Mid-Cycle Review Meeting
BLA: STN 125259
Manufacturer: GlaxoSmithKline Biologicals
Product: Human Papillomavirus Vaccine (AS04 Adjuvant-Adsorbed) Intramuscular Injection
Meeting Date: July 24, 2007
Meeting Location: WOC-1, Room 200S
Filing Action: 24-May-2007
No Deficiencies Identified: 24-May-2007
Action Due: 27-Jan-2008
BLA Review Team:
Gopa Raychaudhuri, Committee Chair
Helen Gemignani, Regulatory Project Manager
Vada Perkins, Electronic Integrity Reviewer
Nancy Miller, Clinical
Martha Lee, Statistics
Robin Levis, Product, Facility, Pre-Clinical Immunogenicity
Lev Sirota, Assay Validation Statistics
Marion Gruber, Reproductive Toxicology
Liz Sutkowski, Adjuvant Toxicity, CMC for MPL
Steve Kunder, Pharmacology and Toxicology
Rebecca Olin, Facility CMC, Inspector
Solomon Yimam, Bioresearch Monitoring
Manette Niu, Epidemiology
Lisa Stockbridge, Promotional Labeling
Gennady Rezapkin, Potency Assay Testing
Review Team Meetings:
19-Apr-2007 First Committee Meeting
03-May-2007 Filing Meeting
24-July-2007 Mid-Cycle Review
30-Aug-2007 Monthly Team Meeting (scheduled)
27-Sep-2007 Monthly Team Meeting (scheduled)
29-Oct-2007 Monthly Team Meeting (scheduled)
Correspondence with GSK:
Priority Review Denied: May 4, 2007
April 25, 2007
May 21, 22, 23, 2007
Clinical/Stats: May 7 and 16; June 5; July 6, 10, 18, 19, 20, and 23
Product testing: June 20; July 11, 2007 (Tech Transfer)
June 20; July 11, 2007 (Tech Transfer)
14, 18, 20, 2007 (Removal of -(b)(4)- Filling Line)
Amendments Submitted to the BLA:
Request for clinical PID datasets
Request for BiMo info on site 4923,
Priority Review Summary
Request for BiMo protocol deviations
Request for clinical data RE: eppcon: Biopsy Results
Request for facility info RE: removal of -(b)(4)- filling line
Mid-Cycle Review Summaries:
Review Team members were asked to provide a summary of their review area of the BLA:
- Vada Perkins, Electronic Integrity
Through the midpoint, there have been no major issues related to accessibility of the submission. Many of the requests from the review team were related to identifying the location of information within the submission. This was addressed by providing a quick team session on utilizing the GS Review tool to access their review information.
- Rebecca Olin, Facility CMC, Inspector
Review Summary not submitted for Mid-Cycle Meeting
- Nancy Miller, Clinical
See attached memos
- Martha Lee Biostatistics
See attached memo
- No major deficiencies have been identified in this BLA submission
- Some minor issues including discrepancy in numbers (Tables) but will be discussed with GSK.
- Robin Levis Product CMC
See attached memo.
-Preclinical immunogenicity study results w/r/t MPL
-Cell substrate issues
-CMC process development throughout clinical development.
-Adventitious agents testing and viral clearance studies
-Stability testing and product shelf life
-Draft Lot Release protocols
- Gennady Rezapkin, Potency Assay
The SOP for the potency assay was just received by CBER. This will be reviewed. CBER has requested that reagents/standards/samples for the potency assay be submitted to CBER in mid-September.
- Lev Sirota, Assay Statistics
Review Summary not submitted for Mid-Cycle Meeting but Dr. Sirota has found no issues with the two assays, potency and serological.
- Liz Sutkowski, Adjuvant Toxicity
Has not identified any deficiencies thus far and has the following few issues/questions raised so far in her review:
RE CMC -
-It is noted that the bioactivity of MPL ---(b)(4)--- has been characterized by an -------(b)(4)-------- assay. Have the ----------(b)(4)------------ and the relative bioactivity of each of them been evaluated in this assay?
RE Toxicology -
GSK was advised on which toxicology studies conducted with MPL alone should be submitted to the BLA. It seems that all AS04 alone data submitted consists of data from AS04 alone (control) arms included as part of studies conducted with Cervarix. CBER should ask GSK to confirm that data from all available toxicology studies conducted with AS04 have been submitted to the BLA.
Report incidental toxicology findings with very high doses of MPL administered IV for 8 days in rats
- Marion Gruber Reproductive Toxicity
Four final study reports contained in module 184.108.40.206 were reviewed and draft reviews have been completed
a.) Study report -(b)(4)- 249/033160 “HPVPro/AS04D Prophylactic Human Papillomavirus Type 16 and Type 18 Candidate Vaccine Adjuvanted with AS04D: Study of effects on Pre and Post natal Development in -(b)(4)- Rats by Intramuscular Administration (including pre mating immunization phase),”
- Annex 1: Serological report of reproduction toxicity study -(b)(4)- 249/033160
- Annex 2: Serological report of the preliminary immunogenicity study with L1VLP16/L1VLP18 vaccine (HPVpro/AS04D) in female rats PIMS 20020475
- 220.127.116.11.2. Fertility and early embryonic development
18.104.22.168.2.1 Study report –b(4)-249/033160
- Addendum 1: Pre- and post-natal development study with VLP16/VLP18 vaccine (HPVpro/AS04D) administered IM in rats
This study -(b)(4)- 249/033160 is the pivotal study to assess the effect of the HPV/adjuvant vaccine combination on embryo-fetal pre-and postnatal development and fertility of the F1 female generation.
b.) Study report 1729/8 – D6154
MPL: Subcutaneous Study of embryo-fetal development in the rabbit
Study 1729/8 – D6154 was requested by CBER to obtain additional data on the MPL adjuvant and to assess the effects of MPL on the embryonic and fetal development of the rabbit when administered subcutaneously
c.) Study report 1729/7 – D6154
MPL: Subcutaneous Study of embryo-fetal development in the rat
Study 1729/7 – D6154 was requested by CBER to obtain additional data on the MPL adjuvant and its potential effects on the embryonic and fetal development of the rat when administered subcutaneously
d.) Study report 1729/17 – D6154
MPL: Subcutaneous Study of pre-and postnatal development in the rat
Study 1729/17 – D6154 was requested by CBER to obtain additional data on the MPL adjuvant and to assess the effects of MPL on the pre-and postnatal development, including maternal function, in the rat when administered subcutaneously
What is reviewed to date:
All studies assigned have been reviewed and draft reviews completed
Synopsis of review findings:
The test article does not appear to have an adverse effect on embryo/fetal and pre-and postnatal development including fertility of the F1 female generation with the exception of the findings discussed below.
Items for internal discussion
Weak anti-VLP16 and anti-VLP-18 antibody responses were observed in 100% of dams receiving AS04D adjuvant. The sponsor’s investigation as to the cause of this finding revealed no deviations or deficiencies were identified. Although an explanation as to why adjuvant treated animals displayed low levels of circulating anti-VLP16 and anti-VLP18 L1 antibody titers has not been found, this would not jeopardize the conclusion of the study results regarding effects of the vaccine on embryo/fetal pre- and postnatal development.
List of items for the sponsor
1. Of note, in the pivotal study -(b)(4)- 249 conducted in rats treated before and after mating with HPVpro/AS04D, group 3, one fetus out of 166 evaluated (0.6 % fetuses affected) was observed to have a small ventricular septal defect. In group 4 of the pivotal study treated with AS04D alone before and after mating, one fetus out of 169 (0.69 % fetuses affected) treated was observed to have a small ventricular septal defect. The sponsor stated at that time that a review of recent studies conducted in the same laboratory revealed that this observation had not been reported in the control population in the last 15 studies. The sponsor did then perform an extended review of the incidence of small intraventricular septal defect (IVSD) covering 98 studies performed between 1996 and 2005 at ------------(b)(4)------------- (included as Annex 3 in 22.214.171.124.2 study report -(b)(4)- 249/033160). Four (4) cases of IVSD occurred in control animals (12259 fetuses examined, 0.033%) with slightly higher incidences in treated groups whereby treatment was not specified (e.g., “high dose” group had 9 cases of IVSD [9406 fetuses examined, 0.096%]).
2. In addition, among the malformations observed in study 1729/8-D6154 conduced in rabbits treated with MPL there were 2 cases of major ventricular septal defects, one in groups 3 (MPL intermediate dose group, 10 ug/kg/day) and one in group 4 (MPL high dose group, 100 ug/kg/day). The incidence (mean % fetuses) was 0.6 in group 3 and 0.5 in group 4. This malformation did not occur in the low dose MPL group and/or in the saline control group. Sponsor has provided laboratory standard data for ---------(b)(4)--------- rabbits, supplied by -----------(b)(4)----------- used in embryo-fetal studies at ---(b)(4)--- since February 1994. The cumulative incidence of ventricular septal defect (major) in rabbits was 0.12%.
It is not clear whether this finding of ventricular septal defect observed in the pivotal study -(b)(4)- 249 and study 1729/8 – D6154 is a treatment related finding, since it is isolated in nature, i.e.,1 fetus per litter/group and was also observed in the histrorical control data. However, the incidence of ventricular septal defect in both, the rabbit study conducted with MPL (1729/8-D6154) as well as the pivotal study (-(b)(4)- 249) conduced in rats with HPV/AS04D is higher than in the historical control. Furthermore, in the rabbit study treated with MPL, this finding occurred in the higher dose groups only and in the pivotal study conducted in rats treated with HPV/AS04D groups 3 and 4 received additional doses of adjuvant prior to mating.
The sponsor should be asked to perform a statistical analysis of the data from pivotal study -(b)(4)- 249 and study 1729/8 to hopefully conclude that the finding is not significant. It is recognized that this analysis would be post-hoc. I am not sure what particular statistical test would be appropriate. In addition, the sponsor should provide a reference supporting the statement that this finding represents a delay in development and an explanation of their finding of the IVSD being “small” as used to describe the finding in study -(b)(4)- 249.
- Steve Kunder, Pharmacology and Toxicology
The following studies have been reviewed.
HPV pro/AS04D prophylactic Human Papilloma virus type 16 and type 18 candidate vaccine adjuvanted with AS04D was studied in:
1) single dose i.m. studies in rabbits
2) repeat dose i.m. toxicity studies in rabbits including local tolerance
3) repeat dose i.m. toxicity studies rats
4) immunotoxicity in rabbits
The toxicity findings for the complete vaccine are typical of the findings for adjuvanted vaccines including injection site inflammation, erythema and edema, myofibril necrosis and degeneration,; a decrease in platelets was seen in one rabbit repeat-dose toxicity study but not in a subsequent rabbit repeat-dose study nor in repeat-dose studies in rats.
AS04D (MPL) nonclinical studies including:
1) Safety pharmacology (cardiovascular and respiratory)
2) in vivo genotoxicity MPL ----------------(b)(4)----------------- Test
3) in vitro genotoxicity: ------------(b)(4)-------------- assay, -(b)(4)------------ assay
4) safety pharmacology studies with MPL had no adjuvant related effects.
5) genotoxicity studies with MPL were not positive
All studies were acceptable without deficiencies; no additional information from the sponsor is necessary. No additional nonclinical studies appear necessary at this time.
- Lisa Stockbridge Promotional Labeling
The Cervarix BLA submission includes prescribing information (PI) that is in the correct PLR format. The proposed proper name seems long and will take up two lines in the PLR formatted label. We should consider shortening it. The dosage form and route of administration should appear as a separate line under the proper name. Overall, the PI proposal is adequate and will be evaluated in more detail when decisions are made regarding clinical outcomes and risk information.
The proposed carton and container labels are acceptable, but would also benefit from a shortened proper name.
- Solomon Yimam, Bioresearch Monitoring
Status of Bioresearch Monitoring Inspections
As of the date of this memo, only one of the three assigned inspections has been completed. The Bioresearch Monitoring Inspections for three of the clinical investigators are pending.
Four clinical investigator inspection assignments were issued on June 11, 2007. The BIMO inspection assignment included specific questions in the study entitled A phase III, double-blind, randomized, controlled, multi-center study to evaluate the efficacy of GlaxoSmithKline Biologicals’ HPV-16/18 VLP AS04 vaccine compared to hepatitis A vaccine as control in prevention of persistent HPV-16 or HPV-18 cervical infection and cervical neoplasia, administered intramuscularly according to a 0, 1, 6 month schedule in healthy females 15-25 years of age (HPV-008). The assignment included instructions to compare data from the BLA and the source documents and to verify and answer questions regarding the study.
The four Clinical investigator inspections assigned included Centers 4924 ( Pennsylvania), 4929 ( New Mexico), 4951 ( Kentucky), and 4923 ( Utah; complaint inspection assignment):
Christopher Chambers, MD Inspection Pending Center 4924 Karl Doghramji, MD 1015 Walnut Street; Suite 401 Philadelphia, Pennsylvania 19107
Daniel Derksen, MD & Cosette Wheeler, PhD
University of New Mexico
1 University of New Mexico
Albuquerque , New Mexico 8710
Inspection Report Pending;
No 483 issued
James Hedrick, MD
Kentucky Pediatric Research 201 South 5th Street
Bardstown , Kentucky 40004
Christopher Hutchison, MD
Wasatch Clinical Research
4001 South 700 East, Suite 105
Salt Lake City , Utah 84107
PRELIMINARY INSPECTIONAL FINDINGS
The inspection for center 4929 is completed and the preliminary inspectional findings indicated that there was no 483 issued. It should be noted that this finding are solely from communication with the FDA investigator and have not been verified by the BIMO branch through review of the EIRs and exhibits. Three of the four BIMO inspections are pending.
Manette Niu, Epidemiology
CBER/OBE/DE/VSB comments regarding safety outcomes:
- Important missing information:
- GSK will be asked to clarify whether the demographics of the National Health Service (General Practitioner database) in Scotland reflect those of the U.S. population and to consider adding a study which will assess the general safety of Cervarix, including new onset autoimmune disease in the U.S.
- Timelines for protocol submission and pharmacovigilance activities:
- CBER will request that GSK provide deadlines for completion of pharmacovigilance protocols after licensure.
- CBER will request that GSK provide deadlines for finalizing the studies and for reporting and submission of results.
- Routine Pharmacovigilance:
- For the first three years following vaccine licensure, CBER will request that GSK provide FDA with monthly batches of all adverse events reports not included among the serious and unexpected (15-day) reports received by the sponsors. Also, to ask GSK to consider including all available follow-up information obtained from previous adverse event reports in these monthly batches.
- GSK will be advised to consider providing FDA with monthly electronic submissions of vaccine lot distribution data during the first three years after licensure.
- GSK will be advised to consider including plans for analysis of safety signals identified after licensure through the Vaccine Adverse Events Reporting System (VAERS) among the outcomes to be studied.
- Regarding the pregnancy registry:
- GSK will be advised to consider addressing elements in the Guidance for Industry: Establishing Pregnancy Exposure Registries - 9/20/2002
- AID Post-Licensure Observational study:
- CBER will request that GSK add the following outcomes to the AID study: rheumatoid arthritis, transverse myelitis.
- CBER will request that GSK monitor the following specific outcomes in your study: thrombotic events (deep venous thrombosis, pulmonary emboli), thrombocytopenia, seizure, syncope, proteinuria, arthritis, arthralgia, arthropathy.
- GSK will be advised to consider adding a controlled (e.g. cohort or case control) observational sub-study of abnormal pregnancy outcomes including congenital anomalies and spontaneous abortion, for pregnancy exposures.