In a Perspective, Lucy Chappell and Anna David discuss ways to develop and test pharmacological treatments in pregnancy

Chappell, LC

David, AL

UCL Discovery

PERSPECTIVEImproving the Pipeline for Developing andTesting Pharmacological Treatments inPregnancyLucy C. Chappell1*, Anna L. David21 Women’s Health Academic Centre, King’s College London, London, United Kingdom, 2 Institute forWomen’s Health, University College London, London, United Kingdom* lucy.chappell@kcl.ac.ukThe mismatch between the burden of disease for pregnant women and their infants on the onehand and investment in developing and testing pharmacological treatments on the other con-tinues to be a barrier to successfully reducing morbidity and mortality in this important group.Physiological changes in pregnancy commonly, but not universally, result in increased drugclearance and decreased exposure to total drugs (bound and unbound to plasma proteins) at agiven dose. In a systematic review in this week’s PLOS Medicine, Shinya Ito and colleaguesdraw attention to the relative paucity of knowledge about how these pregnancy-inducedphar-macokinetic changes impact on clinical outcomes for the mother and fetus after drug treatment[1]. More studies exploring the pharmacodynamic impacts on clinical efficacy in relation tothese pharmacokinetic changes are urgently needed to inform drug dosing in pregnancy. Thiswould ensure that pregnant women receive adequate concentrations of an active drug whilstavoiding unnecessary and excessive exposure of their embryo or fetus to potentially teratogeniccompounds.Many drugs used in pregnancy are borrowed or repurposed frommainstream therapeutics,with comprehensive evidence of efficacy and safety in pregnant women often lacking despiteawareness of the pharmacokinetic changes describedby Ito and colleagues. Despite the well-publicised accounts of teratogenicity—including limb deformities in the fetus—associatedwiththalidomide (used for hyperemesis) [2] and of the association of diethylstilbestrol (used to pre-vent early miscarriage) with clear cell adenocarcinoma of the vagina and cervix in daughters ofexposed pregnant women [3], the majority of drugs prescribed in pregnancy are unlicensed foruse in this setting (i.e., used off-label), with much less safety testing than that undertaken fororiginalmarketing authorisation. The strengthening of pharmaceutical regulatory proceduresafter thalidomidemeans that it is hardly surprising that, for these and other reasons, the phar-maceutical industry has invested far less in development of new drugs in pregnancy comparedto other areas, where the safety hurdles may be less overwhelming and the duration of treat-ment longer than the time-limited use in pregnancy. This was enumerated in 2007 through areview of an industry database reporting that only 17 drugs were under active development formaternal health indications; this was a fraction of the number for cardiovascular health (660drugs) and fewer than for a single rare disease such as amyotrophic lateral sclerosis (34 drugs)[4].Estimates of medication use in pregnancy using interviews or population-based cohortsreveal high usage: in one longitudinal study from the United States, 96% of the pregnantwomen took prescription medications, 93% self-medicatedwith over-the-counter medications,PLOS Medicine | DOI:10.1371/journal.pmed.1002161 November 1, 2016 1 / 4a11111OPENACCESSCitation: Chappell LC, David AL (2016) Improvingthe Pipeline for Developing and TestingPharmacological Treatments in Pregnancy. PLoSMed 13(11): e1002161. doi:10.1371/journal.pmed.1002161Published: November 1, 2016Copyright: © 2016 Chappell, David. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, whichpermits unrestricted use, distribution, andreproduction in any medium, provided the originalauthor and source are credited.Funding: LCC is supported by a National Institutefor Health Research Professorship, RP-2014-05-019. AD is supported by the National Institute forHealth Research University College LondonHospitals Biomedical Research Centre. The fundershad no role in study design, data collection andanalysis, decision to publish, or preparation of themanuscript.Competing Interests: AD is Director and cofounderof Magnus Growth, part of Magnus Life Science, acompany that is aiming to take to market a noveltreatment for fetal growth restriction.Provenance: Commissioned; not externally peerreviewedand 45% used herbal medications [5]; other studies show similar use and reflect the increasingcomorbidities of pregnant women (e.g., diabetes, hypertension, asthma, depression) for whichmedication is commonly prescribed. A review of inpatient antenatal prescriptions in a UnitedKingdommaternity unit reported that of 235 drugs prescribed, only 16% were licensed for usein pregnancy; one quarter (24%) of drugs were prescribed off-label but were considered safe bythe manufacturers (e.g., erythromycin, prochlorperazine); for over half (58%) of these 235drugs, the manufacturer advised caution or contraindication. [6] As the majority of drugs usedby pregnant women are not specifically licensed for use in pregnancy, detailed pharmacoki-netic and pharmacodynamic studies have often not been undertaken to evaluate efficacy (orsafety) in this distinct physiological setting. Ito and colleagues show that associated alterationsin clinical responses and outcomes, or lack thereof, remain largely unknown. Drugs with mini-mal side effects, when taken by a nonpregnant adult, may have specific fetotoxic effects whentaken during pregnancy, particularly in the first trimester. For example, many antiepilepticdrugs are associated with fetal neural tube defects and cardiac abnormalities, most likelybecause of disruption of folic acid metabolism.However, stopping such drugsmay confer risksof uncontrolledmaternal seizure activity, which in itself may be life-threatening to mother andfetus. For some drugs, the pattern of potential teratogenicity is not always predictable from ani-mal studies and may only reveal itself once the drug is taken by pregnant women. Distinct dif-ferences in placentation (the human placenta contains one layer of cells betweenmaternal andfetal blood, whereas most other animal species have multiple layers), placental metabolism,clearance, and availability of active drugmay be responsible. This reinforces the need for pre-authorisation research in pregnant women, but undertaking reproductive toxicology studies, tothe extent that will satisfy the regulatory agencies, is time-consuming and expensive.The difficulty of adequate testing is compounded by the paucity of suitable animal modelsfor several pregnancy-specificdiseases such as pre-eclampsia and preterm labour, both ofwhich have heterogeneous pathophysiological pathways in the human and no clear animalequivalent. The development of novel drugs for these indications—such as atosiban, a competi-tive oxytocin receptor antagonist for the treatment of threatened preterm labour—has beenbeleaguered by controversy, such as uncertainty over appropriate clinical endpoints in trials(i.e., hard neonatal outcomes rather than prolongation of gestational age) [7] and licensing insome geographical areas (e.g., Europe) but not others (e.g., in the US) because of differences ininterpretation of trial data. Teratology information services [8] play a key role in screening forpotential new human teratogens, particularly in gathering information about newly marketedmedications.We find ourselves, however, in the relatively unsatisfactory position that, cur-rently, the use of new drugs in pregnant women creeps into clinical practice and is evaluatedvia postmarketing surveillance or registry studies, if at all [9], with pregnancy even being a con-traindication to participation in many phase IV studies.Two strands of development are now urgently needed: a greater understanding about theimpact in pregnancy of drugs commonly used for coexistent medical conditions—includinginfections (e.g., antibiotics, antivirals, antimalarials) and chronic diseases (e.g., hypertension,epilepsy, asthma, diabetes, rheumatological diseases)—and a coordinated strategy to invest inthe development of drugs for pregnancy-specific conditions such as pre-eclampsia, fetal growthrestriction, and preterm labour, where disease-modifyingpharmacological treatments couldhave a major impact on ameliorating short- and long-term adverse outcomes for mother andbaby. The importance of the intrauterine environment on adult health is well known [10], butestimating the cost-effectiveness of drugs given in pregnancy that ameliorate adult disease ischallenging. Databases for the “repurposing” of drugs with licenses for use in obstetrics areemerging, but further work is needed to understand the potential market revenues for obstetrictherapeutics and to encourage investment from the pharmaceutical industry.PLOS Medicine | DOI:10.1371/journal.pmed.1002161 November 1, 2016 2 / 4Clinical trials in pregnant women can be challenging and require collaborative effortsacross clinical and research networks along with the active involvement of the pharmaceuticalindustry. In parallel, there is a need for ongoing postmarketing surveillance (with good linkageto paediatric developmental outcome data) of drugs licensed for other medical conditionsthat are used commonly but without adequate knowledge on dosing (e.g., antibiotics, or low-molecular-weight heparin for thromboprophylaxis) or used rarely but where there are com-pelling reasons to continue treatment (e.g., biologics). New European Union regulationsintroduced in 2007 mandated the requirement for a Paediatric Investigational Plan for allapplications for marketing authorisation for newmedicines (unless the medicine is exemptbecause of a deferral or waiver) [11]. Such an obligation could be proposed for pregnancy at alegislative level to increase the formal testing of medicines on women who are pregnant. Thiscommitment would require considerable financial resources and willingness for change, butthe ongoing economic, health, and psychosocial costs associated with diseases in pregnancynecessitate a transformational approach. The recent changes to the US Food and DrugAdministration rules on labelling of medications in pregnancy and lactation, which replacesthe previous letter categories (A, B, C, D, X) with an informative narrative description ofpotential benefits and risks and establishes links to pregnancy exposure registries, are to bewelcomed [12]. We and others [13] now propose that the following avenues (Box 1) need tobe explored by all those involved with medical care for women of reproductive age and thelifelong consequences of pregnancy-associated diseases to ensure that this gap in our researchand clinical knowledge is addressed.AcknowledgmentsThe views expressed in this publication are those of the authors and not necessarily those ofthe NHS, the National Institute for Health Research, or the Department of Health.Box 1. Strategies to Improve the Development and Testing ofPharmacological Treatments in Pregnancy• Development of appropriate models in which to test placental transfer and evaluateteratogenesis• Funding initiatives for pharmacokinetic and pharmacodynamic studies of existingdrugs, particularly those unlicensed but commonly used• Consideration of novel approaches to overcome current ethical, regulatory, and deliv-erability hurdles for clinical trials in pregnancy• Institution of funded registries (with obligatory reporting), particularly for drugs forwhich there is overwhelming clinical need but limited safety data (e.g., new antiepilep-tic drugs; biologics), with short- and long-termmaternal and child neurodevelopmen-tal follow-up• Establishment of a Maternity Investigational Plan to match that introduced acrossEurope for medicines in children• Involvement of pregnant women and their families in all such initiatives such that ethi-cal risks and benefits are explored openly and transparently.PLOS Medicine | DOI:10.1371/journal.pmed.1002161 November 1, 2016 3 / 4Author ContributionsConceptualization:LCCALD.Writing – original draft: LCC.Writing – review& editing: LCCALD.References1. Ito S, Pariente G, Leibson T, Carls A, Adams-Webber T, Koren G. Pregnancy-associated changes inpharmacokinetics: a systematic review. PLoS Med. 2016.2. Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N. Thalidomide induces limb defects bypreventing angiogenic outgrowth during early limb formation. Proceedings of the National Academy ofSciences of the United States of America. 2009 May 26; 106(21):8573–8. PMID: 19433787. PubmedCentral PMCID: 2688998. doi: 10.1073/pnas.09015051063. Goodman A, Schorge J, Greene MF. The long-term effects of in utero exposures—the DES story. TheNew England journal of medicine. 2011 Jun 2; 364(22):2083–4. PMID: 21506735. doi: 10.1056/NEJMp11044094. Fisk NM, Atun R. Market failure and the poverty of new drugs in maternal health. PLoS Med. 2008 Jan22; 5(1):e22. PMID: 18215109. Pubmed Central PMCID: 2211556. doi: 10.1371/journal.pmed.00500225. Glover DD, Amonkar M, Rybeck BF, Tracy TS. Prescription, over-the-counter, and herbal medicineuse in a rural, obstetric population. American journal of obstetrics and gynecology. 2003 Apr; 188(4):1039–45. doi: 10.1067/mob.2003.223 PMID: 12712107.6. Herring C, McManus A, Weeks A. Off-label prescribing during pregnancy in the UK: an analysis of18,000 prescriptions in Liverpool Women’s Hospital. The International journal of pharmacy practice.2010 Aug; 18(4):226–9. PMID: 20636674. doi: 10.1211/ijpp.18.04.00077. van Vliet EO, Boormans EM, de Lange TS, Mol BW, Oudijk MA. Preterm labor: current pharmacother-apy options for tocolysis. Expert opinion on pharmacotherapy. 2014 Apr; 15(6):787–97. PMID:24533566. doi: 10.1517/14656566.2014.8896848. UK Teratology Information Service. http://www.uktis.org/ (accessed 8 September 2016)9. Chambers C. The role of teratology information services in screening for teratogenic exposures: chal-lenges and opportunities. American journal of medical genetics Part C, Seminars in medical genetics.2011 Aug 15; 157C(3):195–200. PMID: 21748849. doi: 10.1002/ajmg.c.3030310. Godfrey KM, Barker DJ. Fetal programming and adult health. Public health nutrition. 2001 Apr; 4(2B):611–24. doi: 10.1079/PHN2001145 PMID: 11683554.11. Van Riet-Nales DA, Kozarewicz P, Aylward B, de Vries R, Egberts TC, Rademaker CM, et al. Paediat-ric Drug Development and Formulation Design-a European Perspective. AAPS PharmSciTech. 2016Jun 7. E-pub ahead of print. 27270905. doi: 10.1208/s12249-016-0558-3 PMID: 2727090512. Food U.S. and Drug Administration. Pregnancy and Lactation Labeling (Drugs) Final Rule. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm(accessed 8 September 2016)13. David AL, Thornton S, Sutcliffe A, Williams P. Developing New Pharmaceutical Treatments for Obstet-ric Conditions: Scientific Impact Paper No. 50. Royal College of Obstetricians and Gynaecologists,2015. https://www.rcog.org.uk/globalassets/documents/guidelines/scientific-impact-papers/sip-50.pdfPLOS Medicine | DOI:10.1371/journal.pmed.1002161 November 1, 2016 4 / 4

Improving the Pipeline for Developing and Testing Pharmacological Treatments in Pregnancy

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Improving the Pipeline for Developing and Testing Pharmacological Treatments in Pregnancy

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