By Deborah Borfitz

April 9, 2019 | Researchers have long believed that ethics generally precludes conducting clinical studies with pregnant women, which also spares investigators the administrative burden of their involvement. But ethics in fact requires their inclusion, according to Anne Drapkin Lyerly, professor of social medicine and associate director of the Center for Bioethics at the University of North Carolina at Chapel Hill.

“There is no ‘better safe than sorry’ route available,” says Lyerly. Overlooking pregnant women for studies has real and potentially dire consequences for expectant mothers in the real world. Without research data to guide prescribing physicians, “many pregnant women will reasonably decide to forego needed treatment, leaving them and their fetus exposed to the potential harm of untreated disease that can range from uncomfortable to dangerous.”

Pregnant women who face treatable illnesses are not rare. In the U.S., diabetes, hypertension  and psychiatric disorders are all relatively common. Worldwide, at least 1.5 million women giving birth each year are HIV-positive, says Lyerly. In parts of South Africa, that applies to one-third of all pregnancies.

Lyerly is co-founder of the decade-old Second Wave Initiative, a collaborative academic effort to ensure women are fairly represented in biomedical research, given access to studies that have a prospect of direct benefit and have an evidence base allowing them to optimize their health. Change has been slow in coming, she says, but the tide is finally starting to turn.

Lyerly’s optimism is based on two significant developments last year. The Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) issued a report to the Secretary of Health and Human Services drawing national attention to the problem of evidence gaps and the need for research on therapies for these populations. As noted in the 388-page report, over six million women are pregnant in the U.S. each year and more than 90% of them take at least one medication.

The Food and Drug Administration also issued draft guidance for industry on the inclusion of pregnant women in clinical trials, calling the evidence gaps around pregnancy and medications a “critical public health need,” says Lyerly.

The Industry View

One of the primary reasons pregnant women and even women of childbearing potential have historically been under-represented in industry trials is out of an “overabundance of caution,” says Christina Bucci-Rechtweg, global head of pediatric & maternal health policy at Novartis. The health of the developing fetus and the product’s marketing approval might be inadvertently jeopardized by their inclusion.

“We know at the end of the day women who have medical conditions while pregnant can’t just magically stop their therapies,” says Bucci-Rechtweg, adding that she is “fighting from within for change” to not always automatically exclude them. As a member of PRGLAC, she more broadly advocates for organizations to consider what can be gleaned about the profile of drugs from preclinical and early clinical studies that could potentially allow for pregnant women to be better represented in later phase trials.

Formerly a practicing pediatrician, Bucci-Rechtweg saw first-hand the repercussions of their exclusion—patients whose moms at their own peril took themselves off medicines because they were breastfeeding or continued taking a drug for seizures or diabetes but worried it was harming their baby.

PRGLAC’s internal advocacy approach extends to ethical considerations and the consent process, prompting “difficult conversations” with researchers designing studies, and ethics committees and health authorities reviewing protocols, Bucci-Rechtweg says. The dialogue focuses on how potential and evolving safety signals could be best monitored in pregnant study participants and making the language in consent forms less “terrifying” by talking about risks more broadly—including the risks posed by not adequately managing underlying and comorbid conditions in women who happen to be pregnant.

The starting point is wherever significant inroads can be made, most immediately ensuring ICH global guidance about how data get generated and analyzed in the preclinical arena keeps pace with the downstream need to be more inclusive in the clinic, she continues. Safety evaluations, including reproductive toxicology, are among the topics of interest.

FDA guidance on the inclusion of pregnant women in trials has no parallel elsewhere in the world, but the agency’s recommendations are likely to positively impact the protocols of global drug development companies, says Bucci-Rechtweg. The bigger hurdle in some regions is that women can’t consent for their participation without the approval of their husband or a tribal elder, which may impact country selection for a study.

Pregnant women, she adds, tend to be “very good trial participants and very informed.” The only real difference is that sponsors need to think about the impact of the physiologic changes of pregnancy during a study when designing protocols.

More Collaboration Needed

Bucci-Rechtweg is particularly excited to see the issue on the radar of public-private partnerships. In early April, the Innovative Medicines Initiative is expected to launch a call for partners to participate in a research and innovation action (IMI-ConcePTION) so scientists can explore ways to generate reliable, timely data on medicine safety in pregnancy and during breastfeeding, she says. There is also a well-funded partnership (IMI-PROTECT) looking at the epidemiology of pregnancy research outcomes and the how drug exposure during pregnancy relates to drug transmission during breastfeeding.

Progress has admittedly been slow, especially among companies with a new molecular entity whose toxicity profile is not fully known. “We haven’t yet overcome the risk equation, nor should we get too comfortable in overcoming it,” Bucci-Rechtweg says. “We struggle with ethics committees, investigators, the legal representation of innovator companies and family members who tell women they’re jeopardizing their baby’s health.”

Although definite progress has been made over the last few years, she adds, to her knowledge there has yet to be any notable industry-sponsored studies involving pregnant women. Meanwhile, physicians have patients to treat and in the absence of evidence those with research training are doing their own investigations to fill the void.

They’re already taking on risk by making clinical decisions with limited information, Bucci-Rechtweg notes. “Industry needs to be working to change that paradigm by working collaboratively with physicians to design smarter, hypothesis-driven research earlier in our development programs.”

Lessons Learned in HIV Research

The Second Wave Initiative has emphasized changes that are “immediately actionable” and don’t require changes in laws and regulations—especially since quite a bit is already allowed but overlooked, Lyerly says. The group was particularly intrigued by the global HIV research community that has a rather lengthy and successful track record of conducting research with pregnant women, and the infrastructure and philosophies in place to support it.

Lyerly is principal investigator of the multi-year Pregnancy & HIV/AIDS: Seeking Equitable Study (PHASES), funded by the National Institutes of Health, which launched in 2015. Participating researchers periodically publish intermediary findings and processes and will soon issue guidance that is both specific to HIV but relevant to the broader research community working toward greater inclusion of pregnant women.

In the HIV context, the singular goal has been preventing the transmission of HIV from a woman to her fetus—which has also been highlighted as one of the greatest successes in pediatric research, notes Lyerly. The risk of transmission was in some regions as high as one out of every three births, and at a time when it was a life-ending disease. Today, that risk has been reduced to around 1% in the U.S., and less 5% globally with treatment.

“The remarkable thing about HIV is that outside of the question of prevention of maternal-to-child transmission, pregnant women have generally been excluded from research,” says Lyerly. Pregnant women have not only been excluded from prevention research, but also removed from studies if they become pregnant. And this, she adds, is despite evidence showing pregnant women are more likely to get HIV for various social and biological reasons. If they become infected with HIV while pregnant, the odds of transmitting it to their fetus is also considerably higher.

Pregnant women have likewise been excluded from treatment research on comorbidities, such as malaria and tuberculosis, which when combined with HIV can be deadly, Lyerly says. Many of the new antiretroviral drugs on the market have also not been studied prospectively in pregnant women, putting their fetus at risk of unknown adverse effects. The black hole similarly exists for multiple other conditions that can afflict pregnant women, including connective tissue disorders.

The forthcoming guidance from PHASES includes recommendations applicable to the larger research enterprise that can “nudge people in the right direction,” says Lyerly, including:

• When reviewing studies that affect women, institutional review boards should ask researchers to offer a justification for excluding as well as including pregnant women.
• Sponsors should include in study protocols a plan for managing “incident” pregnancies that goes beyond an exit interview and automatic removal from a trial. This might include allowing women to stay on the study after a “robust” re-consent process, says Lyerly. “In all circumstances, we encourage research teams to collect outcomes on pregnant women and their fetus exposed to the study drug.”

On the other hand, the exclusion of pregnant women would be reasonable for studies of drugs known to cause significant harmful effects on the fetus and those targeting diseases unlikely to occur during pregnancy.

Optimizing Glucose Control

The first artificial pancreas study in the U.S. for pregnant women only recently got underway, funded by the National Institutes of Health. Principal investigator on the multi-institutional study team is Eyal Dassau, director of the Biomedical Systems Engineering Research Group at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS). He’s joined by specialists and longtime collaboration partners from the Icahn School of Medicine at Mount Sinai, Mayo Clinic and the Sansum Diabetes Research Institute.

Two prior clinical studies in the U.K. found an artificial pancreas—also called an automated insulin delivery or hybrid closed-loop system—could safely and effectively control glucose levels in a broad range of pregnant women with type 1 diabetes, says Dassau. The results were “impressive” given that the population requires tight glycemic control to avoid disease complications. “It’s really hard, requires a lot of micromanagement and not always feasible.”

Dassau came to Harvard from the University of California Santa Barbara where he was mentored by the late Lois Jovanovic, chief executive and chief scientific officer Sansum Diabetes Research Institute who made it her life’s work to help diabetic women have babies, and Frank Doyle, now dean of the SEAS. “We figured the best way to move forward was to establish a consortium with engineers and clinicians, including obstetrics and endocrinology.”

The research mission is to evaluate an experimental, pregnancy-specific closed-loop system tied to a cell phone app, eliminating the need for a second device to send dosing instructions to the insulin pump, he says.

The initial study hopes to enroll at least 50 participants with type 1 diabetes and will focus on tracking changes in their insulin resistance throughout pregnancy up until six weeks post-birth. Study participants will wear a Dexcom G6 continuous glucose monitor and be asked to self-monitor their blood sugar levels with routine finger sticks. A half dozen women are already enrolled, Dassau says, and will use the G6 sensor to help with their own endocrine supervision as data gets collected.

Researchers plan to use the data collected from this first study as a comparison point for data collected in future studies with pregnant women with type 1 diabetes, says Dassau. Insights will also be used to develop and refine an algorithm for the pregnancy-specific insulin delivery system. “Glucose control is very different between the first, second, and third trimester all the way to delivery and the post-partem period,” he explains, making it difficult to achieve time-in-range via manual insulin dosing.

Getting the approval of an institutional review board for any study involving pregnant women is never easy, says Dassau, but doable with the right safeguards in the protocol and working “step by step” with the FDA. “Don’t give up,” is Dassau’s main advice. “Just do the proper science and then, based on that, go on to the next challenge.”