Industry Observation I FDA Launches New Regulations for the Pilot Application of Generic Drugs

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On September 12, 2023, the FDA's official website ANDA updated the content, and the FDA's generic drug program launched a new pilot rule to provide a meeting opportunity for generic drug applicants to use Model Integration Empirical (MIE) methods to establish bioequivalence (BE) in their simplified new drug application (ANDAs) submissions.

The use of MIE methods to establish BE is becoming increasingly common, especially in the development of challenging products such as long-acting injections, oral inhalation drugs, and topical dermatology drugs. The pharmaceutical industry regularly seeks feedback from the FDA on the implementation of MIE regulatory practices, including general modeling methods and official guidance on solving complex scientific and regulatory issues.

The main goal of the MIE pilot program is to promote interaction between the industry and the FDA on preliminary and joint issues, discuss scientific advancement issues related to MIE methods, and establish BE in generic drug development. This pilot project will promote stronger scientific exchanges between generic drug developers and the FDA, with a particular focus on using quantitative methods and modeling techniques.

The new MIE pilot program aims to:

• Addressing common issues in multiple products and challenging issues with non complex drugs beyond the scope or focus of current Pre ANDA and ANDA conferences

• Provide a dedicated platform for in-depth discussions on scientific and technical issues related to MIE implementation during the product development cycle, preferably in the early stages of planning.

According to the MIE pilot plan, the meeting can be approved if it involves the following aspects:

• Innovative BE establishment methods with a focus on MIE, which cannot be effectively addressed at existing GDUFA scientific conferences

• Non complex products with complex methods/modeling based on the Biopharmaceutical Classification System (BCS) - based on biological exemptions and/or other research exemptions

• New data analysis tools and methods for BE establishment and evaluation (such as machine learning and artificial intelligence)

Overall, this pilot program is a specialized regulatory platform for the industry to explore the proposed MIE method, obtain FDA recommendations on its feasibility and progress, and address relevant scientific and technological issues.

The FDA Office of Genetics will begin accepting meeting requests for pilot projects on October 1, 2023. The FDA will continue to receive meeting requests under the MIE pilot program until a sufficient number of MIE meetings are held. The FDA will evaluate the pilot plan at the end of the first year or after five meetings (whichever occurs first) to determine the next stage of the pilot plan.

A flowchart describing the process and timeline for evaluating requests and conducting MIE meetingsⁱ

Model based drug development (MIDD) is a method that utilizes preclinical and clinical exposure data, biological and statistical models to guide drug development and decision-making. It aims to integrate information from different data sources, generate information that cannot or cannot be obtained through experiments through Modeling&Simulation, and help reduce uncertainty and failure rates. Model guided drug development is a powerful method to support drug development and regulatory review. The US Food and Drug Administration (FDA) has a rich history of MIDD applications. MIDD applications span the lifecycle of new drug, generic drug, and biological product development.

The Evolution of FDA MIDDⁱⁱ

The above figure briefly summarizes the main highlights and future prospects of FDA for each decade. Abbreviations: ICIVC in vitro in vivo correlation; PK/PD in pharmacokinetics/pharmacodynamics; popPK in population pharmacokinetics; D/R in dose response; E/R in exposure response; CTS in clinical trial simulation; EOP2A-2A phase end; PBPK in physiology based pharmacokinetics; DDI in drug interactions; DDT in drug development Sending tools; MIDD - Model based drug development; QCP - Quantitative Clinical Pharmacology; PBBM - Physiological based biopharmaceutical model; RWD/RWE - Real World Data/Real World Evidence; RTRT - Real time release testing; MIE - Empirical Model Integration; PDUFA - Prescription drug user payment method.}

In 2020, CDE also released the first Model Guided Drug Development (MIDD) Guidelines (Draft III), which provide a detailed description of the basic concept of MIDD, the role of drug research and development centers, the types of model analysis, and the implementation process of model analysis.

Schematic diagram of MIDD application in the drug development lifecycle

Image cited from 'Draft for Comments'

As the FDA receives more information and knowledge after approving new drug applications (NDAs), a new conceptual model integration empirical (MIE) has emerged as a continuation system of MIDD in the field of generic drug development. MIE refers to the use of model generated information, such as virtual bioequivalence (VBE) research models, which can not only plan key studies but also serve as confirmatory evidence. Combined with relevant BE testing, MIE can support alternative approaches to traditional in vivo BE studies, including but not limited to PK, PD, or comparative clinical endpoint BE studies as confirmatory information.

Comprehensive drug development model for new drugs^iv

The x-axis represents the time of product development and the y-axis represents the confidence interval for the clinical performance of new drugs. The three lines from bottom to top represent the model, data, and model integration evidence axis in drug development. The model integration evidence line is a dashed line that represents the level of confidence hidden behind regulatory decisions. From this perspective, the model integration evidence represents the integration of data and knowledge that drive quantitative relationships in clinical outcomes

Innovation is essentially doing research that has not been done before, taking a path that friends have not taken... New model methods can more efficiently and scientifically solve current drug research and development problems, bringing new opportunities, especially in the research of complex formulations, such as long-acting injections, oral inhalation drugs, and topical dermatology drugs. We look forward to the successful convening of this year's FDA MIE pilot meeting, which will bring new evaluation theories and practical examples to the pharmaceutical industry and drug regulatory agencies in various countries.

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