OVERVIEW: Mamadou Diallo, PharmD, MS is a Director of Chemistry, Manufacturing and Controls at Cardinal Health Regulatory Sciences, and Ana Barata is a Supervisor of Submissions Operations – Publishing at Cardinal Health Regulatory Sciences. These two experts will discuss the Biologics License Applications (BLA) – a necessary regulatory license request for biologic products in the drug development process.
What is a BLA and why is it necessary?
A Biologics License Application (BLA) is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce (21 CFR 601.2). The BLA is regulated under 21 CFR 600 – 680. A BLA is necessary to obtain a biologics license to market the drug. The issuance of a biologics license is a determination that the product, the manufacturing process, and the manufacturing facilities meet applicable requirements to ensure the continued safety, purity, and potency of the biological product.
What are the requirements and essential information that must be included in BLA submissions to U.S. Food and Drug Administration (FDA)?
A BLA is submitted by an applicant (manufacturer or licensee) and must contain data derived from non-clinical laboratory and clinical studies, which demonstrate that the manufactured product meets prescribed requirements of safety, purity, and potency (21 CFR Part 601.2). Form 356h specifies the requirements for a BLA. This includes applicant information, product/manufacturing information, pre-clinical studies, clinical studies, and labeling.
Do you recommend that sponsors meet with FDA prior to BLA preparation and submission?
Timely review of IND submissions with appropriate feedback to sponsors can result in greater efficiency of the drug development and approval process by reducing wasteful expenditures of time and resources. The milestone meetings include pre-IND, end-of-phase 1 (EOP1), end-of-phase 2 (EOP2), and pre-NDA (New Drug Application)/BLA meetings.
We suggest the “Pre-BLA (Type B) meetings for Original Submissions and Efficacy Supplements” as the primary purpose of a pre-BLA meeting is to discuss the planned content of the marketing application. The sponsor should submit the meeting request as an amendment to the existing IND. The meeting request should include a list of the specific objectives of the meeting and a list of questions [grouped by discipline, e.g., Chemistry, Manufacturing, and Controls (CMC), pharmacology / toxicology, clinical, statistical]. Further details regarding meeting timeline can be found in: OTP Pre-BLA Meetings | FDA. In addition, meetings are useful in resolving questions and issues raised during the life cycle of drug development. There are important reasons for sponsors to discuss development plans with FDA. FDA can provide valuable scientific and regulatory advice, resulting in more efficient and robust development programs. FDA can also help sponsors define adequate evidence of effectiveness, safety, and product quality. It is critical to efficient drug development for sponsors to ascertain FDA’s views on the applicable statutory and evidentiary requirements well in advance of submission of an application.
How important is communication between sponsors and FDA during BLA review?
Communication between FDA and sponsors during drug development and at critical stages in drug development may in due course facilitate earlier accessibility of safe and effective drugs to patients. The FDA released a draft guidance that describes why, what, when, and how to conduct interactions between FDA and sponsors efficiently and consistently in a clear, concise, and timely manner: Best Practices for Communication Between IND Sponsors and FDA During Drug Development.
Based on your experience, are there parts of a BLA that might receive special attention or additional scrutiny by FDA reviewers?
One of the most critical sections of a BLA is the Chemistry, Manufacturing, and Controls (CMC) section. This section details the manufacturing process, quality control, and analytical methods used to produce the biological product. A well-written CMC section can help to ensure a smooth regulatory approval process and reduce the risk of delays or rejections. The FDA has several CMC (Chemistry, Manufacturing, and Controls) guidelines for developing and writing a Biologics License Application (BLA) to approve a biological product. Cardinal Health Regulatory Sciences can assist in navigating the FDA guidance labyrinth to ensure an efficient experience with the BLA filing.
Can you offer some suggestions on how to best organize, format, and prepare a BLA for submission to FDA?
A well-written BLA can help to ensure a smooth regulatory approval process and reduce the risk of delays or rejections. For example, the reviewer may issue information requests based on poor navigation to specific sections, tables, or figures. If the information cannot be readily found by the reviewer, it may require additional submissions to answer the questions, when a simple and consistent hyperlink could have been the answer to the question.
Referring to the FDA guidance to ensure hierarchy is correctly followed is a good starting point to organizing the content of a BLA. For example, several sections can be merged into one document, while others should be granular and split into separate documents within an eCTD backbone. The formatting goal of any BLA submission should be FDA eCTD compliance. The use of an experienced document specialist (DS) team for formatting the documents of a BLA at an early stage is key for a successful and compliant submission to the FDA. A dedicated document specialist team, such as the CHRS DS team, can identify intra-document navigation needs at an early stage of the scientific writing process and ensure that all the hyperlinks are functioning correctly for ease of review. Another important item is to ensure consistency on how content is referenced or identified across the various content of a BLA.
A submission tracker or map is critical to ensuring each document expected in the submission is catalogued throughout the project. For the Cardinal Health Regulatory Sciences publishing team, perfection is the goal, and the team strives to come as close as possible to this goal. The publishing team will take care of all the publishing needs of a sponsor intending to file a BLA to the FDA by ensuring eCTD compliance, and generating a submission package that is easily validated by the FDA Electronic Submissions Gateway (ESG).
What are the next steps in the review process after BLAs are submitted to FDA?
According to the FDA guidance on “Good Review Management Principles and Practices for PDUFA Products”: The NDA/BLA review process is divided into five phases: (1) filing determination and review planning; (2) review; (3) advisory committee meeting preparation and conduct; (4) action; and (5) post-action. This guidance also clarifies the roles and responsibilities of review staff in managing the review process and identifies ways in which NDA and BLA applicants may further the effectiveness and efficiency of the review process. Cardinal Health Regulatory Sciences can help navigate this process for an effective BLA submission.
After a BLA is filed, how long does it typically take for FDA to review the application and render a decision?
The FDA standard review timeline for an NDA or BLA is 12 months for an initial application and 10 months for a supplemental application (both timelines include a 60‐day filing review period).
Let’s go into more details on critical aspects of the submission. Can you please discuss the main differences between BLAs submitted for original (innovator) biologics as compared with biosimilar molecules? Are there different regulatory requirements?
Biologics contain substances that have been created by using living cells or organisms often used to treat many severe and life-threatening diseases. Biologics are large molecule products, which comprise monoclonal antibodies, tissues, gene therapies, proteins, and stem cell therapies. Biologics differ from traditional small molecule drugs in terms of material sources, structural complexities, manufacturing process, and regulatory requirements. The Biologics Price Competition and Innovation (BPCI) Act of 2009 created a regulatory pathway for the approval of biosimilars. The BPCI was enacted to increase treatment options, open access to medications, and foster competition for lower healthcare costs.
The FDA defines a biosimilar as “a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product” in terms of safety, purity, and potency. In other words, biosimilars are equivalent to the biologic medications they were developed to mimic. On March 23, 2020, the BPCI Act went into effect. Along with introducing an abbreviated approval pathway for highly similar biological products (i.e., biosimilars), this act mandated that moving forward, all biological products must be submitted for marketing approval through a BLA, and not a NDA. For biological products that had been previously approved via NDA (e.g., protein products), the approved marketing application will be “deemed to be a license” (i.e., serve as an approved BLA) for the biological product under Section 351 of the PHS Act.
Under what circumstances will a BLA receive Fast Track or Breakthrough Drug Therapy designations?
To be eligible for Fast Track designation, the proposed drug should be intended to treat a serious condition and nonclinical or clinical data should demonstrate the potential to address unmet medical need. Alternatively, the drug should have been designated as a qualified infectious disease product.
What are the differences between Accelerated Approval and Priority Review designations?
Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need and a Priority Review designation means FDA’s goal is to act on an application within 6 months. Speeding up the availability of drugs that treat serious diseases are in everyone’s interest, especially when the drugs are the first available treatment or if the drug has advantages over existing treatments. The FDA has developed four distinct and successful approaches to making such drugs available as rapidly as possible: Priority Review, Breakthrough Therapy, Accelerated Approval, and Fast Track. Refer to the table and link below for further details.
Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review | FDA
What are some strategies and best practices that can be employed by sponsors to ensure an expeditious BLA submission, review, and successful outcome?
An early use of experienced Regulatory Affairs professionals, such as the Cardinal Health Regulatory Sciences team, is paramount to achieving expeditious BLA submission, review, and successful outcome. The Cardinal Health Regulatory Sciences team is a collection of very experienced individuals with diverse backgrounds working together to provide the best regulatory services our industry has to offer. We work with multiple biopharmaceutical companies, large and small.
Currently, Cardinal Health Regulatory Sciences is actively supporting multiple BLAs from various sponsors at various stages of the approval and post-approval process.
For example, we provide outstanding document specialist support to our clients. Document specialists are well versed in Word formatting and using the AMA style guide. Our DS team can implement existing client styles as well as create client-specific styles for a given project. This collaboration and support results in consistent content that showcases the science in the submission.
Our publishing team, working with document specialists, then converts the documents to acceptable eCTD format for further submissions criteria compliance. This whole-team approach is both effective and efficient in producing consistencies that are key to a reviewer’s simple access to the science of the BLA.
All aspects of the BLA submission are carefully monitored from the time the Cardinal Health Regulatory Sciences receives content from the sponsor to the time the successful Electronic Submissions Gateway (ESG) acknowledgement messages are received.
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This information is provided for educational purposes only. Cardinal Health is not responsible for any use of the information contained herein, or any implemented recommendations or results therefrom. The opinions and recommendations expressed are solely those of the author and not necessarily those of Cardinal Health, or its subsidiaries or affiliates.