The 505(b)(2) new drug application (NDA) pathway offers a unique opportunity for small molecule developers to bring innovative products to market more efficiently by leveraging existing data they do not own or have right of reference to. Unlike the traditional 505(b)(1) pathway, which requires extensive original investigations, the 505(b)(2) pathway allows developers to rely on information contained in published literature and/or from studies not conducted by the applicant, which can significantly reduce development time and cost. However, the success of a 505(b)(2) application hinges on a tailored development strategy that carefully considers the specific characteristics of the newly proposed drug product, and the nature of the changes made in comparison to a prior US FDA-approved listed drug (LD) or the drug reported in literature. Because each 505(b)(2) program is unique, they can differ widely in study requirements and therefore, time and cost to market.

Below we explore three 505(b)(2) case studies, all involving changes in formulation, and consider the strategies and approaches utilized to support drug approval. Please note that case study 2 is a fictional example inspired by real-world situations our team regularly encounters.

Case study 1: Bendeka®

Bendeka® (bendamustine HCl) injection is an anti-cancer agent for chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma with annual sales of approximately $350 million.

The LD was Treanda®, an intravenous (IV) powder that had to be reconstituted prior to administration. Bendeka is differentiated from Treanda in that it is formulated as a ready-to-use IV solution containing different excipients. This re-formulation addressed an unmet need and was shown to be compatible with closed system transfer components containing certain plastics; a noted restriction for the use of Treanda.

The 505(b)(2) submission for Bendeka included a complete chemistry, manufacturing, and controls (CMC) package, but relied on the drug master file (DMF) for Treanda. In addition, a small, abbreviated nonclinical program was conducted to compare the safety of the different products. A comparative bioavailability (BA) study evaluating the systemic exposures of bendamustine from Bendeka and Treanda was also performed. With the comparative BA study, the sponsor was able to establish the scientific bridge necessary to rely on the Agency’s previous findings of safety and efficacy for Treanda to support Bendeka’s approval.

Case Study 2: GT123

GT123 is an oral extended release (ER) capsule indicated for analgesic use. GT123 has a different dosage form and excipients than the LD, AB456, which is a subcutaneous (SQ) solution. Novel excipients were used to facilitate absorption. The anticipated value of the change to an oral ER capsule lies in an easier route of administration (RoA) and dosing regimen (i.e., daily versus four times daily dosing).

The overall development strategy for GT123 was to include a complete CMC package. Since there was no change in drug substance, the sponsor was able to reference the DMF. However, the change in RoA required a single-species, one-month good laboratory practice (GLP) toxicology study. This nonclinical study required good manufacturing practice (GMP) drug product, sham product, and vehicle to qualify the novel excipient used to modify absorption. From a clinical pharmacology perspective, the sponsors also needed to establish a scientific bridge for relying on the data contained in the product labeling of the LD. To do this, the sponsor conducted a phase 1 bioequivalence study comparing the absolute maximum absorption (C_max) and the overall exposure (AUC) of GT123 and AB456 both on the first day of dosing and at steady state. Since there was no change in indication, the sponsor did not need to conduct any additional clinical safety or effectiveness studies to support their 505(b)(2) submission.

Case Study 3: Sustol®

Sustol® (granisetron) was developed as an ER SQ injection for the prevention of acute and delayed nausea and vomiting associated with chemotherapy. The sponsor developed this new formulation using a novel polymer that would provide for ER of granisetron and differentiate the product from the approved reference, Kytril (granisetron HCl) injection, for IV use. However, the use of this novel polymer posed several challenges related to:

• The number of qualification studies required, including large nonclinical safety and clinical evaluations due to the changes in the dosage regimen, RoA, pharmacokinetics (PK), and use of a novel polymer.
• Human factors. The new formulation resulted in a drug product that was very viscous. Since the product was put into a prefilled syringe, it was necessary to understand how the patient or caregiver would interact with the delivery device and whether dosing could be performed properly.
• Pediatric considerations. The change in dosage regimen and RoA triggered the Pediatric Research Equity Act (PREA), which resulted in a post-marketing requirement to evaluate product usage within the pediatric population.

These challenges made the 505(b)(2) submission for Sustol larger and more complicated than the previous examples discussed, resulting in large nonclinical and clinical programs and robust post-marketing requirements.

Key takeaway

Every 505(b)(2) development program is unique and must be tailored to the drug product, indication, and scope of change compared to the approved LD. While the 505(b)(2) pathway offers the opportunity for quicker and more cost-effective approval, we have observed a wide spectrum of program requirements and strategies from paper-only (i.e., literature based) to those that more closely resemble 505(b)(1) programs. Program customization is key to addressing regulatory expectations for product safety and efficacy and achieving a favorable outcome in the 505(b)(2) approval process.

To learn more about leveraging the 505(b)(2) pathway, click here.