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.

To ensure that the benefit/risk ratio in the trial is acceptable, I would recommend strict protocols to ensure patient understanding of the intervention. This may also involve allowing time for the patient to review participation with her ob/gyne and partner. Understanding the potential side effects with a higher dose would be clearly stated as well as the rate of side effects that are currently understood/experience with the standard dose. In order to ensure that consent is informed and voluntary, the subject could be asked to read the purpose of the study to confirm literacy and to verbalize what the purpose is to confirm understanding. A witness that is a friend or family member could sign the consent as well as a health professional who is unrelated to the recruitment efforts. (L. Park)

In addition to the earlier comments, I would also require that the investigation team map out all possible routes that the treatment can take and what they will do in these situations. For example, if the treatment were to cause an unwelcome effect, the team will know how to adjust the trial and treatment to patients to reduce the risk. To ensure that the consent is informed and voluntary I would require patients to attend a session that informs them of the trial and its risk/benefits, this would be signed off by a staff member of the investigation team. They will also have to write a letter that shows their understanding and voluntary participation in the trial.

Edwin makes a great point- it's very important for the investigators to put some thought into possible adverse effects that can occur. The subjects need to be completely aware of these and the information session would be highly beneficial.

To make sure that the benefit/risk ratio is acceptable, as others have said, I would restrict the study to individuals for whom the benefit of the intervention would be greatest (during flu season, when they are most likely to catch the flu) and for whom the risk is smallest, individuals who are in the 2nd/3rd trimester, where as mentioned earlier, risks to fetal development would be somewhat lower. I would also restrict the study to women without comorbidities as to the goal is to understanding dosing of oseltamavir in pregnancy, and including women with certain cormobidities (hypertension, diabetes) may complicate interpretation of the results. In addition, I would also require that the authors consider all possible adverse events (in the form of closed-ended questions) as well as open ended questions to maximize diagnosis of adverse events. To monitor these events, I would also require a safety monitoring board, as well as encourage multiple methods for adverse events to be ascertained (staff to follow up with women after the intervention, phone hotlines etc.). Regarding informed consent, I would require that it be more involved than the standard written consent (involving a teach back component, figures/diagrams to compensate for low health literacy) to better assess the woman's understanding of the foreseeable risks and benefits to both her and the fetus.

I like the idea of having multiple methods for adverse event ascertainment. In particular, I think the proposed phone hotlines will be useful and would go as far to institute a web-based hotline/feedback system. Pregnant women are generally more mindful of their health because they realize that they need to care for the fetus as well. This would make them more likely to utilize methods for self-reporting of adverse events. Dosing of an oral medication like oseltamivir occurs daily (or several times daily) and it would be difficult to monitor this with clinical check-ups all the time. Frequent obligation to clinical check-ups may tire pregnant women and may increase the rate of dropout in the trial. Self-report of adverse events would be a great stand-in for a more formal questionnaire for adverse event reporting.

I agree with this and think that restriction of enrollment is a great idea. Also, limiting the study to peak months (during flu season) will amplify the benefit of the intervention as described above.

In order to protect the safety of the fetus, who is also a participant in clinical trials involving pregnant women, a well-thought out plan for detecting adverse fetal outcomes would be an essential part of the protocol. This includes monitoring during pregnancy and follow-up post-partum. If imaging or other procedures might be necessary to detect or ascertain adverse fetal outcomes during the clinical trial, its ramifications need to be discussed as part of informed consent. With close monitoring, the probability of picking up fetal anomalies might be higher. It may not always be possible to ascertain the cause of the anomaly or adverse event. It must be kept in mind that even discussing this possibility can be distressing to the study subject and has to be handled sensitively in the process of obtaining informed consent.

I would recommend the following IRB procedures: - Having "consent" forms with the following statement: "Your participation in the experiment is voluntary and you can withdraw at any time without penalty - Having a 'debriefing statement" that is written in non-technical language, taking care to make it clear enough to be understood by younger participants, offering the option to withdraw their data, and giving information about some health resources if they feel discomfort (This may be another outlet for information about side-effects). Patients should be closely monitered and be checked on at various points during the study. - It must also be clear to participants that they should not disclose research procedures and hypotheses to anyone who might participate in this study between now and the end of the data collection as this could affect the results of the study. To ensure consent is informed and voluntary I would have the patients review all material prior to the study, and fill out a questionairre to enforce their understanding.

In addition to all the methods Lucia outlined, it might also be necessary to have a third party medical staff member educate and council participants to assess their comfort/motivation for enrolling in the trial. Using someone who is not directly involved in the trial helps make patient assessment prior to enrollment more accurate and less biased. Furthermore, care should be taken to not provide any excessive monetary incentive before enrolling in the trial to prevent suspicions on whether patient consent was voluntary.

In addition to all the methods Lucia outlined, it might also be necessary to have a third party medical staff member educate and council participants to assess their comfort/motivation for enrolling in the trial. Using someone who is not directly involved in the trial helps make patient assessment prior to enrollment more accurate and less biased. Furthermore, care should be taken to not provide any excessive monetary incentive before enrolling in the trial to prevent suspicions on whether patient consent was voluntary.

There are many good comments written thus far! The most important points, in my opinion, are the following. First of all, the trial is necessary in order to understand how this flu can be prevented in pregnant women and prevent future potentially worse outcomes. Secondly, the consent process needs to be detailed enough to convey the risk and benefits, but simple enough for all levels of education. In addition, the person who leads the consenting process should be well-schooled in this area and able to tailor the process for different levels of understanding. The "teaching back" method is therefore an essential step in the process to ensure that participants are well informed before they consent.

The higher rates of morbidity and mortality among pregnant women during influenza season have been well-described, and unfortunately, during the H1N1 flu season, providers faced this dilemma without being equipped with studies that would help guide therapy. On the one hand, underdosing oseltamivir might lead to poor response to the medication and potentially to resistance. On the other hand, overdosing the medication carries potential risks for side effects and unknown fetal effects. Because women in later pregnancy are at higher risk for worse outcomes and since this is a safer time to expose fetuses to antiviral medication, initially targeting late-trimester (and even early post-partum) women for the high-dose oseltamivir study seems warranted. The target population for this study should be the population with the highest risk for morbidity, since this population would have the highest potential benefit from the antiviral medication. This population should include women in the third trimester of pregnancy or the early post-partum period with comorbidities (obesity, hypertension, diabetes), who require admission to the hospital for influenza. It also would be important that the protocol clearly delineated the timing of antiviral therapy, as it is most effective when started early in the course of influenza symptoms. To maximize benefit of the oseltamivir, women should only be allowed to enroll within 48 hours of developing symptoms. As mentioned in prior posts, close monitoring of side effects and fetal outcomes would be crucial for this study. The consent form would need to include information about the potential for harm to the fetus and would need to make clear (as all consent forms should) that participation in such a study would be optional.

There is no ethic issue for standard dose. If benefit/risk ratio for higher dose is acceptable. I would recommend to do it. Just keep participants informed. If the drug is very toxic at higher blood drug concentration, I would recommend monitoring of drug concentration during the trial, and drop out the subjects immediately if unusual high drug concentrations are detected in some subjects. but keep follow up for toxicity.

From an IRB perspective I would want the protocol to include a summary of the best evidence from animal and human studies, including any evidence that might suggest a dose-response relationship. The question of monitoring for adverse effects is challenging. As far as I know, pregnant women who take H1N1 do not currently undergo increased monitoring for immediate (ie fetal demise) or delayed (ie birth defects, preterm labor) adverse effects. Women who are not hospitalized for their H1N1 could have daily phone calls to report any symptoms while they are taking tamiflu. I would also consider regular ultrasonography/non-stress testing through the duration of pregnancy if my OB co-investigators thought this could be useful. Most importantly though, to ensure detection of fetal adverse events, women need to be followed with regular OB care at least through the end of pregnancy - so I would exclude women planning to move or those without ability to come for regular follow-up. To ensure informed/voluntary consent I would include a clear explanation of current evidence and gaps in knowledge, including sequelae of H1N1 (ie superinfection with PNA requiring even more drugs with potential toxicity). Women may be tempted to join the study based on the free "extra monitoring" for adverse fetal events, so I would also want the consent process to include discussion around the risks/benefits of the monitoring itself.

I would agree with this comment that "extra monitoring" is a good idea to promote the subjects to enroll. Since either receiving just normal dose or higher dose of this drug, they will be worry about the side effect to their fetus and will feel better if they get close monitoring.

Many have mentioned that the clinical trial should be of adequate size so that the results are reasonably powered. At the same time, the dosing of oseltamavir must be high enough to produce a clinically significant difference. This conflicts directly with uncertainty in dosing, which is directly tied with the rate of side effects and adverse events. Yvette proposed to use a clinical trial with various dosing arms, but this may be subjecting many pregnant women (and their fetuses) to potential risks if doses are too high if the necessary sample size is very large. This strategy may be appropriate provided that clearly defined stopping strategies are employed to eliminate particular arms that have an increased number of adverse events during interim monitoring. Alternatively, it may be helpful to hold a separate and smaller, shorter and intentionally underpowered study ahead of time to assess the safety of various higher dosages. Reports of side effects and adverse events from this study will only be used to determine an appropriate dosage to be used in the larger study. This strategy imposes a greater risk on subjects in the safety study, but the greater risk can be justified if the only subjects enrolled in the safety study are pregnant women at high risk of the flu and within the third trimester of pregnancy. The larger study will then be appropriately powered based on the determined dosing of oseltamavir to achieve statistically significant results. At the same time, much of the risk in dosing has already been mitigated because an appropriate dosage of oseltamavir was determined in the safety study.

In addition to the requirements highlighted above, I would also would require that numerous and extensive animal studies have been done so that (a) safety in animals can be used as a jumping-off poing for evaluating it in humans and (b) dosing can be extrapolated to human levels. Maybe it goes without saying that this would have already been done, but with such high risks, all research efforts in animal models must be exhausted before human clinical trials can begin.

I would recommend setting up a DSMB for this trial with data review and interim analysis on regular basis. Make sure the protocol document outcome measures including, pregnancy outcome ,congenital anomalies, infant outcomes, other pregnancy complications, have the sponsor set up blinded adjudication of any potential birth defect or anomaly. Follow the new born babies up to 12 month. Update the IRB on safety issues on regular basis prior to any IRB renewal. Provide in the protocol any preclinical data on this drug. Document the consent process on each patient and the level of patient's understanding of the study, explain the risks of participating in the study, it should be written in the consent, and make sure that the patient can withdraw at anytime without penalty.

I would restrict the trial to women with more severe illness to ensure that the risk/benefit ratio is adequate. Consent needs to be adequate and clear, and women need to have the option of withdrawal. However, it is important to perform trials in higher risk populations to ensure that they receive quality care.

As a physician and researcher I am very aware of the difficulties of clinical research and participant recruitment, which is one of the reasons why I always agree to participate as a subject myself in any clinical trial that I am offered. The other reason is that by participating in clinical research I am contributing not only to the medical or scientific community but to society at large. I believe that participating in well designed, rigorous, ethical clinical trials whenever possible is a social responsibility. However, having been recently pregnant myself, I have to admit that they would have had a very hard time recruiting me to participate in a clinical trial evaluating a drug (I participated in 2 clinical studies during my pregnancy but neither involved taking potentially harmful medications nor interventions). Close monitoring side effects or harmful effects to the fetus may not be enough reassurance as there will be very little to be done after the fact if such problems occur. This makes me acutely aware of the sensitivity of the subject matter as well as concerned for the protection of the study subjects (pregnant women and fetus). Because of that I think that recruitment in any such trial will be extremely difficult if the researchers truly approach subjects with honesty and full disclosure. In this particular case, researchers should be extremely cautious and aware of the conflict of interest that exists in any clinical trial (protection of human subjects vs. recruitment necessary to achieve sound science) but that is accentuated here because of the difficulty in recruiting subjects and the uncertainty around the risks and benefits. As a regulatory body (IRB committee, FDA official, etc), I would require that these studies would be supported with rigorous laboratory and basic science evidence, and that other studies show definitively that the risks for the human subject are minimal in comparison to the benefits (to both the pregnant woman and the fetus). These studies should involve animal models and other models, although they are not perfect in terms of predicting the risks in human subjects and also have their share of ethical conundrums surrounding them. The information presented to the subject during recruitment should be 100% transparent, and understandable and I would require that several mechanisms are in place to ensure that vulnerable populations (minorities, low SES, etc) are not being lured to participate because of lack of awareness or understanding of the risks. As we have discussed, even though subjects participating in clinical trials are told many times that a study will not likely benefit them directly, it has been shown that ultimately most people accede to participate thinking that they will obtain a direct benefit from a study and that their doctors (who are presenting the study to them) would not suggest that they participate in a study that involves significant risk. I worry that in a trial involving pregnant women, recruitment techniques and departure from the strict codes of ethics and honesty may be seen as a “necessary evil” to ensure participation. Alejandra de Alba, MD

In terms of risk/benefit ratio, I would agree with other comments that we should performed in high risk pregnancy patients for maximizing the benefit such as potentially having severe symptoms, immunocompromised etc. For reducing risk, the participants might be limited only in the second or third trimester periods, which would have lower risk for the birth defect. Also close monitoring for adverse effect of drug should be planned. For informed-consent process, I think both pregnant women and their husband should be informed together about unknown risk that might affect their kid and must have consensus agreement in both of them.

Consent issues are obvious in situations such as this where there are fetuses/babies involved, though with such a useful possible outcome, the study definitely has the potential to be more than worthwhile...I would recommend a detailed decision analysis that might be able to quantify this situation to help determine whether certain women over others (or any women at all) should participate in such a trial.

What I worry about most in this type of trial are the perceived incentives potential participants may consider - financial, increased doctor time, or monitoring after birth. The trial is already risky enough that it shouldn't even be considered until all in vitro and animal models have been exhausted. At that point, I would want the researchers to only consider the riskiest patients that would most benefit from taking the drug and that fit all the criteria for successful outcomes. Patients should be educated about non-human results, given the option to say leave at anytime and presented with interim information on the health of their pregnancy which should be collected for monitoring purposes anyway. Lastly, the non treatment benefits of the trial should be carefully constructed.