Biologics License Applications (BLAs) for CBER-Regulated Products

INTRODUCTION

This webpage serves as a resource for industry professionals involved in the submission of a Biologics License Application (BLA) for a CBER-regulated product.

What is BLA?
A Biologics License Application (BLA) is the formal submission to the U.S. Food and Drug Administration (FDA) through which an applicant requests permission to introduce a biological product into interstate commerce (eCFR: 21 CFR Part 601- Licensing). The regulatory framework for BLAs is established under the Public Health Service (PHS) Act and the Federal Food, Drug, and Cosmetic (FD&C) Act, with specific requirements detailed in Title 21 of the Code of Federal Regulations (CFR), Parts 600-680.
The primary purpose of the BLA is to provide a comprehensive data package that allows the agency to conduct a thorough assessment of the product, confirming its safety, effectiveness, and manufacturing quality, thus satisfying the high FDA standard for approval and licensure.

Key Components of BLA
A complete BLA submission must contain sufficient information for the FDA to make the final determination. Key components of the application include:

• Product and Manufacturing Information: This section requires extensive detail on the product's Chemistry, Manufacturing, and Controls (CMC). It must describe the manufacturing facility, the production process, quality control measures, the analytical methods used to characterize the product, and ensure its identity, quality, and consistency between batches.

• Nonclinical Data: The application must include full reports from all nonclinical laboratory and animal studies. This data provides essential information on the product's pharmacology and toxicology, forming the basis for the initial safety assessment before and during human trials.

• Clinical Pharmacological Studies: This section evaluates pharmacological effects of the product on the human body physiology and biochemistry.

• Clinical Data: The BLA must contain the results from all human clinical trials conducted to evaluate the product. This evidence is critical for establishing the product's safety profile in the intended patient population and providing substantial evidence of its effectiveness for the proposed indication.

• Proposed Labeling: The sponsor must submit all proposed labeling, including the Prescribing Information (package insert), patient information leaflets, and container/carton labels. The labeling must accurately and concisely summarize the essential scientific and clinical information needed for the safe and effective use of the product, based on the data provided in the BLA.
Upon filing, CBER undertakes a comprehensive, multidisciplinary review of the BLA. If the agency determines that the data adequately demonstrate the product's safety, effectiveness, and quality, and that the manufacturing facility meets required standards, it will issue a U.S. license, permitting the applicant to market and distribute the biological product in the United States.

What Is Pre-BLA Meeting?
A Pre-BLA Meeting is an opportunity for applicants to engage directly with the FDA to discuss critical aspects of their upcoming submission. These meetings are a collaborative step between the FDA review team and applicants, enabling discussion of the proposed product development, any potential major issues, questions, as well as the content and format of the BLA. For information on formal meetings between the FDA and industry, visit: Formal Meetings and Requests for Feedback for CBER-Regulated Products | FDA

Frequently Asked Questions (FAQs)

Q: How does a Biologics License Application (BLA) differ from an Investigational New Drug Application (IND)?
A: IND: An Investigational New Drug Application (IND) is submitted by a clinical study sponsor to obtain an authorization from the FDA to administer an investigational drug or biological product to humans. Clinical studies are conducted to collect safety and efficacy information required to support a Biologics License Application (BLA) submission.
BLA: A Biologics License Application (BLA) is submitted by an applicant to request FDA approval to market a biological product. It provides comprehensive evidence that in the IND phase, the product demonstrated safety and efficacy and can be consistently manufactured to meet quality standards.
Q: What types of products require BLA for marketing in the U.S.?
A: Some examples of biological products that require a BLA for marketing in the U.S. are vaccines, blood, and blood components, allergenics, somatic cells, gene therapy products, tissues, and recombinant therapeutic proteins.
Q: Who can submit a BLA?
A: BLAs are submitted by drug companies seeking marketing of new biological products in the U.S.
Q: How do I submit a BLA Application?
A: Applicants are encouraged to send applications and other regulatory submissions electronically via the FDA Electronic Submission Gateway (ESG) to CBER. Visit: Regulatory Submissions in Electronic Format for CBER-Regulated Products | FDA webpage for more information. For submissions exempted from 745(A) binding guidance there are alternative ways of submitting. For a detailed information see: Regulatory Submissions in Electronic and Paper Format for CBER-Regulated Products | FDA webpage.
Q: What are the timelines for BLAs?
A: The timelines for BLA review process are primarily governed by the Prescription Drug User Fee Act (PDUFA) goals, which specify milestones for the FDA review of submissions. These timelines include:
• Standard Review: The FDA aims to review and act on standard BLA submissions within 10 months from the date the application is accepted for filing.
• Priority Review: For applications that qualify for priority review, the FDA aims to complete its review within 6 months of the date of the filing.
Q: The current Form FDA 356h has expired. When can I expect the new version? Is using the old version acceptable in interim?
A: On occasion, forms currently in use by the FDA reach their expiration date. FDA staff work with the Office of Management and Budget (OMB) to update and renew the expired form(s) for posting on agency’s website. The forms currently posted on the “forms” web site may be used in interim even if expired. Please continue to use the version of the form that is on the FDA Forms webpage.
Q: Are foreign applicants required to include an U.S. Agent on Form FDA 356h? What are the U.S. Agent’s responsibilities? Can the U.S. Agent also be the Responsible Official?
A:
•    Any foreign applicant in section 1 of the form MUST have a U.S. Agent identified in section 6 with a U.S. address, whether or not you have a Responsible Official based in the U.S.
•    The U.S. Agent is the contact person for the application (e.g., receives all communication from the Agency) and takes responsibility for the application and agrees to comply with all applicable laws and regulations (21 CFR 312.23(a)(1)(viii) and 314.50(a)(5) or 601.2(a)). Additional information regarding U.S. Agents, e https://www.fda.gov/medical-devices/device-registration-and-listing/us-agents.
•    The U.S. Agent may also be identified as the Responsible Official in section 36 and sign in box 37.
Q: If the sponsor/applicant is having issues with electronic submission and the eCTD structure, who should they contact?
A: Visit the following link to find resources, information, and guidance for submitting regulatory documents in electronic format:
https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/regulatory-submissions-electronic-format-biologic-products

Applicants that are new to submitting applications in an electronic format or have issues out of the scope of the website, should contact technical assistance before submitting an application. Assistance is available by contacting esubprep@fda.hhs.gov for CBER submissions.
Q: If the sponsor does not intend to submit an IND, but wants to discuss a future BLA submission, can they submit a meeting request to CBER?
A: There are many ways the sponsors can interact with CBER in discussions related to their planned drug development. See the Formal Meetings and Requests for Feedback for CBER-Regulated Products | FDA for information on an early engagement with CBER for sponsors who are pursuing novel products. For additional information see the Draft Guidance for Industry: Formal Meetings between the FDA and Sponsors or Applicants of PDUFA Products, CDER/CBER.
Q: What regulation provides the statutory requirement for licensure of biological products introduced or delivered for introduction into interstate commerce?
A: § 262 of the Public Health Service (PHS) Act provides the statutory requirement for licensure of biological products introduced or delivered for introduction into interstate commerce.
Q: Which regulations and guidance documents apply to BLAs?
A: See the following resources:
- eCFR : 21 CFR Part 601 -- Licensing
- Search for FDA Guidance Documents | FDA
Q: Are there registration requirements for CBER-related products that are regulated under a BLA?
A: Manufacturers of biological drug products subject to 21 C.F.R. Part 207 need to ensure that their registration and listing information is up to date. See the Biologics Establishment Registration and Important Registration and Listing Reminder for Manufacturers of Biological Drug Products Subject to 21 C.F.R. Part 207 for more information.
• For regulatory questions or requests for general information regarding 21 CFR Part 207 for biologic products email to CBERSPL@fda.hhs.gov or call 301-827-0373.
Q: How does the applicant obtain a tracking number from CBER?
A: CBER will issue a tracking number in advance of electronic submissions in eCTD format. Requests should be emailed to CBERRIB@fda.hhs.gov.
Q: If the applicant has questions about their BLA submission, who should they contact?
A: For questions regarding the BLA submissions, applicants should work directly with their CBER Regulatory Project Manager (RPM) who is assigned to the BLA and whose identity is provided upon acknowledgement of submission receipt.

ADDITIONAL RESOURCES
For all FDA forms visit: FDA Forms
For all FDA guidances visit: FDA Guidances
For Biologics procedures and policies visit: Biologics Procedures (SOPPs)

Miscellaneous:

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