The World Health Organisation (WHO) defines pharmacovigilance (PV) as “the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problems”.
Therefore PV plans are required for studies that are collecting any adverse drug reaction data. If required, these plans should be developed by the investigators or sponsor, whichever is appropriate, and ideally discussed with regulators during protocol development or prior to regulatory approval.
Pharmacovigilance usually applies to an entire development plan, rather than a single research protocol. However there may be circumstances where a PV plan is required for a single study.
The purpose of this document is to explain PV and describe how a plan can be implemented in a whole programme, or a single study.
Purpose of a pharmacovigilance plan
The purpose of a pharmacovigilance plan is to protect the public from medicine-related harm. It achieves this through efficient and timely identification, collection, and assessment of adverse events/reactions.
Such data is required before a new product is registered, but also important for ongoing safety monitoring for rare events and for using existing products for new indications in specific populations, such as in pregnancy, the elderly or renal impairment.
The decision to approve a drug is based on its having a satisfactory risk/benefit ratio which in turn is dependent on the information available at the time of approval. This risk /benefit profile will obviously change over time and it is important that the risks are reviewed on an ongoing basis, in consultation with the regulatory authorities.
Therefore whilst a pharmacovigilance plan is usually developed at the start of a product life cycle, a plan can also be developed for products already on the market e.g., new indication or major new safety concern.
Safety specification plan
It might be beneficial to set out a safety specification plan. For example, this is required by the EU, but it is a helpful process that can be used elsewhere. Such a plan could include the following component and different regulators in other regions may have a recommended pre-defined structure:
This section will have non-clinical safety findings that have not been adequately addressed by clinical data such as:
- Toxicity (including repeat-dose toxicity, reproductive/developmental toxicity,
- nephrotoxicity, hepatotoxicity, genotoxicity, carcinogenicity etc.)
- General pharmacology (cardiovascular, including QT interval prolongation; nervous system; etc.)
- Drug interactions
- Other toxicity-related information or data.
The clinical data should include any limitation to the safety database such as the size of the study population, study inclusion/exclusion criteria and the implications of such limitations with respect to predicting the safety of the product. It should also include populations that have not been studied or have been studied to a limited degree. Populations to be considered should include but not limited to children, the elderly, pregnant or lactating women, patients with relevant co-morbidity such as hepatic or renal disorders, patients with disease severity different from that studied in clinical trials, sub-populations carrying known and relevant genetic polymorphism, patients of different racial and/or ethnic origins
Adverse Events (AEs) / Adverse Drug Reaction (ADRs)
The important AEs/ADRs identified for the product should captured here and are usually grouped under 2 main categories namely:
o Identified risks that require further evaluation - They are the most important identified AEs/ADRs, as well as serious or frequently occurring events that might have an impact on the balance of benefits and risks or having an influence on causal relationship, severity, seriousness, frequency, reversibility and at-risk groups.
o Potential risks that require further evaluation and the evidence that led to the conclusion should be documented separately. For any important potential risk, there should be further evaluation to characterise the association.
Other safety specification considerations include identified and potential interactions, including food-drug and drug-drug interactions. The evidence supporting the interaction and possible mechanism should be summarised, as well as the potential health risks and the different populations affected.
Also, the epidemiology of the indication(s) should be stated as well as the incidence, prevalence, mortality and relevant co-morbidity. It should take into account whenever possible stratification by age, sex, and racial and/or ethnic origin.
Structure of the pharmacovigilance plan
The structure of the pharmacovigilance plan can vary depending on the product in question and the issues identified in the safety specification. The plan should include:
Routine pharmacovigilance practices
This should be conducted for all medicinal products, regardless of whether or not additional actions are appropriate and should comprise of the following:
- Systems and processes to ensure that all suspected adverse reactions are collected and collated in an accessible manner
- Regulatory reports should include expedited adverse drug reaction (ADR) reports and Periodic Safety Update Reports (PSURs)
- Continuous monitoring of approved products including signal detection, issue evaluation, updating of labelling, and liaison with regulatory authorities
- Other requirements, as defined by local regulations.
Action plan for each important safety issue should be presented and justified.
Summary of actions to be completed, including milestones
The milestones for completion of studies, any additional evaluations and the submission of safety results should be included in the Pharmacovigilance Plan. Also, exposure to the product should have reached a level sufficient to allow potential identification and characterisation or resolution of the AEs/ADRs of concern or when the proposed safety studies are expected to be available.
In order for sponsors to fulfil their responsibility in characterising and reporting all safety data they will need to rely on clinicians to carefully assess causal relationship and promptly report safety events. This is not only limited to clinical studies but also reporting events post approval where majority of rare adverse events are most likely to be picked up. The effectiveness of the plan is therefore wholly dependent on all parties working together to ensure that regulators have all the necessary safety data to make a decision on whether potential drugs are safe for use.
You can find many more resources on Global Pharmacovigilance.
European Medicines Agency “Note for Guidance on Planning Pharmacovigilance Activities - (CPMP/ICH/5716/03) Dec 2004
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