Studies with too few subjects may be 'scientifically useless,' thus unethically exposing participants to the risks of human research.

(Philadelphia, PA)-- In an article in the July 17th issue of the Journal of the American Medical Association (JAMA), three researchers at the University of Pennsylvania School of Medicine claim that many clinical trials are both scientifically deficient and unethical because they enroll "too few participants to reliably determine whether or not an intervention works."

The scientific and ethical problems of such "underpowered" trials were first suggested more than 20 years ago. "Because [underpowered trials] may not adequately test the underlying hypotheses (of the study), they have been considered 'scientifically useless,' and therefore unethical in their exposure of participants to the risks and burdens of human research," write the article's authors, Scott D. Halpern, MSCE, Jason H.T. Karlawish, MD, and Jesse A. Berlin, ScD. Despite this earlier consensus that trials must enroll adequate numbers of subjects, the authors found that not only do many investigators continue to enroll too few subjects, but that the practice has recently gained increasing support.

In their article, entitled, The Continuing Unethical Conduct of Underpowered Clinical Trials, the authors review the many scientific problems associated with conducting underpowered trials. And, as Halpern states, "studies that are scientifically deficient are also ethically deficient."

According to the researchers, scientific issues such as statistical power become ethical problems because most investigators do not tell people who enroll in their studies that there will not be enough subjects involved to make a reliable judgment on the study's findings.

"We believe investigators who conduct small or underpowered studies must tell patients that their participation might not provide information that will be of immediate clinical value, though it may provide information that will guide future studies," explains Halpern.

"Because patients often choose to participate in research because they want to help people with similar diseases, or help advance the cause of medicine, it is reasonable to assume that they would rather enroll in studies that have a better ability to provide healthcare benefits than in studies that have a lesser
ability to provide healthcare benefits," he added. "The smaller the study is, the less it is of clinical value. To deny patients the opportunity to know the relative clinical value of a study that they're considering enrolling in is unethical because it prevents them from making a fully informed decision."

Halpern says that what constitutes an adequate number of patients for research varies from study to study, but that as a rule, clinical researchers determine this number by using a specific formula which uses a number of variables including: the effect size being sought, the predicted variance in patients' outcomes, the level of statistical significance being used and the level of power sought. "The prominent factor that goes into determining the number of patients you would need is the magnitude of the effect of an intervention that you're looking for," he explains. "Researchers are generally guided by a clinical consensus among experts in a particular field as to what a clinically important effect is." In cases where such clinical consensus on a meaningful effect does not exist, Halpern and colleagues suggest that researchers use informed predictions of an intervention's likely effect to calculate the number of subjects that will be needed.

The authors say that conducting underpowered trials is only justifiable in narrowly defined circumstances. For instance, it might be difficult for investigators to find enough patients with a rare disease to conduct an adequately powered study. In such cases, Halpern says underpowered trials may be acceptable as long as the investigators can document plans at the trial's outset to combine the results with those from similar trials conducted elsewhere. Such investigators must also tell potential research subjects that it is uncertain whether the trial will yield clinically important information.

The authors write that failing to disclose this information may be deceptive and that "if such deception were publicized, it could undermine people's trust in science, further curtailing future enrollment [in trials]."
In their article, the authors condemn trials in which investigators should know, before commencing recruitment, that too few subjects are planned for inclusion. They do not specifically address trials in which patients drop out or fail to comply with the research, which can also decrease power. Trials suffering from these problems should be considered valid if there were enough subjects at the start, says Halpern. But he adds that, ideally, investigators should plan for a certain number of "drop-outs" when determining the number of subjects needed for a study, and thus attempt to enroll more patients than the minimum number needed.

Halpern is a seventh-year MD/PhD student, a fellow in the University of Pennsylvania School of Medicine's Center for Clinical Epidemiology and Biostatistics, and a co-investigator with the school's Center for Education and Research on Therapeutics; Karlawish is a faculty member in the University's Center for Bioethics, the Department of Medicine and the Leonard Davis Institute for Health Economics; and Berlin is a professor of biostatistics, a Senior Scholar in the Center for Epidemiology and Biostatistics, and also a co-investigator with the Center for Education and Research on Therapeutics.




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