Title: Summary of Industry Responses and Regulatory Perspective
1Summary of Industry Responses and Regulatory
Perspective
- William Tauber, M.D.
- Division of Antiviral Products
- Food and Drug Administration
- October 19, 2006
2Presentation 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
3Introduction
- 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
4Introduction (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
5Respondents (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
6Consensus 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
7Study 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
8Candidates 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
10Inclusion 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
11Definition 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
12Non-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
13Selection 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
14Selection 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
15Summary of ResponsesEndpoints Compensated Liver
Disease
- Primary Endpoints Viral Clearance Goal
- Primary Endpoints Viral Suppression Goal
- Secondary Endpoints
16Sustained 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
17Endpoints Compensated Liver Disease
- Primary Endpoints Viral Clearance Goal
- Primary Endpoints Viral Suppression Goal
- Secondary Endpoints
18Primary 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
19Endpoints Compensated Liver Disease
- Primary Endpoints Viral Clearance Goal
- Primary Endpoints Viral Suppression Goal
- Secondary Endpoints
20Primary 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
21Endpoints Compensated Liver Disease
- Primary Endpoints Viral Clearance Goal
- Primary Endpoints Viral Suppression Goal
- Secondary Endpoints
22Secondary 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
23Endpoints 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
24Endpoints 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
25Endpoints 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)
26Study 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
27Study 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
28Study 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
29Study 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
30Study 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
31Study 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
32Study 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)
33Study 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
34Study 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
35Study 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
36Study 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
37Study 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
38Long-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
39Long-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
40Concluding 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
41Study 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
42Concluding 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
43Concluding 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
44Conclusions 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