Introduction to risk management
Medicinal products are authorised for use on the basis that, at the time of authorisation, the risk-benefit balance is judged to be positive for the target population in the specified indication(s)2. However, although during development associated adverse reactions may be identified for the medicinal product, not all adverse reactions and risks will have been identified at the time of the initial marketing authorisation grant. Limited information on a product’s adverse reactions may be due to many factors including small numbers of subjects in clinical trials, restricted population in terms of age, gender and ethnicity, restricted co-morbidities, restricted co-medications and potentially relatively short duration of exposure and follow up2.
The aim of the risk management plan (RMP) is to document the risk management system required to identify and characterise the product’s important risks and to minimise those where possible. As knowledge of the safety profile of the medicinal product increases, the RMP is updated throughout the product’s life cycle and is therefore considered a ‘living’ document.
In the European Union (EU), companies must submit an RMP to the European Medicines Agency (EMA) at the time of marketing authorisation (MA) application. For medicines that do not have an RMP in place, any significant changes to the marketing authorisation may result in the need for an RMP upon application2.
Although RMPs are required at the point of MA application, pharmaceutical companies may monitor the benefit-risk balance during the development of a medicinal product. Developmental risk management plans (DRMPs) are not a requirement prior to an application for an MA but are a useful tool for achieving the best benefit-risk balance in the long term. They are a ‘living’ document that can be updated and re-evaluated with each significant safety finding, such as pre-clinical and clinical studies and all interim safety findings.
High quality pharmacovigilance is an essential part of clinical programs and thus the creation of a formal DRMP can provide early documentation of known, anticipated or potential risks as well as documenting plans for addressing them during the development of the medicinal product3. If appropriate, the DRMP would eventually evolve into the post-marketing RMP as part of the MA application. The DRMP should be specific to the particular compound or medicinal product in development and can form a section of the overall Clinical Development Plan.
It should be noted that although the DRMP is a guide for safety surveillance during development and is not intended to be a legal or regulatory document, it may be subject to legal discovery. Therefore, it may be necessary to consult the legal department to ensure appropriate language is used to state the DRMP is a working document. In addition, companies should ensure that any action plans within the DRMP are actioned appropriately.
Discussion of DRMPs
The CIOMS VII Working Group focuses on the harmonisation of periodic safety reporting during clinical trials and defines the DRMP as:
‘A plan to conduct activities relating to the detection, assessment, understanding, reporting and prevention of adverse effects of medicines during clinical trials. This plan should be initiated early and modified as necessary throughout the development process for a new drug or drug-use.’
The CIOMS VII Working Group additionally recommends that the DRMP is aligned with the developmental safety update reports (DSUR), including the summary of important risks. Therefore, a minimum of one annual update is recommended in line with the product’s DSUR4.
The CIOMS VI Working Group focuses on the management of clinical trial information ranging from the earliest clinicals trials to the post-marketing environment and states within their guidance that the minimum a DRMP should include is4:
Is a DRMP required?
Although DRMPs are a useful tool for monitoring risk management in the early stages of the drug development cycle, there are a number of factors to think about when considering the need for such a document.
There is potential for overlap of information in the DRMP with other documents such as DSURs, Investigator’s Brochures, Clinical Development Plans and any other periodic updates prepared for investigators or ethic committees. Therefore, companies or sponsors may feel that another plan may be a burden, or the risk management of the product is well covered already between these existing documents. However, the CIOMS VII Working Group note that whilst periodic reports such as DSURs are not meant to serve as a formal benefit-risk assessment of the product, the overall evaluation and conclusions can be directly linked to an RMP4. Additionally, a DRMP is a living document that is continually updated and therefore provides timely and accurate information as opposed to a periodic report such as an annual DSUR.
The DRMP should be viewed as a valuable tool that can streamline the management of safety data and will allow the development of an RMP that is robust and well tested at the time of MA application. Ultimately, the use of DRMPs will very much depend on company’s and sponsor’s appreciation of their benefits weighed against costs and other factors such as their regulatory strategy.
DRMPs are not a requirement but according to current EU legislation, an RMP must be submitted at the time of MA application. Using the current EU RMP template for the DRMP will allow a smooth transition from developmental to an EU RMP document at time of submission.
DRMPs allow for focus on the identified and potential risks which is especially important for new products where risks are not well characterised to begin with. This approach allows for streamlined decision making based on emerging safety data.
Panacea can help with risk evaluation and management at all stages of product development including both DRMPs and EU RMPs.