Exclusive: Drug research on pregnant women could become the norm

Over 60 years have passed since the thalidomide disaster, when around 10,000 babies were born deformed due to a drug their mothers had taken during pregnancy. Thalidomide was promoted as being “as harmless as a sugar cookie,” but almost half of all children exposed to the drug in the womb died shortly after birth. To this day, the majority of healthcare providers are still extremely cautious when it comes to pronouncing any drug safe for pregnant women. Quietly, however, researchers and others are working to change this, and while they claim to have the welfare of pregnant women in mind, their plans indicate that other interests are also at play.

• An article in a prestigious medical journal points the way toward research on pregnant and lactating women
• Main obstacle: fear of legal liability
• Pregnant women no longer considered “vulnerable” in official guidelines; including them in research to become the default position
• Permitted level of risk raised above “minimal” and to be determined by “stakeholders" (which include Pharma)
• Focus on providing researchers and Pharma with protection from liability in case of injury
• Doctors & other healthcare workers (broadly defined to includes doulas and others) to be barred from warning pregnant women against use of medications
• Doctors to be co-opted to recruit patients as trial participants, using both inducements and implied threats
• Large-scale "public awareness” campaign with the aim of creating a “cultural shift”

Breaking taboo

A recent article in JAMA (the Journal of the American Medical Association), written by Margaret Foster Riley JD, is titled “Including Pregnant and Lactating Women in Clinical Research; Moving Beyond Legal Liability,” and the clue is in the title. In this article, Prof. Riley notes that research into use of drugs by pregnant and lactating women is being held back by fears of legal action if anything goes wrong, but that such fears are unfounded.

... until now, there has never been a systematic examination of legal liability in the US for the inclusion of pregnant and lactating women in clinical research and whether this fear of liability is supported by evidence. A new report from the National Academies of Sciences, Engineering, and Medicine asserts that while fear of legal liability is pervasive, actual legal liability is not, and is often conflated with other concerns, such as reputational risk, increased costs, and trial complexity.

Riley also expresses concern that the lack of research means that women many cease taking necessary drugs while pregnant or nursing, with adverse results; or that they take drugs regardless, without having safety data to inform them. While her concerns may be well-founded, it is noteworthy that she does not mention even in passing the risk that research itself would pose to women in vulnerable states.

By excluding pregnant and lactating women from clinical studies due to perceived liability risks, these populations, as well as their fetuses and breastfeeding children, are harmed. In an ideal world, pregnant and lactating women would have the ability to make informed decisions that optimize their perinatal and postpartum health and the health of their children…

Riley has been involved in crafting recommendations for Congress, which, several years ago, tasked the National Academies of Science, Engineering, and Medicine with examining the issue of research and associated liability. Their 83-page report contains a wealth of information from which one may derive the direction in which research is going, not only in the United States, but also in Europe and beyond.

Following is an assessment of the report with selected quotations.

Fetuses and neonates no longer considered “vulnerable”

Pregnant women have historically been considered “vulnerable” when it comes to research (due to concern for the fetus), as have other populations such as prisoners, who are vulnerable to being coerced into participation, and also children, who are unable to give informed consent. No longer. The report's recommendation that pregnant women no longer be classified as vulnerable has already been implemented, with the report’s authors claiming that:

Not surprisingly, a consensus has arisen in recent years that the more ethical and responsible course would be to include pregnant and lactating women in clinical research. 

Pregnant women to be included in trials absent “strong” evidence of risk

The report also recommends a paradigm shift in the attitude toward including pregnant and/or lactating women in clinical trials, making inclusion the default position:

Instead of justifying inclusion of pregnant women or lactating women in clinical research, investigational new drug applications (INDs) for new drugs or biological products (including a proposed study for a new indication to an already approved drug or licensed biological product) should now include justification for excluding these groups…

Pharmaceutical companies will only be granted a waiver from including these populations if:

… available evidence strongly suggests that the drug or biological product would be ineffective or unsafe in pregnant women and/or lactating women…

Permitted level of risk raised above “minimal”

The official code of ethics governing the protection of those who participate in domestic research is called the Common Rule. Clause 46:204 governing “Research involving pregnant women or fetuses” includes as one of the necessary conditions permitting this research:

(d) If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means... [emphasis added]

One of the report’s recommendations is to raise the permitted level of risk entailed in research, permitting not only research “of minimal risk” but also research that involves a “minor increase over minimal risk” (as is currently the rule for research on children).

‘Stakeholders’ to decide what constitutes acceptable risk

Who will define what constitutes a “minor increase” in risk? The report states:

… experts and stakeholders should be convened to reach consensus on the definition of what constitutes a minor increase over minimal risk for both the pregnant woman and the fetus…

Elsewhere, it defines stakeholders as “government, industry [i.e., Pharma], clinicians, and women":

... stakeholders, including industry, could work on topics of mutual interest to further research on therapeutics used by pregnant women and lactating women. Examples include agreeing on the parameters of reproductive/toxicity studies, such as the weight of evidence for reproductive or teratogenic risk required, data standards, and developing a business case around the risk of studying drugs earlier in pregnant women…

The report is light on what can be practically done to ensure that research itself does not pose dangers to women, fetuses, and neonates, merely mentioning the need for more funding to develop more preclinical models and methods, given that, “Current preclinical (animal) models have limitations for extrapolating the findings to humans.”

Appropriate preclinical studies, such as reproductive toxicology studies using animal models, should be conducted for therapeutics still in development with the potential to be used by pregnant women and/or lactating women. Based on data from preclinical studies, decisions about whether to include pregnant women or lactating women in phase III clinical trials should be refocused; the assumption should be inclusion, with a decision on exclusion only if clearly justified by the preclinical data. 

Protection for researchers — but what about mothers?

It is illegal to bribe citizens to participate in medical research which involves a risk (as much, if not all, medical research does). Providing a substantial safety net for those inadvertently injured due to participation in a clinical trial is not considered an improper inducement. The report, however, does not mention providing enhanced compensation to reassure women that if anything goes wrong, they’re covered. Rather, it focuses on “providing researchers with protection against liability."

Convene a panel ... to make recommendations for conducting research that substantially mitigates or avoids incurring liability (absent negligence or malfeasance). These recommendations may include ways to maximize the use of informed consent procedures ... without waiving research participants’ legal rights, while still providing researchers with protection against liability. 

The report also suggests using the Vaccine Injury Compensation Program (VICP) as a model for regulating compensation for mothers injured due to their involvement in a clinical study.

Doctors who don’t play along may lose their licenses

Next, the report turns its attention to the practicalities of recruiting women to clinical trials, and notes that doctors are in a unique position to influence their patients, since,

… studies repeatedly show that healthcare providers remain a trusted source of information about health…

Furthermore, “any hesitation on the part of the trusted healthcare provider about participation diminishes the chance” that women will join a trial, so various measures are proposed to ensure that healthcare providers actively promote participation in research:

… continuing medical education (CME) modules that would be linked to maintenance of board certification or licensure. In addition to content about current knowledge of the therapeutics used by pregnant women and lactating women, these modules should explain how to access and how to communicate this information to a diverse group of potential participants, including information about balancing the risk of taking a medication with that of not treating an underlying condition... [emphasis added]

Warning against drug use during pregnancy or lactation to be outlawed

For those doctors who succeed in recruiting patients to clinical trials, the report suggests a program of rewards:

Explore incentives for healthcare providers to discuss clinical trials with their patients … Behavioral incentives, such as formal feedback that gives credit to healthcare providers for getting their patients involved in trials, or grading metrics from payers, should also be included in this discussion.

However, not only doctors are to be included in the new drive to recruit pregnant and lactating women. The report mentions many other groups who are to be co-opted:

… healthcare providers (including but not limited to clinicians, pharmacists, lactation consultants, dietitians, nursing and allied health professionals, nurse midwives, nurse practitioners); academic and industry researchers; medical, health, and pharmacy associations; teratology information specialists and genetic counselors; and pregnant women and lactating women and family members ... organizations representing women’s and family health interests, such as doula and social work organizations...

If the report’s recommendations are adopted, all the above-mentioned groups will be barred from warning their patients or clients against using any medication during pregnancy or lactation unless there is clear evidence of risk:

For example ... until more studies on medications used by lactating women are completed, the interim messaging to women and their healthcare providers may only reflect that data are lacking, and that they must balance risks and benefits of medication use with continuation of breastfeeding [emphasis added].

How healthcare providers can calculate the risk-benefit ratio in the absence of data is not explained. Furthermore, the report stresses that data that becomes available in the future due to new research is to be shared with doctors, who will be responsible for presenting it in the form of “handouts written for a lay audience.” That is to say, the raw data will not be made available to the public.

Aim: To create a ‘cultural shift’

Parallel to its strategy vis-à-vis the healthcare profession, the report recommends a public awareness campaign to encourage pregnant and lactating women to participate in scientific research:

Rec[ommendation]. 5: Create a public awareness campaign to engage the public and healthcare providers in research on pregnant women and lactating women. For any cultural shift to occur, the associated behavioral change requires a targeted communications strategy. When communicating information relevant to treating pregnant women and lactating women, messages must be concise, consistent, tailored, and actionable for women and their healthcare providers … Highlight the importance of research on therapeutic products in pregnant women and lactating women, including the impact of not taking the medication during pregnancy and lactation…

To provide maximal impact for public messaging, the report suggests that anecdotal evidence be used, even though in general, the scientific community dismisses this kind of evidence as either inferior or misleading and irrelevant:

To assist in illustrating these issues, educational efforts need to include real-life stories about pregnant or lactating women’s experiences to illustrate absolute risk, relative risk, and the trade-off of risks and benefits. These stories may include the consequences of stopping treatment for ongoing conditions, failure to treat emerging conditions, and unintended incorrect dosing due to the physiological changes during pregnancy. Once developed, these messages should be pilot tested to ensure comprehension and acceptability prior to being rolled out to a wider audience.

Tax breaks for Pharma companies that include pregnant and/or lactating women in clinical studies

While behavioral incentives are proposed to encourage doctors to recruit clinical trial participants, for another group of stakeholders, the pharmaceutical companies, the report suggests financial inducements, as JAMA’s article describes:

... the report’s recommendations include a call for Congress to develop incentives, such as extended market exclusivity or tax breaks, to encourage the conduct of clinical studies with pregnant and lactating women…

In fact, the government-appointed task force on research in this area is already collaborating with European Union partnerships between industrial and philanthropic interests, such as the ConcePTION initiative,

… a public-private partnership between the European Union and the European pharmaceutical industry to develop the next generation of vaccines and medications for pregnant women and lactating women...

The report also notes that,

The Bill and Melinda Gates Foundation is funding MHRA in the UK to create repository of information for assessing drug exposure in pregnancy…

Abortion laws and experimenting on pregnant women

Prof. Riley notes that the recent Supreme Court ruling on abortion “could further discourage the conduct of clinical research with pregnant women.” Her concern may be well-founded, but the parallel between laws governing clinical trials and those governing abortion is an intriguing one.

It is claimed, although reliable data are hard to come by, that most pregnant women (perhaps as many as 70 percent) and the majority of lactating women (over 50 percent) use medications during these periods. Riley’s main justification for broadening the permissibility of research rests on the assumption that “drug use is happening anyway, so we should at least find out if it’s safe (even if we risk a few women and babies along the way).” A similar argument is used by those in favor of “safe, legal, and rare” abortions. 

However, just because people are doing something “anyway” does not mean it should be condoned or encouraged by the government. Furthermore, doing so may have deleterious effects that legislators often fail to anticipate.

Large, uncontrolled experiments?

Riley also notes that:

The absence of a sufficient evidence base means that almost all pregnant and lactating women with a condition for which a medical product might be appropriate are, in effect, participants in large, uncontrolled experiments that typically will not produce useful data.

Unwitting and often unwilling participants in another “large, uncontrolled experiment” may have something to say on the topic…