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Summary Basis for Regulatory Action (BLA/STN# 125300/226)
Date: August 1, 2013
From: Cara R. Fiore, Ph. D.
BLA/ STN#: 125300_226
Applicant Name: Novartis Vaccines and Diagnostics, Inc.
Date of Submission (CBER received): April 13, 2011
PDUFA Goal Date: August 1, 2013
Proprietary Name/ Established Name: Menveo [Meningococcal (Groups A, C, Y and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine]
Indication: Active immunization to prevent invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135 for use in children 2 months through 23 months of age.
Recommended Action: Approval
Signatory Authorities Action: Approval
Offices Signatory Authority: Wellington Sun, MD, Director, Division of Vaccines and Related Products Applications
X 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.
Table 1: Review documents used in compiling this SBRA
|Review Category||Reviewer – date of review|
|Clinical Review||Meghan Ferris and Anuja Rastogi – February 16, 2012; July 31, 2013|
|Statistical Review||Barbara Krasnicka – December 12, 2011; April 30, 2012, July 10, 2013|
|Chemistry, Manufacturing and Controls (CMC) Review||Willie Vann – December 11, 2011; July 9, 2013|
|Human serum bactericidal assay (hSBA) Review||Mustafa Akkoyunlu – December 5, 2011 Freyja Lynn – May 28, 2013|
|Bioresearch Monitoring Review||Carla Jordan – December 5, 2011|
|BioAssay Statistical Review||Martha Lee – December 10, 2011; June 18, 2013|
|APLB Review||Michael Brony – June 18, 2013|
|Pharmacovigilance Review||Manette Niu – November 12, 2011 Bethany Baer – June 14, 2013|
|Concomitant Vaccine Serological Assays:|
|Haemophilus influenzae type b||Mustafa Akkoyunlu – December 5, 2011 Brian Mocca – June 11, 2013|
|Polio||Ronald Lundquist – December 5, 2011 Gennady Rezapkin – February 5, 2012|
|Diphtheria, Tetanus and Pertussis||Leslie Wagner – October 21, 2011; June 4, 2013|
|Hepatitis B||Steve Feinstone – December 2, 1011 Marion Major – April 4, 2013|
|Varicella||Shuang Tang – July 18, 2011|
|Measles, Mumps and Rubella||Steven Rubin – June 2, 2011|
|Pneumococcal (PCV7)||Mustafa Akkoyunlu – December 5, 2011; May 31, 2013|
IND 11278 – Meningococcal (Neisseria meningitidis) Tetravalent Oligosaccharide Serogroups A, C, Y, W-135 Conjugate (diphtheria toxin CRM197; Corynebacterium diphtheriae) Vaccine ------------------(b)(4)--------------------------------
On April 13, 2011, Novartis submitted an efficacy supplement to the Biological License Application (sBLA), STN 125300/226, for Menveo [Meningococcal (Groups A, C, Y and W-135) Oligosaccharide Diphtheria CRM197 Conjugate Vaccine] to expand the indication and revise the package insert accordingly. This supplement includes safety and immunogenicity data in children 2 months through 12 months of age receiving four doses of Menveo at 2, 4, 6 and 12 months of age, as well as data supporting the safety and immunogenicity of a two-dose “catch-up” vaccination schedule in infants 7 months to 23 months of age. Previously, Menveo was approved by the FDA for use in the U. S. in individuals 2 years through 55 years of age for prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, W-135 and Y. The original BLA was approved on February 19, 2010, for 11-55 years of age. Subsequently, on March 31, 2010, Novartis submitted sBLA 125300_95, which was approved on January 27, 2011, to expand the vaccine indication to include use in children 2 through 10 years of age.
2. Background and Regulatory History
Menveo (also referred to as MenACWY in this document) is manufactured by Novartis Vaccines and Diagnostics S.r.L. Bellaria-Rosia, 53018 Sovicille, (b)(4), Italy (Novartis, or NVD). Currently, there is no quadrivalent meningococcal vaccine licensed for infants as young as 2 months of age. GlaxoSmithKline produces MenHibrix, Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine, for use in children 6 weeks of age through 18 months of age. Sanofi Pasteur produces Menactra [Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine], which is licensed for use in children as young as 9 months of age, and Menomune-A/C/Y/W-135 [Meningococcal Polysaccharide Vaccine (Groups A, C, Y and W-135)], which is licensed for use in individuals 2 years of age and older.
The applicant submitted on April 13, 2011, an sBLA (STN 125300/226), which was a revision of the sBLA 125300/201 that received a Refuse to File letter, to expand the indication of the MenACWY to infants and toddlers 2 through 23 months of age. A Complete Response (CR) letter was issued on February 10, 2012, listing 55 points that Novartis needed to address. The majority of these points (45 of the 55 points) were related to data collection and analysis during the clinical trials. For the three pivotal studies (V59P14, V59P21, and V59P23), additional information was requested to clarify the percentage of diary cards that that were not returned or were completed based on recall. The CR letter questioned discrepancies between the Clinical Study Report (CSR) and reported data in each of the dataset files as well as deviations in the study protocols. There was no specific safety concern or signal that contributed to the CR letter being issued, but rather there were concerns regarding the data quality. In response, the sponsor conducted the Menveo Metadata Collection project (MMC) to assess the accuracy, reliability, and verifiability of the safety data collected in the pivotal studies. From the MMC, the sponsored concluded that the various methodological concerns raised by CBER, when carefully examined and reviewed, do not fundamentally change any of the overall conclusions regarding the safety profile for MenACWY for the infant and toddler populations. With the results of the MMC and other supplied data, the sponsor addressed these 55 points of the CR letter and resubmitted the application on January 30, 2013. A new clinical study report for Study V59_33, that is the pivotal study of immunogenicity and contributed to the non-detailed safety database, and the final study report for V59P23 were included in the resubmission (the April 13, 2011, submission had an interim study report for V59P23).
The data submitted in STN 125300/226 will satisfy PREA-PMRs 3, 4, 5, and 7 regarding deferred pediatric studies from the approval letter for the original BLA, dated February 19, 2010.
3. Chemistry, Manufacturing and Control (CMC) Information
Menveo consists of four drug substances, each composed of a Meningococcal capsular oligosaccharide covalently attached to the nontoxic genetically modified Diphtheria Toxin CRM197 protein. Each drug substance is prepared from materials purified from two starting products of bacterial fermentation origin: Corynebacterium diphtheriae Cross Reactive Material 197 (CRM197) and capsular polysaccharide (A, C, W-135 and Y obtained from Neisseria meningitidis serogroups A, C, W-135 and Y, respectively).
Each 0.5 mL dose of Menveo contains 10 µg MenA conjugated to --(b)(4)--- µg CRM197, 5 µg MenC conjugated to --(b)(4)--- µg CRM197, 5 µg MenW-135 conjugated to --(b)(4)--- µg CRM197, and 5 µg MenY conjugated to --(b)(4)--- µg CRM197. The vaccine is supplied in two vials that must be combined; the MenA lyophilized conjugate component (single dose vial) is reconstituted with the MenCYW-135 liquid conjugate component (single dose vial) immediately before administration.
Full review of CMC information for Menveo was completed at the time of original licensure on February 19, 2010. All lots of vaccine used in the clinical study of concomitantly administered vaccines were reviewed and released for distribution by CBER. The CMC review in this supplement concentrated on the human serum bactericidal assay (hSBA) and on one question asked by CBER in the Complete Response letter dated February 10, 2011, regarding the use of -----(b)(4)------- in the infant studies (see discussion below.)
Serological Assay Methods
The hSBA (human Serum Bactericidal Assay) was used to measure specific antibody titers (Groups A, C, Y and W-135) in sera from the subjects in the clinical trials in order to evaluate the immune response before and after vaccination with the quadrivalent vaccine directed against the serogroups A, C, Y and W-135 of Neisseria meningitidis(ref 1). In individuals older than 2 years of age, the hSBA response following Menveo was compared to that following a US- licensed meningococcal vaccine. The hSBA as a method for demonstrating effectiveness of meningococcal conjugate vaccines in children under 2 years of age was discussed at a meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) held on April 7, 2011 (ref 2). In brief, the committee agreed that serum bactericidal activity with human complement (hSBA) could be used as an immune measure to infer effectiveness of meningococcal conjugate vaccines for children under 2 years of age. Seroresponse above a pre-defined hSBA titer would indicate that meningococcal-specific functional antibodies present at the time of exposure are protective against systemic infection. Thus, the hSBA was used as a correlate of protection to measure immune response for inferred effectiveness of Menveo in children 2 through 23 months of age.
Briefly, the hSBA is based on the measurement of complement dependent killing of bacteria through the binding of serogroup specific antibodies to the polysaccharide capsule of the meningococcal strains. The C1q subunit of the complement system binds to the Fc portion of the bound antibodies, which activates the classical complement pathway, resulting in lysis of the meningococci. The hSBA titer is defined as the reciprocal value of the interpolated serum dilution that kills 50% of the bacteria used in the test.
The hSBA results presented in this sBLA are based on an assay previously reviewed and considered validated by CBER. In this supplement, the sponsor presented a document that reports on the performance of assay controls since the assay was originally validated. The SOP and the validation protocol of the hSBA were evaluated during the original application of Menveo and found to be satisfactory for the measurement of serum bactericidal activity using an exogenous source of human complement. The sponsor has not made any changes to the hSBA test method since licensure.
Validation and Testing Information for Serological Assays for Concomitant Vaccines
Validation and testing information were submitted for assessment of the immune response to the vaccines to be administered concomitantly with Menveo. The serological assays used to assess functional and/or IgG antibody responses to polio, hepatitis B, pneumococcal, haemophilus influenza type b (Hib), measles, mumps, rubella, varicella, diphtheria, tetanus, and pertussis vaccine antigens were reviewed. CBER CMC reviewers concurred that the assays were validated for their intended use.
Menveo is composed of two components: a lyophilized powder containing MenA glycoconjugate and a liquid containing the MenCWY glycoconjugates. The MenCWY liquid component is presented in either a vial (licensed in the US) or a (b)(4) (not licensed in the US, but used in all the pivotal clinical trials for children under 2 years of age). The information and relevant data to support the use of vial/(b)(4) presentation (including process validation results, consistency, and stability data) were submitted and assessed by CBER with the original BLA. ----------------------------------------------(b)(4)-------------------------------------------------------------------------------------------------. On June 3, 2011, the applicant informed CBER that particulates were observed in the (b)(4) that were used in the clinical studies that were ongoing in children under 2 years of age. As part of the CR letter issued to the firm on February 10, 2012, CBER requested that the sponsor proceed with a more comprehensive investigation and submit the results of the investigation and the Certificates of Analysis/Lot Release testing data and stability data for all (b)(4) lots used in studies V59P14, V59P21, and V59P23. CBER review of the results submitted in the Resubmission did not yield any information that adversely impacted the safety or immunogenicity of the vaccine.
CBER Lot Release
A review from the CBER Product Review Branch (CPRB) indicates that there are no pending lots or issues that would affect approval of this STN.
CBER Compliance Check
There are no ongoing or pending investigations or compliance actions with respect to the above facility or its product(s).
4. Clinical Pharmacology
The secondary objective of the pivotal studies conducted in infants and toddlers was to demonstrate that the immune responses to routine concomitant vaccinations (pneumococcal, IPV, HBV, Hib, DTaP, MMR-V) were non-inferior when given with Menveo as compared to when administered in the absence of Menveo (routine childhood vaccines alone).
A complete set of validation reports and associated SOPs for concomitant vaccines administered to infants and toddlers was submitted in the April 11, 2011, supplement submission. As mentioned earlier, when the applicant submitted the response on January 30, 2013, to the complete response letter issued by CBER on February 10, 2011, the response included a new pivotal clinical study, V59_33. This study used different testing laboratories, with different serological assay validation information, for the diphtheria, tetanus, pertussis, and Hib assays. The CBER assay reviewers concluded that the serological assays used across all testing laboratories to evaluate clinical samples collected in all the pivotal studies appeared adequate for their intended use.
Immunogenicity of Concomitantly Administered Vaccines
The immune responses to routine childhood vaccines (H. influenzae type b, hepatitis B, heptavalent pneumococcal antigens, and tetanus, diphtheria, acellular pertussis, polio and MMR-V) administered with and without Menveo were compared. Co-administration of Menveo with other routinely administered vaccines did not adversely affect the response to most other vaccines as discussed below:
The methodology and validation information for the ELISAs used to assess the anti-Diphtheria, Anti-Tetanus and Anti-Pertussis antibodies were reviewed and found to be acceptable. For the pertussis antigens non-inferiority was demonstrated if the lower limit of the two-sided 95% CI for the ratio of the GMCs (GMCMenACWY + Pediarix / GMCPediarix ) at 1 month after the 6-month vaccination (third dose) was >0.67. In Study V59P14 in which Pediarix was administered non-inferiority was demonstrated if the LL of the two-sided 95% CI for the ratio of the GMCs (GMCMenACWY + Pediarix / GMCPediarix ) at 1 month after the 6-month vaccination (third dose) was >0.67.
In Study V59P14, there was no evidence of a reduced antibody response to pertussis antigens when Menveo was co-administered with Pediarix on the basis of GMC ratio. Please refer to the clinical review of that study for further details. In Study V59_33, Pentacel was administered. The immune response to pertussis antigens was evaluated in sera obtained one month following the third dose administered at 6 months of age. Following the third dose, there was no evidence of a reduced antibody response to the pertussis antigens when Menveo was coadministered with Pentacel on the basis of GMC ratio.
Streptococcus pneumoniae IgG antibodies against the seven pneumococcal polysaccharides in Prevnar were quantified by using a pneumococcal ELISA, which was conducted at the ------------------------(b)(4)--------------------------------------------------.
The key criteria for demonstrating lack of immune interference for each of the seven pneumococcal serotypes in PCV7 administered with Menveo and other routine vaccinations were as follows: for each vaccine serotype, a lower limit of -10% for the two-sided 95% CI for the between group difference (pPCV7+ Menveo minus pPCV7)of subjects with a serum antibody concentration >0.35 mcg/mL (post dose 3); and a LL of 0.5 for the two-sided 95% CI for the ratio of the GMCs [GMCMenveo + PCV7 / GMCPCV7 ] (post dose 4). In Study V59_33, after dose 3, non-inferiority criteria were met for five of the seven PCV7 vaccine serotypes, with the 2 exceptions being serotypes 6B and 23F. However, one month after dose 4, non-inferiority criteria were met for all 7 serotypes included in PCV7 vaccine. Additional criteria assessed included the GMC ratios [GMCMenveo + PCV7 / GMCPCV7 ] post dose 3; for all serotypes, the LL was at least 0.5 for the 95% CI for GMC ratios assessed at this timepoint. Results from Study V59P14 were consistent with those of Study V59_33, except that non-inferiority criteria after dose 3 were satisfied for serotype 23F in Study V59P14.
Haemophilus influenzae type b (Hib) (b)(4).
An (b)(4) was used to determine serum anti-PRP antibody levels in clinical study V59P14. This (b)(4) was performed in the laboratory of ---------------(b)(4)-----------------------------------------------. The proportion of subjects with anti-PRP ≥ 0.15 mcg/mL and ≥ 1.0 mcg/mL, and the GMC was evaluated . Non-inferiority was demonstrated if the LL of the 95% CI for the difference in the proportion of subjects with anti-PRP >0.15 ug/mL post dose 3 (pHib+ Menveo minus pHib) was >-10%. Non-inferiority was demonstrated post dose 3.
For Study V5921, the anti-measles, anti-mumps, and anti-rubella antibodies were measured by ---(b)(4)-------- (by contract) using an “in-house ELISA assay”. The ELISA formats were altered and ----(b)(4)-----. qualified the alterations by showing concordance in results during a qualification of the assay.
The primary immunogenicity endpoints are based on the percentage of initially seronegative subjects who show seroresponse 6 weeks after vaccination. For the primary immunogenicity analyses, the immune response to measles, mumps, and rubella six weeks following vaccination with one dose of MMR-II +Varivax or ProQuad (both referred to as MMR-V) given concomitantly with Menveo is considered non-inferior to the immunogenicity of MMR-II +Varivax or ProQuad administered alone if the lower limit of the two-sided 95% CI of the difference in the percentage of subjects with seroconversion for measles, mumps and rubella is less than 5%.
Subjects with pre-vaccination MMR antibody levels below a certain threshold were considered seronegative. Subjects with a post-vaccination antibody level at or above a specified level were considered seropositive. These values are shown as follows:
Measles seronegative: pre-vaccination <255 mIU/mL, seropositive: post vaccination ≥ 255 mIU/mL
Mumps seronegative: pre-vaccination <10 ELISA Ab units, seropositive: post vaccination ≥ 10 ELISA
Rubella seronegative: pre-vaccination <10 IU/mL, seropositive: post-vaccination ≥10 IU/mL
There was no evidence for interference in the immune response to MMR and varicella vaccines (among initially seronegative children) in terms of percentages of children with anti-measles antibodies ≥255 mIU/mL, anti-mumps ≥10 ELISA antibody units, anti-rubella ≥10 IU/mL administered at 12 months of age 5 concomitantly with MENVEO relative to these vaccines administered alone..
For study V59P21, the anti-varicella antibodies were measured using the glycoprotein enzyme-linked immunosorbent assay (gpELISA). The primary immunogenicity endpoint is based on the percentage of initially seronegative subjects who show seroprotection for varicella (as determined by glycoprotein-based ELISA [gpELISA]) at 6 weeks after vaccination.
The Varicella cut-off for baseline inclusion in the immunogenicity analysis and definition of post-vaccination response was as follows:
Varicella seroconversion pre-vaccination <1.25 gp ELISA units/mL and post vaccination ≥ 1.25 gp ELISA units/mL
Varicella seroprotection pre-vaccination <1.25 gp ELISA units/mL and post-vaccination ≥ 5 gp ELISA units/mL
The submitted data support the conclusion that there is no interference with the anti-varicella immune response when Menveo and MMR-V are administered concomitantly.
The sponsor used a commercial assay for assessing anti-HBs antibodies. The assay used to determine anti-HBs concentrations and seroprotection rates was the same as that used for the other clinical studies include in the original sBLA for Menveo. The assays were performed by the Clinical Serology Laboratory, Novartis Vaccine and Diagnostics GmbH in Marburg, Germany. This commercial assay is not licensed in the U.S. but has been used in Europe and has gone through standard validation procedures.
Individuals with antibody levels ≥10mIU/ml are considered protected from infection. In the clinical studies 96% and 97% of subjects achieved antibody levels >10 mIU/mL post dose 3, and there was no evidence for interference. The lower limit of two sided 95% CI for the ratio of GMCs between groups was greater than the pre-specified value of 0.5. .
The ------(b)(4)------------- assay was used for measuring anti-poliovirus 1, 2 and 3 antibodies. The laboratory of ---------------------------------(b)(4)------------------------------------------------------------ conducted the assays. The proportion of subjects with neutralizing antibody ≥ 1:8 after dose 3 was evaluated. The LL of the two sided 95% CI (pIPV+ Menveo minus pIPV) was greater than -5% for each poliovirus serotype. Thus non-inferiority was demonstrated.
Conclusions Regarding Immunogenicity of Concomitantly Administered Vaccines
In US infants who received MENVEO concomitantly with DTaP-IPV-Hib and PCV7 at 2, 4, and 6 months of age and HBV administered according to ACIP recommendations, there was no evidence for reduced antibody response to pertussis antigens (GMC to pertussis toxin, filamentous hemagglutinin, fimbriae, and pertactin), diphtheria toxoid (antibody levels ≥0.1 IU/mL), tetanus toxoid (antibody levels ≥0.1 IU/mL), poliovirus types 1, 2, and 3 (neutralizing antibody levels ≥1:8 to each virus), Haemophilus influenzae type b (anti-PRP antibody ≥0.15µg/mL), hepatitis B (anti-hepatitis B surface antigen ≥10 mIU/mL), or most serotypes of PCV7 (antibody levels ≥0.35 mcg/mL) relative to the response in infants administered DTaP-IPV-Hib, PCV7 and HBV. The immune responses to DTaP-IPV-Hib, PCV7 and HBV were evaluated one month following dose 3. No interference was observed for pertussis based on GMC ratios, or for the other concomitantly administered vaccines, with the exception of pneumococcal serotype 6B and 23F, for which interference was suggested post-dose 3. No interference was observed post-dose 4 for these serotypes.1
There was no evidence for interference in the immune response to MMR and varicella vaccines (among initially seronegative children) in terms of percentages of children with anti-measles antibodies ≥255 mIU/mL, anti-mumps ≥10 ELISA antibody units, anti-rubella ≥10 IU/mL, and anti-varicella ≥5 gp ELISA units/mL, administered at 12 months of age 5 concomitantly with MENVEO relative to these vaccines administered alone.
The sBLA included the results of eight studies. Studies V59P14, V59P23, and V59_33 were pivotal trials to evaluate Menveo administered as a primary 4-dose series at 2, 4, 6, and 12 months of age. However, CBER had concerns (See Clinical Review) with the study conduct of Study V59P14 and therefore only the unsolicited adverse event data was used from V59P14. The effectiveness of the 4-dose series was demonstrated by the immunogenicity results of Study V59_33, with results from Study V59P14 providing additional support. The pivotal studies that support the safety of Menveo as a primary 4-dose series at 2, 4, 6, and 12 months of age were results from V59P14, V59P23 and V59_33. The effectiveness and safety of the two dose series, with the first dose of Menveo administered at 7 – 9 months of age and the second dose at least 3 months later, were demonstrated by the results of Study V59P21.
Study V59_33 was a Phase 3, randomized, controlled, open-label, immunogenicity and safety study of the 4-dose series. A total of 529 subjects from 55-89 days of age (2 months of age) were randomized in a 1:1 ratio to receive Menveo plus routine childhood immunizations or routine childhood immunizations alone. The primary immunogenicity endpoint was the percentage of subjects with serum bactericidal activity with hSBA titers of ≥1:8 to each of the four meningococcal antigens contained in the vaccine at one month after the fourth Menveo dose. Immunogenicity would be demonstrated if the lower limit of the 95% confidence interval (CI) was greater than 80% for serotype A and greater than 85% for the other serogroups. The results are shown on Table 2.
Table 2: Study V59_33 - Proportion of Subjects with hSBA≥ 1:8 One Month After the Fourth Menveo Dose
|Antigen||Number of Subjects||Point Estimate||95% CI|
Source: Adapted from sBLA 125300/226; Clinical Study Report, p.96
As shown, the lower bound of the 95% CI was greater than 80% for serotype A and greater than 85% for serotypes C, W-135, and Y. The results met the criteria outlined in the study protocol for demonstrating vaccine effectiveness.
Study V59P21 was an open-label, partially randomized, immunogenicity and safety study of the two dose series of Menveo. Approximately 1014 subjects from 7 to 9 months of age were randomized in a 1:1 ratio to receive two doses of Menveo (at 7 to 9 months and at 12 months) plus concomitant MMR-V administration at 12 months of age or two doses of Menveo with MMR-V administered separately at 13.5 months. Another 616 subjects were enrolled at 12 months of age and received MMR-V alone. The primary immunogenicity endpoint for the demonstration of effectiveness for Menveo was the percentage of subjects with an hSBA titer of 1:8 or higher one month after the second dose of Menveo. Effectiveness would be demonstrated if the lower limit of the 95% confidence limit for the percentage of subjects with an hSBA titer of 1:8 or higher was greater than 65% for serogroup A and greater than 85% for serogroups C, W-135, and Y. Results for serogroup A from study V59P21 would have met the higher success criteria established for evaluation of the 4-dose series. The results for this endpoint are shown in the following table.
Table 3: Study V59P21 - Proportion of Subjects with hSBA ≥ 1:8 at 6 Weeks after the Second Menveo Dose by Treatment Arm
|MenACWY+ MMR-V||MenACWY Alone|
|Antigen||# Subjects||Pt Estimate||95% CI||# Subjects||Pt Estimate||95% CI|
Source: V59P21 CSR, page 111/9389 Table 220.127.116.11-1
As shown in Table 3, the criteria for demonstration of immunogenicity were met for each of the serotypes in both of the treatment arms. In Study V59P21, immune responses to the meningococcal antigens contained in Menveo were similar when the second dose of Menveo was administered with or without MMR-V, or MMR+V. Immune response to concomitant administration of Menveo with routinely administered infant vaccinations was assessed in Studies V59_33 and V59P14, while concomitant administration of Menveo with MMR-V, or MMR+V was evaluated in Study V59P21. In Study V59_33, post-dose 3 non-inferiority criteria related to PnC ≥0.35 mcg/mL were met for 5 of the 7 pneumococcal antigens included in PCV7 vaccine, with the 2 exceptions being PnC 6B and PnC 23F. It is possible that there may be some interference based on the CRM197 protein conjugate, which is common to Menveo and PCV vaccines. However, the fact that the lower limits of the 95% CIs for the GMC ratio for all pneumococcal antigens, including PnC 6B and PnC 23F, were within 2-fold after both doses 3 and 4 was reassuring to the clinical reviewers. In Study V59P14, non-inferiority of the response to pertussis antigens was demonstrated on the basis of GMC ratios, which were considered the key pertussis endpoint in this study and were performed at the appropriate timepoint for the pertussis-containing study vaccine. In Study V59P21, non-inferiority criteria for co-administration of Menveo with MMR-V were met.
Statistical Review – Summary of Immunogenicity Results
The statistical criterion for demonstration of immune responses to four doses of Menveo was met in two Phase 3 clinical trials V59P14 and V59_33. The study results were consistent between these trials. There was a high percentage of missing data and the randomness of the missing data was not established. In terms of noninterference with concomitantly administered routine infant vaccines, the evaluation was limited to descriptive analyses, due to sample size. As noted in the clinical review, V59P21 was partially randomized, Menveo recipients and MMR-V alone (no Menveo) were enrolled separately. See Clinical Review for a detailed description). Therefore, it is difficult to determine if bias could have been introduced. The clinical team did not use immunogenicity results from V59P14 for reasons discussed earlier and only immunogenicity results from only V59_33 are considered here.
For the infant 4 dose series (V59_33) the primary and secondary immunogenicity objectives and results were as follows. The primary study hypothesis was tested on the Per Protocol (PP) Menveo toddler immunogenicity population that included 172 (67%) subjects. The objectives were that percentages of subjects has an hSBA ≥ 1:8 at 1 month after the fourth dose of Menveo + Routine vaccines when given to infants at 2, 4, 6, and 12 months of age. Subjects in the PP Menveo Toddler population were required to comply with infant and toddler vaccinations, have serology results pre and post toddler dose within the appropriate windows for blood draws, and not have any major protocol deviations as specified in the analysis plan. The statistical reviewer confirmed that the study met the primary immunogenicity endpoints. Secondary objectives were to demonstrate that the immune responses to routine concomitant vaccinations (DTaP, IPV, HBV, Hib, and PnC) given with Menveo were non-inferior to responses to the routine concomitant vaccinations given alone, based on the pre-defined hypotheses. The non-inferiority objectives for pertussis antigens after the infant series for seroresponse rate were not met. The lower limits of two sided 95% CIs for the differences in the seroresponse rates (PPentacel + Menveo -PPentacel) between groups 1 and 2 for FHA and pertactin were greater than the non-inferiority margin of -10%, suggesting that non-inferiority was demonstrated. Meanwhile, the differences for PT and FIM were -12.1% and -10.6%, respectively, indicating that non-inferiority was narrowly missed for these latter two seroresponses.
For the 2 dose series (clinical study V59P21), the primary immunogenicity objective was as follows: To assess the immune responses of MMR-V, or MMR+V vaccine (as measured by seroconversion rates to measles, mumps, and rubella, as well as seroprotection rates for varicella) administered concomitantly with Menveo vaccine or given alone to healthy young children aged 12 months (as measured by the percentage of subjects with hSBA titer ≥ 1:8 directed against N. meningitidis serogroups A, C, W-135, and Y). The secondary objectives were related to GMTs of the antigens in the vaccines. Please refer to the clinical review for more details of the secondary objectives.
The primary immunogenicity objectives were met, such that Menveo +MMR-V group were non-inferior to those in the MMR-V alone group. The lower limit of the two-sided 95% CI of the difference between the percentage of subjects with seroconversion in the Menveo + MMR-V group and the percentage of subjects with seroconversion in the MMR-V group was -3.4%, -1.0%, and -4.5% for measles, mumps, and rubella, respectively. Additionally, the results showed that the seroprotection rates for varicella in the Menveo + MMR-V group were non-inferior to the seroprotection rates in the MMR-V alone group: the lower limit of the CI for the difference in percentage of subjects with seroprotection between the two groups was -3.9%. Also, the immune response to Menveo given concomitantly with MMR-V (Group I) was non-inferior to that when Menveo was administered alone. The criteria for this hypothesis testing were: the lower limit of the two-sided 95% CI of the estimated differences (PMMR-V+ Menveo - P Menveo) of the percentages of subjects with hSBA ≥ 1:8 at 6 weeks after the second dose of Menveo (concomitantly with MMR-V or alone) given to 12-month old toddlers were to be greater than or equal to -10% for each serogroup (comparison of Group I vs. Group II at Visit 4). The secondary objectives were met as well.
Bioresearch monitoring (BiMo) inspections
Five clinical investigator inspections were performed that covered four clinical investigators in support of this BLA. Inspections of two clinical investigators were performed for each of two pivotal study protocols. Study subject enrollment and previous inspection history related to this product were among the factors used to select the inspected sites. The inspections focused on specific questions concerning the study protocol and the comparison of information in the BLA and source documents. The fifth inspection was to determine whether there were problems with sample shipments to the central laboratory at the request of the committee. The BIMO inspections did not reveal any problems that would impact the data submitted in the BLA. Although the BiMo inspection did not reveal Good Clinical Practice breaches during inspection, the clinical and statistics reviewers noted many inconsistencies in the data submitted with regard to method and consistency of collection and documentation. The review team discussed BIMO re-inspections but agreed that they would be unlikely to adequately address the systematic data quality issues in the CR letter.
Safety data from eight studies were included in this sBLA. There were a total of 8735 subjects across the 4 dose series studies who received Menveo and 1985 subjects in the 2 dose series who received Menveo.
All submitted pivotal clinical trials supplied data for assessment of the safety of Menveo vaccine based on the following categories of safety measures:
1) solicited AEs (i.e., local and systemic reactions) and selected indicators of reactogenicity (e.g., use of analgesic/antipyretic medication) on the day of vaccination and on each of the following 7 days
2) unsolicited AEs (and related concomitant medications), as predefined in the respective study protocols
3) AEs necessitating physician’s visits
4) medically significant AEs, i.e., AEs requiring a physician’s visit, Emergency Department visit, or leading to withdrawal, but excluding the pre-planned visits, medical office visits, or Emergency Room visits for routine medical care and common acute conditions (e.g., upper respiratory tract infection, otitis media, pharyngitis, urinary tract infection, gastroenteritis, superficial skin infection, contact dermatitis)
5) SAEs and AEs leading to premature withdrawal.
Safety data regarding solicited adverse reactions during the seven days (day of vaccination and subsequent six days) post-vaccination were provided by Study V59P23. Subjects were randomized in a 3:1 ratio using a block randomization schema. The study was open-label due to ethical concerns about injection of a placebo vaccine to young infants. In this study, information on solicited and local adverse reactions was collected in two arms of the study, including 1403 subjects who received at least one dose of Menveo. Solicited local adverse reactions were reported in 53% of Menveo recipients and in 56% of control recipients (who received routine childhood immunizations). The most commonly reported solicited local adverse event in both treatment arms was tenderness at the injection site, which was reported in 30% to 46% of subjects after one of the Menveo doses and in 37% to 50% after one of the doses of control vaccines. Solicited systemic adverse reactions were reported in 77% of Menveo recipients and in 73% of controls. The most commonly reported solicited systemic adverse reactions were irritability, sleepiness, and persistent crying, which were observed in similar percentages in the Menveo and the control arm. The only solicited systemic adverse reactions reported with more than a 5% difference between the treatment arms were persistent crying, which was reported in 22% of Menveo recipients and 16% of control subjects after dose 3, and diarrhea, which was reported in 16% of Menveo recipients and 10% of control subjects after dose 1. The rates of fever (T>38.0C) for the MenACWY group and the control group were 3% and 2% respectively after Dose #1; 4% and 6% after Dose #2; 7% and 6% after Dose #3; and 9% and 7% after Dose #4. Temperature ≥40.0° C was reported in <1% of subjects in either study group. Overall, the rates were similar across groups. In addition, the rates of those subjects who experienced severe reactogenicity after any individual solicited systemic reaction were also similar across groups and for subsequent injection doses.
There were 14 serious adverse events that were considered by the investigator to be possibly or probably related to Menveo vaccination. These included four subjects with febrile seizures, one with pyrexia, two with seizures, three with Kawasaki disease, and one each with idiopathic thrombocytopenic purpura (ITP), superventricular tachycardia (SVT), acute disseminated encephalomyelitis, and groin abscess. Two of these SAEs (ITP and SVT) were reported in subjects who received an ---(b)(4)--- formulation of Menveo, which was not the final formulation.
There were 11 subjects who died across the 7 studies submitted as part of this application. This includes 8 deaths in Study V59P23 and 3 deaths in Study V59P14. Of the eleven deaths, ten deaths were in subjects who had received Menveo, and one was in a control subject. Two of the 11 deaths occurred within 30 days of vaccination, both in Menveo recipients. Three of the eleven deaths were US infants, and none of these three died within 30 days of vaccination. Evaluation of these data should consider the relative enrollment in these studies of Menveo recipients and controls, which were at an approximately 3:1 ratio. None of the deaths in Menveo recipients were judged by the investigator as related to Menveo. The clinical reviewers concluded that due to the nature of the events, this judgment is reasonable.
A description of the two deaths within 30 days in the Menveo + routine vaccine recipients follows:
- A 2 month old Hispanic male enrolled in Panama was found unresponsive (b)(6) days after his second dose of Menveo. He had a history of gastroesophageal reflux. Autopsy findings included pneumonitis and lung edema.
- A 3 month old Hispanic male enrolled in Peru died of septic shock (b)(6) days after his first dose of Menveo. No cultures were performed and the data are limited.
No evidence for an increase in severity or seriousness of adverse events in infants was observed. The statistical reviewer noted that there was a high proportion of missing data in the pivotal studies. However, the clinical reviewers noted that the sponsor did not replace missing data; thus, subjects with missing data were not included in the denominators of different safety analyses, including the analysis of the primary endpoint (percentage of subjects experiencing severe systemic reactions). Sensitivity analyses were performed to examine the effect of missing data on the endpoints. Based on a review of the sensitivity analyses, the reactogenicity rates do not appear to be significantly impacted by any of the three scenarios described above. The clinical reviewers concluded that 1) the impact of the missing data therefore does not alter the overall conclusions of her review, and 2) the safety profile of Menveo was acceptable for approval of this application.
Recommendation for Postmarketing Risk Management Activities
No safety issues have been identified that would warrant a Risk Evaluation and Mitigation Strategy (REMS) or Postmarketing Requirement (PMR).
Recommendation for Postmarketing Activities:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70
In this BLA, the applicant proposed as a postmarketing commitment a safety study that would include 20,000 infants and toddlers if there is an ACIP recommendation for routine use of meningococcal conjugate vaccines in children <2 years old. The review committee and the applicant agreed upon two post marketing commitments (PMCs). The first PMC is a study for safety surveillance and the second study looks at safety of Menveo when administered with Prevnar 13. Prevnar 13, a 13-valent pneumococcal conjugate vaccine (conjugated to CRM as well) was licensed during the course of the Menveo studies and thus, was not available for concomitant administration evaluation with all 4 doses of Menveo. The agreed upon PMCs are as follows:
1. To conduct an open label, descriptive, epidemiological safety surveillance study of MENVEO in children 2 months through 23 months of age. The study will include two parts. Part I of the study will begin with the first administration of MENVEO to a child 2 through 23 months of age who receives medical care at the site where the study is being conducted. Part I will continue for 3 years, or until commencement of Part II, whichever occurs first. Part II of the study will be initiated if there is a recommendation by the Advisory Committee on Immunization Practices (ACIP) for routine use of meningococcal conjugate vaccine in at least one birth cohort within the 2 through 23 months age range.
Part II will commence with the effective date of the ACIP recommendation, and will continue until 20,000 children are enrolled, or until 1 year has elapsed, whichever occurs last. If initiated, a final study report for Part II will be submitted 1 year after the last subject has completed study Part II. In the event there is no recommendation for routine use of meningococcal conjugate vaccine in this age group, Part II will be considered fulfilled when Part I is completed.
The agreed upon schedule for the PMC #1 is as follows:
- Final Protocol Submission Date: May 2014
- Study Completion Date: November 2017
- Final Report Submission Date: November 2018
2. To submit results of completed Study V59_36, which evaluated the safety and immunogenicity of concomitant administration of MENVEO and other vaccines recommended for routine use in infants, including Prevnar 13.
The agreed upon schedule for PMC #2 is as follows:
- Final Report Submission Date: August 2014
7. Advisory Committee Meeting
The safety and effectiveness data from the trials conducted to support the use of this vaccine in children 2 through 23 months of age were not presented to the Vaccines and Related Products Advisory Committee because the product did not raise particular concerns or controversial issues which would have benefited from advisory committee feedback. As mentioned above in Section 3, the concept for the use of the hSBA as a correlate of protection to measure the immune response for inferred effectiveness for the licensing pathway of meningococcal vaccines intended for infants was presented and agreed upon by the Advisory Committee on April 7, 2011.
8. Other Relevant Regulatory Issues
No regulatory authority in any country to date has approved Menveo for use in the 2 to 23 month age range. On April 25, 2013, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) determined that the studies submitted to the EMA were not sufficient to support the application to recommend use in children in the 2 to 23 month age range. The EMA cited concerns regarding lack of evidence of effectiveness in this age group. The EMA stated that the applicant did not demonstrate that Menveo was at least as effective as a monovalent meningococcal C vaccine currently available in Europe. EMA also noted that the data showed a fall in antibodies between the third and fourth doses which could lead to a lack of protection between 6 to 12 months of age. CBER is that bases the assessment of effectiveness of vaccines on the efficacy or effectiveness demonstrated after the entire vaccine series (e.g., all 4 doses, in this case) has been completed.
As mentioned previously, data to satisfy Pediatric Research Equity Act (PREA)-PMRs regarding deferred pediatric studies were included in this sBLA. Menveo was discussed during the Pediatric Review Committee meeting on June 12, 2013. The committee concurred with Office of Vaccine Research and Review’s (OVRR’s) recommendation to waive studies of Menveo in children 0 to <8 weeks of age. This supplement will complete the pediatric assessment of Menveo under PREA.
All issues regarding the product labeling were resolved after exchange of information and discussions with the applicant. The package insert (PI) submitted by the applicant was in the format required by FDA’s Final Rule titled “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products” published in January 2006. The Indication, Adverse Reactions, Drug Interactions, and Clinical Studies sections were updated to include safety, immunogenicity and concomitant use data from pivotal studies V59P14, V59P21, V59P23 and V59_33. The carton labeling was updated to indicate the expanded age range and each of the container labels were updated to include new NDC codes.
The sBLA review committee recommends approval of the efficacy sBLA for Menveo. As Chair of the review committee, I concur.
1. I. Goldschneider, E.C. Gotschlich, M.S. Artenstein. Human immunity to the meningococcus I. The role of humoral antibodies. J Exp Med, 129 (1969), pp. 1307–1326.
2. FDA. Vaccines and Related Biological Products Advisory Committee. Rockville, Maryland. April 6 - 7, 2011.