Risk minimisation measures aim to optimise the safe and effective use of a medicinal product throughout its life cycle.
The majority of safety concerns are addressed by routine risk minimisation measures, which include utilising tools such as the summary of product characteristics (SmPC), the package leaflet and the legal (prescription) status of the product. Exceptionally, for selected important risks, routine risk minimisation may be considered insufficient and additional risk minimisation measures (aRMMs) may be deemed to be necessary. These additional measures can come in several forms, including educational programmes, controlled access programmes, pregnancy prevention programmes and direct healthcare professional communication (DHPC).
Risk management is an evolving field and the design, implementation and evaluation of risk minimisation measures should be proportionate, feasible and should not place undue burden on the healthcare system. New tools and initiatives are likely to be developed in the future, and there is recent precedent for marketing authorisation holders (MAHs) working in collaboration to develop and communicate harmonised educational materials to healthcare professionals and patients, in instances where the MAHs hold licences for the same active substance or combination of active substances. Hereafter, these are termed ‘work-sharing initiatives’.
Work-sharing initiatives will differ in their design. In some instances the MAHs within the work-sharing consortium may utilise the services of a third-party service provider, such as a trade association or a specialist contractor. Alternatively, one organisation (for example, the MAH of the innovator product) may be assigned the role of “lead MAH” to coordinate all aspects of the educational programme on behalf of all MAHs within the consortium. Irrespective of the design of the work-sharing initiative, each individual MAH retains legal responsibility to operate a risk management system for its authorised medicinal products (Directive 2001/83/EC as amended, Article 104(3)(c)). The purpose of this blog is to outline the expectations of the MHRA GPvP Inspectorate with regards to the responsibilities of MAHs participating in work-sharing initiatives for aRMMs.
For each work-sharing initiative a signed contract(s) should be in place to describe the arrangements for delegation and the responsibilities of each party. Where records associated with aRMMs are held solely by a third-party, there should be appropriate contractual language to ensure the timely provision of such records to individual MAHs on demand for the purposes of audit and inspection. Examples of such records include the current approved version of the educational materials, approved communication plans and evidence of communication of the materials in accordance with the approved communication plan. The contract should also include provision for audit of third-parties.
GVP Module I – Pharmacovigilance systems and their quality systems
I.C.1.5 “The marketing authorisation holder may subcontract certain activities of the pharmacovigilance system to third parties […] The ultimate responsibility for the fulfilment of all pharmacovigilance tasks and responsibilities and the quality and integrity of the pharmacovigilance system always remains with the marketing authorisation holder. […] When subcontracting tasks to another organisation, the marketing authorisation holder shall draw up subcontracts [IR Art 6(2)] and these should be detailed, up-to-date and clearly document the contractual arrangements between the marketing authorisation holder and the other organisation, describing arrangements for delegation and the responsibilities of each party.”
GVP Module XVI – Risk minimisation measures
XVI.B.6 “These records, the RMP and the associated risk management systems, as well as any documents on risk minimisation measures may be subject to audit or inspection.”
When pharmacovigilance tasks are delegated to a third-party, it is expected that there is a mechanism of oversight by the individual MAHs. This could be achieved in a number of ways and could be outlined in the associated contract(s). Examples include:
- Periodic reporting on the fulfilment of activities by the third-party, along with associated evidence demonstrating that aRMMs have been communicated in accordance with the approved plan.
- Written confirmation that the third-party to whom activities have been delegated has a quality system that would ensure that process deviations are recorded, assessed and remediated, and notified to the relevant MAH. The third-party might also commit to conducting its own audits of the delegated activities, the results of which could be shared with concerned parties. This is reasonable as long as the MAH is content with the qualifications and procedures associated with these third-party audit activities.
- Independent audit conducted by, or commissioned by, the MAHs within the consortium (potentially in collaboration), if the activity is considered sufficiently high risk. It is expected that all MAHs operate a risk-based pharmacovigilance audit programme and that third-parties involved in the delegation of risk management activities undergo a suitable risk assessment.
Oversight activities should be documented.
GVP Module I – Pharmacovigilance systems and their quality systems
I.C.1.5 “Contractual arrangements should be prepared with the aim of enabling compliance with the legal requirements by each party involved. […] Further, they should indicate which processes are in place for checking whether the agreed arrangements are being adhered to on an ongoing basis. In this respect, regular risk-based audits of the other organisation by the marketing authorisation holder or introduction of other methods of control and assessment are recommended.”
GVP Module IV – Pharmacovigilance audits
IV.B.2 “The risk-based approach to audits focuses on the areas of highest risk to the organisation’s pharmacovigilance system, including its quality system for pharmacovigilance activities. In the context of pharmacovigilance, the risk to public health is of prime importance.”
GVP Module XVI – Risk minimisation measures
XVI.B.3 “Quality assurance mechanisms should ensure that the distribution systems in place are fit for purpose and auditable.”
XVI.B.6 “Although many experts may be involved in developing and implementing risk minimisation measures, the final responsibility for the quality, accuracy and scientific integrity of those measures and the plan describing them lies with the marketing authorisation holder and its qualified person responsible for pharmacovigilance in the EU (QPPV).”
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1 comment
Comment by Douglas Hunter posted on
Informative, concise and clearly written blog.