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OTAT Town Hall: Clinical Development of Gene Therapy Products for Rare Disease



Fajar Dumadi, BSc
Regulatory Program Specialist
ISCT Head Office


The FDA’s Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) hosted a virtual town hall to answer stakeholder questions related to the clinical development of gene therapy products for rare diseases. 

This event was held on February 7, 2023 (11:30 AM - 1:00 PM ET). This was part of a series to answer questions from stakeholders about a variety of topics on which OTAT has regulatory oversight. The format of the event is “question and answer” discussion. The participants can either submit their questions before or during the event. Any questions that are out of scope or about specific investigational products or drug applications, however, will not be addressed by the FDA.


Moderator: Tejashri Purohit-Sheth, MD – Division of Clinical Evaluation General Medicine


·         Melanie Blank, MD – Division of Clinical Evaluation General Medicine

·         Elizabeth Hart, MD – Division of Clinical Evaluation General Medicine

·         Lei Xu, MD, PhD – Division of Clinical Evaluation General Medicine


Here is some of the questions that were addressed during the event:


What are the conditions under which it may be appropriate to allow a single arm externally controlled trial to provide the primary evidence of effectiveness for approval for a gene therapy?

Gene therapy requires substantial evidence of effectiveness from adequate and well controlled clinical studies which include features such as a valid comparison with the control.

1.       Placebo or sham concurrent control

2.       The active concurrent control

3.       The dose-ranging concurrent control

4.       No treatment concurrent control

5.       External or historical control  

A blinding and randomization are visible when a concurrent control is used. The blinding, however, would not be visible for the external control. FDA prefers the first three concurrent control because those permit both randomization and blinding. And the next best control is no control because although the study subjects will know if they are or are not receiving the investigation of treatment, they will be otherwise selected, treated, and assessed.  

Trial using external control, such as a natural history control rather than concurrent control, may be appropriate under certain circumstances, such as rare and serious conditions. For example,

·         if the studied disease has well understood underlying pathogenesis, disease course is well documented, highly predictable, and can be objectively measured and verified, OR

·         The study population and the external controls are suitably comparable, and the expected treatment is that is large, self-evident, and closely associated temporarily with the gene therapy administration.


Would it be appropriate to enroll healthy volunteers in a gene therapy?

Healthy adult volunteers may be reasonable for an early phase trial for products with short duration of action, or in a class of products with a well understood safety profile. For most of gene therapy products, however, this is not the case. The risks of most gene therapy products include the possibility of extended or permanent effects along with the risks of any embassy procedures necessary for the products’ administration. Therefore, for most gene therapy trials, the benefits and risk profile are not acceptable for healthy volunteers to be enrolled in the early phase.


Under what circumstances might it be appropriate to enroll pediatric patients in early-phase gene therapy clinical trials prior to testing a product in adults?

When possible, if the disease affects an adult population, it is best to go first in adults, and there’s some preliminary safety before going into children. However, if there are children affected by the disease, it is best to go to older age group first before the younger, unless the disease only affects the youngest group. And it is important to consider risk benefit analysis, because in gene therapy the risk sometimes is not understandable, therefore, a patient population whom obtaining more benefit should be enrolled first.


Can you please discuss the use of real-world data for gene therapies in rare diseases?

Real world data or evidence (RWE) is referring to the registries as well as electronic records and/or medical claims. The use of RWE, however, is something that should be discussed with the FDA. And once it is used, it must be used as an external control. 

CDER and CBER released a draft guidance on ‘Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products’. This draft guidance talks about, how can RWE be potentially used as external control. This guidance is open for public comment until May 2nd, 2023. 


How FDA interacts with other regulatory agencies, such as European Medicines Agency (EMA)?

FDA engages with EMA and Health Canada quite frequently. FDA have a meeting where these 3 agencies sit together and discuss about clinical development program that is shared by these 3 agencies.  

Click here to view the full recording for the OTAT Town Hall on Clinical Development of Gene Therapy Products for Rare Diseases.

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