The Gene Therapy Regulatory Landscape: Progress Made and Challenges Ahead

In this opinion piece recently published in Molecular Therapy, Mantej Chhina, Daniela Drago, and I wrote about the advances made as well as challenges ahead for gene therapy products. We discuss progress made under the Regenerative Medicine Advanced Therapy (RMAT) designation program, barriers to efficient clinical development of gene therapy products, and the role of PDUFA VII in facilitating efficient development of, and access to, gene therapies in the United States.

The article comes at a critical time while we await the reauthorization of PDUFA VII, which will include the largest regenerative medicine package to date. The three key questions in focus are:

1. Is the RMAT designation program delivering on its intended benefits?

2. What are other challenges to the efficient development of gene therapies? and

3. Does PDUFA VII have the potential to address outstanding barriers to the development of gene therapy products? 

The article highlights progress made under RMAT, stating that since the inception of the RMAT program five years ago, 72 RMAT requests have been granted. However, as of March 31, 2022, only three RMAT products have been approved (one of which is a gene therapy)—sharply contrasting the Breakthrough Therapy Designation (BTD) program, which saw 94 approvals in the first five years. The following potential challenges are articulated:  1. securing FDA leadership guidance across all RMAT products; 2. lack of clarity on when to apply and the amount of data that would suffice; and 3. the need to align on expectations regarding the frequency of interactions after the RMAT designation is granted. Additional challenges include determining the ideal approach for first-in-human (FIH) studies given the important goals of ensuring patient safety and adequacy of the dose-selection strategy in light of the inability to re-dose, and the complexity related to the translatability of nonclinical to clinical data. As the field collectively gains more experience with advanced therapies in the clinic, approaches that may have been appropriate in the early days may need to be re-examined and streamlined. The paper further discusses challenges with understanding the ideal approach to aligning with CBER on the use of novel endpoints, an area of importance for gene therapies particularly in the setting of rare diseases. 

The hope is that many of these challenges, especially those related to interactions with FDA, will be addressed with the additional resources expected under PDUFA VII. Additionally, guidances and workshops could provide a useful forum to engage on a common understanding of the data necessary to obtain an RMAT designation. Providing examples highlighting the amount, type, and duration of data (especially for products evaluating efficacy based on biomarker data) will save time and resources for sponsors and the FDA alike. Additionally, brief pre-submission meetings, similar to what is currently in place for BTD, would help reinforce sponsors’ understanding of whether they are ready to submit an RMAT request. Specific recommendations included in the article are as follows:  

1. Leverage the substantially strengthened CBER staff capacity and capability to overcome existing resource limitations, allowing staff to spend additional time on meetings and submission reviews, including those with RMAT designation; expand stakeholder outreach given the critically of staying current in this rapidly evolving field; invest in new policy and guidance; and facilitate development and use of regulatory tools and scientific technologies. 

2. Leverage the soon-to-be formalized PDUFA INTERACT meetings to address challenges with investigational new drug (IND)-enabling and FIH studies. 

3. Explore the utility of Model-informed drug development (MIDD) approaches to help advance and integrate the development and application of exposure-based, biological, and statistical models derived from preclinical and clinical data sources in gene therapy development and regulatory review.  

4. Ensure that the new Type D meeting is leveraged to address novel issues such as innovative technology, novel clinical trial design, patient engagement to provide input on trial design, selection of clinical endpoints, or other clinical outcome assessment tools. 

5. Ensure that the Type C meetings, specifically pertaining to early consultations regarding the use of new surrogate endpoints as the primary basis of product approval, are leveraged more for gene therapy programs. 

6. Ensure active CBER participation in the Rare Disease Endpoint Advancement (RDEA) Pilot Program to inform best practices for novel endpoint development. 

7. Establish a new iterative Question and Answer guidance, leveraging questions received from sponsors through a variety of forums, to allow new Q&As to be addressed in a timely manner and made available to stakeholders.  

Overall, progress has been made with RMAT, however we have more work to do to make these innovative products available for patients, and PDUFA VII has the potential to be transformational for the field.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of Bridgebio or any of its officers. 

Dr. Ndu is chief regulatory officer at Bridgebio and former chair of the ASGCT Regulatory Affairs Committee.