When Enough Is Enough: Decision Criteria for Moving a Known Drug into Clinical Testing for a New Indication in the Absence of Preclinical Efficacy Data

Pulley, Jill M.; Jerome, Rebecca N; Zaleski, Nicole M.; Shirey-Rice, Jana K.; Pruijssers, Andrea J.; Lavieri, Robert R.; Chettiar, Somsundaram; Naylor, Helen M.; Aronoff, David M.; Edwards, David A.; Niswender, Colleen M.; Dugan, Laura L.; Crofford, Leslie J.; Bernard, Gordon R.; Holroyd, Kenneth J.

doi:10.1089/adt.2017.821

Cited by 5 publications

(5 citation statements)

References 85 publications

(83 reference statements)

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“…In this regard, our process presents the importance of complementing quantitative methods with qualitative evidence, as much of the contextual knowledge on obstetric prescriptive practice and pediatric disease assessment remains unavailable in structured databases. This combination of ML and consensus prioritization among human users for accurate outcomes analysis is archetypal of PheWAS and GWAS approaches, as many previous publications affirm 24 , 38 , 67 .…”

Section: Discussionmentioning

confidence: 97%

Medication history-wide association studies for pharmacovigilance of pregnant patients

et al. 2022

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Background Systematic exclusion of pregnant people from interventional clinical trials has created a public health emergency for millions of patients through a dearth of robust safety data for common drugs. Methods We harnessed an enterprise collection of 2.8 M electronic health records (EHRs) from routine care, leveraging data linkages between mothers and their babies to detect drug safety signals in this population at full scale. Our mixed-methods signal detection approach stimulates new hypotheses for post-marketing surveillance agnostically of both drugs and diseases—by identifying 1,054 drugs historically prescribed to pregnant patients; developing a quantitative, medication history-wide association study; and integrating a qualitative evidence synthesis platform using expert clinician review for integration of biomedical specificity—to test the effects of maternal exposure to diverse drugs on the incidence of neurodevelopmental defects in their children. Results We replicated known teratogenic risks and existing knowledge on drug structure-related teratogenicity; we also highlight 5 common drug classes for which we believe this work warrants updated assessment of their safety. Conclusion Here, we present roots of an agile framework to guide enhanced medication regulations, as well as the ontological and analytical limitations that currently restrict the integration of real-world data into drug safety management during pregnancy. This research is not a replacement for inclusion of pregnant people in prospective clinical studies, but it presents a tractable team science approach to evaluating the utility of EHRs for new regulatory review programs—towards improving the delicate equipoise of accuracy and ethics in assessing drug safety in pregnancy.

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Section: Discussionmentioning

confidence: 97%

Medication history-wide association studies for pharmacovigilance of pregnant patients

et al. 2022

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“…The current analysis leverages the methods and experience of an experienced drug repurposing team; the methods employed have been developed and refined for generation of a number of repurposing opportunities across a variety of therapeutic candidates and conditions, as well as identification of potential safety signals associated with various agents ( 4 - 10 , 126 - 128 ). Further, the notable concordance between the PheWAS results and the primary literature provides additional confidence in the strength and validity of the identified connection between NAC and ALF.…”

Section: Discussionmentioning

confidence: 99%

“…In previous work, we have demonstrated that the combination of PheWAS with thorough evidence review and synthesis can yield valuable and actionable insights regarding additional therapeutic uses of existing medicines ( 4 - 10 ). The current analysis applies these methods to one agent from the EML, N-acetylcysteine (NAC), currently listed for “exposure to or harmful effects of undetermined intent of analgesics, antipyretics, or NSAIDs (nonsteroidal anti-inflammatory drugs)”.…”

Section: Introductionmentioning

confidence: 99%

Repurposing N-acetylcysteine for management of non-acetaminophen induced acute liver failure: an evidence scan from a global health perspective

Jerome,

Zahn,

Abner

et al. 2024

Transl Gastroenterol Hepatol

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Background The World Health Organization (WHO)’s Essential Medicines List (EML) plays an important role in advocating for access to key treatments for conditions affecting people in all geographic settings. We applied our established drug repurposing methods to one EML agent, N-acetylcysteine (NAC), to identify additional uses of relevance to the global health community beyond its existing EML indication (acetaminophen toxicity). Methods We undertook a phenome-wide association study (PheWAS) of a variant in the glutathione synthetase ( GSS ) gene in approximately 35,000 patients to explore novel indications for use of NAC, which targets glutathione. We then evaluated the evidence regarding biologic plausibility, efficacy, and safety of NAC use in the new phenotype candidates. Results PheWAS of GSS variant R418Q revealed increased risk of several phenotypes related to non-acetaminophen induced acute liver failure (ALF), indicating that NAC may represent a therapeutic option for treating this condition. Evidence review identified practice guidelines, systematic reviews, clinical trials, retrospective cohorts and case series, and case reports. This evidence suggesting benefit of NAC use in this subset of ALF patients. The safety profile of NAC in this literature was also concordant with existing evidence on safety of this agent in acetaminophen-induced ALF. Conclusions This body of literature indicates efficacy and safety of NAC in non-acetaminophen induced ALF. Given the presence of NAC on the EML, this medication is likely to be available across a range of resource settings; promulgating its use in this novel subset of ALF can provide healthcare professionals and patients with a valuable and safe complement to supportive care for this disease.

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Section: Overall Limitations and Next Stepsmentioning

confidence: 95%

Clinical trial emulation can identify new opportunities to enhance the regulation of drug safety in pregnancy

Challa

Niu

Garrison

et al. 2021

Preprint

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From the perspective of most regulatory agencies, it is usually unethical to perform interventional clinical trials on pregnant people. While this policy recognizes the vulnerability of an expectant mother and unborn child, it has created a public health emergency for millions of pregnant patients through a dearth of robust safety data for many common drugs. To address this problem, we harnessed an enterprise collection of 2.8M electronic health records (EHRs) originally collected from routine primary care, leveraging the data linkage between mothers and their babies to create a surrogate for randomized, controlled drug trials in this population. To demonstrate the feasibility of our clinical trial emulation platform to stimulate new hypotheses for post-market drug surveillance, we identified 1,054 drugs historically prescribed to pregnant patients and developed a medication history-wide association study and follow-up evidence synthesis platform—leveraging expert clinician review and real-world data analysis—to test the effects of maternal exposure to these drugs on the incidence of neurodevelopmental defects in their children. Our results replicate known teratogenic risks and existing knowledge on drug structure-related teratogenic risks. Herein, we highlight 5 common drug classes that we believe warrant further assessment of their safety in pregnancy. We also discuss our efforts to develop a discovery-to-regulatory framework that could allow for pragmatic translation of our results to enhanced regulatory policy. Collectively, our work presents a simple approach to evaluating the utility of EHRs in guiding new regulatory review programs focused on improving the delicate equipoise of accuracy and ethics inherent to assessing drug safety in an extremely vulnerable patient population.

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When Enough Is Enough: Decision Criteria for Moving a Known Drug into Clinical Testing for a New Indication in the Absence of Preclinical Efficacy Data

Cited by 5 publications

References 85 publications

Medication history-wide association studies for pharmacovigilance of pregnant patients

Medication history-wide association studies for pharmacovigilance of pregnant patients

Repurposing N-acetylcysteine for management of non-acetaminophen induced acute liver failure: an evidence scan from a global health perspective

Clinical trial emulation can identify new opportunities to enhance the regulation of drug safety in pregnancy

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