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Summary of Industry Responses and Regulatory Perspective

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Title: Summary of Industry Responses and Regulatory Perspective


1
Summary of Industry Responses and Regulatory
Perspective
  • William Tauber, M.D.
  • Division of Antiviral Products
  • Food and Drug Administration
  • October 19, 2006

2
Presentation Outline
  • Introduction
  • Consensus Definitions
  • Summary of responses re
  • Study Populations-Inclusions and Definitions
  • Selection of Controls
  • Study Endpoints Compensated liver disease
  • Study Endpoints Decompensated liver disease
  • Study Design Options
  • Long Term Follow-up
  • Concluding Remarks

3
Introduction
  • Chronic Hepatitis C is a global problem
  • est. 170M infected worldwide and 3.2M USA
  • Incidence infection USA decreasing but HCV
    related disease cirrhosis, ESLD, HCC increasing
  • long latency,
  • lack of spontaneous resolution,
  • aging of infected population liver related
    complications will increase in the next
    10-20years
  • CHC already the most common reason for transplant

4
Introduction (cont.)
  • Current SOC treatment is interferon based
  • Duration 48 weeks for G1/4 , 24 weeks G2/3
  • SVR endpoint measured 24 weeks after end of
    therapy
  • Expensive with safety issues
  • Effective for 30 to 80 based on genotype and
    patient characteristics
  • New treatment strategies and/or novel agents
    needed

5
Respondents (IND Holders)
  • Achillion Pharmaceuticals
  • Bristol-Myers Squibb
  • Coley Pharmaceutical Grp
  • Hoffmann-La Roche
  • Human Genome Sciences
  • Idenix Pharmaceuticals
  • National Institutes Health
  • NIDDK, NIAID
  • Peregrine Pharmaceuticals
  • Schering-Plough
  • SciClone Pharmaceuticals
  • Vertex Pharmaceuticals
  • Wyeth Pharmaceuticals
  • XTL Biopharmaceuticals

6
Consensus Definitions
All CHC pts including compensated cirrhosis
Evidence of ongoing liver damage and hepatitis C
viral replication during at least 6 months of
observation
Chronic Hepatitis C (CHC)
Compensated Liver Disease
Decompensated Liver Disease
Compensated cirrhosis
Absence of clinical consequences of liver disease
(ascites, variceal bleeding, encephalopathy) and
preserved hepatic synthetic function (albumin
3.5g/dL, total bilirubin 1.5mg/dL and
prothrombin time INR 1.5)
Decompensated cirrhosis
7
Study Population Initial Clinical Development
Program
  • Stage of disease- Compensated/Decompensated
  • Treatment naïve or experienced
  • Genotype 1or 4 vs 2 or 3
  • Co-infection with either HIV or HBV
  • Pre or post liver transplantation
  • Pediatrics
  • Racial or Ethnic Groups

8
Candidates Initial Clinical Development Trials
Preferred Populations
Greatest Need Treatment-Experienced,
non-responder (fasted growing group, more
advanced histology, more urgent need for
effective treatment)
Ideal Treatment-Naïve with early stage histologic
changes, high baseline viral load and genotype 1
(largest group, homogeneous, current treatment
response 40-50)
Compensated liver disease to include cirrhosis,
no cofactors, adults, genotypes 1, 2, 3 and 4
9
Candidates-Initial Clinical Development Trials
  • Most favored inclusion of African Americans and
    Hispanics
  • Registrational trials
  • Also suggested investigator trials or phase 4
    post-marketing due to historically difficult
    enrollment in these groups

10
Inclusion Candidates Post Approval
Pediatric post-approval studies and access
programs during phase 2-3 development of
promising agents
CHC pts co-infected with HIV or HBV

Historically difficult to enroll
Decompensated cirrhosis or in the immediate post
liver transplant period
11
Definition Non-Responder
General agreement with the following components
as inclusion criteria in clinical development
studies of treatment experienced non- responder
patients
Previously treated with 1 or more IFN-containing
regimens that include PEG-IFN and RBV
Failure to achieve a 2 log10 reduction in HCV
RNA at Week 12, or HCV detectability at Week 24
or beyond while on therapy (confirmed by a repeat
test)
AND
Compliance documented over the first 12 weeks of
previous therapy to confirm receipt of at least
80 of the prescribed RBV and PEG-IFN dose
12
Non-Responder Populations
  • Non-responders to prior interferon based
    therapy can refer to a heterogeneous population.
  • patients with no significant response (true
    nonresponder)
  • patients with partial response ( 2 log10
    reduction HCV RNA at Week 12 but detectable at
    Week 24 and beyond)
  • relapsers- undetectable during treatment but
    unable to maintain undetectable during follow-up
  • relapsers/rebounders- temporarily undetectable
    during treatment

13
Selection of Controls
  • Treatment naïve compensated CHC patients
  • consensus most appropriate comparator control is
    parenteral pegylated interferon alfa and oral
    ribavirin for 24 or 48 weeks based on genotype
  • placebo or deferred administration could be
    acceptable if cross over to active treatment
    assured
  • an acceptable delay duration varied between 4 to
    12 wks
  • no parenteral placebo was endorsed

14
Selection of Controls
  • For treatment-experienced compensated CHC pts
  • longer durations of placebo controls or Rx delay
    (up to 24 months) were acceptable.
  • For both populations novel drug monotherapy
    acceptable for short periods, typically 2 weeks
    but longer periods suggested by some IND holders
  • Few commented on patients with decompensated
    liver disease but one ventured placebo
    controlled or treatment delay might be possible

15
Summary of ResponsesEndpoints Compensated Liver
Disease
  • Primary Endpoints Viral Clearance Goal
  • Primary Endpoints Viral Suppression Goal
  • Secondary Endpoints

16
Sustained Virologic Response (SVR)
  • Defined as
  • HCV RNA undetectable (lt 100 copies/mL) by RT-PCR
    after 24 weeks of untreated follow-up
  • Preferred endpoint for all patient populations,
    surrogate for viral clearance
  • Definition problematic with differing treatment
    durations leading to measurements at multiple
    timepoints leading to statistical chaos
  • Timing of SVR measurement more controversial
  • Some noted that 98 of relapses occur within 12
    weeks after treatment discontinued and offered
    SVR 12 as alternative
  • SVR only currently validated for IFN treatment,
    some suggested SVR demonstration for novel drugs
    needed

17
Endpoints Compensated Liver Disease
  • Primary Endpoints Viral Clearance Goal
  • Primary Endpoints Viral Suppression Goal
  • Secondary Endpoints

18
Primary Endpoints
Viral Clearance Goal
  • Treatment-Naïve
  • Consensus for Sustained Virologic Response (SVR)
  • Potential co-primary Rapid Virologic Response
    (RVR4) defined as undetectable HCV RNA (lt100
    copies/mL) at 4 weeks of therapy
  • Treatment-Experience
  • SVR preferred where reasonably attainable
  • Early Virologic Response (EVR12) defined as gt 2
    log10 decrease in HCV RNA 12 weeks recommended as
    futility endpoint for INF based Rx
  • Novel Agents viral clearance may be slower

19
Endpoints Compensated Liver Disease
  • Primary Endpoints Viral Clearance Goal
  • Primary Endpoints Viral Suppression Goal
  • Secondary Endpoints

20
Primary Endpoints Viral Suppression Goal
  • Hypothesis Suppression will decrease
    development of ESLD, HCC
  • Non-Responder population with lack of response
    or intolerance to PEG-IFN/RBV
  • Histologic improvement- usually 2 HAI K/I
  • Biochemical Improvement- normalization of liver
    transaminases
  • Viral Suppression (similar to goals of HIV Rx)
    actual clinically meaningful levels not
    suggested -RVR4 might be applicable in this
    situation

21
Endpoints Compensated Liver Disease
  • Primary Endpoints Viral Clearance Goal
  • Primary Endpoints Viral Suppression Goal
  • Secondary Endpoints

22
Secondary Endpoints
  • For both treatment-naïve and non-responders
    except as noted above, histologic and biochemical
    endpoints were considered appropriate secondary
    endpoints due to their lack of specificity and
    sensitivity

23
Endpoints Decompensated Liver Disease 1
  • Few IND holders responded to this question
  • Without transplantation, 5 year survival 50
  • Primary Goals (transplant avoidance)
  • Slowing progression, improving hepatic function,
    reversing complications, reduced transplant need
  • Secondary Goals (preparation for transplant)
  • Clearance of HCV RNA to prevent recurrence of HCV
    viremia post transplant (nearly universal)
  • Reduction of HCV RNA to reduce severity post
    transplant liver disease

24
Endpoints Decompensated Liver Disease 2
  • Major concern regarding IFN safety with increased
    risk bone marrow toxicity and worsening liver
    function
  • SVR remains favored primary endpoint.
  • Up to 22 SVR prior to transplantation,
    virus-free post transplant
  • SVR post transplant, 36 with decreased fibrosis
    in one study
  • Other studies not as favorable

25
Endpoints Decompensated Liver Disease 3
  • Scoring systems used to prioritize
    transplantation list include
  • Child Turcotte Pugh (CTP)
  • Model for Endstage Liver Disease (MELD)
  • Consider improvements in CTP and MELD scores as
    endpoints. However, threshold values not
    established nor validated for this purpose
  • One suggested composite endpoint
  • Serum HCV RNA reduction of gt1 Log10 WITH
  • Histologic response of (2 points of Knodell HAI
    with no worsening fibrosis)

26
Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding Investigational agent to SOC
Ribavirin substitution
27
Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding Investigational agent to SOC
Ribavirin substitution
28
Study Design OptionsAdding Agent to SOC
  • General agreement adding a third agent to
    PEG-IFN/RBV is the preferred clinical design for
    treatment naïve pts.
  • Other suggestions
  • For the treatment experienced, use RVR4 and EVR12
    to prevent extended monotherapy
  • If investigational agent is oral, an oral placebo
    could be used
  • Depending on efficacy/safety characteristics of
    novel agent, a) triple Rx maintained throughout
    treatment course b) administered for
    defined period followed by consolidation with SOC

    c) administered for
    defined period followed by off-treatment F/U

29
Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
30
Study Design OptionsUse of Non-SOC
PEG-IFN/Novel Agent
  • Consensus decreased dosage and/or duration of
    PEG-IFN with acceptable or improved efficacy
    might be possible with co-administration of novel
    agents
  • However, pivotal studies should include SOC
    comparator arms with and without novel agent

31
Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
32
Study Design OptionsRibavirin Substitution
  • Ribavirins mechanism of improving
    interferon-alfa SVR rates for CHC is unknown
  • Many were reluctant to study a novel agent as
    substitution for RBV until activity as third
    agent to SOC is demonstrated
  • In the presence of such data, a novel agent could
    be combined with PEG-IFN vs SOC and might be
    approvable if non-inferior and comparable or
    better safety/tolerability
  • To test additive or synergistic effects novel
    agent, administration as monotherapy prior to
    PEG-IFN suggested up to 12 weeks (DAVP Concerned)

33
Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
34
Study Design OptionsUse of two or more Novel
Agents 1
  • Ideally, differing mechanisms of action
  • Prior to combination studies, a novel agent would
    need to demonstrate anti-HCV activity over
    specified period up to 14 days, longer if viral
    resistance issues satisfied
  • Drug-Drug interaction studies might be considered
    if metabolism profile of drugs suggests
    interaction potential
  • Novel investigational regimens with 2 novel
    agents with complementary mechanisms considered
    important for difficult to treat CHC populations

35
Study Design OptionsUse of two or more Novel
Agents 2
  • Patient populations to benefit from use of two or
    more agents
  • SOC Non-Responders
  • Multi-drug regimens compared with retreatment SOC
    or deferred treatment with novel regimen to
    establish placebo-like control period
  • A concurrent PEG-IFN/RBV treatment period with
    EVR12 should be incorporated to confirm non
    responder
  • Patients for whom IFN/RBV contraindicated such as
    decompensated liver disease or severe anemia
  • To minimize safety concerns, RVR4 could be used
    depending on viral kinetics of products

36
Study Design Options
Monotherapy
Use of a dose of PEG-INF lower than SOC and/or of
shorter duration investigational agent
Use of two or more investigational agents
Adding investigational agent to SOC
Ribavirin substitution
37
Study Design OptionsMonotherapy
  • Agreement for limited monotherapy treatment
    periods in clinical trials
  • The major concern is high daily turnover of HCV
    RNA and low fidelity of the HCV replicase result
    in development of viral resistance with longer
    durations of monotherapy
  • No support expressed for more than short duration
    of interferon monotherapy except in special
    populations such as those with ESRD

38
Long-Term Follow-up
Confidence with durability of SVR for INF based
treatment
SVR following non interferon based treatment
needs validation with F/U HCV RNA, ALT x 3 years
  • No further follow-up
  • 5-10 Year follow-up

For cirrhotics, transplant recipients, HIV/HCV
coinfected and immune deficit patients, more
frequent follow-up of HCV RNA after SVR suggested
39
Long-Term Follow-up
For patients who fail to achieve SVR, and
continuous treatment not elected
Semi-annual follow-up to monitor the state of
liver function was recommended
For situations where viral suppression is the
goal and histologic and or biochemical endpoints
used
Every 4-5 years to determine if study agent
should be continued
40
Concluding RemarksStudy Populations
  • Inclusion Candidates Initial Approval
  • Adult, compensated liver dz, including
    cirrhotics, minority participation, genotypes 1,
    2, 3 and 4, no co-infections
  • Treatment naïve most homogeneous
  • Treatment experienced heterogeneous, fastest
    growing, greatest need
  • Inclusion Candidates Post Approval
  • Pediatrics, decompensated/transplanted,
    co-infected, minority focused
  • Agency needs representative population to support
    labeling

41
Study Populations/Controls
  • The Non-Responder population
  • Important challenge
  • Substantial opportunity for the development of
    novel drugs or new treatment regimens utilizing
    currently approved products
  • Issues
  • Heterogeneity
  • Proposed inclusion criteria definition appeared
    acceptable but additional advice on increasing
    interpretability is sought
  • Controls
  • SOC comparator recommended whenever possible
  • Placebo or deferred treatment possible with
    shorter durations for treatment naïve

42
Concluding Remarks-Endpoints
  • Consensus primary endpoint SVR problems
  • SVR currently only validated for IFN treatment
  • Timing of endpoint measurement-
  • IND holders recommended set number of weeks after
    treatment stopped
  • Agency prefers standard comparable testing times
  • EVR12 and RVR4 (IFN Study Tools)
  • Histologic and Biochemical Endpoints
  • Clinically meaningful levels of viral suppression
    and changes CTP/MELD not validated

43
Concluding Remarks Study Design Options
  • General agreements
  • Adding third agent to SOC treatment naïve
    preferred
  • RVR4 and EVR12 could prevent prolonged
    monotherapy in treatment experienced
  • Ribavirin substitution-active novel agent
  • Two or more novel agents SOC non-response or
    contraindication, SOC comparator possible
  • Monotherapy limited time, special populations IFN

44
Conclusions Long Term Follow-Up
  • Confidence in SVR with IFN based Rx- range from
    no follow-up to 5-10years
  • SVR with novel agents unknown durability,
    recommend retesting to 3 years post Rx
  • Special populations more frequent follow-up
  • No SVR, no treatment, F/U twice per year
  • Long term suppression, Rx monitor every 4-5 years
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