FDA vs. EMA: Navigating Divergent Regulatory Expectations for Cell and Gene Therapies. What Biopharma Companies Need to Know

Key Takeaways for cell and gene therapies (CGTs)  Stakeholders

• Regulatory divergence increases complexity – US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have different trial design expectations, approval pathways, and post-market requirements, making a single regulatory approach ineffective.
• FDA offers faster approval but with uncertainty – Expedited pathways (RMAT, Fast Track, Breakthrough Therapy) allow earlier market access but rely on surrogate endpoints and real-world evidence, introducing potential unpredictability.
• EMA demands more extensive data and longer follow-up – Approval often takes longer due to stricter efficacy and safety standards, requiring larger clinical datasets and extended monitoring periods.
• Data inconsistencies increase costs – Sponsors must prepare distinct applications for each agency, adapting trial protocols and evidence to meet differing regulatory expectations.
• Post-market surveillance is stricter for CGTs – FDA mandates 15+ years of long-term follow-up (LTFU), while EMA enforces a decentralized pharmacovigilance system with country-specific compliance requirements.
• Proactive regulatory engagement is essential – Companies must align trial designs early, leverage expedited pathways strategically, and invest in global regulatory intelligence to minimize delays and optimize market entry.

The regulatory landscape for cell and gene therapies (CGTs) remains highly fragmented, with significant differences between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). These differences affect clinical trial design, approval timelines, data requirements, and post-marketing surveillance, creating challenges for biopharma companies seeking regulatory approval in both markets.

Why does this matter?

A recent study published in JAMA Internal Medicine found that only 20% of clinical trial data submitted to both agencies matched, revealing major inconsistencies in regulatory expectations. These discrepancies lead to approval delays, increased costs, and complex regulatory hurdles for CGT developers.

So, how can companies successfully navigate these regulatory differences?
This article explores key distinctions between the FDA and EMA in CGT regulation and provides strategies for biopharma companies to optimize their regulatory approach.

Key Regulatory Differences Between the FDA & EMA

While both agencies share the same fundamental goals—ensuring the safety and efficacy of CGTs—their regulatory frameworks, approval pathways, and evidence requirements differ significantly.

One primary distinction lies in the assessment of clinical data. The FDA often exhibits flexibility by accepting real-world evidence, surrogate endpoints, and offering accelerated pathways, especially for therapies targeting rare or life-threatening conditions. Conversely, the EMA typically requires more comprehensive clinical data, emphasizing larger patient populations and long-term efficacy before granting approval. This contrast can result in therapies gaining market access more swiftly in the US, while facing delays or rejections in Europe due to the EMA’s stringent data demands.

These differences impact how companies design clinical trials, compile data, and approach regulatory submissions. Below, we examine the most critical areas of divergence.

Comparison of FDA and EMA Regulatory Processes for Clinical Trials and Drug Approval

Aspect	FDA	EMA
Clinical Trial Approval Process	IND (Investigational New Drug) Application required, including preclinical gene/cell data, CMC (Chemistry, Manufacturing, and Controls) information, and IRB approval. FDA review: 30 days before clinical trials can begin unless the FDA places the study on hold	CTA (Clinical Trial Application) submitted to National Competent Authorities (NCAs) and Ethics Committees. Since 2022, CTIS (Clinical Trials Information System) allows centralized submission for trials across multiple EU states under the EU Clinical Trials Regulation (CTR, 536/2014).
Marketing Approval	Biologics License Application (BLA) required for marketing approval. Demonstrates safety, purity, and potency under the Public Health Service (PHS) Act.	Marketing Authorization Application (MAA) required for approval. CGTs regulated as Advanced Therapy Medicinal Products (ATMPs) under Regulation (EC) No 1394/2007.
Review Timelines	Standard BLA Review: 10 months for most BLAs. Priority Review: 6 months for therapies offering significant improvements over existing treatments.	Standard MAA Review: 210 days (excluding clock stops). Accelerated Assessment: 150 days for therapies of major public health interest.
Regulatory Classification for CGT	RMAT (Regenerative Medicine Advanced Therapy) designation available for expedited review.	CGTs classified as Advanced Therapy Medicinal Products (ATMPs) under EMA’s ATMP framework.
Long-Term Follow-Up (LTFU) for CGTs	Requires 15+ years of post-market monitoring for gene therapies.	Risk-based LTFU requirements, generally shorter than FDA’s.
Expedited Approval Pathways	– RMAT Designation (for CGTs addressing serious diseases). – Fast Track & Breakthrough Therapy programs available. – Accelerated Approval allows approval based on surrogate endpoints. – Priority Review shortens standard 10-month review to 6 months.	– PRIME (Priority Medicines) Scheme for breakthrough ATMPs. – Conditional Marketing Authorization allows early approval based on limited data. – Accelerated Assessment shortens standard 210-day review to 150 days.
Post-Marketing Surveillance for CGTs	– REMS (Risk Evaluation and Mitigation Strategies) for high-risk CGTs. – FAERS (FDA Adverse Event Reporting System) for tracking drug safety. – Mandatory LTFU studies for gene therapies.	– EudraVigilance database for adverse event tracking. – Periodic Safety Update Reports (PSURs) required for ATMPs. – Risk Management Plans (RMPs) mandatory for all CGTs.
Decision-Making Authority	FDA has full approval authority for CGTs under CBER (Center for Biologics Evaluation and Research). Specifically, these products fall under the Office of Therapeutic Products (OTP),	EMA provides scientific opinion, but the final decision is made by the European Commission.

 

The lack of global harmonization in CGT regulation means that a uniform approach is often insufficient, necessitating tailored applications to meet each agency’s distinct expectations.

Best Strategies for Navigating FDA & EMA CGT Approvals

Navigating FDA and EMA regulatory pathways presents unique challenges that biopharma companies must address early in the development process. Companies face data inconsistencies as the FDA and EMA require different trial designs and endpoints. Approval timelines also vary, with the FDA offering accelerated pathways, while the EMA demands more extensive data and enforces decentralized pharmacovigilance.

Key Challenges in CGT Approvals

To mitigate these challenges, companies must adopt a proactive, region-specific strategy, prioritizing early regulatory engagement, harmonized trial designs, and strategic use of expedited pathways. The following steps can optimize approvals and accelerate CGT market entry.

1. Align Regulatory Planning with FDA & EMA Early.

While advance planning with both agencies cannot guarantee a globally harmonized clinical development strategy, this proactive approach is appreciated by FDA and EMA as the program moves through development.

• Engage with both agencies early through FDA Type B meetings and EMA Scientific Advice to anticipate differences.
• Ensure trial designs align with both agencies’ expectations to prevent delays.

2. Tailor Clinical Trial Designs to Meet Both Agencies’ Standards

A uniform approach to regulatory submissions is unlikely to succeed due to different efficacy & safety requirements.

• For FDA: Leverage adaptive trial designs & accelerated endpoints.
• For EMA: Prepare for larger sample sizes & long-term efficacy data requirements.

3. Leverage Expedited Pathways Strategically

FDA enables faster market access through RMAT, Fast Track, and Breakthrough Therapy, while EMA’s PRIME & Conditional Marketing Authorization pathways can expedite reviews.

• Identify which expedited pathway suits your therapy (e.g., RMAT vs. PRIME).
• Ensure supporting data meets both agencies’ evidence requirements.

4. Invest in Global Regulatory Intelligence

Regulatory pathways are evolving – staying ahead of new compliance requirements is crucial.

• Monitor initiatives like FDA’s START Program & Collaboration on Gene Therapies Global Pilot for potential regulatory harmonization.
• Establish dedicated regulatory teams to track changes in approval frameworks.

5. Strengthen Post-Market Compliance & Safety Monitoring

• For FDA: Prepare for 15+ years of LTFU studies & REMS for high-risk CGTs.
• For EMA: Ensure Risk Management Plans (RMPs) and EudraVigilance data reporting meet EU safety requirements.

Conclusion

Regulatory divergence between the FDA and EMA poses challenges but also opportunities. Understanding these differences, planning proactively, and leveraging expedited pathways strategically can help biopharma companies streamline approvals and bring innovative CGTs to market faster.

At Cromos Pharma, we specialize in guiding sponsors through these complexities, ensuring smooth regulatory interactions and efficient trial execution across multiple regions. With deep expertise in FDA and EMA processes, we support biopharma companies in optimizing trial design and accelerating approvals. Our team provides end-to-end clinical trial management, from regulatory submissions to patient recruitment, helping sponsors efficiently bring innovative therapies to market.

As global regulators push toward harmonization, companies must stay informed and engaged to navigate the evolving regulatory landscape successfully. What strategies do you see as most effective for navigating CGT approvals in both regions? Share your thoughts in the comments!

Reference: Elsallab M, Gillner S, Bourgeois FT. Comparison of Clinical Evidence Submitted to the FDA and EMA for Cell and Gene Therapies. JAMA Intern Med. 2025 Feb 3:e247569. doi: 10.1001/jamainternmed.2024.7569. Epub ahead of print. PMID: 39899303; PMCID: PMC11791768.