There are two broad application categories for drugs and biologics regulated by the United States Food and Drug Administration (FDA):
- Requests for authorization for clinical investigations
- Requests for marketing approval
The Investigational New Drug (IND) application falls into the first category, while the New Drug Application (NDA), Abbreviated New Drug Application (ANDA), and Biologics License Application (BLA) fall into the second category. Over-the-Counter (OTC) drugs are regulated slightly differently, either by conformance with an established OTC drug monograph or via the NDA process. Here we describe the differences between these application types and some of the regulatory processes and considerations associated with them.
1. Investigational New Drug Application (IND)
The IND is the launching point for clinical investigations in the United States and is an essential step along the path toward getting a new drug on the market. From the FDA’s perspective, the primary purpose of an initial IND submission is to ensure, as much as possible, the safety and rights of clinical trial participants. Besides allowing clinical investigations, the IND also performs an additional legal function. Because federal law states that only marketed drugs are permitted to be transported across states lines, the IND provides a legal framework that allows Sponsors to transport their investigational products to clinical investigators in different states. INDs may be categorized as either commercial or research. Commercial INDs allow for the development of a drug or biologic with the goal of ultimately submitting a marketing application. Research INDs involve therapies that are not intended for commercialization but are being investigated strictly for research purposes (e.g., to generate a publication or evaluate a potential mechanism). In addition to these two primary designations, emergency INDs (a type of expanded access IND application) may be submitted by physicians to allow treatment of immediately life-threatening conditions when no standard acceptable treatment is available and insufficient time exists to receive Investigational Review Board (IRB) approval. Emergency INDs act upon a different timeline than other types of INDs. Regardless of the type of IND, all IND applications must include information about the quality and nonclinical safety of the investigational product as well as the proposed clinical protocol and investigator.
2. New Drug Application (NDA)
The NDA is a formal request made by a Sponsor to market a new drug in the United States. NDAs are typically regulated by FDA’s Center for Drug Evaluation and Research (CDER). The goals of the NDA are to provide enough evidence to support the safety and effectiveness of the drug and to show that the benefits of its use outweigh the risks. In addition, the FDA will review the proposed labeling for the drug (i.e., package insert) and determine if the manufacturing methods maintain the drug’s identity, strength, quality, and purity. Data collected during the IND phase of the development program will become part of the NDA. However, the NDA is much more comprehensive than the IND and is expected to provide very detailed information about the drug. This includes primary data, reports, and summaries of the results of the nonclinical and clinical studies, analyses related to the body’s effect on the drug and the drug’s effect on the body (PK/PD), characterization of the drug’s ingredients and impurities (including any potential toxicities), and a description of all manufacturing processes and quality control parameters.
3. Biologic License Application (BLA)
Just as an NDA does for a small molecule drug (and select other classes), the BLA is a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce. BLAs are typically regulated by FDA’s Center for Biologics Evaluation and Research (CBER). Similar to an NDA, the BLA contains specific and detailed information on the manufacturing processes, chemistry, pharmacology, clinical pharmacology, and the medical effects of the biological product. Examples of biological products that would be subject to BLAs include monoclonal antibodies for in vivo use, cytokines, growth factors, enzymes, immunomodulators, thrombolytics, therapeutic proteins, and non-vaccine immunotherapies.
4. Abbreviated New Drug Application (ANDA)
An ANDA is submitted to the FDA for the review and approval of a generic drug product. ANDAs are regulated by FDA’s Office of Generic Drugs (OGD) and are considered abbreviated, as they generally are not required to include pre-clinical (animal) and clinical (human) data to establish safety and effectiveness. Instead, an ANDA only needs to demonstrate that the generic product performs in a similar manner to the reference marketed drug (commonly referred to as the Reference Listed Drug [RLD]) that appears in FDA’s Orange Book. Specifically, the generic drug must deliver the same amount of active ingredients into the bloodstream in the same amount of time as the reference product (this is known as bioequivalence) or it must demonstrate therapeutic equivalence if not bioavailable. Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low-cost alternative to the branded product.
5. Over-the-Counter (OTC) Application
Over-the-counter (OTC) drugs are defined as drugs that are safe and effective for use by the general public without needing a prescription from a health care professional. FDA’s review of OTC drugs is primarily handled by FDA’s Office of Nonprescription Drugs (ONPD). There are two pathways by which marketing of OTC products may be achieved:
- Compliance with an OTC drug monograph
- Approval under an NDA or ANDA
An OTC monograph is a set of regulatory standards for different therapeutic drug classes that includes acceptable ingredients, doses, formulations, and labeling requirements. If the standards of an applicable OTC monograph are met, marketing pre-clearance is not required by the FDA. If the OTC drug deviates from the final monograph, however, a formal marketing application (e.g., NDA) or citizen petition may be used to request approval.
Conclusions
It is important to understand the various types of drug applications and when each application is necessary. Allucent consultants have extensive experience across the various application types and approval pathways for a wide variety of drugs and biologics. If you aren’t sure which application you need or if you need help authoring, reviewing, or submitting an application – we can help. Contact us today to see how we may assist with your drug development needs!