The clinical trials gender gap: No tests for pregnant women

This is a POLITICO case study, a look at what works — and what doesn’t  — in the fight against HIV. The article is part of Telescope: The New AIDS Epidemic, a deep-dive investigation into the modern face of a disease that transformed the world.

THE BIG PROBLEM

Pregnant women are generally excluded from clinical trials of medicines and treatments, so there’s no way to know for sure if a new drug or vaccine is safe for mother and baby.

THE BIG IDEA

The international health financing agency Unitaid funded a trial of the new, improved HIV treatment dolutegravir specifically in pregnant women to show why such trials are needed, and to prove that they can be done.

WHY IT MATTERS

Medical orthodoxy has long held that experimental drugs shouldn’t be tested in pregnant women and their fetuses — they need to be protected from the risks inherent from research.

But protecting mothers-to-be from research offers them no protection at all, argues a growing chorus of doctors, researchers, ethicists and women. Instead, it puts pregnant women (and often women of child-bearing age) at the back of the line for access to new medicines and vaccines — meaning they’re stuck with old treatments or at higher risk from the disease itself. 

Worse, when pregnant women start using the medicine, it’s without a full understanding of its effects or reliable guidelines on the proper dose — pregnant women may metabolize drugs differently — as well as lacking an organized way to track when something goes wrong for mom or baby. 

History is littered with examples of inadequate testing causing greater harm for women and children. Problems with the use of the anti-epilepsy drug valproate during pregnancy became clear only after it landed on the market. It’s now estimated that some one in 10 women who took valproate while expecting had babies with congenital defects, and that the risk of other developmental problems is highly elevated among children of those who took the drug. More recently, the past year has seen animated debate over whether pregnant women should be enrolled in coronavirus vaccine trials — even as the specific dangers of COVID-19 in pregnancy were increasingly well-documented.

IN THEIR VOICES

Carmen Perez Casas, senior technical manager for Unitaid’s strategy team, on the imperative of conducting trials in women: 

The resistance to running clinical trials in pregnant women is entrenched: The ethics boards that approve studies are squeamish. They can be more expensive (an OB-GYN needs to be on board, for example), and getting insurance to cover potential harm to the fetus is darn-near impossible, said Maggie Little, a Georgetown University bioethicist focused on how to responsibly study the health needs of pregnant women. 

IN THEIR VOICES

Maggie Little, senior research scholar at Georgetown University’s Kennedy Institute of Ethics, on how regulations discourage studies in pregnant women: 

The debate over pregnancy and research is especially urgent when it comes to HIV drugs. Some 1.3 million women have HIV while pregnant each year, and they need to be on treatment not just for themselves, but for their babies: Mother-to-child transmission is a major risk. It’s an especially big problem in sub-Saharan Africa, where some six in 10 new HIV infections are among women over 15. Infections among women are also on the rise in Eastern Europe and Central Asia. And even in wealthy regions like Western Europe, many women find out they have HIV only as part of a routine test during a prenatal checkup. 

Because regulators don’t require studies in pregnant women, there’s little incentive for drugmakers to take the risk of additional research on the way to approval. Of the more than 20 HIV drugs that have been proven effective over the decades, only one — the now largely antiquated AZT — is officially licensed for use by pregnant women.

IN THEIR VOICES

Nneka Nwokolo, an HIV clinician and senior global medical director for the drugmaker ViiV Healthcare, on the awkward position for doctors caused by the lack of data:  

HOW THEY DID IT

ViiV Healthcare’s antiretroviral Tivicay won European approval in 2014, and its active ingredient, dolutegravir, became a darling of the HIV community worldwide. It offered several advantages over existing treatments: It was less complicated to take, caused fewer side effects and, crucially, it reduced people’s viral load faster than other treatments. Countries both rich and poor started transitioning to the drug as the new default treatment for people living with HIV.

But Unitaid was concerned that dolutegravir was understudied in some of the groups most likely to benefit, including pregnant women. In 2015, the World Health Organization-affiliated funding agency put out a call for projects to address this.

Big money: Unitaid’s deep pockets helped overcome some key barriers to studies in pregnant women, attracting a highly skilled team from the University of Liverpool to lead the project. They teamed up with the Liverpool School of Tropical Medicine and the Netherlands’ Radboud University Medical Centre for monitoring and management, while the University of Cape Town and Uganda’s Infectious Diseases Institute implemented the study on the ground.

Key negotiations: Insurance is a major barrier for this type of trial: It needs coverage to pay potential damages for both mother and infant. The University of Liverpool asked a handful of insurers for quotes. Only one was able to provide a plan.

Early engagement: Working with researchers and clinics in Cape Town, South Africa, and Kampala, Uganda, the team started discussing the pros and cons of dolutegravir with health professionals, authorities and regular people. A first round of trials in 2017 studied basic safety and looked at how pregnant women’s bodies processed dolutegravir compared to the previous go-to treatment, efavirenz. The results looked promising. 

Building evidence: Next, it was time to study how well dolutegravir actually works compared to the older regimen. Recruitment for the DolPHIN 2 trial began in January 2018, with the aim of including 250 HIV-positive women in the third trimester of pregnancy who hadn’t previously been on HIV treatment. Half would receive dolutegravir, the others efavirenz.

Two subjects: When looking for any negative effects from the drug, researchers looked at both the fetus and the mother. But when it came to determining dolutegravir’s efficacy, it was primarily about mom: Researchers measured whether women achieved a desired viral load (50 copies per mL) at birth. Shrinking the mother’s viral load is key to preventing her from passing the virus on to the baby during birth. 

IN THEIR VOICES

Little, on the unusual emphasis on both maternal and fetal health in the DolPHIN 2 trial:

HOW IT WENT

In May 2018, in the middle of recruitment, preliminary findings from an observational study in Botswana suggested increased risks of neural tube defects from early dolutegravir exposure. The findings sent shockwaves around the world. European and U.S. regulators joined the WHO to warn the drug shouldn’t be used in pregnant women or those trying to conceive. In some countries, the response was to restrict its use in women of child-bearing age. 

The bad news about dolutegravir could have killed the study. Instead, it boosted the resolve of both researchers and participants. 

Women in hard-hit sub-Saharan Africa argued that if they were going to be cut off from an otherwise superior drug, there’d better be a good reason. Rather than scaring participants away, the findings seemed to increase demand for more research. 

IN THEIR VOICES

Perez Casas on political pressure from women’s groups to retain access to dolutegravir even after concerning signals:

The findings were not necessarily a reason to give up on dolutegravir, said Thoko Malaba, an epidemiologist at the University of Cape Town who worked on the DolPHIN 2 study. The neural tube flag had come from a small number of women taking the drug early in their pregnancy. DolPHIN 2 was looking at women who had never been on treatment before and already in the third trimester, with an urgent need to slash their viral load before their due dates.

IN THEIR VOICES

Thoko Malaba, a DolPHIN 2 researcher at the University of Cape Town, on how efforts to protect pregnant women risked making them more vulnerable:

In the end, convincing women to join the trial wasn’t so hard. Some women declined to participate because of the demands on their schedules. Others worried that getting regular checkups, even after giving birth, would make it obvious that they were participating in an HIV study, and they didn’t want to deal with the stigma associated with the disease. 

Fears about potential harm from an experimental substance to the fetus weren’t a big factor for women, who understood the risk-benefit calculation, said Malaba. It was the men who took convincing on that front. 

IN THEIR VOICES

Malaba on the gendered response to potential study participation:  

RESULTS

The findings were enough to justify recommending the new drug be used for pregnant women — while also showing the need for ongoing research specifically in pregnant women.

Successful suppression: 74 percent of the women taking dolutegravir had the targeted viral load by birth, compared to just 43 percent taking efavirenz. 

Concerning signs: Twice as many women taking dolutegravir — 22 percent — experienced “serious adverse events,” researchers found. It’s not clear whether they had any relationship to the drug, so researchers called for further monitoring. 

Another puzzling finding: Three babies tested positive for HIV after birth in the dolutegravir group, while none from the efavirenz group did. Researchers determined that the fetuses had likely been infected in the womb (again, all study participants didn’t start any HIV treatment until the third trimester) — as opposed to during birth, when the late reduction in viral load would have helped. Still, more study is needed, the report authors said, noting that they’d also be tracking potential transmission during breastfeeding.

Meanwhile: The early signs of increased neural tube defects didn’t end up bearing out as the Botswana study entered later stages.

New guidelines: The WHO changed its guidelines to recommend dolutegravir for pregnant women in 2019, following a preliminary presentation of results from DolPHIN 2. The EMA softened its own guidance in July 2020, saying pregnant women should have a discussion about risks and benefits of dolutegravir, especially for use in early in pregnancy — though with much less fanfare than the 2018 warning.

THE TAKEAWAY

DolPHIN 2 showed that trials in pregnant women are possible — and that hesitation by those women isn’t the main barrier to carrying them out. 

Start early: Whether it’s performing early studies on pregnant animals, designing studies with early input from ethics committees or recruiting health professionals as allies before recruiting study participants (because the study participants will trust their providers’ advice), experts at different stages of the R&D process said expanding trials in pregnant women will require lots of groundwork. 

From precedent to practice: The DolPHIN 2 team also eased the path for future studies by convincing an insurer to get on board: That’ll make it easier for insurers to calculate the risk in the future. 

But there’s not much evidence that testing in pregnant women is becoming standard, absent major outside backing. The rush to get coronavirus vaccines to market, for example, without the complication of trials in pregnant women, is likely to reduce uptake in a group that could benefit most from COVID-19 prevention. 

IN THEIR VOICES

Little, on the consequences of skipping pregnant women in coronavirus vaccines trials: 

Signs of change: The HIV research community is leading the push for more systematic pregnancy research. In the PHASES initiative, Little and a panel of 25 other researchers, ethicists, lawyers and advocates published landmark guidelines last year for reducing the evidence gap, and a group of experts convened by the WHO said revisions to the current approach are “urgently needed.”

IN THEIR VOICES

ViiV’s Nwokolo, on how authorities’ clampdown on dolutegravir for women after the 2018 warnings from Botswana’s Tsepamo study marked a tipping point:

Next steps: A large, ongoing set of U.S. government-backed studies, IMPAACT, is taking an even broader look at how different antiretrovirals measure up in pregnant women. ViiV is running a trial of another drug — cabotegravir — that has promise as a long-acting, injectable form of HIV prevention, and women are allowed to stay in the trial if they become pregnant. Nwokolo envisioned a process that would see trials gradually expand from safety studies in the third trimester (where there’s generally thought to be the least risk to a developing fetus) to testing exposure earlier and earlier in pregnancy.

A BIG QUESTION

Absent public funding, will industry and regulators find routine ways to study drugs in pregnant women — or continue shifting risk to women themselves, forcing them to make decisions without evidence?

Audio production by Cristina Gonzalez.

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