FDA regulation of health products will adapt to emerging technologies
The FDA review of product classification and pre-market approval process for cell and gene therapy will lead to better-informed product development and planning decisions for companies in this space.
FDA responsibilities for human health products are divided among centers within the agency: Center for Drug Evaluation & Research (CDER), Center for Devices & Radiological Health (CDRH), and Center for Biological Evaluation & Research (CBER), which handle drugs, medical devices, and biologics, respectively. Where a product shares attributes of two or more categories, enforcement or marketing authorization may involve participation from more than one center.
FDA centers or offices therein address emerging regulatory topics including the regulation of novel medical products. CDER’s Office of Pharmaceutical Quality created the Emerging Technology Program for pharmaceutical companies using novel production techniques; CDRH reviews De Novo applications for novel medical devices; and the FDA’s Tissue Reference Group (composed of members from CBER and CDRH) serves as a single point of contact for questions regarding human cells and tissues (including for questions regarding whether such materials are regulated as devices, human tissues, or under a different biologic classification). These groups are pivotal in determining the regulatory pathway of novel medical products.
Novel medical products with recent approvals and more on the horizon include biological products for cell and gene therapy. Such products carry a unique set of characteristics and have therefore prompted special focus from the FDA. To determine the regulatory classification of such novel products, there are three primary resources for doing so: FDA regulation and guidance, information from the regulatory landscape (e.g., classification of any similar products), and communication with the FDA. These resources are typically consulted in this order until the appropriate categorization (biologic, device, drug, or combination product), and thus regulatory pathway, is confirmed. A combination product typically has features or mechanisms of action of two or more of these categories (e.g., a drug-eluting stent is a drug/device combination product). For combination products (and in a few other cases as described below), a product may be subject to the regulatory requirements of more than one product classification.
FDA regulations 21 CFR 600, 21 CFR 820 and 21 CFR 314
Criteria and definitions for medical products are defined in regulations 21 CFR 600, 21 CFR 820, and 21 CFR 314 for biological products, medical devices, and drug products, respectively. Furthermore, the FDA issues guidance documents for the industry to inform the regulatory pathway of many novel products. Specifically, a number of draft and final guidance documents have been issued for Cellular & Gene Therapy1. These guidance documents, in some cases, explicitly define the requirements that apply to a specific product and more generally may be consulted to understand the FDA’s thinking on classification where specific guidance does not exist.
FDA guidance documents for cellular and gene therapies generally reference the Biologics License Application (BLA) as the regulatory pathway for the full market approval of such products. Like a drug, the investigational use (i.e., clinical trial) of a cellular and gene therapy product prior to full approval must be approved by the FDA via an Investigational New Drug (IND) application. A clinical trial is necessary to determine the safety and efficacy of a biological product and in turn provide the supporting data for a BLA to request full market approval. The same form (FORM FDA 356h)2 is used for both BLAs and New Drug Applications (NDAs); however, the remainder of the application (BLA or NDA) may vary significantly due to the differences in the methods of the production and mechanism of action for these products.
As can be expected based on the pre-market pathway for cellular and gene therapies, manufacturers or sponsors of cellular and gene therapy products must comply with the regulatory requirements for production and quality as required for drug products. However, other regulations may apply based on the materials and processes used to produce these therapeutic products. For example, some cellular and gene therapy products are derived from human cells and tissues. In these cases, regulatory aspects of human tissue regulation (21 CFR 1271) apply to the sourcing, handling, and processing of these human-derived materials. For example, donor testing and screening for cells and tissues used in the production of these biologics must conform to 21 CFR 1271, Subpart C – Donor Eligibility, and conformance to the related guidance3 is also recommended.
FDA classification of combination products
For combination products or where the regulation, available guidance, and classification of similar products are not accessible or detailed enough to determine the classification, communication with the FDA through FDA’s Request for Designation (RFD) Process4 is the process for establishing formal concurrence from the FDA on classification. A written RFD letter of request is submitted by the manufacturer or sponsor requesting the regulatory classification (i.e., biologic, device, or drug) and the responsible center (i.e., CBER, CDRH, or CDER). A meeting with the FDA is not a required element of the RFD Process but may be requested by the sponsor if such a meeting may be helpful for the FDA to understand the product.
Currently, some organizations are marketing stem cell therapies without FDA pre-market approval. While the FDA was previously exercising enforcement discretion around the marketing of these unapproved biologics (meaning, they were not taking enforcement action), the agency has since begun increased enforcement efforts and is taking enforcement action with organizations marketing such biologics without pre-market approval. Most recently, a firm was issued an untitled letter by the FDA in which the agency stated that the stem cell therapy offered by the firm required an IND application and that the advertised therapy may not be marketed as a human cell, tissue, or cellular-based or tissue-based product regulated under 21 CFR 1271.5 The letter specifically states that premarket approval is required for such products, unlike cells and tissues regulated under 21 CFR 1271, which do not require premarket approval for marketing in the US.
Medical Device Component Classifications
One last related topic that is frequently raised by manufacturers and sponsors pertains to the use of products and components for the manufacturing of products regulated as medical devices, drugs, and biologics. For example, medical devices or medical device components may be used for:
- handling cells and tissues from donor cadavers for transplant or incorporation into a biological product
- bioprocessing for the production of cellular and gene therapies, biological drugs, other non-device therapeutic products, or products outside of the scope of medical products (e.g., bioreactors for industrial purposes)
- containing biological or drug products (e.g., vials) for delivery to the user
It is important to note that the use of such products is outside of the definition of medical devices according to Section 201(h) of the Food, Drug & Cosmetic Act. While the device or device components are used for the production of therapeutic products, they are not directly used “in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease” or “to affect the structure or any function of the body of man.” Therefore, medical device regulation does not apply to the manufacturer’s use of such equipment for the production of biological products. Such components or products need not be approved for these uses and manufacturers do not need to verify such approvals. However, the use of approved medical devices—or components used in the manufacture of approved medical devices—provides added assurance of safety and effectiveness compared to materials not specifically intended for medical purposes.
In summary, a detailed and cogent regulatory strategy is a critical first step towards marketing any new medical product. The regulatory strategy defines the product, establishes the classification of the product, and outlines the regulatory pathway (e.g., pre-market application). Where such information is not clear in regulation or guidance, communication with the FDA is a prudent step in ensuring the proposed regulatory strategy for the device will be recognized by the agency.