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BIOEQUIVALENCE TESTING

BIOEQUIVALENCE TESTING. Roger K. VERBEECK, Ph.D. SCHOOL OF PHARMACY UCL – Brussels BELGIUM. roger.verbeeck@uclouvain.be. OUTLINE. Concept of bioavailability Historical cases of bio-inequivalence Bioequivalence testing : EMA and FDA guidelines Study designs Bioequivalence criteria

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BIOEQUIVALENCE TESTING

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  1. BIOEQUIVALENCE TESTING Roger K. VERBEECK, Ph.D. SCHOOL OF PHARMACY UCL – Brussels BELGIUM roger.verbeeck@uclouvain.be

  2. OUTLINE Concept of bioavailability Historical cases of bio-inequivalence Bioequivalence testing : EMA and FDA guidelines Study designs Bioequivalence criteria Special issues

  3. A representative sample of the slides that will be presented and discussed during the course is displayed hereafter.

  4. PHARMACOKINETICS Temporal characteristics of drug effect and relationship to the therapeutic window (e.g., single dose, oral administration).

  5. BIOAVAILABILITY • The extent and the rate to which a drug substance or its therapeutic moiety is delivered from a pharmaceutical form into the general circulation  absolute bioavailability  relative bioavailability

  6. ABSOLUTE BIOAVAILABILITY

  7. RELATIVE BIOAVAILABILITY  tablet A □ tablet B

  8. BIOAVAILABILITY AUC1AUC2AUC3 AUC1=AUC2=AUC3 Cmax Tmax Changes in extent and/or rate of absorption influence the drug plasma concentration-time profile and may therefore affect the therapeutic efficacy

  9. BIOAVAILABILITY formulation and physicochemical factors influencing drug absorption and bioavailability

  10. BIOAVAILABILITY • The practical importance of BA/BE testing has been demonstrated by a number of clinical reports in the 60’s and the 70’s documenting medical problems due to bio-inequivalence • To allow prediction of the therapeutic effect the performance of the pharmaceutical dosage form containing the active substance should be known and reproducible

  11. BIOAVAILABILITY • Outbreak of phenytoin intoxication around 1970 in Queensland, Australia • Calcium sulphate dihydrate in the phenytoin capsules had been replaced by lactose Tyrer et al.: Outbreak of anticonvulsant intoxication in an Australian city. Brit. Med. J. 4: 271-273, 1970.

  12. BIOAVAILABILITY Lindenbaum et al.: Variation in the biologic availability of digoxin from four preparations. New Engl. J. Med. 1344-1347, 1971.

  13. BIOEQUIVALENCE • “Two medicinal products containing the same active substance are considered bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives and their bioavailabilities (rate and extent of absorption) after administration in the same molar dose lie within acceptable predefined limits. These limits are set to ensure comparable in vivo performance, i.e. similarity in terms of safety and efficacy.” GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE, EMA (LONDON), 2010.

  14. BIOEQUIVALENCE TESTING BE tests are not only required for the registration of generic drugs but are also carried out during the development of new drugs: e.g. during scale-up and for post-approval changes (SUPAC).

  15. IMMEDIATE RELEASE DOSAGE FORMS http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf

  16. FDA Guidance for Industry http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072872.pdf

  17. EMA Guideline on the Investigation of Bioequivalence, 2010 STUDY DESIGN - standard design: randomized, two-period, two-sequence, single dose cross-over design - alternative designs: parallel design (substances with very long half-lives) and replicate designs (in case of highly variable drugs or drug products)

  18. 2 x 2 CROSS-OVER DESIGN RANDOMIZATION period 1 period 2 R T WASHOUT sequence 1 subjects T R sequence 2

  19. TWO-GROUP PARALLEL DESIGN RANDOMIZATION group 1 TEST subjects group 2 REFERENCE

  20. REPLICATE DESIGN4-period, 2-sequence, 2-formulation design period RANDOMIZATION I II III IV T R T R sequence 1 subjects sequence 2 R T R T wash-out

  21. STUDY SUBJECTS - the number should be based on an appropriate sample size calculation ( 12), - healthy volunteers to reduce variability, - strict inclusion/exclusion criteria, - subjects could belong to either sex, - preferably non-smokers and without a history of alcohol or drug abuse, - patients, if the investigative active substance is known to have serious adverse effects considered unacceptable for healthy volunteers EMA Guideline on the Investigation of Bioequivalence, 2010

  22. SAMPLING TIMES “The sampling schedule should include frequent sampling around the predicted tmax to provide a reliable estimate of peak exposure. In particular, the sampling schedule should be planned to avoid Cmax being the first point of the concentration-time curve.” EMA Guideline on the Investigation of Bioequivalence, 2010 o Sampling times: 0, 0.5, 1, 2, 4, 6, 8 and 12 hours.

  23. SAMPLING TIMES “The sampling schedule should also cover the plasma concentration time curve long enough to provide a reliable estimate of the extent of exposure which is achieved if AUC0-t covers at least 80% of AUC0-. At least 3 to 4 samples are during the terminal log- linear phase in order to reliably estimate the terminal rate constant, which is needed for a reliable estimate of AUC0-.” EMA Guideline on the Investigation of Bioequivalence, 2010

  24. PRIMARY PARAMETERS: - AUC0-tor AUC0-72h: extent of absorption - Cmax: extent and rate of absorption - Tmax: rate of absorption EMA Guideline on the Investigation of Bioequivalence, 2010

  25. RATE OF ABSORPTIONpartial AUC • For drug products where rapid absorption is of importance, partial AUCs can be used as a measure of early exposure (FDA Guidance for Industry, 2003). • The partial area can in most cases be truncated at the population median of Tmax values for the reference formulation: AUCtmax

  26. BIOANALYTICAL METHODOLOGY The bioanalytical part of BE trials should be performed in accordance with the principles of Good Laboratory Practice (GLP). EMA draft Guideline on Validation of Bioanalytical Methods, London, November 2009. EMA Guideline on the Investigation of Bioequivalence, 2010

  27. BIOEQUIVALENCE CRITERIA: are based on the calculation of a 90% confidence interval according to the two one-sided tests procedure of Schuirmann EMA Guideline on the Investigation of Bioequivalence, 2010 D.J. Schuirmann: A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokinet. Biopharm. 15: 657-680, 1987.

  28. The pharmacokinetic parameters under consideration (e.g. AUC0-t, Cmaxin case of a single dose BE study) should be analysed using ANOVA. The data should be transformed prior to analysis using a logarithmic transformation. The terms to be used in the ANOVA model are usually sequence, subject within sequence, period and formulation. A statistical evaluation of tmax is not required. However, if rapid release is claimed to be clinically relevant and of importance for onset of action or is related to adverse events , there should be no apparent difference in median tmax and its variability between test and reference product. EMA Guideline on the Investigation of Bioequivalence, 2010

  29. 90% CONFIDENCE INTERVAL a 90% confidence interval has to be calculated around the ratio of geometric means obtained for AUC (and Cmax) following administration of test and reference preparation this ratio of geometric means is called the point estimate

  30. For Cmax and AUC0-t the 90% confidence interval for the ratio of the test and reference products should be contained within the acceptance interval of 80.00-125.00%. In specific cases of products with a narrow therapeutic range, the acceptance interval may need to be tightened. Moreover, for highly variable drug products the acceptance interval for Cmax may in certain cases be widened (by using the reference scaled average bioequivalence approach). EMA Guideline on the Investigation of Bioequivalence, 2010

  31. 90% CONFIDENCE INTERVAL 90% CI  1.04(0.91 – 1.20) point estimate   0.80 1.25 1.04

  32. NARROW THERAPEUTIC INDEX DRUGSEMA BE guideline - 2010 In specific cases of products with a narrow therapeutic index (NTI), the acceptance interval for AUC should be tightened to 90.00-111.11%. Where Cmax is of particular importance for safety, efficacy or drug level monitoring the 90.00-111.11% acceptance interval should also be applied for this parameter. It is not possible to define a set of criteria to categorise drugs as NTI drugs and it must be decided case by case if an active substance is and NTI drug based on clinical considerations.

  33. BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) solubility, dissolution and permeability are the 3 major factors controlling the oral absorption of drug substances from IR oral medicinal products permeability dissolution solubility

  34. BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) Amidon et al.: A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 12: 413-420, 1995.

  35. BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS) the BCS was developed for regulatory applications: to provide a basis for replacing, in certain cases, in vivo BE studies by equally or more accurate in vitro tests biowaiver: an acceptance for replacing an in vivo BE study with in vitro dissolution testing

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