Center for Professional Advancement Generic Drug Approvals Course

1. Center for Professional AdvancementGeneric Drug Approvals Course Bioequivalence & Bioavailability Michael A. Swit, Esq. Vice President

3. Definitions • Statutory • “Bioavailability” Means The Rate And Extent To Which The Active Ingredient Or Therapeutic Ingredient Is Absorbed And Becomes Available To The Site Of Drug Action. § 505(j)(7)(A) • A Generic Drug Will Be Considered To Be “Bioequivalent” To A Listed Drug If: • The Rate And Extent Of Absorption Of The Generic Does Not Show A Significant Difference From The Rate And Extent Of Absorption Of The Listed Drug. § 505(j)(7)(B)(i). • The Extent Of Absorption Of Drug Does Not Show Significant Difference From The Extent Of Absorption Of The Listed Drug … If The Difference … In Rate … Is Intentional. § 505(j)(7)(B)(ii).

4. Definitions … • Regulatory • “Bioavailability” means the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action. 21 C.F.R. § 320.1(a). • “Bioequivalence” means pharmaceutical equivalents whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions. 21 C.F.R. § 320.1(e).

5. Definitions … • Regulatory … • “Pharmaceutical Equivalents” means drug products that contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, in identical dosage forms, but not necessarily containing the same inactive ingredients, and that meet the identical compendial or other applicable standard of identity, strength, qaulity, and purity, including potency and, where applicable, content uniformity, disintegration times and/or dissolution rates. 21 C.F.R. § 320.1(c).

6. Bioequivalence • Procedures For Determining Bioavailability Or Bioequivalence. 21 C.F.R. §§ 320.21-.63. • Considerations For Bioequivalence. • Statutory/Regulatory. • Proof that drug is not only pharmaceutically equivalent (same active ingredient in same strength and dosage form), but also bioequivalent. • Systemic bioequivalence testing is based on assumption that therapeutic effect of A drug is A function of the concentration of the active ingredient in the systemic circulation of A person and is thus related to its bioavailability. • Clinical bioequivalence is based on clinical data from the reference listed drug (“RLD”) and generic that demonstrate the generic has the same safety and effectiveness as the RLD. Often, a placebo is required to assure that both drugs are superior to the placebo.

7. Requirements For Submission Of Bioequivalence Study Data. 21 C.F.R. § 320.21. • Evidence Demonstrating Bioequivalence To Listed Drug. • Or Information Establishing That A Waiver Is Appropriate

8. Criteria For Waiver Of In Vivo Bioequivalence21 C.F.R. § 320.22 • Drug Products Whose Bioequivalence Is Self Evident. • Parenterals, ophthalmics, and otics with the same concentration of active and inactive ingredients as the listed drug. (Qualitative and quantitative “Q&Q”) • Oral or topical solutions with the same concentration of active ingredient and dosage form as the listed drug, and any difference in inactive ingredients will not significantly affect the drug's absorption. • DESI Drugs Without Known Or Potential Bioequivalence Problems. • Drug Products Whose Bioequivalence Can Be Established Through In Vitro Evidence. • For Good Cause, If Waiver Is Compatible With Protection Of Public Health.

9. Types Of Evidence To Establish Bioequivalence 21 C.F.R. § 320.24. • In Vivo Testing Of Blood Or Related Biological Fluid. • In Vivo Testing Of Urinary Excretion. • In Vivo Testing To Measure Pharmacological Effect. • Well-Controlled Clinical Trials. • In Vitro Testing That Ensures In Vivo Bioavailability

10. Components Of Bioequivalence Study • Protocol • Clinical Report • Analytical Report • Pharmacokinetic and Statistical Report • Statistical Tables, Listings and Graphs

11. Guidelines For Single Dose In Vivo Bioavailability Study (Blood Level). 21 C.F.R. § 320.26. • Investigational New Drug (IND) application not required. • Protocol Example • At least 24 healthy human volunteers (male and female). • Age 18 - 45 • Weight –10% - +15% for frame size • No concomitant medications allowed • Single dose comparison. • Fasting state of volunteers. • 10 hours • No water/fluids ± 1 hour dosing • Two-way crossover. • In first leg, half receive the test (generic) product and half the listed drug. • Adequate wash-out period (at least three times the half life of elimination of active ingredient or metabolite)

12. Key Measures During BE Study • Samples must be collected with sufficient frequency to permit estimate of peak concentration (CMax), area under the concentration time curve (AUC), and time to peak (TMax). • CMax = the observed peak drug concentration obtained directly for the experimental data without interpolation. • TMax = the observed time to reach peak drug concentration obtained directly from the experimental data without interpolation. • AUC(0-t) = area under the concentration versus time curve from time = 0 to time of last quantifiable concentration, calculated by the trapezodial rule. • CMax is a surrogate to indicate rate of absorption. • AUC defines extent of absorption

13. Other Key Aspects of BE Studies • Treatment of systemic blood sample: centrifuge, measure volume, ph, color, temperature control • In Vitro Dissolution testing using water and acid solutions (simulated gastric fluid) to determine that potency of generic is within 5% of RLD. • Validation of assay method. • Pharmacokinetic parameters. (See Exhibits A and B.)

14. Exhibit A – Pharmacokinetics from Generic Drug Subject 1 Tmax = 6 hours Cmax = 47 ug/m/ Conc. (ug/ml) 4 8 12 12 0 4 8 0 Time (hr)

15. Generic RLD 4 8 12 Time (hr) Exhibit B – Pharmacokinetic Data from Generic and RLD • • 0 Conc. (ug/ml) • • Conc. (ug/ml) • • • • • • • • 10 12 0 0 2 4 6 8 2 6 10

16. Multiple Dose In Vivo Biostudy Guidelines For Multiple Dose In Vivo Bioavailability Study (Blood Level)21 C.F.R. § 320.27. • Purpose is to determine steady-state levels of the active drug ingredient or therapeutic moiety in the body. • Sufficient blood or urine samples necessary to establish maximum and minimum blood concentrations on 2 or more consecutive days.

17. Clinical Bioequivalence Study • Submission of protocol for review or reliance on guidance • Dosage Forms -- At present time, clinical trials in patients is about only methodology available to establish bioequivalence where dosage form makes systemic blood level studies not possible or unreliable. • Oral drugs that are not systemically absorbed. (e.g., Sucralfate) • Most topically administered drugs • Intrauterine • Surgical antibacterial scrubs

18. Clinical Bioequivalence Study • Must show RLD and generic are superior to placebo • Must show RLD and generic are equivalent as to clinical effect. • Example – Draft 1990 Guidance For Performance Of A Bioequivalence Study For Topical Antifungal Products requires: • Placebo – normally generic without active ingredient • RLD – usually from single lot of RLD manufacturer • Generic drug • Clinical study that is probably identical to or very similar to study used by RLD to obtain approval • IND required • Measurements • Mycological • Clinical • Therapeutic (combination of mycological and clinical)

19. Statistical Evaluation Required For Any Bioequivalence Tests • Average Bioequivalence Method • Systemic Blood Level Studies • 90% Confidence Interval Using The Two One-Sided T-Test. CMax And AUC = 80% - 125%. • July 1992 Guidance: Statistical Procedures For Bioequivalence Studies Using A Standard Two-Treatment Crossover Design • Clinical Study • Statistical model will be determined by FDA usually in guidance • Statistical analysis to demonstrate RLD and generic are bioequivalent

20. Collateral Issues for BE Studies • Guidance On Food-Effect Bioavailability And Fed Bioequivalence Studies (Dec. 2002) (seewww.fda.gov/cder/guidance/5194fnl.pdf) • Retention Of Bioequivalence Samples. 21 C.F.R. § 320.63. • OGD does not distinguish between systemic blood level studies and clinical studies so retention samples must be held by clinical investigator or third party and not sponsor. • See 21 C.F.R. § 320.38 and § 320.63, www.fda.gov/cder/ogd/retention_samples.htm. • See also August 2002 Draft Guidance for Industry, Handling and Retention of BA and BE Testing Samples www.fda.gov/cder/guidance/4843dft.pdf.

21. BE Guidances • FDA has available approximately 70 guidances for bioequivalence tests, including: • Design of study. • Number of subjects to use. • Identification of reference product. • Duration of study. • Collection times. • Suggested methods for assay. • Dissolution testing methodology and specifications

22. Factors That Can Impact BE Study • Physicochemical Properties of Drug. • Physiological Factors. • Biopharmaceutical Factors. • Formulation Factors. • Pharmaceutical Factors. • Analytical Control. • Statistical Analysis and Acceptance Criteria.

23. Settled Bioequivalence Study Parameters Are Binding On FDA • Provision added by Food And Drug Administration Modernization Act Of 1997 (FDAMA) • Applicant to provide written request to FDA for determination of acceptable biostudy • Purpose is to reach agreement on the design and size of bioavailability and bioequivalence studies needed for approval • Agreements regarding study parameters reached between FDA and the applicant are binding • Cannot be directly or indirectly changed by field or compliance personnel • Cannot be changed after testing begins, with two exceptions: • When applicant agrees to changes in writing • When director of reviewing division determines that A substantial scientific issue essential to determining the safety or effectiveness of the drug has been identified

24. Challenging BE Issues • Racemic Drugs, Metabolites • Gender and Age (Including Pediatrics). • Long Shelf-Life Drugs. • Locally Acting Drug Products. • Estrogenic Drugs • Narrow Therapeutic Index Drugs