Recommendations Regarding Request for Partial Waiver of Pediatric Studies - Pentacel 

MEMORANDUM

DEPARTMENT OF HEALTH & HUMAN SERVICES
FDA/CBER/OVRR/DVRPA

Date: April 25, 2008

From:
Karen Farizo, M.D.
Medical Officer
Vaccines Clinical Trials Branch

Theresa Finn, Ph.D.
Scientific Reviewer
Bacterial Vaccines Branch

Subject: Pentacel [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine]: Recommendations regarding request for partial waiver of pediatric studies

To: Pediatric Review Committee

Through: Norman Baylor, Ph.D.
Director
Office of Vaccines Research and Review
Center for Biologics Evaluation and Research

cc: BLA STN #125145

Background

Pentacel is expected to be approved for active immunization against invasive disease caused by Haemophilus influenzae type b, diphtheria, tetanus, pertussis, and poliomyelitis, in children 6 weeks through 4 years of age (prior to the fifth birthday). The dosage schedule for Pentacel consists of a total of four doses, with a single dose routinely administered at 2, 4, 6, and 15-18 months of age. As presented in the clinical safety and immunogenicity reviews for Pentacel, in clinical studies, Pentacel was administered to subjects ranging in age from 6 weeks to 18 months.

In the clinical development of Pentacel, the rationale for the lower age limit of 6 weeks for administration of Pentacel was based on current immunization practices and the limitations of the neonatal immune response. With the exception of Hepatitis B vaccine, which is routinely administered shortly after birth, in part, to prevent unrecognized perinatal transmission of hepatitis B virus, the infant immunization program in the U.S. is initiated at a minimum of 6 weeks of age. In general, limitations of the neonatal immune response (e.g., weak and short-lived antibody response and inhibitory influence of maternal antibodies) have been significant barriers to effective immunization earlier in life.

For the age group 19 months through 4 years of age, use of Pentacel would be for catch-up immunization in unvaccinated children and those with delayed vaccinations. The requested upper age limit for administration of Pentacel, 4 years (prior to the fifth birthday), coincides with the age beyond which H. influenzae type b conjugate vaccines are no longer recommended for routine use.

Support for Safety and Effectiveness of Pentacel in Children 19 Months through 4 Years

Use of Pentacel in children 19 months through 4 years of age is supported by clinical evidence of the safety and effectiveness of Pentacel in children 6 weeks to 18 months of age. Extrapolation of immunogenicity data from children 6 weeks to 18 months of age to older children 19 months through 4 years of age is supported by the generally mature, robust immune response to inactivated vaccines observed in children during and beyond the second year of life. In clinical studies, the safety of Pentacel was evaluated at each of four consecutive doses, administered at 2, 4, 6, and 15-18 months of age, respectively. Although rates of local reactions following Pentacel were generally higher in children 15-18 months of age compared with infants, this finding is thought to represent a higher risk of local reactions with increasing dose number, rather than an age effect. Rates of fever and other solicited systemic adverse events following Pentacel were not higher in children 15-18 months of age compared with infants. Thus, it is anticipated that adverse reaction rates following catch-up vaccination with Pentacel in children 19 months through 4 years would not be meaningfully higher than those observed in younger children and infants following the analogous doses in the four-dose series. Furthermore, DTaP and IPV vaccines are recommended for and routinely administered to U.S. children 6 weeks through 6 years of age. Haemophilus influenzae type b conjugate vaccines are recommended for use among U.S. children 6 weeks through 4 years of age.

Partial Waiver of Pediatric Studies

As requested by the applicant, we recommend that CBER grant waivers of pediatric studies of Pentacel for infants 0 to 5 weeks of age (before age 6 weeks) and children 5 to 16 years of age (5 years to prior to 17th birthday). Justification for waivers of pediatric studies for these age groups is provided in the attached waiver form required by FDA’s Pediatric Review Committee.

Attachment

Pediatric Research and Equity Act Waivers

Product Name: Pentacel [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine]

Active Ingredients: Diphtheria Toxoid, Tetanus Toxoid, Pertussis Antigens (Detoxified Pertussis Toxin, Filamentous Haemagglutinin, Pertactin, Fimbriae Types 2 and 3), and polyribosyl-ribitol-phosphate capsular polysaccharide (PRP) of H. influenzae type b covalently bound to tetanus toxoid

Dosage Form: Suspension for Intramuscular Injection

BLA #: 125145 (original submission)

Sponsor: Sanofi Pasteur Limited

Requested Indication(s): Pentacel vaccine is indicated for active immunization against diphtheria, tetanus, pertussis, poliomyelitis, and invasive disease caused by H. influenzae type b in infants and children 6 weeks through 4 years of age (prior to fifth birthday).

The dosing regimen is a 4 dose series, with a single dose administered at 2, 4, 6, and 15-18 months of age.
1.Pediatric age group(s) to be waived: ?birth to 5 weeks (before age 6 weeks)
?5 to 16 years (5 years to prior to 17th birthday)


2.Reason(s) for waiving pediatric assessment requirements:

a) Studies are impossible or highly impractical, and
c) The product fails to represent a meaningful therapeutic benefit over existing therapies for pediatric patients and is unlikely to be used in a substantial number of patients in these age groups.

3.Justification for waiver-- birth to 5 weeks
For infants from birth to 5 weeks of age, the justification for waiver of studies with Pentacel is based on the following sections of the Pediatric Research Equity Act of 2007:


Section 505B(a)(4)(B)(i): necessary studies are impossible or highly impracticable.

Section 505B(a)(4)(B)(iii): the drug or biological product—(I) does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in that age group; and (II) is not likely to be used by a substantial number of pediatric patients in that age group.

Necessary studies are impossible or highly impracticable

Because of the following considerations, it would be difficult to enroll sufficient numbers of subjects from birth to 5 weeks of age in studies of Pentacel and inappropriate to require such studies.

a) Lack of Need

Among the diseases targeted for prevention by Pentacel, neither diphtheria, tetanus, nor poliomyelitis occur in U.S. infants too young to be protected from vaccination with products approved for use beginning at 6 weeks of age.

b) Potential for Diminished Immune Responses to Subsequent Vaccination

Clinical data from one published study suggest that administration of Diphtheria and Tetanus Toxoid (DT) to newborn infants may be associated with suppression of antibody responses to subsequently administered diphtheria toxoid and H. influenzae type b conjugate vaccines.1 In another study, neonatal vaccination with an acellular pertussis vaccine interfered with the immune response to an H. influenzae type b conjugate vaccine.2 In addition, the applicant has indicated that vaccination with DTaP at birth may suppress the antibody responses to diphtheria toxoid and pertussis antigens.3

c) Potential for Clinically Significant Adverse Reactions

As with all preventive vaccines, a high standard of safety would be expected for vaccines administered to healthy neonates. Moreover, the vulnerability of the neonate poses unique safety considerations for clinical studies of preventive vaccines. For example, post-vaccination fever assumes greater clinical significance in neonates than in older infants or children because of the high risk for serious bacterial infection and the difficulty in predicting the presence of invasive disease by physical exam and laboratory testing in the neonatal period. Hospitalization, diagnostic evaluation including cerebrospinal fluid studies, and administration of intravenous antibiotics represent the standard of care in the U.S. for febrile neonates. Administration of Pentacel in infants from birth to 6 weeks of age poses at least a theoretical concern for excess fever due to vaccination. In clinical studies, approximately 5-20% of older infants had fever =38.0oC within 0-3 days following receipt of Pentacel.

Pentacel does not represent a meaningful therapeutic benefit over existing therapies and is not likely to be used by a substantial number of infants 0-6 weeks of age

Vaccinating U.S. infants from birth to 6 weeks of age against diphtheria, tetanus, and poliomyelitis does not represent a meaningful therapeutic benefit over vaccination according to the currently recommended schedule which begins at a minimum age of 6 weeks. In view of the potential risks of neonatal vaccination and the lack of added benefit to earlier vaccination against diphtheria, tetanus, and poliomyelitis, Pentacel is not likely to be used by a substantial number of U.S. infants from birth to 6 weeks of age.
4.Justification for waiver—5 to 16 years of age


The justification for waiver of studies of Pentacel in children and adolescents 5 to 16 years of age is based on the following sections of the Pediatric Research Equity Act of 2007:

Section 505B(a)(4)(B)(i): necessary studies are impossible or highly impracticable.

Section 505B(a)(4)(B)(iii): the drug or biological product—(I) does not represent a meaningful therapeutic benefit over existing therapies for pediatric patients in that age group; and (II) is not likely to be used by a substantial number of pediatric patients in that age group (for children 10 to 16 years of age).

Necessary studies are impossible or highly impracticable

In the pediatric population 5 to 16 years of age, necessary studies are impossible or highly impracticable because too few children, geographically dispersed, would need vaccination with all of the antigens contained in Pentacel. Specific considerations are presented below.

a) Too Few Children 5 to 16 Years of Age in Need of Vaccination against Invasive Disease due to H. influenzae type b

A fourth dose of H. influenzae type b conjugate vaccine, administered at age 12 to 15 months, completes the routinely recommended series for this vaccine. Because of the negligible risk of developing invasive disease due to H. influenzae type b, catch-up vaccination is not generally recommended for children 5 years of age and older. Vaccination is recommended for children 5 years of age and older who are unimmunized and who have an underlying disease possibly predisposing to invasive disease due to H. influenzae type b. Such children are expected to be few in number and geographically dispersed.

b) DTaP Vaccines not Administered to Children 7 Years of Age and Older

DTaP vaccines are not administered to children 7 years of age and older. A single dose of Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine Adsorbed (Tdap) is routinely recommended at 11-12 years of age. Tdap vaccines were specifically formulated to contain lower amounts of diphtheria toxoid than DTaP vaccines to reduce the potential for reactogenicity that may be associated with booster vaccination.

c) Limited Need for Polio Vaccination in this Age Group

The routinely recommended IPV series consists of four doses. The school entry requirements for some States require a dose of IPV at age 4 to 6 years. For other States, the last dose in the IPV series may be administered before age 4 years. Thus, many children may fulfill the IPV requirements before 5 years of age. IPV is not routinely recommended for children 7 to 16 years of age.

Pentacel does not represent a meaningful therapeutic benefit over existing therapies and is not likely to be used by a substantial number of children and adolescents 10 to to 16 years of age

For children and adolescents 10 to 16 years of age, Pentacel does not represent a meaningful therapeutic benefit over Tdap vaccine. Pentacel is not likely to be used by a substantial number of children and adolescents 10 to 16 years of age because Tdap vaccines were specifically formulated to reduce the potential for reactogenicity that may be associated with booster vaccination. Although IPV is not routinely used in this age group, Pentacel does not represent a meaningful therapeutic benefit over IPV.

References
1.Lieberman JM, Greenberg DP, Wong VK, et. al. Effect of neonatal immunization with diphtheria and tetanus toxoids on antibody responses to Haemophilus influenzae type b conjugate vaccines. J Pediatr 1995;126:198-205.
2.Knuf M, Schmitt H-J, Wolter, et. al. Neonatal vaccination with an acellular pertussis vaccine accelerates the acquisition of pertussis antibodies in infants. J Pediatr 2008;152:655-660.
3.Halasa NB, O’Shea A, Shi JR, et. al. Poor immune responses to a birth dose of diphtheria, tetanus and acellular pertussis vaccine. J Pediatr 2008, in press

