Peter Marks, MD, PhD, Director Center for Biologics Evaluation and Research at U.S. Food and Drug Administration answered some of my questions about the current state of the FDA’s regulations around cell and gene therapies, its stance on international harmonization required to make cell and gene therapies more streamlined, the reasons why it is critical for companies to begin working with the FDA early in the development process, and more. Read on for Dr. Marks' insightful responses.
Harris: What is the current state of FDA regulations around cell & gene therapies? And, what is the state of the suite of the guidances surrounding cell and gene therapies?
Marks: Human cells and tissues intended for use in humans are regulated by CBER as human cellular and tissue-based products (HCT/Ps). FDA has a risk-based approach to the regulation of HCT/Ps. Under the authority of Section 361 of the Public Health Service (PHS) Act, FDA established regulations for all HCT/Ps to prevent the transmission of communicable disease. These regulations can be found in Title 21 of the Code of Federal Regulations. HCT/Ps that meet all of the criteria in 21 CFR Section 1271.10(a) are regulated solely under Section 361 of the PHS Act. If all of the criteria in 21 CFR Section 1271.10 are met, then no premarket review (application to FDA) is required and only provisions necessary to prevent the transmission of communicable diseases must be followed. HCT/Ps that do not meet all of the criteria of 21 CFR Section 1271.10 are also regulated under Section 351 of the PHS Act and/or the Federal Food, Drug, and Cosmetic Act as drugs, devices, and/or biological products and require premarket approval prior to distribution. See FDA guidance, “Regulatory Considerations for Human Cells, Tissues, and Cellular, and Tissue-Based Products: Minimal Manipulation and Homologous Use.”
In July 2018, FDA issued six draft guidance documents that, when finalized, will detail FDA’s current thinking on the manufacture and clinical development of gene therapies. Three of these draft guidance documents related to the development of gene therapies for specific disease categories.
Draft Guidance for Industry: Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)
In response to requests, the FDA recently announced that it is extending the comment period for all six of the July draft guidance documents to allow interested persons additional time to submit comments and any new information.
Harris: Why is it important for companies to begin working with the FDA early in the development process?
Marks: The development and clinical study of cellular and gene therapy products can be quite complex, time-consuming, and expensive, particularly for a relatively new field of medicine. While the guidance documents mentioned above are aimed at addressing some of the challenges, the value of early communication with FDA cannot be overstated. While formal meetings with FDA have been routine for some time, CBER believes that early communication is so important that it has instituted a program to encourage even earlier, informal communication.
In June, 2018, CBER officially launched the INTERACT meeting program (INitial Targeted Engagement for Regulatory Advice on CBER ProducTs). The program was created to help foster the development of products regulated by the CBER by encouraging early discussions and feedback from the Center. The program applies to all CBER products, and aims to address the many questions product sponsors have during the transition from preclinical to clinical development. This early engagement can help sponsors meet the FDA’s science-based requirements more effectively and help avoid costly delays that can unnecessarily impede access to beneficial new products.
Harris: What is the FDA’s stance on international harmonization required to make cell and gene therapies more streamlined?
Marks: The FDA shares public information with international regulatory counterparts in several venues. Of note, the working groups are under the aegis of the International Pharmaceutical Regulators Programme (IPRP). The European Medicines Agency (EMA) is an active participant in these working groups. Specific to gene therapies, there is an IPRP Gene Therapy Working Group (GTWG). Information on this group and its mandate can be found at the legacy website of the IPRP’s predecessor organization, the International Pharmaceutical Regulators Forum (the IPRP was launched in January 2018 and its website is under development): https://www.i-p-r- f.org/index.php/en/.
The FDA and EMA also offer sponsors the opportunity to engage in Parallel Scientific Advice – further information on this engagement can be found at
Harris: Without naming specific companies, names, etc. what mistakes do you see companies making with regard to their work with the FDA on cell & gene therapies? How can companies avoid such mistakes?
Marks: Though by all means not applicable to all sponsors, those developing cell and gene therapies need to be more forward leaning as they develop products, both in manufacturing and clinical trials. In manufacturing, they need to focus on producing quality products by design in scalable processes, so that if early clinical trials are promising, they can advance development rapidly. In clinical trials, they need to be bold enough to take the chance to look at well-conceived clinical end points that can conclusively demonstrate whether a product is both safe and effective.
FDA guidance documents also give a good indication of where additional input from the Agency is needed. Efficient drug development requires collaboration among many stakeholders.
Sponsors often fail to engage these various stakeholders (e.g., scientists with expertise in manufacturing and drug development, academicians, patients, and patient advocacy groups) early in product development. As a result, sponsors may not be adequately prepared for their meetings with FDA, potentially limiting the value of those meetings. We strongly recommend that sponsors begin working with other stakeholders early in drug development. These interactions with other stakeholders allow sponsors to maximize the utility of their meetings with FDA.