Stemming from the new EU regulations around pharmacovigilance, the EU is also considering the role of post-marketing efficacy studies (PAES). In a position paper seeking feedback, found here, the EU lays out its perspective that the new PV legislation also refers to the possibility of requiring the market authorization holder to develop PAES to complement the efficacy data used to grant marketing authority. That power is granted where “concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed.”
The position paper goes on to lay out the regulatory purpose of PAES and suggest that after the results of a required PAES were provided to the regulatory agencies, they would be free revisit the authorization decision and determine if “…the marketing authorization should be maintained as granted, varied or even withdrawn on the basis of the new data resulting from the study.”
While regulatory agencies have always been free to revisit their decisions, this approach seems to imply that they are obligated to reconsider their decision after the required PAES. This makes thoroughly changes the role of the non-PV focused P4 trial from today’s approach to a much more high-stake trial. Under this approach, these types of P4 trials would have much higher risk and would likely need to be treated much more like we treat P3 studies. This means a likely significant increase in cost for these trials.
Efficacy vs. Effectiveness
The next section of the position paper focuses on the question of efficacy vs. effectiveness. The paper comes down clearly on the side of efficacy. Again, this could be a major change for P4 trials, many of which are focused on developing real-world effectiveness data to provide support for reimbursement decision makers. This change may also force a significant revisiting of the P4 approach followed today. Additional P4 trials may be needed if the mandated trials focus on efficacy and cannot be tasked with also considering effectiveness. This will have a significant impact on time and budget as well.
Situations Where PAES May Be Required
The paper then proposes a set of 7 situations where PAES may be required. They are:
|Situation Where PAES May Be Required||Comment|
|1. Studies aimed at determining clinical outcome following initial assessment based on surrogate endpoints||This type seems very logical. If surrogate end points were used to get authorization, then a study may be required investigating the underlying endpoint sought. But, this may significantly add to the cost of using surrogate endpoints for approval, since surrogates are sometimes used because of the time (and cost) of gathering data on the underlying endpoints.|
|2. Studies on combinations with other medicinal products||Acknowledging that testing for authorization can only cover a limited range of combinations, P4 trials may be required to test additional combinations.|
|3. Studies in sub-populations||Given the limitations on the number of sub-populations, additional sub-populations may be required to be tested.|
|4. Studies in the context of the European standard of care||If the trial uses subjects primarily from outside of the EU, the EU may request additional information from patients treated within the EU. This would negate any cost savings a company might hope to garner by working in other markets.|
|5. Studies linked to a change in the understanding of the standard of care for the disease and/or the pharmacology of the medicinal product||This is a scary one. It proposes that if the standard of care for a disease had changed, the authorization holder may be required to develop new efficacy data addressing the new standard of care. This could result in a never-ending need for new efficacy trials – a major change in way we think of authorized products.|
|6. Studies aimed at determining the long-term efficacy of a medicinal product||This is one of the “traditional” reasons for P4 is long-term analysis. Difference is focus on efficacy instead of effectiveness.|
|7. Studies in everyday medical practice||The proposals suggests that these would be required when “…there is clear evidence that the benefits of the medicinal product underdiscussion as shown by randomised controlled clinical trials might be significantly affected by|
the real-life conditions of use.” This seems to open the door for any misgivings or concerns by the regulatory authorities to result in the requirements for a trial – and when they get results they will be obliged to revisit the approval.
While this is still in proposal stage, the direction is clear. PAES is going to become a new tool for regulators who have efficacy concerns about both new approved and legacy products to address their concerns. It is likely to have a significant impact on the cost, risk and structure of Medical Affairs if it comes into effect.
I urge you if you have comments to follow the process found in the document to express them. I will be doing so.
What are your thoughts? Am I overreacting? Please leave a comment.