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Statistical Review and Evaluation BLA, December 12, 2011 - Menveo

DEPARTMENT OF HEALTH AND HUMAN SERVICES                                                                                                                         Public Health Service


                                                                                                                            Food and Drug Administration
Center for Biologics Evaluation and Research
Office of Biostatistics and Epidemiology
Division of Biostatistics              

 

DATE:                                                12/12/2011

FDA NUMBER:                                 STN 125300/226

PRODUCT NAME:               MENVEO® (Novartis ACYW-135 Vaccine)

SPONSOR:                            Novartis Vaccines & Diagnostics, Inc          

SUBJECT:                             Statistical comments related to the sBLA MENVEO® infant/toddler vaccine

INDICATION:                       Active immunization of infants from 2 months to 2 years of age for the prevention of invasive disease caused by                          Neisseria   meningitidis serogroups A, C, W-135 and Y

FROM:                                               Barbara Krasnicka, Ph.D.                                          

 

THROUGH:                          Tammy Massie, Ph.D., Team Leader 

                            A. D. Horne, Dr. P.H., Chief, Vaccine Evaluation Branch

                                                           

TO:                                                     Cara Fiore, Ph.D. HFM-478

CC:                                                                        

ChronFile/HFM-210

Meghan Ferris, MD/HFM-475
Amelia D. Horne, Dr. P.H/HFM-217
Estelle Russek-Cohen, Ph.D./HFM-215
Tammy Massie, PhD/ HFM-217


 

Executive Summary

Introduction

MENVEO® (referred to as MenACWY), produced by Novartis Vaccines and Diagnostics Inc., is a meningococcal CRM197 oligosaccharide conjugate vaccine for prevention of invasive disease caused by Neisseria meningitides, serogroups A, C, W-135, and Y, bacteria. Administration of a vaccine single dose in adolescents and adults 11 to 55 years of age was approved in February 2010, and indication for the vaccine use in children 2 to 10 years of age was approved in January 2011. The goal of this efficacy sBLA 125300/226 (revision of the sBLA 125300/201), submitted on April 13th, 2011, is to expand the indication of the MenACWY® to infants starting at 2 months of age.

The same vaccine formulation as for individuals aged 2 years and above is being proposed for children ages 2 to 23 months. While the formulation remains the same, the proposed dosing regimen for infants and toddlers differs from that approved for the older populations. Based on the applicant’s research, a single dose of MenACWY led to adequate immune responses for subjects 2 to 55 years of age. However, for infants and toddlers, multiple doses of MenACWY vaccine appear to be necessary for protection. Some studies carried out in infants and toddlers indicated that the dosing regimen for MenACWY for younger infants, i.e., between the ages of 2 to < 6 months, can be 3 doses separated by at least 6 weeks, with the fourth dose in the complete series to be administered in the second year of life. For older infants/toddlers (i.e., ≥6 months of age), 2 doses separated by at least 2 months may be adequate for the complete series, with the second dose to be administered in the second year of life. The evidence supporting the proposed schedules was generated in some studies by using different dosing regimens and formulations.

Brief Overview of Clinical Studies

The applicant submitted safety and/or immunogenicity data from seven clinical trials in infants/toddlers aged 2-23 months to support the proposed expansion of licensure of MENVEO®.  These seven clinical trials include three pivotal clinical studies (V59P14, V53P23 (only safety), and V59P21) conducted in the US, Argentina, Colombia, and Saudi Arabia and four supportive studies conducted in various countries. The profiles of the studies are listed in Table 1.2.1.

The statistical evaluation of the safety and immunogenicity of the four- dose regimen of MENVEO administered in infants/toddlers at 2, 4, 6, and 12-16 months of age, is based mainly on the data derived from the Phase III safety and immunogenicity clinical trial V59P14 (conducted in the US and Latin America) and from safety clinical trial V59P23 (conducted in the US and other countries).

Summary of Clinical Study Characteristics

Study

Primary

Study

Study

Test Product

# of

Protocol:

Objectives

Population

Design

 

subjects

 

 

Age

 

 

 

Pivotal Studies

 

 

 

 

V59P14

Safety of and Immune

Infants

Open -Label

MenACWY

3022

 

response to MenACWY

2 months

Randomized

 

 

USA

given with routine infant 

 

Multicenter

Routine Vaccines

1511

Argetyna

vaccine vs routine infant

 

Phase III

 

 

Colombia

vaccine alone

 

 

 

 

V59P23

 

 

 

 

 

USA

Safety of MenACWY

Infants

Open -Label

MenACWY

1973

S.&C.

 given with or without

2 months

Randomized

 

 

America

routine Infant vaccines

 

Multicenter

Routine Vaccines

1973

Saudi Arabia

 

 

Phase III

 

 

V59P21

Safety of and Immune

 

 

MenACWY+ProQuad

500

USA

response to MenACWY

Infants

Open -Label

MenACWY followed

 

 

given with 

7 - 12 months

Randomized

by ProQuad

503

 

or after ProQuad

 

Multicenter

 

 

 

or ProQuad alone

 

Phase III

ProQuad

600

Supplemental Studies

 

 

 

 

V59P9

Safety of and immune

 

Open -Label

MenACWY

125

Canada

response after one or

Infants

Partialy-Randomized

Menjugate followed

 

 

two doses of

6 - 12 months

Multicenter

by MenACWY

50

 

MenACWY

 

Phase II

 

 

V59P8

Safety of and Immune

Children

Single-Blind

MenACWY

453

 

response to MenACWY

2-7 y

Partialy-Randomized

MenACWY +PCV7

71

USA

vs Menomune

Toddlers

Multicenter

MenACWY + DTaP

73

 

 

12-23 months

Phase II

Menomune

310

V59P7

Safety of and Immune

Toddlers/Children

Observer-Blind

MenACWY (b)(4)

205

Finland

response to MenACWY

12-35 months

Randomized

MenACWY

331

Poland

-----(b)(4)----------               ------------

Children

Phase II

Mancevax followed

 

 

vs Mancevax

36-59 months

Multi-center

by MenACWY

81

V59P5

Safety of and Immune

Infants

Open -Label

MenACWY  (b)(4) Boost

229

UK

response to MenACWY

2 months

Randomized

MenACWY (b)(4)

49

 

given with routine infant 

 

Multicenter

MenACWY(b)(4) then

 

Canada

vaccine

 

Phase II

1/5th of Menomune

98

 

Persistence of antibodies

 

 

MenACWY with

 

 

Booster and memory

 

 

MenACWY Boost

135

 

response

 

 

MenACWY(b)(4) then

 

 

 

 

 

1/5th of Menomune

45

 

 

 

 

Menjugate with

 

 

 

 

 

MenACWY (b)(4) Boost

45

Statistical Issues

There are several concerns related to this sBLA submission. Please see Questions to Applicant for a comprehensive list of recommendations/questions to the Applicant.

Questions to Applicant

Study V59P14

  1. The PP population for testing the first primary hypothesis consists of only about 59% of the infants enrolled into the US 1a group. Please assess the impact of missing data on the results of testing the primary hypothesis and on the robustness of the results. Please include in your response the relevant SAS program(s).
  1. Please submit detailed information related to the reasons why so many subjects were not included in the dataset on which the first primary hypothesis was tested.
  1. Some important secondary hypotheses were formulated to evaluate concomitant use of MenACWY and routine infant vaccines. They were to address the question of whether immune responses to concomitant vaccines in subjects who received MenACWY with routine vaccines were similar to the responses in subjects who received routine vaccines only. From the statistical standpoint, to answer this question appropriately, the multiplicity problem should be addressed properly and the procedure pre-specified in the study protocol. However, this issue was not addressed in the protocol or during statistical analyses. Therefore, ideally, results for the secondary endpoints should be viewed as descriptive rather than inferential. Please comment.
  1. According to your Figures 10.1-1A and B, some subjects (25 subjects from US immunogenicity groups, 38 subjects from US safety groups) withdrew from the study, but their safety follow-up was continued for 6 additional months. Please evaluate the statistical impact of these 62 subjects on the safety descriptive analyses. Additionally, please clarify the way in which safety data were collected for these 62 subjects and what kind of information was collected for them.
  2. In the “comments.xpt” dataset, there are some comments related to the diary cards and other events/situations which occurred during the course of the study. Please note that currently only the date at which the comment was entered into the study dataset is shown, but no vaccination date to which this comment is related is given. Therefore, please include in the “comments.xpt” dataset additional variables that would help to identify the visit number, the date of vaccination related to the comment, and then please resubmit the updated dataset.
  1. In the CSR, Appendix 16.2.2.1, you supplied a listing of protocol deviations. Please submit the relevant dataset and SAS program used for creation of this listing of protocol deviations.
  1. In the “Listing of Protocol Deviations” and the “comments.xpt” dataset, there are some comments related to the procedure of recording Diary Card data in the relevant CRF. It appears that for some subjects, reactogenicity data are not documented in real time but are “reconstructed” based on the parents’ memory. Therefore, please perform safety reactogenicity statistical analyses, by study groups and for two periods of time: from 6 hrs to Day 3 and from Day 4 to Day 7 after each vaccination dose, on a subset of the safety study population which would contain only subjects for whom diary cards were returned to the clinic for evaluation and review.
  1. Per the study protocol, every time a subject received an injection, the parent(s)/legal representative(s) of the subject received a diary card. The Diary Card consisted of two parts: Diary Card-A and Diary Card-B. As it appears that no information on the compliance of returned diary cards was included in the Clinical Study Report, please submit diary card completion rates during 7 days after each vaccination, by the study group and separately for Diary Card–A and Diary Card-B. Without diary card documentation, we recommend that the relevant data should be treated as missing.
  1. Per the “Listing of Protocol Deviations” and the “comments.xpt” dataset, there are some comments related only to the procedure of recording Diary Card-B data in the relevant CRF. Please supply a summary of AEs, by study group, after each vaccination dose, based on a study population that contains only subjects for whom diary cards (Diary Card-B) were returned to the clinic for evaluation and review.
  1. Regarding some comments related to the diary cards, such as “Diary cards not returned,” please explain whether the term “diary card” means both Diary Cards-A and Diary Cards-B.
  1. Per the “immun.xpt” dataset, “other” vaccines were administered to enrolled subjects. Please supply information about these “other” vaccines, by visit and study group.
  1. In your Table 10.2-1A (Clinical Study Report, page 115), you supplied Number (%) of subjects with major protocol deviations for US immunogenicity subjects. However, some of these numbers and percentages are misleading. For instance, in the above mentioned table, information related to “Incomplete Toddler Series” for the US 1b group shows numbers “5 (3%).”  However, based on the “immun.xpt” data, it appears that only 120 of 166 subjects enrolled into the US 1b group received MenACWY vaccine at the subjects’ fifth visit, i.e., the number should be at least 46 not 5. Please clarify, or revise Table 10.2-1A.
  1. Based on Table 12.2.1-18, there were less than 251 LA subjects who experienced at least one SAE during the course of the study. However, based on the “adverse.xpt” dataset, there were at least 269 LA subjects who experienced at least one SAE during the course of the study. Please comment and, if needed, please revise Table 12.2.1-18.
  1. Based on Table 12.2.1-19, it appears that there are noticeable differences between US and LA groups in numbers (percentages) of subjects reporting at least one AE by SOC (System Organ Class). Therefore, ideally, the safety data from the LA and US groups should not be pooled. Taking into account this issue, we recommend that some tables in the ISS be revised. Please comment.
  1. In the “postinn.xpt” dataset, the data for the variable visit number (“visnum”) are completely missing. Please resubmit this dataset with the corresponding values of the “visnum” variable.
  1. It is very important, for clinical and statistical analyses, to have full information on the time intervals between adverse events and prior vaccinations. Therefore, please resubmit an improved “adverse.xpt” dataset that includes information on the most recent vaccination day before occurrence of an adverse event and the corresponding visit number.  
  1. Table 12.2.1-17 presents an overview of AEs for the US subjects. However, in the US groups, the number of participating subjects diminished over the course of the study. Additionally, as methods of safety information collection in US1 and US2 were different from those used in US3 and US4 study groups, Table 12.2.1-17 may not supply an accurate picture of the differences in the percentages of subjects with AEs across the vaccination groups and over the course of the study. Please construct a statistical model for severe and/or serious AE events which occurred over the course of the study. This model should take into account the structure of the data (e.g., withdrawals over the study course). Please present justification for the chosen model.

Study P23

  1. In SAS dataset “immun.xpt,” it appears that information about vaccines given to the enrolled subjects during each study visit is missing. Therefore, please resubmit the “immun.xpt” dataset. It should contain additional information on: (a) concomitant vaccines given during a visit, and (b) an indicator of whether MenACWY vaccine was given or not during a visit.
  2. According to your Figures 10.1-1, some subjects (39 subjects from NDS groups, 36 subjects from DS groups) withdrew from the study, but they were still followed. Please show the statistical impact of these 75 subjects on the safety descriptive analyses. Additionally, please clarify: (a) the procedure of safety data collection for these 75 subjects; (b) how long they were followed, and (c) what information was collected for them.
  3. In the “comments.xpt” dataset, there are some comments related to the diary cards or other events/situations which occurred during the course of the study. Please note that currently only the date of the comment being entered into the dataset is shown, but no date of vaccination to which this comment is related is given. Therefore, please add to the “comments.xpt” dataset additional variables that could help to identify: (1) the visit (or injection) number, (2) the date of vaccination related to the comment. Please resubmit the revised dataset.
  4. It appears that diary cards were not returned to the clinic for evaluation and review for some subjects. Therefore, please perform additional safety reactogenicity statistical analyses for two periods of time: from 6 hrs to Day 3 and from Day 4 to Day 7 after each vaccination dose, on the DS study groups subsets containing only subjects for whom diary cards were returned to clinic for evaluation and review.
  5. It appears that no information on the compliance of returned Diary Cards was included in the Clinical Study Report. Therefore, please submit diary card completion rates during 7 days after each vaccination, for the DS study group. Subjects without diary card documentation should be treated as missing data. Additionally, please submit compliance of returned worksheets and completion rates for the follow-up period.
  6. In the CSR for study V59P23, on page 89 (of 20775), you supplied the results of testing the safety hypothesis. Please comment on the issues listed below related to the primary objective:
  1. You performed a post-hoc statistical analysis utilizing an adjusted categorical linear model, in which you adjusted for factors: vaccination group, center, and interaction of vaccination group by center. Your analysis revealed significance of variables “center” and “vaccination group by center interaction.” Based on this model, the primary safety objective criterion was met. One hundred twelve centers supplied data for testing this hypothesis. However, on average, there were only 16 subjects (median 11) per center. There were 4 centers with only one subject, and only 4 centers with more than 59 subjects. Thus, numbers of subjects per center were small. Please provide the statistical justification for the model you selected.
  2. Please perform testing of the primary hypothesis on a dataset that comprises only subjects for whom diary cards were returned to clinic for evaluation and review.
  3. In the dataset you used to test the primary hypothesis, about 60 vaccinated subjects did not have any data related to the systemic part of the diary cards. Please provide summary information about these subjects.
  4. In the “postinj.xpt” dataset, some subjects had more than one severe systemic reaction in Days 1 to 7 after any vaccination. Therefore, please construct a statistical model for severe systemic reaction events. This model should take into account the structure of the data (e.g., withdrawals over the study course). Please present statistical justification for the chosen model.                 

 

  1. Please comment or supply information on the issues listed below related to AEs and SAEs.
  1. Based on Figure 1-0.1-1 and Tables 12.2.1-4 and 14.3.1.1.8.1, there were 27 and 34, respectively, subjects who prematurely withdrew from the study due to AEs. Based on the “adverse.xpt” dataset, there were 31 subjects who withdrew from the study due to AEs. However, according to the “studyterm.xpt” dataset, there were 29 subjects who were “terminated” from the study due to AEs. By merging these two datasets, it appears that 33 subjects were “terminated” or withdrew from the study due to AEs. Please explain this apparent inconsistency. Additionally, please provide the SAS program used for creation of Table 12.2.1-4.
  2. Based on the “adverse.xpt” and “studyterm.xpt” datasets, there were some subjects who experienced an adverse event (e.g., 0065060, 0670013, 0675012, 0670013, 1570001, and 1575019) and were “terminated” from the study within approximately 30 days. However, the stated reasons for terminations were not AEs, but, for example, withdrawal of consent, administrative reason, or lost to follow-up.  Subjects 0670013 and 1575019 experienced AEs, and the next day and the same day, respectively, these subjects were “terminated” with the reason given as lost to follow-up. Please supply the definition/rules and specification of the procedure for subject “termination.” 
  3. A summary of the percentage of US subjects with at least one SAE by vaccine group and study period is provided (CSR, page 93). However, Table 12.2-4 did not show the full profile of the differences in the percentages of subjects with SAEs across the vaccination groups and over the course of the study. Therefore, please construct a statistical model for SAEs which occurred during the course of the study. This model should take into account the structure of the data (e.g., withdrawals over the study course). Please present justification for the chosen model.

Study P21

  1. Due to known differences between safety and immunogenicity profiles of ProQuad™ vs. MMR™ II and Varivax™, please perform a statistical analysis for the primary objectives, adjusting for the following factors: study group and MMRV type. Additionally, please provide descriptive statistics for safety (AEs and SAEs) and immunogenicity (primary objectives) based on two separate datasets: (1) the dataset for subjects who received ProQuad™ and (2) the dataset for subjects who received MMR™ II and Varivax™. Please provide results of the above mentioned statistical analyses.
  1. In the CSR (page 111 of 9389), you stated that “no pre-identified immunogenicity subset was used in this study; all subjects were to have blood drawn, which could potentially have been used for analysis.”  A randomly selected group of subjects was chosen for the analysis of C, W-135, and Y serogroups, while all available samples were tested for the MMRV antigens and serogroup A. Please describe the procedure that was used for selection of subjects for the C, W-135, and Y serogroups analysis. Additionally, please show that each selected group was representative of the whole relevant study group (e.g., by taking into account age at the time of vaccination, sex, GMT for MenA, AEs, and SAEs).
  1. Please submit diary card completion rates during 7 days after each vaccination, by study group. Note that data for subjects without diary card documentation should be treated as missing.
  1. It appears that some subjects’ diary cards were not returned to the clinic for evaluation and review. Therefore, please perform additional safety/reactogenicity statistical analyses, for two periods of time: from 6 hrs to Day 3 and from Day 4 to Day 7 after each vaccination dose, by study group on the dataset containing only subjects for whom diary cards were returned to the clinic for evaluation and review.   

ISS analysis

  1. In the integrated analyses for four doses, the data that contributed to some ISS analyses were taken: (1) from the V59P14 pivotal study (4-dose series given at ages 2-4-6-12 months (US 1a, US3, LA5), 2-4-6-13 months (US1b), 2-4-6-16 months (LA3a), or 2-4-6-17 months (LA3b)) and (2) from the V59P23 safety pivotal clinical trial (4-dose series given at 2-4-6-12 months of age). Altogether 7186 subjects were included in the integrated summary of safety, in that 5563 subjects were in the 4-dose MenACWY population, while the control population consisted of 1623 subjects. Because the dose schedule and health care in different countries may have influence on the occurrences of adverse events (see for instance study P14, US vs. LA groups), please perform safety analyses by dose schedule number and continent (country).  
  2. In the ISS (page 31), Table 1.2-7 presents a summary of reasons for withdrawal from studies V59P14 and V59P23. Based on this table, in the 4-dose MenACWY group, 29 subjects withdrew due to AEs, while in the 4-dose control group, only 4 subjects withdrew. However, according to the CSR for V59P23 (page 101 of 2075, US subjects), 34 subjects withdrew from only this clinical trial (30 and 4 subjects, in ACWY-All and RVAX-All groups, respectively).  Note that the tables in the ISS should be consistent with appropriate CSRs and datasets. Please comment.