IV Pan-American Conference BE PANDRH Working Group

1. IV Pan-American Conference BE PANDRH Working Group Draft - Progress Report Salomon Stavchansky PhD Alcon Centennial Professor of Pharmaceutics The University of Texas at Austin College of Pharmacy Austin, Texas 78712 stavchansky@mail.utexas.edu PAHO -WHO. Dominican Republic March 2, 2005

2. Working Group • Ricardo Bolanos Argentina • Silvia Giarcovich ALIFAR • Silvia Storpitis Brazil • Conrad Pereira Health Canada • Lizzie Sanchez FDA - USA • Justina Molzon FDA – USA • Roger Williams USP – USA • Regina Pezoa Chile • *Helgi Jung Mexico • Lidiette Fonseca Gonzalez Costa Rica • *Ana Lucia Valle Guatemala • Eugene Brown Jamaica • Rosario D’Alessio PAHO • Sabbine Kopp – Kubel WHO • Loreta Marquez FIFARMA • Irene Goncalves Venezuela

4. Genesis of PANDRH The II Pan American Conference (November 1999) established the Pan American Network for Drug Regulatory Harmonization (PANDRH) and rules and regulations for the Network and its working groups. According to those regulations, harmonized proposals developed by the Working Groups are to be presented at the Conferences for their adoption or approval.

5. Mission of BA-BE PANDRH Working Group • to contribute to the development of harmonized bioequivalence criteria for the interchangeability of pharmaceutical products in the Americas through the promotion of technical basesto assure interchangeability of multisource products, within an international and a national context, by proposing the establishment of reference materials as comparators for bioequivalence testing.

6. Regulatory ConsiderationsPharmaceutical Quality

7. CMC Product release Specifications DISCOVERY DEVELOPMENT DELIVERY

8. Performance Tests • Performance tests are measures that relate to drug-product efficacy and safety • What are the appropriate performance tests for a drug product? • Are performance tests necessary for control of drug product quality? • How do performance tests, surrogate markers and specifications inter-relate? • What value can we expect from a performance test? (Q of the product to its expiry date)

9. Public Health ACCESS POLICY QUALITY REGULATION RISK TO BENEFIT COST CLEAR RECOMMENDATIONS

10. Post Approval Changes

11. Parent Compound Metabolite(s)? P’dynamic Response Single Dose Multiple Dose

12. Background Documents • Guidelines Published by the Food and Drug Administration • Health Canada’s Guideline on Preparation of DIN Submissions • WHO document (1999) entitled “Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products: a Manual for Drug Regulatory Authorities, Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability.” • ICH documents • Note for Guidance on the Investigation of Bioavailability and Bioequivalence, Committee for Proprietary Medicinal Products (CPMP), 26 July 2001 (CPMP/EWP/QWP/98) • WHO QAS/04.093 Draft Guidance – Working Document Revision #3, September 13, 2004. Revision of the Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability

13. Therapeutic Equivalence of Multisource Product Therapeutic Equivalence can be assured when the multisource product is: pharmaceutically equivalent and bioequivalent. TE = PE + BE The concept of interchangeability applies to: 1. - the dosage form and 2. - the indications and instruction for use.

14. Equivalence Documentation COST • Comparative bioavailability (bioequivalence) studies, in which the active drug substance and/or one or more metabolites is measured in an accessible biologic fluid such as plasma, blood or urine. • Comparative pharmacodynamic studies in humans. • Comparative clinical trials. • Comparative in vitro tests • In vitro dissolution tests in combination with the Biopharmaceutics Classification System

15. Oral Drug Products for which in vivo documentation of equivalence is considered especially important • (a) Oral immediate release pharmaceutical products with systemic action when one or more of the following criteria apply: • (i) Indicated for serious conditions requiring assured therapeutic response; • (ii) Narrow therapeutic window/safety margin, steep dose-response curve; • (iii) Pharmacokinetics complicated by variable or incomplete absorption or absorption window, nonlinear pharmacokinetics, presystemic elimination/high first-pass metabolism >70%; • (iv) Unfavorable physicochemical properties, e.g., low solubility, instability, metastable modifications, poor permeability, etc., • (v) Documented evidence for bioavailability problems related to the drug or drugs of similar chemical structure or formulations; • (vi) Where a high ratio of excipients to active ingredients exists.

16. Oral Drug Products for which in vivo documentation of equivalence is considered especially important • (b) Non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (such as transdermal patches, suppositories, etc.). • (c) Sustained or otherwise modified release pharmaceutical products designed to act by systemic absorption. • (d) Fixed combination products • (e) Non-solution pharmaceutical products which are for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc. application) and are intended to act without systemic absorption. In these cases, the bioequivalence concept is not suitable and comparative clinical or pharmacodynamic studies are required to prove equivalence. This does not, however, exclude the potential need for drug concentration measurements in order to assess unintended partial absorption.

17. USA Present Statistical Criteria • Comparison between test and reference product • Use natural log transformation of Cmax and AUC • Criterion: 90% confidence intervals about geometric mean test/reference ratios for both Cmax and AUC must fall within 80 – 125% • Applies to all systemically acting drugs (i.e., not locally acting) with measurable blood or urine levels without regard to the drug’s inherent variability • Same criteria used by pioneer firms to support formulation changes

18. Some International Criteria

19. Comparator Product • The innovator product is usually the most logical comparator product. Quality, safety and efficacy have been well assessed. • If an innovator product cannot be identified or is not available in the market. • What to do? • The selection of the comparator product is usually made at the national level by the drug regulatory authority. A national drug regulatory authority has in principle three options: • choose the innovator product which has been established for quality, safety and efficacy (international comparator), or to • choose the market leaderfor which the pharmaceutical quality, safety and efficacy has been established (national comparator), or • in the case the above are not available, the drug regulatory authority is encouraged to consider a product available on another market, that has been assessed for quality, safety and efficacy, and/or was chosen by another national or a regional regulatory authority (regional specific comparator). • It should be noted that a possibility exists for significant differences to emerge between comparator products used in different countries.

20. Criteria recommended for waiver of evidence of in vivo bioavailability or bioequivalence • When multisource pharmaceutical are to be administered parenterally (e.g., intravenous, intramuscular, subcutaneous, intrathecal administration) as aqueous solutions and contain the same active substance(s) in the same concentration and the same excipients in comparable concentrations; • (b) When multisource pharmaceutical products are solutions for oral use, contain the active substance in the same concentration, and do not contain an excipient that is known or suspected to affect gastro-intestinal transit or absorption of the active substance; • (c) When multisource pharmaceutical products are a gas; • (d) When the multisource pharmaceutical products are powders for reconstitution as a solution and the solution meets either criterion (a) or criterion (b) above;

21. Criteria recommended for waiver of evidence of in vivo bioavailability or bioequivalence • When multisource pharmaceutical products are otic or ophthalmic productsprepared as aqueous solutions and contain the same active substance(s) in the same concentration and essentially the same excipients in comparable concentrations; • (f) When multisource pharmaceutical are topical products prepared as aqueous solutions and contain the same active substance(s) in the same concentration and essentially the same excipients in comparable concentrations; • (g) When multisource pharmaceutical are inhalation products or nasal sprays, tested to be administered with or without essentially the same device, prepared as aqueous solutions, and contain the same active substance(s) in the same concentration and essentially the same excipients in comparable concentrations. Special in vitro testing should be required to document comparable device performance of the multisource inhalation product.

22. BA-BE may be demonstrated by evidence obtained in vitro in lieu of in vivo data. ( Waiver of in vivo Data) • 1.- The drug product is in: • the same dosage form • in a different strength, • is proportionally similar in its active and inactive ingredients • manufactured at the same site • 2. Both drug products meet an appropriate in vitro test approved by a Drug Regulatory Authority and/or accepted reference pharmacopeias, or has demonstrated in vivo – in vitro correlation ( e.g., correlation level A, etc)

23. BA-BE may be demonstrated by evidence obtained in vitro in lieu of in vivo data. ( Waiver of in vivo Data) • 3. Both drug products are proportionally similar in their active and inactive ingredients. • 4. The drug product is a reformulated product that is identical, except for a different color, flavor, or preservative that could not affect the bioavailability of the reformulated product • 5. Regulatory Authorities, for good cause, may require evidence of in vivo bioavailability or bioequivalence for any drug product

26. Special Consideration for Antiretroviral Products • At the present time, the BA-BE working group strongly recommends that in the case of anti-retroviral drug products, proof of pharmaceutical equivalence and bioequivalence be required to infer therapeutic equivalence. However, further discussion is warranted.

27. Biopharmaceutics Classification System (BCS) • BCS is a scientific framework for classifying drug substances (API’s) based on their aqueous solubility and intestinal permeability. • Class 1: High Permeability - High Solubility • Class 2: High Permeability - Low Solubility • Class 3: Low Permeability - High Solubility • Class 4: Low Permeability - Low Solubility • In addition, immediate release solid oral dosage forms are categorized as having rapid or slow dissolution.

28. Basis of BCS SIMILAR IN VIVO DISSOLUTION Dissolution of drug in vivo determines Drug Concentration in the Membrane Domain SIMILAR IN VIVO ABSOPRTION proportional SIMILAR SYSTEMIC AVAILABILITY Intestinal Absorption

30. WHO Essential Drugs: Oral WHO US DRUGS 325 Medicines 200 Drugs Products 260 Drugs 141 Oral 123 Oral IR 43 On WHO List Maximum Strength Solubility mg/ml Dose Number clogP LogP pKa Therapeutic Class Kasim, N. A., et.al. Molecular Pharmaceutics, 1, 85, (2004)

31. Solubility Classification High Solubility Drugs Source: Amidon, G.L Personal Communication

32. Solubility Conclusions • Majority of Drugs (67%) are High Solubility (Do<1) • Similar on WHO and FDA lists • A Dissolution BE test is the best test

33. What is the question? Is it advisable to grant bio-waivers based on BCS and in vitro Dissolution? If it is advisable, when to grant the bio-waiver? Waiver of in vivo studies… Not waiver of bioequivalence

34. Immediate Release Products. Solubility Considerations • highest dose strength of an IR product • A drug substance is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1-7.5 • The volume estimate of 250 ml is derived from typical BE study protocols that prescribe administration of a drug product to fasting human volunteers with a glass (about 8 ounces) of water.

35. pH = 1 – 6.8 ?

36. Immediate Release Products. Solubility Considerations • The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans • a drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose.

37. Permeability Methods • (1) in vivo intestinal perfusion studies in humans; • (2) in vivo or in situ intestinal perfusion studies using suitable animal models; • (3) in vitro permeation studies using excised human or animal intestinal tissues; or • (4) in vitro permeation studies across a monolayer of cultured epithelial cells.

38. Where are we going? • Waiver of In Vivo Bioequivalence Study Requirements • Waiver Based on the Pharmaceutical Dosage Form (Solutions) • Waiver Based on the Biopharmaceutics Classification System • Waiver Based on the Dose. (Highest Strength should be tested)

39. Waiver of in vivo BA and BE for IR products based on BCS • BCS Class 1: - Highly Soluble (Highest dose soluble in 250 ml in water over pH range of 1.2 - 6.8 - Highly Permeable (Extent of absorption greater than 85%) - Rapidly dissolving (Basket at 100 rpm, paddle at 50 rpm in 900 ml of pH 1.2, and 6.8 buffer) • For a waiver of BE, the test and the reference product should exhibit similar dissolution profile, f2 criteria

40. Proposal Discussed with Professor Amidon

41. Stavchansky’s Proposal

42. Intestinal Transporters • Mrp2 Multidrug resistance associated protein 2 • Pept 1 Oligopeptide transporter • Oatp 3 Intestinal organic anion transporting polypeptide 3 • OCT 1 Organic cation transporter • CNT Nucleoside transporter N1 (purine) N2 (Pyrimidine) • MDR1 Multidrug resistance protein 1 • BCRP Breast cancer resistance protein

43. Metabolites and Bioequivalence • The Concentration-time profile of the parent drug is more sensitive to changes in formulation performance than a metabolite, which is more reflective of metabolite formation, distribution, and elimination. • When may Metabolite concentrations be necessary: • The measurement of concentrations of therapeutically active biotransformation product is essential if the substance studied is a pro-drug. • If an active metabolite is formed as a result of gut wall or other presystemic metabolic process(es) and the metabolite contributes meaningfully to safety and/or efficacy, it is recommended that both the metabolite and the parent drug concentrations be measured. • Measurement of a metabolite may be preferred when parent drug levels are too low to allow reliable analytical measurement in blood, plasma, or serum for an adequate length of time or when the parent compound is unstable in the biological matrix. • It is important to note that measurement of one analyte, drug or metabolite, allows the risk of making a Type-I error (the consumer risk) to remain at the 5% level

44. Drugs with Long Half-Life • A single dose cross-over pharmacokinetic bioequivalence study provided an adequate wash-out period is used. • If the cross-over study is problematic, a pharmacokinetic bioequivalence study with a parallel design can be used. • sample collection time should be adequate to ensure completion of gastrointestinal transit (approximately 2 to 3 days) of the drug product and absorption of the drug substance. • Blood sampling up to at least 72 hours should be carried out, unless shorter periods can be justified. However, subject variability should be low • The number of subjects should be derived from statistical calculations but generally more subjects are needed for parallel study design compared with cross-over study design. • Powering parallel studies depends on between-subject variability, not within-subject variability

45. Highly Variable Drugs in the Context of Bioequivalence • To date, there is no regulatory definition for these drugs or drug products. Any drug whose rate and extent of absorption shows large dose-to-dose variability within the same patient • Commonly understood to include those drugs whose intrasubject coefficient of variation (Cmax and/or AUC) is approximately 30% or more

46. Concerns with HVD • Resources - Cost of studies due to the large number of subjects required for a bioequivalence study to be able to pass the “goalpost” • Ethical concerns because exposing so many healthy subject to drugs • Potential failure of the reference product

47. Examples of Highly Variable Drugs • atorvastatin, esomeprazole, pantoprazole, clarithromycin, paroxetine (CR), risedronate, metaxalone, itraconazole, balsalazide, acitretin, verapamil, atovaquone, disulfiram, erythromycin, sulfasalazine.

48. Why Current 80-125% Criteria Are Not Appropriate For HVDs • dose-to-dose variability within a patient is much larger than the width of the criteria • HVDs are “wide therapeutic index” drugs – i.e., have shallow dose response curves, and wide safety margins • One Size Does Not Fit All !!!!!!

49. Recommendation for HVD • The confidence interval reflects the degree of consumer risk (Type I error) A reduction in the level of confidence from 90% to 85%, implies a possible increase in the consumer risk • In contrast, the width of equivalence limits represents the allowable boundary for the ratio (or difference) of the means between products in comparison. Statistically, widening the bioequivalence limits can be accomplished: • through expansion of the allowable boundary or • by scaling the criteria based on the high variability of the reference product. • by using sequential designs

50. Critical dose drugs • "Critical dose drugs" are defined as those drugs where comparatively small differences in dose or concentration lead to dose- and concentration-dependent, serious therapeutic failures and/or adverse drug reactions which may be persistent, irreversible, slowly reversible, or life threatening event