Aside from its place in the history books as a global pandemic that nearly locked down the world, COVID-19 could have a lasting, more positive legacy of finally opening U.S. biopharmaceutical clinical trials to greater diversity.
Clinical trial enrollment that ignores much of the population has long been an issue in clinical research, generating public outcry, congressional soundbites and pointed questions about inclusivity at FDA advisory committee meetings. Yet fewer than 5% of participants in trials registered with Clinicaltrials.gov in 2014 were non-Caucasian, according to a BioWorld series that year on the lack of diversity in drug development.
While some biopharma companies have taken steps to be more inclusive and representative in their trials, many continued to use the same old selection criteria and trial sites with no thought of the populations being excluded and the valuable information being lost because of those exclusions. For instance, 98% of drugs approved in the U.S. today have no labeling information about their use or dosage during pregnancy because pregnant people continue to be routinely excluded from drug and vaccine trials.
Now the health care disparities brought to light by COVID-19 are forcing sponsors and regulators to acknowledge that the status quo can’t be justified any longer. “The silver lining here is access,” Jamie Freedman, head of U.S. Medical Affairs for Genentech, part of the Roche Group, told BioWorld. “The inefficiencies in our health care system were magnified and exacerbated due to COVID-19, and as a result we have been motivated to explore new ways of working.”
That includes reassessing clinical trial protocols to take advantage of new technologies and reimagining the conduct of trials in a way that makes them more accessible to communities that have largely been shut out of drug development.
“There is an opportunity for change as we work to build a more equitable world, as we think of clinical trials and inclusive research,” Freedman said. “There is no longer an excuse to have little to no diversity in research. The tools and information are there, and as we double-down on our efforts to address health disparities in clinical research, we recognize that affecting real change requires deliberate investments.”
COVID-19 has “forced the clinical community to do some pretty radical adapting,” agreed Greenphire Inc. CEO Jim Murphy. For instance, the increased use of telehealth and home health nurses has led to a rapid evolution of clinical trials, with sponsors understanding that not every trial visit needs to be in person, he said.
Getting serious about diversity
Recognizing the opportunity to address demographic and medical factors that lead to disparities, the FDA issued final guidance in November aimed at broadening eligibility criteria in clinical research through inclusive trial practices, trial designs and methodological approaches.
In releasing the guidance, which finalized a draft issued before the coronavirus emerged, then-FDA Commissioner Stephen Hahn said the disparities in how different populations were being impacted by the pandemic “illustrates why we must encourage developers of any medical product such as treatments or vaccines for COVID-19 – as well as medical products more broadly – to endeavor to include diverse populations to understand their risks or benefits across all groups.”
In the past, biopharma has been one of the most risk-averse industries in the world, Murphy told BioWorld. He expects the FDA guidance, with its pragmatic mechanisms to improve trial diversity, will help biopharma embrace inclusivity in trials.
On the heels of the FDA guidance, the Pharmaceutical Research and Manufacturers of America issued the first industrywide principles on clinical trial diversity. “It is encouraging to see this important progress being made across the health care industry,” Freedman said. “Being part of a collaborative effort to drive meaningful industrywide change and advance health equity is key to driving lasting and impactful change.”
In the future, Murphy said he’s certain there will be a marked improvement in trial diversity, as sponsors recruit trial sites in diverse communities and as patient, community and professional groups raise awareness of the need for clinical research in people representative of the intent-to-treat population.
Representative trials are “important because communities of different ancestral . . . backgrounds can have distinct genetic variations. These changes can be medically relevant and may inform how a patient responds to a medicine,” Freedman said.
If COVID-19 isn’t lesson enough of the need for greater trial diversity, drug sponsors also could face increased pressure from lawsuits to not only be more inclusive in their trials but to more carefully assess the data for various subpopulations and to be up front in disclosing it.
As a case in point, a state judge in Hawaii this week ordered Bristol Myers Squibb Co. (BMS), of New York, and Sanofi SA, of Paris, to pay more than $834 million for failing to disclose early on that their blood thinner, Plavix (clopidogrel), could have little to no effect for some people, particularly those of East Asian and Pacific Island ancestry.
BMS and Sanofi, which are facing at least one similar suit, plan to appeal the Hawaii decision, which revolved around Plavix labeling from the time it came to market in 1998 until the FDA approved a new label in March 2010.
The 2010 label included a boxed warning that said the effectiveness of the drug “depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.” It added that poor metabolizers treated with Plavix had higher cardiovascular event rates than those with normal CYP2C19 function. The warning advised doctors to use available testing to identify a patient's CYP2C19 genotype and then consider alternative treatment in those who likely would be poor metabolizers.
The boxed warning itself didn’t connect “poor metabolizers” to a specific population. However, further down in the prescribing information, the labeling went into more detail about the specific CYP2C19 alleles linked to patients who were poor metabolizers. “Published frequencies for poor CYP2C19 metabolizer genotypes are approximately 2% for whites, 4% for blacks and 14% for Chinese,” the label said.
Plavix labeling before 2010 didn’t note safety/efficacy differences based on genotypes. The label approved in 2002, for example, indicated in the “special populations” section that “pharmacokinetic differences due to race have not been studied.”