Category: Formulation and Quality
Purpose: The objective is to analyse the trends in development of novel drug formulations of existing drugs through 505(b)(2) regulatory pathway and identifying the regulatory barriers associated with approval of 505(b)(2) products, primarily focusing on the development of different formulations, combinations and new uses for existing drugs. Moreover providing regulatory strategies to address the issues connected to the approval of these drugs.
Methods: Repurposed drug products approved during the period of 2010 to 2018 under 505(b)(2) pathway are investigated systematically to determine the type of studies needed to support the similarity to the reference listed drug (RLD), bridging studies required for approval of the repurposed drugs, clinical studies needed to establish safety and efficacy of repurposed drug and whether in-vitro studies are sufficient for the approval.
The drugs approved during 2010 to 2018 are retrieved from FDA drug search database (drug@FDA) and orange book database and are segregated into year wise[1,2] . Additionally the drugs are further categorized into different formulations (i.e reformulations), combinations and drugs approved for new indications (i.e repositioning) for further analysis. The regulatory information including drug approval packages, product labels and other regulatory information for each drug, both original and repurposed drug are collected from the FDA drug search database and analysed descriptively to outline the regulatory requirements like additional bridging studies conducted for the approval in a detailed case study manner for each category
Results: During 2010 to 2018, a total of 532 drugs are approved through 505(b)(2) regulatory pathway and the number of drugs approved per year represented in the figure 1. There was a sustained increase in the approvals during period and the highest number of drugs approved in 2018. Out of 532 drugs, highest number of approvals are of different formulations including new formulations and new dosage forms followed by combinations and new indications as described in the figure 2. As per the analysis, the different new formulations / new dosage forms are approved based on a single dose bioavailability/bioequivalence (BA/BE) study and food effect study to support the similarity and bridging to RLD. Some of the applicants have been conducted both single and multiple dose BA/BE studies under fasting/fed conditions and dose proportionality studies to show the steady state comparisons. Clinical efficacy studies were conducted to support new indication or due to indecisive data of BA/BE studies. Both BA/BE studies and clinical efficacy studies were conducted to demonstrate the effectiveness of combination drugs. The studies conducted for the approval of different novel formulations 505(b)(2) regulatory pathway is presented in figure 3.
Conclusion: Clinical BA/BE studies are to be conducted to compare the human pharmacokinetics of the proposed formulation or dosage form with RLD and phase 2/3 clinical efficacy studies are not required to perform in case of new dosage forms since substantial safety and efficacy can be demonstrated through bridging studies. However, clinical efficacy/safety studies to be performed to support a new indication/combination, if there is no supported literature to show therapeutic benefit and/or new dosage regimen. Dose proportionality studies to be conducted when new dose strengths are introduced which are not eligible for biowaiver. Since the requirement of studies is a case by case determination, a strong integration of drug product development plan and regulatory needs to be understand clearly for a successful development of drugs under 505(b)(2) pathway.
Ramakrishna Nirogi– Suven Life Sciences Ltd., Hyderabad, Telangana, India
Manthan Janodia– Manipal, Karnataka, India
Koteshwara Mudigonda– Hyderabad, Telangana, India
Mohan Pichiguntla– Hyderabad, Telangana, India