What are the ethical issues involved when the US Food and Drug Administration considers whether to ask a pharmaceutical company to conduct postmarketing studies on an approved drug already in clinical use? A committee of the Institute of Medicine has released a new report that offers the FDA—at its own request—a conceptual framework for making decisions on when to require further study on an approved drug (see box).
Public law 110-85, the Food and Drug Administration Amendments Acts of 2007 expanded the FDA’s regulatory authority over approved drugs during the postmarketing period. This expanded authority allows the agency to require clinical trials or other studies after a drug has been approved when they are deemed necessary to protect the health of the public.
The law states that the FDA can order postmarketing studies to assess a known serious risk related to use of the drug in question; to assess signals of serious risk; and to identify an unexpected serious risk when the available data suggest that the potential for such a risk is there. The law also requires the FDA to establish an active surveillance system for monitoring drugs by using electronic data from health care organizations. According to the FDA, the effectiveness of any US national postmarketing surveillance system is directly dependent on the active participation of clinicians, whose ongoing experience with patients can identify adverse events and complications that were not apparent in premarketing clinical trials.
The 15-page report, “Ethical Issues in Studying the Safety of Approved Drugs,” is a preview of a more comprehensive and detailed report on postmarketing studies the IOM committee plans to release next spring. The report was triggered by the mid-July FDA meeting on the case of the diabetes drug Avandia, but the report does not focus specifically on that drug, instead providing a general framework for decision-making that would be applicable to other cases.
The IOM committee that wrote the letter report is co-chaired by Ruth R. Faden, PhD, MPH, the Philip Franklin Wagley Professor of Biomedical Ethics and Director of the Berman Institute of Bioethics at Bloomberg School of Public Health at Johns Hopkins University, and Steven N. Goodman, MD, MHS, PhD, Professor of Oncology, Pediatrics, Epidemiology and Biostatistics, also at the Bloomberg School of Public Health.
‘Life-Cycle’ Approach to Drug Safety
The committee takes a “life-cycle” approach to drug safety, noting that drug safety issues apply during the course of the drug’s use. The committee states that “FDA, to fulfill its public health mission, should allow a drug to enter and remain on the market only if the balance of the risk to the benefit is appropriate for its intended use.”
Thus the committee concluded that “it is appropriate for FDA to require that a randomized controlled trial be conducted to provide additional evidence about an approved drug’s efficacy and safety only when (i) uncertainty about the risk/benefit balance is such that a responsible policy decision cannot be made based either on the existing evidence or on evidence from new observational studies, and (ii) the trial is properly designed and implemented to reduce uncertainty about the risk-benefit balance sufficiently for a responsible policy decision to be made.”
FDA Commissioner Margaret A. Hamburg, MD, is on record as wanting to accelerate the pace of new drugs from bench to bedside (OT, 3/25/10). In order to accomplish that goal, the FDA and the National Institutes of Health are collaborating by forming a joint NIH-FDA Leadership Council to address critical needs in public health together. Dr. Hamburg said she is committed to turning the agency into a catalyst for innovation and placing a new emphasis on the best regulatory science. But she also stresses that the safety mandate of her agency is paramount.
Delicate Balancing Act
Accelerating the process of approving new drugs while also ensuring safety is a particularly delicate balancing act, according to a 2007 white paper report chaired by Robert C. Young, MD, OT Editorial Board Chair and President of RCY Medicine.
That white paper, Drug Safety & Drug Efficacy: Two Sides of the Same Coin, focused on ensuring access to new drugs while also improving safety at FDA. The white paper, which was endorsed by many cancer groups including the American Society of Clinical Oncology, made the point that FDA should improve its existing tools for adverse event reporting, such as its MedWatch program for adverse reactions. According to Dr. Young, it is impossible to put in place a drug approval system that prevents all unique adverse events—what he calls “unanticipatable complications” before a new drug goes on the market.
Dr. Young points out that the majority of newly approved drugs have simply not been tested in enough people before marketing to catch every unanticipated side effect or adverse reaction. The IOM committee agrees, stating that “because of the infrequency and delayed occurrence of some adverse events, there is often more uncertainty about the risk posed by a new drug at the time of approval than there is about its efficacy.”
Ethical Considerations in Postmarketing Studies
In order to ensure that FDA-requested postmarketing studies are ethical, the IOM committee recommends that they be started if and when:
1. A drug safety signal, if it represents a true risk, would warrant an FDA policy decision to protect the public health, and new knowledge is needed to delineate the magnitude of the risk and thereby inform agency decision-making based on the highest principles of regulatory science and analytic techniques, done in a transparent way to ensure public accountability;
2. Risks of the trial are judged acceptable by oversight bodies whose members have the skills and expertise to assess those risks, including toxicity, and risks are communicated clearly to participants and continually monitored to ensure that they remain acceptable;
3. Comprehensive informed consent is obtained and is ongoing and study subjects are promptly advised of changes in clinical practice or new research findings that could affect their willingness to participate in the postmarketing trials;
4. The postmarketing trial is designed carefully and precisely—adequately powered and rigorous in inclusion and exclusion criteria—to provide the data needed to assess the specific safety issues raised by use of the drug. As the IOM committee states, “Without a reasonable prospect of contributing to scientific knowledge, the exposure of research participants to even minimal risk or inconvenience can never be justified. In the case of postmarketing clinical trials required by FDA, that ethical precept requires further specification and strengthening.”