Towards the end of last month, the European Medicines Agency (EMA) released its first batch of good pharmacovigilance practices (GVP) modules for public consultation. These modules will eventually serve as guidance for how the EMA wants to see pharmacovigilance activities conducted in the EU, in light of the new pharmacovigilance legislation passed at the end of 2010, and which goes into effect from July 2012.
Here comes the PASS...
As a result of the new legislation, competent authorities may now impose an obligation on manufacturers to conduct a post-authorisation safety study (PASS) – either as a condition to receiving marketing authorisation, or after the granting of a marketing authorisation, at such time as they require. These studies will be designed to better characterise safety hazards, the safety profile of a medicine, and/or the effectiveness of risk management measures. The procedure will become fully operational sometime in 2012 for centrally authorised medicines, and the EMA will focus on nationally authorised ones after this year.
The GVP put out to consultation on PASS has included an appendix of potential study methodologies, which range from active surveillance processes (e.g., onsite intensive monitoring schemes) and use of registries to traditional observational methods (e.g., cross-section, cohort and case-control studies.) These are only the non-interventional options – the EMA has confirmed that additional clinical trials may also be required, as well as alternatives such as drug utilisation studies (e.g., to estimate the economic burden of adverse events).
.... soon to be joined by PAES
Competent authorities will also be able to impose the obligation to conduct post-authorisation efficacy studies (PAES), although the draft scientific guidelines to be published on these (and which will support any future delegated act) are due sometime later this year. Here the intent is to better characterise “efficacy in everyday medical practice.”
At the tail-end of last year, France passed into law its own pharmacovigilance reform. One key component of this reform is the ability of the French regulatory agency to now request active-comparator trials for marketing authorisation – manufacturers may decline this request, although they are then required to provide justification. France has been lobbying for this framework to be applied at European level.
It is interesting to consider what shape the scientific guidelines on PAES will take – will there be circumstances in which national competent authorities will be able to require active-comparator trials? The focus on efficacy in “everyday medical practice” would suggest a real-world setting, but one could envision cases where regulators might still, for example, like to see a pragmatic trial design.
This scenario poses a number of questions, not least of which is:
- Given that the most appropriate active comparator might vary from Member State to Member State, would there be cases where manufacturers could in theory be expected to undertake multiple trials?
- For the same reason, how would the EMA approach centrally authorised medicines?
- Finally, would any such requirement follow the French model in allowing manufacturers to decline with justification, or would it represent a more stringent market access hurdle?
What seems clear is that the new pharmacovigilance legislation will, in one way or another, add to the debate that has emerged over the role relative efficacy (and/or effectiveness) should play in the marketing authorisation space.
The other interesting angle is how PAES will work in relation to pricing and reimbursement. With the expanded remit of the regulators, it will be interesting to see what the practical ramifications of ongoing risk-benefit assessment are on P&R decision-making timelines, and the amount and kinds of data available for that decision making. Certainly the step toward PAES is a bold one –one, I am realising, with more and more potential ripple effects.