The U.S. NIH’s Feb. 17 announcement that it’s funding a study of the effects of remdesivir in treating COVID-19 in pregnant women is welcome news, but it begs the question of why it took so long given the risk of more severe disease in that population.
“Pregnant women with COVID-19 are at high risk for hospitalization, for intensive care admission and for needing ventilator support,” said Diana Bianchi, director of the NIH’s National Institute of Child Health and Human Development. “There is an urgent need to identify effective treatments for this population and to determine whether drugs prescribed for other adults are appropriate for use in pregnancy.”
It could be at least a year before the NIH-funded study, IMPAACT 2032, produces results, according to ClinicalTrials.gov. The phase I prospective, open-label, non-randomized opportunistic study will evaluate the pharmacokinetics (PK) and safety of Gilead Sciences Inc.’s Veklury (remdesivir) when used to treat pregnant vs. nonpregnant women of childbearing potential who are hospitalized with COVID-19. It’s expected to enroll 40 participants.
In addition to documenting potential side effects and adverse events and evaluating the drug’s PK in the women, researchers will analyze samples from the plasma and umbilical cord, from trial participants treated with Veklury within five days of delivery, for insight into the PK in the placenta. In addition, breast milk will be tested for remdesivir among women who are lactating.
Meanwhile, doctors continue to use Veklury to treat pregnant women despite the absence of vital information in that population. Like 98% of the trials listed in ClinicalTrials.gov, the trials Gilead conducted to support FDA emergency use authorization, and later full approval, of its antiviral excluded pregnant women and required women participants of childbearing potential to be on effective birth control.
Subsequently, only 37% of participants in Gilead’s trials were women, according to the FDA’s Veklury trial snapshot, which pooled the results from three Gilead trials. (Diversity by race for the trials exceeded that of the country as a whole, with 57% of participants identifying as white, 18% as Black, 14% as Asian, and 1% American Indian or Alaska Native. Additionally, 21% of the trial participants identified as Hispanic.)
Although pregnant women were excluded from Gilead’s trials, they aren’t excluded from Veklury’s approved indication as a treatment for adult and pediatric patients, 12 and older and weighing at least 88 pounds, who are hospitalized with COVID-19.
The FDA-approved patient labeling does inform women, in bold type, “Tell your health care provider right away if you are pregnant.” The label adds, “It is not known if Veklury can harm your unborn baby.” Similar advice is given to women who are breastfeeding or planning to do so.
However, the full prescribing information (PI) used by doctors to guide treatment decisions provides a brief discussion of remdesivir testing in pregnant animals. The PI also notes that available data of Veklury use in pregnant women “are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes” and that “the estimated background risk of major birth defects and miscarriage for the indicated population is unknown.”
Rethinking standard selection criteria for phase III trials could go a long way in closing such information gaps and taking the guesswork out of treating pregnant women and other excluded populations once a drug like Veklury comes to market.
The easiest way to do that is for companies to demand a better understanding of why certain populations are being excluded from a particular trial, Christina Bucci-Rechtweg, global head of pediatric and maternal health regulatory and development policy at Novartis Pharmaceuticals Corp., said at a Duke-Margolis Center/FDA webinar on scientific and ethical considerations for the inclusion of pregnant women in clinical trials earlier this month.
In the past, biopharma companies have been apprehensive about enrolling more at-risk populations, Greenphire Inc. CEO Jim Murphy told BioWorld. But today, with companies expected to provide a clear view of how effective a drug is in various populations, they need to make an extra effort in phase III trials to recruit participants that are more representative of the patients who would be treated with the drug once it’s approved, he said.
Some companies are already doing that. For instance, the Roche Group’s Genentech is making a concerted effort to open its clinical trials to people who have been excluded, for various reasons, from clinical research. “We evaluate clinical protocol inclusion and exclusion criteria language to ensure eligibility criteria are based on clinical/scientific rationale that limits unnecessary barriers to trial enrollment,” Jamie Freedman, head of U.S. medical affairs at Genentech, told BioWorld.
“In order to create a more efficient and sustainable health care paradigm where the right patient gets the right medicine at the right time, we needed to reflect all patients in our strategies and tools. . . . Clinical and genetic data enriched by including more representative patient populations will enable us to evolve the promise of personalized health care to achieve more accurate diagnoses, improve access to therapies and optimize treatment outcomes for all patients,” Freedman said.
He suggested a few other best practices to improve trial diversity:
- start with the fundamentals like asking site investigators to be more intentional about recruiting diverse patients;
- talk to patients, and engage and build trust with communities to understand their experience with the health care and clinical trial system;
- actively speak to communities about the importance of clinical research and how they can be helped through it;
- take trials to the community and expand site networks to include potentially smaller, newer sites with more diverse catchment areas – involving the community doctor in the clinical research process is essential to ensure all patients are served in the evolving world of personalized health care;
- take a hyper-local approach on a global scale;
- keep time and financial burdens for participants in mind when designing trials;
- re-assess protocols for medicines to see if they can be administered at home rather than in a health care environment;
- explore ways to alleviate trial participation barriers such as travel, parking and childcare.
The burden of participation has become much bigger as clinical trials have become more specific and sponsors are compelled to collect more data from each patient, Murphy said. Those trends often translate to more visits, effort and time on the part of participants, which can impact retention and long-term follow-up, as well as recruitment of more diverse populations.
In planning trials, sponsors need to remember that “people don’t do clinical research for money. They do clinical research for their own health” and to help others, said Murphy, whose company provides software that helps sponsors alleviate some of the barriers to participation. Those good intentions could fade away if participation becomes too large a burden, he added.