Do you really know how to accelerate the approval of your innovative product in Europe?
European Expedited Regulatory Programs: The FDA’s incentives for promising new medicines are widely known. Accelerated approval, priority review, fast track designation and breakthrough therapy designation are frequently discussed by the media and investors, even if the details of those programs are often misunderstood.
The European Medicine Agency (EMA) has its own suite of regulatory incentives which, in our experience, are not well understood, especially among US-based Sponsors. Following Brexit, the newly independent Medicines and Healthcare products Regulatory Agency (MHRA) has also developed its own unique incentives, offering new pathways to accelerate access in the UK.
Understanding these programs, and especially how they differ from those designed by FDA, will help you optimize your development program and reach patients across Europe, which remains the world’s second largest pharmaceutical market.
Conditional Marketing Authorization (CMA)
This is roughly the equivalent of the Accelerated Approval pathway in the US but is granted less commonly (around 5% of new drug approvals in 2007-2017, compared to ~13% receiving accelerated approvals in the same timeframe).
For CMA, there must be an unmet medical need – either for a seriously debilitating/life-threatening disease, an emergency situation, or an orphan disease. Unmet need is defined as a lack of satisfactory treatment methods, or a major improvement over existing method(s).
Although a new medicine is granted CMA on basis of less complete clinical data (e.g., Phase 2 uncontrolled trials), it must still demonstrate a positive benefit-risk balance at the time of filing. It must also be likely that comprehensive data can be provided (through mandatory Specific Obligations post-approval). Usually, a confirmatory trial has started recruiting at the time of filing.
Don’t assume that a product granted accelerated approval in the US will be eligible for CMA, or vice versa. There is not a strong correlation, and each pathway requires its own robust regulatory argumentation.
Exceptional Circumstances Marketing Authorization
An exceptional circumstances marketing authorization is granted in cases where there is not enough data to draw a confident conclusion on benefit-risk, nor will there ever be. This is typically applied in ultra-rare diseases, or for vaccines and antidotes where large field trials are unfeasible (e.g., Ebola vaccines).
Not to be confused with ‘accelerated approval’ (FDA terminology), accelerated assessment in Europe is conceptually similar to FDA’s Priority Review. The timetable for review of the marketing authorisation application is shortened from 210 days to 150 days (excluding clock stops for questions). In many cases, however, the review reverts to the standard timetable again when major objections from the Agency require more time to be addressed.
Accelerated assessment is granted for only about 10% of Marketing Authorization Applications (MAAs), far more rarely than Priority Review. The product must be of ‘major public health interest’ from the viewpoint of therapeutic innovation, offering a major therapeutic advantage for a condition with no satisfactory method of diagnosis, prevention, or treatment.
Whereas rolling review is a regulatory tool commonly used by FDA, this usually only applies in the EU in case of a public health emergency, such as COVID-19 vaccines. The UK however does envisage rolling reviews under the new ILAP scheme (see below).
Launched in 2016, the PRIority MEdicines (PRIME) scheme was the EMA’s response to FDA’s Breakthrough Designation. PRIME is based on the same eligibility criteria as accelerated assessment as mentioned above, but can be granted earlier in product development. The vast majority are orphan medicines.
The rewards for PRIME designation include early appointment of the Rapporteurs – the reviewers selected from Member States of the EU who will be appointed to review the MAA. In practice, Scientific Advice for PRIME designated products is also guaranteed to be issued in 40 days rather than extending to 70 days as may happen for products without PRIME designation.
Statistically, it is even more difficult to gain PRIME than FDA’s Breakthrough Designation. Only 25% of applications are successful. Even for advanced therapy medicinal products (ATMPs, comprising cell and gene therapy products and tissue-engineered products) the success rate for PRIME is only 40%. Most refusals are due to failure to demonstrate a major therapeutic advantage over existing treatments, often related to study design issues or a questionable magnitude of benefit.
Compassionate Use Programs
Unauthorised medicines can sometimes be administered to patients prior to obtaining marketing authorisation in case of an unmet medical need. This can be done on a named patient basis, or through compassionate use cohorts. Unfortunately, the regulations and procedures are complex, and differ country by country within Europe.
New Incentives in the UK
In January 2021, the UK launched the Innovative Licensing and Access Pathway (ILAP). Although the eligibility for ILAP is somewhat similar to EMA’s PRIME, the regulatory collaboration is deeper. MHRA will help the Sponsor develop the target product profile and roadmap to approval and will accept the clinical data for MAA evaluation under a rolling review.
In the field of oncology, the UK has joined Project Orbis, where it is able to coordinate with FDA in reviewing new applications. And the UK has retained the EU concepts of CMA and exceptional circumstance marketing authorisations.
And last but not least, don’t forget Market Access!
Sponsors often make the mistake of focusing entirely on regulatory approval, with market access as a subsequent step. This stepwise approach can result in delays of a year or more until product launch, as robust data packages are prepared for Health Technology Assessment (HTA) bodies in each jurisdiction to demonstrate clinical effectiveness and/or cost effectiveness. In addition to indirect comparisons against local standards of care, the HTA bodies will often request evidence that could have been collected in the pivotal trial program, but the opportunity was missed.
For products eligible for ILAP in the UK, discussions with the UK’s payers are built into the process by default. The EMA routinely offers parallel consultations in collaboration with EUnetHTA, the umbrella group for HTA bodies across the EU, although these have been suspended during the pandemic. While the resulting advice is not binding, these meetings can be helpful for Sponsors to identify gaps in their market access strategy and to optimize the data collection in their pivotal trials before it’s too late.
Can Sponsors take advantage of more than one expedited program?
Yes! Companies with novel therapies with outstanding efficacy in an area of high unmet need will frequently take advantage of multiple expedited programs. For example, PRIME designated products are likely to benefit from accelerated assessment (the criteria being the same), and more likely to gain a CMA.
Contact ProPharma Group for Expert Guidance
Our consultants have decades of experience in global development programs and know how to navigate the requirements of FDA and European agencies. If you think your drug may be eligible for one of these expedited programs and have additional questions, contact ProPharma Group today. Our team of regulatory experts is ready to assist using our extensive knowledge and experience working directly with the Agencies to help ensure a successful interaction. Contact us to learn more about our services and get started today.
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