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By Gary Evans
With the revised Common Rule removing pregnant women from the list of “vulnerable populations” in 2019, it is time for IRBs to reconsider the default exclusion of expectant mothers from clinical trials, a bioethicist argued in a new paper.1
Author Pamela Payne, BSN, MSN, NP, is a maternal-infant nursing instructor at the Patricia A. Chin School of Nursing at California State University in Los Angeles. The Common Rule change reflects the concern that a “paternalistic view” of pregnant women denies their participation in trials that may be beneficial for mother and fetus, she says. Although the revised rule “permits pregnant women to participate in clinical research under appropriate conditions, some research sponsors, researchers, and IRBs may still be reluctant to allow them to do so,” Payne emphasized in the paper.
The current situation can be traced to birth defects from the sedative thalidomide in the mid-20th century, and the cancer risks of the synthetic estrogen diethylstilbestrol that arose in the same period.
“[Those incidents] made people very reluctant to include pregnant women in clinical drug trials,” Payne tells IRB Advisor. “Certainly, no one in the drug industry wants the bad publicity, or to harm mothers or their children. But it was that and other smaller studies and issues that just made it a little bit easier to not include pregnant women at all.”
While pregnant women are no longer considered a vulnerable population, there are longstanding criteria in the Common Rule that IRBs should consider before including them in a clinical trial. Ethics panels should review these criteria and consider whether pregnant women could be included in research, Payne says.
“We are just asking them to think about them,” she says. “My concern is that because it is a little complicated, and IRBs are under a lot of strain and have a lot of work to do, that rather than look through the list of criteria they have said, ‘Let’s not even deal with it.’”
If there is a risk to the pregnant woman or fetus, they would not be included in a trial, Payne emphasizes. But she is trying to reopen this issue, and urges IRBs to hold these discussions.
Payne has four recommendations to assist IRBs in reconsidering inclusion of pregnant women in clinical trial research while providing appropriate protections:
• Include experts in obstetrics and maternal-fetal medicine as regular IRB members;
• Interpret traditional ethical principles in a manner that justifies, rather than presumes, exclusion;
• Incorporate the regulatory conditions of subpart B of the Common Rule to justify the exclusion of pregnant women;
• Consider additional safety monitoring to ensure that regulatory protections are met.
“Maybe doing these trials would require more frequent reporting of any adverse events, and seeing how participants are faring,” she says. “If harm is developing, we could cut it off early.”
IRB Advisor asked Payne to comment further on this issue in the following interview, which has been edited for length and clarity.
IRB Advisor: Will removal of pregnant women as a vulnerable population open a new avenue for revisiting this issue?
Payne: Yes. It acknowledges the fact that the change in terminology is important. “Vulnerable” implies that they are not in a position to be able to decide for themselves, or that they are more at risk for exploitation because we include children in vulnerable populations. The Common Rule also lists prisoners and military personnel because of the potential for undue influence and coercion to participation. [For a pregnant woman] I think it somewhat discounts her decision of whether she believes [a trial] would be beneficial to her and her child by just assuming that she needs extra protections. I am not saying we should take away protections; it is important, and they do have a different situation. But I believe that the Common Rule precautions already allow for judging whether a particular trial is appropriate.
IRB Advisor: You note that excluding pregnant women raises ethical issues regarding the principle of justice in the Belmont Report.
Payne: The principle of justice says that people deserve to be treated equally and appropriately. Excluding any particular group on sort of a knee-jerk reaction is not fair or just. As a clinician, I practiced as a women’s health nurse practitioner in prenatal care. We were always concerned with what to do with women who had pre-existing health issues that required treatment — [conditions] that could affect the fetus if they were not treated properly. If something developed during the pregnancy, sometimes we didn’t know what was safe to use and what wasn’t. A lot of times, we would either use something and cross our fingers, or not use something that could have been of benefit. Because of this, there is a growing consensus among a lot of clinician groups and even the NIH that we are not benefiting pregnant women [by excluding them from research].
IRB Advisor: Does the default to protection also mean researchers are unlikely to discover therapies of benefit to women?
Payne: Most of the information on the harmful effects of drugs in pregnancy is essentially anecdotal. If you use a medication in pregnancy with one of your patients, and she or the fetus suffer an adverse effect, then you report that to a drug registry at the FDA. That’s how we have been gathering all this data over time, but it is not really a good, sound scientific evaluation of risks and benefits.
Obviously, we are not asking pregnant women to participate in all drug trials. It is only those [drugs] that would specifically be of benefit to a pregnant woman or the fetus. Given that women’s bodies change so dramatically during pregnancy, the metabolic environment is entirely different. For example, a woman was taking medication for a thyroid condition. That may need to be changed perhaps to be an efficacious dose during pregnancy, because of the metabolic differences. That [dose adjustment] might be helpful for her fetus.
IRB Advisor: You also recommend that IRBs add pregnancy experts to their panels?
Payne: Yes, IRBs should consider having an obstetrician or a maternal/fetal expert as a routine member of their clinical staff, as opposed to someone you call on when you are thinking about conducting a trial that might include pregnancy. I think someone being there all the time allows the expert to become really familiar with the decision-making process of the IRB, and how you apply ethical analysis. They would advise the IRB appropriately, saying, for example, “This medication is too much like this other medication that we already know is dangerous.” Or, “This is something that we really do need to know about efficacious dosing changes.” In light of the changes with the Common Rule, perhaps some of the larger IRBs may be more inclined to this.
IRB Advisor: What about issues of informed consent?
Payne: You can’t separate the mother from the fetus, and she is the one making the decision because they are one unit. Her informed consent also consents on behalf of the child. It is very similar to the way that parents give permission for their child to receive a vaccine, for example. The child does not understand well enough to consent, so the parents do so for their child.
IRB Advisor: What about the fetus and the ethical principle of autonomy?
Payne: Respect for a person’s autonomy also is respect for the fetus. Who is in a better place to respect the fetus than the mother? She is the one who is invested in the health of this child, so her viewpoint should carry more moral weight than simply saying, “We don’t want to harm the fetus.” She doesn’t want to harm it, either.
IRB Advisor: You mention that researchers have been reluctant to perform these studies. Is that another mindset that has to change?
Payne: Yes, and it is going to take some education. I think some of the education may begin with an IRB being at least willing to entertain a research proposal. I think a lot of researchers and drug sponsors have just [felt] that IRBs have been historically reluctant to include pregnant women, so why go to all the work of preparing a proposal? Part of the education that would be involved could include [an explanation] that these are our guidelines should you choose to propose a research study that might include pregnant women.
Financial Disclosure: Author Melinda Young, Medical Writer Gary Evans, Editor Jill Drachenberg, Editor Jonathan Springston, Editorial Group Manager Leslie Coplin, and Physician Editor Lindsay McNair, MD, MPH, MSB, report no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study. Nurse Planner Kay Ball, PhD, RN, CNOR, CMLSO, FAAN, is a consultant for Ethicon USA and Mobile Instrument Service and Repair.