How can the EBM methodology support drug recalls?

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In this article, Samantha Lane from the UK Medicines Safety Research Unit discusses the development of evidence-based medicine (EBM) methodology to assess the positive impact of withdrawing or revoking medicines licenses on public health. The approach relies on electronic health records to model the estimated number of adverse effects averted by removing drugs from the market and aims to help regulators make these decisions in the future.

Withdrawing drugs for safety reasons requires careful analysis of health benefits and risks by regulatory agencies.1 But while adverse reaction data is rightly used to help with these decisions, there is currently no additional modeling of the positive impact regulatory action could have on public health.

Our research paper, which is submitted for publication this summer, aims to create an evidence-based medicine (EBM) methodology that can assess this positive impact, to further assist regulators in determining appropriate risk minimization measures.

Support regulators

Monitoring and studying the side effects of approved drugs is an essential part of drug development to ensure public safety. Known as pharmacovigilance, our epidemiological research records and investigates adverse drug reactions when drugs are used by the general public. This usually occurs on a much larger scale than is possible in clinical trials and may reveal less common side effects.2

3D illustration of a benefit versus risk matrix with pills and tablets positioned on it

National regulators use pharmacovigilance research to decide whether risk minimization measures should be imposed. The most severe measures are the temporary or permanent withdrawal of products.3

To help with decisions about potential product withdrawals, we set out to develop a new EBM methodology to show the positive impact this could have; with quantifiable modeling of the estimated number of adverse effects that would be avoided if a specific drug were withdrawn from use.

Purpose of the study

Our research looked at products that were voluntarily withdrawn, or whose license was revoked or suspended in the EU for safety reasons between 2012 and 2016. It focused on data from France , Germany and the United Kingdom.

Six products were withdrawn or revoked for safety reasons during the study period.

The drugs withdrawn were:

  • meprobamate – a sedative used to treat anxiety
  • nicotinic acid/laropiprant – used to lower cholesterol
  • almitrine – a respiratory stimulant
  • calcitonin – able to control calcium levels, it was used for conditions such as osteoporosis.

The medications revoked were:

  • certain formulations of metoclopramide – an anti-disease drug
  • certain formulations of domperidone – used to prevent nausea and nausea.

Three products have been suspended:

  • cyproterone acetate/ethinylestradiol (Diane-35 and generics) – birth control
  • tetrazepam – a muscle relaxant
  • ketoconazole – an antifungal drug.

Actual data and results

Pharmaceutical development/industry concept

Actual data was collected from the IQVIA Medical Research Data (IMRD) electronic health record (eHR) databases for France, Germany and the United Kingdom to determine how many patients were using each drug during 12 months before and after the regulatory action. An estimate of the number of people exposed to the drug each year before withdrawal or suspension was calculated.

Next, records from the European Medicines Agency (EMA) were used to identify adverse drug reactions, and a systematic review was performed to quantify the risk of adverse reactions in patients exposed to each withdrawn drug.

The types of adverse effects examined included low blood pressure, diabetes, cancer, bleeding, involuntary movements and weight loss.

An absolute risk for each withdrawn drug was calculated using the published literature. This risk, expressed as a percentage of people using the medicine, was based on the estimated annual number of people exposed and the number of adverse effects.

An estimate of the number of side effects stop following each product withdrawal, revocation or suspension was also calculated based on exposure and absolute risk figures. The total was estimated at 3,020 per year.

Limits

There were, of course, limitations to the study. Specifically, we found that the use of withdrawn drugs did not always drop to zero within 12 months of regulatory action. This could be because other dosages and formulations that remained on the market were misclassified. In the case of meprobamate, an anti-anxiety drug, we know that it was phased out over the study period. During this time, some suspended drugs have been put back on the market.

The dataset for Germany included drug exposures in secondary care (inpatients), but this was not available for the France and UK databases. Therefore, it is possible that exposure estimates in France and the UK are less precise and that the public health impact of drug withdrawals and suspensions in these populations has been underestimated.

Likewise, the data we used does not record over-the-counter medications used by patients, which could impact the results. Although pooling data from different sources, in line with our methodology for calculating the absolute risk of each event, is not always appropriate.

Wider benefits and future research

Pharmacovigilance measures are never imposed lightly. But quantifiable evidence of the expected positive impact of regulatory measures on public health will help regulators make those decisions.

One of the main advantages of our research is that the new EBM methodology can be applied to any other drug whose use can be measured. It can be used with any database where exposure can be estimated and results can be stratified by demographics and patient subgroups, such as the elderly, if the data permits.

Pharmacovigilance measures are never imposed lightly. But quantifiable evidence of the expected positive impact of regulatory action on public health will help regulators make those decisions in the future.

This is one of several ongoing studies within the UK’s Independent Medicines Safety Research Unit (DSRU) that are examining new methodologies to quantify the impact of pharmacovigilance measures. We plan to expand our research to examine the impact of other marketing authorization restrictions, such as limiting use to specific age groups, and the public health impact of people switching to alternative medicines when their current treatment is withdrawn.

Our research was conducted under the auspices of the DSRU Institute of Pharmacovigilance Sciences and the European Network of Centers for Pharmacoepidemiology and Pharmacovigilance (ENCePP).

The DSRU institute focuses on research on EBM methodology, including the expansion of existing benefit-risk assessment methods, as well as the development of new methods, such as the application of artificial intelligence in the pharmacovigilance. Researchers also study the long-term effects of drugs and vaccines, as well as the safety of new and advanced products.

About the Author

Samantha Lane is a Senior Research Fellow and Pharmacoepidemiologist at the Drug Safety Research Unit (DSRU), where she is primarily involved in methodological research within the Institute for Pharmacovigilance Sciences. Samantha often assists with study design and statistical analysis, and has experience with the CPRD electronic health record database. She has a background in biomedical sciences and trained in epidemiology, obtained an MSc from the London School of Hygiene & Tropical Medicine (LSHTM) and holds a PhD in pharmacovigilance.

References

  1. Pharmacovigilance – how the MHRA monitors the safety of medicines [Internet]. MHRA; [cited June 2022]. Available at: https://assets.publishing.service.gov.uk/government/…
  2. Boyko E. Observational research – opportunities and limitations. Journal of diabetes and its complications. 2013;27(6):642-648.
  3. The Human Medicines Regulations 2012, UK Regulatory Instruments, 2012 No 1916, PART 5, Revocation, Variation and Suspension of Marketing Authorisation. Available at: https://www.legislation.gov.uk/uksi/2012/1916/part/5/crossheading…

Related drugs

Almitrine, calcitonin, cyproterone, domperidone, ethinylestradiol, ketoconazole, laropiprant, meprobamate, metoclopramide, nicotinic acid, tetrazepam

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