The biological license application (BLA) is one of the many requests for marketing approval received by the FDA. Unlike the New Drug Application (NDA) which is usually the go-to submission for chemically synthesized, low molecular weight drugs BLAs grant sponsors the ability to introduce Biologics into interstate commerce. BLAs are evaluated by the Center for Biologics Evaluation and Research (CBER), an entity distinct from the Center for Drug Evaluation and Research (CDER) but the regulation of certain therapeutic biological agents may involve both centers. Here, we discuss a few points involving this regulatory submission which those interested in biologics might find enlightening.
Products under CBER’s Purview
CBER regulates Biologics. Biological products (also referred to as biologics) are defined in section 351 of the Public Health Services act1. According to the act, a biological product is any “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.”
Technically, biologics are a subset of the class “drugs” as defined by the Food, Drug, and Cosmetics act. Biologics, however, are not usually small molecules, are derived from living material, and are generally not fully characterized1. These attributes demand that BLA sponsors take certain precautions. For example, 21 CFR 610.40 places a requirement that establishments which collect blood – either for transfusion or as a raw material – test for evidence of transfusion transmitted infection (including but not limited to: HIV, HBV, Syphilis, West Nile virus, and Chagas disease).

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In 2003 there were several changes to the responsibilities of CDER and CBER which gave CDER regulatory oversight over some categories of biological products2. In the update, the FDA notes that Proteins, Monoclonal antibodies, immunomodulators, growth factors, and cytokines with certain intended uses were transferred to CDER for regulation. They also state that Cell Products, Gene Therapy products, and Vaccines (among other products) stayed with CBER. The reader is encouraged to review the post for more details.
BLA Submission and FDA Review
Those preparing a BLA submission are instructed to include five sections: Applicant information, Product/Manufacturing information, pre-clinical studies, clinical studies, and labeling3. Each section is intended to provide the FDA with the information it needs to determine a reasonable assurance of safety and effectiveness. Advertising, promotional material, labeling, and carton/container text can also be the subject of FDA review4. The submitted document is a substantial one with a standard review time of 10 months. Moreover, federal law authorizes the FDA to collect User Fees to facilitate the agency’s operations5. These user fees apply to several submission types and change depending on the fiscal year6. The standard fee for a BLA submission for FY 2024 is $483,560, but there are other costs which go into the process6. The review itself is broken up into five phases: filing determination and review planning, review, advisory meeting preparation and conduct, action, and post-action7.
There are four mechanisms the FDA has made available to sponsors to cut down review time, each with requirements on the drugs ability to fill medical needs. The FDA guidance document titled Expedited Programs for Serious Conditions – Drugs and Biologics provides a more comprehensive treatment on these tracks.
Priority Review
The Prescription Drug User Act gives sponsors the option to request priority review designation. In this case, the FDA seeks to shorten the review time to 6 months – but the medication must represent a significant improvement in safety and effectiveness compared to currently available treatment options8. Sponsors are notified of the designation decision by day 60 after original BLA receipt8.
Fast Track
Drugs which treat serious conditions and/or fill an unmet medical need are eligible for the fast-track process. Drugs which receive this designation are eligible for more frequent meetings with the FDA to discuss the drug’s development plan, eligibility for accelerated approval/priority review, rolling review (where the BLA is submitted in sections rather than all at once), among other benefits9.
Breakthrough Therapy
This designation is available for drugs which prove themselves to be an improvement on existing therapies through preliminary clinical evidence and are intended to treat a serious condition10. Drugs placed in this program need to continue demonstrating that they are a substantial improvement in later data, otherwise, the FDA may rescind the designation10. Some of the features include intensive drug development guidance, senior management involvement, and rolling review10.
Accelerated Approval
Accelerated approval is granted based on surrogate or intermediate endpoints which may predict clinical benefit11. These endpoints can be selected to save time, but studies confirming clinical benefit would still need to be conducted11. For example, accelerated approval was granted to the T-cell immunotherapy TECELRA (afamitresgene autoleucel) for unresectable or metastatic synovial sarcoma. The main efficacy outcome was tumor shrinkage (i.e., overall response rate according to RECIST V1.1). To get this approval, the applicant didn’t need to assess overall survival (an endpoint that would’ve taken much longer to evaluate). Instead, data on tumor shrinkage and an agreement to assess clinical benefit in an ongoing trial was sufficient.
Approval Notification and Post-Approval Efforts
At the end of review, the FDA issues a letter to the sponsor with the decision1. If approved, the manufacturer is granted a license number and permission to introduce the product into interstate commerce1. The FDA publishes lists documenting which biologics have been approved during the year12. If a change to an already approved product needs to occur, there is a three-tier reporting system; the reporting category depends on the significance of the change13,14.
References
- Center for Drug Evaluation and Research. (2019). Frequently Asked Questions About Therapeutic Biological Products. U.S. Food and Drug Administration (FDA).
- Office of the Commissioner. (2018). Transfer of Therapeutic Biological Products to the Center for Drug Evaluation and Research. FDA.
- (2021, January 27). Biologics License Applications (BLA) Process (CBER). FDA.
- Center for Biologics Evaluation and Research. (2022). Submitting Biologics Advertising & Promotional Labeling. FDA.
- Center for Drug Evaluation and Research. (2020, February 5). Prescription Drug User Fee Amendments. FDA.
- Center for Devices and Radiological Health. (2020, February 5). Medical Device User Fee Amendments (MDUFA). FDA.
- Office of Regulatory Affairs. (2019). What information is provided to sponsors during the human drug product application review process? FDA.
- Office of the Commissioner. (2018a). Priority Review. FDA.
- Office of the Commissioner. (2018a). Fast Track. FDA.
- Breakthrough Therapy. (2018). FDA.
- Accelerated Approval. (2018). FDA.
- Center for Biologics Evaluation and Research. (2022b). Biological Approvals by Year. FDA.
- Center for Biologics Evaluation and Research. (2021, June 21). Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products. FDA.
- 21 C.F.R § 601. FDA.