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1
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
2
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
3
Status of HCV Guidance
4
5
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)
6
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
7
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
8
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)
10
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
11
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
Phase 2/3 Trial Design
DAA(s) +/- RBV Follow-upImmediate
0 12
Placebo DAA(s) +/- RBV Follow-up
SVR12
SVR12
Deferred
weeks
0 12 24 48
4824
weeks
Phase 2/3 Trial Design
• 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)
15
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
16
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.
Trials in DAA-Experienced Patients:Examples for Early POC Studies
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.
Trials in DAA-Experienced Patients:Examples for Early POC Studies
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
22
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
23
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
24
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”
25
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
26
Special Populations
• HIV/HCV Co-infection
• Decompensated cirrhosis
• Pre/Post Transplant
• Pediatrics
• Bleeding Disorders
• Opiate Substitution/IDUs
27
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
28
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
29
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
30
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
31
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
32
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
33
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
34
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