CTSI Blogs

The Research Ethics Blog by Bernard Lo, MD

What Would You Recommend? - Case 1: Clinical Trials Involving Pregnant Women

During the 2009 H1N1 influenza pandemic, pregnant women had higher complication rates.  It is hypothesized that this might be because standard doses of oseltamivir, the recommended treatment for the prevention and treatment of H1N1, are inadequate during pregnancy because of changes in renal and hepatic function and drug volume of distribution.  More generally, over 50% of pregnant women take prescription drugs.  However, evidence of safety and efficacy of drugs in pregnancy is weak, placing pregnant women and the fetuses at risk.

Carrying out clinical trials of drugs administered to pregnant women who is carrying the fetus to term is ethically sensitive both because of concerns about birth defects in the developing fetus and also because the fetus cannot consent to be a research subject.  The federal regulations for the protection of human subjects require for clinical trials involving pregnant women and fetuses that the risk to the fetus is caused solely by interventions or procedures that offer the prospect of direct benefit to the woman or fetus, that any risk is the least possible for achieving the objectives of the research, and that the woman be informed of the reasonably foreseeable impact of the research on the fetus.  Many Institutional Review Boards (IRBs) are very conservative about approving clinical trials involving pregnant women who are carrying their fetus to term, even if the federal criteria are met. 

 In another example, clinical trials of HIV prevention -- including microbicide, vaccine, and pre-exposure prophylaxis trials -- commonly exclude pregnant women and withdraw women from the study if they become pregnant.  That is, they discontinue the study intervention, but they continue to be followed for outcomes.  Such exclusions result in a weaker evidence base regarding the benefits of risks of interventions in pregnant women. 

What Would You Recommend? Suppose you are a member of an IRB reviewing a randomized controlled trial of standard vs. higher dose oseltamavir for pregnant women diagnosed with H1N1 influenza.  First, to ensure that the benefit/risk ratio in the trial is acceptable, what protocol requirements and IRB procedures would you recommend?  And second, what measures would you require to ensure that consent is informed and voluntary? 

Comments

In addition to ensuring that the federal regulations are met (as outlined in the question), I would: - Closely scrutinize the protocol to ensure that the important adverse effects as well as the benefits will be measured, with clinically relevant endpoints. - Make sure there is a data safety monitoring board so that if there were clear benefit or clear harms associated with the intervention (higher dose medication) this would be detected early enough to stop the trial (and if there was a clear benefit, to start changing clinical practice based on the findings). - Scrutinize the sample size calculations, and ensure that the study would be powered to detect a difference in outcomes, if one exists. In this study, it would be important to enroll adequate numbers in a timely way (e.g. during the pandemic flu season) for conclusions to be drawn, so that the risks of the study aren't "wasted" on an underpowered study. - Require that the protocol have a plan in place for backing off on the dose if it seemed that the subject was not tolerating the higher dose. Regarding the consent process, in addition to written, informed consent (available in multiple languages), I would ask the women to complete a questionairre to demonstrate understanding of the most important elements of the study. I would make sure that subjects know that if they decline to participate they will still be treated with the current standard of care (so they don’t feel like there will be a penalty for not participating). I would also make sure they know that, should they choose to enroll, they can withdraw from the study at any time without any consequences to their medical care.

In addition to simply monitoring the sample size calculations, I would also try to ensure that the sample size is more than would be considered necessary for a typical trial, to compensate for the probably greater chance of dropout. Yes, this increases the number of individuals risked by the trial, but it also ensures the trial won't be "wasted", and would be more likely to catch any safety issues that might exist. I would also take care to make sure that the drug safety monitoring board has some experts on drugs taken during pregnancy, fetuses, etc., because of the obvious importance of this to the trial.

To ensure that the benefit/risk ratio in the trial is acceptable, the protocol requirements should include a sensitive method of assessing adverse events in a timely manner. For example, research staff can closely follow the patients both during and immediately after treatment, as well through the pregnancy, using open-ended questions to record adverse events. To ensure that consent is informed and voluntary, the protocol requirements should include strict methods of obtaining consent as well as assessment of consent. For example, consent can be done by someone other than the treating physician, through discussion instead of a consent form only, and include information for the patient to bring home to review. Also, the patients can be asked about their decision to join the study and refusal rates can be monitored. Natalie Lui

I really like the idea of closely following the patients and using open-ended questions to record events. In my opinion, I would also add a detailed questionnaire that incorporates all of the staff's predicted adverse events.

We could also consider restricting the trial to pregnant women who are most likely to benefit from the higher dose and least likely to have harm to the fetus--i.e. women in the second or third trimester of pregnancy. This is presumably when the renal/hepatic function changes are more pronounced. And generally prescription drug use--and particularly higher doses of drugs--is more lenient in the second/third trimester when concerns about causing developmental anomalies is somewhat reduced. As for consent, women should be carefully informed that there can be side effects on the fetus--and informed about what they can realistically expect from oseltamivir treatment in terms of shortened course of disease.

That is an excellent suggestion to restrict the use of higher dose oseltamivir for mothers in their second/third trimester based on safety concerns for the fetus during the first trimester phase. Particularly with the higher incidence of nausea and vomitting in the first trimester, this may be the smart way to go. Although it limits the generalizability of the results to those in the middle-late stages of pregnancy, it protects the mother and fetus early on. Human subject protection is a critical part of conducting research. I would propose maintaining the standard dose the first trimester and higher dose for the second/third trimesters. (L. Park)

I would also think about the infant follow up if the mother was exposed to the study drug during first trimester. Is there a plan in the protocol to adjudicate congenital anomalies reported within this trial?

Although there may be additional risks in conducting clinical trials of pregnant women, such trials are needed in order to ensure safe and effective therapies that can be used during pregnancy. It is, however, important to ensure that the risk/benefit ratio for pregnant women is acceptable. In this case, the medication should have been tested and found to be safe in non-pregnant women of all ages. In addition, women with pregnancy-related complications should be excluded from the trial. The trial could include various arms, with different dosages of oseltamavir, in order to identify the dose that is most effective and safe for pregnant women. Finally, there should be very close monitoring of the women and their fetuses while on the medication, as well as throughout the end of their pregnancies. Pregnancy outcomes should be tracked, to identify differing risks of adverse pregnancy outcomes, such as miscarriage of still-births. After the pregnancy, it would be useful to be able to follow the children born, in order to identify adverse effects. In order to ensure that consent is informed and voluntary, potential participants should be informed of their rights. This includes the fact that non/participation should not affect the other care that they receive at the clinical site, and that they can withdraw from the trial at any point. After women are informed about the study, it may be useful to ask them questions about the protocol and the potential risks, to ensure that they fully understood the information that was given to them. If they do know answer the questions correctly, the information can be provided again, but if they still do not answer correctly, they should be excluded from the study. Only pregnant women who are not vulnerable in other ways (eg. prisoners, underage) should be included in the study, to ensure that they are not being taken advantage of. Participant incentives should be kept at a minimum, so that women are not participating solely in order to earn money.

I agree with Yvette on the importance of ensuring that the pregnant women who choose to participate in the study are fully aware of the potential consequences of the intervention, and testing them on their knowledge of what the researchers explain seems to me like an effective means of ensuring their understanding. I would add that potential participants should be made well aware of known case-studies in which the effects of an increased drug dosage are known on pregnant women. For instance, if a certain drug when increased in dosage caused harmful side effects in pregnant women relative to when the pregnant women were taking a lower dosage, this type of drug should be made fully aware to potential participants of this study to make the potential risks for this study more concrete and understandable.

I agree with Yyvette's comments. I would add a few words: (1) in order to closely monitor subjects while on medication, real time drug quantification would recommend. (2), if excluded women with pregnancy-related complications, future use of higher recommended dose will not be justified for those patients.