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Monitoring literature for Benefit-Risk Evaluation: a Life-Time Responsibility

Posted on January 15th, 2016 by in Pharmacovigilance

Medical Literature

Monitoring worldwide experience

The purpose of drugs is to cure or alleviate symptoms of disease. However, drugs do not only have therapeutic effects, they may also cause adverse drug reactions (ADRs). ADRs can be very common (e.g., minor symptoms like headache and nausea), as well as very rare and severe, such as anaphylactic reactions and liver failure.

When a Marketing Authorisation Holder (MAH) applies for marketing authorisation of a product, they are required to review the worldwide experience with the medicinal product in the period between the submission of the authorisation application and the granting of it.

The worldwide experience includes monitoring published scientific and medical literature. During this literature screening, information that may influence the benefit-risk assessment of the product under evaluation for marketing authorisation may be identified.

When the marketing authorisation application is approved by the regulatory authorities, the benefit-risk balance for the approved indications and the target population is assumed positive.

However, one may wonder whether this is actually true for all new drugs. It’s generally accepted that the available safety information of a drug is limited at the moment it’s approved for marketing. Due to restrictions of clinical trials, the benefits and risks of a newly approved drug may not apply to patients using it in real life situations.1

Restrictions of clinical trials:

  • Only a limited number of patients are exposed
  • Patients are only exposed for a relatively short time of period
  • Certain groups of patients (women, children, elderly, high risk patients) are often excluded from clinical trials
  • Statistical limitations

There may be specific patients for whom the specific risks are increased compared to the risk determined during the clinical trial, for which the beneficial effects are less clear.

Not all real risks will be clear at the time a drug first enters the market either. Every drug has multiple risks associated with it, and the individual risks will vary in terms of severity, effect on individual patients and public health impact.

Many of these risks will only be discovered and identified once the drug is being used in real life population.

For example, in daily practice, a drug will be used not only for the approved indications but also for all kinds of off-label indications. And, as recently described, off-label drug use is associated with a raised risk of adverse events.2

Reviewing literature for information about use, during every day use, such as information about long-term use, off-label use, lack of effectiveness, misuse or abuse, and information about use by specific patient groups (i.e., elderly, children, pregnant or breastfeeding women) is one of the pillars of the periodic benefit-risk evaluations.

Systematic review

Benefit-risk evaluations are a life-long responsibility. FDA Adverse Event Reporting (FAERS) Quarterly Data show that scientific literature is the 4th largest source of ADRs.3 Therefore, monitoring literature for ADRs is highly relevant to improve patient safety (see the recent Pharma R&D Today blog post on the role of screening scientific literature for ADRs).

However, sometimes single studies are too limited to provide a clear picture of the benefit-risk balance of the product. Combining results from multiple relevant studies may be able to give a better idea of the benefit-risk balance.

This relevant information can be obtained from review articles, meta-analyses, observational studies, epidemiologic studies, etc. In particular, epidemiologic studies are important when detecting ADRs that are not-detectable within spontaneous reporting systems for adverse drug reactions. For this reason, MAHs need to perform a systematic review of scientific and medical literature as part of the benefit-risk evaluation of their drugs. Systematic literature reviews result in a more reliable benefit-risk profile and may improve the quality of evidence-based decision making in drug safety.

In summary

Evaluating the benefits and risks of a medicine after marketing is a complicated process because it involves reviewing a large amount of data from different sources. It may include investigating the benefits and risks of a drug in patients, and circumstances that were not part of the pre-authorization clinical trials.

Still, there will always be some uncertainty about the actual benefits and risks of a medicine because they can only be determined by looking at the information that is available at a given point in time. Therefore, it is inevitable that monitoring the benefit-risk balance of a drug is necessary during the whole product life-cycle and requires planning. And, depending on the results of the benefit-risk monitoring, MAHs might need to implement additional risk minimization measures and assess the effectiveness of these measures over time.


  1. Harpaz R et al. Novel datamining methodologies for adverse drug event discovery and analysis. Clin Pharmacol Ther 2012; 91(3):1010-21
  2. McCarthy M. Off- label drug use is associated with raised risk of adverse events. BMJ (online) 351 article number h5861

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