PRIME versus ILAP: Selecting the right pathway for gene therapy innovators
To all intents and purposes, EMA’s PRIME and MHRA’s Innovative Licensing and Access Pathway (ILAP) were developed with the same goal in mind: to bring promising treatments to patients faster.
Given the potential shown by gene therapy products in offering a curative therapy to currently unmet medical conditions, both schemes are of enormous benefit to gene therapy developers.
While both programmes have earlier and sustained interaction with the Agency at their core, the two pathways differ in several ways, with ILAP giving earlier access to support strategic product development.
Established in 2016, PRIME seeks to support early dialogue and scientific advice with EMA and its scientific committees. It defines criteria for eligibility, including that the medicine addresses an unmet need and a major public health interest, that preliminary clinical data is available to demonstrate its potential and that the product in question is under development.
There are many benefits to PRIME applicants, including gaining access to a rapporteur from a relevant committee to provide ongoing support and help the applicant build their knowledge of the marketing authorization application process. In the case of advanced medicinal therapeutic products (ATMPs), the rapporteur would be from the Committee on Advanced Therapies (CAT). Applicants benefit from scientific advice at key development milestones and the potential for accelerated assessment, taking the process from 210 days down to 150 days.
PRIME applicants must demonstrate evidence of clinical response, typically generated from clinical exploratory data. There are exceptions for small and medium-sized enterprises (SMEs), which can enter the program based on robust nonclinical data and tolerability data from initial clinical trials.
Over the first two years since the establishment of PRIME, eight requests were submitted by SMEs at the proof of principle stage. Out of these, three were granted eligibility to PRIME at this early stage of development, with one of the Sponsors subsequently providing the Agency with exploratory clinical data to enable confirmation of PRIME eligibility.
ILAP, which was initiated in early 2021, allows earlier access to the program based on evidence gathered from the pivotal nonclinical studies. With application through the Innovation Passport, it is open to innovators from pre-clinical through mid-development program points for life-threatening or seriously debilitating conditions or where there is a significant patient or public health need. Among the advantages of ILAP are that it provides useful tools that support companies throughout the process, including facilitating the development of alternative clinical protocols and facilitating patient recruitment via a centralised search of health records databases. These benefits are invaluable for complex products such as gene therapies, which typically target very small patient populations and therefore rely on reduced clinical data sets. Another useful ILAP tool is the review of sections of the Common Technical Document (CTD) on a rolling basis, with multidisciplinary teams performing a regulatory assessment of the data, thus indicating to the Sponsor potential major deficiencies and offering further scientific advice to address identified gaps.
Time and resources
One important consideration is that both programs require significant time and resource investment by the regulators and the sponsors because of the expected acceleration of the overall approval pathway, thus compressing timeframes. There is perhaps not quite so much pressure with ILAP, simply because it offers the option to enter the scheme when sponsors might not yet have entered clinical development.
With PRIME, where the final target of submitting a Marketing Authorisation Application (MAA) is much closer, companies are expected to provide updates and meet milestones much quicker. While this can put pressure on Chemistry, Manufacturing and Controls (CMC) activities, PRIME offers the sponsors alternative approaches to populating the quality package of the MAA. Alternative strategies to process validation, control strategy, stability, comparability, and deferral of certain process validation activities to post-approval are discussed within the PRIME toolkit guidance document1, with a view to avoiding delays in the submission of the associated quality packages within the Marketing Authorisation Application (MAA), thus facilitating earlier access to patients.
While the programs do require a large commitment, they have both proven to be popular with drug developers. Of the nearly 100 products accepted into the PRIME program since it was initiated, 44 were ATMPs for rare diseases. In the more than 5 years since the program began, 18 PRIME-supported treatments (including 7 ATMPs) have, as of early 2022, been authorized for use across Europe.
As noted in our previous article earlier this year (How MHRA’s Innovative Licensing Access Pathway seeks to improve patient access), ILAP has had rapid uptake, with 71 applications as of the end of December 2021 – just a year into the start of the program.
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1.EMA/CHMP/BWP/QWP/IWG/694114/2019. Draft toolbox guidance on scientific elements and regulatory tools to support quality data packages for PRIME marketing authorisation applications. Available at https://www.ema.europa.eu/en/toolbox-guidance-scientific-elements-regulatory-tools-support-quality-data-packages-prime-certain. Last accessed on 20th of May 2022.
|Eligibility Criteria||Product Under Development; Major Public health interest; Targets unmet medical need; Major therapeutic advantage: Demonstrated potential clinical meaningful impact||Life threatening or seriously debilitating condition; significant patient or public health need; innovative medicine, or new biological entity or novel drug device; targets rare disease and/or other special populations; potential to offer benefits to patients|
|Eligibility Procedure Timing||40 days||12 to 14 weeks|
|Main Benefits||Appointment of a Rapporteur; kick-off meeting and scientific advice at key development milestones; confirmation of eligibility for accelerated assessment; regular monitoring of program development||Development of a Target Development Profile (TDP) with the support of product-specific experts; definition of road map for access to patients; dedicated PM|
|Earliest Entry Point||Exploratory Clinical phase; application based on compelling nonclinical data (potential exceptions for SMEs)||Nonclinical development|
|Total number of programs enrolled in the scheme||97 (30 ATMPs)||41|
|Success Rate (granted/rejected)||95/274; success rate for ATMP is 46%||41/71 as of 28th Dec 2021|