Date: October 28, 2010
From: Melisse S. Baylor, M.D.
BLA/STN#: 125297 / 1.0
Applicant Name: Novartis Vaccines and Diagnostics, Incorporated
Date of submission: December 30, 2009
PDUFA Goal Date: October 30, 2010
Proprietary Name / Established Name: Agriflu®
Indication: Agriflu is a vaccine indicated for the active immunization of individuals 18 years of age and older against influenza disease caused by influenza subtypes A and type B contained in the vaccine.
Recommended Action: Approval
Signatory Authorities Action:
Offices Signatory Authority: Wellington Sun, M.D., Division Director, Division of Vaccine and Related Product Applications
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.
Material Reviewed / Consulted
Melisse Baylor, M.D.
Clinical Pharmacology Review
Tsai-Lien Lin, Ph.D.
Pharmacology / Toxicology Review
Establishment Inspection Report
Advisory Committee Transcript
Agriflu was approved for active immunization against influenza in adults 18 years of age and older on November 27, 2009. Agriflu was originally approved using the accelerated approval mechanism because of the shortage of influenza vaccine. The accelerated approval was based on immunogenicity and safety data from studies using a surrogate marker (anti-hemagglutinin antibody response) for clinical efficacy. Consistent with provisions of the accelerated approval regulations (21 CFR 601.41), Subpart E, the November 27, 2009 approval letter included a postmarketing requirement to conduct a clinical endpoint efficacy study in adults to confirm clinical benefit. With this Supplement, STN 125297/1.0, the Applicant has submitted results of the study that evaluated the clinical efficacy of Agriflu in adults 18 to 49 years of age in support of traditional approval of Agriflu.
No new chemistry, manufacturing, or pharmacology / toxicology information was included in this sBLA.
The Advisory Committee on Immunization Practices (ACIP) recommends routine influenza vaccination annually for all persons six months of age and older. Influenza vaccines have been available in the U.S. since the 1940s. There are currently five trivalent, inactivated vaccines licensed in the U.S. for prevention of seasonal influenza in adults. Three of these were approved using the accelerated approval mechanism because of the shortage of influenza vaccine. Accelerated approval was based on immunogenicity and safety data from studies using a surrogate marker (anti-hemagglutinin antibody response) for clinical efficacy.
Agriflu received regulatory approval initially in Italy in 1986 as Agrippal, and is now approved for use in more than 50 countries worldwide. The initial formulation of Agrippal contained thimerosal as a preservative. The formulation was changed resulting in a trace-thimerosal vaccine that was marketed outside the U.S. starting in 2001. The applicant subsequently began producing a thimerosal-free formulation in 2003. According to the applicant, more than --b(4)--------- have been distributed worldwide including more than --b(4)----------- of the thimerosal-free formulation that the applicant is marketing in the U.S. Agriflu was approved for use in the United States under accelerated approval on November 27, 2009.
- Chemistry Manufacturing and Control
- Product Quality
No information regarding assays to assure product quality was needed to approve this sBLA.
- CBER Lot Release
No lot release plan was needed to approve this sBLA.
- Facilities Review / Inspection
No facility inspection information was necessary to approve this sBLA.
- Environmental Assessment
No environmental assessment was needed to approve this sBLA.
- Product Quality
- Nonclinical Pharmacology / Toxicology
No non-clinical information was needed to approve this sBLA.
- Clinical Pharmacology
No clinical pharmacology data were needed to approve this sBLA.
- Clinical / Statistical
- Clinical Program
Novartis first submitted an IND (-b(4)-) for Agriflu on February 20, 2007. Agriflu was approved for use in the United States on November 27, 2009 under the accelerated approval regulations. The conclusions about the safety and immunogenicity of Agriflu, for the original approval, were based on the safety and immunogenicity results from two pivotal trials, three additional studies to support immunogenicity, and 11 additional studies to support safety. None of these studies were conducted under U.S IND.
The applicant conducted a single, clinical efficacy study to support the effectiveness and safety of Agriflu for traditional approval. The results of this study, V58P13, were included in this sBLA. The protocol for Study V58P13 was submitted to IND -b(4)- on June 22, 2007.
A protocol for an immunogenicity and safety study of Agriflu in children from 3 to 18 years of age was submitted to FDA in May 2008. The results of this study will be submitted in a sBLA to support the licensure of Agriflu in children. Submission of this sBLA is expected in the next calendar year. The applicant has also agreed to conduct a second immunogenicity and safety study in children from 6 months to 3 years of age.
- Other Special Populations
Although the safety and effectiveness of Agriflu has not been established in pregnant women, the applicant has agreed to establish a pregnancy registry to prospectively collect data on spontaneously reported exposures to Agriflu during pregnancy.
The applicant is currently conducting a safety and immunogenicity study of Agriflu in adults 50 years of age and older. In this study, the immune response to Agriflu will be compared to a U.S. licensed comparator.
- Overall Comparability Assessment
This sBLA included the results from a single clinical study, Study V58P13, a randomized, observer-blind, placebo-controlled clinical efficacy study in 11,299 healthy adult volunteers from 18 through 49 years of age. Subjects were randomized in a 1:1:1 ratio to receive Agriflu, an investigational cell-derived seasonal influenza vaccine manufactured by the applicant, or phosphate buffered saline. The study was conducted during the 2007-2008 influenza season and the virus strains included in Agriflu were those recommended for that influenza season:
- A/Soloman Islands/3/2006 (H1N1-like),
- A/Wisconsin/67/2005 (H3N2-like), and
- B/Malaysia/ 2506/2004-like.
Active and passive surveillance for influenza-like illnesses (ILIs) was conducted through out the influenza season. An ILI was defined as any two of the following signs/symptoms: fever/feverish, body aches, cough, sore throat, chills, headache, and runny/snuffy nose. Nasal and throat swabs were collected from subjects with ILIs within 72 hours of onset; these swabs were sent for influenza culture and for identification of influenza by PCR. The primary efficacy endpoint was the protection against illness caused by virus culture-confirmed community acquired influenza wild type strains antigenically similar to those contained in the vaccines. The sample size was based on the assumption of an influenza attack rate of 3% in placebo recipients, a vaccine efficacy estimate of 70%, and 94% power to demonstrate vaccine efficacy with a lower limit of the 95% confidence interval for efficacy greater than 40%. Efficacy in the two active arms (Agriflu and investigational vaccine) was to be evaluated based on independent comparisons to the placebo arm.
The percentage of subjects who were culture positive for any strain of influenza was 1.35% in Agriflu recipients and 3.64% in placebo recipients. Of these, 0.25% of subjects in the Agriflu arm and 1.14% in the placebo arm were culture positive for influenza strains matching those contained in the vaccine. The results for the primary endpoint are shown in the following table.
Table 1: Attack Rates and Vaccine Efficacy with One-Sided, Lower Bound 97.5% Confidence Interval (CI) against Vaccine Matched, Culture-Confirmed Influenza in Study V58P13
Total # subjects
# Subjects with Influenza
Vaccine Efficacy (vs. Placebo)
Source: BLA 125297/1, CSR for V58P13, Table 188.8.131.52.1-1, page 73
As shown above, the vaccine efficacy for Agriflu was 78.4% with a lower bound, one-sided 97.5% confidence interval of 52.1%. The results met the criteria specified in the study protocol to demonstrate vaccine efficacy.
Vaccine efficacy by strain is shown in the following table;
Table 2: Point Estimate and One-Sided, Lower Bound 97.5% Confidence Interval (CI) for Vaccine Efficacy by Vaccine Strain against Vaccine Matched Influenza Strains (Per Protocol Efficacy Population)
Vaccine Matched Strains Only
Vaccine Efficacy (97.5% CI)
Vaccine Efficacy (97.5% CI)
Vaccine Efficacy (97.5% CI)
Source: BLA 125297/1, CSR for V58P13, Tables 184.108.40.206.1-1, page 73
The overwhelming majority of influenza disease in Study V58P13 was due to influenza subtype A/H1N1. Of note, this study was conducted during the 2007-2008 influenza season prior to the widespread circulation of the pandemic H1N1 2009 influenza strain. Since there was only a single case of influenza disease due to A/H3N2 and a single case of disease due to influenza B, the efficacy of Agriflu for these two strains cannot be determined.
- Clinical Program
In Study V58P13, solicited adverse reactions and unsolicited adverse events were collected for the day of vaccination and the six subsequent days. Information on serious adverse events and new onset chronic illnesses was collected for the entire study period, which lasted approximated six months (through the influenza season).
The most common adverse events associated with Agriflu in Study V58P13 were pain and erythema at the injection site and headache, fatigue, and myalgia. Pain at the injection site was reported in 24% of Agriflu recipients compared to 10% of placebo recipients. Erythema at the injection site was observed in 13% of Agriflu recipients compared to 10% of placebo recipients. No other solicited local adverse reactions were reported in more than 10% of Agriflu recipients. Although headache was the most commonly reported solicited systemic adverse reaction, it was reported in 15% of both Agriflu and placebo recipients and was, therefore, unlikely to be related to Agriflu. Fatigue was also observed in a similar percentage of subjects in the Agriflu (11%) and placebo (10%) arms. Myalgia was reported in 10% of Agriflu recipients and 7% of placebo recipients.
Serious adverse events were reported in 1% of subjects in both the Agriflu and the placebo arm. Only two serious adverse events in the Agriflu arm were reported within 21 days of vaccination; neither was judged to be vaccine related. There was a single death in the Agriflu arm; a 37 year old male was murdered 99 days after vaccination. There were no cases of Guillian-Barré syndrome or of anaphylaxis reported. Overall, the safety findings were consistent with those previously described in the package insert for Agriflu and for other trivalent inactivated influenza vaccines. No new safety signals were identified in the review of this supplemental BLA.
- Advisory Committee
This sBLA did not meet any of the factors for presentation to an advisory committee as described in FDA Draft Guidance, “Guidance for the Public and FDA Staff on Convening Advisory Committee Meetings.” Therefore, the application was not discussed at a meeting of the Vaccines Related Products Advisory Committee.
- Other Relevant Regulatory Issues
There were no other notable issues in this review.
The package insert was revised to include the immunogenicity, safety, and vaccine efficacy from Study V58P13. The major revisions were included in the Indication, Adverse Reactions, and Clinical Studies Sections.
- Recommendations and Risk / Benefit Assessment
- Recommended Regulatory Action
In the opinion of this clinical reviewer, the data submitted by the applicant support the traditional approval of Agriflu for active immunization of adults 18 years of age and older against influenza disease caused by influenza virus subtypes A and B contained in the vaccine.
- Risk / Benefit Assessment
Influenza infection in the United States is characterized by seasonal epidemics, usually occurring during the winter months. These epidemics are associated with considerable morbidity and mortality. During the years 1990-1999, influenza infection was responsible for an average of 36,000 deaths per year in the United States, and influenza infection was responsible for approximately 226,000 hospitalizations per year from 1979 to 2001. Influenza vaccination is the primary method for preventing influenza illness and its severe complications, and clear evidence of the efficacy of Agriflu in the prevention of influenza disease was demonstrated in the data provided in this sBLA. The most common adverse events associated with Agriflu use were local injection site reactions. Serious adverse events were uncommon. Therefore, the potential benefits of Agriflu use outweigh the risks.
- Recommendation for Postmarketing Risk Management Activities
There are no recommendations for Postmarketing Risk Management activities.
- Recommendation for Postmarketing Activities
There are no recommendations for new postmarketing activities.
- Recommended Regulatory Action