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Paths to Approval: Understanding U.S. Regulatory Pathways for Drug Products

Manufacturers in the pharmaceutical industry range from large brand names with global presence to small startups operating out of rented lab space. However, when it comes to bringing a drug to the U.S. market, the company bringing in billions of dollars and the company with no profits to speak of both must go through the appropriate regulatory pathways to seek FDA approval for their products.

Bringing a drug product to market is an expensive endeavor - a nearly $2.6B endeavor - according to research by the Tufts Center for the Study of Drug Development. With this in mind, it is imperative to understand the regulatory pathways that all products must go through before they enter the market.

This article details the 3 potential regulatory approval pathways that new drug products must go through in order to receive approval in the United States, including 505(B)(1) or NDA, 505(B)(2), and 505(J) or ANDA. Other articles cover data and market exclusivities that go along with new product applications as well as the FDA’s role in the approval process.

Regulatory Approval Pathways

Companies seeking approval to market a new drug product can follow one of several potential regulatory approval pathways in the United States:

  1. The 505(b)(1) pathway

  2. The 505(b)(2) pathway

  3. The ANDA/505(j) pathway

505(b)(1) New Drug Application

If a company owns all the data around safety and efficacy for its product, then it will file a 505(b)(1) new drug application. Commonly referred to as an NDA, this type of application is normally associated with a new brand product.

An NDA contains full reports of investigations (clinical studies) of safety and effectiveness. The clinical studies relied on for potential approval of the new drug product are conducted by the applicant or for the applicant by a third party (such as a Contract Research Organization (CRO)). Additionally, the applicant can obtain a right of reference or use for the clinical studies.

505(b)(2) New Drug Application

A company may wish to develop drugs that often contain the same active ingredients as already-approved drugs, but differ in areas such as dosage form, combination of active ingredients, or route of administration. Instead of submitting these differentiated products through the 505(b)(1) approval process and duplicating studies of similar drugs that have already been approved, a company can pursue approval through the 505(b)(2) pathway.

While products seeking approval through the 505(b)(2) pathway must demonstrate safety and efficacy to the same standards as an NDA application, products under a 505(b)(2) application are supported at least in part by data not developed by the applicant itself. This data may include existing published literature or FDA findings of safety and efficacy for previously approved drug products. This allows for a faster and less expensive path to approval, while also giving companies opportunities to bring new, differentiated products to market.

Products related to bendamustine hydrochloride are examples of medications approved under the 505(b)(2) pathway:

  • In March 2008, Cephalon (since acquired by Teva) received approval for Treanda, a purine alkylator hybrid chemotherapy agent indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) and relapsed indolent non-Hodgkin’s lymphoma.

  • In 2015, the Eagle Pharma received approval for Bendeka through the 505(b)(2) pathway with Treanda as its reference product.

  • Treanda is a powder that requires reconstitution. The 505(b)(2) application for Bendeka used a modified dosage form of a ready-to-dilute solution that provided for multiple doses and less infusion time.

Orange Book Ratings and Drug Interchangeability

When more than one drug is approved by the FDA that has the same dosage form, route of administration, and strength, the FDA evaluates the drugs for therapeutic equivalence; products that are therapeutically equivalent are expected to have the same clinical and safety effects.

In the Orange Book, therapeutic equivalence codes have 2 letters. The first letter indicates whether the approved product is therapeutically equivalent to a previously approved product (called the “Reference Listed Drug” or “RLD”). If a product is therapeutically equivalent to the RLD, then it will be given an “A” rating. The second letter refers to the route of administration. For example, if a product that is therapeutically equivalent to the RLD is topically applied, then it will be given an “AT” rating.

If FDA believes a product has an actual or potential bioequivalence issue, but the application was able to meet the necessary bioequivalence requirements, then it will be given an “AB” rating. If a 505(b)(2) applicant obtains this determination from the FDA, then its product would be substitutable for the branded product.

If the FDA identifies a product as having actual or potential bioequivalence issues and the application was not able to show therapeutic equivalence, then it will be given a “BX” rating. Finally, there are products that the FDA does not rate at all.

ANDA/505(j) Application

If a company is seeking approval for a generic drug, then it will file an abbreviated New Drug Application (ANDA), also known as a 505(j) application, which is an expedited approval pathway. An ANDA includes information to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics, and intended use to an RLD.

ANDAs do not contain clinical studies but are required to contain information establishing bioequivalence to the RLD. Generally, the bioequivalence determination allows an ANDA to rely on clinical studies submitted along with the RLD as well as FDA findings of the RLD’s safety and efficacy. As part of the approval process for a generic product, the FDA requires many rigorous tests and procedures to assure that the generic drug is interchangeable with the branded drug under all indications and conditions of use for which the generic drug is approved.

Generic Drug Label Carve Outs

In limited circumstances, the FDA allows the labeling for a generic product to differ from the labelling for the RLD in cases when it would not jeopardize the safe or effective use of the product. When the labeling of the RLD includes multiple indications, a company filing an ANDA can propose omitting, or “carving out,” one or more indications from the label. This often occurs when newer indications in the labeling an RLD are protected by patents or regulatory exclusivities. FDA will sometimes allow generic manufacturers to “carve out” to such indications from the label in order to avoid violating a brand manufacturer’s patent rights or regulatory exclusivities.

Gleevec (imatinib mesylate) is a notable example of a generic label carve out. Gleevec is approved for the treatment of various forms of cancer, including certain Gastrointestinal Stromal Tumors (GIST). Most of the patents on Gleevec expired in 2015 and 2019, but the brand manufacturer (Novartis) owned a patent on the GIST indication that is protected by a patent and regulatory exclusivity until 2022. FDA has approved several generic products with a labeling carve out that omits the protected GIST indication from the generic labeling.

Another example regards a combination therapy approval. If an RLD is approved as both a monotherapy and as a combination therapy (use in combination with one or more drugs) then, in certain circumstances an ANDA applicant may seek a generic label for the use of the active ingredient as a monotherapy for another indication.


A supplement is a request to approve a change in a drug application that has already been approved. Each indication or claim is considered a separate change for which a separate supplement should be submitted. This policy allows the FDA to approve each indication or claim as it is ready for approval, rather than delaying approval until the last of a group of indications or claims is ready to be approved.

The Need for Sound Regulatory Strategy

In the high-stakes environment of drug development and commercialization, knowing the appropriate regulatory pathways to pursue is essential to successfully bringing products to market in the United States. Formulating the right regulatory strategy around a new product can help cement future blockbuster products, while regulatory mistakes can block a product from ever reaching consumers.

To learn more about how IPD Analytics helps companies navigate the U.S. regulatory landscape, from drug pipeline to loss of exclusivity and beyond, take a look at our Life-Cycle Insights solution.


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