Role of Pharmacokinetic Data in the Evaluation of Alternative Antiretroviral Dosing Regimens

1. Role of Pharmacokinetic Data in the Evaluation of Alternative Antiretroviral Dosing Regimens Meeting of the Antiviral Drugs Advisory Committee July 25, 2000

2. Continuum of Drug Development Approval Innovator Generic New formulation Prodrug Alternative dosing Coadministration with PK enhancer

3. Reasons/Advantages of Post-Approval Changes • Manufacturing improvements • Better bioavailability • Improved tolerability • Simplified dosing

4. Evidence Standard: A Spectrum Approval Innovator: Controlled trials Generic New formulation Prodrug Alternative dosing Coadministration with PK enhancer

5. “Substantial Evidence” Food, Drug, and Cosmetic Act • Evidence consisting of adequate and well-controlled investigations • Conducted by experts qualified to evaluate effectiveness • Allow conclusion that the drug will have the effect it purports

6. Evidence Standard: A Spectrum Approval Innovator Generic: Bioequivalence New formulation Prodrug Alternative dosing Coadministration with PK enhancer

7. Evidence Standard: A Spectrum Approval Innovator Generic New formulation Prodrug Alternative dosing Coadministration with PK enhancer ?

8. Guidance For Industry (May 1998):Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products • Agency’s current thinking on quantity of evidence to support effectiveness • Effectiveness may be extrapolated from efficacy data for another claim or product, e.g., • Pediatric uses • Bioequivalence • Modified-release dosage forms • Different doses, regimens or dosage forms

9. Exposure-Response Understood “Even if blood levels are quite different, if there is a well-understood relationship between blood concentration and response … it may be possible to conclude that a new dose, regimen, or dosage form is effective on the basis of PK data without an additional clinical efficacy trial.”

10. Exposure-Response Not Understood “Where the relationship between blood concentration and response is not so well understood and the pharmacokinetics of the new dose, regimen, or dosage form differ from the previous one, clinical efficacy data will likely be necessary … a single additional efficacy study should ordinarily be sufficient. ”

11. Current DAVDP Recommendation • Single, adequately powered 48-week “equivalence” design clinical trial • Submission of 24-week interim results for regulatory review • Submission of 48-week results as phase IV commitment • Supportive PK and safety data

12. Pros and Cons of this Approach • Greater certainty about safety and effectiveness of new regimen, but ... • Large sample size / limited available patients • Longer delay in product availability • Resource intensive • Label may lag behind clinical practice

13. Meeting Objectives • Explore current knowledge of exposure-response relationships for approved antiretrovirals • Explore role and limitations of this data in evaluating new formulations and regimens • Discuss amount, duration, and circumstances when clinical data are necessary • Discuss implications for special populations • Create basis for Industry Guidance

14. Review of Relevant Data • Letter requesting data addressing exposure-response relationships • Acknowledgements • Abbott Laboratories • Agouron Pharmaceuticals, Inc. • DuPont Pharmaceuticals Company • Gilead Sciences • Glaxo Wellcome, Inc. • Hoffmann-La Roche, Inc. • Merck & Co., Inc. • Triangle Pharmaceuticals • Provide overview of data in public domain

15. Agenda • Clinical Pharmacology Overview from the Antiviral Perspective • Kellie Reynolds, Pharm.D. • Anti-infective Perspective • Alex Rakowsky, M.D. • PK/PD Relationships for Antiretroviral Drugs • Richard Hoetelmans, Pharm.D., Ph.D • Future Considerations for PK/PD Research • Terrance Blaschke, M.D. • Open Public Hearing • Charge to the Committee and discussion • Kimberly Struble, Pharm.D.