(M1230-01-06) Generic Long-Acting Injectable Product Availability and Approval Standards

Purpose: Long-acting injectable (LAI) drug products enable the controlled release of a drug over an extended duration of time to achieve a prolonged therapeutic effect. Extended therapeutic effects offer several benefits including increased medication adherence, improved safety and efficacy, decreased healthcare costs, and improved patient outcomes. The objective of this study is to survey generic LAI approvals by the European Union (EU) and the United States (US) regulatory agencies and compare the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval standards for generic LAIs.

Methods: The EMA medicines database was utilized to collect centrally approved new and generic/hybrid LAI products by limiting the search category to human medicines. In addition, national registers of authorized medicines were used to collect LAI products approved via national procedures in EU. Drugs@FDA was used to discern LAIs approved via a new drug application (NDA) or abbreviated new drug application (ANDA) by identifying LAI drug products and reviewing respective approval letters and labeling. EMA product-specific bioequivalence guidances (PSGs), FDA product-specific guidances (PSGs), EMA approval summaries, and the EMA’s guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms were utilized to collect information about approval standards of generic LAIs. Regulatory recommendations between agencies for each model drug product were compared.

Results: LAI products include suspended solids, polymer microspheres, multi-vesicular liposomes (MVLs) or other liposomes, oily solutions, and in situ forming (ISF) polymer implants. The FDA has approved 52 NDAs including all LAI product types mentioned and 10 ANDAs containing suspended solids of medroxyprogesterone acetate and paliperidone palmitate, respectively. Currently, the EMA has at a minimum 16 centrally approved new LAI products and one centrally approved generic LAI. Exenatide powder for suspension, lanreotide acetate injection, octreotide acetate powder for suspension, and paliperidone palmitate suspension received approval in several European countries via national procedures. Regarding guidance development for LAIs, EMA’s guideline on the pharmacokinetic and clinical evaluation of modified release dosage forms included strength and study type recommendations for intramuscular and subcutaneous depot formulations. In addition, to aid in the development of generic/hybrid LAIs, EMA has published four PSGs for the following APIs: exenatide, lanreotide acetate, octreotide acetate, and paliperidone palmitate. FDA does not have a general guidance for LAI products but has published 21 PSGs to guide the development of generic LAI products. The PSGs of four LAI drug products, exenatide powder for suspension, lanreotide acetate injection, octreotide acetate powder for suspension, and paliperidone palmitate suspension published by both the FDA and EMA were compared for their bioequivalence study recommendations in PSGs. Some noteworthy similarities and differences include: 1) For lanreotide acetate injection, both EMA and FDA recommend a single dose, parallel in vivo pharmacokinetic (PK) BE study in healthy subjects with possibility of a waiver. Furthermore, EMA proposes specific analytical methods for in vitro characterization studies and partial AUCs (pAUCs) as BE matrices. 2) For exenatide powder for suspension and paliperidone palmitate suspension, EMA recommends conducting both a single dose study and multiple dose in vivo PK BE study with the possibility of a multiple dose BE study waiver in patients, while the FDA recommends either a single dose study or a multiple dose BE study in patients for exenatide and a multiple dose PK BE study in patients for paliperidone palmitate. 3) For octreotide acetate powder for suspension, FDA recommends a fasting, single dose in vivo PK BE study in healthy subjects, while EMA proposes conducting a single dose study and multiple dose study with a potential multiple dose study waiver if the single dose PK is well characterized in healthy subjects. In the single dose PK BE study, both agencies recommend Cmax, AUC, and pAUCs with the same time intervals as BE matrices.

Conclusion: Despite significant benefits of LAI drug products, there are limited generic LAIs available on the global market. This work identifies similarities and differences between EMA and FDA regulatory standards of generic LAIs and serves as a foundation for future work on the potential harmonization of generic approval standards for LAIs. Convergency among agencies globally would provide applicants with clear objectives, enabling improved allocations of resources, and consequently adding more complex generic competition.

References: O’Brien MN, Jiang W, Wang Y, Loffredo DM. Challenges and opportunities in the development of complex generic long-acting injectable drug products. J Control Release. 2021; 336:144-158.

Disclaimer: The contents in this abstract reflect the views of the authors and should not be construed to represent U.S. FDA’s views or policies.
Acknowledgements: Krista Anim Anno was supported in part by an appointment to the Oak Ridge Institute for Science and Education (ORISE) Research Participation Program at CDER administered by the ORISE through an agreement between the U.S. Department of Energy and FDA.