New Drug Postmarketing Requirements and Commitments in the US: A Systematic Review of the Evidence

Moneer, Osman; Brown, Beatrice L; Avorn, Jerry; Darrow, Jonathan J.; Mitra-Majumdar, Mayookha; Joyce, Krysten W; Ross, Murray N.; Pham, Catherine; Kesselheim, Aaron S.

doi:10.1007/s40264-022-01152-9

Cited by 10 publications

(10 citation statements)

References 40 publications

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“…Preapproval trials of investigational drugs have limited duration and size and often exclude certain populations. Furthermore, the US Food and Drug Administration (FDA) has recently approved drugs based on fewer clinical trials or less rigorous study designs than in previous years through increased use of expedited pathways and often instructs manufacturers to conduct postapproval studies, which may be delayed or incomplete . Because data are lacking about the timeliness of postapproval studies for new drugs approved after 2012, we studied 2013-2016 approvals with follow-up through the end of 2020.…”

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confidence: 99%

Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016

et al. 2022

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Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016

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“…Bedaquiline, which received marketing authorization based on the smallest number of study participants and trials among the NCEs examined here, has faced constraints to its use [ 46 , 51 ]. It is clear from this experience, together with that on the aforementioned limited compliance with postmarketing expectations for orphan and accelerated approvals [ 52 ], that the pre-approval window is the optimal time to provide complete research on the individual components, their combination, and their use in target populations [ 46 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Comparing timelines and evidence available to support new TB, HIV, and HCV drug approvals: The same, only different

et al. 2022

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Background Tuberculosis (TB), human immunodeficiency virus (HIV), and hepatitis C virus (HCV) share a global presence and propensity to disproportionately affect marginalized populations. However, over recent decades, many fewer drugs have been brought to market for TB than for the others. Although three new anti-TB drugs have been approved in the US or Europe in the last 10 years, uptake of these drugs has been limited. Using case examples of drugs developed recently for TB, HIV, and HCV, we explore possible reasons. We examine the use and effect of regulatory pathways intended to address weak economic incentives in the face of urgent, unmet needs; evaluate the extent of data underpinning authorizations for these indications; document development timelines and evidence available at the time of each approval; consider explanations for observed differences; and discuss the implications for clinical guidelines and use. Methods and findings For each indication, we selected two drugs: one recently approved and one approved between 2012 and 2014, when the first new anti-TB drug from a novel class in more than 40 years received marketing authorization. We calculated time from first published peer-reviewed evidence of activity to date of approval; the number of phase 1, 2, and 3 trials; the number of trial participants randomized to treatment arms containing the drug; and the total number of participants in each trial from the individual drug approval packages. We found that the two TB drugs took longer to gain approval (8.0 and 19.2 years for bedaquiline and pretomanid, respectively) despite availing of special regulatory pathways meant to expedite approval, when compared to the HIV (2.6 years for dolutegravir and 4.7 years for doravirine) and HCV drugs (3.2 and 1.6 years for sofosbuvir and glecaprevir/pibrentasvir, respectively). Moreover, fewer participants were studied prior to TB drug approvals (380 and 879) than prior to approvals for HIV (1598 and 979) and for HCV (2291 and 2448) drugs. Conclusions The dramatic disparities observed in TB drug development reaffirm the importance of several actions. Increased investment in TB research and development is necessary to rapidly advance drugs through the pipeline. Development plans and partnerships must provide safety and efficacy evidence on combinations and durations that are relevant to real-world use in heterogeneous populations. Reliable, validated surrogate markers of relapse-free cure are essential to decrease the duration and cost of TB treatment trials and increase the confidence and speed with which new regimens can advance. Lastly, regulators and normative bodies must maintain high evidentiary standards for authorization while ensuring timely and broad approval for TB drugs and regimens.

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“…Patients reasonably presume that all potential safety risks of a marketed drug have been rigorously reviewed by the FDA and hence some of them who co‐administer potentially interacting medications with the NME may be uncertain about why they could be restricted from using certain medications. Moreover, timely completion and reporting of information from transporter‐based PMRs/PMCs studies is critical to maximize the overall value and utility of this information 25 …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, timely completion and reporting of information from transporter-based PMRs/PMCs studies is critical to maximize the overall value and utility of this information. 25 The fulfillment of clinical PMRs/PMCs (n = 10) resulted in changes in labeling language issued in seven cases; in three cases, the recommendations were loosened (from avoid coadministration to either monitor for AEs or no dose adjustment (n = 2) and from monitor for AEs to no dose adjustment (n = 1)), whereas in the other four cases, the recommendation went from describing the in vitro findings with no associated action to dose adjustment and monitor for AEs recommendations. The fulfillment of all in vitro PMRs/PMCs lead to the same conclusion that the NME is not a substrate or inhibitor of transporters and hence no clinical studies were requested, and no restrictive labeling language was included.…”

Section: Articlementioning

confidence: 99%

Trends in FDA Transporter‐Based Post‐Marketing Requirements and Commitments Over the Last Decade

Younis

Manchandani

Hassan

et al. 2022

Clin Pharma and Therapeutics

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Characterizing interactions between new molecular entities (NMEs) and drug transporters is a critical element of drug development that helps in assessing potential transporter‐based drug–drug interactions (DDIs). However, not all NME new drug applications (NDAs) include a full characterization of NMEs transporter‐based DDIs, which necessitates the issuance of post‐marketing requirement (PMR)/post‐marketing commitment (PMC) by the US Food and Drug Administration (FDA) to characterize these potential interactions. The objective of this analysis is to identify trends in transporter‐based PMRs/PMCs issued by the FDA between 2012 and 2021. A decrease in the number of transporter‐based PMRs/PMCs was observed from 2012 to 2016 and an increasing trend in the number of PMRs/PMCs was observed after 2017. The majority of these transporter‐based PMRs/PMCs requested clinical evaluation (48%), some requested in vitro assessment (38%), and 2.5% requested modeling and simulation assessment. Most of the PMRs/PMCs requested evaluation of NMEs as perpetrator with the efflux transporters, P‐gp and/or BCRP (53%). Forty‐eight percent of the PMRs/PMCs were fulfilled with 67% resulted in labeling updates. On average, 2.5 years were needed for the information related to PMRs/PMCs to show in NMEs labeling. In conclusion, this analysis highlights the increased emphasis from the FDA on proper characterization of transporter‐based DDI and call for the need of early characterization of NMEs‐transporters interaction before initial NDA approval.

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New Drug Postmarketing Requirements and Commitments in the US: A Systematic Review of the Evidence

Cited by 10 publications

References 40 publications

Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016

Fulfillment of Postmarket Commitments and Requirements for New Drugs Approved by the FDA, 2013-2016

Comparing timelines and evidence available to support new TB, HIV, and HCV drug approvals: The same, only different

Trends in FDA Transporter‐Based Post‐Marketing Requirements and Commitments Over the Last Decade

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