Some clinical trials include only one participant. In individualized therapy trials, researchers use patients as their own controls to evaluate treatments. “Our team had seen several publications of so-called ‘n of 1’ clinical trials. We thought there were a number of important ethical, scientific, and conceptual issues that were going underattended, both in publications as well as in news reports,” says Jonathan Kimmelman, PhD, director of biomedical ethics at McGill University in Montreal.
Kimmelman and colleagues authored a paper to address this gap.1 “Some researchers view these trials as merely a form of medical care with additional data collection,” Kimmelman notes.
Certain individualized therapy trials could be considered “expanded access” or “nonvalidated practice.”
“Many such studies, oddly, go through IRB review for assessment of consent. It is a strange contradiction that doesn’t get talked about enough,” Kimmelman observes.
IRBs are supposed to review research, not care, but these endeavors are considered care, not research. “This practice asks IRBs to stick their beak into an area where they have no business,” according to Kimmelman.
In their paper, Kimmelman and colleagues argued even individualized trials pose the same tensions between research and care that exist in traditional trials. “For example, multicrossover trial series reduce sample size while increasing burdens for research volunteers,” Kimmelman offers.
According to Kimmelman and colleagues, individualized therapy studies should be publicly and prospectively registered in a clinical trial database. The authors should report results regardless of outcomes. “We worry that individualized therapy trials, if not done right, are a step backward in terms of transparency and reporting bias,” Kimmelman explains.
If the trials go unreported, side effects or other issues could remain unrecognized. A lack of efficacy remain unreported. Kimmelman offers this example: People in individualized therapy trials try a drug for a medical condition on 20 occasions. For 18 of those people, the drug does not work. On two occasions, the drug works, and the authors publish only those successful results. “When you want to try attempt 21, you search the literature and it looks like it worked two for two. You’d be crazy not to use the drug,” Kimmelman says.
Kimmelman says using an individualized approach should be thoroughly justified to IRBs. This is especially important for “before and after” studies, which measure outcomes before and after an intervention and do not involve blinding or randomization. Because these studies use methods that put them at substantial risk of bias, they are likely to produce results that are spurious. “That harms the risk/benefit balance, because some of the benefit is the knowledge value of the study,” Kimmelman says. “Also, why use a poor method when a better one can be used?”
IRBs must ensure researchers use the best methods possible. Another ethical concern is trials are patient-funded. This raises important questions about the independence of the sponsor and the researcher, along with equity. Additionally, because “before and after” studies look so much like individualized care, IRBs might erroneously treat them as such. “That ought not to be the case if researchers are trying to assert a hypothesis that will generalize to other patients,” Kimmelman says.
Studies should be based on a protocol and they should be prospectively registered and reported in full, even if they are exempt from regulatory requirements to do so, Kimmelman asserts.
Kimmelman says IRBs should ask several questions when reviewing study protocols for individualized therapy trials. Did the study undergo a proper scientific merit review? Is the science sound, and is it likely to be informative? Is it unlikely patients will experience substantial medical benefit from the study? If so, does the consent form state that clearly? Do scientists intend to assert a generalizable finding from what they observe?
If so, says Kimmelman, “they are doing science, and the study protocol should evidence design decisions that will support interpretation when the study is complete.”
REFERENCE
1. Kane PB, Bittlinger M, Kimmelman J. Individualized therapy trials: Navigating patient care, research goals and ethics. Nat Med 2021;27:1679-1686.
Individualized therapy studies should be publicly and prospectively registered in a clinical trial database. The authors should report results regardless of outcomes. If these trials are not handled right, it might be a step backward in terms of transparency and reporting bias.
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