Should US FDA Refuse Approval If Women Under-Represented In Clinical Trials?

Idea suggested during 'Great Debate,' but agency official says no adlibbing is allowed in the regulations.

The US FDA could be more forceful, even threatening, with drug sponsors to ensure more women are included in clinical trials, but regulations may get in the way.

Rita Redberg, a cardiologist and professor at the University of California, San Francisco and chief editor of JAMA Internal Medicine, suggested the agency could push harder to entice pharma to recruit women for drug trials.

Redberg said May 16 during an FDA-sponsored "Great Debate" on the right number of women in clinical trials that if the agency began refusing to approve drugs with inadequate data on women or said the indication would only include men, industry would adapt quickly.

"I think if the FDA used its power to say no to a cardiovascular trial – 'We can't review this new drug application, you don't have enough women,' they would all the sudden find ways to enroll women in clinical trials, I guarantee it," she said.

"FDA is extremely interested in getting participation of women and various minorities in clinical trials in proportion to their representation in the population and we do what we can to ensure that this happens. "But we also have to consider the ramifications." – Ellis Unger, director of the Office of Drug Evaluation I.

Ellis Unger, a cardiologist and director of the Office of Drug Evaluation I in FDA's Office of New Drugs, who represented the agency in the debate, acknowledged that more women need to be included in clinical trials, but said that it is unfortunately not as simple as refusing to approve drugs with inadequate numbers.

"If we're concerned about it then we do demand other data," he said. "Although you may think we have a lot of power, we can't just flex our arm and say do this or we're not going to approve your applications. We have regulations and we have to live by them and we can't adlib."

The event, sponsored by FDA's Office of Women's Health in recognition of National Women's Health Week, illuminated an issue that has been recognized as a problem for some time. Clinical trials for many years have under-represented female populations, even though drugs could behave differently in them than men.

FDA has tried to combat the problem for several years. The agency issued a Manual and Policies and Procedures document in 2013 encouraging staff to avoid allowing unnecessary exclusions in clinical trials. (Also see "FDA’s Clinical Trial Inclusion Policy Sold As Mild And Gentle" - Pink Sheet, 31 Jan, 2014.)

But FDA has largely rejected calls for it to require specific subgroup representation in clinical trials. The agency prefers freedom within the regulations to ensure trials can be completed rather than a blanket mandate to enroll subgroups based on disease prevalence. (Also see "Clinical Trial Diversity: FDA Rejects Calls For Enrollment Mandates" - Pink Sheet, 7 Mar, 2016.)

Indeed, Unger argued during the debate that mandating subgroup sizes could make trials undoable and very costly, another issue FDA is combating. He said most drug companies power their efficacy studies based on the overall population so they can be done as quickly and cheaply as possible.

"FDA is extremely interested in getting participation of women and various minorities in clinical trials in proportion to their representation in the population and we do what we can to ensure that this happens," Unger said. "But we also have to consider the ramifications. There are practical ramifications to ensuring enrollment equal to proportion of the population."

But Redberg said that while trials may be more expensive up front, having that information could save money later.

"The trade-off is that I have to take care of patients and I can't tell them if this drug is safe or effective," she said. "So you've essentially said we're going to save money for the company on the trial by accepting a less than adequate trial and then spend billions on drugs and devices that are not just not effective but sometimes dangerous."

Multiple stakeholders have tried to tackle the issue. The Pharmaceutical Research and Manufacturers of America launched an effort in 2014 intent on encouraging more minority investigators and trial participants. (Also see "PhRMA’s “I’m In” Campaign Looks To Connect Minorities To Studies" - Pink Sheet, 12 Mar, 2014.)

FDA also has held public meetings on the subject, where it solicited opinions on the amount of subgroup data that should be sufficient. (Also see "Clinical Trial Subgroup Data: How Much Is Enough?" - Pink Sheet, 7 Apr, 2014.)

Unger said during the debate that there can be no pre-set percentage of subgroup data that is required and Redberg agreed.

FDA Finds Adequate, Over-Representation Of Women In Some CV Trials

The debate coincided with the recent publication of a paper in the May issue of the Journal of the American College of Cardiology that considered female participation in clinical trials used to approve cardiovascular drugs.

The analysis, which Unger co-authored along with several others from FDA, found that in some diseases, women were well-represented in the clinical trials and in the case of pulmonary hypertension, they were over-represented.

The agency considered 57 total trials used in 36 approvals of cardiovascular indications for 35 drugs between Jan. 1, 2005 and Sept. 15, 2015. FDA used participation to prevalence ratio to determine whether participation was sufficient. It divides the percent of women in the trial by the percent of women in the disease population.

Women were represented at rates similar to or greater than their share of the disease population in pulmonary arterial hypertension, atrial fibrillation and hypertension trials. But there were fewer women represented than the disease population in heart failure, coronary artery disease, and acute coronary syndrome trials, according to the paper.

The authors concluded that more research is needed to define the barriers limiting participation in CV trials by women, particularly occurring before screening. They added that there was no evidence that exclusion criteria contributed to under-participation off women.

"As we move into the era of precision medicine, that is, assessing the impact of a wide range of patient and disease characteristics on drug effects, it is imperative that clinical trial participants represent the full spectrum of patients for whom the drug will be prescribed," the authors wrote. "Clinical researchers, patient advocacy groups, federal agencies, and industry must work together to ensure that representative patient populations are enrolled."

FDA Educating, Training Providers On Female Trial Recruitment

Unger and Redberg acknowledged that while progress has been made in recruiting more women in clinical trials, more work is necessary.

During the debate, Unger said stereotypes about cardiovascular disease affecting mostly men need to be broken down and that there needs to be more education about coronary disease affecting women.

Redberg added that cardiovascular trials need more female investigators.

"Most of the PIs are men," she said. "And I think male PIs don't notice that they're not enrolling women in the trials."

FDA launched the Diverse Women in Clinical Trials Initiative earlier this year, which includes a consumer awareness campaign and training for providers and researchers to improve recruitment of women in clinical trials. Commissioner Scott Gottlieb also said in a speech before the debate that FDA is funding and conducting research that facilitates "FDA’s regulatory decision making to advance the understanding of sex differences."