Improving the Pipeline for Developing and Testing Pharmacological Treatments in Pregnancy

Chappell, Lucy C; David, Anna L.

doi:10.1371/journal.pmed.1002161

Cited by 31 publications

(28 citation statements)

References 9 publications

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“…More work is still needed in this area; however, especially since the current heterogeneity within these three ‘diseases’ also complicates the design and conduct of clinical trials for obstetric therapies. This, in turn, increases the risk that a pharmaceutical company will not see a return on their investment and so deters their participation in the field …”

Section: Discussionmentioning

confidence: 99%

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Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

Spencer

Rossi

Lees

et al. 2019

BJOG

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Objective To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. Design Incidence estimation based on literature review and published national and EU statistics. Setting and population European Union. Methods Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. Results The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93–3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07–3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. Conclusions Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life‐threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. Tweetable abstract Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

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Section: Discussionmentioning

confidence: 99%

“…This, in turn, increases the risk that a pharmaceutical company will not see a return on their investment and so deters their participation in the field. 4,66…”

Section: Strengths and Limitationsmentioning

confidence: 99%

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

Spencer

Rossi

Lees

et al. 2019

BJOG

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“…These examples show how some of the barriers caused by regulatory and other trial processes can be overcome to include pregnant and breastfeeding women even within a rapidly evolving pandemic. As increasing numbers of women are entering pregnancy with pre-existing conditions and may potentially benefit from newer therapies, now is the time to default to including, rather than excluding, pregnant and breastfeeding women in general clinical trials 12. The RECOVERY trial is an example of success in equity for pregnant women, but the number of included women remains small and planned international meta-analyses of trial subgroup data on pregnant women will be essential.…”

Section: Changing the Defaultmentioning

confidence: 99%

Include pregnant women in research—particularly covid-19 research

Knight

Morris

Furniss³

et al. 2020

BMJ

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“…Bearing in mind the burden of disease caused by pre-eclampsia and FGR, it may be reasonably asked why there have been so few advances in therapeutic options available to the obstetrician over the last 30 years or so and why there are so few clinical trials in this area ( Fisk & Atun 2008 , Chappell & David 2016 ). The main reason is probably the difficulty of developing drugs for conditions where there are two people involved, mother and fetus, and the consequent increased risk of side effects.…”

Section: Pre-clinical Strategies For Testing Potential Therapeutic Trmentioning

confidence: 99%

“…delaying labour or inducing labour). In fact, there have been very few therapeutic advances in obstetrics in the last 30 years ( Fisk & Atun 2008 , Chappell & David 2016 ). Whilst aspirin prophylaxis for women at high-risk pre-eclampsia, for example, is now a recommendation ( https://www.nice.org.uk/guidance/qs35/chapter/quality-statement-2-antenatal-assessment-of-pre-eclampsia-risk ), it is only recently that researchers have considered the possibility of treating the dysfunctional placenta itself.…”

Section: Introductionmentioning

confidence: 99%

Treating the dysfunctional placenta

Sibley

2017

Journal of Endocrinology

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Placental dysfunction underlies major obstetric diseases such as pre-eclampsia and fetal growth restriction (FGR). Whilst there has been a little progress in prophylaxis, there are still no treatments for placental dysfunction in normal obstetric practice. However, a combination of increasingly well-described in vitro systems for studying the human placenta, together with the availability of more appropriate animal models of pre-eclampsia and FGR, has facilitated a recent surge in work aimed at repurposing drugs and therapies, developed for other conditions, as treatments for placental dysfunction. This review: (1) highlights potential candidate drug targets in the placenta – effectors of improved uteroplacental blood flow, anti-oxidants, heme oxygenase induction, inhibition of HIF, induction of cholesterol synthesis pathways, increasing insulin-like growth factor II availability; (2) proposes an experimental pathway for taking a potential drug or treatment for placental dysfunction from concept through to early phase clinical trials, utilizing techniques for studying the human placenta in vitro and small animal models, particularly the mouse, for in vivo studies; (3) describes the data underpinning sildenafil citrate and adenovirus expressing vascular endothelial growth as potential treatments for placental dysfunction and summarizes recent research on other potential treatments. The importance of sharing information from such studies even when no effect is found, or there is an adverse outcome, is highlighted. Finally, the use of adenoviral vectors or nanoparticle carriers coated with homing peptides to selectively target drugs to the placenta is highlighted: such delivery systems could improve efficacy and reduce the side effects of treating the dysfunctional placenta.

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Improving the Pipeline for Developing and Testing Pharmacological Treatments in Pregnancy

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

Cited by 31 publications

References 9 publications

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

Include pregnant women in research—particularly covid-19 research

Treating the dysfunctional placenta

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