# Presentation: 093359

## Summary of Industry Responses and Regulatory Perspective

- William Tauber, M.D.
- Division of Antiviral Products
- Food and Drug Administration
- October 19, 2006

## 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

## 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

**Notes:**
Chronic Hepatitis C is a global problem with est. 170M infected worldwide and est. 3.2M USA
Incident infections USA decreasing from 240K ’80s to 26K 2004 but long latency, lack of spontaneous resolution, aging of infected population = liver related complications will increase in the next 10-20yrs.
CHC already the most common reason for transplant
Current interferon based treatment effective for up to 80% but large population segments have significantly lower responses. 
New treatment strategies and/or novel agents needed

## 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

**Notes:**
Chronic Hepatitis C is a global problem with est. 170M infected worldwide and est. 3.2M USA
Incident infections USA decreasing from 240K ’80s to 26K 2004 but long latency, lack of spontaneous resolution, aging of infected population = liver related complications will increase in the next 10-20yrs.
CHC already the most common reason for transplant
Current interferon based treatment effective for up to 80% but large population segments have significantly lower responses. 
New treatment strategies and/or novel agents needed

## 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

**Notes:**
Entities known to the Agency as having interest in pursuing new treatment strategies and/or novel agents for Chronic Hepatitis C were contacted and were asked to respond to a series of questions very similar but not identical to those currently posed to the Committee.
Of the entities contacted, the following 14 responded and their feedback constitutes much of what I will be sharing with you today. I have sought to identify consensus thought wherever possible but have tried at the same time to give all respondents a voice. Where response was low, I have attempted to supplement with the medical literature. I will    attempt to articulate the Agency’s thoughts where relevant. 

## Consensus Definitions

**Chronic Hepatitis C (CHC)**

**Compensated Liver Disease**

**Decompensated Liver Disease**

**Compensated cirrhosis**

**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)**

## 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

## Preferred Populations

**Preferred 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%)**

##  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

**Notes:**
Treatment naïve adults with early stage histologic changes, high baseline viral load and genotype 1 represent the majority of pts in US and Europe and were favored as the ideal population (homogeneous, current treatment response ≈ 50%).Treatment experienced were recognized as often having more advanced histology and more urgent need for effective treatment.

African Americans higher incidence of genotype 1 and lower response to IFN Rx of geno 1 but similar 2/3. Most favored inclusion of AA and Hispanics in registrational trials but suggested investigator trials or phase 4 post marketing due to historically difficult enrollment in these groups

## 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**

## 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 log****10 ****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**

## 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

**Notes:**
These disparities may represent subpopulations with implications for retreatment and novel agents
When describing a study population for inclusion in clinical trials or in product labeling, greater precision is necessary.

## 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

## 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

## Summary of ResponsesEndpoints Compensated Liver Disease

- Primary Endpoints: Viral Clearance Goal
- Primary Endpoints: Viral Suppression Goal
- Secondary Endpoints

## 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

## Endpoints Compensated Liver Disease

- Primary Endpoints: Viral Clearance Goal
- Primary Endpoints: Viral Suppression Goal
- Secondary Endpoints

## 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 (<100 copies/mL) at 4 weeks of therapy**

_**Treatment-Experience**_
**SVR preferred where reasonably attainable**
**Early Virologic Response (EVR12) defined as **_**>**_** 2 log****10 ****decrease in HCV RNA 12 weeks recommended as futility endpoint for INF based Rx **
**Novel Agents viral clearance may be slower**

## Endpoints Compensated Liver Disease

- Primary Endpoints: Viral Clearance Goal
- Primary Endpoints: Viral Suppression Goal
- Secondary Endpoints

## 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

## Endpoints Compensated Liver Disease

- Primary Endpoints: Viral Clearance Goal
- Primary Endpoints: Viral Suppression Goal
- Secondary Endpoints

## 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

## 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

## 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

## 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 >1 Log10 _**WITH**_
- Histologic response of (2 points of Knodell HAI with no worsening fibrosis)

**Notes:**
2 scoring systems Child Turcotte Pugh (CTP) and Model for Endstage Liver Disease (MELD) used to prioritize transplantation list Both scoring systems seek to quantify residual liver function which correlates with disease complications and transplant need
Improvements in CTP and MELD scores could potentially be used as endpoints and were used in study of decompensated HBV published in the medical literature. Threshold values have not been established and neither has been validated for this purpose
One IND holder suggested that a composite endpoint of serum HCV RNA reduction of >1 Log10 with a histologic response of (2 points of Knodell HAI with no worsening fibrosis) might be clinically meaningful

## 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 Investigational agent to SOC**

**Monotherapy**

## 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 Investigational agent**** ****to SOC**

**Monotherapy**

## Study Design OptionsAdding 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

**Notes:**
General agreement: adding a third agent to PEG-IFN/RBV is the preferred clinical design for treatment naïve pts. 
For the treatment experienced, use RVR 4 and EVR 12 to prevent extended monotherapy
If investigational agent is oral, an oral placebo could be used. 
Parenteral placebos more challenging
Depending on efficacy/safety characteristics of novel agent, triple Rx maintained throughout treatment course, administered for defined period followed by consolidation with SOC or administered for defined period followed by off treatment F/U

## 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 investigational agent to SOC**

**Monotherapy**

## Study Design OptionsUse 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

**Notes:**
There was consensus among the IND holders who addressed this issue that while decreased dosage and/or duration of PEG-IFN with acceptable or improved efficacy might be possible with co-administration of novel agents, it would be important that pivotal studies include SOC comparator arms with and without novel agent

## 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 investigational agent to SOC**

**Monotherapy**

**Notes:**
The objectives of a drug interaction program are several fold
One - Explore if a new agent significantly affects the metabolic elimination of approved drugs and visa versa
Determine if any interactions are clinically significant to necessitate dose adjustment, warning or contraindication
Understand dose adjustments or how to avoid interaction 
may allow marketing for drug that otherwise been associated with unacceptable level of toxicity

## Study Design OptionsRibavirin 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)**

**Notes:**
Ribavirin’s mechanism of improving interferon-alfa SVR rates for CHC is unknown
Many IND holders were reluctant to study a novel agent as substitution for RBV until it had demonstrated activity as third agent to SOC
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 up to 12wks prior to PEG-IFN suggested

## 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 investigational agent to SOC**

**Monotherapy**

## Study Design OptionsUse 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

## Study Design OptionsUse 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

## 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 investigational agent to SOC**

**Monotherapy**

## Study Design OptionsMonotherapy

- 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

## Long-Term Follow-up

**Confidence 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**

## 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**

## Concluding RemarksStudy 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

## 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

## 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

## 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

## 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