Regulatory Pathway and Market Approval Process

Prior to marketing of branded and generic pharmaceutical products in the United States, approval is required by the FDA. [Figure 8] 

Small Molecule Drug Applications 

The traditional small molecule approval pathway through the FDA was instituted with the passing of the Food Drug and Cosmetic Act of 1938.26. First, a New Drug Application (NDA) 505(b)(1) is submitted to the FDA by the manufacturer. The goals of the NDA are to provide enough information to permit FDA reviewers to answer questions about the product’s safety and effectiveness in its proposed use. It also allows FDA reviewers to determine if the benefits outweigh the risks, if the drug’s proposed labeling is appropriate, and if the quality controls and methods used in manufacturing the drug are adequate. This NDA package is delivered to CDER at FDA for review.27 For generic drugs, an Abbreviated New Drug Application (ANDA) 505(b)(2) is required. This document proves equivalence to an innovator drug in dosage form, strength, route of administration, quality, performance characteristics, and intended use. These documents are “abbreviated” because they do not require preclinical and clinical data to establish safety and effectiveness.28

Similar to approval of small-molecule drugs, a Biologics License Application (BLA) 351(a) is the required document for submission of a biologic drug for approval. Therapeutic biologic products include monoclonal antibodies for in vivo use, cytokines, growth factors, enzymes, immunomodulators, thrombolytics, and proteins extracted from animals, vaccines, and microorganisms. The BLA contains specific information on manufacturing processes, chemistry, clinical pharmacology, and safety and efficacy of the product.29 Biosimilars, the generic equivalent of biologic drugs, must file a Biosimilar Biologics License Application 351(k). The goal of this application is to show that the biosimilar is “highly similar” to the biologic reference product. Interchangeability of biosimilars and their reference biologic product may require further evidence and documentation to the FDA. Both the CDER and CBER are responsible for reviewing BLAs, depending on the therapeutic area of the product. 

Approval Decision by the FDA 

After the initial NDA or BLA submission, the manufacturer waits for a response from the FDA. The Prescription Drug User Fee Act (PDUFA) plays a major role in expediting the drug approval process by the FDA in the United States. PDUFA was first authorized in 1992 and is currently authorized through September 2022. This program was initiated due to a backlog of new drug applications in the 1990s in order to help improve the FDA’s resources and ability to approve drugs within a reasonable time after submission. With the PDUFA program, all drug manufacturers pay application and program fees while submitting an NDA in order to guarantee timely review by the FDA for an NDA or BLA submission.30 

Under PDUFA, the FDA is given 10 months to review an NDA or BLA. However, if priority review is designated by the FDA, the review process is reduced to 6 months. Not every drug can be given priority review and this often includes breakthrough therapies where no or few other treatment options exist. Upon the receipt of an NDA or BLA, the FDA has 60 days to respond with a decision to file or reject the document; if it is accepted the PDUFA date countdown begins.31 

The FDA can exercise 3 options when reviewing an NDA or BLA: 

  • Approval Letter – Drug is determined to be safe and effective as submitted in the original NDA or BLA. Approval becomes effective on the date of the letter and allows for marketing to begin. 
  • Complete Response Letter – The drug has not been approved and information is presented to the sponsor outlining the materials required or conditions that need to be met for approval. 
  • Delay PDUFA Date – The FDA may, ahead of the scheduled PDUFA date, push back the date for further internal review of the product. 


Regulatory Pathway
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