Product Approval Information
Summary Basis for Regulatory Action
Date |
June 23, 2008 |
|---|---|
From |
Michael P. Schmitt, Ph.D., Chair |
Subject |
Summary Basis for Regulatory Action |
BLA# |
125260/0 |
Applicant |
GlaxoSmithKline Biologicals |
Date of Submission |
April 9, 2007 |
PDUFA Goal Date |
July 6, 2008 |
Proprietary Name |
KinrixT |
Dosage Forms |
Single dose 0.5 ml syringe and vials |
Proposed Indication |
A single dose in children 4 through 6 years of age for active immunization against diphtheria, tetanus, pertussis, and poliomyelitis as the fifth dose in the DTaP series and the fourth dose in the inactivated poliovirus vaccine (IPV) series. |
Recommended Action |
Approval |
Signatory Authority(ies) Action
|
Offices Signatory Authority: X I concur with the summary review □ I concur with the summary review and include a separate review or addendum to add further analysis □I do not concur with the summary review and include a separate review or addendum. |
Review documents used in compiling SBRA
Review Category |
Reviewer--date of review |
|---|---|
Clinical Review |
Karen Farizo, M.D.--1/31/08 |
Statistical Review |
Martha Lee, Ph.D.--12/14/07 |
Pharmacovigilance Review |
Soju Chang, M.D.--1/11/08 |
CMC Review |
Michael Schmitt, Ph.D.--12/21/07 |
Facilities Review |
Daniel Kearns--1/2/08 |
Biomonitoring |
Joseph Manik--12/11/07 |
Advisory Committee Transcript |
N/A |
Labeling |
Steve Rosenthal M.D., consult |
1. Introduction
On April 6, 2007 GlaxoSmithKline Biologicals, Rixensart, Belgium (US License 1617) submitted a Biologics License Application (BLA) for Diphtheria and Tetanus Toxoids, Acellular Pertussis Vaccine Adsorbed and Inactivated Poliovirus; DTaP-IPV. The proprietary name KinrixT is proposed for the candidate vaccine. KinrixT contains no preservative and is supplied in 0.5 ml pre-filled syringes or vials and is administered intramuscularly (IM). KinrixT is intended for immunization of children 4-6 years of age as a 5th dose of DTaP and 4th dose of IPV.
2. Background
Clinical evaluation of KinrixT consisted of a phase III pivotal study (213503/048) that evaluated immunogenicity, lot-to-lot consistency and safety, and two smaller supportive studies (213503/046 and Study 213503/047). A DTaP-IPV vaccine from GSK that is identical to KinrixT, except that it contains the preservative 2-phenoxyethanol, has been used outside the US for over ten years, and post-marketing evaluation of this vaccine has provided additional supportive safety data. The DTaP and IPV components in KinrixT are the same as those in the currently licensed Pediarix vaccine (GSK). There have been no changes in the methods used for testing (release or stability) from those currently licensed for Infanrix or Pediarix, and the DTaP and IPV components are manufactured in the same facilities and using the same equipment as currently used for Pediarix. During review of the BLA, no substantive issues were identified, and all minor concerns were resolved after discussions with the sponsor. A Complete Review letter was sent to the firm on February 6, 2008 due to outstanding compliance issues noted in a Warning Letter issued to Novartis Vaccines and diagnostics GmbH & Co., the manufacturer of the bulk diphtheria and tetanus toxoids, on January 24, 2008. CBER received a response to the CR letter on May 6, 2008.
3. Chemistry Manufacturing and Controls (CMC)
General Manufacturing Summary
The KinrixT vaccine contains the same DTaP components at the identical concentration as those in the currently licensed Infanrix and Pediarix vaccines. The IPV components are also identical to those in Pediarix. CMC reviews included an evaluation of manufacturing, testing, and analysis of the validation data that supported the clinical serology assays for the D, T, aP and IPV components.
The DT components for KinrixT are produced by Novartis Vaccines and Diagnostics GmbH & Co. KG, Marburg, Germany (US License 1754), under a shared manufacturing arrangement, and are supplied to GSK as a DT adsorbed concentrate.
Drug Substance
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The aP and IPV components are manufactured by GSK at their Rixensart Belgium facility. The IPV components are evaluated using the same methods as those previously described for Pediarix. However, because the IPV component of Kinrix is produced using well-characterized working viral seeds grown in Vero cells, the tissue culture tests currently required for poliovirus harvests incorporated into Pediarix will not be required for polio harvests incorporated into Kinrix.
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Drug Product
The DTaP-IPV vaccine contains the following components:
| Active Ingredients | Quantity (per dose, 0.5 ml) |
|---|---|
| Pertussis toxin (inactivated) FHA PRN Diphtheria Toxoid Tetanus Toxoid Inactivated Poliovirus Type 1 Inactivated Poliovirus Type 2 Inactivated Poliovirus Type 3 |
25 ug 25 ug 8 ug 25 Lf 10 Lf 40 D 8 DU 32 DU |
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Adjuvant Aluminum hydroxide |
--------- |
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Excipients NaCl Water for Injection |
150 mM q.s. ad 0.5 ml |
The method used to formulate the KinrixT final drug product is indicated below:
During the development of the KinrixT vaccine a series of intermediate lots were produced and tested in clinical studies. The early series lots did not include all the manufacturing changes that will be used for commercial formulation. The manufacturing changes are indicated below:
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Release Tests and Specifications
Release tests and specifications for DTaP-IPV final bulk lots
Test |
Method |
Specification |
|---|---|---|
Sterility |
Membrane filtration |
Absence of growth |
Residual PT |
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Potency |
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Pertussis antigens |
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Tetanus |
Guinea pig |
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Polio |
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Release tests and specifications for DTaP-IPV final container lots
Test |
Method |
Specification |
|---|---|---|
Sterility |
Membrane filtration |
Absence of growth |
Description |
Visual inspection |
Turbid liquid |
pH |
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Identity: |
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Volume |
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Aluminum |
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Endotoxin |
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General safety guinea pig and mice |
21 CFR 610.11 |
No weight loss/ abnormal reactions |
Potency IPV |
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Lot Release
KinrixT will be released by CBER based on final bulk test results. A Testing Plan for KinrixT was developed by the Division of Product Quality in OVRR with concurrence from the review committee. For routine lot release the firm will submit to CBER samples from final bulk and a Lot Release Protocol for each lot. The product cannot be distributed without written approval from CBER. During review of the BLA, the firm agreed to include testing for aluminum and pH in the Lot Release Protocols. The firm submitted three launch lots in support of approval,-------------------------------------------------------- The three lots were tested at CBER for formaldehyde, aluminum, and sterility, and all lots met specifications. Completed lot release protocols for the three launch lots were reviewed and approved by CBER.
Stability testing
Final formulated bulk lots of DTaP-IPV have a hold time of --------- before filling into final container. Appropriate stability studies in which final bulk lots were stored for up to ------- at ------ before subsequent filling into final container lots were performed to demonstrate that the final bulk can be stored for this period without any impact to product.
Final container stability studies were performed on the clinical consistency lots (2nd series lots) out to 36 months. The results from this study are the primary data that support the recommended 36-month expiration period for this product. Stability testing performed for the clinical consistency lots included all of the tests listed for final and bulk container release as well as container closure and adsorption measurements. Testing was done at 0, 6, 12, 18 24, 30 and 36 months. Stability testing on four commercial demonstration lots is ongoing and data through the 9-month time point has been submitted to CBER.
In the stability study with the three clinical consistency lots, it was noted that all three lots failed to meet specification at the 18-month time point for the ELISA potency test for the IPV type I component. Following internal discussions at CBER and additional discussions with sponsor, it was agreed that the reason for the stability failures was due to testing issues and not associated with any loss in potency of the product. It was determined that the test for the type I IPV antigen had a high level of variability and that adsorption of the antigen reduced its recovery/detection in the ELISA. To resolve this issue, it was agreed that the test would be performed in duplicate and that the stability specification would be reduced to the current level that is used for testing in the -------------- recovery or -------).
Clinical Serology Assays
Validation studies on the ELISA assays that are used to measure antibody levels in the clinical serology samples were reviewed for pivotal study 048 and for the supportive study 047. The validation studies were found to be acceptable for all antigens in study 048, but were acceptable only for the IPV antigens in study 047. The validation data that was submitted for study 047 was found to be inadequate and incomplete for the D, T and pertussis antigens, such that a thorough review of the information could not be done. Immunogenicity data for these antigens was not considered in the evaluation of study 047.
Facilities Review
Based on CBER's extensive experience with the manufacturing of all of the components in the candidate vaccine and since there are no substantive changes to the current production methods, a waiver for conducting a pre-approval inspection was approved. It was further noted that the firm's validation scheme appears to be in accord with advice given to the firm by CBER in a series of pre-submission meetings. The data, procedures, and validation studies provided in this submission appear satisfactory to conclude that the firm has provided the requisite information to support approval from a DMPQ review perspective.
Environmental Assessment
Regarding environmental assessments, it was noted that GSK states that this submission meets 21 CFR 25.31(c), i.e., a categorical exclusion from environmental assessment requirements. The DMPQ reviewer agreed that this product is categorically excluded from an environmental assessment
4. Non-clinical/Toxicology
The active ingredients and the excipients that comprise the DTaP-IPV Combined vaccine are well known and used in the production of the US-licensed Infanrix, Pediarix, and Boostrix. Their respective concentrations are within ranges that conform to the relevant requirements. Based on these observations, no toxicological and pharmaceutical studies, other than the tests performed for routine lot release, have been conducted. These tests include:
- Specific toxicity in guinea pigs for diphtheria and tetanus
- Residual pertussis toxin activity (--------------------------------------)
- General safety test (abnormal toxicity)
- Potency assessment of the diphtheria, tetanus, pertussis and polio components.
5. Clinical Pharmacology
No pharmaceutical studies, other than the tests performed for routine lot release, have been conducted. See response to section 4 above.
6. Clinical/ Statistical-Efficacy
Three clinical studies were conducted to evaluate the candidate DTaP-IPV vaccine when administered as a booster dose to children 4-6 years of age who were previously primed with four doses of DTP vaccine (children in two of the clinical studies, 048 and 047, were primed with four doses of Infanrix) and three doses of poliovirus vaccine. The objective of the clinical development program was to evaluate the immunogenicity and safety of DTaP-IPV vaccine in this age group, as compared to the separately administered DTaP and poliovirus vaccines.
The clinical development plan consisted of two supportive studies to evaluate the safety and immunogenicity of DTaP-IPV vaccine (Study 213503/046 and Study 213503/047) and one pivotal phase III study to evaluate the safety, immunogenicity and lot-to-lot consistency of DTaP-IPV vaccine (Study 213503/048). Study 213503/046 was performed outside of the US, and this study provides supportive safety data. Studies 213503/047 and 213503/048 were both conducted in the US and provide safety and immunogenicity data in support of the candidate DTaP-IPV vaccine. All three studies were controlled and randomized. A total of 3537 subjects were vaccinated with the candidate DTaP-IPV vaccine.
KinrixT Clinical studies:
| Study (Country) | Priming history | Groups | Total vaccinated cohort Planned/Actual |
|---|---|---|---|
Non-IND study |
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213503/046 ( Australia) |
4 doses DTaP + 3 doses of IPV, OPV or sequential IPV/OPV during the first 2 years of life; 1 dose of MMR in 2nd year of life |
DTaP-IPV + Priorix™ INFANRIX + IPOL + Priorix |
212/181 |
IND studies |
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213503/047 ( U.S.) |
4 doses I nfanrix + 3 doses of polio vaccine (either 2 IPV and 1 OPV, or 3 IPV) during the first 2 years of life, and 1 dose of MMR in 2 nd year of life |
DTaP-IPV + MMR II
|
200/200 |
213503/048 ( U.S.) |
4 doses Infanrix+ 3 doses of IPV during the first 2 years of life, and 1 dose of MMR in 2nd year of life |
KINRIX lot 1 + MMR II |
1050/1053 |
Pivotal study 213503/048
The primary objectives of the pivotal study 048 were to 1) demonstrate the lot-to-lot consistency of three manufacturing lots of the DTaP-IPV candidate vaccine in terms of D, T, PT, FHA, and PRN antibody geometric mean concentrations (GMCs) and in terms of poliovirus antibody geometric mean titers (GMTs) one month after vaccination when co-administered with MMR vaccine; 2) demonstrate the non-inferiority of the DTaP-IPV vaccine as compared to DTaP and IPV vaccines administered separately in terms of anti-D, anti-T, anti-PT, anti-FHA, anti-PRN booster responses and anti-poliovirus GMTs one month after vaccination; and 3) demonstrate the non-inferiority of the DTaP-IPV vaccine as compared to DTaP and IPV vaccines administered separately in terms of the incidence of increased circumferential swelling at the DTaP-based injection site. Secondary objectives included descriptive analyses of immune responses to DTaP-IPV vaccine antigens and to influenza vaccine (permitted as a co-administered vaccine, at the investigator's discretion when indicated); local and general solicited events, serious adverse events (SAEs) and unsolicited adverse events (AEs).
Supportive study 213503/047
This study was a Phase II study conducted in 400 healthy children 4-6 years of age. The primary study objective was to evaluate the non-inferiority of the DTaP-IPV vaccine as compared to DTaP and IPV vaccines administered separately, in terms of D, T, PT, FHA, and PRN booster responses and in terms of poliovirus GMTs one month after vaccination, when co-administered with MMR vaccine. The formulation of DTaP-IPV used in Study 213503/047 was the same as that of the vaccine intended for U.S. licensure except that it also contained 2-phenoxyethanol.
As indicated previously, the pertussis, diphtheria, and tetanus immunogenicity data from this study are not being considered by CBER in the evaluation of KinrixT because information submitted on the validation of the assays was not adequate.
Study 213503/047 provides supportive polio immunogenicity data for the evaluation of KinrixT. Among the subset of subjects primed with three doses of IPV, post-vaccination GMTs and booster response rates for anti-poliovirus type 1, type 2, and type 3 were comparable between the DTaP-IPV and Infanrix + IPOL groups.
Supportive study 213503/046
Because of the priming history of the study population, CBER considered the immunogenicity data from this study (not included in the BLA) to be of limited relevance to the evaluation of KinrixT for licensure in the U.S. The safety data from this study were considered supportive for the evaluation of KinrixT, and were submitted in a synopsis format.
Bioresearch Monitoring
Inspections of three clinical investigators were performed in support of this BLA. Information from the BLA was compared to source documents during the inspections. The inspections focused on specific questions concerning the study.
Results of three bioresearch monitoring inspections of three clinical sites did not reveal any problems that impact the data submitted in the application.
Clinical Study Conclusions
All primary immunogenicity endpoints for lot consistency were met, and KinrixT was shown to be non-inferior to separately administered Infanrix + IPOL with regard to booster responses to diphtheria, tetanus and the pertussis antigens and GMTs to the IPV components. The safety and immunogenicity data included in the BLA support approval of KinrixT as a single dose in children 4-6 years of age who have previously received four doses of DTaP vaccine, using Infanrix and/or Pediarix for the first three doses and Infanrix for the fourth dose, and who have previously received three doses of IPV. Sufficient data are not available to support the safety and effectiveness of KinrixT following vaccination with DTaP vaccines from other manufacturers.
7. Safety
In pivotal study 213503/048, information on the occurrence and severity of injection site pain, redness, swelling, and increase in mid-upper arm circumference within four days (Days 0-3) after vaccination was recorded daily by the subjects' parents or guardians. Within four days post-vaccination, injection site pain, redness, swelling, and increase in mid-upper arm circumference at the DTaP-based administration site was reported by 57%, 37%, 26%, and 36% of KinrixT subjects, respectively, and by 53%, 37%, 27%, and 38% of Control subjects, respectively. During this period, pain (at the KinrixT or Infanrix injection site) that prevented normal activities was reported in 1.6% of KinrixT subjects and 0.6% of Control subjects. The incidence of any pain and of pain that prevented normal activities were statistically significantly higher (p-value <0.05) at the KinrixT injection site than at the Infanrix injection site. Rates of the other solicited local reactions at the KinrixT or Infanrix injection sites were not statistically significantly different between groups.
Increased circumferential swelling, defined as injection site swelling involving <50% of the upper arm length and associated with a >30 mm increase of the mid-upper arm circumference, within four days following vaccination, was reported for the KinrixT injected arm in 0.6% of subjects and for the Infanrix injected arm in 1.0% of Control subjects. Based on pre-specified criteria, KinrixT was non-inferior to Infanrix with regard to increased circumferential swelling within four days following vaccination.
Body temperature was monitored daily for the 15 day period post-vaccination. Within four days post-vaccination (Days 0-3), 6.5% of KinrixT subjects and 2.1% of Control subjects reported fever >38.0oC (p-value <0.05). Rates of fever >38.5oC, >39.0oC, >39.5oC, and >40.0oC were not statistically significantly different between groups.
No deaths were reported among subjects during any of the three studies. Across the three studies, serious adverse events within 30 days post-vaccination were reported in three DTaP-IPV subjects (cerebrovascular accident; hypernatremia and dehydration; and dehydration and gastroenteritis) and in four Control subjects (constipation; foreign body trauma; periorbital cellulitis; and fever). The cerebrovascular accident was an ischemic stroke of undetermined etiology that occurred 30 days following KinrixT in a four-year old female in Study 213503/048. This subject was reported to have a strong family history of thrombotic events. In view of the occurrence of a cerebrovascular accident, at the request of CBER, GSK Biologicals provided a review of their global safety database for reports of adverse events following DTaP-IPV, Infanrix and Pediarix that are medically consistent with cerebrovascular accident, thrombosis, or hypercoagulable states. For this review, global distribution of DTaP-IPV, Infanrix, and Pediarix were estimated to be approximately ---------------------------------------------------------------- doses, respectively. Three reports consistent with diagnostic criteria for cerebrovascular accident were identified and three reports consistent with diagnostic criteria for thrombosis, thromboembolism or hypercoagulable states were identified. Each case was thought to have other more likely causes of these events than vaccination.
The BLA also included a global review of post-marketing safety surveillance data on GSK Biologicals' DTaP-IPV (formulation distributed outside of the U.S. contains 2-phenoxyethanol) and Infanrix for identification of events that may have a possible causal association with vaccination. For DTaP-IPV, the review covered a period of approximately 10 years during which approximately-------------- doses were distributed. Based on the review, the applicant identified injection site vesicles and pruritis for inclusion in the post-marketing section of the KinrixT package insert. For Infanrix, the review covered a period of approximately 13 years during which approximately -------------- doses were distributed. Based on the Infanrix review, the applicant identified the following events for inclusion in the post-marketing section of the KinrixT and Infanrix package inserts: anaphylaxis, urticaria, angioedema, apnea, febrile convulsions, lymphadenopathy, and thrombocytopenia.
Pharmacovigilance
A pharmacovigilance plan (PVP) was not included in the original submission of the BLA. After discussions with the firm, a plan was submitted as an amendment to the BLA file. The proposed PVP was determined to be inadequate. Reviewers requested that the firm develop a revised plan that would include additional safety evaluation and monitoring and specified timelines for the submission of safety reports. A revised PVP was submitted on May 16, 2008, and after review by OBE, the PVP was found to be acceptable.
Post Marketing Commitments
GSK has committed to conduct a post-licensure study in approximately 400 children 4-6 years of age to evaluate the safety and immunogenicity of KinrixT when given concomitantly with varicella vaccine. The following comment is in the approval letter:
You have committed to conduct a randomized, open label, comparative trial to evaluate the safety and immunogenicity of KinrixT when given concomitantly with varicella vaccine. The primary objectives of the study will pertain to the immunogenicity of KinrixT. The study will be conducted in approximately 400 children 4-6 years of age who previously received three doses of DTaP using Infanrix and/or Pediarix and a fourth dose of DTaP using Infanrix. The final study protocol will be submitted by August 30, 2008. The study will be initiated no later than January 30, 2009. The final study report will be submitted by July 31, 2011.
8. Advisory Committee Meeting
Based on CBER's extensive safety and manufacturing experience with the component antigens in the KinrixT vaccine it was determined that review of the vaccine by the Vaccines and Related Biological Products Advisory Committee was not required.
9. Pediatrics
The Sponsor has requested waivers of pediatric assessments for the age groups 0-6 weeks, 6 weeks-4 years, and 7-18 years. The committee agrees with sponsor that a waiver for these age groups is appropriate. The request for waiver was reviewed and approved by CBER's Pediatric Review Committee on 1/23/08.
10. Other Relevant Regulatory Issues
N/A
11. Labeling
The labels for the carton and associated container were reviewed and found to be acceptable. The proprietary name KinrixT was approved by the Advertising and Promotional Labeling Branch. Review of the prescribing information (PI) identified numerous deficiencies, most of which required only minor modifications to the text. However, a more significant revision was requested in the Indications and Usage section, in which language was introduced to indicate that previous DTaP vaccine doses had been with Infanrix or Pediarix for the first three doses and Infanrix for the fourth dose.
Following internal discussions within OVRR, it was also agreed that the Dosage Forms and Strength section of the PI would not list the specific pertussis antigens or provide quantitative information for any antigen in the vaccine. This decision regarding the language in the Dosage Forms and Strengths section is not specific for KinrixT, and will likely impact the package insert for other vaccines.
After negotiations with the sponsor, it was determined by the committee that the prescribing information for KinrixT is acceptable.
12. Recommendations
The committee recommends approval of the BLA.