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In response to the debate over allowing patients timely access to new therapies and ensuring safety, the EMA launched the PRIority MEdicines (PRIME) scheme in March. The aim of this initiative is to build upon existing regulations in Europe to support product development in cases of unmet medical need.
The industry trend to focus new development on indications where there are few or no existing therapies continues. Targeted indications are often rare, translating into a significant proportion of new approved products having “orphan” status. (From January to April this year, roughly one-third of the new medicines approved in Europe were for orphan products.1) The logistics associated with studying new drugs in very small populations is challenging, but perhaps even more challenging is achieving the right balance between allowing timely access to new therapies and ensuring safety. This much debated balance-allowing patients timely access to new therapies while requiring sufficient data to allow a thorough risk benefit assessment-means that optimizing the regulatory approval pathway for these types of products remains high on the priority list for industry regulators.
Following a period of planning and consultation, the European Medicines Agency launched in March the latest regulatory initiative in this vein: the PRIority MEdicines (PRIME) scheme.
Existing Regulatory Tools in Europe to Speed Patient Access
Existing pharmaceutical legislation in Europe provides developers regulatory tools to speed availability of new products. These tools include the scientific advice/protocol assistance procedure, a compassionate use opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP), as well as newer development support initiatives such as the adaptive pathways scheme and the EMA’s innovation task force.
Aside from these, two further regulatory tools are open to applicants. A conditional marketing authorization allows a product to be approved on the basis of a reduced clinical data package with specific postmarketing obligations to provide additional confirmatory data within an agreed period, to be reviewed annually. Conditional marketing authorizations (MA) are granted for one year only, but can be renewed. Another option for earlier market approval is for a product to be granted an expedited review at EMA under the accelerated assessment procedure. This reduces the review period from a maximum of 210 days to 150 days. Specific criteria are applied when considering if a product may be eligible for either a conditional MA or accelerated assessment.
Given that eligibility is restricted, uptake of these is relatively low compared with the numbers of products approved via the EMA’s centralized procedure under standard mechanisms. In 2015 specifically, just three of the 93 new medicines approved (39 new active substances) had a conditional marketing authorization and just five were approved under the accelerated assessment procedure.2
aAdapted from table included in “Development support and regulatory tools for early access to medicines” (EMA, 1 March 2016); http://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/03/WC500202631.pdf
EMA’s New PRIME Scheme
With the launch of the new PRIME scheme on March 7, the EMA aims to build on the existing regulatory framework in Europe to support product development in cases of unmet medical need. By doing so, the EMA strives to encourage development in products likely to make a real difference to patients. Eligibility criteria for PRIME mirror those for accelerated assessment-namely that products are “of a major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation (unmet medical need)” and fall within the scope of the centralized procedure.3
PRIME’s principal advantage is that it allows sponsors to have an early and proactive regulatory dialogue with the EMA, which should help them optimize clinical trial design and generate robust data to support an eventual marketing authorization application (which would in turn be expected to be eligible for accelerated assessment).
Under the scheme, additional benefits include the early appointment of a rapporteur from either the CHMP or Committee for Advanced Therapies (CAT) to allow knowledge build at the EMA committee level ahead of a future MAA, as well as identification of a dedicated contact person with EMA. In addition, a kickoff meeting with the rapporteur and a multidisciplinary group of experts is envisaged to provide guidance on the overall development plan and regulatory strategy.
An eligibility request, accompanied by a justification, should be submitted in order to apply for the benefits of the scheme. There is no fee associated with the request. The timing of the request is expected to be early in development once preliminary clinical evidence (proof of concept) is available for the product. In recognition that academic research groups and small or medium-sized enterprises (SMEs) may be less knowledgeable about the regulatory framework and may benefit from earlier interaction, access may be granted in these cases on the basis of compelling nonclinical data and tolerability data in humans.
PRIME vs. FDA Breakthrough Therapy Designation
Parallels have been drawn between the new PRIME scheme and the U.S. FDA’s breakthrough therapy designation program, available since July 2012. The broad scope and intent of both initiatives are indeed similar, aimed at optimizing development and accelerating approval for new products that potentially may fulfill an unmet need. To that end, both also encourage early and frequent dialogue between regulators and sponsors.
While PRIME is a development support program that leverages existing early access regulatory tools that are specifically permitted by EU legislation (e.g., accelerated assessment), the legal basis for the breakthrough designation program is itself defined within the Food and Drug Administration Safety and Innovation Act (FDASIA). Breakthrough designation is limited to products aimed at treating serious conditions.4 Although not explicitly stated within the scope for the new EMA scheme, by virtue of it being limited to products falling within the scope of the centralized procedure, as well as the eligibility criteria that will be applied, the same may be said of PRIME.
Additionally, both require preliminary clinical evidence of effectiveness (PRIME allowing some leeway for academia and SMEs to participate even earlier in development, more closely reflecting the criteria for the FDA’s fast track designation program). Guidance documents providing more detail regarding the preparation of PRIME eligibility requests, including what may be required by way of justification, are available on the EMA website.3,5
Breakthrough designation does differ in one respect, in allowing for “rolling review” of the licensing application dossier, a benefit that is not yet allowed within existing pharmaceutical legislation in Europe. Notwithstanding, an initial assessment suggests that the two schemes appear more alike than they are different; however, this will become clearer as experience with the new PRIME scheme grows.
Discussion and Conclusion
The scale of uptake for the PRIME scheme remains to be seen given that it is still in its infancy. The U.S. FDA’s breakthrough designation program has been encouraging with a total of 129 drugs or biologics receiving the designation since the program launched in 2012, and 43 of these subsequently obtaining market approval (figures accurate to March 31/April 1, 2016).6 Monthly reports from the CHMP, released after each meeting, will include information on any recommendations given regarding PRIME eligibility requests (although only products confirmed as being eligible will have the active substance or INN shared publicly) and therefore its use will gradually become apparent.
PRIME is a welcome addition to the development support tools offered by the EMA in Europe and looks well placed to contribute to the EMA’s stated objective of optimizing clinical development to ensure safe and timely access to novel medicines for patients.
Emma Beausang PhD MRPharmS is the Associate Director of Regulatory Affairs at Chiltern