Journal of Bioequivalence & Bioavailability

Bioequivalence Guidelines Requirements for Orally Administered Generics (IR Products) in Gulf Cooperation Council Countries, European Union and United States of America

Elambharathy Elangovan^* Department of Bioequivalence, Research & Development, Jamjoom Pharmaceuticals, P.O. Box # 6267, Jeddah-21442, Kingdom of Saudi Arabia
^*Correspondence: Elambharathy Elangovan, Department of Bioequivalence, Research & Development, Jamjoom Pharmaceuticals, P.O. Box # 6267, Jeddah-21442, Kingdom of Saudi Arabia, Tel: +966 558652821, Email:

Received: 27-Nov-2018 Published: 15-Feb-2019, DOI: 10.35248/0975-0851.19.11.387

Abbreviations

GCC: Gulf Cooperation Council; EMA: European Medicines Agency; USFDA: U.S. Food & Drug Administration; C_max: Maximum Plasma Concentration; AUC(0-t): Area Under the Plasma Concentration Curve from Administration to Last Observed Concentration at Time t; AUC(0-∞): Area Under the Plasma Concentration Curve Extrapolated to Infinite Time; Residual Area: Extrapolated Area (AUC(0-∞) - AUC(0-t))/ AUC(0-∞); T_max: Time Until C_max is Reached; λz: Terminal Rate Constant; t1/2: Plasma Concentration Half-life; AUC(0-72 h): Area Under the Plasma Concentration Curve from Administration to 72 h; AUC(0- τ): AUC During a Dosage Interval at Steady State; C_max,ss: Maximum Plasma Concentration at Steady State; t_max,ss: Time Until C_max,ss is Reached; C_min: Concentration at the End of a Dosing Interval; Cav: Average Concentration During a Dosing Interval; Ae(0-t): Cumulative Urinary Excretion of Unchanged Drug from Administration until Time t; R_max: Maximal Rate of Urinary Excretion; NTIDs: Narrow Therapeutic Index Drugs; OGD: Office of Generic Drugs; PK: Pharmacokinetics; BA: Bioavailability; BE: Bioequivalence; Stat: Statistics; RLD: Reference Listed Drug; CI: Confidence Interval; HVDP: Highly Variable Drug Products; USP: United States Pharmacopeia; BCS: Biopharmaceutics Classification System; IR: Imeediate Release; FIP: International Pharmaceutical Federation; CV: Coefficient Variation; BMI: Body Mass Index.

Introduction

This review article mainly focuses on the bioequivalence study requirements in the Gulf Cooperation Council countries, European union countries and the United States of America. The comparison between the GCC, USFDA and EMA regulatory requirements will be useful for fraternity in the pharmaceutical industry, those who are in the generic product development to understand the local regulatory requirements in comparison with well-established regulatory such as USFDA and EMA. Since, GCC guidelines adherence to the EMA guidelines approaches to establish bioequivalence is almost similar and however in some aspects difference are there between both guidance. This comparison will give clear aspects in understanding the similar and difference between these regulatory requirements for conducting the studies. It also helpful to the academic professionals, to understand the regulatory requirements for conduct the bioavailability and bioequivalence studies.

General Approaches to Establish Bioequivalence

Design of the study

Two-way crossover study is the unique standard study design recommended by GCC, EMA & USFDA. For long half-life drugs EMA & GCC recommends parallel design. USFDA recommends parallel design, if they have faced any problem with crossover study. For highly variable drugs EMA & GCC recommends replicate design. USFDA recommendation is reference scaled average bioequivalence study.

Sample size

USFDA recommends pilot study, before proceeding with a full bioequivalence study. EMA & GCC not specific in the requirement of pilot study, at the same time EMA recommends 12 subjects for bioequivalence study. Hence, it confirms EMA recommends minimum 12 subjects required for either pilot or pivotal study. GCC recommends 24 subjects for pivotal bioequivalence study. USFDA not specific in minimum subject requirement, but in the earlier guidance mentioned about sample size requirements (e.g., 12).

Selection of reference product

Reference product should be marketed in EU as per the EMA recommendations. RLD (Reference Listed Drug) is the reference drug for USFDA submissions. GCC recommends the reference product must be the original brand-name (i.e. manufactured in the country of origin of the original brand name); if unable to get the product in that market then the brand-name regarding the same company but different country of origin is used, marketed in GCC region, ICH region, or in any stringent regulatory authority. If unable to get the original brandname product in the market or not manufactured, then the local country market leader may be used as a reference product. However, sometimes it’s difficult to get the details of innovator and its country of origin. It means whether it’s first launched in the U.S. or Europe or some other places. Hence, in the GCC guidelines, acceptancy of both U.S. and Europe region available reference product in consideration of well-established market, would be helpful to do the selection of the reference product.

Study conditions

As per the EMA & GCC, fasting time for the subjects is minimum at least 8 hours before dosing of the drug products. USFDA recommends minimum 10 hours fasting before dosing. Food instructions are similar to these for fed studies to all these three regulatory. For fed studies, generally high fat (approximately half of the total caloric content of the meal), high-calorie (approximately 800 to 1000 calories) meal is recommended as a breakfast. Accordingly, the breakup for 1000 calories are 150 calories from protein, 250 calories from carbohydrate and 500-600 calories from fat.

Pharmacokinetic (PK) parameters

Pharmacokinetic parameters such as AUC (0-t), AUC(0- ∞), residual area, C_max, t_max, λz , and t1/2 need to be evaluated in the bioequivalence study. The requirement of steady state studies submission in EMA & GCC are AUC (0-τ), C_max,ss, and t_max,ss. USFDA recommends C_min (concentration at the end of a dosing interval), Cav (average concentration during a dosing interval), degree of fluctuation [(C_max- C_min)/Cav], and swing [(C_max-C_min)/C_min] if steady-state studies are employed. Ae(0-t) and, if applicable, R_max need to be evaluated when using urinary data for EMA & GCC. Product specific guidance need to be followed for USFDA submission.

Acceptance criteria for PK parameters

The acceptance criteria is the point estimate between test and reference products for 90% CI values within the acceptance range of 80.00 – 125.00%. For NTI drugs, GCC and EMA recommends the acceptance range for AUC & C_max should be tightened to 90.00- 111.11%. As per USFDA, if it is mentioned in the product specific guidance accordingly it will be applicable to the products. USFDA guidance describes, the general acceptance range of 80% to 125% for non-NTI products will not be changed for the bioavailability measures (AUC and C_max) of NTI drugs. For Highly variable drugs, GCC and EMA guidance states that C_max can be extended (i.e. 75-133%). USFDA suggests, scaled-average BE analysis approach for highly variable drugs.

Baseline correction

GCC, EMA and USFDA highlights that authorities to check the baseline endogenous levels in plasma and subtract these plasma concentrations from the total endogenous amount measured from every subject after the post dose. In GCC & EMA subtracting individual endogenous pre-dose AUC, is recommended.

Measurement of metabolite

As per USFDA, the analytes to be quantified in biological fluids collected in BA and BE studies are either the active drug ingredient or parent drug or, if it’s required then active metabolites. GCC and EMA recommend, bioequivalence need to be concluded upon determined amount of the drug. It’s because of that C_max of a drug is generally high sensitive to determine the differences between drugs in absorption. In certain conditions, particularly for some pro-drugs demonstrating bioequivalence only for the main active metabolite is acceptable.

Drug proportion difference

USFDA, EMA and GCC recommends, 5% difference is acceptable for the assay content between the test and reference product and it shouldn’t be >5%.

Retention period for drugs and documents and quantity of drugs

As per USFDA, remaining samples of both the test and the reference drugs to be retained at the study site for a period of 5 years. This is because, OGD to do the release tests for five times. The maximum limit of 300 units each for the test and reference drugs can be considered enough to do the release test in consideration of the oral solid dosage forms. No specific recommendations from the GCC and EMA for retention period and quantity of drugs.

Guidance for Industry, Handling and Retention of BA and BE Testing Samples, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) [1].

European Medicines Agency, London, 20 January 2010, (Doc. Ref.: CPMP/EWP/QWP/1401/98 Rev. 1/ Corr), Committee for Medicinal Products for Human Use, Guideline on the investigation of bioequivalence [2].

Executive Board of the Health Ministers’ Council for GCC States, the GCC Guidelines for Bioequivalence, Version 2.4, MAR 2016 [3].

Enantiomers

EMA and GCC guidelines states, achiral bioanalytical methods are usually acceptable. The below mentioned conditions to be met when the individual enantiomers to should be measured:

1) The enantiomers exhibit different pharmacokinetics

2) The enantiomers exhibit pronounced difference in pharmacodynamics

3) The exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption.

It is enough to demonstrate the bioequivalence for the active enantiomer, if one is pharmacologically active and another one is inactive or low active. USFDA requirements are, for BA studies, important one is quantification of individual enantiomers. For BE studies, important one is quantification of the racemate using an achiral assay. The below mentioned conditions to be met when the individual enantiomers to should be measured:

(1) The enantiomers exhibit different pharmacodynamic characteristics

(2) The enantiomers exhibit different pharmacokinetic characteristics

(3) Primary efficacy and safety activity resides with the minor enantiomer

(4) Nonlinear absorption is present for at least one of the enantiomers. In such cases, we recommend that BE factors be applied to the enantiomers separately. In comparison with the EMA requirements, USFDA recommends additionally to ensure the efficacy and safety activity for the minor enantiomer.

Endogenous substances

Endogenous compounds are drugs that body already having either because it naturally present in the body and getting from the normal diet. Endogenous substances are identical to drug and hence its quiet difficult to find the quantification of drug released from the dosage and absorbed by the body.

EMA and GCC guide us, baseline correction need to be performed to understand the additional concentrations due to the treatment during the endogenous substance analysis.

However, before study proceedings the correcting baseline to be mentioned and justified in the protocol. Baseline correction usually follows the normal subtraction, it means individual mean endogenous pre-dose concentrations to be subtracted or endogenous pre-dose AUC is recommended for subtraction.

USFDA recommends specifically for periods. If a baseline corrected values in negative, the value should be set equal to 0 before the baselinecorrected AUC calculation. Final PK & stat analysis to be conducted on the both corrected and uncorrected data. However, conclusion of bioequivalence based on the baseline- corrected data.

Investigation strength

GCC and EMA recommends, either one or two strength is sufficient to conclude the bioequivalence, it depends on the proportionality of the different strengths and other product related issues described below. Drug linearity is important factor to finalize the strength to be selected for BE. If the drug doesn’t obeys the linearity that means non-linear pharmacokinetics (i.e. if we increase the dose the AUC increase is not proportional), then it would be the difference of different strengths in the sensitivity to identify the differences between formulations. Linearity is described as if the dose adjusted mean AUCs is not > 25% difference in comparison with the BE study conducted drug strength and for the biowaiver strengths. Generally, higher strength would be selected for the bioequivalence study. If the drug obeys the linearity in PK and also high solubility and then selection of a lower strength is acceptable instead of higher strength. However, in consideration of safety/tolerability issues lower strength also can be selected with justification. USFDA accepts the lower strength in consideration of safety, as per the below mentioned conditions acceptancy: i) Linear elimination kinetics has been documented over the therapeutic dose range. ii) The higher strengths of the test and RLD products are proportionally similar to their corresponding lower strength. iii) Comparative dissolution testing on the higher strength of the test and RLD products has been submitted and found to be acceptable. In general, waiver can be accepted based on (i) acceptable BE study on the designated strength, (ii) acceptable in vitro dissolution testing of all the strengths, and (iii) proportional similarity of the formulations across all strengths.

Evaluation

The assay content difference, in general should not be adjusted in the PK parameters of the test and reference batch as per the EMA and GCC bioequivalence guidelines recommendations. The same can be acceptable if the assay content difference is less than 5% for test product in comparison with reference and can’t be found content correction. In protocol, it should be pre-specified if content correction is to be done and also justified by inclusion of the results from the assay.

Subject accountability: Statistical analysis need to be done in the all dosed subjects. However, in a crossover study if the evaluable data is not available then both test and reference products should not be included.

Subject exclusion: Exclusion of any of the subject to be decided before initiation of the bioanalysis and the reason for exclusion need to be mentioned in the protocol. Excluding data is not usually acceptable in consideration of statistical analysis or due to PK reasons, because it’s not possible to differentiate the formulation effects from other effects influencing the pharmacokinetics.

However, some exceptions are as mentioned below;

1) Any subject is having lack of measurable concentration or very low plasma concentrations for reference medicinal product. If the subject AUC is less than 5% of reference medicinal product geometric mean AUC then it is considered as very low plasma concentrations. This reason is usually accepted in exceptional cases for exclusion of data; however it may question the validity of the study.

2) Any subjects having non-zero baseline concentrations of more than 5% C_max, that data need to be excluded from bioequivalence calculation. It is applicable for immediate release formulations, due to the reason of subject non-compliance and an insufficient wash-out period, respectively, and poor internal dosing and study procedures such as mouth check of subjects after dosing to ensure the subjects have swallowed the study medication and study design with adequate wash out. Even though the subjects excluded from the statistical analysis, the samples to be assayed and the results listed. Moreover, AUC (0-t) should cover at least 80% of AUC (0-∞). If any of the subjects, covers AUC (0-t) less than 80% of AUC (0-∞) should not be excluded from the statistical analysis. However, it’s not acceptable if less than 80% in more than 20% of the observations. If it is more than 20% then the validity of the study is questionable. This procedure is not applicable for the truncated study design (72 h).

PK parameters: C_max, AUC(0-t), or, if it is required AUC(0-72h) are the parameters need to be evaluated and the 90% CI for the ratio of the test and reference products should be within 80.00- 125.00% for these parameters.

Statistical analysis: In general, all the data need to be transferred to logarithmic transformation and follow up with it should analysed by using ANOVA for all the pharmacokinetic parameters. The 90% CI for the T/R of both products would be considered for the bioequiovalence assessment. This procedure is equivalent to two one-sided tests with the null hypothesis of bioinequivalence at the 5% significance level.

Carry-over effects: During statistical evaluation, subjects will be excluded in that period if the pre-dose concentration of C_max is more than 5%. In this type of case, the subject will be removed from the analysis if it as a two-way crossover study. However, due to these exclusions if the sample size is reduced to less than 12 subjects, then the study will not be acceptable. This statistical exclusion procedure is not applicable for the endogenous drugs.

Study design with two-stage: Study design with two-stage is acceptable and it should be mentioned in the protocol. In case the bioequivalence has not established in the first study then an additional or second stage study can be conducted and the results from two stages combined in the final analysis results.

Narrow therapeutic index drugs

Narrow therapeutic index drugs (NTIDs) required range for pharmacokinetic parameters such as AUC and C_max to be narrowed to 90.00-111.11%, in consideration of safeness and effectiveness of the drug.

Requirements for highly variable drug products (HVDP)

In USFDA, EMA & GCC, if the drug products show more than 30% intra subject variability and it would be considered as Highly Variable Drug Products (HVDP). Replicate study design approach is recommended by USFDA for HVDP products. In these replicate study design, both reference-scaled and complete replicate designs are acceptable as per the product requirements. In this reference-scaled approach intra subject variability of the reference product is getting average and the range is 0.8 to 1.25 on the geometric mean ratio. In EMA and GCC, the same replicate cross-over design study can be carried out. Moreover, widened C_max difference is acceptable by proper clinical justification with an increased passing limits. In addition, C_max can be increased to 69.84 – 143.19% and 75-133% respectively for EMA and GCC. Moreover, in EMA based on the different variabilities the different acceptance limits as mentioned in the below table. The procedure of widening the C_max passing limits is only applicable for the study if we have applied the replicate design in which the ISCV should be >30% in the C_max. This ISCV should not be the inclusion of outlier and the same to be justified by the calculated intra-subject variability is a reliable estimate by the applicants (Table 1).