly submitted study reports, and also do site visits in person. The sponsor's site visitor checks for protocol deviations, looks for adverse events that may not have been reported, ensures data integrity, and ensures that the study is being properly conducted using good clinical practice.

Sometimes, the physician investigator at an institution is also the sponsor, as appears to be the case in the above FDA Warning letter. Unfortunately, this removes one of the supervisory mechanisms to double-check the proper conduct of the study.

Humans have biases and blind spots. When the clinical investigator and the sponsor are the same person, their biases and blind spots are the same, and the errors that occur may be harder to detect at an early stage.

Clinical Research Coordinator Responsibility

Clinical Research Coordinators (CRC) do much of the day-to-day work in a research study overseen by the clinical investigator. Sadly, with physicians' clinical and time pressures, the oversight may often be inadequate.

Occasionally, a CRC might cut corners and not follow the protocol strictly. Good oversight by the principal investigator can hopefully catch this problem early on and correct it by either education or dismissal.

In this specific study, the New York Times reported that the CRC said "recruiting for the study had been challenging and that some criteria had been relaxed to increase enrollment." Other protocol violations were also noted. The CRC said the experience left her disillusioned and contributed to her decision to leave the field: “I was disappointed at the rigor of the research there.” This appears to be a case of the clinical investigator cutting corners and pushing the CRC to cut corners so much that the CRC left the job and the industry. The clinical investigator should be a model of good research behavior and promote the careers of those he supervises, not be destroying their ethics and careers.

Institutional Responsibility

The institution the study is being conducted within must ensure that research on its campus is done properly. This may involve regular education for clinical investigators and clinical research coordinators. There should be a quality assurance or audit program for research. It should be incredibly intense when the clinical investigator is also the sponsor. For FDA-regulated studies created at the institution, a scientific committee should review the protocol for changes needed before it goes to the IRB.

Deaths in Medical Research

Bad things, including death, can happen in medical research even if everyone does everything correctly. There may be ethical studies in terminal patients where death is expected soon, and the new experimental drug might hasten it, but the patient fully consents in the hopes of helping others and knowing there are no other treatments left for them. IRBs must sort out the ethical issues on a case-by-case basis, as the devil is in the details.

A death must be investigated. However, it may have happened even if the participant never joined the research study. Or it may not be due to the research study even though there is suggestive information that the study contributed to the death. In many cases, it is impossible to be entirely sure of the cause.

In a very large study, one can see that the treatment was or was not statistically associated with various bad outcomes, including death. An interim analysis is often planned in large studies to check if there is a trend that should stop the trial early. See the paper on this by my colleagues and me on Considerations for Stopping a Clinical Trial Early.

In small studies, the sponsor analyzes the adverse event data as it comes in and investigates each death or other unexpected problem involving risks to participants or others to determine if the study needs to stop or safety changes made.

In this depression study the FDA warning letter is referring to, the death triggered an FDA audit that uncovered numerous protocol violations, problems with research oversight at the institution, and perhaps investigator misconduct. I wonder if the death never occurred, would all these problems have ever been noticed? Is institutional research oversight at all our institutions adequate enough? Do people really have to die to bring attention to the need for research institutions to fund and staff properly the research oversight and audit and quality control programs?