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Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies.

ABSTRACT: Information on rare adverse effects is often limited when a medication is initially approved for marketing. Medicines regulators use safety advisories to warn health professionals and consumers about emerging harms. This study aimed to identify characteristics and advice provided in cardiac safety advisories released by regulators in Australia, Canada, the United Kingdom, and the United States. This was a retrospective study of safety advisories about cardiac-related adverse events issued by these four international medicines regulators between 2010 and 2016. A descriptive overview was followed by a more detailed content analysis, focusing on recommended actions for health professionals, including monitoring advice. For the latter, we applied the systematic information for monitoring (SIM) scale to assess adequacy. Over this period, 164 safety advisories about cardiac harms were issued by the four regulators. There were 61 drugs with advisories of cardiac risk, only 9 (14.7%) of which had advisories from all regulators in countries where the drug was approved. The most common adverse events were cardiac arrhythmias (n = 97, 59.1%) and coronary artery disorders (n = 39, 23.8%). The most frequent advice to prescribers was to monitor patients (n = 74, 45.1%), although only 41.2% of these advisories provided detailed advice on how monitoring should occur. We found many differences in the decision to warn and the advice provided. Patient monitoring was most often recommended, but key information such as frequency or thresholds for action was often lacking. Healthcare professionals and consumers need consistent information about rare serious harms so that they can make informed decisions.

SUBMITTER: Hooimeyer A

PROVIDER: S-EPMC7652786 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies.

Hooimeyer Ashleigh A Bhasale Alice A Perry Lucy L Fabbri Alice A Mohammad Annim A McEwin Eliza E Mintzes Barbara B

Pharmacology research & perspectives 20201201 6

Information on rare adverse effects is often limited when a medication is initially approved for marketing. Medicines regulators use safety advisories to warn health professionals and consumers about emerging harms. This study aimed to identify characteristics and advice provided in cardiac safety advisories released by regulators in Australia, Canada, the United Kingdom, and the United States. This was a retrospective study of safety advisories about cardiac-related adverse events issued by the ...[more]

PMID: 33169534

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Project description: To investigate the practice of post-marketing studies in Germany during a three year period and to evaluate whether these trials meet the aims specified in the German Medicinal Products Act. Survey of notifications submitted to German regulatory agencies before post-marketing studies were carried out, 2008-10. Notifications obtained through freedom of information requests to the three authorities responsible for registering post-marketing studies in Germany. Descriptive statistics of post-marketing studies, including the products under study, intended number of patients, intended number of participating physicians, proposed remunerations, study plan and protocol, and availability of associated scientific publications and reports on adverse drug reactions. Information was obtained from 558 studies, with a median of 600 (mean 2331, range 2-75?000) patients and 63 (270, 0-7000) participating physicians per study. The median remuneration to physicians per patient was €200 (€441, €0-€7280) (£170, £0-£6200; $215, $0-$7820), with a total remuneration cost of more than €217m for 558 studies registered over the three year period. The median remuneration per participating physician per study was €2000 (mean €19?424), ranging from €0 to €2?080?000. There was a broad range of drugs and non-drug products, of which only a third represented recently approved drugs. In many notifications, data, information, and results were, by contract, strictly confidential and the sole property of the respective sponsor. No single adverse drug reaction report could be identified from any of the 558 post-marketing studies. Less than 1% of studies could be verified as published in scientific journals. Post-marketing studies are not improving drug safety surveillance. Sample sizes are generally too small to allow the detection of rare adverse drug reactions, and many participating physicians are strictly obliged to maintain confidentiality towards the sponsor. High remuneration and strict confidentiality clauses in these studies could influence the physicians' reporting behaviours of adverse drug reactions.

Project description:There are currently four anti-cancer medicinal products approved for a tissue-agnostic indication. This is an indication based on a common biological characteristic rather than the tissue of origin. To date, the regulatory experience with tissue-agnostic approvals is limited. Therefore, we compared decision-making aspects of the first tissue-agnostic approvals between the Food and Drug Administration (FDA), European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (PMDA). Post-marketing measures (PMMs) related to the tissue-agnostic indication were of specific interest. The main data source was the publicly available review documents. The following data were collected: submission date, approval date, clinical trials and datasets, and PMMs. At the time of data collection, the FDA and PMDA approved pembrolizumab, larotrectinib, and entrectinib for a tissue-agnostic indication, while the EMA approved larotrectinib and entrectinib for a tissue-agnostic indication. There were differences in analysis sets (integrated vs. non-integrated), submission dates and requests for data updates between agencies. All agencies had outstanding issues that needed to be addressed in the post-market setting. For pembrolizumab, larotrectinib and entrectinib, the number of imposed PMMs varied between one and eight, with the FDA requesting the most PMMs compared to the other two agencies. All agencies requested at least one PMM per approval to address the remaining uncertainties related to the tissue-agnostic indication. The FDA and EMA requested data from ongoing and proposed trials, while the PMDA requested data from use-result surveys. Confirmation of benefit in the post-marketing setting is an important aspect of tissue-agnostic approvals, regardless of agency. Nonetheless, each approach to confirm benefit has its inherent limitations. Post-marketing data will be essential for the regulatory and clinical decisions-making of medicinal products with a tissue-agnostic indication.

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Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies.

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Regulatory post-market drug safety advisories on cardiac harm: A comparison of four national regulatory agencies.

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