Faster Drug Approvals by FDA Raise Concerns About Transparency and Beneficence in Clinical Trials

David Morin, MD, FACP, CPI, FACRP, Director of Research, Holston Medical Group

With recent studies from Oregon State University (OSU) raising essential points about drug safety and research transparency in an era when the U.S. Food and Drug Administration (FDA) seems to be approving drugs after fewer trials (accelerated approval) and releasing less data from those trials, one experienced principal investigator (PI) cautions that public perceptions of clinical research may take a hit.

According to the OSU research, the FDA is approving more novel pharmaceutical drugs based on single clinical trials and with less public disclosure about those trials than was the norm just a few years ago.

“As part of the federal 21st Century Cures Act passed in 2016, the FDA may allow surrogate markers instead of long-term outcome studies in some instances to speed up access to drugs,” notes David Morin, MD, FACP, CPI, FACRP, who was not involved in the OSU studies. Morin is the immediate past Chair of the Association Board of Trustees for ACRP and a PI who has conducted hundreds of Phase I–IV clinical trials since 1989. “Grading the importance of earlier access to potentially effective medications depends on the prognosis of the targeted disease and access to established alternative therapies. But in what might look like a rush to get new drugs to market, we must remember that ‘beneficence’ is an ethical research principle that safeguards study participants’ well-being and protection from harm by maximizing benefits and minimizing risks.”

A surrogate marker is usually a relatively easily measured, distinct molecular entity that substitutes for a clinical outcome, which may take years or decades to develop, Morin explains. He says that a typical example is the use of low-density lipoprotein (LDL) as a marker for cardiovascular risk; its presence increases risk, and reduction decreases risk. However, it’s important to know if the surrogate is a risk marker or a risk factor, Morin adds. A risk marker is one where a substance’s presence or elevated level is associated with a higher adverse outcome or disease severity. However, reducing that substance does not decrease the condition’s risk or result in improvement.

“A risk factor,” on the other hand, “is both associated with an illness and has a causal relationship such that reducing it results in decreased disease burden,” Morin notes. “Using a surrogate marker that is not a proven risk factor may lead to the approval of a drug without clinical effectiveness. And while a surrogate marker may be the primary endpoint in a study to determine efficacy, fewer studies with a shorter duration and less enrollees could impact the opportunity for a more complete evaluation of safety. With that understanding, public (patient) access to study results is essential to transparency and trust. There are many vocal skeptics of the research process and outcomes whose message may be amplified if data are hidden, or access to them is denied.”

As a clinician, Morin observes that when novel therapies make the news as a “breakthrough” for currently untreatable conditions with high morbidity and mortality, the media often fail to disclose the “fine print.”

“Patients may have a false sense of hope and become emotionally devastated when they discover the treatment’s effectiveness is marginal or doesn’t apply to their specific disease subcategory,” Morin says. “When these novel therapeutics are approved and enter the clinical space, it then falls on physicians and other providers to ensure their proper use assuming the costs are at least partially covered by payors. This then becomes a case where the analysis of cost/benefit is an important addition to the analysis of risk/benefit. Having new therapies in this exciting time of discovery provides hope for many, but let’s remain mindful of how fragile the public perception and trust in the clinical research enterprise can be.”

Edited by Gary Cramer