To formally request approval for marketing a new drug in the United States, sponsors are required to submit either a New Drug Application (NDA) or a Biologics License Application (BLA) to the FDA. The purpose of the NDA is primarily for traditional small molecule drugs, whereas the BLA specifically pertains to biological products. Although their ultimate aim is to obtain marketing approval, these applications do vary slightly in terms of their content and scope. In this article, we will delve into the similarities and differences between the two marketing applications, as well as discuss special considerations based on recent regulatory changes.
The New Drug Application (NDA) is the official procedure regulated by the Food and Drug Administration (FDA) in the United States. It serves as the means through which drug sponsors formally seek approval for the sale and marketing of a new pharmaceutical product [1][2]. It is worth noting that only around 30% or less of the initial drug candidates progress through the extensive and lengthy process of drug development, ultimately culminating in an approved NDA, if successful.
The goals of the NDA are to provide enough information to permit FDA reviewers to establish the complete history of the candidate drug. Among facts needed for the application are:[2]
- Patent and manufacturing information
- Drug safety and specific effectiveness for its proposed use(s) when used as directed
- Reports on the design, compliance, and conclusions of completed clinical trials by the Institutional Review Board
- Drug susceptibility to abuse
- Proposed labeling (package insert) and directions for use
Exceptions to this process include voter driven initiatives for “medical” marijuana[3] in certain states.
A biologics license application (BLA) is defined by the U.S. Food and Drug Administration (FDA) as follows:
The biologics license application (BLA) is a formal submission seeking authorization to introduce or distribute a biologic product in interstate commerce, as defined in 21 CFR 601.2. The regulatory framework for BLA is governed by 21 CFR 600 – 680. It can be submitted by any legal individual or entity involved in manufacturing or an applicant seeking a license, taking responsibility for ensuring compliance with product and establishment standards. The requirements for a BLA are outlined in Form 356h, which includes the following specifications:
- Applicant information
- Product/manufacturing information
- Pre-clinical studies
- Clinical studies
- Labeling[1]
Certain biological products fall under the regulatory oversight of the Center for Drug Evaluation and Research (CDER), while others are subject to regulation by the Center for Biologics Evaluation and Research (CBER) [2].
After the approval of an investigational new drug, the submission of a BLA becomes necessary. Should the Form 356h be incomplete or lacking information, the FDA will provide a response within 74 days [3]. The BLA serves to assert that the product is deemed “safe, pure, and potent,” and confirms that the manufacturing facilities are capable of inspection. Additionally, each package of the product must bear the assigned license number. Following approval, annual reports, adverse event reports, manufacturing changes, and labeling changes are among the required submissions.
What are New Drug Applications (NDA) & Biologics License Applications (BLA)?
An NDA serves as an application seeking permission for the sale and marketing of a new drug within the United States. A typical NDA encompasses extensive data acquired from both nonclinical and clinical studies, alongside comprehensive summaries of formulation development, manufacturing processes, and proposed labeling information intended for the drug’s packaging. Generally, an NDA should provide adequate data to enable the FDA to determine the drug’s safety and effectiveness for its intended use. It should demonstrate that the benefits of the drug outweigh the risks, and that the manufacturing processes maintain its identity, strength, quality, and purity. Drugs authorized through the NDA pathway are regulated under Section 505 of the Food, Drug, & Cosmetics (FD&C) Act. On the other hand, a BLA is a formal request to introduce or distribute a biological product in interstate commerce. Similar to an NDA, a BLA should encompass all relevant information acquired during the product’s development and should effectively demonstrate the biological product’s safety, purity, and potency. The BLA also includes suggested labeling information for the product’s packaging. As of March 23rd, 2020, in line with the Biologics and Price Competition and Innovation (BPCI) Act of 2009, all biological products must be approved through the BLA pathway and, as a result, will be licensed under Section 351 of the Public Health Service (PHS) Act. Furthermore, they will continue to be regulated by the FD&C Act.
What is a Biological Product?
Biological products, as defined by Section 351 of the Public Health Service (PHS) Act, are a specific subset of drugs encompassing a range of substances such as viruses, therapeutic serums, toxins, antitoxins, vaccines, blood, blood components or derivatives, allergenic products, and analogous products. These products are designed for the prevention, treatment, or cure of diseases or conditions in human beings. The definition was subsequently modified by the Biologics and Price Competition and Innovation (BPCI) Act of 2009 and the Further Consolidated Appropriations Act of 2020 to include proteins, excluding peptides. A notable characteristic of biological products is their origin from living systems, resulting in large and complex structures that can pose challenges in characterization. This sets them apart from traditional drug molecules, which are chemically synthesized and comparatively simpler and smaller in size. The manufacturing process for biological products is inherently more complex due to genetic variations in the source material. Consequently, it becomes crucial to provide a comprehensive description of product development and relevant manufacturing procedures within BLAs. Additionally, the BLAs should outline the steps taken to ensure consistent performance of the final biological product across different batches.
Key Differences Between BLAs & NDAs
While BLAs and NDAs serve the same purpose of gaining approval to market a drug in the United States, they differ slightly in terms of their application content and submission requirements. Regarding approval criteria, NDAs must fulfill three conditions:
- The drug is safe and effective for the proposed use and that the benefits outweigh the risks
- The labeling is appropriate and contains all necessary information about the drug
- Manufacturing methods preserve the drug’s identity, strength, quality, and purity
Similarly, contents of a BLA should establish that the biological product is safe and potent; however, because biological products are processed from living material, BLA content must also demonstrate purity specifically in terms of showing that the final product does not contain extraneous material.
Due to the complexities of manufacturing biological products, a pre-license inspection of the facility is generally required before a BLA is approved. Pre-approval inspections sometimes also take place during an NDA review, but are typically conducted based on risk assessment by the Agency.
Once a BLA is approved, the Sponsor is granted a license for the biological product, which permits its introduction into interstate commerce per Section 351 of the PHS Act. This licensing process is not a part of the NDA, as drugs that are approved by NDA are regulated only by the FD&C Act, and not the PHS Act.
Until very recently, certain biological products could be approved under an NDA rather than a BLA. However, according to the Biologics Price Competition and Innovation Act (further discussed below) this is no longer the case, and all biological product approvals now occur through a BLA.
Regulatory Agencies
The FDA comprises two centers responsible for reviewing and approving drug marketing applications and providing general regulatory oversight: the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CDER regulates all conventional drug products, primarily small molecules, while the regulation of biological products can fall under either CDER or CBER, depending on their specific classification. While the majority of Biologics License Application (BLA) submissions are assigned to CBER, certain categories of biological products, including monoclonal antibodies for in vivo use, most therapeutic proteins (such as cytokines, enzymes, and other novel proteins), immunomodulators, and growth factors, are reviewed by CDER. However, all New Drug Applications (NDAs) for drug products, regardless of category, fall within the jurisdiction of CDER.
Key Similarities Between BLA & NDA
Just like an NDA, a BLA serves as a submission to the FDA for marketing a new drug within the United States. NDAs and BLAs share the common objective of obtaining marketing approval, thus necessitating comprehensive information to demonstrate the efficacy, safety, and favorable risk-to-benefit ratio of the drug. Moreover, both types of applications adhere to similar regulations encompassing labeling and advertising rules, accelerated approval pathways, pediatric study requirements, and PDUFA (Prescription Drug User Fee Act) fees. Irrespective of whether sponsors submit an NDA or BLA, they must comply with the same pre-marketing regulations. This includes the initial filing of an IND (Investigational New Drug) and the ongoing maintenance of the IND throughout the drug development program until the marketing application is submitted. It is important to note that the structure and contents of the IND remain consistent for drugs and biological products, regardless of the application type.
Biologics Price Competition and Innovation Act
Since March 23, 2020, the implementation of the Biologics Price Competition and Innovation (BPCI) Act has been significant. This act not only established an abbreviated approval pathway specifically designed for highly similar biological products known as biosimilars, but it also mandated a shift in the marketing approval process for all biological products. Moving forward, it became compulsory for all biological products to be submitted for marketing approval through a Biologics License Application (BLA) rather than a New Drug Application (NDA). Consequently, for those biological products, such as protein products, that had been previously approved via NDA, their previously approved marketing application is now considered a “deemed license” serving as an approved BLA for the respective biological product under Section 351 of the Public Health Service (PHS) Act.
Conclusions
When seeking FDA approval to market a new drug in the United States, two types of applications, NDAs and BLAs, are typically submitted. While both applications share the goal of obtaining FDA approval, they differ in terms of product categories, approval criteria, and specific regulations. At Nuventra, our consultants possess extensive expertise in preparing and submitting both BLAs and NDAs for various drugs and indications. If you require guidance in preparing your marketing application or need assistance with its development, Nuventra is dedicated to providing the support you need. Reach out to us today to explore how we can assist you on your journey towards obtaining FDA approval.
Parts of the above were inspired by: Anginelle Alabanza, M.S., R.A.C.