Advancing Clinical Research with Pregnant and Lactating Populations Overcoming Real and Perceived Liability Risks (2024) / Chapter Skim
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Appendix B: Scope of Liability Related to Pharmaceuticals Dispensed to Pregnant and Lactating Women
Appendix B: Scope of Liability Related to Pharmaceuticals Dispensed to Pregnant and Lactating Women
Pages 217-288
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From page 217... ...
NASEM also asked that we identify, where applicable, any insights, patterns, or conclusions this legal landscape reveals, particularly with respect to the question of "What is the true legal risk associated with pharmaceutical products researched in, and dispensed to, pregnant and lactating women? " RESEARCH METHOD To address this research question, we consulted a variety of sources, including but not limited to legal research websites (e.g., Westlaw, Lexis)
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The "Legal Landscape Overview" is appended to this memoran dum as "Appendix A." The charts are divided by subtopic: (1) case law involving drugs used in lactating women; (2)
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does not evidence a materially greater risk of liability with respect to pregnant/lactating women as compared to other participants in clinical trials, such as children -- a 2 For completeness, we note that there are a few cases involving a medical experiment conducted by the University of Chicago and Eli Lilly & Company to determine the value of DES in preventing miscarriages.
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and/ or her child is injured as a result of clinical trial conduct. Based on our experience and expertise, potential claims are most likely to be asserted against the drug manufacturer and/or clinical trial sponsor and often include strict liability, negligence, and/or inadequate informed consent.10 4 The absence of case law may also reflect, to some extent, differences in the compensation systems for injuries resulting from clinical trials and FDA-approved products.
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• State in the informed consent that the investigational product is being provided during the study free of charge and is not otherwise available to the study participant in the stream of commerce to provide documentary evidence to support the defense to a strict liability that such a cause of action is not appropriate for a product that is not in the stream of commerce. 11 Clinical trial precedent -- outside the of the pregnancy/lactation space -- includes a line of "expanded access" cases involving claims for continued access to an experimental treatment after the study has ended.
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In the years leading up to the Parlodel litigation, serious adverse event reports caused FDA first to encourage manufac turers to include a warning in their labeling and alert doctors to the potential hazards of using the drug for lactation suppression, and later, to initiate withdrawal proceedings for this indication for Parlodel based on the agency's conclusion that the possible risks outweighed the utility 12 The following search terms were used to collect case law and secondary sources from Westlaw: "breastfeeding" or "lactation/ing", "drug," and "malpractice," "clinical trial," "liability," or "consumer protection." Based on these searches and supplemental internet searches, the only litigation identified with respect to lactating persons involved the drug Parlodel. 13 Many cases were decided in Sandoz's favor on summary judgment motions on the basis that testimony offered by plaintiffs' expert witnesses lacked critical indicia of scien tific reliability as set forth in the Supreme Court's Daubert to establish causation.
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;17 • The pregnant woman ingested the drug in utero, and the drug subsequently caused injury to the woman's child; • The injury alleged is a birth defect, of varying types; • The plaintiffs consist of either the child, the mother, or both individuals; and • Common causes of action include violation of state consumer protection law, negligence, breach of warranty, failure to warn, fraud and strict liability. And, as demonstrated by the below sub-sections of this Memorandum, the majority of the case law involving a pregnant woman's post-market 14 See 60 F.R.
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1. Products liability and related claims.18 As demonstrated by Tables B-2 and B-3, defendant-manufacturers are often successful in dismiss ing personal injury claims by filing dispositive legal motions (e.g., motions to dismiss or motions for summary judgment)
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The Accutane label included a black-box warning disclosing the high risk of birth defects since 1984. Therefore, courts frequently ruled in favor of the defendant-manufacturer in Accutane birth defect suits because the warnings were deemed "adequate" as a matter of law.
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Warnings are generally admis sible when accompanied by expert testimony, but the drug's labeling is not considered conclusive evidence of a violation of the standard of care.30 To hold otherwise would undermine physician discretion to act in the patient's best interest, including by prescribing products off-label. Nev ertheless, failure to provide warnings or to adhere to strict prescription guidelines may be strong evidence of a breach of the standard of care.31 Further, a common fact pattern in the medical malpractice cases we found involved physicians who failed to properly diagnose a plaintiff's pregnancy before prescribing a drug contraindicated for pregnant women and/or failed to warn the pregnant person of the risk of birth defects asso ciated with a particular drug product.32 Like in products liability cases, plaintiffs must establish medical causation in medical malpractice cases.33 To that end, plaintiffs are much more likely to meet their burden of proof in such cases where it is well established that the drug ingested causes birth defects (e.g., Accutane, Provera)
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.36 Thalidomide-exposed children suffered a variety of injuries, including developmental disabilities, kidney malformations, and ocular anomalies, among others.37 In 1961, two independent clinicians confirmed that thalidomide caused severe birth defects in children, and "[t] he evidence that thalidomide causes birth defects is now undoubted."38 Fortunately, thalidomide was never FDA approved for use in pregnant women in the United States, and litigation in countries outside of the United States spanned decades.
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The court did not approve the settlement, and a trial was held for 818 Bendectin cases in federal court in Ohio. After hearing the evidence, the jury decided in favor of Merrell and found that plaintiffs failed to establish that Bendectin was a proximate cause of human birth defects.41 Unlike thalidomide, no causal link between Bendectin and birth defects was ever scientifically established.42 Possibly a testament to Bendectin's safety, in 2013, the FDA approved a rebranded version of Bendectin, Diclegis, for use in the treatment of "nausea and vomiting of pregnancy in women who do not respond to conservative management."43 We were unable to find any reported litigation involving Diclegis, despite Bendectin's litigious history.
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, involving pharmaceutical products 46 DES cases can be found at Appendix B-1 47 See Women and Health Research, supra note 45, at 239. 48 See supra note 1; see, e.g., Lalor v.
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Most notably, the case law does not corroborate stakeholders' fear that including pregnant or lactating women in clinical studies will result in significant litigation risk. At the very least, there is no indication that the legal risk of including pregnant or lactating women in clinical studies exceeds the risk drug manufacturers and clinical trial sponsors typically assume when conducting human trials on any pharmaceutical product.
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News sources report that a number of early cases settled out of court.10 Nevertheless, many cases were decided in Sandoz's favor on summary judgment motions on the basis that testimony offered by plaintiffs' expert witnesses lacked critical indicia of scientific reliability as set forth in PREPUBLICATION COPY -- Uncorrected Proofs the Supreme Court's Daubert to establish causation, in spite of the adverse regulatory action (e.g., Soldo, Hollander) .11 In addition to the issues of expert testimony and causation, other disputes that arose out of this litigation related to consolidation, statutes of limitations and collateral estoppel based on adverse agency action (e.g., Yacub)
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implied and thus, consolidation would 1994, Sandoz express warranty be unfair to the jury and voluntarily • Fraud parties. withdrew the indication; a The judge agreed that the few months cases raised common issues later, FDA related to testing of Parlodel also proposed and the manufacturer's withdrawing the correspondence with indication and it FDA about the same.
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; see (negligent and testimony was sufficiently on joint also Brasher v. strict liability)
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234 TABLE B-1 Continued Settlement Amount / Labeling Jury Verdict Case Drug Information Plaintiff / Injury Claims Case Description (If Applicable) The court held that, although an epidemiological study may be the best evidence, A02260_Advancing_Clinical_Research_AppB.indd 234 "Daubert only requires only that reliable evidence be presented, and that evidence here consists of the animal studies, the medical literature reviews, the ADRs reported to the FDA, and the "general acceptance" of the association between stroke and Parlodel, reflected in several neurology and toxicology textbooks and treatises." From this evidence, causation can be inferred in the absence of other likely causes.
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Pa. • Design defect causation (Daubert 2003)
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TABLE B-1 Continued Settlement 236 Amount / Labeling Jury Verdict Case Drug Information Plaintiff / Injury Claims Case Description (If Applicable) • Caraker Hollander: affirming v.
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Statute of limitations: PREPUBLICATION COPY -- Uncorrected Proofs denying the defendant's motion for summary judgment and holding that review of medical report did not trigger statute of 237 limitations continued 3/20/24 2:45 PM
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Plaintiff later brought suit after reading a newspaper article stating that Sandoz was discontinuing the product and noting pending personal injury litigation. The court rejected Sandoz's PREPUBLICATION COPY -- Uncorrected Proofs argument, holding that the cause of action did not accrue until the plaintiff read the newspaper article; suspecting that Parlodel may have caused the injury did not trigger the statute of limitations.
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A02260_Advancing_Clinical_Research_AppB.indd 239 23, 2000) The trial court concluded that the products liability cause of action accrued on the date of the plaintiff's stroke, and was therefore, time barred.
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Sandoz Parlodel See above Postpartum • Products liability Denying defendant's Uncertain -- Pharma. Corp., (on-label lactating woman (design defect and motion for summary settlement 208 F.3d 907 (8th prevention of (stroke)
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Zamfirova Makena N/A Mother • Violation of Granting the defendant's N/a A02260_Advancing_Clinical_Research_AppB.indd 241 v. AMAG (prevent states' consumer motion to dismiss the Pharmaceuticals, preterm birth protection laws / class action complaint on Inc., 2021 WL on-label)
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Ortho (birth control) against used (unreasonably summary judgment to the Pharmaceuticals, in pregnant dangerous)
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(emotional and negligent summary judgment in N.E.2d 194 distress) and product liability defendant's favor on the (Ill.
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or suspected eventual death) of summary judgment (D.D.C.
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Barcal v. EMD Serophene See above Child (born • Design defect Denying the motion for Uncertain -- Serono, Inc., 2016 (fertility prematurely with • Failure to warn summary judgment on settlement WL 1086028 (N.D.
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Squibb & was probably merchantable knew or should have Sons, Inc., 682 effective in quality and known that progestational P.2d 832 pregnant fitness for use agents, including Delalutin, (Utah 1984) women to • Strict liability had teratogenic effects, and prevent habitual sufficient evidence that the and threatened child's mother would not abortion and have been injected with was safe for that the drug if the defendant purpose had conducted proper PREPUBLICATION COPY -- Uncorrected Proofs testing and/or given a proper warning as to the teratogenic effects of Delalutin.
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It is estimated that several million pregnant women ingested DES over a 25-year period, resulting in an estimated 1,000+ individual or class action products liability lawsuits against the pharmaceutical companies that manufactured DES.22 The majority of the cases were filed in the PREPUBLICATION COPY -- Uncorrected Proofs 1980s/1990s, and the most recent reported case -- Netherland v. Eli Lilly & Co., described below -- was filed in 2006.
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Eli DES Approved for "DES daughter" • Negligence; strict Granting motion for N/a Lilly & Co., Prod. treatment of suffering from liability; breach summary judgment Liab.
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preterm labor, daughter" that warranty, not liable for personal 1979) and related was prenatally strict liability injuries suffered by pregnancy exposed to DES in tort, false daughter born to mother complications ingested by her representation who ingested DES PREPUBLICATION COPY -- Uncorrected Proofs in 1947.
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. Summary judgment was previously granted for all defendants that were not in the chain of distribution.
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NOTE: this case and its holding appear dated and/ or likely impose a higher duty on manufacturers than in other jurisdictions Accutane cases: The teratogenic effects of Accutane were well documented when it was approved as an acne treatment. Accutane has had a black-box warning disclosing the high risk of birth defects since 1984.
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contraindicated ("NJPLA") for women of • Failure to warn Plaintiff filed complaint childbearing under the seeking to recover for birth potential unless NJPLA; defects allegedly caused by the patient • Breach of implied ingestion of Accutane meets certain warranty under Learned intermediary requirements the NJPLA; doctrine not an absolute • Punitive damages Pregnancy defense because warnings under the Prevention were provided directly common law and Program, to patients.
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27 that the drug Named plaintiff • Breach of implied IIED based on: by 2018, most "can produce was a child with and express of these cases teratogenic spina bifida warranty • Expert testimony were pending effects" such as and many other • Misrepresentation that the label misled in the Southern spina bifida, so physical and by omission readers about the causal District of use in women cognitive injuries • Fraud and relationship between Illinois. The of childbearing misrepresentation Depakote and birth case was put potential • Intentional defects, failed to warn on hold for requires that the infliction of that Depakote was parties to focus benefits of its emotional associated with numerous on settlement use be weighed distress (IIED)
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distress resulting from the birth defects to support a negligent infliction of emotional distress claim.
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injuries) grounds because there was clear evidence the FDA would not have approved a change to the Depakote label adding a developmental delay warning prior to the plaintiff's injuries (and design defect as PREPUBLICATION COPY -- Uncorrected Proofs duplicative)
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bifida and many products liability when considering the $38 million S.W.3d 795 other physical • Negligence evidence in plaintiff's ($15 million in (Mo.
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Pa. complications, birth defects)
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23, pregnant, had manufacturer provided 2015. The breastfeeding, or a stronger warning about the motion does plan to become risks of birth defects and not mention a pregnant whether plaintiff ingested settlement.
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first trimester ductus arteriosus, • Strict liability With respect to the fraud/ (E.D.
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Prescribers indicated that had the drug been labeled as a Category D or had the warnings disclosed the risk of cleft palate, they likely would have altered their prescribing decisions. Court held that preemption does not apply because there were ways that Janssen could have strengthened its warnings before the label is actually changed; also rejected learned intermediary defense PREPUBLICATION COPY -- Uncorrected Proofs because evidence at trial demonstrated Jannsen knew of a causal relationship between drug and specific birth defects, including cleft palate, but failed to disseminate the information to physicians 3/20/24 2:45 PM
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31, 2023) other ethical/safety concerns related to clinical trials due to mismanagement by A02260_Advancing_Clinical_Research_AppB.indd 261 research group tasked with managing clinical trials for Pfizer's COVID-19 vaccine.
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cardiovascular Held: on issues of fraud and malformations" breach of express warranty, for prenatal court found that allegations exposure that label did not adequately Dec 2005 changed inform physician of from Category C prescribing risk was sufficient to D and added to survive motion to dismiss; PREPUBLICATION COPY -- Uncorrected Proofs new data to preemption defense rejected Warnings section because facts do not show under Teratogenic that FDA would have refused Effects a stronger warning label -- no efforts from GSK; stronger warnings were added in consult with FDA.
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Over-the-counter drug In re OTC "If pregnant or MDL (ASD, • Failure to warn Plaintiffs alleged that had Ongoing Acetaminophen acetaminophen breastfeeding, ASD-ADHD) • Strict liability for they known acetaminophen – ASD-ADHD (on-label use)
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Court rejected preemption argument on the basis that regulations permitted Walmart (OTC manufacturer) to include more specific warnings in addition to the required warnings 2023 WL 3045802 (consumer protection and products liability)
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. 13 The majority of jurisdictions do not recognize an exception to the learned intermediary doctrine for manufacturers of contraceptive.
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1992) (granting defendant's motion for summary judgment under learned intermediary doctrine, concluding that manufacturer warned prescribing doctor of risks associated with Accutane)
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2015) (affirming $11 million jury verdict, awarded based on the finding A02260_Advancing_Clinical_Research_AppB.indd 267 that manufacturer failed to adequately warn of the risk of birth defects; the appellate court agreed that the claim was not preempted because the defendant could have unilaterally changed its label warnings per FDA's Changes Being Effected regulations)
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(antiemetic contraindicated children • Negligence summary judgment granted Products Liab. off-label for for pregnancy (primarily • Fraudulent on preemption grounds31 Litig., 541 F
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knew of risk of birth defects from preclinical and from adverse event reports and medical literature. Based on these assertions, plaintiffs A02260_Advancing_Clinical_Research_AppB.indd 269 claim that GSK failed to perform an adequate study of the safety of ingesting Zofran during pregnancy and promoted Zofran for use in pregnancy despite knowing its teratogenic risks; further, plaintiffs allege liability extends to patients who ingested the generic because it is reasonably foreseeable that such promotion would result in patients being prescribed the generic continued PREPUBLICATION COPY -- Uncorrected Proofs 269 3/20/24 2:45 PM
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liability hospital's motion for pending: LLC, 523 P.3d summary judgment review accepted A02260_Advancing_Clinical_Research_AppB.indd 270 132 (Oregon Ct. because a genuine issue by Oregon App.
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2017) 32 used off-label injuries, misrepresentation the trial court to grant on information to prevent including (based on alleged plaintiffs leave to amend for Case No.
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272 TABLE B-3 Continued Settlement Amount / Labeling Jury Verdict A02260_Advancing_Clinical_Research_AppB.indd 272 Case Drug Information Plaintiff / Injury Claims Case Description (If Applicable) Held: brand-name manufacturers have a duty to use ordinary care in warning about the safety of their drugs, regardless of whether the injured party was dispensed the brand name or generic version of the drug (in reliance on the brand-name manufacturer's warning)
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Trial court also dismissed failure to warn claims against a generic manufacture as preempted under Mensing v. PLIVA in PREPUBLICATION COPY -- Uncorrected Proofs an earlier case 31 See also Nate Raymond, GSK Defeats 425 Lawsuits Alleging Zofran Causes Birth Defects, Reuters (June 1, 2021)
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. Trial and that the court dismissed based on "possibility that plaintiff's failure to offer PREPUBLICATION COPY -- Uncorrected Proofs a woman of child expert testimony on the bearing potential standard of care required of may be pregnant an OBGYN.
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Supp. 2d 35 defects (granting summary judgment motion as to the 275 manufacturer)
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prescribed an antibiotic for a sore throat, the day after which her fetus was dead. The plaintiff alleged that PREPUBLICATION COPY -- Uncorrected Proofs she was not warned that the drug might pose a risk to the fetus, and the doctor claimed that he prescribed the drug based on his professional opinion that the risks outweighed the benefits.
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fetus) that defendants breached the standard of care in failing to properly interpret the laboratory diagnostics indicating a positive pregnancy test, in referring a pregnant patient to radiology, and in PREPUBLICATION COPY -- Uncorrected Proofs administering medications contraindicated for pregnant patients.
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events reported off-label use of drug in when drug is question more probably administered than not affected outcome intravenously of trial, requiring vacation of verdict and new trial. Among other things, the court held that the prescription drug's labeling or its reference in Physician's Desk Reference, when introduced along with other expert evidence on standard of care, is admissible in PREPUBLICATION COPY -- Uncorrected Proofs medical malpractice action to assist in determining whether drug presented unacceptable risk to patient; 3/20/24 2:45 PM
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summary judgment reflex) • Negligent in selling drug Learned intermediary contraindicated doctrine extends A02260_Advancing_Clinical_Research_AppB.indd 279 for pregnant to pharmacies, and women pharmacist was under no (pharmacy)
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congenital prove by a preponderance microcephaly, of the evidence that drug A02260_Advancing_Clinical_Research_AppB.indd 280 developmental prescribed during pregnancy delays) caused child's cerebral palsy.35 Although an expert testified that the physician violated the standard of care by prescribing phenobarbital to a pregnant person, no expert testimony establishing that the drug caused the birth defects was obtained Hogle v.
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156 (also Delalutin insert indicated (physical malpractice summary judgment in A.D.2d 987 (N.Y. (miscarriage that Delalutin was deformities)
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The court also consent affirmed the trial court's finding that the defendants breached their standard of care by failing to conduct a literature search or to consult other sources, in regard to the effects of Dilantin during pregnancy, even though the plaintiffs Leonard and Jean Harbeson specifically asked all three Madigan physicians PREPUBLICATION COPY -- Uncorrected Proofs of possible birth defects associated with the mother's consumption of Dilantin during pregnancy.
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that progestational agent recommendation posed to fetus was not, of to advise itself, sufficient evidence pregnant to establish a standard women of risk of care for purposes of of congenital wrongful birth action. abnormalities PREPUBLICATION COPY -- Uncorrected Proofs continued 283 3/20/24 2:45 PM
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Bertocci, Depakote Blackbox warning Mother + Child • Medical Reversing jury verdict Outcome 299 A.D.2d 335 (antiseizure) cautioned (spina bifida)
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and summary judgment on WL 2117386 (N.M. risk of neonatal the basis that the plaintiff's Ct.
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App. that "the first birth defects)
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1991) (granting summary judgment in favor of defendant pharmacy on the basis that under learned intermediary doctrine, the pharmacy and its pharmacist owed no duty to warn customer of potential side effects of drug prescribed by customer's treating physician)
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PREPUBLICATION COPY -- Uncorrected Proofs A02260_Advancing_Clinical_Research_AppB.indd 288 3/20/24 2:45 PM
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