The European Medicines Agency has released a draft guidance to assist drug developers using its Priority Medicines (PRIME) scheme to accelerate authorization of new therapies.
“Experience to date has shown that applicants face challenges to complete quality and manufacturing development and data requirements during development of products in early access approaches,” wrote EMA in the executive summary of the guidance.
Challenges for those developing breakthrough therapies via accelerated and early access mechanisms were explored in a November 2018 workshop co-hosted by EMA and the US Food and Drug Administration (FDA) that “sought to identify scientific and regulatory solutions to challenges commonly experienced” by these applicants.
The guidance comes in the form of a toolbox that pulls together existing regulatory tools and scientific guidance for sponsors of medicines holding the PRIME designation. EMA hopes to support PRIME applicants in speedier and more complete filings of Module 3 quality data packages, thus smoothing the path for marketing authorization of these therapies, which address currently unmet medical needs.
Scientific tools
The bulk of the draft toolbox guidance outlines general scientific tools available to drug developers under the PRIME scheme. For example, the guidance points to “prior knowledge,” a regulatory term of art used in International Council on Harmonization (ICH) and EMA guidance. When prior knowledge is available, for example, some early-stage development studies may be redundant. The guidance outlines when to refer to previous filings, and when to consider studies that extend from established prior knowledge, as with related molecules.
The guidance also points to risk assessment tools available for PRIME designees, as well as to dedicated EMA guidelines for advanced therapy medicinal products (ATMPs).
The continuum of process validation is also addressed in the guidance, which gives examples of when some validation protocols can be accepted as substitutes for final validation reports at the time of marketing authorization application. Whether some process validation steps can be deferred to the post-authorization phase will be a risk-based, case-by-case decision, according to EMA.
Whether the exceptional circumstances of the PRIME scheme would justify concurrent validation is also a case-by-case decision. EMA provides guidance about when prior knowledge may be useful and when clinical batches from commercial manufacturing can be used to support validation. The draft guidance points to ICH Q8, which opens the door for continuous process verification to be used as an alternative to “traditional process validation.”
Turning to control strategy, the draft guidance notes that “the more knowledge an applicant has of their product and process, the more flexibility can be afforded in the approved control strategy.” However, EMA also acknowledges that this knowledge may still be evolving under an accelerated timeline. “Thus, the amount of data available to support its control strategy at the time of approval may be reduced compared to a product undergoing a standard development,” wrote EMA.
The document outlines a strategy PRIME developers may wish to employ, where an initial filing uses a more constrained control strategy with tight control of manufacturing, with plans for a robust post-filing program of process development and evaluation studies.
The guidance acknowledges that ICH M7 looks to increased use of in silico models to assess mutagenic impurities; statistical process control measurements can also be used in some cases. However, EMA cautions applicants to err on the side of transparency: “[I]n many cases the programs and algorithms used by Applicants for carry-over calculations have not been fully transparent to the Authorities, in some cases hampering the assessment and acceptability of in-silico purge calculations.”
The guidance walks PRIME designees through approaches to good manufacturing practice (GMP) compliance, including the circumstances that might allow launching from an investigational medicinal product site, aligning quality review and GMP inspections, and when it might be permissible in biologics production to use starting material that was manufactured under lower-level GMP.
Stability testing considerations and tools for comparability studies for biologics and ATMPs are also covered in the draft document.
Regulatory tools
EMA also outlines the procedures developers can use “to establish an early dialogue with regulators and support prospective planning.”
These include early-stage scientific advice and assistance with protocols, as well as pre-submission meetings between applicants and EMA rapporteurs; the latter should happen about 7 months before submission is planned.
Accelerated assessment, “a procedure reserved to medicinal products of major therapeutic interest,” can shorten active review time to 150 from 210 days, speeding patient access to new therapies.
Conditional marketing authorization is another regulatory option for some PRIME-designated medicines, notes EMA. The draft guidance outlines the circumstances where the regulator might consider granting conditional authorization.
Post-approval change management protocols “enable a stepwise approach in the assessment of changes,” according to the guidance. For example, the protocol might specify a new manufacturing site that would come online during the product lifecycle and outline what data from pre-defined studies could be used post-approval in support of this change.
Finally, post-authorization measures – “means for regulators to request any additional data that from a public health perspective, are needed to complement the available data” – may be required by EMA. Which post-authorization measures are required of a marketing authorization holder will depend on the specifics of the medicine’s characteristics.
The draft guidance is open for consultation until 31 July 2021.
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