1 summary of industry responses and regulatory perspective william tauber, m.d. division of...

1

Summary of Industry Responses and Regulatory

Perspective

William Tauber, M.D.Division of Antiviral Products

Food and Drug AdministrationOctober 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

Chronic Chronic Hepatitis C Hepatitis C

(CHC)(CHC)

Compensated Compensated Liver DiseaseLiver Disease

Decompensated Decompensated Liver DiseaseLiver Disease

Compensated Compensated cirrhosiscirrhosis

All CHC pts including

compensated cirrhosis

Decompensated cirrhosis

Evidence of ongoing liver damage and hepatitis C viral replication during at least 6

months of observation

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)

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 PopulationsPreferred Populations

Compensated liver disease to include: cirrhosis, no cofactors, adults, genotypes 1, 2, 3 and 4

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%)

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 nonresponder 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 (< 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




18

Primary Endpoints

Viral Clearance Goal

Treatment-NaïveTreatment-Naïve

•Consensus for Sustained Virologic Response (SVR)

•Potential co-primary = Rapid Virologic Response (RVR4) defined as undetectable HCV RNA (<100 copies/mL) at 4 weeks of therapy

Treatment-ExperienceTreatment-Experience

•SVR preferred where reasonably attainable

•Early Virologic Response (EVR12) defined as > 2 log10

decrease in HCV RNA 12 weeks recommended as futility endpoint for INF based Rx

•Novel Agents viral clearance may be slower

19





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





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


• 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


• 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 >1 Log10 WITH– Histologic response of (2 points of Knodell HAI with

no worsening fibrosis)

26

Study Design Options

Use of two or more

investigational agents

Use of a dose of PEG-INF lower

than SOC and/or of shorter duration +

investigational agent

Ribavirin substitution

Adding Adding Investigational Investigational agent to SOCagent to SOC

MonotherapyMonotherapy

27


Use of two or more






Adding Adding Investigational Investigational agentagent to SOCto SOC


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


Use of two or more






Adding investigational agent

to SOC


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


Use of two or more







to SOC


32

Study Design OptionsRibavirin Substitution

• Ribavirin’s 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


Use of two or more







to SOC


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


Use of two or more







to SOC


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 treatmentConfidence with durability of SVR for INF based treatment

For cirrhotics, transplant recipients, HIV/HCV coinfected and immune deficit patients, more

frequent follow-up of HCV RNA after SVR suggested

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

39

Long-Term Follow-up

Semi-annual follow-up to

monitor the state of liver function

was recommended

For patients who fail to

achieve SVR, and continuous treatment not

elected

Every 4-5 years to determine if

study agent should be continued

For situations where viral

suppression is the goal and

histologic and or biochemical endpoints used

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

1 summary of industry responses and regulatory perspective william tauber, m.d. division of...

Documents