Patients are astonished when they learn that the development of most drugs has, historically, not incorporated human differences into the design equation. How and why age, ethnicity, gender and race haven't been woven into most clinical trial designs makes most people in the industry cringe because the issue is immensely complicated. And though there has been a lot of chatter in recent years about changing this – including updated regulatory guidances – achieving proper diversity in clinical trials is still just a goal.
In reality, if medicines were approved only for the populations they are adequately tested in, most would be indicated only for Caucasian men younger than 65.
From the clinical trial design can of worms, consider these issues:
• In the U.S., where about 22 percent of people consider their race to be something other than Caucasian, fewer than 5 percent of participants in trials registered with ClinicalTrials.gov are non-Caucasian.
• Pain medications developed via trials of mostly men, are given to women even though it's commonly known that there are gender differences in pain receptors.
• Women's complex physiology, particularly hormones, is the reason they haven't been properly represented in clinical trials. But it is that very difference which prompted the FDA, in an unprecedented move in 2013, to require a change in dosage of blockbuster sleep aid Ambien (zolpidem tartrate). Women metabolize drugs differently.
• More than half of all trials for coronary artery disease (CAD) in the past decade didn't enroll a single patient older than 75 even though more than one-third of men and approximately one-quarter of women in that age group have CAD.
In a series of articles starting Monday, BioWorld examines what some have called a blind spot in clinical trial design related to age, gender, race and ethnicity. In fact, the BioWorld team points out that it's not a blind spot. It's a deliberate avoidance because homogeneity is virtually required to gain regulatory approval of most drugs.
The series is focused primarily on the U.S. because the FDA is the world's leading drug regulatory body, but similar problems and efforts to change the status quo exist globally.
Despite the good news that regulators are acting to correct the problems on several levels, it's not enough to force the sector to fully depress the clutch and shift into high gear. In fact the business case, particularly the high cost of drugs, may be the strongest impetus to force developers to improve trial designs since payers are demanding more data on effectiveness.
• The business case. Staff writer Marie Powers kicks off the series with a broad overview of the problem, focused primarily on the business case and how drug development firms have an opportunity to work collaboratively with regulators because the alternative to proactive cooperation is a more onerous regulatory environment that establishes difficult-to-meet enrollment targets.
• Gender. Science editor Anette Breindl then examines what may be the largest part of this epic failure of trial design. . . . The underrepresentation of women in clinical trials. She identifies the conundrum: "Signal is easiest to distinguish from noise when trial populations are homogenous. Adding heterogeneity of trial participants means you're adding heterogeneity of response. More generally, the notion that one sex is data and the other, somehow, noise, is itself a consequence of considering male physiology the norm."
• Ethnicity and race. Next, staff writer Michael Fitzhugh explores race, particularly in light of the age of personalized medicine. Do race and ethnicity really count for anything more than a crude stand-in for a patient's genetic ancestry, a profile that's significantly more evaluable in light of the ever-falling cost of genetic testing? Fitzhugh reports that the consensus seems to be "yes."
• Age. Regulatory editor Mari Serebrov tackles the issue of age differences in clinical trials, with a particular focus on the fact that elderly patients – the fastest-growing patient population – are sorely underrepresented. Changes in metabolism, weakened immune systems, memory issues, co-morbidities and a higher potential for adverse drug-drug interactions make the geriatric population more vulnerable than the typical adult patient enrolled in trials.
Serebrov wraps up the series with a look at how diversity in clinical trials is a common refrain at FDA advisory committee meetings, but that could be too little too late. Instead of relying on postmarket studies to fill in the knowledge gaps, it may indeed come down to regulatory requirements to test therapies in a more diverse population to begin with.