The eliminator

Evidence use for product withdrawal is leaning toward observational research

With vaccination calls and medicine restrictions never far away from headlines, the spotlight is firmly on pharmacovigilance practices and decisions.

Before they get to market, drugs and medicines are subject to rigorous evaluation for their quality, safety and efficacy.

Years of work goes into ensuring the safety of each dose. Decisions to withdraw pharmaceuticals from the market are just as weighty and hinge on a thorough examination of all available evidence to strike a balance between benefits and risks.

Various sources contribute to this evidential landscape, including randomised controlled trials (RCTs), observational research and spontaneous reporting. However, the landscape has evolved over time, witnessing shifts in the prevalence of different types of evidence used in regulatory decision-making.

Since the early 2000s, the Drug Safety Research Unit has researched the types of evidence used in regulatory decisions for products withdrawn due to safety concerns in Europe.

We have discovered a diverse range of evidence supports such critical decisions, which is only increasing over time. Spontaneous reports and published case studies emerged as the bedrock, underpinning a significant majority of regulatory actions.

There is, however, a growing reliance on epidemiological and observational research, which involves research where investigators have no role in assigning which patients are exposed or unexposed.

Instead, investigators observe patients’ experiences in the real-world clinical practice setting instead of under the artificial conditions of a clinical trial.

Our research showed that in Europe between 1999 and 2016, 35 products were withdrawn for safety reasons.

91% of withdrawals were supported by spontaneous reports and/or published case reports or case series, 60% were supported by RCTs, 49% were supported by non-randomised trials and 40% were supported by observational studies. Meta-analyses contributed least frequently (31.4%).

The use of observational studies to support product withdrawals has increased considerably during the study period.

Between 1999 and 2001, it supported 17% of withdrawals, between 2002 and 2011, it supported 26% of withdrawals and by 2012 to 2016, 80% of withdrawals were supported by observational studies – cohort, case-control or other epidemiologic design.

These findings signify a promising trend towards a more comprehensive and diversified approach in regulatory decision-making, offering insightful perspectives on the interplay between evidence, regulatory measures and their direct impact on public health.

Observational studies, often overshadowed by the prominence of RCTs, which are seen as the gold standard of drug development, play a vital role in understanding the real-world effectiveness and safety of medicines and vaccines.

Observational studies can be more representative of the population that the drug will serve – they are larger in numbers and take place over a longer period of time. They also include many of the common ‘exclusions’ in RCTs, such as pregnant women, children, elderly people and patients on multiple medications.

Rather than viewing observational studies as competitors to RCTs, they should be seen as complementary. Breaking down silos and fostering an integrated approach to evidence-based decision-making is imperative for safeguarding public health.

The UK, with its robust NHS system, is poised to lead in observational studies. The comprehensive health records of more than 62 million people registered with GP practices in England, which follow them throughout their lives, offer a wealth of data for researchers.

These records facilitate various study designs, allowing researchers to compare exposure to medications with non-exposure periods within the same patient.

The detail of our medical records is also an advantage for observational researchers.  Information on demographics, prescribed medications, vaccine history, health screening, diagnosed conditions and potential confounders such as body mass index and ethnicity, are all logged in detail in our records.

Disease epidemiology studies can be conducted using anonymised health record data, looking at risk factors for disease and disease progression for example, as well as assessing drug utilisation patterns amongst exposed patients, including how and why drugs are prescribed and to whom.

All this information is available to researchers subject to the right approvals. Initiatives in the UK such as the Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN) and OpenSAFELY support UK, as well as European and international studies.

It is also possible to link to other databases for additional detail, including pregnancy records, hospital admissions and ONS death data.

Despite the prevailing perception of observational studies as secondary to RCTs, their advantages are becoming more recognised.

In 2012, an update to pharmacovigilance legislation aimed to produce more rapid regulatory decisions based on more robust data and our research supports this aim.

To continue this trend into the future, it is important that infrastructure is developed to allow for background data, including background incidence of events in the population, to be available as they are needed.

Part of this infrastructure may be technological advancements, or international networks of databases with planned structure and processes in place to allow for rapid production and earlier delivery of epidemiological results.

Additionally, methods to analyse and synthesise multiple sources of data should be progressed, including statistical techniques for observational studies and the use of ‘living’ designs to continually update the evidence produced by studies such as systematic review or benefit/risk assessments.

Interim reports at periodic and planned points during the study process should also be built in when designing a study, ensuring that results are shared with key stakeholders in a timely manner.

Work from the International Working Group (IWG) on New Developments in Pharmacovigilance – a consortium of international experts in pharmacovigilance founded and coordinated by the Drug Safety Research Unit – aims to support this even further.

The IWG has recognised that there is a lack of readily accessible guidance resource to aid in the selection of the most appropriate data source for the pharmacovigilance activity, such as appropriate data sources to study the impact of adverse drug events on patients.

Given the multitude of data sources in pharmacovigilance, the IWG aims to create a guidance document that aids in the selection of the most appropriate data sources for specific pharmacovigilance activities.

This initiative will contribute to the field by summarising the strengths, weaknesses and risk of bias associated with each data source.

A scoping review is being undertaken to identify and evaluate appropriate data sources for discrete pharmacovigilance activities, for example signal detection, signal evaluation including quantification of the magnitude of the risk and impact analysis of regulatory decision-making, and will suggest appropriate data sources available to use in these activities.

We will also be speaking to members of the pharmacovigilance community from industry, academia and regulatory agencies to determine types of data sources that are accessible and used in their daily activities.

Ultimately this project will provide a single reference document, enabling end users to select the optimal data sources for their specific pharmacovigilance activity.

Our extensive research on data sources underscores the necessity of a holistic approach to evidence utilisation in regulatory decisions and our work with the IWG will enhance that activity.

Embracing a web of complementary evidence, rather than pitting different types against each other, holds the promise of better-informed decisions for the benefit of all.

Samantha Lane is Head of Research at the Drug Safety Research Unit Centre for Pharmacovigilance Sciences. dsru.org