FDA Perspective on Direct Acting Antiviral Trials

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FDA Perspective on Direct Acting Antiviral Trials

Wendy Carter, D.O.Medical Officer

Division of Antiviral ProductsUS Food and Drug Administration

The views in this presentation represent the author’s opinion and not necessarily official policy of the Food and Drug Administration

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Outline

• Status of HCV Direct Acting Antiviral (DAA) Guidance

• Early development considerations• Histologic considerations• Documentation of prior response• Phase 2/3 trial design• Efficacy endpoint • Safety database• Follow-up• Special populations

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Status of HCV Guidance

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Combination DAA Therapy

• IFN-free regimens are desired– Broaden access to unmet populations

• Early trials– Various designs – number of DAAs, duration etc.– Design/regimen based on population (genotype,

experience) – Combination needs to be scientifically justified– Role of ribavirin in various patient populations

• Timing

– Depends on available data and risk benefit assessment– Need preclinical, virology and safety/activity on each

agent (not necessarily studied individually)

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Early Development ConsiderationsPhase 1 and 2

• Phase 1– Short duration monotherapy

• Proof of concept (activity)

– Small numbers– Limited safety data

• Phase 2– Various combinations, doses and durations– Active control with IFN may not be needed, but if

DAA regimen approved and becomes SOC, then inclusion as the active control recommended

– Safety and activity

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Development Considerations Support for Phase 3

• Reasonable confidence– Dose– Duration– Safety – Efficacy

• SVR4 on all patients and all available SVR12 for EOP2 meeting

• Drug-Drug Interaction data

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Drug Development Population

• Overall population should have adequate numbers of patients representative of the disease demographics– African Americans/Latinos– Females– Cirrhosis – IVDU/opiate substitution– Bleeding disorders– Transplant– IFN-contraindicated/intolerant or averse

Drug Development Population

• Share with FDA pre-trial initiation work to ensure selected trial sites provide opportunity for sufficient enrollment of diverse population

• Can target specific genotype (e.g. GT1 vs GT 2/3) or subtype (e.g. GT1b)

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Biopsy Considerations

• Correlations between presence or absence of cirrhosis and subsequent efficacy or safety may be important for labeling

• Stage of baseline fibrosis may be important to determine differences in activity, safety or PK data

• Biopsy not required/appropriate in all subjects– Subjects should not be excluded because they can not have

a biopsy (bleeding disorders)

• Non-invasive diagnostic modalities may be used to determine presence or absence of cirrhosis

• Sponsors to provide summary information and references on the performance characteristics of the modalities proposed

• Enroll ~30% cirrhosis

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Documentation of Prior Response

• Difficult to obtain 100% documentation– A leading reason for screen failure

• May be differences in responses between prior nulls and prior partial responders

• Need data in an adequate representation of well documented to allow evaluation by prior response

Phase 2/3 Trial Design

• Meeting with Forum for Collaborative HIV Research October 18, 2011– Approval of BOC and TVR resulted in a new SOC

for genotype 1– Re-evaluation of the control arm for trials of DAAs

(+/- PegIFN/RBV)

• Future trial designs need to consider many factors– Ethical, feasibility of enrollment, blinding with

different regimens and durations, RGT rules– How can we get some comparative safety data?

• Immediate vs. Deferred; PBO controlled (12-24W or less)– Allows for some comparative safety data– Need to maintain the blind and minimize placebo arm drop

out


DAA(s) +/- RBV Follow-upImmediate

0 12

Placebo DAA(s) +/- RBV Follow-up

SVR12

SVR12

Deferred

weeks

0 12 24 48

4824

weeks


• Single arm historical control– lacks comparative safety data– Sufficient information needed to justify the

historical control

• Dose- response and Duration comparison– Lacks comparative safety data

• Once new regimen approved– defacto SOC, then Superiority or NI with New DAA(s) vs. current SOC (whatever it is at the time)

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Phase 3 Considerations: Naives

• Traditional naives and contraindicated/averse are expected to respond similarly

• INF-free regimens – possible trial designs– Immediate vs. deferred; PBO controlled (12-24W or less)– Single arm/historical control – Dose and Duration Comparison– Superiority or NI with new drug vs. current SOC (whatever it

is at the time)• Include a rescue strategy

– May be challenging in IFN contraindicated• Even if a regimen is somewhat less effective, it may

be approvable if shorter duration, improved safety, and/or IFN-free

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Phase 3 Considerations: Experienced

• Different populations– Null, partial responders, relapsers, DAA-experienced

• Need to maximize response– Limited options for retreatment of DAA failures

• IFN-free regimens – possible trial designs– Essentially same as for treatment-naïve, but consider the subpopulation

(null, partial, relapser, DAA exp) along with available treatment to guide design

– Immediate vs. deferred placebo controlled; Historical control; Dose-response/Duration; Superiority or NI design once there is an approved IFN-free regimen

• IFN-containing regimens – possible trial designs– If Phase 2 data is robust, active control may not be necessary or feasible

and may be specific to the subpopulation (e.g. prior PR null responders)– If active control is not feasible, then immediate vs. deferred, dose-response/duration

comparison or single arm historical control may be appropriate

DAA-experienced Population

• Currently, enough promising classes to construct reasonable regimens (+/- Peg-IFN) for most circumstances of first round DAA failures

• We strongly encourage cross-company collaboration when needed to construct a scientifically justified regimen

• Top priority for early trials: identify a highly effective treatment regimen– not the time to push the envelope on short treatment

duration

• Should have proof-of-concept efficacy (i.e., SVR) in DAA-naïve patients– Ideally, in P/R null responders or other difficult to

treat, DAA-naive populations

– Could be direct evidence, or extrapolated from studies of individual components

Drug A + Drug B + P/R never studied, but each increase SVR rates when dosed individually with P/R (or other DAAs)

• Resistance screening may be necessary

• Efficacy based on SVR12, confirm with SVR24

DAA-experienced Population

Trials in DAA-Experienced Patients:Examples for Early POC Studies

1. BOC or TVR + P/R Experienced P/R + ≥ 2 “new” DAAs (neither are NS3/4A PIs) P/R + ≥ 1 “new” DAA + 1 NS3/4A PI, for first cohort

exclude those with detectable key resistance substitutions for the new PI*

IFN-free DAA combination that is highly effective in P/R null responders, w/o use of NS3/4A PI (PI can be added if hypothesized to enhance efficacy)

*Notes:- Sequencing assay sensitivity depends on emerging data. Currently recommend

population-based sequencing in most circumstances. - Resistance screening may not be necessary for second generation PIs with activity against

key HCV genotype 1a and 1b resistance pathways.


2. IFN-free, Combination DAA Experienced P/R + ≥ 2 HCV DAAs, naïve to at least one class Peg-IFN-free, combination ≥ 2 DAA (+/- RBV) regimen

with demonstrated efficacy in DAA-naïve, Peg-IFN/RBV null responders or other difficult to treat populations

In both examples, the need for drug resistance screening depends on specific drug classes in the regimen and HCV DAA exposure history.


3. Patients exposed to non-therapeutic DAA regimens, for example:

– Phase 1 monotherapy trials– Discontinued treatment early for tolerability/safety

reasons (while responding virologically)

Can be eligible for later Phase 2 or Phase 3 trials of regimens with proof-of-concept efficacy in DAA-naïve patients

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Efficacy Endpoint Considerations

6 drug developmentprograms

15 studies

12,000 subjects

Data from fifteen Phase 2 and 3 trials were combined to assess the concordance between SVR24 and SVR12 or SVR4

Trials were submitted under the Antiviral Information Management System (AIMS) initiative (Jadhav et al., 2010, JCP)

Multiple treatment regimens (PR, PR+DAA) and durations were included in the dataset

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Concordance was observed between SVR12 and SVR24 for all treatments

SVR 24 Assessment

‘Y’ ‘N’

SVR12 Assessment

‘Y’ 5551 114

‘N’ 55 4342Sensitivity:

99%Specificity:

97.4%

PPV: 98%

NPV: 99%

SVR 24 Assessment

‘Y’ ‘N’

SVR4Assessment

‘Y’ 4245 425

‘N’ 54 3030

PPV:90.9%

NPV:98.2%

Sensitivity:98.7%

Specificity:87.7%

• ~2% of patients with SVR12 relapse by SVR24 assessment (false positive)

• Less agreement between SVR4 and SVR24

• SVR4 may be useful for guiding dose selection

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Safety Database Considerations

• 1000-1500 subjects – proposed dose and duration

• Some flexibility if substantial improvement in efficacy and improved safety– Depends on pre-clinical and Phase 2 data

demonstrating increased efficacy and improved safety

– Depends on first or subsequent indication and population (initial NDA in decompensated ~300)

– May be willing to have smaller safety database for regimen that is truly “game changing”

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Follow-Up Considerations

• Responders– at least 3 years to assess durability of SVR, liver

related morbidity/mortality

• Non-responders– At least 1 year (or until start of alternative HCV

therapy) for resistance • ph1/2 for preliminary resistance data prior to ph3• Some mutations can persist for years

– Difficult to follow• May roll into other studies or are treated with other

regimens

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Special Populations

• HIV/HCV Co-infection

• Decompensated cirrhosis

• Pre/Post Transplant

• Pediatrics

• Bleeding Disorders

• Opiate Substitution/IDUs

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Special Populations

• Prerequisite data are needed to study special populations and are encouraged to be collected early in development– Safety and antiviral activity data in patients

with compensated cirrhosis, PK in hepatic impairment, and drug-drug interactions

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HIV/HCV Co-Infected• Strongly encourage data at time of NDA submission

– Drug-drug interaction with commonly used HIV drugs prior to dosing in co-infected

• Need to understand how to use drugs together

– Safety data from a cohort who took proposed dose/duration• Are there any important safety issues that may need to be

described in the label?

• To expand indication to co-infected – ~300 subjects treated with regimen (alternatives may

acceptable with justified rationale)• Trial design based on preliminary data and other available

treatments (immediate vs deferred, single arm, dose/duration) • Endpoint SVR12• Safety evaluation includes loss of HIV efficacy

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Decompensated Cirrhosis

• Multiple DAA combination IFN-free preferred• Single arm or dose/duration trials with multiple

DAAs (+RBV) if supported by efficacy data in subjects with less advanced disease – Primary efficacy endpoint: SVR 12– Other important endpoints include: progression of liver

disease, transplantation and mortality • Safety database of about 100 may be adequate for

sNDA, but influenced by:– First indication and stand alone indication would likely

require more (~300 subjects)• Expanded access or safety trials should be

considered

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Pre/Post Liver Transplantation

• Studies could be designed to– Eradicate HCV RNA pre-transplant– Prevent recurrence post-transplant– Treat recurrence

• SVR and relapse as endpoints

• DDI studies with commonly used immunosuppresants should be performed early

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Pediatrics• A pediatric development program should include

– Development of an age appropriate formulation– PK across the pediatric age range (3-17 years)– Clinical safety and efficacy data – Treatment naïve and experienced patients

• Pediatric trials should be initiated once PK, PD, antiviral activity, and safety are reasonably well-defined in adults – Peds trials can begin once adult ph2 safety and SVR data are

available• Safety database ~100 patients at the to-be-marketed dose or

higher for the proposed length of treatment• Follow-up to assess growth and development, durability of

response, and status of liver disease – At least 5 years

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Bleeding Disorders

• Encourage inclusion into clinical trials• Multiple DAA combination regimens may

avoid need for IFN • PEG/RBV trials traditionally exclude patients

with various bleeding disorders• Population is getting older and developing

more end-stage liver disease– Many have never been treated

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Opiate Substitution/IDU

• Many methadone-maintained IDUs are infected, but few initiate treatment

• Reluctance to enroll because of concerns about adherence, psychiatric co-morbidity, or ongoing drug use

• Optimal HCV management approaches for IDUs remain unknown

• Encourage inclusion into clinical trials– Methadone interaction study should be conducted

early – Buprenorphine if an interaction is suggested by

drug metabolism

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Summary

• Exciting time with rise of multiple DAA regimens and IFN-free treatment options. Things to remember:– Phase 2 work is important! Establish appropriate dose and

duration with target population– Have adequate safety data for the proposed

regimen/duration– Establish efficacy for the target population– Make a case for where product/regimen fits into expanding

armamentarium – things are moving fast!– Drug-drug interaction studies completed early– Consider the DAA-experienced population– Special populations and need for specific DDI studies to

adequately evaluate these populations• FDA Guidance on development of DAAs is being revised

Thank You

Acknowledgments: Russ Fleischer, PA; Patrick Harrington, PhD; Jeffry Florian, PhD– contributed slides from their prior

presentations; Debra Birnkrant,MD; Jeffrey Murray MD; Kimberly Struble, PharmD; and many others from DAVP

Documents

FDA Perspective on Direct Acting Antiviral Trials