Letter - Study-097 - Hiberix 

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
Associate Director
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 March 31, 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, which contained a revised concept protocol for Study HIB-097, was submitted simultaneously to the above BLA and to IND -b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

 

We have the following comments and requests for information as they relate to the BLA and IND. Please promptly submit your written response to the following items regarding your  revised concept protocol for Study HIB-097 so that we may continue evaluating your BLA:
1.In your cover letter for the March 31, 2009, submission to the Hiberix BLA and in the concept protocol for Study HIB-097, -------------b(4) .
2.Since the February 2, 2009, pre-BLA meeting for Hiberix, you have modified the booster vaccination phase of Study HIB-097 to include a group who will receive Hiberix and Kinrix at 15-18 months of age.  ------------------b(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------  The Advisory Committee on Immunization Practices (ACIP) recommends routine administration of IPV at 2, 4, 6-18 months and 4-6 years of age.  A current ACIP polio vaccination working group has decided to recommend a clarification to the schedule, specifying that if four doses of IPV were administered prior to age 4 years, an additional dose of IPV should be administered between 4 and 6 years of age. This recommendation will be considered by the ACIP at their June 2009 meeting.  If this recommendation is adopted by the ACIP, your plan to administer ----------b(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.
3.In the booster phase of Study HIB-097, you plan to compare children 15-18 months of age who receive --b(4)-- + Hiberix to children who receive Infanrix + Hiberix in terms of responses to diphtheria, tetanus, and the pertussis antigens.  You plan to compare children who receive --b(4)-- + Hiberix to children who receive Pentacel in terms of responses to the polioviruses.  These primary non-inferiority analyses are --------------b(4)------------------------------------------------------------------------------------------------------------------.  The acceptability of using Hiberix as a concomitant vaccine in the investigational and control arms, -----------------b(4)-------------------------------------------------------------, is contingent upon traditional approval of Hiberix for booster --------------b(4)--------------, respectively. Please acknowledge.
4.As conveyed in our January 30, 2009, FAX regarding the questions posed in your Hiberix pre-BLA meeting package, to support approval of Hiberix for ----b(4)-------------, we continue to recommend a safety database of at least 3,000 subjects who receive Hiberix and at least 1,000 control subjects who receive a US licensed Hib vaccine in a comparative trial in which safety is closely monitored.  For the booster vaccination phase of Study HIB-097, we consider the proposed size of the safety database (1,650 subjects to receive Hiberix, 275 subjects to receive ActHIB and 275 subjects to receive Pentacel, minus an expected 20% dropout rate from the primary phase to the booster phase) to be adequate.  --------------------------b(4)------------------------------------------------------------, the booster group Hiberix ---b(4)---- could not be used to support traditional approval of Hiberix for booster immunization. Please respond.
5.We acknowledge your argument for a 2-fold equivalence margin for lot-to-lot consistency of PRP-T, in response to our comment conveyed in the January 30, 2009, FAX.  However, we continue to recommend that the criterion for success be that the two-sided 95% confidence bounds on the anti-PRP GMC ratio between lots are within the [0.67, 1.5] interval.  Please respond.
6.We acknowledge your response to the comment in our January 30, 2009, FAX regarding the non-inferiority evaluation of anti-PRP response following primary vaccination. However, we continue to recommend a non-inferiority evaluation of the percent of subjects with post-dose 3 anti-PRP levels >0.15 mcg/ml as co-primary.  We view this as an important endpoint that should be included in the Hiberix package insert.  We continue to recommend a non-inferiority margin of 5% because of the expected high (>95%) rate of seroprotection, the seriousness of invasive Hib disease, and the absence of clinical efficacy data with Hiberix.  Please respond.
7.We acknowledge your response to the comment in our January 30, 2009, FAX regarding the recommendation for co-primary non-inferiority evaluation of post-dose 3 anti-PT, anti-FHA, and anti-PRN seroresponse rates.  We note that the evaluation of pertussis responses based on GMTs alone for Study HibMenCY-TT-009 was an oversight by CBER.  In the absence of a serological correlate of protection for pertussis, we continue to recommend an evaluation of both GMTs and seroresponse as co-primary endpoints in Study HIB-097.  We are aware of instances in which differences between groups have been detected by seroresponse data but not by GMTs, and vice versa.  Furthermore, assessment of seroresponse provides per-subject information not captured by GMTs.

In view of your concerns that a pre-vaccination blood sample, not otherwise required for Study HIB-097, could negatively impact recruitment, in lieu of assessing pertussis seroresponse rates, we may consider an evaluation of pre-specified post-vaccination levels of anti-PT, anti-FHA, and anti-PRN.  However, because of assay variability and the large proportion of subjects expected to achieve antibody concentrations --b(4)-----, the cut-off of the assays, we do not concur with the post-dose 3 seroresponse definition you have proposed for secondary analyses.  The level of antibody selected for each antigen should be sufficiently discriminatory to detect potentially important differences that may exist between groups.  We recommend that you use existing data on antibody responses following three doses of Pediarix to identify such levels and that you provide your rationale and justification for the selected levels for our review.  While this approach potentially may be acceptable for the evaluation of a licensed pertussis vaccine administered concomitantly with an investigational vaccine, as in Study HIB-097, currently, an evaluation of seroresponse based on pre- to post-vaccination antibody concentrations is still required for the immunogenicity evaluation of a new pertussis vaccine.  Please respond.
8.We acknowledge your response to the comment in our January 30, 2009, FAX regarding the non-inferiority evaluation of anti-poliovirus responses following three doses of Hiberix.  We also note that CBER’s concurrence with a non-inferiority margin of 10% for the evaluation of poliovirus seroprotection rates for Study Hib-MenCY-TT-009 apparently was an oversight on our part.  Consistent with the immunogenicity data in the Pediarix package insert, we typically use a non-inferiority margin of 5% for the evaluation of poliovirus seroprotection rates.  The rationale for using a non-inferiority margin of 5%, rather than 10%, is based on the expected high seroprotection rates and the seriousness of the disease.  In view of these factors, we also recommend an acceptability criterion of >90% (i.e., lower limit of the two-sided 95% confidence interval for the poliovirus seroprotection rates should be >90%).  We view these criteria for evaluation of poliovirus responses as applicable to the evaluation of a new vaccine containing IPV as well as to the evaluation of a licensed vaccine containing IPV that is administered concomitantly with an investigational vaccine.  Please respond.
9.We acknowledge your response to our recommendation in the January 30, 2009, FAX to evaluate non-inferiority in responses to Prevnar based on seroresponse rates, rather than GMCs, as primary analyses.  We acknowledge that in Study Hib-MenCY-TT-005/006, responses to Prevnar were assessed based on GMCs.  However, in view of recent WHO consultations to develop serological criteria for the evaluation of pneumococcal conjugate vaccines, we currently recommend evaluation of pneumococcal seroresponse rates as primary analyses.  Please provide a definition for seroresponse to the pneumococcal serotypes contained in Prevnar and your rationale and justification for the selected definition.  We continue to recommend secondary analyses of pneumococcal antibody GMCs.. Please respond.
10.You have proposed secondary analyses of responses to PT, FHA, and PRN following three doses of Pediarix based on GMCs and seropositivity (anti-PT, anti-FHA, and anti-PRN concentrations >5 EU/ml).  These analyses include between group GMC ratios for antibodies for the pooled Pediarix group and the Pentacel group.  As explained in comment #7 above, we do not view your definitions of post-dose 3 seroresponse for the pertussis antigens as meaningful endpoints.  Please also note that given the differences between Pediarix and Pentacel in terms of manufacturing and content of pertussis antigens, we do not view comparisons of anti-PT, anti-FHA, and anti-PRN between the Pediarix and Pentacel groups as meaningful.  We do not foresee including any data on pertussis responses to Pentacel from Study HIB-097 in the Hiberix package insert. Please respond.
11.For the booster vaccination phase, we note that you have not proposed any non-inferiority analyses for responses to the diphtheria, tetanus, and pertussis antigens following Infanrix administered concomitantly with Hiberix relative to ActHIB.  Please note that for confirmation of effectiveness of Hiberix for booster immunization, we will require primary non-inferiority evaluations of the immune responses to a US licensed DTaP vaccine administered concomitantly with Hiberix vs. a US licensed Hib vaccine.  ------------b(4)-----------------------------------------------and if post-dose 3 non-inferiority analyses for the diphtheria, tetanus, and pertussis antigens are met for Hiberix + Pediarix vs. ActHIB + Pediarix, then additional non-inferiority analyses of responses to these antigens in the booster phase will not be needed.  --------------b(4)------------------------------------------------------------------------------------- data raise concerns about interference in immune responses to the diphtheria, tetanus, or pertussis antigens, then such analyses in the booster phase would be needed.  Please respond.
12.With regard to --------------------b(4) (4) -------------------------------------------------------------------------------------------------------------------------------------------------------------------.
13.----------------b(4) .
14.-------b(4)-----------  .
15.For the booster phase of the study, you have proposed secondary analyses to evaluate the immunogenicity of Infanrix, Kinrix, and Pentacel, in terms of D, T, PT, FHA, and PRN antibodies.  The endpoints proposed for these analyses include anti-D and anti-T >0.1 IU/mL and anti-PT, FHA, and PRN concentrations >5 EU/ml. a.As explained previously, we do not view these seroresponse endpoints as providing very meaningful assessments of the response to booster vaccination. Please see our recommendations in Items 12 and 13 above regarding appropriate definitions for responses to these antigens following booster immunization with Infanrix or Kinrix. Please respond.
b.As conveyed in Item 10 above, we do not view comparisons of the pertussis immune responses following Pentacel vs. Infanrix or following Pentacel vs. Kinrix to be meaningful.  It would also be inappropriate to compare data on pertussis immune responses to Pentacel using your assays to data on pertussis immune responses generated using other assays.  Please respond.


1.You have proposed a secondary evaluation of the immunogenicity of a 2-dose vaccination course of Rotarix co-administered with Pediarix, Hiberix and Prevnar compared to that of Rotarix co-administered with Pediarix, ActHIB, and Prevnar and to that of Rotarix co-administered with Pentacel, Prevnar, and Engerix-B in terms of anti-rotavirus antibody concentrations >20 U/ml.  In the absence of a serological correlate for protection for rotavirus, the clinical relevance of these comparisons is unclear.  In addition, the data may be difficult to interpret in the absence of information on pre-vaccination seropositivity status.. Please acknowledge.

2.Based on the intervals between study visits provided in Table 4, it appears that an interval of 21 to 48 days would be allowed between vaccination and post-vaccination blood draws.  We are concerned that this relatively wide interval potentially could confound interpretation of the immunogenicity data.  We recommend use of a narrower interval such as 28-48 days.  We also recommend that the protocol specify the interval that will be used to determine eligibility for inclusion in the ATP immunogenicity analyses.  Please respond.     

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.

Sincerely yours,

 

Wellington Sun, M.D.
Director
Division of Vaccines and Related Products Applications
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research
