Blog Post

505(b)(2) Regulatory Pathway: What are the Advantages and Does Your Product Qualify?

November 19, 2020

Under the Food, Drug, and Cosmetic Act, there are three regulatory pathways for drugs to gain marketing approval in the United States:

  • 505(b)(1) New Drug Application (NDA): An application for a new drug with a novel active ingredient, with the requirement to provide complete information to support the drug’s efficacy and safety, derived from studies for which the applicant has right of reference
  • 505(b)(2) NDA Pathway: An application for a new drug product that includes one or more studies (clinical or nonclinical) that are necessary for approval but were not conducted by the applicant and for which the applicant does not have right of reference
  • 505(j) Abbreviated NDA: An application for a drug that is a generic equivalent of a previously approved drug, relying upon data demonstrating bioequivalence to a previously approved “reference listed drug”

Over the past two decades, the development of drug products that fall somewhere “between” a brand new drug with a novel active ingredient and a pharmaceutically-equivalent generic drug (in other words, drugs that could qualify for a 505(b)(2) pathway) has grown extensively. This growth is due to the advantages offered by the 505(b)(2) pathway for more expeditious development of a new product, as well as the breadth of products that may qualify for this pathway.

Advantages of the 505(b)(2) Pathway

The advantages conferred upon the 505(b)(2) pathway by the 1984 Drug Price Competition and Patent Restoration Act (Waxman/Hatch Act) derive from Congress’s attempt to provide the public with lower-priced options for medications already on the market. The Waxman/Hatch Act is probably better known for ushering in the generic drug industry legislation with the ability for pharmaceutically-equivalent copies of existing approved drugs to be approved and marketed, thus generating competition for the sole approved branded drug on the market. However, the advantages conferred on companies submitting a 505(b)(2) marketing application are no less significant for developing products which may differ from a branded product by small formulation changes or different routes of administration. The goal of the legislation was to allow for drugs to be marketed without requiring duplicative studies to be conducted by each applicant.

Prior to 1984, FDA allowed drugs bearing formulation differences and altered routes of administration from marketed products to be approved on the basis of literature-based argument, and the burden of evidence for safety and efficacy of the new product depended entirely on the evidence provided by the new product sponsor in a literature review. What the Waxman/Hatch Act provided the new applicant was the ability to also reference the safety and efficacy data residing in the marketing application of the innovator company without the need for a right of reference. Since the active pharmaceutical ingredient in the new product had not been altered, the Waxman/Hatch Act argued that the basic preclinical and clinical safety and efficacy information was equivalent between both the original product and the new product.

Of course the different formulations (e.g., extended release vs immediate release) or new routes of administration may render the new product sufficiently different to require the 505(b)(2) applicant to also perform clinical studies; however, these studies are less comprehensive than those the innovator company was required to conduct. Often times a simple bioequivalence study is sufficient to generate the data to convince FDA of the sufficient similarity of the two products. However, in some cases one adequate and well-controlled clinical study is necessary for FDA to approve the new product, but this is still an advantage compared to the standard requirement of FDA for two adequate and well-controlled clinical studies for the innovator’s product.

In summary, the advantages afforded the 505(b)(2) applicant are significant in that the applicant is able to reference safety and efficacy data in the marketing application of the innovator product rather than conduct costly preclinical and clinical studies. In addition, if clinical studies are required to convince FDA of the new product’s safety and efficacy, the clinical program will undoubtedly be less comprehensive than the clinical program conducted by the innovator company due to the 505(b)(2) applicant’s ability to reference the innovator’s marketing application. It is important to note that the quality/chemistry, manufacturing, and controls section of the marketing application must stand alone in the 505(b)(2) application as there is no substitute for a company being able to manufacture the product to standards demonstrating its identity, strength, quality, potency, purity, and stability.

Does Your Product Qualify for the 505(b)(2) Pathway?

As described above, for a 505(b)(2) NDA, an applicant can rely on either published literature or the FDA’s previous findings of safety and effectiveness for an approved drug, or both. And as outlined in FDA’s 1999 Draft Guidance for Industry:  Applications Covered by Section 505(b)(2), a 505(b)(2) NDA can be submitted for:

  • A new chemical entity (NCE) when relying upon published studies for which the applicant doesn’t have right of reference
  • A change to a previously approved drug, relying upon the safety and efficacy of a previously approved listed drug as well as any additional new information required to support the change from the approved drug

The vast majority of 505(b)(2) development programs and NDAs fall into the second category as a change to a previously approved drug. Such new drug products run the entire range from slight changes that don’t otherwise qualify as a generic drug, to more extensive changes that require a significant amount of new data while still relying on safety or efficacy information for an approved drug (the “listed drug”).

Examples of changes to approved drugs that could qualify for the 505(b)(2) pathway include changes in dosage form, strength, formulation, route of administration, dosing regimen, or indication, as well as combinations of these changes. For example, a sponsor may develop a new formulation of an approved drug, with a different strength and route of administration to treat a new indication, and the sponsor could still follow the 505(b)(2) pathway and rely on safety information of the approved “listed drug”, as long as the sponsor can provide an appropriate scientific bridge from the new product to the “listed drug.”

So overall, a new drug product consisting of a change to a previously approved drug could follow the 505(b)(2) pathway, if the applicant can provide the appropriate scientific bridge to the approved drug and if the applicant does not have right of reference to the data that supported approval of the previously approved drug.

Rho has extensive experience in supporting our clients in the development of 505(b)(2) products and in the preparation and submission of 505(b)(2) NDAs. Future blog posts will cover important topics for the development of products under the 505(b)(2) pathway, including nonclinical and CMC strategy and considerations for a 505(b)(2) product development program, how to select the appropriate listed drug to reference in your 505(b)(2) NDA and what constitutes an appropriate scientific bridge to the listed drug, what clinical studies are required for this pathway, and how to engage with FDA in your development program.

Kevin Barber, PhD, RAC, PMP, Vice President of Regulatory Strategy & Submissions, has more than 20 years of experience in regulatory affairs and product development, working for both sponsor companies and CROs, across all stages of development from pre-clinical through product launch and post-approval life cycle management. He has led the preparation and execution of integrated regulatory strategy and clinical development plans for drug, biologic, and medical device products in therapeutic areas including dermatology, nephrology, urology, women’s health, CNS/neurology, cardiovascular diseases, virology, oncology, immunology, infectious diseases, blood products, and gene therapy. Dr. Barber has significant experience preparing and filing regulatory submissions, including more than 45 US INDs and more than 40 marketing applications in the US, Canada, Europe, Latin America, Australia, and New Zealand. He also has experience with medical device and in vitro diagnostic development programs and regulatory submissions including pre-IDE meetings, IDEs, 510(k)s, and PMAs.


Dr. David Shoemaker, PhD, Senior Vice President of  Research and Development, has been a trusted regulatory advisor to international clientele for close to 30 years, providing regulatory and scientific expertise for integrated product development programs across a wide range of therapeutic areas.  Dr. Shoemaker has extensive experience in all stages of investigational product development, has moderated dozens of regulatory authority meetings, and has managed and contributed to over one hundred INDs, over a dozen IMPDs, and dozens of successful marketing applications across the majority of reviewing divisions at FDA and several international regulatory authorities.  At Rho, Dr. Shoemaker serves as an expert scientific and regulatory reviewer for documents destined for regulatory authorities and as an advisor to integrated product development program teams.  For the past 10 years, Dr. Shoemaker has also served as the Vice Chair of the Product Development Review Counsel and as a Product Development Review Committee Study Section Chair for the Cancer Prevention and Research Institute of Texas. He has helped oversee the distribution and management of over $440 million dollars in grants to 46 early stage pharmaceutical, biotechnology, and medical device companies.  Dr. Shoemaker’s primary areas of interest focus on the development of clinical protocols and clinical development plans for novel therapeutic products.