Summary of Public Response and Regulatory Perspective

1. Summary of Public Response and Regulatory Perspective Katherine Laessig, M.D. Division of Antiviral Drug Products January 11, 2001

2. Presentation Outline • Defining terms • Summary of responses re: • study components (pt. pop’n, study regimen, endpoints, duration • review of study designs (historical-controlled, open-label vs. blinded, intensification, concentration-controlled/dose-response, factorial) • elaboration on 3 possibly useful designs (add-on, two-part hybrid, modified factorial) • Regulatory Conclusions

3. Defining Terms • Heavily Treatment Experienced (H.T.E.) Therapy • a new/recycled drug REGIMEN used to treat pts who have experienced therapeutic failure (efficacy or safety) • unlikely that a SINGLE new drug will suffice as “salvage therapy” • for regulatory purposes, the contribution of a new DRUG to the regimen is of interest • for clinical management strategies, the REGIMEN is the entity of interest • H.T.E. pts=previous rx with > 2 HAART regimens containing > 1 agent from each class (NRTIs, NNRTIs, PIs)

4. Defining Terms • “Drug of last resort” vs. “broad use” • crucial distinction because impacts overall drug development plan • has activity but would be “restricted” for use only in H.T.E. because of toxicity, route of administration or other reasons • in contrast to a first-in-class or next-in-class that can be used for both early rx or for H.T.E.

5. Summary of Responses: Patient Population • Broad representation of H.T.E. pts including: • low CD4 (<50) • high HIV RNA (>100,000 copies/ml) • Also include patients whose prior regimens have failed due to: • PK • tolerability • adherence

6. Summary of Responses: Patient Population • Stratification historically based on: • HIV RNA • CD4 count • Well-powered, randomized trials will control for heterogeneity rendering extensive stratification unnecessary • Examination of pt. subsets useful for exploratory analyses

7. Summary of Responses: Study Regimen • Agreement regarding use of: • resistance testing to construct background regimen • allow expanded access agents • include pharmacologic enhancers • Number of background agents • flexibility in number of background agents • use of pK enhancers does not count in total • megaHAART may decrease tolerability and adherence; and increase overlapping toxicities, drug interactions, and number of dropouts

8. Summary of Responses: Study Duration • Traditional approval based on demonstration of durability of viral suppression • 48 week data • Accelerated approval • based on 24 week data • consider earlier assessment of antiviral effect for this pop’n with longer term safety • When should the determination of an antiviral effect (for these patients) be made?

9. Summary of Responses: Virologic Endpoints: • Proportion undetectable may not be feasible • except for multiple investigational or highly potent agents • Alternatives: • Mean change from baseline in HIV RNA • Proportion with > X log drop in HIV RNA • AUCMB • Other suggestions?

10. Summary of Responses: Clinical Endpoints • Clinical endpoint • new CDC class C events (~ 20 conditions) • Suggestions for alternative clinical endpoints • including fewer Class C Events e.g. CMV, MAC • composite endpoint of efficacy and safety/toxicity • DAVDP perspective • better collection and adjudication of clinical endpoints regardless of the primary endpoint or the pt. population • difficult to weight toxicity for composite endpoint, i.e. nausea vs. CMV • Agency needs to examine efficacy and safety separately for risk-benefit assessment

11. Summary of Responses: Study Designs • Historical-controlled • Open label vs. blinded • Intensification • Concentration-controlled/dose-response • Factorial

12. Summary of Responses: Historical-controlled • General agreement • historical results not obtained in equivalent population • heterogeneity of the H.T.E. pts • evolving standard of care • incomplete data from historical cohorts • Natural hx of H.T.E. pts on failing or currently available “salvage” therapy regimens is not disputed

13. Summary of Responses: Historical-controlled • DAVDP position • when concurrent control is feasible, single arm trials not advocated • use of concurrent observational cohort data possible

14. Summary of Responses: Blinded vs. Open Label • Agreement that blinding all drugs is difficult • pill burden • unavailability of placebo • use of resistance testing to choose OBR • Partial blinding (test/control) is sufficient • Statistical considerations for open label studies • blinding reduces bias • patient/physician expectations when assignment is known • differential dropout (switches, loss to follow-up) • need to account for these in analysis

15. Summary of Responses: Blinded vs. Open Label • Method to assess potential for differential dropout • monitor subsequent enrollment of patients who discontinue trial into Expanded Access programs

16. Summary of Responses: Intensification • Intensification=adding on new agent to preexisting regimen with incomplete viral suppression • Concerns • may promote resistance as essentially monotherapy • may exhaust an option that could have been used later • Potential Uses • acceptable if resistance develops slowly • duration of intensification should be minimal and include early escape option

17. Summary of Responses: Concentration-controlled and Dose-response • Community feedback: • avoids suboptimal levels (conc. controlled) • higher levels overcome resistant mutants • Industry concerns: • real time reporting for dose adjustment is difficult • high intra- and inter-subject variability • patient adherence may impact results • unclear which specific exposure measurement is best correlated with response (for investigational drugs) • MTD (maximally tolerated dose) should be used in this population

18. Response from Public: Concentration-controlled and Dose-response • Dose-response • previous use for registration • to discern a rx effect, need to study doses on the steep part of dose-response curve • some participants may receive suboptimal doses • Higher doses may be necessary to suppress resistant virus • illustrated by the following graph

19. Dose Response vs. Strain Susceptibility Dose 3 Dose 2 Dose 1 ? log [drug X]

20. Response from Public: Concentration-controlled and Dose-response • Concentration-controlled • no precedent for registration purposes for antiretroviral agents • assay considerations (unapproved; not widely available)

21. Summary of Responses: Factorial • Industry concerns • drug interactions • overlapping toxicities • timely availability of drug supply • ownership of IND and data • Community and FDA in favor of this approach • industry concerns valid but not insurmountable • factorial design can be modified • randomized trial that participants are more likely to complete • expenses for one trial shared by two or more companies • blinding and provision of placebos easier

22. Three Examples for Discussion • Noncollaborative studies of single investigational agents • Add-on to OBR • Two-part hybrid • Collaborative design for >1 investigational agent • Modified factorial

23. #1: Add-on to OBR • OBR + placebo vs. OBR + study drug • two arm trial for one investigational agent • randomization and blinding preferred • less desirable than modified factorial • risk to pts of receiving placebo is decreased by early escape option

24. #2: Two-Part Hybrid Design Assess Contribution Assess Durability All receive OBR+X days weeks

25. #2: Two-Part Hybrid Design Prospective Phenotypic Cohorts P.S. -log < 4 fold -2.2 4-10 fold -1.2 > 10 fold -0.5 >20 fold +0.1 OBR + Drug X

26. #2: Two Part Hybrid Design • Two part refers to • initial randomization + prospectively defined observational cohort • direct assessment of antiviral effect during first 10 d then indirect dose response via correlation with baseline PT • Assumes that lead-in period is brief enough that: • pts on OLD + Drug X don’t develop resistance • pts continuing OLD regimens won’t have adverse consequences due to not changing therapies • However, lead-in period needs to be long enough to assess antiviral effect • May provide supportive evidence in NDA package

27. #3: Modified Factorial Design • Four arm trial for 3 investigational agents (Drugs A, B, and C): • OBR + A + B • OBR + A + C • OBR + B + C • OBR + A + B + C • Assumption is that OBR or OBR + single study drug alone is inferior • N is 33% less than needed for 3 separate trials • The same active arm is compared against 3 control arms

28. Regulatory Conclusions • Focus of today’s meeting is DRUG specific and not centered on regimens or management strategy • Contribution of a drug to safety and efficacy in broad pt populations as well as H.T.E. needs to be determined • Caveats about these trials • need to know drug interactions up front • dose selection is extremely important and may be different for H.T.E. • baseline resistance testing is useful for construction of OBR and for outcome analysis

29. Regulatory Conclusions • Additional points to consider: • multiple agents make determination of adverse event causality for drug toxicity difficult • trials of shorter duration affect safety database • resistance may develop to first-in-class agents and compromise later virologic response to next-in-class agents

30. Regulatory Conclusions • Provide data for spectrum of patients, particularly H.T.E. for first-in-class or promising next-in-class • Important to consider strength of NDA package • one controlled, traditional study plus other well-designed studies in H.T.E. may be preferred over 2 identical studies in naïve and less rx experienced patients • Study designs must take into account targeted use-- H.T.E. vs. all patients