Wyeth-Lederle To Submit Monthly Adverse Events Reports For Prevnar

Wyeth-Lederle Vaccines is required to submit monthly reports of adverse events for Prevnar in its first year following approval.

"For Prevnar, FDA requests that such reports be prepared for the agency on a monthly basis (instead of quarterly) for the first year following approval and be submitted to the agency within 30 days of the end of each month," the agency's Feb. 17 approval letter for the pneumococcal vaccine states.

After the first year, Wyeth may revert to quarterly adverse event reports, the letter adds. Wyeth plans to launch Prevnar in early March.

The agency may be concerned about quickly identifying any potential adverse events with a vaccine that is expected to receive widespread use.

Wyeth withdrew its rotavirus vaccine, RotaShield, after data reported to FDA's Vaccines Adverse Event Reporting System suggested links to intussusception, a bowel blockage disorder (¹ (Also see "Wyeth Withdraws RotaShield Ahead Of Rotavirus Season And ACIP Review" - Pink Sheet, 18 Oct, 1999.)).

The Advisory Committee on Immunization Practices has recommended full use of Prevnar in children under two years, and partial use for children from two years up to five years old (² (Also see "Healtheon Paying $5 Bil. For CareInsite, Symbolic Role As New Medco" - Pink Sheet, 21 Feb, 2000.)).

The routine schedule for Prevnar is two, four, six and 12-15 months of age. However, labeling describes dosing for children up to nine years of age.

The pneumococcal 7-valent conjugate vaccine is indicated for "active immunization of infants and toddlers against invasive disease caused by S. Pneumoniae due to capsular serotypes included in the vaccine (4, 6B, 9V, 14, 18C, 19F, and 23F)."

Prevnar is the first multivalent conjugate pneumococcal vaccine for children under the age of two. Currently marketed pneumococcal polysaccharide vaccines are approved for immunization of children at high risk for pneumococcal disease over the age of two.

There are 16,000 cases of pneumococcal disease and 1,400 cases of pneumococcal meningitis each year among children under the age of five, Wyeth reported.

Prevnar contains the seven serotypes of pneumococcus that cause approximately 80% of invasive pneumococcal disease in children under than six years of age in the U.S., the labeling states.

Prevnar was found to be 100% effective in preventing invasive pneumococcal disease caused by the seven serotypes in the vaccine and 90% effective in preventing invasive disease caused by all subtypes of pneumococcus.

The labeling warns that Prevnar "will not protect against S. Pneumoniae disease other than that caused by the seven serotypes included in the vaccine, nor will it protect against other microorganisms that cause invasive infection such as bacteremia and meningitis."

The pivotal safety and efficacy study was conducted at Northern California Kaiser Permanente in Oakland, Calif. and involved 37,816 children. Prevnar was administered to 18,906 children and the other 18,910 children received an investigational meningococcal group C conjugate vaccine. Routinely recommended vaccines were also administered.

"The primary endpoint was efficacy against invasive pneumococcal disease due to vaccine serotypes. The per protocol analysis of the primary endpoint included cases which occurred more than 14 days after the third dose," labeling notes.

An intent-to-treat analysis that included "all cases of invasive pneumococcal disease due to vaccine serotypes in children who received at least one dose of vaccine" was also conducted. The two different analyses both resulted in 100% efficacy for Prevnar.

Adverse events reported with Prevnar include injection site reactions, fever, irritability, drowsiness, restless sleep, decreased appetite, vomiting and diarrhea, labeling states.

For previously unvaccinated older infants and children, the dosing schedule will vary, Prevnar labeling explains.

Infants seven to 11 months of age would receive three doses of Prevnar. The first two doses should be at least four weeks apart and the third dose after the child's first birthday. Children from one to two years old would receive two doses, separated by at least two months. Children from two to nine years old would get one dose.

Among Wyeth's Phase IV commitments for postmarketing studies, the company will initiate a study in April in previously unvaccinated children who receive Prevnar for "catch-up" immunizations. The study "will evaluate reactogenicity of vaccination for the age groups seven months to less than two years, two years to less than five years," and over five years, FDA's approval letter states.

The company has also agreed to collect "comparative immunogenicity data for pertussis, Haemophilus influenzae type b, and poliovirus responses" for children who received DTaP (diphtheria, tetanus, acellular pertussis), Hib, IPV (inactivated polio vaccine) and Prevnar during the primary immunization series. Wyeth will provide this data to FDA in April.

Safety and immunogenicity data will also be generated by the firm on concomitantly administered vaccines with a fourth dose of Prevnar in "12 to 15 month old children who previously received three doses of DTaP, IPV, Hib with Prevnar. "This study will be initiated in January 2001 as subjects in the Phase IV safety study reach 12 to 15 months of age," the approval letter states.

Another Phase IV study will evaluate adverse effects of simultaneous use of Prevnar with DTaP, Hib, IPV, hepatitis B, measles mumps and rubella, and varicella vaccines.

Concern about concurrent administration of the vaccines was voiced during the review of Prevnar by FDA's Vaccines & Related Biological Products Advisory Committee on Nov. 5 (³ (Also see "Wyeth To Seek Prevenar Otitis Media Indication In Future Submission" - Pink Sheet, 15 Nov, 1999.)).

Wyeth will follow the children enrolled in the Kaiser Permanente study for invasive pneumococcal disease indefinitely.

Wyeth has also committed to provide safety and immunogenicity data on the administration of Prevnar "to high-risk children, e.g., HIV-infected infants, subjects with sickle cell disease and bone marrow transplant recipients."