1 fda review perspective – entecavir for hepatitis b linda l. lewis, m.d. medical officer division...

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FDA Review Perspective – Entecavir for Hepatitis B

Linda L. Lewis, M.D.Linda L. Lewis, M.D.

Medical OfficerMedical Officer

Division of Antiviral Drug Division of Antiviral Drug ProductsProducts

22

Outline of PresentationOutline of Presentation

OverviewOverview EfficacyEfficacy Safety Safety Virology/ResistanceVirology/Resistance Risk-benefit assessment Risk-benefit assessment Pharmacovigilance planPharmacovigilance plan Questions for the committeeQuestions for the committee

33

OverviewOverview

44

OverviewOverview

Current treatment for chronic HBVCurrent treatment for chronic HBV– Interferon (IFN)Interferon (IFN)

Approved 1992Approved 1992 Requires parenteral administration, significant Requires parenteral administration, significant

side effect profileside effect profile

– Lamivudine (LVD) Lamivudine (LVD) First effective oral therapy, approved 1998First effective oral therapy, approved 1998 Emergence of resistance limits effectivenessEmergence of resistance limits effectiveness

– Adefovir (ADV)Adefovir (ADV) Approved 2002Approved 2002 Known renal toxicity may limit use in some Known renal toxicity may limit use in some

populationspopulations

55

Overview Overview

Entecavir (ETV) development Entecavir (ETV) development program included diverse population program included diverse population – Multi-national sites in North and South Multi-national sites in North and South

America, Europe, and Asia (U.S. America, Europe, and Asia (U.S. subjects about 10%)subjects about 10%)

– 25% women, mix of Asian/non-Asian 25% women, mix of Asian/non-Asian (Black/African Americans under-(Black/African Americans under-represented - 2%)represented - 2%)

– Different stages of disease and Different stages of disease and treatment (insufficient data to review treatment (insufficient data to review in patients with decompensated liver in patients with decompensated liver disease)disease)

66

OverviewOverview

Key studies – all compare ETV to LVD Key studies – all compare ETV to LVD – 022 - Nucleoside-naïve, e antigen positive, 0.5 022 - Nucleoside-naïve, e antigen positive, 0.5

mg mg – 027 - Nucleoside-naïve, e antigen negative, 0.5 027 - Nucleoside-naïve, e antigen negative, 0.5

mgmg– 026 - Persistent viremia despite LVD treatment 026 - Persistent viremia despite LVD treatment

(LVD-refractory), e antigen positive, 1 mg(LVD-refractory), e antigen positive, 1 mg– 014 - LVD-refractory, dose-finding Phase 2 014 - LVD-refractory, dose-finding Phase 2

studystudy Studies 022, 027, and 026 – primary Studies 022, 027, and 026 – primary

endpoint histologic improvement in liver endpoint histologic improvement in liver biopsy after 48 weeks of treatment biopsy after 48 weeks of treatment

77

OverviewOverview

Supportive studies in special Supportive studies in special populationspopulations– 015 – Post-liver transplant pilot study015 – Post-liver transplant pilot study– 038 – HIV/HBV co-infected patients038 – HIV/HBV co-infected patients– 048 – Patients with decompensated 048 – Patients with decompensated

liver disease, compares ETV to ADV, liver disease, compares ETV to ADV, still enrollingstill enrolling

No histologic endpoints; used No histologic endpoints; used virologic, serologic, and virologic, serologic, and biochemical endpointsbiochemical endpoints

88

Efficacy ReviewEfficacy Review

99

Efficacy ReviewEfficacy Review

FDA statistical review confirmed FDA statistical review confirmed BMS’ primary efficacy analysis BMS’ primary efficacy analysis

Secondary endpoint analyses were Secondary endpoint analyses were in agreement with BMS’ conclusionsin agreement with BMS’ conclusions

Multiple sensitivity analyses and Multiple sensitivity analyses and subgroup analyses were performed subgroup analyses were performed that supported the primary analysisthat supported the primary analysis

1010

Histologic Endpoints in Phase 3 Histologic Endpoints in Phase 3 ETV Studies – Primary Efficacy ETV Studies – Primary Efficacy EndpointEndpoint

Study 022 Study 027 Study 026

ETV 0.5 mg

(N=314)

LVD100mg(N=314

)

ETV 0.5 mg(N=296

)

LVD100mg

(N=287)

ETV 1 mg

(N=124)

LVD100mg

(N=116)

Overall histologicimprovement

72% 62% 70% 61% 55% 28%

Fibrosis no worse 89% 82% 84% 79% 87% 70%

Necroinflammatory

> 2 point decrease

74% 64% 73% 64% 55% 32%

Ishak fibrosis score

improvement39% 35% 36% 38% 34% 16%Primary analysis: Only patients with evaluable baseline

biopsy included, missing/inadequate Week 48 biopsy counted as failures

1111

Sensitivity Analysis of Sensitivity Analysis of Primary EndpointPrimary Endpoint


ETV 0.5mg

LVD 100mg

ETV 0.5mg

LVD 100mg

ETV 1mg

LVD 100mg

Overall histologic

improvement72% 62% 70% 61% 55% 28%

FDA sensitivityanalysis C 77% 72% 78% 70% 62% 33%

FDA sensitivityanalysis D 64% 55% 64% 56% 48% 22%

C: Missing/inadequate baseline or Week 48 biopsy excluded

D: Includes all treated patients, missing/inadequate Week 48 biopsy counted as failures

1212

Selected Secondary Efficacy Selected Secondary Efficacy EndpointsEndpoints


ETV 0.5mg

LVD100mg

ETV 0.5

mg

LVD100mg

ETV 1

mg

LVD100mg

HBV DNA PCR < 400

copies/mL72% 42% 95% 77% 22% 1%

Log HBV DNA by

PCR (meanchange frombaseline)

-7.0 -5.5 -5.2 -4.7 -5.1 -0.5

HBeAgseroconversion

21% 18% NA NA 8% 3%

ALT normalization

(< 1 x ULN)

69% 61% 78% 71% 65% 17%

1313

Efficacy – Subgroup AnalysisEfficacy – Subgroup Analysis

The treatment effect measured by the The treatment effect measured by the primary endpoint was comparable primary endpoint was comparable across the following strata:across the following strata:– GenderGender– RaceRace– Age (by quartiles)Age (by quartiles)– Geographic regionGeographic region– HBV subtypeHBV subtype– Baseline ALT (by quartiles)Baseline ALT (by quartiles)– Baseline bDNA or PCR (by quartiles)Baseline bDNA or PCR (by quartiles)– Prior LVD or IFNPrior LVD or IFN

1414

Efficacy – Subgroup AnalysisEfficacy – Subgroup Analysis

The treatment effect measured as The treatment effect measured as proportion of patients with ALT proportion of patients with ALT normalization or HBV DNA by PCR normalization or HBV DNA by PCR < 400 copies/mL at Weeks 24 < 400 copies/mL at Weeks 24 or 48 was similar according to:or 48 was similar according to:– GenderGender– RaceRace– Age (quartiles)Age (quartiles)

1515

Subgroup Analyses – Subgroup Analyses – Primary endpoint by Primary endpoint by baseline covariatesbaseline covariates

% HIST_IMP, ETV - LVDTRIALS 26, 22, 27

-60%

-40%

-20%

0%

20%

40%

60%

80%

100%

BASELINE COVARIATE GROUP

ME

AN

DIF

FE

RE

NC

E &

95

% L

IMIT

S

Favors ETV

Favors LVD

1616

Safety ReviewSafety Review

1717

Safety ReviewSafety Review

FDA clinical review confirmed general FDA clinical review confirmed general safety assessment of ETVsafety assessment of ETV– No significant differences in rates or pattern No significant differences in rates or pattern

of common AEs or laboratory abnormalities of common AEs or laboratory abnormalities compared to LVDcompared to LVD

– Rates of SAEs (8% both treatment groups), Rates of SAEs (8% both treatment groups), discontinuations due to AEs (1% ETV, 4% discontinuations due to AEs (1% ETV, 4% LVD), and deaths (< 1% both groups) were LVD), and deaths (< 1% both groups) were low low

– ALT flares, CNS adverse events, and ALT flares, CNS adverse events, and malignancies reviewed in detailmalignancies reviewed in detail

1818

Safety Review – ALT FlaresSafety Review – ALT Flares

In nucleoside-naïve subjects, mean ALT In nucleoside-naïve subjects, mean ALT values decreased from baseline to Week 48 values decreased from baseline to Week 48 in both treatment groupsin both treatment groups

On-treatment ALT flares uncommon - 15/679 On-treatment ALT flares uncommon - 15/679 (2%) ETV, 27/668 (4%) LVD(2%) ETV, 27/668 (4%) LVD

Study design allowed only patients who met Study design allowed only patients who met Response criteria to discontinue treatment Response criteria to discontinue treatment and be followed off therapy; more subjects and be followed off therapy; more subjects met the criteria in Study 027; analysis of off-met the criteria in Study 027; analysis of off-treatment flares represents selected subjectstreatment flares represents selected subjects

Off-treatment ALT flares slightly more Off-treatment ALT flares slightly more common both groups - 15/414 (4%) ETV, common both groups - 15/414 (4%) ETV, 30/377 (8%) LVD30/377 (8%) LVD

1919

Safety Review – ALT FlaresSafety Review – ALT Flares

In LVD-refractory subjects, on-treatment In LVD-refractory subjects, on-treatment flares in 4/183 (2%) ETV subjects and flares in 4/183 (2%) ETV subjects and 19/190 (10%) LVD subjects 19/190 (10%) LVD subjects

Smaller proportion of LVD-refractory Smaller proportion of LVD-refractory subjects met the Response criteria, subjects met the Response criteria, discontinued therapy, and were followed discontinued therapy, and were followed off-treatment; selected subgroup off-treatment; selected subgroup

Off-treatment flares occurred in 3/56 (5%) Off-treatment flares occurred in 3/56 (5%) ETV subjects and 0/31 LVD subjectsETV subjects and 0/31 LVD subjects

2020

Safety Review – Nervous System Adverse Events in Study 005

Incidence of grouped CNS events increased with increasing doses, trend toward more frequent AEs of dizziness and insomnia with 0.5 mg

2121

Safety Review – On-Treatment Safety Review – On-Treatment Nervous System Adverse Events in Nervous System Adverse Events in Pivotal StudiesPivotal Studies

Nucleoside-naive LVD-Refractory

ETV 0.5 mg(N=679)

LVD 100 mg

(N=668)

ETV 1.0 mg(N=183)

LVD 100 mg

(N=190)

Percent with anyCNS AE

33% 32% 36% 32%

Anxiety 2% <1% 3% 3%

Dizziness 6% 6% 8% 6%

Headache 20% 19% 21% 19%

Insomnia 4% 5% 5% 6%

Migraine <1% <1% 2% 1%

Paresthesia 1% 1% <1% 2%

Somnolence 1% 2% 2% 2%

Syncope or Syncopevasovagal

<1% <1% 1% 0

Percent with Grades

2-4 CNS AEs

9% 9% 15% 9%

2222

Safety Review – Safety Review – Malignancies Reported in Malignancies Reported in Clinical Trials Clinical Trials

Malignancies were tracked in all Malignancies were tracked in all clinical trialsclinical trials

37 subjects reported malignancies 37 subjects reported malignancies in ETV development programin ETV development program– 19/1497 (1.3%) ETV subjects19/1497 (1.3%) ETV subjects– 9/899 (1%) LVD subjects9/899 (1%) LVD subjects– From special population studies From special population studies

3/83 receiving ETV alone3/83 receiving ETV alone 2/28 receiving ADV alone2/28 receiving ADV alone 4/849 receiving ETV + LVD4/849 receiving ETV + LVD

2323

Safety Review – Safety Review – Malignancies Reported in Malignancies Reported in Clinical TrialsClinical Trials Malignancies reported in more than one Malignancies reported in more than one

subject in either treatment group subject in either treatment group included in the NDA safety database included in the NDA safety database (1497 ETV, 899 LVD):(1497 ETV, 899 LVD):– HCC (7 ETV subjects, 4 LVD subjects)HCC (7 ETV subjects, 4 LVD subjects)– Basal cell carcinoma (2 ETV subjects, 1 LVD Basal cell carcinoma (2 ETV subjects, 1 LVD

subject)subject)– Breast cancer (1 ETV subject, 2 LVD Breast cancer (1 ETV subject, 2 LVD

subjects including one with carcinoma in subjects including one with carcinoma in situ)situ)

– Prostate cancer (3 ETV subjects) Prostate cancer (3 ETV subjects) Six subjects reported to have Six subjects reported to have

malignancies were known to have had malignancies were known to have had previous malignancies previous malignancies

2424

Virology/Resistance ReviewVirology/Resistance Review

2525

ETV Resistance Profile – ETV Resistance Profile – Nucleoside-Naïve Subjects Nucleoside-Naïve Subjects (N=434)(N=434) No genotypic or phenotypic evidence No genotypic or phenotypic evidence

of ETV-resistance detected among 434 of ETV-resistance detected among 434 nucleoside-naive subjects analyzed at nucleoside-naive subjects analyzed at 48 weeks of ETV treatment (Studies 48 weeks of ETV treatment (Studies 022 and 027)022 and 027)– 2 subjects in Study 022 experienced 2 subjects in Study 022 experienced

confirmed virologic rebound but no confirmed virologic rebound but no resistance mutations identifiedresistance mutations identified

Follow-up needed after 48 weeks to Follow-up needed after 48 weeks to determine the ETV resistance pathway determine the ETV resistance pathway in naïve subjectsin naïve subjects

2626

ETV Response in LVD-ETV Response in LVD-refractory Subjects (N=189)refractory Subjects (N=189) LVD-refractory subjects less likely than naïve LVD-refractory subjects less likely than naïve

subjects to achieve HBV DNA < 400 subjects to achieve HBV DNA < 400 copies/mL (21% vs 83% when data pooled)copies/mL (21% vs 83% when data pooled)

> 2 log reductions in viral load and > 2 log reductions in viral load and suppression HBV DNA < 400 copies/mL can suppression HBV DNA < 400 copies/mL can occur in subjects with LVD-resistant HBV at occur in subjects with LVD-resistant HBV at baseline when treated with 1 mg ETV baseline when treated with 1 mg ETV

LVD-resistance substitutions L80V, L180M, LVD-resistance substitutions L80V, L180M, M204V or I can emerge in the HBV of M204V or I can emerge in the HBV of subjects on 1 mg ETV by week 48. subjects on 1 mg ETV by week 48. – These substitutions often arise in the context of These substitutions often arise in the context of

mixtures at these sites and other LVD-resistant mixtures at these sites and other LVD-resistant mutations at baselinemutations at baseline..

2727

ETV Resistance Profile – ETV Resistance Profile – LVD-refractory SubjectsLVD-refractory Subjects ETV-associated resistance substitutions in HBV ETV-associated resistance substitutions in HBV

polymerase:polymerase:

I169, T184, S202, and/or M250I169, T184, S202, and/or M250 Emerged only when LVD-resistant mutations Emerged only when LVD-resistant mutations

at L180 and/or M204 were present at baseline at L180 and/or M204 were present at baseline 14/189 (7.4%) of evaluated LVD-refractory 14/189 (7.4%) of evaluated LVD-refractory

subjects treated with ETV developed subjects treated with ETV developed resistance mutations at 48 weeks resistance mutations at 48 weeks

Mutations can be associated with virologic Mutations can be associated with virologic rebound during prolonged therapy (3/14 at rebound during prolonged therapy (3/14 at Week 48)Week 48)

2828

Cross-ResistanceCross-Resistance

LVD-resistant HBV clinical isolates LVD-resistant HBV clinical isolates showed 3- to 52-fold reduced showed 3- to 52-fold reduced susceptibility to ETV by in vitro assayssusceptibility to ETV by in vitro assays

HBV developing ETV-associated HBV developing ETV-associated resistance substitutions in the clinical resistance substitutions in the clinical trials were susceptible to ADV in vitro trials were susceptible to ADV in vitro but remained resistant to LVDbut remained resistant to LVD

ADV-resistant HBV was susceptible to ADV-resistant HBV was susceptible to ETV in vitroETV in vitro

2929

ETV Resistance – SummaryETV Resistance – Summary

No ETV resistance has been detected No ETV resistance has been detected in nucleoside-naïve subjects treated in nucleoside-naïve subjects treated with ETV through 48 weeks; longer with ETV through 48 weeks; longer term data are neededterm data are needed

ETV resistant mutations can emerge ETV resistant mutations can emerge on ETV treatment when LVD mutations on ETV treatment when LVD mutations are present; emerge at a rate of <10% are present; emerge at a rate of <10% at 48 weeksat 48 weeks

These ETV resistance mutations are These ETV resistance mutations are associated with virologic reboundassociated with virologic rebound

ETV is cross-resistant with LVD but not ETV is cross-resistant with LVD but not ADV by in vitro assaysADV by in vitro assays

3030

Risk-benefit Assessment and Risk-benefit Assessment and Pharmacovigilance PlanPharmacovigilance Plan

3131

Risk-benefit assessmentRisk-benefit assessment

Patients with chronic HBV have Patients with chronic HBV have increased risk of HCC and probably increased risk of HCC and probably other malignanciesother malignancies

Accumulating evidence that treatment Accumulating evidence that treatment of chronic HBV may decrease the of chronic HBV may decrease the progression of diseaseprogression of disease

Efficacy of ETV as measured by liver Efficacy of ETV as measured by liver histology, HBV DNA, or other endpoints histology, HBV DNA, or other endpoints better or equivalent to that of LVD better or equivalent to that of LVD over 48 weeks of treatmentover 48 weeks of treatment

General safety and tolerability profile General safety and tolerability profile of ETV similar to that of LVDof ETV similar to that of LVD

3232

Risk-benefit assessmentRisk-benefit assessment

Positive carcinogenicity findings in Positive carcinogenicity findings in animal studies are not rare and are animal studies are not rare and are described in approved product labelsdescribed in approved product labels

Animal carcinogenicity studies identify Animal carcinogenicity studies identify hazard signal not level of riskhazard signal not level of risk

Quantifying the human cancer risk is Quantifying the human cancer risk is difficultdifficult

Mechanism of carcinogenicity is likely Mechanism of carcinogenicity is likely to be different for different drugsto be different for different drugs

Risk-benefit assessment has been Risk-benefit assessment has been made on a case-by-case basismade on a case-by-case basis

3333

Pharmacovigilance planPharmacovigilance plan

Increased monitoring and analysis Increased monitoring and analysis of post-marketing safety reports of post-marketing safety reports and reporting to FDAand reporting to FDA

Continued tracking of subjects in Continued tracking of subjects in clinical trials (through ongoing clinical trials (through ongoing rollover and observational studies) rollover and observational studies)

Proposed large simple safety study Proposed large simple safety study to evaluate occurrence of major to evaluate occurrence of major events in broader clinical useevents in broader clinical use

3434

Pharmacovigilance plan – Pharmacovigilance plan – Proposed post-marketing Proposed post-marketing studystudy Strengths of proposed studyStrengths of proposed study

– Study design with randomization, active Study design with randomization, active control, stratification by prior treatment, control, stratification by prior treatment, pertinent endpoints and planned analysespertinent endpoints and planned analyses

– Will evaluate international population, Will evaluate international population, “real-life” use, allow enrollment of patients “real-life” use, allow enrollment of patients with concomitant HCV and HIV and with concomitant HCV and HIV and spectrum of HBV diseasespectrum of HBV disease

– Size of study (12,500), enrollment through Size of study (12,500), enrollment through many local physicians each following many local physicians each following relatively small number of patientsrelatively small number of patients

3535

Pharmacovigilance plan – Pharmacovigilance plan – Proposed post-marketing Proposed post-marketing studystudy Potential limitations of proposed studyPotential limitations of proposed study

– Length of study may not be adequate to Length of study may not be adequate to identify malignancies with long latencyidentify malignancies with long latency

– Subjects may switch from original Subjects may switch from original assigned treatment to comparator groupassigned treatment to comparator group

– Number lost to follow-up may be higher Number lost to follow-up may be higher than anticipatedthan anticipated

– No specific tumor type can be targetedNo specific tumor type can be targeted– No way to stratify for all possible co-No way to stratify for all possible co-

factors for malignancy in populationfactors for malignancy in population

3636

Pharmacovigilance plan – Pharmacovigilance plan – Proposed post-marketing Proposed post-marketing studystudy Study would be similar in size and Study would be similar in size and

scope to some others that have been scope to some others that have been requested by FDA or that have requested by FDA or that have identified other risk factorsidentified other risk factors

Study might identify changes in 5-8 Study might identify changes in 5-8 year risk of HCC or other tumors in year risk of HCC or other tumors in patients receiving treatment for HBVpatients receiving treatment for HBV

Negative findings at the end of the Negative findings at the end of the study may not equate to a conclusion of study may not equate to a conclusion of “no risk”“no risk”

3737

Pharmacovigilance plan – Animal carcinogenicity findings in context Antiviral drugs with positive animal Antiviral drugs with positive animal

carcinogenicity findings; risk-benefit carcinogenicity findings; risk-benefit decisionsdecisions– ZidovudineZidovudine – Consequences of untreated – Consequences of untreated

HIV, uninfected infants exposed perinatally HIV, uninfected infants exposed perinatally followed in long-term outcome study followed in long-term outcome study (PACTG 076/219)(PACTG 076/219)

– RitonavirRitonavir – Consequences of untreated HIV – Consequences of untreated HIV– GanciclovirGanciclovir – Consequences of untreated – Consequences of untreated

CMV, boxed warning in labelCMV, boxed warning in label– CidofovirCidofovir – Consequences of untreated – Consequences of untreated

CMV, boxed warning in labelCMV, boxed warning in label– FamciclovirFamciclovir – Treatment for HSV, weak – Treatment for HSV, weak

hazard signal based on animal datahazard signal based on animal data

3838

Pharmacovigilance plan – Animal carcinogenicity findings in context Drugs with positive animal Drugs with positive animal

carcinogenicity findings approved carcinogenicity findings approved for other indications for other indications – Lipid-lowering drugs Lipid-lowering drugs – AnticonvulsantsAnticonvulsants– OsteoporosisOsteoporosis– ADHDADHD– Gastroesophageal refluxGastroesophageal reflux

3939

Pharmacovigilance plan Pharmacovigilance plan

The FDA has requested post-marketing The FDA has requested post-marketing studies to assess the risk of human studies to assess the risk of human cancer for some approved drugscancer for some approved drugs– Long-term prospective observational study Long-term prospective observational study

of a drug compared to an appropriate of a drug compared to an appropriate control groupcontrol group

– Registry of patients using the drug long Registry of patients using the drug long term term

– Post-marketing surveillance programPost-marketing surveillance program– Retrospective cohort study to measure the Retrospective cohort study to measure the

incidence of a specific tumor and the incidence of a specific tumor and the contribution of a drugcontribution of a drug

4040

FDA SummaryFDA Summary

In well-conducted clinical trials ETV was In well-conducted clinical trials ETV was shown to provide superior efficacy shown to provide superior efficacy compared to LVD in multiple analyses of compared to LVD in multiple analyses of histologic, virologic, biochemical, and histologic, virologic, biochemical, and composite endpointscomposite endpoints

Treatment benefit of ETV over LVD Treatment benefit of ETV over LVD greatest in LVD-refractory subjectsgreatest in LVD-refractory subjects

General safety and tolerability of ETV General safety and tolerability of ETV was similar to LVD in all populations was similar to LVD in all populations studiedstudied

Safety and tolerability profile of ETV Safety and tolerability profile of ETV similar in nucleoside-naïve and LVD-similar in nucleoside-naïve and LVD-refractory subjects refractory subjects

4141

FDA SummaryFDA Summary

Pre-clinical studies identified ETV as Pre-clinical studies identified ETV as carcinogenic in mice and ratscarcinogenic in mice and rats

Clinical relevance of animal Clinical relevance of animal carcinogenicity data is unknowncarcinogenicity data is unknown

To date, no increase in human To date, no increase in human malignancies has been identified in the malignancies has been identified in the clinical trialsclinical trials

BMS has proposed a large simple safety BMS has proposed a large simple safety study designed to identify increased study designed to identify increased cancer risk in patients receiving ETV as cancer risk in patients receiving ETV as part of their pharmacovigilance program part of their pharmacovigilance program

4242

Questions for the Questions for the CommitteeCommittee

4343

Question 1Question 1

How would you assess the risk-How would you assess the risk-benefit of ETV in the context of benefit of ETV in the context of the available clinical safety, the available clinical safety, efficacy, resistance, and non-efficacy, resistance, and non-clinical carcinogenicity data? clinical carcinogenicity data?

4444


A.A. Does the risk-benefit Does the risk-benefit assessment for entecavir assessment for entecavir support the approval of support the approval of entecavir for the treatment of entecavir for the treatment of chronic HBV in adult patients? chronic HBV in adult patients?

B.B. If the answer to #2A is no, what If the answer to #2A is no, what information would be needed to information would be needed to support a resubmission? support a resubmission?

4545


A.A. If the answer to #2A is yes, discuss If the answer to #2A is yes, discuss whether the results of the rodent whether the results of the rodent carcinogenicity studies should carcinogenicity studies should impact the Indication and Usage impact the Indication and Usage section of the product labeling. section of the product labeling.

B.B. Based on the available data, Based on the available data, discuss the potential role of discuss the potential role of entecavir in the HBV treatment entecavir in the HBV treatment armamentarium. armamentarium.

4646


A.A. Assess the potential risks and Assess the potential risks and benefits of proceeding with benefits of proceeding with development of entecavir for the development of entecavir for the treatment of chronic HBV in treatment of chronic HBV in pediatric patients. pediatric patients.

B.B. What, if any, additional What, if any, additional information is needed in order to information is needed in order to proceed?proceed?

4747


Discuss the applicant’s proposed Discuss the applicant’s proposed pharmacovigilance plan to pharmacovigilance plan to address human cancer risk, address human cancer risk, including comments on the including comments on the design of the proposed large design of the proposed large simple study. simple study.

4848


Are there other issues that you Are there other issues that you would like to see addressed would like to see addressed through post-marketing through post-marketing commitments?commitments?

1 fda review perspective – entecavir for hepatitis b linda l. lewis, m.d. medical officer division...

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