By Md. Saddam Nawaz, ACI HealthCare Limited
Generic drugs have become an essential component of the pharmaceutical market due to their cost-effectiveness and improved accessibility for patients worldwide. To ensure the therapeutic equivalence of generic drugs to their respective comparator products, it is important to conduct bioequivalence (BE) studies. However, the current regional guidelines and variations in scientific and technical standards pose significant challenges to global development and marketing of generic drugs. The reflection paper on "Further Opportunities for Harmonisation of Standards for Generic Drugs," endorsed by International Council for Harmonisation (ICH) in November 2018,1 represents a significant step forward in the global development and marketing of generic drugs. The paper outlines a strategic approach to harmonize scientific and technical standards for generic drugs, from non-complex to more complex products. In response to this, ICH developed the M13 series of guidelines (M13A-C), with the aim of harmonizing the scientific and technical aspects of study design and data analysis to support BE assessment for orally administered immediate-release solid oral dosage forms to their respective comparator products. M13A is the first guideline in this foreseen series and is currently in the Step 3 Public Consultation stage as of May 20232,3 and is slated for adoption by November 2023. This article provides an overview of its scope, key objectives, and study design recommendations.
The M13A guideline aims to provide recommendations on conducting BE studies during product development and post-approval phases for immediate release (IR) solid oral dosage forms, such as tablets, capsules, granules, and powders for oral suspension.
The objectives of the M13A guideline include harmonizing current regional guidelines/guidances, reducing the need to conduct multiple BE studies for multiple jurisdictions, and supporting streamlined global drug development. The guideline also provides recommendations for study population, design, test and comparator products, and fasting/fed conditions for BE studies.
However, some topics are considered out of scope for this guideline. These include discussions on how regulatory decisions are made based on BE assessments, how different regions accept comparator products, BE assessments for additional strengths of immediate-release drugs, BE assessments for drugs that are highly variable or have narrow therapeutic indexes, and study designs or data analysis to support bioavailability assessments for new drugs. These topics are not the primary focus of the M13A guideline.
The M13A guideline recommends a randomized, single-dose, two-period, two-sequence crossover study design with healthy subjects in general. For safety/tolerability reasons, a multiple-dose study in patients may be necessary. For drugs with a long elimination half-life, a parallel design may be appropriate.
The guideline states that when determining the number of human subjects to be included in a study, an appropriate sample size calculation should be conducted to ensure a pre-specified power and type 1 error rate. For a crossover study design, the minimum number of evaluable subjects should be 12. And for a parallel study design, it should be 12 per treatment group. It's important to note that these are minimum requirements, and the actual sample size may vary depending on factors such as the expected variability in the study population and the sensitivity of the bioanalytical method being used.
The test product used in BE studies should be representative of the product to be marketed, while the comparator product should be accepted by regulatory authorities and suitable for comparison with the test product in the BE study. The guideline also allows for BE studies with multiple comparator products or multiple test formulations.
Fasting and/or fed conditions are important considerations in the design of BE studies. The selection of the type of BE study (fasting or fed or both) and meal type(s) depends on the dosing instructions of the comparator product, the properties of the drug substance, and the properties of the products being compared ("non-high risk" or "high risk"). High-risk products may require both fasting and fed conditions to reduce the risk of BE failure.
The dose or strength to be studied should be dependent on the pharmacokinetics and solubility of the drug. The highest strength should be administered if the pharmacokinetics are dose-proportional, and if there is more than a dose-proportional increase in pharmacokinetics, the highest strength should be used. If there is less than a dose-proportional increase, the lowest strength should be used if the cause is due to saturation of absorption, and both the lowest and highest strengths should be used if the cause is due to solubility or an unknown reason.
The guideline also covers specific topics such as endogenous compounds, other IR dosage forms (e.g., orally disintegrating tablets, chewable tablets, and oral suspensions), fixed dose combination products (where BE should be demonstrated for all components in the fixed-dose combination), and pH-dependency. The guideline recommends an additional BE study with concomitant treatment of a pH-modifying drug product for drug substances with pH-dependent solubility/dissolution.
Documentation requirements include the complete documentation of the study protocol, conduct, and evaluation in accordance with ICH E3, Structure and Content of Clinical Study Reports.4 List all relevant BE studies conducted in Module 2.7.1 of the Common Technical Document. Provide full study reports for the BE study(ies) upon which the applicant relies for approval. For all other studies, synopses of the study reports in accordance with ICH E3 are sufficient.
If individuals or organizations are interested in providing feedback on the M13A guideline, you should check the specific deadlines set by your local regulatory authority, as these may vary. For instance, the FDA in the U.S. required comments to be submitted by April 3, 2023, and other agencies, such as China's National Medical Products Administration, have already concluded their public comment period. However, there are still opportunities to submit comments to regulatory authorities, such as Europe's European Commission, Canada's Health Canada, Japan's Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency, or Switzerland's Swissmedic. Instructions for submitting comments can be found here. Harmonizing global standards for generic drug development can improve access to generic medicines and reduce the burden of multiple clinical trials. Adopting the M13A guideline in November can pave the way for more efficient and streamlined drug development and approval processes, ultimately improving patient access to safe, effective, and affordable medicines.
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2019). ICH Reflection Paper on "Further Opportunities for Harmonisation of Standards for Generic Drugs." https://admin.ich.org/sites/default/files/2019-04/ICH_ReflectionPaper_GenericDrugs_Final_2019_0130.pdf.
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2022). Draft Guideline M13A: Bioequivalence for Immediate-Release Solid Oral Dosage Forms. https://database.ich.org/sites/default/files/ICH_M13A_Step2_draft_Guideline_2022_1125.pdf
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (2023). M13A Step 2 Presentation. https://database.ich.org/sites/default/files/ICH_M13A_Step2_InformationalPresentation_2023_
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). (1995). E3: Structure and Content of Clinical Study Reports. https://database.ich.org/sites/default/files/E3_Guideline.pdf
About The Author:
Md. Saddam Nawaz serves as the site quality management head at ACI HealthCare Limited. He is an experienced GMP, regulatory, and quality management systems (QMS) expert with experience in developing, implementing, and improving QMSs. He has extensive knowledge of GMP regulations and technical processes, has led greenfield pharmaceutical projects, and has secured several generic drug approvals. He has implemented initiatives to streamline operations, reduce costs, and enhance compliance. At conferences, he frequently speaks on the topics of data integrity, pharma 4.0, and quality culture. You can reach him on LinkedIn.