Department of Health & Human Services
Public Health Service
Food and Drug Administration
Rockville, MD 20852-1448
Our STN: BL 125347/0
GlaxoSmithKline Biologicals, S.A.
Attention: Elisa Harkins
North American Regulatory Affairs - Vaccines
2301 Renaissance Blvd.
P.O. Box 61540
King of Prussia, PA 19406
Dear Ms. Harkins:
We are reviewing your biologics license application (BLA) dated March 17, 2009 including the May 21, 2009 amendment to the BLA for Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) for active immunization as a booster dose for the prevention of invasive disease caused by Haemophilus influenzae type b. This amendment provided a response to our April 23, 2009 letter which included requests for information for Study Hib-097. This study is intended to provide confirmatory data for Hiberix for booster immunization ----------b(4)-------------------------------------------------------------------------------------------------------
We have the following comments and requests for information as they relate to the BLA. Please promptly submit your written response to the following items regarding your proposed study, Study Hib-097 so that we may continue evaluating your BLA:
- We acknowledge your response to Item 4 of our April 23, 2009 letter, in which you have requested that we reconsider your proposal to base the sample size of Study Hib-097 on the power calculations for evaluation of immunogenicity endpoints. You have proposed a sample size of 1920 subjects who will receive Hiberix and 640 control subjects who will receive ActHIB or Pentacel. We acknowledge the previous clinical studies and post-marketing experience with Hiberix, as you have outlined in Attachment 1 of your response. However, we note several limitations of the available clinical studies database.For example,
- the data do not reflect use of Hiberix in the context of currently recommended vaccines that likely would be concomitantly administered with Hiberix in the U.S;
- as with the data submitted to the Hiberix BLA for booster immunization, we anticipate that the additional clinical studies data were obtained in study populations that were almost exclusively of Caucasian origin, and thus, will not be representative of the U.S. population of infants and children with regards to race/ethnicity;
- the comparative data relative to a U.S. licensed Haemophilus B Conjugate vaccine were obtained using a non-U.S. vaccination schedule; and,
- the duration of safety monitoring was approximately one month following vaccination, whereas we currently recommend safety follow-up for serious adverse events and new onset chronic medical conditions through 6 months following vaccination.
Considering the limitations of the available clinical studies data, the availability of other Haemophilus B Conjugate vaccines for primary immunization, and the target population of healthy infants and children for administration of Hiberix, we continue to recommend that Study Hib-097, the pivotal study for licensure of Hiberix for primary vaccination, include close safety monitoring in at least 3,000 infants who receive Hiberix and at least 1,000 control subjects. Please respond.
- We acknowledge your response to Item 6 of our April 23, 2009 letter, in which you have proposed evaluation of post-dose 3 anti-PRP levels >0.15 mcg/ml as a powered secondary objective. We view an evaluation of post-dose 3 anti-PRP levels >0.15 mcg/ml, as well as >1.0 mcg/ml, as critical to support the effectiveness of Hiberix. As conveyed in our April 23, 2009 letter, for Study Hib-097, we continue to recommend a non-inferiority evaluation of the percent of subjects with a post-dose 3 anti-PRP level >0.15 mcg/ml, using a non-inferiority margin of 5%, as a co-primary analysis.
- Comments ‘a’ through ‘e’ below pertain to your response to Item 7 of our April 23, 2009 letter, in which you have proposed to add the following objective to Study Hib-097:
To rule out a 10% decrease in seroresponse to PT, FHA and pertactin in the Subcohort Hiberix-CoAd as compared to the ActHIB-group, following 3 primary doses where seroresponse is defined as the percentage of subjects showing a titer above a threshold that leads to 95% seroresponse in the control group.
- Based on the Reverse Cumulative Curves for anti-PT, FHA, and pertactin from Study HibMenCY-TT-005 that were included in the study report submitted to IND –b(4)- (amendment 144), we find the definitions of seroresponse for PT, FHA, and pertactin that you have proposed to use in Study Hib-097 to be acceptable.
- We do not concur with your plan to evaluate anti-PT, FHA, and pertactin seroresponse rates as a powered secondary objective. We view these as important analyses for inclusion in the Hiberix package insert, and as conveyed in our April 23, 2009 letter, we continue to recommend evaluation of anti-PT, FHA, and pertactin seroresponse rates as co-primary objectives. However, we also acknowledge that missing an endpoint(s) evaluating concomitantly administered vaccines will not necessarily preclude licensure of Hiberix for primary immunization.
- Your criterion for evaluation of anti-PT, FHA, and pertactin seroresponse is: p-value < 2.5% for each antigen (p-value computed by integrating on the p-value for the null hypothesis that the seroresponse rate in the Hiberix group is < 85% and the a-posteriori probability of the cut-off in the control group). Please address whether your proposed evaluation method is as rigorous as a traditional non-inferiority evaluation using a 10% non-inferiority margin. In your response, please explain how you will combine the probabilities from the two steps to produce the combined significance level.
- In the final report for Study Hib-097, please include Reverse Cumulative Curves for anti-PT, FHA, and pertactin following the third dose of Pediarix.
- As exploratory analyses for Study Hib-097, we recommend that you also evaluate anti-PT, FHA, and pertactin seroresponse rates following 3 doses of Pediarix, where seroresponse is defined as the percentage of subjects with a titer above a threshold that leads to 90% seroresponse in the control group.
- Regarding your response to Item 8 of our April 23, 2009 letter, we do not concur with your plan to evaluate achievement of an acceptable seroprotection rate of 90% for each of the polioviruses following three doses of Pediarix as a powered secondary objective. As conveyed in our April 23, 2009 letter, we continue to recommend evaluation of acceptability of the seroprotection rate for each poliovirus (i.e., lower limit of the two-sided 95% confidence interval for the poliovirus seroprotection rates should be >90%) as co-primary objectives. Please respond.
- In your response to Item 9 of our April 23, 2009 letter, you have proposed to evaluate pneumococcal antibody concentrations using your -----b(4)-----------. For the primary evaluation of non-inferiority of seroresponse rates to Prevnar, you plan to use a threshold of -b(4)- mcg/ml, which you state corresponds to -b(4)- mcg/ml in the ---b(4)------ used for Prevnar evaluation. For threshold pneumococcal antibody levels identified by WHO for registration of new pneumococcal conjugate vaccines, you refer to “WHO guidance and the attached publication”. However, it appears that there was no publication attached. Furthermore, it is our understanding that the threshold based on your --------b(4)------------- that corresponds to -b(4)- mcg/ml using the ----b(4)------ has not been conclusively decided by WHO. Thus, we do not view your justification for using a threshold of -b(4)- mcg/ml for evaluation of pneumococcal seroresponse rates in Study Hib-097 as adequate. Unless this level is considered by WHO to be equivalent to a level of -b(4)- mcg/ml using the --b(4)-- --b(4)--, we recommend that you use a level of -b(4)- mcg/ml for the primary analyses. Please respond.
- In response to Item 14a of our April 23, 2009 letter, you have indicated that in the booster phase of Study Hib-097, secondary analyses to evaluate the immunogenicity of Infanrix administered concomitantly with Hiberix or ActHIB, in terms of diphtheria, tetanus, PT, FHA, and pertactin antibodies are no longer relevant because you have decided to remove the evaluation of Kinrix from the study. We do not concur with this view. Even though the study will no longer evaluate Kinrix, we continue to recommend that you conduct secondary analyses of diphtheria, tetanus, PT, FHA, and pertactin responses in the booster phase of the study. As conveyed in Items 12 and 13 of our April 23, 2009 letter, we recommend that you consider at least a four-fold increase in antibody concentration after booster vaccination for evaluation of diphtheria, tetanus, and pertussis seroresponse. Please respond.
- Please submit a protocol for Study Hib-097 to the Hiberix BLA.
- For Study Hib-097, please provide the anticipated dates of the protocol submission, the study initiation and the submission of the final study report
Please submit your response in a timely manner or submit a partial response, so we may continue the review of your application. If we determine that your response to this information request constitutes a major amendment, we will notify you in writing. If we receive your major amendment during the last three months of the review period, we will extend the review period an additional three months.
If you have any questions, please contact the Regulatory Project Manager, Jason Humbert, at (301) 827-3070.
Wellington Sun, M.D.
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research