Global harmonization of immediate‐release solid oral drug product bioequivalence recommendations and the impact on generic drug development

Abstract Immediate‐release (IR) solid oral drug products constitute a significant portion of approved drug products and products under development. Bioequivalence (BE) assessment for these oral products is important for establishing therapeutic equivalence for generic products to their respective comparator products. In December 2022, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) published the first new draft guideline on BE for IR solid oral dosage forms (M13A). To support the development of ICH M13A, we comprehensively reviewed the landscape of oral IR products approved by the U.S. Food and Drug Administration (FDA) and compared BE recommendations for these products in the current U.S. FDA and European Medicines Agency (EMA) BE guidances. We utilized databases including Drugs@FDA, Orange Book, and product‐specific guidances (PSGs) published on the U.S. FDA and EMA websites to collect information. Oral IR products account for 46% of all FDA‐approved new drug applications currently listed in Orange Book with 82.5% solids, 0.9% semi‐solids, and 16.6% liquids. For all published U.S. FDA PSGs for solid oral IR products, in vivo BE studies with pharmacokinetic (PK) endpoints account for 88% of BE approaches recommended. Of these PK BE studies, 86.5% recommended fasting and fed BE studies, while only 15.9% EMA PSGs recommended both fasting and fed BE studies. This review helps clarify the scope of U.S. solid oral IR products impacted by the new ICH M13A draft guideline and demonstrates how recommendations in draft ICH M13A could significantly harmonize BE recommendations for IR oral products to facilitate global drug development.


INTRODUCTION
Oral drug products account for most approved medications due to the predominantly systemic effects, combined with non-invasive administration, convenience, and high patient compliance.A market report from Future Market Insights predicts the solid oral drug product market to surpass US$550 million in 2022 with tablets accounting for 53% of the market share.Market demand in solid oral drug products is projected to grow at a compound annual growth rate of 6.4% between 2022 and 2032, maintaining popularity. 1 Solid oral drug products are typically administered as immediate-release (IR) products that instantly disintegrate and release their active pharmaceutical ingredient (API) for systemic absorption, popularizing them as a common therapy option.After ingestion of IR oral products, typically more than 85% of the labeled amount dissolves within the first 30 min.The remaining portion of the API is absorbed within 4 h following the dose. 2 The U.S. Food and Drug Administration (FDA) routinely evaluates in vivo pharmacokinetic (PK) studies of oral drug products to understand drug absorption, distribution, metabolism, and excretion (ADME), and develops product-specific guidances (PSGs) for these products to facilitate generic drug development.Since the Generic Drug User Fee Amendments (GDUFA II) in 2017, FDA has published PSGs for new chemical entity oral products (noncomplex) within 2 years of approval. 3For generic oral drug products, applicants must show that the generic drug product is pharmaceutical equivalent and bioequivalent to the reference listed drug (RLD) or the comparator product.The generic drug product is considered a pharmaceutical equivalent if the drug product is identical in dosage form, route of administration, and strength of the RLD.For bioequivalence (BE), per FDA regulations in 21 CFR 320.24(b), an applicant must use the most accurate, sensitive, and reproducible approach to demonstrate the generic and the RLD have the same rate and extent of absorption.The approaches to demonstrate BE include comparative PK studies, in vitro tests predictive of human in vivo performance, comparative pharmacodynamic (PD) studies, comparative clinical endpoint BE studies, or other studies deemed appropriate by FDA. 4 Although guidances or guidelines on BE assessment exist for most regulatory agencies and international health organizations with generally similar approaches, there are differences in general guidance and/or PSGs for BE recommendations which could hamper global generic drug development.Unharmonized BE study designs and standards result in drug developers having to generate multiple sets of data to support approval in different countries, which can lead to increased drug development time, costs, and/or lack of approval in some markets.

WHAT QUESTION DID THIS STUDY ADDRESS?
What are considered IR solid oral products?What are the key differences between current U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidances for BE demonstration of these products?What are the major considerations of ICH M13A regarding BE study design (e.g., food conditions and others)?

WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
This study clarified the scope of the IR solid oral product landscape, identified key differences between FDA and EMA regarding BE demonstration of these products, supported the development of M13A, and highlighted the impact of M13A on regional guidelines.

HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
The study demonstrates how M13A could harmonize BE recommendations for IR solid oral products to facilitate global drug development and improve patient access to affordable medications globally.
Use (ICH) published the first draft multidisciplinary guidelines (M13A) to globally harmonize scientific recommendations for BE assessments of IR solid oral drugs designed to deliver drugs to the systemic circulation during both development and post-approval stages. 5The draft guidance describes the scientific and technical aspects of study design and data analysis to support BE assessment, currently seeking public comment.
The goals of this study were (1) to survey the U.S. FDA-approved oral IR product landscape; (2) to evaluate the current BE recommendations by reviewing PSGs from both the U.S. FDA and European Medicines Agency

METHODS
U.S. FDA-approved drug product information was obtained via the Orange Book (OB): Approved Drug Products with Therapeutic Equivalence Evaluations, as well as Drugs@FDA, from January 1938 to December 2022.All approved applications listed in OB were included based on an application with an effective approval that has not been withdrawn for safety or efficacy reasons. 6Reference products with multiple strengths were grouped together and counted as one drug product in the analysis.IR solid oral product terminology used throughout the article is indicative of IR solid oral reference products currently listed in OB (with multiple strengths grouped together).
All currently approved IR solid oral products were categorized as either solids, liquids, or semi-solids.IR solid oral products were further characterized to specific dosage forms based on United States Pharmacopeia (USP) ⟨1151⟩ Pharmaceutical Dosage Forms General Chapter. 7lready prepared liquids, such as solutions, suspensions, and emulsions, as well as semi-solid dosage forms such as oral pastes and chewable gums, were excluded in our further analysis.
Published PSGs for IR solid oral products were obtained through the FDA's PSG database (September 2008-December 2022) and the EMA's website (January 2009-December 2022). 8,9

Current FDA-approved IR solid oral drug product landscape and dosage form distribution
Based on FDA-approved drug product data collected between January 1938 and December 2022, oral drug products account for approximately 54% of all new drug applications (NDAs) listed in current OB.IR oral products account for ~46%, while modified-release (MR) oral drug products account for ~8%.The IR oral products include over 20 different dosage forms, containing over 2000 unique APIs.Further, the IR oral products consist of 82.5% solid dosage forms, 0.9% semi-solid dosage forms, and 16.6% liquid dosage forms.For the IR solid oral products, most common dosage forms include tablets and capsules, accounting for 64.5% and 22.7% of all IR solid oral products, respectively (Figure 1).The remaining 12.7% consists of specialty dosage forms including orally-disintegrating tablets (ODTs), granules, chewable tablets, sublingual/buccal tablets, effervescent and dispersible tablets, troches/lozenges, and powders for solution or suspension (Table 1).The most common specialty dosage forms are powders for solution and suspension, chewable tablets, and ODTs, each totaling 3.4%, 2.9%, 2.3%, and 2.0%, respectively.All other specialty solid dosage forms account for less than 1% of the FDA-approved IR solid oral drug products (Figure 1).In addition, approximately 4.4% of the IR solid oral products are designated as complex products based on GDUFA definition.The concepts of complex product were further delinated in the FDA Manual of Policies and Procedures (MAPP), 'Classifying Approved New Drug Products and Drug-Device Combination Products as Complex Products for Generic Drug Development'.Complex IR solid oral drug products are primarily either locally-gastrointestinal (GI) acting or contain complex APIs per GDUFA II definition, such as APIs with a mixture of components, distribution of molecular weights, and some peptide-based products. 10In total, 84% of the complex IR solid oral products are locally-GI acting, while the remaining 16% is due to containing a complex API.

Availability of generic IR solid oral products and their respective PSGs
Excluding granules, effervescent tablets, and oral powders, all other IR solid oral dosage forms have over 50% of the drug products with approved generics by U.S. FDA.Similarly, for all IR solid oral dosage forms excluding powders, over 50% of drug products have PSGs available at FDA's website.In total, 1051 PSGs were published by FDA for IR solid oral products as of December 2022.There are fewer product-specific BE guidances published by EMA, with a total of 63 PSGs for IR solid oral drug products as of December 2022 (Table 2).
PSGs from the U.S. FDA provide recommendations on how to develop generic drug products therapeutically T A B L E 1 Recommendation on drug administration in U.S Food and Drug Administration and European Medicines Agency productspecific guidances for specialty immediate-release solid oral drug products.

Special administration considerations in EMA PSGs
Orallydisintegrating tablet • Solid oral dosage form containing medicinal substances that disintegrate rapidly, usually less than 30 s, when placed upon the tongue 14  2).][13] There may be special consideration in the products' labeling on how to take the drug product for ODTs, chewable and effervescent tablets, oral powders, and troches/ lozenges.Administrative instructions were found to not be consistent among different products of the same dosage form.For dosage forms such as ODTs, which disintegrate and solubilize in the mouth, patients are advised to either take with water, without water, or with water following administration of the drug, based on RLD labeling. 14If the labeling indicates with or without water options, the FDA PSG will recommend the BE study to be conducted by advising subjects to take the drug product without water.Table 1 highlights recommendations from FDA PSGs on how to administer these IR solid oral dosage forms when conducting BE studies.Premixing with a liquid to allow the API to solubilize is often recommended for effervescent tablets while mixing with soft foods prior to patient consumption was commonly recommended for oral granules.Chewable tablets are often recommended to be completely chewed and then followed by a glass of water.EMA product-specific BE guidances mostly do not incorporate administration instructions.
Study population is another important aspect of BE study considerations.Per FDA guidance, both male and female healthy subjects over the age of 18 years should be enrolled for BE studies if a product is intended for use in both sexes, unless the study drug may pose serious risks

U.S FDA EMA
General recommendation regarding PK BE study fasting/fed conditions FDA generally recommends both a fasting and fed BE study 15 Conducted under fasting conditions; fed BE study is recommended based on labeling recommendations or specific formulation characteristics 17 General recommendation regarding PK BE study subject selection Generally performed in healthy subjects, unless the drug carries safety concerns that make this approach unethical 15,17 PSGs published as of 31 December 2022 to healthy subjects. 15For PSGs that an in vivo BE study population, 94.3% recommend the study to include healthy males and/or non-pregnant, healthy females.Patient population was recommended in 5.5% of the solid oral IR PSGs.The remaining 0.2% recommended both patients and healthy subjects.The PSGs that recommend patients only for the BE studies involve mostly antipsychotic, antiviral, and chemotherapy drug products.Aligning with FDA recommendations, EMA product-specific BE guidances routinely recommend healthy subjects in 92.1% of their published guidances (Table 2).Of the available 63 PSGs for IR solid oral products by EMA, ~6% had no corresponding PSG by U.S. FDA.For PSGs that matched in API, dosage form, and route of administration, 68% of the PSGs did not align on fasting/ fed study recommendations between EMA and U.S. FDA, while 26% of the PSGs aligned (Table 3).As for recommendation on subject selection in PK BE studies, 84% aligned versus 10% did not align between the two agencies (Table 3).

ICH M13A recommendations
ICH recently published the first draft guideline on BE for IR solid oral dosage form drug products (ICH M13A) for public consultation. 5The new draft ICH M13A guideline recommends BE studies be conducted under standardized conditions that minimize overall variability with the ability to detect potential PK differences.For IR solid oral dosage forms, a single-dose BE study conducted under fasting conditions provides the greater discrimination between PK profiles of a generic and comparator product.ICH M13A recommends a risk-based approach where the risk refers to "risk of BE failure".For drug products that are considered as "nonhigh-risk" oral IR drug products, it is recommended that a single BE study may be conducted under fasting conditions only.For drug products that are considered "high-risk" products, both fasting and fed BE studies are recommended unless there is safety concern with either condition, because food can have a formulation-dependent impact on BE of these "high-risk" products which would preclude the extrapolation of BE under fasting conditions to fed conditions.ICH M13A also recommends standardization of special administration instructions for different IR solid oral dosage forms.ODTs, chewable tablets, and oral suspensions should be conducted according to product labeling regarding intake of water and food.Regarding study population for BE studies, healthy subjects are generally recommended to be selected with the aim of permitting detection of differences in the in vivo release characteristics between pharmaceutical products.However, if the investigated API is known to have adverse effects and the pharmacological effects or risks are considered unacceptable for healthy subjects, the study may instead be conducted in a targeted patient population due to the ethical considerations.

DISCUSSION
Based on the landscape analysis, over 80% of oral IR product NDAs currently listed in Book fall within the scope of ICH M13A (i.e., orally administered IR solid oral dosage forms designed to deliver drugs to the systemic circulation, such as tablets, capsules, and granules/ powders for oral suspension).All dosage forms that are prepared into solution or suspension before administering orally to a patient, such as powders for solution and effervescent/dispersible tablets, are included into the IR solid oral dosage form landscape.Already prepared liquids, such as solutions, suspensions, and emulsions, as well as semi-solid dosage forms, such as pastes and chewable gums, were not considered IR solid oral products.
It is noteworthy that many systemically-acting products, regardless of dosage forms, share similar BE recommendations as IR solid oral products.Therefore, ICH M13A, once finalized, will significantly impact large portions of generic drug development.Some oral IR products, where the drug substance(s) exhibit high solubility and either high permeability (Biopharmaceutics Classification System [BCS] Class I) or low permeability (BCS Class III), may be eligible for BCS-based biowaiver to substantiate in vivo BE.ICH M9, 'Biopharmaceutics Classification System-Based Biowaivers', has already been implemented to reduce the need for in vivo BE studies for these IR oral products that meet the BCS-based biowaiver criteria. 16urrently, for most IR oral products, apart from the BCS-based biowaiver option, FDA generally recommends both a fasting and fed BE study, while several regulatory agencies including EMA, Health Canada, Pharmaceuticals and Medical Devices Agency (Japan), Therapeutic Goods Administration (Australia), Ministry of Public Health (Thailand), The Brazilian Health Regulatory Agency (Brazil), and the World Health Organization (WHO) generally recommend a BE study under fasting conditions only.FDA's most recent draft guidance for industry, 'Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application', states that in addition to a BE study under fasting conditions, a BE study under fed conditions for all orally administered IR drug products is recommended. 15The majority of U.S. FDApublished PSGs for IR solid oral products (about 87%) recommend both a fasted and fed BE study, in alignment with the FDA's current draft general BE guidance (Figure 2). 15he current EMA's 'Guideline on the Investigation of Bioequivalence' states the number of studies and study design can vary depending on the physicochemical characteristics of the drug. 17A BE study should be conducted under fasting conditions, as this is the most sensitive condition to detect potential differences in formulations.A fed BE study is recommended based on either labeling recommendations for taking the drug product in a fed state, or if the product contains specific formulation characteristics (e.g., microemulsions, solid dispersions). 17Available EMA-published PSGs generally reflect their overall guidelines, as 69.8%, 14.3%, and 15.9% recommended a fasting BE study only, a fed BE study only, and both fasting and fed BE studies, respectively (Table 2).
When comparing PSGs published by EMA with matching FDA PSGs, the 6% with no corresponding FDA PSG included ursodeoxycholic acid, paracetamol, agomelatine, and acenocoumarin.Except paracetamol (also known as acetaminophen), all other drug products are not approved by U.S. FDA.Though FDA does not have a PSG for acetaminophen IR product, FDA did publish a PSG for acetaminophen ER tablet.Differences regarding recommendations on fasting/fed conditions that we observed between FDA and EMA PSGs are mainly because PSGs generally align with the general BE guidances in their jurisdictions.
The new draft ICH M13A guideline harmonizes the food intake conditions for BE studies using a risk-based approach to determine if a fed BE study is needed where the risk refers to "risk of BE failure".Most IR oral drug products are designated as "non-high-risk" products and BE may be demonstrated in a single fasting BE study, unless labeling indicates the drug should be taken with food due to PK reasons.However, for "high-risk" products where a complex formulation design or manufacturing process will likely impact in vivo performance differently based on variable GI conditions in the fasting and fed state, both fasting and fed BE studies are recommended.These high-risk products include low solubility drug substances and drug products with a complex formulation or manufacturing process, such as solid dispersion, microemulsions, lipid-based formulations, and/or nanotechnology products.Once ICH M13A is finalized and implemented, it is expected that a fasting BE study only will be recommended for a majority of the IR solid oral products in all ICH member regions.The PSGs from the U.S. FDA are expected to be aligned with recommendations in the final ICH M13A guideline.
ICH M13A also provides specific administration instructions regarding the intake of water and food based on product labeling for specialty IR dosage forms such as ODTs and chewable tablets.While FDA PSGs already include standard administration instructions in line with current ICH M13A recommendation, EMA PSGs routinely do not specify on administration instruction (Table 1).ICH M13A helps provide clarity and aligns the way product administration in the BE study, specifying about both food and water intake.As regards study population, current EMA and FDA general BE guidances are consistent with ICH M13A recommendations, namely that studies should generally be performed in healthy subjects, unless the drug carries safety concerns that make this approach unethical.In situations where it is unsafe to use healthy subjects, it is recommended to enroll patients for whom the drug is indicated, and the disease process is stable.Though the general principle for study subject selection is similar between EMA and FDA, there could be some discrepancy in safety evaluation and clinical judgment on recommendations to conduct BE studies in healthy subjects for specific drug products.Based on a comparison of FDA and EMA PSGs (Table 3), 10% of the current guidances contained inconsistencies in various chemotherapeutic agents where the FDA recommends patients while the EMA recommends heathy subjects such as in PSGs for vandetanib, sunitinib malate, pazopanib, and imatinib mesylate oral tablets.Inconsistencies were also seen in one antipsychotic drug product guidance, asenapine sublingual tablet. 8,9There are fewer cases where EMA recommends patients while FDA recommends healthy subjects.One case was found in lapatinib ditosylate oral tablet PSG. 9 If differences between EMA and FDA regarding study population for BE studies for specific products can be further aligned, it will further benefit generic drug development so that generic applicants may avoid having to incorporate multiple study population groups to seek approval in various global markets.
PSGs serve an important role in the generic drug development process.A recent study by Eastern Research Group in accordance with U.S. Department of Health and Human Services suggested that PSGs can save "several years" of development, especially for complex generic drugs, potentially reducing early development as well as BE study costs. 18Eastern Research Group's study included literature review, structured interviews with industry representatives, and an analysis of IQVIA National Sales Perspectives® data on monthly drug sales from January 2013 through June 2021.The report estimated that these savings could reduce the expected capitalized costs of a generic drug developer by 22.3% (US$25.9 million) on average.In vivo BE studies constitute a major portion of the overall generic development costs. 18Further, type of study population (healthy subjects versus patients) is one of the primary drivers of BE study cost, duration, and phase transition success probabilities.Thus, once FDA and EMA PSG recommendations are aligned with ICH M13A, eliminating in vivo fed BE studies for most IR solid oral products as well as selecting the same type of study population, there will be significant savings in both costs and time for generic drug development, increasing generic drug access to patients globally.

CONCLUSIONS
IR solid oral drug products constitute a significant portion of the approved drug products, representing over 20 different oral IR dosage forms and over 2000 unique APIs.At the conclusion of GDUFA II (2022), the FDA has published over 1000 PSGs for IR solid oral products.
The most significant difference in current BE recommendations for IR solid oral drug products among regulatory authorities lies in whether BE studies need to be conducted under both fasting and fed conditions or one condition only (fasting or fed).Risk-based determination on the need to conduct BE studies under both fasting and fed conditions or one condition only (fasting or fed) as recommended by ICH M13A will significantly reduce the number of BE studies under fed conditions for generic IR solid oral drug product development compared to the current FDA recommendations, thus shortening development duration and lowering study costs.Streamlined generic drug development under harmonized guidance will improve patient access to generic medications globally.
(EMA); (3) to understand the scope of U.S. IR solid oral drug products impacted by the new draft ICH M13A guideline; and (4) to demonstrate how recommendations in the draft ICH M13A could significantly harmonize BE recommendations for IR solid oral products to facilitate global generic drug development.

T A B L E 2
U.S. Food and Drug Administration and European Medicines Agency recommendations on fasting/fed conditions and subject selection in bioequivalence studies.
To support efficient development of generic drugs globally, in December 2022, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human potentially hampering global drug development.The first International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) draft multidisciplinary guidelines (M13A) to harmonize scientific recommendations for BE assessments of IR solid oral products was published in December 2022.

recommendations from FDA and EMA for solid oral IR products
• Per PSGs, patients advised to either take with or without water based on RLD labeling • If labeling indicates with or without water options, PSG will indicate to take without water • Other critical aspects: Abbreviations: API, active pharmaceutical ingredient; EMA, European Medicines Agency; FDA, Food and Drug Administration; PSG, product-specific guidance; RLD, reference listed drug.a Recommendations in PSGs are in general aligned with the FDA Draft Guidance 'Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application' (August 2021).equivalent to specific RLDs.In general, separate PSGs are for drug products of the same API but in different drug dosage forms.For example, there are three separate PSGs for acyclovir oral tablet, acyclovir oral capsule, and acyclovir oral suspension. 8In contrast, EMA in general combines orally administered dosage forms of the same API into one guidance possibly because EMA's generic products can have different dosage forms.For example, of EMA's 63 PSGs for IR solid oral drug products, 12 PSGs cover multiple IR solid oral dosage forms including tablets, capsules, granules, dispersible tablets, and powder for suspension dosage forms of the same API; 6 PSGS covered both IR solid oral dosage forms and solution/suspension dosage forms of the same API. 9Current BE and fed BE studies, 9.2% recommend a fasting BE study, 1.2% recommend a fed BE study, and 3.0% have no specific recommendations with regard to food intake (e.g., steadystate BE studies and studies with patients) (Figure 2).As a comparison, approximately 69.8% of EMA PSGs for IR solid oral products recommend a fasting BE study, 14.3% recommend a fed BE study, and 15.9% recommend both fasting and fed BE studies (Table
F I G U R E 2 *Designates percentage of each respecƟve subcategory based out of 100% of the specified secƟon T A B L E 3 Direct comparison of European Medicines Agency product-specific guidances (PSGs) on immediate-release solid oral drug product with corresponding U.S. Food and Drug Administration PSGs.Abbreviations: EMA, European Medicines Agency; FDA, Food and Drug Administration; PK, pharmacokinetic; PSG, product-specific guidance.