Involve pregnant women in clinical trials

International campaign launched over locking pregnant women out of clinical trials

Kampala, Uganda | RONALD MUSOKE | You would think that with all the potential complications that affect women during and after pregnancy, thousands of drugs have been developed specifically for them, says Dr. Metin Gülmezoglu, the executive director of Concept Foundation, an international non-profit that works to ensure equitable access to sexual and reproductive health commodities for both women and men around the world.

Concept Foundation has just launched an international campaign titled #OnlyTwoDrugsEver which focuses on three goals; ensuring equity and access to technologies for women in low and middle income countries, ensuring increased participation in clinical trials globally for women, and pushing for the development of new medicines for pregnancy-specific conditions.

Gülmezoglu says since the 1990s, there have been just two drugs developed and registered for pregnancy-specific conditions; Carbetocin and Atosiban which were developed in the 1990s and 2000s. Carbetocin is used to prevent bleeding after childbirth while Atosiban is used to stop women having premature contractions and birth. These drugs are yet to get into low and middle income markets like Uganda.

“If pregnant women are not given the opportunity to participate in research, then how can we change the fact that only two drugs ever exist to tackle specific pregnancy-related conditions.

“How can we live in a world where the capabilities of technology are far beyond our imagination yet pregnant women are routinely left behind in the medical field?”

He says when pregnant women go to buy drugs in pharmacies; they encounter many medicines with phrases like, “Do not take this medication if you are pregnant,” writings which give the impression that medical research was carried out on pregnant women and the drug was found to be harmful.

In actual sense, he says, it is because research was never done and the safety of the drug (for pregnant women) is actually not known. This challenge has been more pronounced over the last two years of the COVID-19 pandemic.

“In the wake of the pandemic and COVID vaccine trials, there is a growing consensus for the need to include pregnant women; not only in vaccine trials but in medical research that directly impacts their health during pregnancy.”

Dr. Gülmezoglu told The Independent in an email that the issue of pregnant women being excluded from clinical trials has been ongoing for decades yet maternal mortality remains a major public health issue that disproportionately affects countries like Uganda, and the deaths are most commonly a direct consequence of pregnancy complications.

“Some women are still unsure whether they can take the vaccine before, during or after pregnancy, leaving them more vulnerable to serious infection and death,” he said, “This is all because pregnant women are routinely excluded from clinical trials.”

Maternal deaths

The World Health Organisation (WHO) says maternal mortality—defined as the death of a woman while pregnant or within 42 days of termination of a pregnancy from any cause related to or aggravated by pregnancy or its management, but not from accidental or incidental causes—has declined worldwide by more than a third over the past 20 years thanks to advancements in technology and care which has led to affordable quality health care services.

Still, the UN health agency reckons about 303,000 women die around the world from complications related to pregnancy or childbirth. The majority of the deaths, approximately 85% in 2017, occurred in sub-Saharan Africa and South Asia especially in regions with low numbers of skilled health care workers. Sub-Saharan Africa alone accounted for roughly two-thirds.

Women in sub-Saharan Africa suffer from the highest maternal mortality rate: 533 maternal deaths per 100,000 live births or 200,000 maternal deaths a year.

According to WHO, the likelihood of a woman dying of pregnancy-related causes is about one in 37 in Africa.  But some authorities say maternal death rates may even be inaccurate in this sub-region due to deaths that occur in lower-level facilities and outside hospital settings going unrecorded, incomplete or misclassified.

Many women who experience maternal deaths in sub-Saharan Africa live in poverty and do not receive adequate care in time to address complications.

But the main complications that account for nearly 75% of all maternal deaths are; severe bleeding (mostly bleeding after childbirth), infections (usually after childbirth), high blood pressure during pregnancy (pre-eclampsia and eclampsia), complications from delivery and unsafe abortion.  However, if all countries had access to available technology and medical knowledge, maternal mortality rates could be reduced to zero.

Historical injustice?

Health experts The Independent has talked to say medical research has often struggled with how and whether to include pregnant women and even women at all in certain studies. They told The Independent that the reasons to exclude pregnant people from clinical trials can range from biological to the legal.

Dr Peter Waiswa, an Associate Professor at Makerere University School of Public Health has done extensive research on maternal, child health and vaccines over the years. He told The Independent on Jan.27 that he understands why clinical trials tend to be cautious when it comes to involving pregnant women in some studies.

“Medicine always tries to be on the side of caution,” he says, “Do no harm is the guiding principle in medicine. The Hippocratic Oath says ‘if you choose to do something, it must be in the best interest of the patient.”

Charles Ssemugabo, a researcher based at Makerere University School of Public Health told The Independent on Jan.27 that pregnant mothers fall in the category of vulnerable people. “So, those doing clinical trials might not want to expose them to clinical trials which might go either way and have the researchers legally liable,” he said.

Dr. Othniel Musana, an Obstetrician and Gynecologist told The Independent that involving pregnant women in clinical trials is generally avoided because no one can determine the outcome of the trial drugs on the expectant mother and the baby.

Dr. Musana who also doubles as the president of the Association of Obstetrics and Gynecology Association of Uganda (AOGU) said this is especially the case during the first 16 weeks or four months of a pregnancy.

“This period is critical because it is the period after fertilization when the cells multiply and begin differentiating into distinct organs and body parts,” he said, “At this point, trial drugs could potentially be poisonous and may lead to abnormalities in the baby who is forming in the mother’s womb.”

History of fear

The researchers who are wary of legal liability in case of adverse outcomes possibly recall the 1950s clinical studies of thalidomide, a prescription drug that was meant to treat morning sickness in pregnant women but led to devastating side effects including birth defects.

Within a few years, the use of thalidomide during pregnancy was associated with certain congenital disabilities. The fallout associated with thalidomide directly led to changes in U.S Food and Drug Administration (FDA) regulations.

In 1977, based on fears that new drugs would harm foetuses, the FDA excluded all women of childbearing potential from Phase-I and early Phase-II clinical trials. Although the FDA eventually relaxed that broad ban in the 1990s, the agency still generally excludes pregnant individuals from drug trials.

Some say, the history of thalidomide could have led some to the clinical trial exclusions that still go on up to today. But, other researchers argue that it is difficult to divorce the exclusion of pregnant women from clinical trials from the general prioritization of foetal health over maternal health.

This exclusion pushes pregnant women to avoid necessary treatment during pregnancy due to a lack of evidence. They also argue that pregnant women and their foetuses deserve timely access to safe, effective evidence-based care.

But, healthcare advocates argue that there is need for drug and vaccine developers to include pregnant women in future clinical studies. They say exclusion of pregnant women from clinical trials has led to inequities in healthcare during pregnancy.

Without clinical data, pregnant patients lack the drug safety evidence available to most other patients and this further denies pregnant women autonomy in medical decision making.

Moses Mulumba, the Director General at Afya na Haki (AHAKI), a health, human rights and sexual reproductive health institute told The Independent that the general exclusion of pregnant women from certain clinical trials could be understandable given the ethical and health considerations but, the practice cannot go on forever because pregnant women end up missing out on drugs that could have gone a long way in helping them overcome so many healthy conditions they endure when pregnant.

“It is actually a missed opportunity for pregnant women not to be included in some of these clinical trials.”

He told The Independent that the Ethics Board in agencies like the National Drug Authority (NDA) needs to come out and compel researchers to include pregnant women in clinical trials when it comes to the efficacy of vaccines and other health commodities.

In a video message shared by Concept Foundation, Prof. Cathy Nelson Piercy, a specialist in Obstetric Medicine at Guy’s and St. Thomas’ Trust in London says the reason why there have not been advances in medicines for pregnancy-related complications is because the venture is not attractive to drug companies to develop those drugs in the first place.

“It’s harder for them to get phase three trials; to try the drug in humans after trying it on animals, insured, because it involves pregnant women,” she said.

But, she says, the problem can actually be fixed. She says pregnant women may be asked to take part in clinical trials where they may not receive what are called active drugs. “Usually, there is a 50% chance you will receive a dummy drug or a placebo. That is what we call a randomized clinical trial.”

“So to come into the trial, the researchers have to be happy that it’s not dangerous for you to get one or the other, and you have to be happy with the chance that you might get the active treatment or the dummy treatment.”

Going forward, Dr Gülmezoglu told The Independent that he hopes this campaign will catalyse the necessary conversations and advocacy engagements to effectively tackle the stigma surrounding inclusion of pregnant women in clinical trials.

“It is not easy to conduct the research because one has to consider both the mother and the baby’s health but, if the research is not conducted, we will always be in the dark as to whether the drug is safe and effective to use during pregnancy,” he told The Independent.

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