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Summary Basis for Regulatory Action - Ixiaro

Date:  September 23, 2010

From: Jeff Roberts, M.D., Chair of the Review Committee 

BLA/ STN#:  125280/19

Applicant Name:  Intercell AG

Date of Submission:  December 17, 2009

PDUFA Goal Date:  October 17, 2010

Proprietary Name/ Established Name:  Ixiaro (Japanese Encephalitis Vaccine, Inactivated, Adsorbed)

Addition to “Dosage and Administration” Sought Under This Biologics License Application (BLA) Supplement:  If the primary series was administered more than 1 year previously, a booster dose may be given prior to potential re-exposure.

Recommended Action: Approval

Signatory Authorities Action: Approval

Offices Signatory Authority:
Wellington Sun, M.D.
Director, Division of Vaccines and Related Products Applications
Office of Vaccine Research and Review
Center for Biologics Research and Review
Food and Drug Administration

I concur with the summary review.
I concur with the summary review and include a separate review to add further analysis.
I do not concur with the summary review and include a separate review.

Review documents used in compiling this SBRA:
Clinical Review                       Sixun Yang, M.D., Ph.D.
Statistical Review                   Mridul Chowdhury, Ph.D.
Labeling Review                     Jean Makie, M.S., R.D.

1. Introduction

Ixiaro (Japanese Encephalitis Vaccine, Inactivated, Adsorbed) is a formalin-inactivated, aluminum-adsorbed vaccine produced in Vero cell culture using the attenuated Japanese encephalitis virus (JEV) strain, SA14-14-2.  It was licensed by FDA in March 2009 for prevention of disease caused by JEV in persons 17 years of age and older.  The recommended vaccination regimen is one dose intramuscularly (IM) on Day 0 and Day 28.   

In this supplemental BLA, the applicant, Intercell AG, has submitted immunogenicity and safety data in support of proposed revisions to the package insert (PI) concerning use of a booster dose and long term follow-up after the primary series.

2. Background

Japanese encephalitis virus is the most common cause of viral encephalitis in Asia, with ~50,000 cases reported annually. Infection is frequently subclinical; only 1 in 250-500 infected individuals manifest clinical disease. However, symptomatic disease results in ~ 25% death rate and 30%-40% of survivors are left with serious neurological sequelae. No effective treatment exists; intervention consists of supportive measures.

There are no reports of Japanese encephalitis (JE) occurring in North America, so the risk to residents of the U.S. is based on travel to endemic regions or work in a laboratory studying virulent JEV strains.

Because safe and effective vaccines against JE are available, a placebo-controlled field trial of true efficacy of a JE vaccine in development would be considered unethical. Broad consensus has developed around the use of the Plaque Reduction Neutralization Test (PRNT) as a surrogate measure of JE vaccine efficacy. FDA agrees with defining seroconversion (SCR) and/or seroprotection (SPR) as PRNT50 titer of ≥1:10, referred to herein as PRNT50(+). 

In the original BLA review, FDA granted licensure based on demonstration of non-inferiority on the PRNT50(+) endpoint compared with the U.S.-licensed JE vaccine, JE-VAX.  Similarly, the current BLA supplement data on response to a booster dose and durability of the immune response was evaluated based on the PRNT50(+) endpoint.

3. Chemistry Manufacturing and Controls (CMC)

Full CMC review of the product was completed at the time Ixiaro was originally licensed in March 2009.

In addition, the PRNT50 assay validation data was reviewed and accepted by CBER during the original BLA review cycle.  The applicant confirmed that no changes were made to the PRNT50 assay used to support the current application.

4. Nonclinical Pharmacology/Toxicology

No new pharmacology/toxicology data were requested or submitted in the context of this submission.

5. Clinical

The clinical reviewer completed a detailed evaluation of the following studies:

  • IC51-303:  an uncontrolled long-term immunogenicity and safety follow-up study.  The primary endpoint was PRNT50(+) at 24 months after primary immunization. Subjects who completed study IC51-301 or IC51-302 (pivotal in the original BLA for efficacy and safety, respectively) were enrolled into this trial on a “first come, first served” basis.  Subjects were to be evaluated for immunogenicity and safety at 6, 12, 24, 36 and 60 months after the primary series.  The sample size was 181.  This study is still ongoing.  The submission contained data collected up to 36 months after the primary series.
  • IC51-305:  an open label, non-randomized, long-term immunogenicity and safety study of a booster dose.  The primary endpoint was PRNT50(+) at Month 24 after the primary series.  For the review of the BLA supplement, the most important secondary endpoint was PRNT50(+) at Day 28 following a booster dose (the algorithm for administering the booster dose is explained below).  All subjects who completed the preceding dose-finding and rapid immunization study, IC51-304 (Group A: 6 µg intramuscularly (IM) on Days 0 and 28; Group B: 12 µg IM on Day 0; Group C: 6 µg IM on Day 0), were enrolled into this trial and were evaluated at 6, 11, 12, 23 and 24 months after the primary series.  Subjects who were PRNT50 negative at Month 6 received a booster dose of Ixiaro 6 µg at Month 11, and subjects who were PRNT50 negative at Month 12 received a booster dose of Ixiaro 6 µg at Month 23.  The sample size for long-term immunogenicity was 349, and the sample size for a booster dose study was 250. 
  • IC51-311:  an open label, uncontrolled study to investigate long-term immunogenicity and safety following a booster dose.  The primary objective was PRNT50(+) at Month 12 after the booster.  Subjects who completed the primary series (6 µg IM on Days 0 and 28, per protocol) in the preceding lot consistency study, IC51-309, were enrolled and received a booster dose of Ixiaro 6 µg at Month 15 after the primary series.  The sample size was 198. 

Immunogenicity

Long Term:
Immunogenicity results (% of subjects PRNT50(+) and geometric mean titer (GMT)) in the ITT population following the primary series from study IC51-303 were as follows:

6 months – PRNT50(+):  95% [95%CI 90.8,97.4]; GMT:  83.5 [95%CI 70.9,98.4]
12 months – PRNT50(+):  83.4% [95%CI 77.3, 88.1]; GMT:  41.2 [95%CI 34.4, 49.3]
24 months – PRNT50(+):  81.8% [95%CI 75.5, 86.7]; GMT:  44.3; [95% CI 36.7, 53.4]
36 months – PRNT50(+):  84.9% [95%CI 78.3, 89.7]; GMT:  43.8 [95% CI 36.5, 52.6]

The above analyses removed from the denominator all subjects lost to follow-up.  In a sensitivity analysis in which the values for subjects lost to follow-up were imputed as PRNT(-), the PRNT50(+) rates were lower.  As an example, in this scenario, PRNT50(+) rate at Month 24 was 75.7% [95%CI 68.8, 81.8].

It was also noted that in general, persistence of neutralizing titer varied across studies.  In study IC51-305 PRNT50(+) rates were lower than those observed at the comparable time points in IC51-303; for example, in IC51-305, the PRNT50(+) rate at Month 24 after the primary series (standard regimen) was 49.6% [95%CI 40.5, 58.6].  Similarly, in Study IC51-311, at Month 15 after the primary series, the PRNT50(+) rate was 69.2% (95% CI 62.4, 75.2).

The variability in persistence of the immune response across studies was likely due to the use of different batches of vaccine in the clinical development program.  Therefore, the percentage of subjects who remain PRNT50(+) at 2 years following the primary series is best represented by a range:  approximately 50% to 80%.

Following a booster:
IC51-305: 
Among subjects who became PRNT(-) at Month 6 or at Month 12, and were therefore boosted at Month 11 and Month 23, respectively, PRNT(+) rate ranged from 99%-100% and GMT ranged from 504 to 6623 at Day 28 following the boost.  [This range includes all three groups in the study – Group A (6 µg Days 0 and 28); Group B (12 µg on Day 0); and Group C (6 µg on Day 0).]

IC51-311: 
Immunogenicity results (% of subjects PRNT50(+) and GMT) in the ITT population at Month 12 after a booster dose (which was administered 15 months after the primary series) were as follows:

PRNT50(+):  98.5% [95%CI 95.6,99.5]
GMTs ranged from 19 to 511, depending on the PRNT50 status of the subject following the primary series and immediately prior to the booster dose.  The lowest GMTs were among the few subjects who became PRNT(-) by Day 56 following initiation of the primary series.

Safety

Overall, 448 subjects from studies IC51-305 and IC51-311 received a booster dose after receiving at least one dose as the primary immunization.

Following a booster dose in Study IC51-311, 35.4% of subjects (N=198) experienced at least one AE within 28 days and 56.1% experienced at least one AE within 12 months.  An evaluation of diary cards in which subjects reported on local reactogenicity revealed that 30.8% of subjects reported at least one injection site reaction within 7 days of the booster.  The rates of all these safety outcomes were lower after the booster dose than the comparable rates that occurred after primary vaccination.

No deaths occurred during the study period following booster vaccination.

Overall, 11 subjects (8 in IC51-311 and 3 in IC51-305) experienced serious adverse events (SAE) after receiving a booster vaccination.  The reported SAEs include epilepsy, thrombosis (due to fibula fracture), injury, cystitis noninfective, carotid artery stenosis, bursitis, open wound, anemia following breast cosmetic surgery, intervertebral disc protrusion, colon cancer, and hand fracture.  All the SAEs were assessed by the investigator as being unlikely related or not related to the vaccine.  The clinical reviewer agreed with the causality assessment.

Pediatrics

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), this application to expand the dosing regimen is required to contain an assessment of the safety and effectiveness of the product for the expanded dosing regimen in pediatric age groups. 

The proposed studies in the pediatric development program submitted with this application are adequate to establish immunogenicity and safety of booster vaccination for ages 12 months to 17 years.  The requirement to study booster vaccination in subjects less than 12 months was waived under PREA because studies in this age group would be impossible or highly impractical.  Insufficient numbers of suitable study subjects exist, because (1) maternally derived JE-neutralizing antibodies are common in infants less than 2 months of age who are born in endemic areas and (2) non-travelers in non-endemic regions could not be ethically enrolled in a study from which they could not expect any potential benefit.

Clinical Reviewer Overall Conclusions

A booster dose of Ixiaro 1 to 2 years after the primary vaccination series is highly effective in stimulating neutralizing antibody responses, regardless of the primary vaccination regimen administered (1 versus 2 doses) and regardless of PRNT50 titer prior to receipt of the booster. 

Review of the safety data following a booster dose did not identify any safety signals.  In terms of both local and systemic reactogenicity, the tolerability of a booster dose is at least comparable to, if not better than, the tolerability of primary vaccination.

6. Statistical

The conclusions of the statistical reviewer are as follows:

  • PRNT50(+) rates varied across studies.  The lower end of the range was 48% at Month 24 in study IC51-305.
  • The decline in neutralizing titer after the primary series stabilized after Month 12.
  • The data support boosting when the time elapsed since primary vaccination exceeds 12 months.
  • Irrespective of booster timing, the 1-month post booster increases in PRNT50(+) rate (>99%) and GMT were very high.   
  • Based on the data reviewed, no concern about the general safety profile was discerned in this review.

7. Bioresearch Monitoring

Data audits and bioresearch monitoring inspections conducted during the review of the original BLA did not reveal any problems that affected the quality or integrity of the submitted data.  No clinical sites were added and no additional subjects were enrolled in order to complete the studies submitted to the supplement.  Therefore, no new bioresearch monitoring inspections were conducted for the review of this application.

8. Labeling

The reviewer from the Advertising and Promotional Labeling Branch (APLB) evaluated the PI and the patient package insert (PPI) and concluded that they are acceptable from a promotional and comprehension perspective.

After minor revisions to the wording of the PI, which were agreed to in a series of discussions with the applicant, the review committee determined that the prescribing information as it pertains to the booster regimen is acceptable.

9. Postmarketing

No safety signals were identified in the long term follow-up data from subjects immunized with the primary series of Ixiaro or in the data from subjects who received a booster dose.  Therefore, the review team did not recommend any changes to the pharmacovigilance program that the applicant implemented at the time initial licensure was granted.

10. Recommendation

The committee recommends approval of the BLA supplement.