Bioequivalence Guidelines

Guidelines for Bioequivalence

• This document provides guidelines for bioequivalence, effective from May 3, 2021.
• Inquiries and comments can be sent to [email protected].
• The document is adapted from the EMEA guideline on bioequivalence investigation.
• The SFDA aims to be a leading international, science-based regulator, focused on public health.
• The SFDA's mission involves protecting the community through regulations and controls guaranteeing the safety of various products.

Bioequivalence and Medicinal Products

• Two medicinal products with the same active substance are bioequivalent if they are pharmaceutically equivalent or alternatives.
• Bioavailability (rate and extent) must lie within acceptable limits after administering the same molar dose.
• These limits are designed to ensure comparable in vivo performance, relating to both safety and efficacy.
• Plasma concentration-time curves assess the rate and extent of absorption in bioequivalence studies.
• Pharmacokinetic parameters and pre-set acceptance limits determine the final decision on bioequivalence of tested products.
• Generic medicines must demonstrate bioequivalence to a reference product through bioavailability studies.
• Generic medicines must have the same qualitative/quantitative composition in active substances and pharmaceutical form as the reference product.

Study Design and Requirements

• Module 2.7.1 to list all relevant studies carried out, whether bioequivalence studies demonstrate the applied formulation.
• Full study reports should be provided regardless of outcome, and study report synopses from formulation development also included.
• Sound alternative desings could be considered such as parallel design for substances with very long half-life.
• The study should distinguish formulation effects from other factors.
• A randomized, two-period, two-sequence, single-dose crossover design is recommended.
• Treatment periods require washout periods to ensure drug concentrations are below the bioanalytical quantification limit.
• A period of at least 5 elimination half-lives is needed.
• Alternatives to the standard design include parallel designs for long half-life substances and replicate designs for highly variable pharmacokinetics.
• Multiple-dose studies in patients may be acceptable if single-dose studies are not feasible or pose tolerability concerns.
• Using a multiple-dose study instead of a single dosed study due to limited sensitivity of the analytical study will only be accepted in exceptional cases.
• For steady-state studies, the washout period of of the treatment can overlap with build-up provided it is sufficiently long.
• In steady-state studies, the washout period of the previous treatment can overlap with the build-up of the second treatment, provided the build-up period is sufficiently long (at least 5 times the terminal half-life).

Reference and Test Products

• Reference Products must be the original brand-name (i.e. manufactured in the country of origin of the original brand name).
• If the original brand-name is unavailable, the brand-name from the same company, but from a different country, can be used.
• It must be marketed in the GCC, the ICH Region or in any other stringent regulatory authority.
• In the absence of the original brand-name, the local market leader may serve as the reference product.
• Selection should be based on assay content and dissolution data; batch content should not differ more than 5% from the reference.
• The test product should represent the product being marketed.
• Test products for oral use should come from batches of at least 1/10 production scale or 100,000 units.
• Batches should ensure feasibility on an industrial scale.
• Characterization and specification of key quality attributes of drug product should be determined from the clinical batch.
• Samples from additional pilot batches intended to support the application should be compared with those tested for bioequivalence.
• Comparative dissolution profile testing should be undertaken on the first three production batches.

Conduct of Bioequivalence studies

• The number of subjects should statistically adequate, usually 24 normal, healthy and no-smoking individuals, fitting specific health criteria.
• Number of subjects lower than 24 (minimum 18 subjects) may be accepted when statistically justifiable.
• Sponsors should ensure sufficient subjects to allow for dropouts; replacing subjects can complicate statistical analysis.
• Enrolled subjects must be between 18 years of age and older, and with a Body Mass Index between 18.5 and 30 kg/Sq.m.
• Subjects need medical screening which includes clinical laboratory tests, medical history, a physical examination and risk assessment.
• Test conditions should be standardized for diet, exercise, and fluid intake.
• Subjects should fast for at least 8 hours before administering products unless there is another justification.
• A standardized volume of fluid (at least 150 ml) should be co-administered with the products.
• In fed conditions, drug administration timings should align with the originator SPC.
• Subjects should avoid foods/drinks that interact with circulatory, gastrointestinal, hepatic, and/or renal function such as grapefruit juice.
• Concomitant medication except for contraceptives is not allows.
• If concomitant medication is unavoidable, use must be reported (dose and time of administration) and possible effects on the study outcome addressed.
• A sufficient number of samples are a must to describe the plasma concentration-time profile.
• Plasma Creatinine, and Potassium within normal range.

Bioequivalence Evaluation parameters

• AUC, Cmax, and tmax should be determined in studies to determine bioequivalence after a single dose.
• Studies with a sampling period of 72 h, and where the concentration at 72 h is quantifiable, AUC(0-∞) and residual area do not need to be reported.
• Studies to determine bioequivalence for immediate release formulations at steady state, AUC(0-7), Cmax,ss, and tmax,ss should be determined.
• If urine is used as the sample, urine should normally be collected over no less than three times the terminal elimination half-life.
• The statistical evaluation of tmax is not a requirement but is considered clincally relevant and of importance for onset of action.
• For endogenous drugs baseline correction to calulate pharamcokinetic should be performed.
• For a sound bioequivalence study the sponsor should enroll a number of subjects sufficient to ensure adequate statistical results, which is based on the power function of the parametric statistical test procedure applied.

Bioequivalence study evaluation

• Pharmokinetic parameter should not be adjusted for difference in test and refrence batch.
• All treted subject should be included statistically, not just "spare" replacements.
• Permitted reasons for exclusion must be pre-specified in the protocol, and should involve any event that would affect testing conditions.
• If one of these events occurs it should be noted in the CRF as the study is being conducted as it pertains to bioanalysis.
• For example, excluding for vomiting at or before two times median TMax for IR release or anytime during dosing interval for MR.
• When determining bioequivalence after a single dose the 90% CI for the ratio of test and reference products should remain within 80-125%.
• Assessment of bioequivalence is based upon 90% confidence intervals for the ratio of the population geometric means (test/reference) for the parameters.
• Carry-over effects are not considered relevant, but they can be directly addressed and examined by looking at pre-treatment plasma concentrations.

Study strengths and dissolution.

• If the non-linearity is not caused by limited solubility but is due to e.g. saturation of uptake transporters and provided that conditions a) to d) above are fulfilled and the test and reference products do not contain any excipients that may affect gastrointestinal motility or transport proteins, it is sufficient to demonstrate bioequivalence at the lowest strength (or a strength in the linear range).
• Where bioequivalence assessment at more than two strengths is needed, e.g. because of deviation from proportional composition, a bracketing approach may be used.
• Comparative dissolution testing needs to be conducted on 12 dosage units of each batch to decide whether to waive additional in vivo bioequivalence testing
• Refer to the EMA "Guideline on bioanalytical method validation".
• In specific cases of products with a narrow therapeutic index, the acceptance interval for AUC should be tightened to 90.00-111.11%.
• It is not possible to define a set of criteria to categorize drugs as narrow therapeutic index drugs (NTIDs) and it must be decided case by case if an active substance is an NTID based on clinical considerations.
• For in vitro dissolution tests The results of in vitro dissolution tests at three different buffers (normally pH 1.2, 4.5 and 6.8) and the media intended for drug product release (QC media), obtained with the batches of test and reference products that were used in the bioequivalence study should be reported.

Information on Study Reporting

• Study report includes reference product name, strength, pharmaceutical form, batch number, manufacturer, expiry, and country of purchase.
• Additionally, the name/composition of test products used should also be provided as well.
• Concentrations, pharmacokinetic data, and statistical analyses conducted need to be presented in sufficient detail within the report.
• Applicants must state that the test product shares the same quantitative composition and process with the one submitted for authorization.
• A CRO must be listed in the GCC list or accredited by at least two stringent authorities within the last 2 years of conducting the bioequivalence study.
• Appendix 1 outlines general aspects of in vitro dissolution experiments, and how to use the similarity factor for F2 testing

Variation Application Requirements

• For a reformulated product, an in vivo bioequivalence study is required unless otherwise justified.

Appendix II

• When the test product contains a different salt, ester, ether, isomer, mixture of isomers, complex or derivative of an active substance than the reference medicinal product, bioequivalence should be demonstrated in in vivo bioequivalence studies.
• Tests apply to tablets, capsules, and oral suspensions, which requires oral solutions, unless biowaiver is applicable.
• A decision towards bioequivalence is often determined case-by-case and based on clinical testing.
• For fixed combinations, a study should be designed to detect the possibility of a pharmacokinetic drug-drug interaction.

Definitions

• Pharmaceutical equivalents contain like amounts of the same active substance(s) that meet comparable standards.
• Pharmaceutical alternatives are medicinal products that contains different salts, isomers, esters, or dosage for strength.

Appendix III

• Applying for a BCS-based biowaiver is restricted to highly soluble drug substances with known human absorption and considered not to have a narrow therapeutic index
• The drug substance is considered highly soluble if the highest single dose administered as immediate release formulation(s) is completely dissolved in 250 ml of buffers within the range of pH 1 – 6.8 at 37±1°C

Annex 1

• A bioequivalence study summary template should contain information such as a test product's trade name, list of active ingredients and therapeutic classification.