The rapid advancement of cell and gene therapies (CGT) has created a dynamic regulatory environment that is complex and can be difficult to navigate. The lack of precedent and established frameworks for novel and evolving formats makes regulatory compliance especially difficult for biopharmaceutical manufacturers. To bridge this disconnect and meet evolving regulatory mandates in the US, you should consider the following:
- Creating a clear, effective strategy that addresses regulators’ concerns
- Understanding and utilizing agency programs and various special designations
- Standardizing complex, variable manufacturing processes to meet quality and compliance requirements
The following strategies can help you better understand how to fulfill your regulatory obligations and help avoid delays in commercialization.
Creating a clear, effective regulatory strategy
Challenge:
US regulatory agencies have introduced a variety of initiatives designed to facilitate a faster drug development process. These initiatives sometimes have similar or overlapping schedules, benefits, or requirements. It can be unclear which pathways to pursue so you can obtain the most valuable advice from these agencies.
Recommendation:
A clearly defined regulatory strategy helps you with engaging regulators so you can maximize both efficiency and value. Your strategy also shows the regulatory agency your understanding of requirements and commitment to meet them, building trust and confidence.
Develop a Target Product Profile (TPP) to inform your regulatory engagement strategy. The TPP guides the development of therapeutic candidates, driving activities toward desired outcomes as well as identifying how you’ll proactively mitigate potential regulatory risks.
Target Product Profile (TPP)
A well-executed TPP for your drug candidate outlines the following:
- Characteristics
- Benefits
- Target population and its identified unmet needs
- Treated disease definition and stage
- Differentiation from existing treatment options
- Potential side effects and associated risks
- Administration and dosage considerations
- Contingency planning
Early engagement in agency meetings will help you understand the regulatory agency and build key relationships. Each meeting has specific prerequisites and timelines. Knowing which meetings are required and how to frame your position can increase your odds of success. Examples of agency meetings include:
- Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products (INTERACT): This is an informal, exploratory meeting with the FDA that allows sponsors to receive early input on their development plans, as well as ask questions.
- Pre-IND (Investigational New Drug): This meeting with the FDA takes place before you submit the IND and is more structured and focused on your clinical study strategy.
Understanding the requirements of special programs and designations
Several special programs are available to help address CGT development burdens. The purpose of these programs ranges from expediting conditional approvals to accelerating development timelines. Each has different criteria and designations, making the requirements difficult for manufacturers to navigate and take advantage of their benefits.
Recommendation:
Create a plan that can help you take advantage of these special programs and pursue those that fit your therapy model and program goals (See table). Collaborating with an experienced consulting team will help position you for success.
Examples of the FDA’s special programs relevant to CGT
| Support for clinical Trials Advancing Rare disease Therapeutics (START) Pilot Program1 | Regenerative Medicine Advanced Therapy (RMAT) Program2 | Chemistry, Manufacturing, and Controls Development and Readiness Pilot (CDRP) Program3 | Accelerated Approval (AA) Program4 | |
| Program purpose | To accelerate drug development for rare diseases by boosting communication with regulators | To accelerate development timelines, enhance guidance, and grant priority review to qualifying drugs | To improve the quality and efficiency of chemistry, manufacturing, and controls (CMC) development for new drug candidates, especially for rare disease and gene therapies | To enable expedited conditional approval of qualifying drugs |
| Key program features |
- Enhances early communication between agency and developers |
- Provides enhanced guidance and communication with FDA |
- Streamlines CMC review and agency response |
- Allows surrogate and intermediate endpoints
|
| Eligibility criteria |
- Address a serious or life-threatening condition |
- Address a serious or life-threatening condition |
- Engage early in the development process |
- Address a serious condition
|
| When to request | Early in development, when in clinical trials under an active IND | Once the potential for significant improvement over existing therapies can be demonstrated, with an IND submission as an amendment to an existing IND | Before end of Phase 2, when under an active IND with an expedited clinical development timeframe | Once the pivotal study has begun and after meeting with agency to discuss requirements and appropriateness |
Standardizing manufacturing processes to meet CMC requirements
Challenge:
CMC requirements are designed to ensure safety, efficacy, and consistency in the drug development and production process. However, it’s challenging to standardize manufacturing processes for complex biologicals that contain variable materials, have inherent variability between batches, and may be difficult to scale up. You must address two major hurdles that are crucial for meeting regulatory requirements:
- Potency, which ensures the product elicits the desired therapeutic effect at the intended dose, is challenging to accurately measure and maintain.5 This is due to the products’ biological variability or nuances in manufacturing.
- Comparability, which ensures that different batches maintain consistent quality, efficacy, and safety profiles, is difficult to demonstrate for some CGTs.6 Changes made over the course of clinical development or in manufacturing processes can significantly impact product characteristics and performance.
What is chemistry, manufacturing, and controls (CMC)?
Recommendation:
Save time and money by monitoring process changes during development. Consulting experts in process development and technology transfer can help you establish effective methods for comparative analysis across the development journey.
Reduce the risk of delays and align product quality testing with regulatory expectations by identifying critical quality attributes (CQAs) for your product’s safety, efficacy, and quality. For instance, a potency CQA, which relates to your drug’s mechanism of action and clinical efficacy, helps ensure the final product is consistently manufactured “as it may relate to the safety or effectiveness of the product.”7 A potency CQA should be measurable, scalable, and reasonable to assess during the compressed timelines of a commercial program.
For effective batch comparability tests, retain samples from Phase 1 trials so you can establish parameters for later phases and establish a comparability narrative throughout development. The ideal potency assay should be quantitative, indicate stability, and confirm lot-to-lot consistency. Since manufacturing processes and potency assays may change during development, monitoring and controlling them is crucial to ensure the final product meets regulatory standards for drug substance safety and quality.6
References
1. US Food and Drug Administration. FDA Launches Pilot Program to Help Further Accelerate Development of Rare Disease Therapies. 29 September 2023. Accessed on 27 February 2025. Available online at: https://www.fda.gov/news-events/press-announcements/fda-launches-pilot-program-help-further-accelerate-development-rare-disease-therapies
2. US Food and Drug Administration. Regenerative Medicine Advanced Therapy Designation. 21 July 2023. Accessed on 27 February 2025. Available online at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapyproducts/regenerative-medicine-advanced-therapy-designation
3. US Food and Drug Administration. Chemistry, Manufacturing, and Controls Development and Readiness Pilot (CDRP) Program. 14 November 2024. Accessed on 27 February 2025. Available online at: https://www.fda.gov/drugs/pharmaceutical-quality-resources/chemistry-manufacturing-and-controls-development-and-readiness-pilot-cdrp-program
4. US Food and Drug Administration. Accelerated Approval Program. 24 December 2024. Accessed on 27 February 2025. Available online at: https://www.fda.gov/drugs/nda-and-bla-approvals/accelerated-approval-program
5. Salmikangas, P. et al. Potency testing of cell and gene therapy products. Frontiers in Medicine. May 2023. Accessed on 22 April 2025. Available online at https://pmc.ncbi.nlm.nih.gov/articles/PMC10196484/
6. US Food and Drug Administration. Guidance for Industry: Drug Substance Chemistry, Manufacturing, and Controls Information. 6 August 2010. Available online at: https://www.fda.gov/media/69923/download
7. US Food and Drug Administration. Draft Guidance for Industry: Potency Assurance for Cellular and Gene Therapy Products. December 2023. Accessed on 5 May 2025. Available online at: https://www.fda.gov/media/175132/download
Disclaimer: This article may contain marketing statements and shall not constitute legal or regulatory advice. Cencora, Inc. strongly encourages readers to review the references provided with this article and all available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto.
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