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The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.

ABSTRACT: We characterized the size of the premarket safety population for 278 small-molecule new molecular entities (NMEs) and 61 new therapeutic biologics (NTBs) approved by the US Food and Drug Administration (FDA) between October 1, 2002, and December 31, 2014, evaluating the relationship of premarket safety population size to regulatory characteristics and postmarket safety outcomes. The median size of the safety population was 1,044, and was lower for NTBs than NMEs (median: 920 vs. 1,138, P = 0.04), orphan products than nonorphan products (393 vs. 1,606, P < 0.001), and for products with fast-track designation (617 vs. 1,455, P < 0.001), priority review (630 vs. 1,735, P < 0.001), and accelerated approval (475 vs. 1,164, P < 0.001), than products without that designation. The median number of postmarket safety label updates and issues added to the label were higher with larger premarket exposure among nonorphan products, but not among orphan products. Products with accelerated approval using a surrogate end point had a higher median number of safety issues added to the label than those with full approval, but this did not vary with the size of the safety population; fast-track and priority review were not associated with the number of safety issues added to the label. A smaller safety population size was associated with a longer time to first safety outcome for nonorphan products but not orphan products. For orphan and nonorphan products combined, smaller premarket safety population size is not associated with the number or timing of postmarket safety outcomes, regardless of expedited program participation.

SUBMITTER: Cherkaoui S

PROVIDER: S-EPMC8595500 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.

Cherkaoui Sanae S Pinnow Ellen E Bulatao Ilynn I Day Brendan B Kalaria Manish M Brajovic Sonja S Dal Pan Gerald G

Clinical pharmacology and therapeutics 20210708 6

We characterized the size of the premarket safety population for 278 small-molecule new molecular entities (NMEs) and 61 new therapeutic biologics (NTBs) approved by the US Food and Drug Administration (FDA) between October 1, 2002, and December 31, 2014, evaluating the relationship of premarket safety population size to regulatory characteristics and postmarket safety outcomes. The median size of the safety population was 1,044, and was lower for NTBs than NMEs (median: 920 vs. 1,138, P = 0.04) ...[more]

PMID: 34057195

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Project description:ObjectivesTo compare the premarket and postmarket evidence of safety and efficacy of direct oral anticoagulants approved for stroke prevention in atrial fibrillation patients across four major regulatory agencies.DesignCross-sectional.SettingEuropean Medicines Association (EMA), US Food and Drug Administration (FDA), Health Canada and Australian Therapeutic Goods Administration (TGA).ParticipantsApixaban, dabigatran, edoxaban and rivaroxaban marketing authorisations.Outcome measuresConcordance among regulatory agencies with respect to (1) premarket evidence used to establish efficacy and safety and (2) postmarket safety boxed warnings and postmarketing study requirements.ResultsApixaban, dabigatran and rivaroxaban were approved by each of the four regulatory agencies; edoxaban was only not approved by TGA. For premarket efficacy evidence, there was concordance across all agencies in terms of phase 3 trials for three (75%) drugs, sample size for three (75%) drugs, primary endpoints for four (100%) drugs, numerical results for three (75%) drugs, agency interpretation of results for four (100%) drugs and number of phase 2 trials for three (75%) drugs. For the premarket safety evidence, there was concordance across all agencies in terms of phase 3 trials for three (75%) drugs, sample size for two (50%) drugs, primary endpoints for four (100%) drugs, numerical results for three (75%) drugs, agency interpretation of results for three (75%) drugs and number of phase 2 trials for zero (0%) drugs. For postmarket safety information, FDA was the only agency that issued boxed warnings (for three (75%) drugs). Additionally, EMA and TGA required postmarketing studies (for four (100%) and two (50%) drugs, respectively), while FDA and Health Canada did not have any postmarketing requirements.ConclusionsThere was a high degree of concordance in the phase 3 trial premarket evidence used to establish efficacy and safety of direct oral anticoagulant approvals across four major regulatory agencies, but discordance in the phase 2 trial premarket evidence used, as well as in postmarket safety boxed warnings and postmarketing study requirements. These discrepancies highlight opportunities for further harmonisation in the evaluation and regulation of medical products globally.

Project description:IntroductionLong-term anticoagulation therapy using vitamin K antagonists (VKA) is used in millions of patients worldwide to reduce the risk of thrombotic or thromboembolic events. Control and monitoring of VKA therapy is improved by the regular self-measurement of international normalized ratio (INR) using a home monitoring device. This retrospective analysis of a large cohort of patients in the Netherlands seeks to determine whether the choice of INR monitor could have a clinical impact on patient outcomes.MethodsThe National Thrombosis Service provides medical supervision, training and support to anticoagulant patients eligible for home-monitoring of INR in the Netherlands. Two INR monitors (CoaguChek XS and INRatio2) have been distributed at random to patients since June 2011, and patient self-testing data (INR measurements and other clinical parameters) have been recorded to measure and improve treatment outcomes. The data have been retrospectively analyzed to determine any effect of the choice of monitor. Univariate and multivariate statistical tests are used to assess any differences between groups in terms of efficacy and safety parameters.ResultsData from 4,326 patients were collated, and 156,507 INR values were included in the analysis. Over half the patients (54.3%) were being treated for atrial fibrillation, and 77.6% were prescribed acenocoumarol. There were few differences between the patient populations using the two different monitors. Anticoagulant control overall was good, with high percentage of time (87.9%) in the appropriate INR range and low incidence of excessively high or low INR values (0.085/month). Minor clinical events related to safety were low (0.78 per patient-year) and showed few differences between monitors. Mortality rates were similar [hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.65-1.70].ConclusionSelf-testing data from a large cohort of patients in the Netherlands suggest that there is no clinically relevant effect of the choice of coagulation monitor (CoaguChek XS or INRatio2) on the time in therapeutic range (TTR), minor or fatal outcomes of long-term anticoagulation management.

Project description:BackgroundClinical quality registries (CQRs) are playing an increasingly important role in improving health outcomes and reducing health care costs. CQRs are established with the purpose of monitoring quality of care, providing feedback, benchmarking performance, describing pattern of treatment, reducing variation and as a tool for conducting research.ObjectivesTo synthesise the impact of clinical quality registries (CQRs) as an 'intervention' on (I) mortality/survival; (II) measures of outcome that reflect a process or outcome of health care; (III) health care utilisation; and (IV) healthcare-related costs.MethodsThe following electronic databases were searched: MEDLINE, EMBASE, CENTRAL, CINAHL and Google Scholar. In addition, a review of the grey literature and a reference check of citations and reference lists within articles was undertaken to identify relevant studies in English covering the period January 1980 to December 2016. The PRISMA-P methodology, checklist and standard search strategy using pre-defined inclusion and exclusion criteria and structured data extraction tools were used. Data on study design and methods, participant characteristics attributes of included registries and impact of the registry on outcome measures and/or processes of care were extracted.ResultsWe identified 30102 abstracts from which 75 full text articles were assessed and finally 17 articles were selected for synthesis. Out of 17 studies, six focused on diabetes care, two on cardiac diseases, two on lung diseases and others on organ transplantations, rheumatoid arthritis, ulcer healing, surgical complications and kidney disease. The majority of studies were "before after" design (#11) followed by cohort design (#2), randomised controlled trial (#2), experimental non randomised study and one cross sectional comparison. The measures of impact of registries were multifarious and included change in processes of care, quality of care, treatment outcomes, adherence to guidelines and survival. Sixteen of 17 studies demonstrated positive findings in their outcomes after implementation of the registry.ConclusionsDespite the large number of published articles using data derived from CQRs, few have rigorously evaluated the impact of the registry as an intervention on improving health outcomes. Those that have evaluated this impact have mostly found a positive impact on healthcare processes and outcomes.Trial registrationPROSPERO CRD42015017319.

Dataset Information

The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.

Publications

The Impact of Variability in Patient Exposure During Premarket Clinical Development on Postmarket Safety Outcomes.

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