Advancing Clinical Research with Pregnant and Lactating Populations: Overcoming Real and Perceived Liability Risks (2024)

2

Legal Liability

As introduced in Chapter 1, fear of legal liability arising from potential harm—to the pregnant woman and particularly to the fetus—is frequently cited as a significant obstacle to the participation of pregnant women in clinical research. It is unclear to what degree fear of legal liability related to the participation of lactating women in clinical research is thought to be a barrier to their inclusion in research, because liability concerns for lactating women are consistently cited alongside other concerns for pregnant women (Bianchi et al., 2021; Sewell et al., 2022). This chapter examines and analyzes the liability landscape related to the participation of pregnant and lactating women in the clinical research of medical products.

The generation of high-quality data is necessary to ensure that health care providers and their patients have the best possible evidence on safety, dosage, and effectiveness to treat and prevent diseases and health conditions. Society has determined that the responsible and ethical conduct of clinical research is essential to creating this evidentiary base. Sufficient data on safety and effectiveness allow the health care provider and the patient to make an informed decision about an intervention’s potential benefits and the risks of harm. In the face of insufficient evidence, the health care provider and patient are in a difficult position: A decision to forgo any intervention may result in harm to the woman, their fetus, and/or their child from an untreated or unprevented condition, and a decision to use an intervention puts the patient, their fetus, and/or their child at uncertain risk of harm for uncertain benefit (Weld et al., 2022).

Many have reached the conclusion that by excluding pregnant and lactating women from clinical research, the risk of harm—to pregnant

women, lactating women, the fetus and/or child—is instead magnified and exported to the much larger clinical population (Lyerly et al., 2008; NASEM, 2023; Saenz et al., 2017). This is because once a product is approved for marketing in the general adult population, a product is eligible for use by health care providers to treat pregnant and lactating women in the clinical setting regardless of whether data on the safety, dosage, and efficacy of the product have been evaluated in pregnant or lactating populations. In other words, the risks of harm from the product have not been evaluated in the controlled and monitored setting of a clinical trial, and without the generation of high-quality data through controlled clinical trials, health care providers and pregnant and lactating women are left to experiment—with respect to safety, dosage, and effectiveness—in the clinical setting. Yet there is reason to believe that manufacturers of approved products that cause harm to pregnant and lactating women, or their fetus or child, might be shielded from liability. Manufacturers may argue that they had neither knowledge of possible risks relating to use of the product in pregnant and lactating women nor a duty to acquire such knowledge in the absence of any FDA requirement to test in these populations (American Law Institute, 2010).

Notably, the potential for legal liability is rarely discussed as an impediment to conducting clinical research in the general adult population even though all clinical research on medical products involves some risk of harm to study participants. Society has determined that research is ethically permissible provided regulatory and ethical safeguards are in place (Emanuel et al., 2008). The potential for harm is minimized through several existing oversight mechanisms, including regulatory review and approval processes, research ethics committee review of the protections for human participants (i.e., to ensure that risks are minimized and the prospect of potential benefit outweighs the risks, there is adequate informed consent, and participant selection is equitable), and where appropriate, the work of data safety monitoring boards.

Research conducted in pregnancy raises distinct risk and benefit considerations. The research may be designed to offer the potential for direct medical benefit to both the pregnant woman and fetus, to only the fetus, to only the pregnant woman, or to neither the pregnant woman or fetus. Clinical research may place either or both at risk of harm despite all efforts to minimize the potential for harm, even when one or both may benefit from the research (Kaye, 2019). It is that distinct interrelationship and uncertainty related to potential fetal morbidity and mortality that prompts liability concerns in the clinical research setting (IOM, 1994). There are also unique liability considerations related to birth injuries, which are discussed in this chapter. Assumptions about liability for potential fetal harm in the clinical research setting have led to the routine exclusion of pregnant women from clinical trial participation (Sewell

et al., 2022). Exclusion of pregnant women may occur either at the outset of the study through established exclusionary criteria or during the study because pregnancy unexpectedly occurs during research participation. The fear of potential fetal harm also is reflected in the dearth of clinical research and drug development for pregnancy-specific conditions (Fisk and Atun, 2008).

Lactating women are also excluded from clinical studies, using exclusionary criteria at the study’s outset or at the level of the research agenda. Despite the fact that pregnancy and lactation are two distinct biological states, they are often conflated in the eligibility criteria of clinical trials (Van Spall, 2021). In contrast to pregnant women, where it is impossible to completely avoid any exposure to a fetus, human milk need not be given to a child if there is a concern for the safety of the child. Current Food and Drug Administration (FDA) guidance requires lactating women discontinue breastfeeding if they are administered an investigational drug as part of a clinical trial because in those cases the potential drug exposure is a research risk that has uncertain benefit to the infant (FDA, 2019). As discussed in Chapter 3, this interruption of breastfeeding is not without risk to the child. In that context, liability is not anticipated to be any greater than with the general population; the only drug exposure is to the lactating woman and yet lactating women are also frequently excluded from clinical study.

The committee’s examination of civil liability includes both a review of the potential liability for harm to pregnant and lactating women and their fetus and/or child in the clinical research setting as well as the clinical setting. The term liability may be used colloquially to refer to any form of risk. However, liability is defined by state laws; the specific legal requirements vary from state to state. In general, a finding of civil liability requires that the individual bringing a lawsuit (the plaintiff) show (1) the defendant had a duty to the plaintiff, (2) the defendant breached their duty to the plaintiff, (3) the plaintiff suffered a cognizable harm, and (4) the breach of duty was the cause of the harm. The basis of any liability claim is harm to the plaintiff; without harm there is no case. If the harmed individual believes the harm was caused by the action or inaction of another who had a duty to prevent harm or make evident the potential for harm, the harmed individual may or may not decide to sue. Once a lawsuit is filed, the defendant may decide to settle the lawsuit before litigation begins.

Settlements do not constitute a finding of liability and frequently include statements in which the defendant denies liability. If a lawsuit does proceed to trial, the case could resolve in favor of the defendant (a finding that there is no liability), or in favor of the plaintiff, which constitutes a finding of liability. There are a number of possible outcomes if an individual is harmed in clinical research, many of which will not result in liability.

The risk of liability and its potential costs is a factor that is considered among many in decisions about whether to conduct clinical research.

The committee’s statement of task asks for an examination of the state of “real and perceived liability around research conducted in pregnant and lactating persons.” The committee interprets “real” liability to mean evidence of legal cases that resulted in a legal opinion in addition to those that resulted in a settlement. A literal reading of the term liability would be limited to a formal finding by the court in favor of the injured party. In considering legal liability risks, the committee includes settlements in its interpretation to also include an examination of published cases and other reports that reveal the breadth of litigation surrounding a particular product that does not assign responsibility for alleged harm to a defendant. This includes cases deciding in favor of the defendant, settlements, the formation of multidistrict litigation, and other litigation-related activity.

A SURVEY OF REPORTED LEGAL LIABILITY RISK

A search of the literature revealed no existing survey on the legal liability risk associated with medical products researched in, and dispensed to, pregnant and lactating women. The committee therefore commissioned lawyers from the law firm Hogan Lovells US LLP to conduct such a survey (see Appendix B for full survey). The requested search was designed to capture all potential case law related to drugs, biologics, or medical devices studied in or used by pregnant or lactating populations. A description of their search methodology and a detailed reporting of results can be found in Appendix B. A brief summary of the results is presented below, followed by a discussion of the committee’s insights. As noted in the discussion, any claims of injury may be resolved privately without litigation through a claims process or discussion with the investigator, study site, or the sponsor of the clinical trial. These settlements are usually not made public, and therefore, the survey provided is an informative, yet incomplete picture of actions resulting from an alleged injury.

Overview of Findings

As discussed below, the survey reveals no reported legal cases involving liability related to a pregnant woman’s participation in a clinical study, at least since the development of formal regulations for clinical research in 1962. However, the survey unveiled a considerable number of cases involving liability related to a pregnant woman’s postmarketing use of medical products. The survey also found no cases relating to a lactating woman’s participation in a clinical trial, although it did find a number of cases involving lactating women’s postmarketing use of one product.

Liability for Pregnant Women’s Participation in Clinical Research

The search did not identify any reported cases alleging injuries based on the administration of an investigational medical product to a pregnant woman after FDA adopted regulations governing clinical research in 1963; no reported cases raise legal claims alleging injury resulting from participation of pregnant women in a clinical study.

There have been reported cases brought on behalf of children whose mothers participated in Richardson Merrell’s study of Kevadon (thalidomide) in the 1950s and1960s—in reality, the unapproved drug was distributed for marketing purposes without legitimate investigatory use, explained in Box 2-1 (Vanderbes, 2023). Similarly, cases have been brought for long-tail effects of clinical trials involving diethylstilbestrol (DES), but again, the clinical trials themselves took place in the 1960s before modern FDA regulations were promulgated.^1,2 In addition, a case was brought under the False Claims Act against a sponsor (Pfizer) of a COVID-19 vaccine for protocol violations, including the administration of the vaccine/placebo to pregnant women. No injuries were alleged in that case, though an appeal is pending.³

Postmarketing Liability for Pregnant Women

In contrast to the dearth of legal cases in the clinical research setting, there are over 1,000 filed cases associated with pregnant women’s postmarketing use of medical products, both on-label and off-label, involving products prescribed for pregnancy-related conditions (e.g., Zofran—morning sickness) and for general conditions nonspecific to pregnancy (e.g., Zoloft—antidepressant). The case law search revealed liability claims against 36 unique FDA-approved products being used by pregnant women in the clinical setting, excluding claims against DES. Those cases were typically brought against the developer of the product or the generic drug manufacturers or distributors (in the case of drugs that are off-patent). Less frequently, cases were also brought against the health care providers (and the associated medical system) who had prescribed the therapy. Parental injuries alleged were limited to emotional distress.

Most of the cases involving pregnant women’s use of postmarketing medical therapies involved birth anomalies in the infant that were apparent at birth. Some of these cases, however, involved fetal harm that

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¹ Wetherill v. University of Chicago, 570 F.Supp.1124 (N.D. Ill. 1983).

² Mink v. University of Chicago, 460 F.Supp.713 (N.D. Ill. 1978).

³ United States of America ex rel. Brooks Jackson v. Ventavia Research Group, LLC. Et al., No. 1:2021cv00008 (E.D. Tex. 2023).

only became apparent considerably later after birth. For example, a case that may potentially involve thousands of litigants alleges that children’s attention deficit hyperactivity disorder (ADHD) and autism spectrum disorders are caused by in utero ingestion of acetaminophen—though a judge recently ruled that the plaintiffs’ evidence was inadmissible.⁴ In the case of DES, claims of injury to subsequent generations have been made, and actions relating to drugs that were ingested decades previously continue to be filed. Some drugs have been the subject of large numbers of claims involving hundreds or even thousands of cases.

Liability for Lactating Women’s Participation in Clinical Research

There are no reported legal cases related to a lactating woman’s use of an investigational medical product in the clinical research setting.

Postmarketing Liability for Lactating Women

No cases were identified involving injury to a child caused by a medical product used by a lactating woman. The reported cases that involve postmarketing liability for lactating women all involved a single drug for use in lactation, bromocriptine (Parlodel), a lactation inhibitor, and all of those cases alleged injury to the mother (e.g., stroke and seizure). Parlodel is no longer indicated for lactation inhibition.

Discussion of the Case Survey Data

Several conclusions may be drawn with a reasonable degree of confidence based on the available data and general knowledge regarding the regulatory context and litigation involving medical products. In the most conservative interpretation, there is limited liability risk relating to the use of medical products in lactating women either in clinical research or through the use of approved medical products on the market. There is little liability risk relating to the use of medical products by pregnant women in clinical trials. There is evidence of liability risk relating to pregnant women’s use of approved medical products on the market, and there is some evidence that some aspects of that liability might be obviated by clinical trials in pregnant women.

For several reasons, even with the more expansive view of legal risk used by the committee in its analysis, this review offers an informative,

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⁴ In re Acetaminophen – ASD – ADHD Prods. Liab. Litig. 22md3043 (DLC) (S.D.N.Y. Apr. 27, 2023).

yet unavoidably incomplete picture of actions initiated as a result of alleged injury. First, not all filed cases result in published written opinions. For example, opinions of state trial courts usually are not reported nor are claims that are settled out of court. Second, there is very little transparency in the civil justice system, including no systematic information on how many cases go to trial in federal court, so there is no information on how many legal actions have been filed (Saks, 1992). The committee also has no way to determine how many pregnant or lactating women have participated in clinical research to understand the extent to which the inability to find evidence of liability in clinical research is caused by there being few trials that enroll pregnant and lactating women; ClinicalTrials.gov does not appear to have the necessary search criteria. Although pregnancy and lactation are searchable conditions in ClinicalTrials.gov, the results are both overinclusive and underinclusive. For example, using pregnancy as the search condition displays every trial that mentions the word pregnancy, including not pregnant. However, this search does not show trials that include pregnant women but are not treating conditions specific to pregnancy.

Further, for the trials that do appear in the search, inclusion and exclusion criteria may not be reported and results may not be reported by whether participants are pregnant or lactating. Similarly, although there are rough estimates of percentages of pregnant women who use medical products during pregnancy, there is no comprehensive reporting on how many pregnant women use those products or in what combinations. Nonetheless, this effort has produced a general profile of the landscape of legal liability relating to pregnant and lactating women’s use of medical products.

Limited Presence of Liability in Clinical Research

The committee’s review suggests that the risk of liability resulting from the use of investigational products by pregnant women and lactating women is currently substantially less than the risk of liability from the use of marketed drugs by pregnant women and lactating women outside of the clinical research context. The limited liability for clinical research involving these populations is likely attributable to multiple factors.

General Factors

First, there are currently few clinical trials that include pregnant or lactating women as participants relative to the number of clinical trials being conducted generally. For example, of the actively recruiting NIH-funded Phase III and IV trials reported in clinicaltrials.gov as of

2022, 69 percent excluded pregnant participants and 50 percent excluded lactating participants (Thiele, 2022). However, given the incomplete reporting of inclusion and exclusion criteria, the percentage of trials that exclude pregnant and lactating women is likely much higher (Smith, 2020). As a result, if the total number of pregnant and lactating trial participants is low, the number of adverse events is also expected to be quite low. That means that there is likely to be limited litigation since there will be fewer instances of injuries for which compensation can be sought.

Second, in all medical research contexts, a much smaller number of people use a medical product in clinical research studies compared to general use in ordinary medical practice following FDA approval for marketing. That number is only gradually increased as a medical product proceeds through the phased research process required under FDA regulations. A late-phase trial for a drug, Phase III, typically includes only 300 to 3,000 participants; a Phase III trial for an orphan indication would include far fewer people. Even trials for therapies indicated for a very broad population (e.g., vaccines) typically include only tens of thousands of participants, while the therapy may be used by millions. The more people that use any therapy, the more likely it is that there will be adverse events. Some of those may be attributable to background risk, and others may be caused by the rarer effects of the drug that only occur in particular populations.

There are also aspects of clinical research that make lawsuits less likely to be filed, and if filed, to succeed, than other medical liability cases. Those factors continue to hold true even though there was an uptick in the number of clinical research claims (that did not involve pregnant and lactating women) filed in the late 1990s and early 2000s (Mello et al., 2003).

The vast majority of clinical research is subject to extensive regulatory oversight to ensure that the rights and welfare of human participants are protected. The research is reviewed by institutional review boards (IRBs) to ensure that informed consent is appropriate, risk is minimized, benefits and risks are appropriately balanced, and that participant selection is equitable.

Clinical studies usually also have rigorous inclusion and exclusion criteria that are designed to limit the likelihood of adverse events. In addition, participants in clinical studies are typically monitored more closely than patients in ordinary medical practice. The comprehensive nature of informed consent processes in clinical research, including documentation requirements, may be a factor that limits the likelihood of harm and ensuing litigation in the clinical trial context. Indeed, in the medical context, while surgery usually requires documentation, much prescription of drugs in medical practice is done without much discussion or any documentation. In contrast, current federal regulations require that informed consent for clinical trials be fully documented identifying the prospect of medical

benefit as well as potential risks posed to the participant and the fetus or child, including that those potential risks be updated regularly as adverse events are detected. It is important to emphasize that in the context of clinical trials, informed consent does not create an “assumption of risk” defense that might bar any claims by a participant, even if the risks were unreasonable. Instead, the informed consent provides information about potential risks and the federal regulations require that those risks be reasonable.

Finally, the federal human subject protection regulations require that the informed consent indicate whether compensation for research-related injuries is available, but they do not require that such compensation be provided. Nonetheless, several institutions provide compensated medical care for research injuries and a few institutions provide broader compensation for research injuries (Resnik et al., 2014). Such compensation for research-related injuries and related care may also limit interest in litigation (Mariner, 1994).

All of this, however, does not negate the overall finding from this survey. There have been no reported cases based on injuries to pregnant or lactating participants in clinical trials since the 1962 promulgation of FDA investigational drug regulations. This would indicate that evidence of legal liability risk is not the driver of reticence in including pregnant and lactating women in clinical research.

While a thorough analysis of liability for conducting research with pregnant and lactating women in the international context was beyond the scope of this report, the committee’s findings of limited liability for including pregnant and lactating women in clinical trials do merit a comparison to other countries. There are notable differences between U.S. tort law and the systems of tort law in other countries. For example, punitive damages are rewarded less frequently in European countries than in the United States, though they are also uncommon in the United States (Koziol, 2015). U.S. tort law also relies more heavily on jury-determined awards, which tend to be higher than those determined by a judge, than in Europe. Perhaps most importantly, clinical trials conducted in European Union member states are required to obtain insurance to cover compensation for research-related injuries.⁵ Yet pregnant and lactating women are also routinely excluded from clinical studies in European countries despite the greater protections from liability in comparison to the United States (Nooney et al., 2021). This supports the notion that legal liability is not a primary reason that pregnant and lactating women are excluded from clinical studies in the United States.

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⁵ Clinical Trials on Medicinal Products for Human Use, Regulation EU No 536/2014 (Apr. 16, 2014).

Considerations Specific to Lactation

Under current FDA guidance, an infant would not be fed human milk during a clinical lactation study unless the lactating mother was already taking a medication and breastfeeding prior to enrollment in a clinical study. Therefore, the risk of liability resulting from the use of investigational medical products in clinical lactation studies will likely be limited to injuries to the lactating woman.

Liability Associated with the Use of Postmarketed Products

As the case law demonstrates, there are legal liability risks to the use of medical products by pregnant and lactating women in the postmarketing setting. Interestingly, there is arguably a scenario in which conducting clinical research in pregnant and lactating women could generate additional liability for the use of medical products in the clinical setting.⁶

Considerations Specific to Pregnancy

It is not surprising that most of the cases involving injuries alleged to have been caused by in utero exposure to marketed medical products involve birth anomalies. Although there is an approximately 3 percent background risk of serious birth anomalies with every pregnancy (March of Dimes, 2019), that level of background risk is not well known by the public and may vary by population (Petersen et al., 2015). It is possible that fetal harm temporally associated with in utero exposure to a medical product will be attributed to that medical product. This is not enough by itself to establish causation, but it does increase the risk of litigation. In fact, that is what happened with pyridoxine/doxylamine (Bendectin), a drug that was approved for morning sickness and prescribed to more than 30 million people between 1956 and 1983 when it was voluntarily withdrawn from the market by the manufacturer (Green, 1996; Lee and Saha, 2013).

No causal link between Bendectin and birth anomalies was ever scientifically established, but the high cost of litigation still led the drug’s sponsor to remove it from the market (Goldberg, 1996). While a typical defense against a liability claim related to the use of a medical product might argue that the harm was caused by factors not related to the product (e.g., smoking, drinking, physical activity, medical history), such a defense would be difficult to mount in the context of fetal injuries because of relatively fewer potential alternative causation factors in comparison

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⁶ As presented to the committee in open session by John Beisner on March 23, 2023.

to adults.⁷ Along similar lines, analyzing clinical trial results in smaller subpopulations, such as pregnant and lactating women, may lead to a false finding of a safety signal, since the randomization of the full data set is not preserved (EMA, 2019). This false finding could potentially cause liability in the postmarketing setting both for use in pregnant and lactating women and to cast doubt on the overall safety profile of a product. At the same time, the thalidomide story, and its associations with corporate malfeasance, is relatively well known (see Box 2-1). This could present a greater risk that a jury would find liability and award higher damages than in many other cases.

An additional characteristic that contributes to the legal risks inherent in the use of marketed medical products by pregnant women is the potential for long-tail effects. In drug liability cases, long-tail claims involve latent bodily injury that becomes apparent only many years after the alleged harm-causing conduct occurred. The DES cases provide an example of particularly extended long-tail effects, manifesting even in the next generation (Box 2-1). Because long-tail claims often involve hundreds of claimants, “in part because it is easier to spot a pattern emerging when there is a larger number of parties suffering the same kind of harm,” they pose significant liability risks (Appendix B). The long-tail risks also present challenges for conducting trials to properly assess these risks. To identify a potential long-term, relatively rare effect would require conducting a decades-long clinical trial with thousands of patients to generate enough data for a signal. This presents challenges with participant retention, false safety signals, and false negative results. Therefore, real-world evidence collection once the product is on the market is likely the only way to identify long-tail effects (see Chapter 3 for a more thorough discussion of postmarketing commitments).

Drug manufacturers might face liability for a defective product or a failure to warn if postmarketing experience indicates that the drug is more dangerous or less effective for women and the company failed to test the product in women (Flannery and Greenberg, 1994). The manufacturer of a drug that was “in widespread use while its teratogenic effects were ‘unknown but knowable’. . . might harm many children, and their lawyers may argue that the manufacturer had a duty to find out about these effects” (Clayton, 1994). The potential for liability could be increased to the extent that the manufacturer encouraged use of the drug by or marketed the drug to pregnant and lactating women, such as by promoting it to OB-GYNs. These ideas are captured in the Restatement of the Law (Third) of Torts that provides that medical product “manufacturers have the responsibility to perform reasonable testing prior to marketing

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⁷ As presented to the committee in open session by John Beisner on March 23, 2023.

a product and to discover risk and risk-avoidance measures that such testing would reveal.” The committee looked for evidence of those arguments in the case law data. There is evidence of claims that include those arguments; for example, plaintiffs in the Paxil and Zofran cases did allege a failure to conduct studies about pregnancy risks.

PERCEIVED LIABILITY

Because the examination of legal liability risks associated with the participation of pregnant and lactating women in clinical research revealed little evidence of such risks, the committee then considered the potential drivers for the perception of liability. First, it is important to note that the disconnection between actual liability and people’s perceptions of liability is not unique to research with pregnant and lactating women. IRBs are more likely to focus on the potential magnitude of harm than the likelihood of that harm taking place, thus overestimating the risk (NRC, 2014). Physicians have a distorted notion of the likelihood of malpractice liability (Engstrom, 2014). Fear of liability seems to exist in uncertainty; the exact contours of that liability, how liability interacts with harms, and what factors exacerbate the likelihood of liability are not well understood by many of the actors involved in clinical research (Mastroianni et al., 2017). The fact that potential harms attendant to research with a pregnant woman may also involve a fetus who cannot consent likely worsens this uncertainty.

There may also be a conflation of risks generally already associated with pregnancy; obstetricians face among the highest rates of malpractice cases (Sakala et al., 2013). In addition, the terrible experience of thalidomide and DES inevitably colors the decision making involved. Although the harm resulting from the thalidomide event is actually an argument for the inclusion of pregnant women in research, and likely would have been obviated if current research standards had been required, these events provide a stark, well-known narrative with graphic images of what has gone wrong in the past.

Perceptions of liability involving lactating women are perhaps more perplexing. While a lactating woman is certainly scientifically complex, the liability concerns that extend to research with pregnant women are not present because any potential risks in the research context are generally borne by the lactating woman. A child can be fed the milk of a lactating woman who is using a medical product in a clinical research study, but only when the lactating individual had already chosen to use the medical product independent of the research. Indeed, the U.S. Department of Health and Human Services (HHS) human subjects regulations applicable to pregnant women, discussed in detail in Chapter 3, do not apply to lactating women.⁸ It is possible that people simply view lactating women as part of a continuum from potentially pregnant to lactating and fail to disaggregate the different risks that are present at each stage. Regardless of the reason, conflating pregnant and lactating women does harm to lactating women by associating them with liability risk that evidence does not support.

Finally, too much focus on liability risks makes it easier to imagine harms that might be associated with inclusion in clinical research, but this ignores the risks of harms that might be associated with not doing the research. Although it may seem counterintuitive, harms that result from omission of activity may exceed the harms from commission of activity. Thus, it feels safer to avoid interventions with pregnant and lactating women than it does to conduct research with these populations. This feeling is often based on scant evidence and speculation (Baylis and Ballantyne, 2016). Risk assessment is already one of the most challenging aspects of medical research and treatment, and there is evidence that in the context of pregnant women, that assessment is rife with the influence of cognitive biases (Lyerly et al., 2009). There appears to be a widespread cultural significance to any potential risk to the fetus that neglects to acknowledge the high degree to which the health of the pregnant woman

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⁸ Subpart B – Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research, 45 CFR 46 66 FR 56778.

and that of the fetus are intertwined (Lyerly et al., 2008). This combination of cultural reticence toward fetal risk and lack of understanding of relative risk may make sponsors, clinicians, IRBs, and pregnant women assume that research is the riskier proposition when in fact it may be the best way to reduce harm for both pregnant women and the fetuses (Minkoff and Marshall, 2016).

LAW AND LIABILITY IN CLINICAL RESEARCH

The statement of task asks the committee to conduct data collection and analysis of federal and state laws and regulations governing liability for conducting research. While the committee has found very limited indications of legal liability risk in the context of clinical research with pregnant and lactating women, it is useful to understand the contours of that potential liability both to reduce uncertainty and to mitigate potential future liability, especially if clinical research involving pregnant and lactating women is to be expanded.

Stakeholders

Legal liability for research relating to the use of an investigational product by pregnant and lactating women involves medical product companies and other research sponsors (e.g., contract research organizations), research institutions, IRBs, clinical investigators, and potentially in some states, the pregnant or lactating participants themselves if their participation in clinical research could be considered negligence. Separately, there is potential criminal liability for pregnant women, which is discussed later in this chapter. The government is not usually at risk for legal liability in such contexts owing to principles of sovereign immunity. An exception is where the Federal Tort Claims Act (FTCA) provides an exception to sovereign immunity for the direct actions of federal employees within the scope of their employment. That exception may be applicable to vaccine contexts that are quite different and are described separately below.

Theories of Legal Liability

The types of injuries that could give rise to potential claims of legal liability are similar for injuries related to both clinical research and marketed products and include harm suffered directly by a pregnant or lactating woman, harm to a fetus or child who was exposed to the drug in utero or through human milk—respectively, and harm to subsequent generations resulting from pregnant and lactating women’s drug exposure or fetal or breastfed child drug exposures (long-tail effects). Box 2-2 defines

terms for theories of legal liability. The legal bases for liability for injury resulting from research involving pregnant and lactating women are no different than the bases for any claim that arises in the context of clinical research generally. These claims arise under state law, mostly as torts, and include product liability, strict liability, breach of warranty, negligence, inadequate informed consent, failure to warn, and medical malpractice. Because these claims arise under state law, there may be variations in legal requirements that can have important consequences for the viability of any claim. Nonetheless, under any theory of liability, the plaintiff must establish that the defendant breached a legal duty and that the breach caused harm. At a minimum, the plaintiff must demonstrate through competent scientific evidence that the research caused the alleged injury. While the elements of causes of action for personal injury vary from state to state, in general, the plaintiff must show that the defendant failed to warn of a risk that the defendant knew or should have known of or that the defendant failed to meet an applicable standard of professional care.

Causation is a core element of a personal injury claim; even if the plaintiff can prove that the defendant acted negligently in a clinical study or failed to provide adequate warnings of risk, the plaintiff must still show that the defendant’s actions were among the proximate causes of their injuries (DeBoy and Wang, 2020). To prove causation, plaintiffs may be required to present expert testimony that explains the scientific merits of their claims, and defendants will usually present expert testimony that counters those claims. The standard under which courts are to evaluate scientific expert testimony was actually created in one of the Bendectin cases. In Daubert v. Merrell Dow Pharmaceuticals,⁹ the Supreme Court ruled that to admit scientific expert opinion into evidence, courts must examine the experts’ methodology to ensure scientific validity. Nonetheless, despite these efforts to improve the standards for admissibility of scientific evidence, this process continues to be fraught with uncertainty for both plaintiffs and defendants.

Damages for torts relating to clinical research include compensation for lost wages and for medical and other expenses, damages for pain and suffering, and punitive damages for particularly egregious violations. In cases involving congenital anomalies or permanent harm caused during delivery, expenses for a lifetime of care may be very substantial. Punitive damages may also be in play in egregious cases or where fraud is involved (Mello et al., 2003).

Clinical research is fundamentally different from medical practice in that the core function is not to treat the patient (although therapeutic trials do confer a potential for direct medical benefit to the pregnant or lactating woman, fetus, and child), but rather to deliver generalizable scientific knowledge. Clinical research litigation is also a relatively new and rare phenomenon, and there are limited cases from which to glean information about the relative duties of the various stakeholders and how legal principles applicable to medical product liability generally may apply.

Potential Liability for Sponsors

Courts have had different responses to what duties a medical product sponsor may owe a participant injured in a clinical trial (DeBoy and Wang, 2020). Several courts have found that the sponsor owes no legal duty to the participant because sponsors have limited, if any, contact with the participant.¹⁰ Instead, it is the duty of the clinical investigator and the IRB to protect the participant (Feehan and Garcia-Diaz, 2020; White, 2020). Other courts have found that the sponsor may have, at a minimum, duties

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⁹ Daubert v. Merrell Dow Pharmaceuticals, 09 U.S. 579 (1993).

¹⁰ Wholey v. Amgen, Inc., 165 A.D.3d 458 (N.Y. App. Div. 2018).

to ensure that clinical research protocols protect participants’ safety, that potential risks are appropriately conveyed to clinical investigators, and that appropriate mechanisms (e.g., data safety monitoring boards) are in place to coordinate and identify safety signals (DeBoy and Wang, 2020).^11,12,13,14

Relatedly, there is no consensus among legal scholars about the applicability of the learned intermediary doctrine to clinical research liability actions. The learned intermediary doctrine, which is relevant to a claim based on a failure to warn, holds that a manufacturer of prescription medications or medical devices has a duty to advise the prescribing medical professional of the proper use and potential risks of its products, rather than a duty to advise the patient or the public (American Law Institute, 2010). In the clinical setting, if a patient suffers an injury from a prescription medication, the learned intermediary doctrine might shield the manufacturer from liability, which is passed down to the prescriber. There is no consensus among states as to the source or the scope of the learned intermediary doctrine as a defense, although every state now acknowledges the defense in some form (McQuain, 2018). A number of courts have indicated that the learned intermediary doctrine may apply to clinical research products liabilities claims in the same way that it applies to cases involving products already on the market, but there are not enough cases to determine that definitively (DeBoy and Wang, 2020).^15,16 In addition, if the information provided to the clinical investigator for the informed consent does not match information held by the sponsor, the learned intermediary doctrine may not apply.¹⁷

Finally, it is unclear how preemption doctrine may work to insulate a medical product sponsor from liability for failure to warn in a clinical research context. The theory of a preemption defense is that a manufacturer cannot be liable for injuries caused by a failure to warn if the applicable warnings were approved by FDA (Grossi and O’Connor, 2023). However, in Butler v. Juno Therapeutics, the manufacturer tried to claim that the plaintiffs’ state law claims were preempted because the study was subject to an investigational new drug application (IND) issued by FDA. The court rejected that claim because preemption claims are dependent on FDA’s approval of a product and a product’s label. Such a claim may be stronger if a clinical study involves an approved drug in a postmarketing

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¹¹ Kernke v. Menninger Clinic, 172 F. Supp 2d 1347 (D. Kan. 2001).

¹² Zeman v. Williams, CIVIL ACTION NO. 11-10204-GAO (D. Mass. Feb. 4, 2015).

¹³ Liu v. Janssen Research & Dec., LLC, B269318 (Cal. Ct. App. Jan. 3, 2018).

¹⁴ Butler v. Juno Therapeutics, 541 F. Supp. 3d 774 (S.D. Tex. 2021).

¹⁵ Kernke v. The Menninger Clinic, 173 F. Supp. 2d 1117, 1121 (D. Kan. 2001).

¹⁶ Tracy v. Merrell Dow Pharmaceuticals, 569 N.E.2d 875, 878–80 (Ohio 1991).

¹⁷ Butler v. Juno Therapeutics, 541 F. Supp. 3d 774 (S.D. Tex. 2021).

study.¹⁸ A complication to these claims is that a product’s patent status can influence the success of such an argument. While generic drug holders and medical device manufacturers may avail themselves of such a defense, medical product sponsors whose drug is still on patent must show there was “clear evidence” FDA would not have approved the labeling change the plaintiff claims was needed to prevent his or her injury in order to avoid liability.¹⁹

Potential Liability for Researchers and Research Institutions

Questions surrounding the duties and liability of clinical researchers and their research institutions are also complex. At a minimum, investigators are required to obtain a valid informed consent from study participants, and investigators must also fulfill various duties. These include the duty to adhere to the applicable standard of care and a duty to reasonably protect the participant’s safety by adhering to the protocol and human subjects research regulations (DeBoy and Wang, 2020). Investigators may have conflicting interests as both researchers and health care providers, and research may involve procedures that are not in the patient’s best interests (Shepherd and Riley, 2012). In the context of the research, the applicable standard of care is set by regulation and by what a “reasonable” IRB would require (Mello et al., 2003). Research institutions are responsible for overseeing the activities of their affiliated investigators and may be responsible for overseeing the applicable IRB. In all of this, they are bound by human subjects regulations to protect the safety of research participants, and failure to meet those requirements could threaten their larger research enterprise.

IRBs, contract research organizations, and data safety monitoring boards all have duties to provide safety oversight. IRBs have significantly more duties, including reviewing informed consent, determining an acceptable risk–benefit ratio for the research, reviewing the research design and protocols, and assuring and monitoring the safety and welfare of participants (DeBoy and Wang, 2020). In its review, the IRB must also consider risks to especially vulnerable populations and the influence of any potential conflict of interest (Mello et al., 2003). IRBs were not originally a focus of drug-liability claims, even when clinical trials were involved, but creative claims by plaintiff’s lawyers since the 1990s have greatly increased their exposure (Mello et al., 2003).

As is made clear above, the duties involved in clinical trial litigation hew closely to the regulations surrounding human subjects research.

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¹⁸ Murthy v. Abbott Labs, CIVIL ACTION NO. 4:11-cv-105 (S.D. Tex. Mar. 6, 2012).

¹⁹ Wyeth v. Levine, 555 U.S. 555 (2009).

Federal regulations govern the conduct of most clinical trials in the United States. Most research institutions commit to abide by the Federal Policy for the Protection of Human Subjects, which is known as the Common Rule, because it is codified in separate regulations by each of its 15 federal agency and department signatories.^20,21 The Common Rule is administered by HHS and addresses IRB review and approval of research protocols and other ethics protections for human research participants, such as informed consent, risk–benefit assessment, and the equitable selection of participants. Research conducted as part of FDA’s premarket review is governed by FDA’s regulations, which are very similar although not identical to the Common Rule. FDA’s regulations appear in two parts, rules for IRBs and rules that govern informed consent.^22,23

HHS has specific regulations that apply to research supported or conducted by HHS with pregnant women (Subpart B),²⁴ but there are none for lactating women. Although FDA does not have specific regulations for pregnant women, it has issued draft guidance for both pregnant and lactating populations (FDA, 2018). Draft guidance, and guidance documents generally, are not legally binding but are usually followed closely by industry (Seiguer and Smith, 2005). FDA-regulated research with pregnant or lactating women that is conducted or supported by HHS is subject to both FDA and HHS regulations and guidance.

In addition, a number of states have laws that may apply to research involving pregnant and lactating women (Appendix C).²⁵ Generally, these include laws concerning the permissibility of fetal research, laws that grant the designation of personhood to a fetus, and laws that interpret child abuse and substance abuse during pregnancy or lactation. The specifics of the laws vary from state to state, and not every state has a relevant statute that could apply to research involving pregnant and lactating women.

A number of fetal personhood statutes went into effect after the U.S. Supreme Court decision in Dobbs v. Jackson Women’s Health Organization (Guttmacher Institute, 2023). In a growing number of states, prosecutors have brought actions for fetal endangerment against pregnant women who have used illegal drugs. Since many research studies include routine

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²⁰ Federal Policy for the Protection of Human Subjects, 82 Federal Register 7149-7274 (Jan. 19, 2017).

²¹ The HHS version of the Common Rule, for example, is codified at 45 CFR part 46, Subpart A.

²² Institutional Review Boards, 21 C.F.R. Part 56.

²³ Protection of Human Subjects, 21 C.F.R. Part 50.

²⁴ Subpart B – Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research, 45 CFR Part 46.

²⁵ Appendix C can be viewed online at https://nap.nationalacademies.org/catalog/27595.

toxicology testing, this could pose an increased risk for some pregnant participants and privacy protections will be needed. Even more troubling, there have been increased prosecutions alleging fetal endangerment against women who have experienced pregnancy losses through miscarriage or stillbirth. While the courts in most states have overturned convictions relating to charges of fetal endangerment (only the supreme courts in Alabama and South Carolina upheld convictions), in some states it has not slowed prosecutors’ zeal in bringing such charges (Boone and McMichael, 2021). Moreover, although the courts have limited criminal convictions, many women face civil actions including temporary or permanent deprivation of parental rights after a positive drug screen (Boone and McMichael, 2021).

In addition, there is also existing state legislation that has a bearing on research requirements that has nothing to do with abortion politics. For example, New Mexico has a law the prohibits clinical research involving pregnant women except to “meet the health needs of the mother or the fetus and the fetus will be placed at risk only to the minimum extent necessary to meet such needs; or (2) there is no significant risk to the fetus.”²⁶ Researchers and their institutions must become and stay familiar with any applicable state law to protect their research and participants. (Sugarman, 2023). The table in Appendix C provides a “snapshot” of some of the state statutes that may affect research studies enrolling pregnant and lactating women.²⁷ Unfortunately, it is impossible to provide a comprehensive table of all of the laws that might be relevant for conducting research in these populations. Moreover, new statutes and new cases interpreting the listed statutes can be expected over time, so this table is only meant to represent some relevant statues as of January 2024.

Noncompliance with federal regulations can put a sponsor, institution, IRB, or clinical researcher in jeopardy of reputational harm, losing IRB approval of research projects, or in more extreme situations, exclusion from federally funded activities. Failure to adhere to federal and state human subjects research regulations does not in itself create a liability claim for someone who believes that they have been injured by clinical research, but that failure may be important evidence in a negligence claim brought under state law. At the same time, while compliance with federal regulations or guidance is generally not an absolute defense to liability, it can bolster the defense to be able to demonstrate compliance with detailed federal requirements or recommendations for how to study or label a drug.

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²⁶ Maternal, fetal and infant experimentation, N.M. Stat. Ann. § 24-9A-3 (May 6, 2021).

²⁷ Appendix C can be viewed online at https://nap.nationalacademies.org/catalog/27595.

Aspects Specific to Pregnant Women

While the legal bases for liability relating to research with pregnant and lactating women are no different than those that might arise from claims from the general population, there are specific situational aspects and differences in requirements that may affect the nature of that liability, especially for pregnant women.

Informed Consent

Both HHS and FDA have specific rules for informed consent that apply to pregnant women. Subpart B distinguishes between (1) research for the benefit of the pregnant woman or of mutual benefit for the woman and fetus, and (2) research that is done solely for the benefit of the fetus. Regarding research for the sole benefit of the pregnant woman or for the benefit of both the pregnant woman and the fetus, researchers must obtain the informed consent of the pregnant woman. If the research holds out the prospect of direct benefit solely to the fetus, then the consent of both the pregnant woman and the father must be obtained. There are exceptions to the father’s consent for unavailability, incompetence, or if the pregnancy is the result of rape or incest.²⁸ However, Subpart B does not provide a definition for father, so it is unclear if that person is the provider of the sperm, which could be a known or anonymous donor, or if that person is the intended coparent, regardless of sex or gender. In addition, HHS regulations provide that if a baby is born, that baby becomes a separate study subject, for whom consent must be given, and special rules apply to research involving neonates.²⁹

FDA’s draft guidance provides additional guidance for informed consent in studies that involve or may involve pregnant women (FDA, 2018). If the trial is supported or conducted by HHS, then the research must also comply with Subpart B. Informed consent principles dictate that, for a woman who is or may become pregnant, the informed consent process must include any potential risks and the chance of unknown risks to the embryo or fetus, should the woman become pregnant. This information should be included in the informed consent document and the investigator’s brochure.³⁰ Consenting individuals are to be informed of the reasonably foreseeable effect on the fetus or neonate. If animal reproductive toxicity studies are complete, the results should be presented, with some explanation of their significance in humans. Or, if no such studies have been completed, other pertinent information such as a general assessment

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²⁸ Research involving pregnant women or fetuses, 45 C.F.R. 46.204 (e).

²⁹ Research involving neonates, 45 C.F.R. 46.206.

³⁰ Precautions in Clinical Trials Including Women of Childbearing Potential, 58 Fed Reg. 39411. (g) (Jul. 22, 1993).

of fetal toxicity in drugs with related structures or pharmacologic effects should be provided. If no relevant information is available, it is important for the informed consent to explicitly note the potential for fetal risk.³¹

If a participant gets pregnant during a trial, then unblinding would need to occur to determine exposure, and the risks and benefits would need to be reviewed with the participant to determine whether to continue treatment with the investigational drug. A second informed consent process appropriate for pregnant women would then need to take place. Whether or not the pregnant woman continues on the investigational product, it is best practice to collect data from the exposure to the investigational product (FDA, 2018).

Federal regulations maintain the pregnant woman’s autonomy to make decisions for themselves and for their fetus. However, when the research is for the benefit of the fetus alone, regardless of whether the research presents less than minimal risk, the consent of the father is also to be obtained.³² It is not clear how state rules of fetal personhood might affect this framework (Appendix C).³³ To date, there is no indication that state laws on fetal personhood anticipate this question, but some may be interpreted to treat the fetus as legally similar to a child. It is therefore possible that a state may maintain that both parents should legally consent to any research that may affect a fetus (Appendix E).³⁴ There is an argument that federal human subjects regulations preempt state laws in the context of clinical research, but that is an issue that has not yet been litigated in the courts.

Finally, there may be concerns in some states with restrictive abortion laws. In some states, it may be inappropriate to do some types of research involving pregnant women because the potential legal risks for pregnant women (and potentially their health care providers) are too high (see Appendix E for a full analysis).³⁵ For example, medication abortion drugs could not be studied. Any drug known to increase pregnancy loss might carry attendant legal risks that are too high. Even in studies that can go forward, the informed consent may need to include risks associated with potential pregnancy loss, availability of abortion or contraception, possible effects on the fetus, and the risks of pregnancy information and outcomes being recorded, reported, or assessed by state officials. The use of certificates of confidentiality may obviate some of these privacy risks, but it may not be possible to eliminate all of these risks. The frequent,

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³¹ Precautions in Clinical Trials Including Women of Childbearing Potential, 58 Fed Reg. 39411. (g) (Jul. 22, 1993).

³² Research involving pregnant women or fetuses, 45 C.F.R. 46.204 (e).

³³ Appendix C can be viewed online at https://nap.nationalacademies.org/catalog/27595.

³⁴ Appendix E can be viewed online at https://nap.nationalacademies.org/catalog/27595.

³⁵ Appendix E can be viewed online at https://nap.nationalacademies.org/catalog/27595.

often back-and-forth changes being seen in abortion laws, particularly as some laws are being challenged in courts, means that sponsors may want to engage experienced legal counsel to ensure their trials remain compliant with changing state laws, which remain in a constant state of flux (Sugarman, 2023). Restrictive abortion laws should not affect clinical trials with lactating women, unless the lactating woman is also pregnant.

Long-Tail Effects

One important aspect that may affect liability related to pregnant women is the potential for long-tail claims. A long-tail claim “involves tortious or other liability-creating conduct that causes latent bodily injury or property damage that then manifests itself only many years, and sometimes decades, after the harm-causing conduct occurred” (Abraham, 2021). Another characteristic of long-tail claims is that because the damage or harm is hidden for years, they may involve hundreds or even thousands of claimants. One of the best-known examples of long-tail liability in tort involved DES, which was prescribed to pregnant women to prevent miscarriages but was later linked to cancers for them and their daughters, infertility, reproductive anomalies, and poor pregnancy outcomes in their female children and urogenital and sperm abnormalities in their male children (see Box 2-1). It has been estimated that up to 10 million people (pregnant women and their offspring) were exposed to DES (Hammes and Laitman, 2003). Long-tail claims are not unique to the context of pregnant women or even to medical product litigation, although the first recognized long-tail case involved an anticholesterol drug that caused cataracts.³⁶ Because certain harms can take years to manifest in a child exposed in utero to particular medical products—and the statute of limitations does not start to run until the child reaches the age of majority (i.e., age 18, in most states)—this creates a longer window of time for plaintiffs to file suit. In addition, long-tail effects may mean that the conduct gives rise to at least two categories of potential future litigants: the pregnant woman and their offspring (Mastroianni et al., 2017).

It must be emphasized that long-tail liability concerns, while real, do not make such cases any more likely to prevail. These cases are subject to the same requirements described above, and the obstacles to meeting those requirements, starting with proof of causation, remain high. Moreover, long-tail liability is not a reason to avoid clinical research with a medical product that is expected to be used broadly by pregnant women. Clinical trials are the gold standard for accurately determining causation versus association and likely the best way to develop an accurate signal

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³⁶ Roginsky v. Richardson-Merrell, Inc., 378 F.2d 832, 834 (2d Cir. 1967).

of more common adverse events and may help avoid additional liability later. Nonetheless, long-tail liability concerns are likely to affect medical product development and marketing risk–benefit calculations for sponsors, particularly with respect to rarer adverse events that are unlikely to be identified during preapproval clinical studies. Cases that potentially involve hundreds of claimants may pose litigation risks that sponsors are unwilling to undertake. Even in cases where the defendant may be relatively certain that their product did not in fact injure the claimants, the certainty provided by settlement, even for very large amounts, may be preferable to the risk posed by a legal trial (Abraham, 2021).

Parental Liability

The case law analysis provided in Appendix B does not reveal any legal liability exposure related to parents’ participation in clinical research. Many states have some level of parent–child immunity that would preclude such litigation. There are a few atypical cases, however, that have recognized a potential claim by a child against a mother whose negligence caused damages in utero (Clayton, 1994), one of which is a case against a mother who took medication while pregnant that claims she failed to exercise “reasonable parental discretion.”³⁷ Participation in clinical research might insulate against such claims since the independent review may serve as additional evidence of “reasonableness,” unless, of course, the research itself were subject to inquiry. In addition, in the general context of whether a mother can be held liable to her child for negligence while pregnant, courts tend not to recognize such a claim although they would likely recognize a claim against a third-party.³⁸ As noted by the Massachusetts Supreme Court, “recognizing a pregnant woman’s legal duty of care to her unborn child would present an unlimited number of circumstances that would likely give rise to litigation.”³⁹ This is also addressed in the Third Restatement of Torts, which reads “A number of courts have decided that mothers owe no duty of care to their unborn fetuses because of the infringement on autonomy and personal choice that such a duty would impose” (American Law Institute, 2010).

Following the U.S. Supreme Court decision in Dobbs v. Jackson Women’s Health Organization, overturning its previous rulings that the U.S. Constitution protected the right to an abortion, research participants may

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³⁷ Grodin v. Grodin, 301 N.W.2d 869 (Mich. App. 1981).

³⁸ See, e.g. Remy v. MacDonald, 801 N.E.2d 260, 263 (Mass. 2004); Stallman v. Youngquist, 531 N.E.2d 355, 359 (Ill. 1988); Chenault v. Huie, 989 S.W.2d 474, 477 (Tex. App. 1999) (specifically rejecting Grodin v. Grodin).

³⁹ Remy v. MacDonald, 440 Mass. 675 (Mass. 2004).

be exposed to new legal liability risks depending on state laws and local enforcement (Appendix E).⁴⁰ The Dobbs decision has also contributed to creating a climate of uncertainty owing to a changing legal landscape in some states. A number of states have broad child abuse statutes that might be interpreted to expose a mother to liability because of medications taken while pregnant. Privacy concerns have long been a necessary consideration for research involving pregnant women, and there is evidence that some states could attempt to expand their reporting requirements to clinical trial sponsors if they become aware of an induced or spontaneous abortion that might take place during clinical research.

Liability for Vaccines

The liability landscape for vaccines differs from that of most other medical products because of the availability of a federal no-fault compensation scheme for certain on-market vaccines. Notably, however, with one narrow exception applicable to vaccines in public health emergencies, there is no such scheme applicable to research-related vaccine injuries.

The Vaccine Injury Compensation Program (VICP) addresses injuries stemming from covered vaccines. As a result, manufacturers of those vaccines and providers who administer them are largely shielded from vaccine-related liability (Jacobs, 2012). The VICP, which is funded by a small excise tax on covered vaccines, provides compensation for vaccine injuries related to vaccines recommended by the Centers for Disease Control and Prevention (CDC) for routine administration to children and/or pregnant women.⁴¹ The Cures Act amended the Vaccine Act to permit VICP claims filed on behalf of live-born children for injuries allegedly sustained in utero that are attributable to maternal vaccination.⁴² Notably, not all vaccines are part of the VICP. For example, the shingles vaccine, which is designed only for adult populations, is not covered by the VICP.

The VICP was created in the 1980s after litigation against both vaccine companies and health care providers threatened to create vaccine shortages and reduce vaccination rates (HRSA, 2023). Compared to drugs designed to treat medical conditions, vaccines are known to carry a higher risk of liability because they are distributed widely to the general, healthy public; therefore, there are disincentives for pharmaceutical companies

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⁴⁰ Appendix E can be viewed online at https://nap.nationalacademies.org/catalog/27595.

⁴¹ National Vaccine Injury Compensation Program, CDC; 42 U.S.C. §§ 300aa-10 et seq. (Dec. 19, 1989).

⁴² Petitions for compensation, 42 U.S.C. 300aa–11(f). (2016).

to engage in the research and development of vaccines. The availability of the VICP encourages companies to pursue vaccine research and development by counterbalancing concerns about the unpredictability of the law, potential for large damages awards, and negative press attention (Winter et al., 2021). The VICP only applies to marketed vaccines; it does not protect companies during vaccine development.

Although injured persons can reject a no-fault award and sue the vaccine manufacturer, the statute creates disincentives for doing so, and lawsuits involving covered vaccines are relatively rare. In addition, in 2011, the Supreme Court ruled that design-defect claims are preempted by federal law.⁴³ While the VICP has been very successful in mitigating liability for vaccine manufacturers and promoting vaccine production, there is evidence that it is suffering strains owing to significant growth in complaints and inadequate staffing, leading to long wait times for petitioners (Gentry and Hughes, 2023).

Another liability protection program for vaccine manufacturers was created in the PREP Act, enacted in 2005 as an amendment to the Public Service Act. The PREP Act allows the secretary of HHS to issue a declaration providing immunity from tort liability for vaccines and other countermeasures developed to combat a public health emergency. In addition, the PREP Act authorizes compensation by the Countermeasures Injury Compensation Program (CICP) for individuals who are seriously injured by covered countermeasures such as vaccines. Unlike the VICP, the CICP can apply to products in development and those that have received an emergency use authorization from FDA.

The PREP Act was invoked in March 2020 to provide liability protection to parties developing countermeasures against COVID-19. Despite the broad no-fault compensation scheme, pregnant and lactating women were excluded from the COVID-19 vaccine trials that preceded FDA’s authorization of the vaccines for use in the adult population. However, according to records from ClinicalTrials.gov, only two clinical studies with pregnant women were conducted. These were started after the initial authorizations, and there have been no resulting publications catalogued in the study record (ClinicalTrials.gov, 2023a,b). No clinical studies on the COVID-19 vaccines for lactating women were reported in ClinicalTrials. gov. Postmarketing studies and surveillance of the vaccine in pregnant and lactating women eventually demonstrated its safety and effectiveness for these populations long after the vaccine was available (Muyldermans et al., 2022; Prasad et al., 2022). This led to confusion and hesitancy to receive the vaccine among pregnant and lactating women (Bianchi et al., 2022), which particularly for pregnant women, who are at higher risk

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⁴³ Bruesewitz v. Wyeth LLC., 562 U.S. 223 (2011).

of severe symptoms and death from COVID infection, is likely to have resulted in poorer health outcomes for the pregnant women and their offspring (Rubin, 2021).

CONCLUSIONS

REFERENCES