How Do Cell & Gene Therapy Requirements Differ Between FDA & EMA?
By Michael Cooper, Clinical and Regulatory Affairs, Pharmatech Associates
Cell and gene therapies (CGT) are the new frontier of medicine, offering life extension and sometimes cures for previously untreatable conditions. These revolutionary therapies are expensive and follow nontraditional routes to approval. In this article, we compare and contrast how the U.S. FDA and the European Medicines Agency (EMA) approach cell and gene therapies, including the additional reimbursement approval step required in the European Economic Area (EEA).
Not surprisingly, the FDA and EMA use different terminology to describe CGT. While the steps required to pull together an approvable marketing application are the same, sponsors need to be familiar with appropriate terminology and language to locate guidance documents and for use in agency communications.
For a start, EMA uses the term advanced therapy medicinal products (ATMP) instead of CGT. ATMPs are further categorized into gene therapy medicinal product (GTMP), somatic cell therapy medicinal product (SCTMP), tissue-engineered therapies (TET), and combined advanced therapies.
Approvals In Each Market
The FDA has approved 27 CGTs to date: 14 cell therapies and 13 gene therapies. The EMA has approved 24 CGTs to date: 16 GTMPs, 4 SCTMPs, and 4 TETs. We note that 13 products received approval in both regions. Products receiving approval in both regions include CAR T cell therapies that have proven so effective at treating blood cancers (e.g., Kymriah, Yescarta, Tecartus, etc.).
The FDA approved eight cord blood products (stem cells derived from umbilical cord blood) to treat hematopoietic system disorders, whereas the EMA has not approved any, although two received orphan designation: NiCord and NLA101. Conversely, Holoclar is approved in the EEA as a stem cell therapy to treat corneal tissue, whereas it only received orphan designation in the U.S. No U.S. approved products have been withdrawn from the market after receiving approval, whereas seven out of 24 EEA products have been.
Clinical Trial Design
In both regions, sponsors face similar challenges when demonstrating safety and efficacy. Patient populations are small for target indications — to be expected in the case of such rare diseases. And for life-threatening indications without approved therapies, it is unethical to administer placebo. As a result, the gold standard, randomized control trial (RCT), cannot be employed. Fortunately, sponsors can borrow strategies from orphan drug developers.
In place of a placebo arm, sponsors can use the standard of care (SOC). If there is no SOC, then natural history or observational studies provide a comparison of disease progression in the absence of treatment. Note that employing this strategy may result in post-approval studies as a condition of approval.
Another hallmark of RCT is a “classical” endpoint that is clearly tied to the condition being treated. Examples include progression-free survival and objective response rate. Many CGT developers rely on “surrogate” endpoints, those likely to predict long-term clinical benefit, to demonstrate efficacy. For example, blood pressure can predict mortality from cardiovascular disease. Agencies are open to this approach if the surrogate endpoint is validated to show correlation with the intended clinical outcome.
Industry and regulators are developing alternatives to the RCT: basket trials, umbrella trials, and platform trials (collectively known as adaptive clinical trials) and pragmatic clinical trials, which incorporate real-world evidence.
In both markets, developing manufacturing processes and analytical methods to ensure batch-to-batch consistency is no easy feat. Demonstrating comparability during phases of product development (e.g., scaling up or site transfers) may require an additional clinical trial to satisfy agencies.
Cell therapy manufacturing can be plagued by cell count variability over time. Gene therapy manufacturing contends with genomic titers that decrease over time and unstable reference standards. CGTs are commonly manufactured using single-use technology (e.g., disposable plastic bioreactors). Both agencies are concerned about a toxic potential leachate, bis(2,4-di-tert-butylphenyl) phosphate (bDtBPP). In our company’s experience, EMA will ask about two more leachable compounds: perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Sponsors employing single-use technology should be prepared for these questions.
Developing and validating analytical methods can be particularly grueling for CGTs. The potency assay, a bedrock for biological products since it determines dose, is difficult to qualify when working with unstable reference standards. Recognizing the challenges of qualifying the potency assay, the FDA issued a guidance document specific to CGT in 2011. Additionally, gene therapies require a specific method to differentiate between full, partial, and empty capsids.
CGT Submissions To FDA
Sponsors follow the same procedures as for other therapies: submitting an IND application for clearance, conducting clinical trials, preparing and submitting a biologics license application (BLA) for approval, milestone meetings (e.g., pre-BLA, etc.), and responding to agency questions. Sponsors should request entry into the Regenerative Medicine Advanced Therapy (RMAT) program concurrently with IND submission. RMAT accelerates development of promising therapies that treat, modify, reverse, or cure serious or life-threatening diseases for which there is an unmet medical need. Expedited pathways, such as fast track designation, breakthrough therapy designation, accelerated approval, and priority review designation can be accessed although sponsors apply for each program separately.
Additional RMAT benefits include: (1) meetings to discuss surrogate endpoints to support accelerated approval and (2) obtaining agreement on post-approval requirements such as an additional clinical trial.
CGT Submissions To EMA
Sponsors follow the same procedures as for other therapies: submitting and receiving approval for clinical trial applications (CTAs), conducting clinical trials, preparing and submitting a marketing authorization application (MAA) for approval, requesting scientific advice, and responding to agency questions. EMA’s Committee for Advanced Therapeutics (CAT) oversees CGTs, rather than the Committee for Medicinal Products for Human Use (CHMP).
Eligible sponsors apply for EMA’s PRIME scheme, for prioritizing development of medicines that target an unmet need. Sponsors receive additional feedback (e.g., clinical trial design), and the therapy is eligible for accelerated assessment. EMA assigns a dedicated point of contact for the therapy’s review. This individual may even obtain feedback from health technology assessment (HTA) bodies to facilitate reimbursement negotiations. Similar to the U.S., orphan designation is available.
The Additional Hurdle In Europe: Reimbursement
Once marketing authorization approval is granted in Europe, sponsors must negotiate reimbursement with an HTA body in each Member State, per the European Economic Area Agreement. Failure to achieve an acceptable price has led some sponsors to withdraw their products entirely from this region. In response, EMA rolled out the EUnetHTA 21 consortium in 2022, to obtain concurrent feedback from regulators and HTA bodies on required evidence-generation plans.
When comparing and contrasting requirements to obtain approval for cell and gene therapies between the FDA and the European Medicines Agency (EMA), one is struck by the variance in terminology. However, scratch beneath the surface and you quickly find that sponsors face similar challenges in both markets.
- Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, Guidance for Industry, Food and Drug Administration, Center for Biologics Evaluation and Research, February 2019
- Fishawack Health, “The Fast-Paced Future of Cell and Gene Therapies,” November 2022
- Natalie F. Nidetza, Michael C. McGee, Longping V. Tse, Chengwen Li, Le Cong, Yunxing Li, Weishan Huang, “Adeno-associated viral vector-mediated immune responses: Understanding barriers to gene delivery,” Pharmacology & Therapeutics, March 2020, Volume 207.
About The Author:
Michael Cooper is associate director, clinical and regulatory affairs, at Pharmatech Associates. He has over 20 years of experience in the biopharmaceutical industry, with expertise in regulatory affairs chemistry, manufacturing, and controls (CMC) submissions; GMP inspections for biologics and vaccines; QA lot release of drug substance and drug product; deviation and CAPA resolution; and facilities, utilities, and equipment validation.