Summary of Public Response and Regulatory Perspective

Katherine Laessig, M.D.

Division of Antiviral Drug Products

January 11, 2001

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

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)

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.

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

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

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

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?

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?

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

Summary of Responses: Study Designs

• Historical-controlled• Open label vs. blinded• Intensification• Concentration-controlled/dose-response• Factorial

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

Summary of Responses: Historical-controlled

• DAVDP position– when concurrent control is feasible, single arm trials

not advocated– use of concurrent observational cohort data possible

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

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

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

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

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

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Dose Response vs. Strain Susceptibility

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Response from Public: Concentration-controlled and Dose-response

• Concentration-controlled– no precedent for registration purposes for antiretroviral

agents

– assay considerations (unapproved; not widely available)

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

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

#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

#2: Two-Part Hybrid Design

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#2: Two-Part Hybrid Design

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Prospective Phenotypic Cohorts

P.S. -log

< 4 fold -2.2

4-10 fold -1.2

> 10 fold -0.5

>20 fold +0.1

#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

#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

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

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

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