1. Vaccines and Related Biological Products Advisory Committee Meeting
November 16, 2011
Prevnar 13 for Adult Use Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM197 Protein)
Applicant: Wyeth Pharmaceuticals, Inc
Nicolette deVore, Ph.D.
Regulatory Reviewer
FDA / CBER / OVRR / DVRPA

2. Outline Approved Pneumococcal Vaccines and Indications
Accelerated Approval Regulations
Prevnar 13 Regulatory History and use of Accelerated Approval Pathway

3. Currently Licensed Pneumococcal Vaccines
Prevnar 13 (PCV13)
Manufactured by Wyeth
Licensed in 2010
13-valent conjugate vaccine
Prevnar (PCV7)
Licensed in 2000
7-valent conjugate vaccine
PNEUMOVAX 23 (23vPS)
Manufactured by Merck
Licensed in 1983
23-valent polysaccharide vaccine

4. Prevnar 13 (PCV 13) PNEUMOVAX 23 (23vPS) Current Indications
Approved for use in children 6 weeks through 5 years of age
for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes
1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F 23F and 6A.
for the prevention of otitis media caused by S.pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F.
PNEUMOVAX 23 (23vPS)
Approved for use in persons 50 years of age or older and persons aged ≥ 2 years who are at increased risk for pneumococcal disease.
for active immunization for the prevention of pneumococcal disease caused by S. pneumoniae serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F, and 2, 8, 9N,10A, 11A, 12F, 15B, 17F, 20, 22F, 33F.

5. Prevnar 13: Proposed Indication and Usage
Active immunization for prevention of pneumococcal disease (including pneumonia and invasive disease) caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F.
Administered as a single intramuscular injection to adults aged ≥ 50 years.
Includes those previously vaccinated with pneumococcal polysaccharide vaccine, Pneumovax 23 (23vPS).
Note: The adult formulation of PCV13 is identical to the formulation currently licensed for use in children 6 weeks through 5 years of age.

6. Accelerated Approval 21 CFR 601 Subpart E
Applies to biological products that have been studied for safety & effectiveness in treating serious or life-threatening illnesses
Provides meaningful therapeutic benefit over existing treatments
Approval based on a surrogate endpoint
Reasonably likely to predict clinical benefit
Effect is established via adequate & well-controlled trials
Approval is subject to required confirmatory study, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit
Confirmatory study:
Verifies & describes clinical benefit
Is adequate & well-controlled
Usually underway at approval

7. Surrogate Endpoint
Surrogate endpoints are generally defined as endpoints that predict clinical outcome.
In the case of accelerated approval pathway the surrogate should be “reasonably likely to predict” clinical benefit.

8. Vaccines Approved using the Accelerated Approval Pathway
Surrogate
Confirmatory trial
AFLURIA®
(inactivated influenza vaccine)
HAI
Pending
Agriflu®
Complete
FluLaval®
Fluarix®
Hiberix® (Haemophilus b conjugate vaccine)
ELISA and RABA

9. Status of Pneumococcal Disease in Adults
Invasive Pneumococcal Disease (IPD)
Defined by isolation of S. pneumoniae from a normally sterile site (i.e. blood, cerebrospinal, pleural or peritoneal fluid).
Rates in 2002 – 2003 were / 100,000 for those 50 to 64 and 41.7 / 100,000 for those 65 years and older.2
Pneumococcal Pneumonia
Community acquired pneumonia is the most common infectious cause of death in the US.5 Streptococcus pneumoniae is the leading cause of community acquired pneumonia in adults.
Rates of pneumococcal pneumonia (including invasive) during were estimated to be 14.8/ 100,000 for years of age and 59.3/ 100,000 for those 65 years and older.3
Effectiveness of Pneumovax (23vPS)
Protects against invasive disease.1
Effect on pneumococcal pneumonia is not clear.1,4
1. Int J of Antimicrob Agents, 2002; 19(2) 85– JAMA. 2005; 284 (16)
3. Lancet. 2007;369: Eur J Epidemiol. 2004;19(4)
5. Am J Med Feb;124(2):

10. Basis for Use of Accelerated Approval Pathway
A comparative clinical endpoint study with Pneumovax 23 would be impractical.
There is a significant burden of pneumococcal disease in adults ≥50.
Protection of adults against pneumococcal pneumonia or pneumococcal pneumonia combined with IPD is the “meaningful therapeutic benefit over existing treatment” required by the accelerated approval pathway regulations.

11. November 17, 2005 VRBPAC - Licensure Pathways for New Pneumococcal Vaccines in Adults
Presentations
Changing epidemiology since PCV7
Use of opsonophagocytic assay (OPA)
Proposed development plans from manufacturers
Committee discussion on licensure pathways
Immunogenicity vs clinical endpoint studies
VRBPAC considerations
Emphasized the need for clinical endpoint studies while acknowledging the challenges
Accelerated Approval is a reasonable path to follow

12. Regulatory History of Prevnar 13 for Adults
June & November 2006; November meetings held with sponsor on adult program
Phase 3 clinical development program
Use of Accelerated Approval for licensure
Design of Phase 4 Confirmatory Trial
September Recruitment for phase 4 confirmatory study (CAPITA) began
February U.S. licensure of Prevnar 13 for infants and children
(6 weeks - 5 years of age)
December 2010 – submission of efficacy supplement for use of Prevnar 13 in adults ≥50 of age under accelerated approval

13. Prevnar 13 Phase 3 Studies Study N Age Range Immunization history
Primary endpoints
-004
1235
50-64 yrs
23vPS-naïve
Compare PCV13 and 23vPS immunogenicity by OPA titers
-3005
936
≥ 70 yrs,
23vPS-
preimmunized
-3010
650
60-64 yrs
Compare sequential use of PCV13 and 23vPS immunogenicity by OPA titers
-3001
1081
50-59 yrs
Compare immunogenicity of PCV13 administered alone or with TIV using IgG ELISA
-3008
1152
≥ 65 yrs
-3000
1049
≥ 68 yrs
Safety study

14. Opsonophagocytic Assay (OPA)
Opsonophagocytosis is an important mechanism of protection against pneumococcal disease.
Opsonophagocytosis can be measured using the functional antibody assay (OPA) which is reasonably likely to predict clinical benefit.
During Prevnar 13 studies in children OPA titers were used as exploratory endpoints.
For Prevnar 13 studies in adults:
a high through-put version of the assay was validated – microcolony OPA.
comparison of OPA titers between the approved Pneumovax 23 vaccine and Prevnar 13 is a primary endpoint for phase 3 studies.

15. Prevnar 13 Confirmatory Study
Community Acquired Pneumonia Immunization Trial in Adults (CAPITA)
Conducted in the Netherlands
Fully enrolled 84,503 subjects ≥65 years old
Randomized 1:1 Prevnar 13 or placebo
Many vaccinated on a background of a Trivalent Influenza Vaccine

16. Prevnar 13 Confirmatory (CAPITA) Study
Primary Efficacy Objective
Demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed vaccine-type (VT) pneumococcal pneumonia (including bacteremic and non-bacteremic pneumonia)
Secondary Efficacy Objectives
Demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of confirmed non-bacteremic VT pneumococcal pneumonia
Demonstrate the efficacy of Prevnar 13 in the prevention of a first episode of VT-IPD
Expect results to be submitted in 2013

17. Summary
Prevnar 13 is currently approved for use in infants and toddlers for prevention of otitis media and invasive disease.
Proposed Prevnar 13 indication is active immunization for prevention of pneumococcal disease (including pneumonia and invasive disease) in adults ≥ 50 years of age.
Wyeth is seeking accelerated approval of adult indication for Prevnar 13.
Protection of adults against pneumococcal pneumonia or pneumococcal pneumonia combined with IPD is the “meaningful therapeutic benefit over existing treatment” required by the accelerated approval pathway regulations.
OPA is surrogate endpoint “reasonably likely to predict clinical benefit” and is used in all Phase 3 trials in which immunogenicity of Prevnar 13 is compared to Pneumovax 23.
CAPITA trial is the ongoing Phase 4 trial to verify clinical benefit.

18. Today’s Presentations
Epidemiology Matthew Moore, M.D., M.P.H (CDC)
Wyeth William C. Gruber, M.D.
Daniel A. Scott, M.D.
OPA Mustafa Akkoyunlu, M.D., Ph.D. (FDA)
Immunogenicity Tina Khoie, M.D., M.P.H. (FDA)
Safety Rosemary Tiernan, M.D., M.P.H (FDA)

19. Questions for the Committee
1. Are the immunogenicity data adequate to support the effectiveness of Prevnar 13 under the accelerated approval regulations for the prevention of pneumococcal disease caused by serotypes in the vaccine in adults ≥50 years of age?
Please vote yes or no.

20. Questions for the Committee
2. Are the available data adequate to support the safety of Prevnar 13 when administered to adults ≥ 50 years of age?
Please vote yes or no.

21. Questions for the Committee
Given that a confirmatory clinical endpoint study is ongoing, are there any additional studies needed to further evaluate the safety or effectiveness of PCV13?
Please discuss.

22. Thank you