1 Prevnar 13 for Adult Use (Age >50 Years) (Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM 197 Protein) Applicant: Wyeth Pharmaceuticals, Inc.

Slides:



Advertisements
Similar presentations
Prevnar 13™ Pneumococcal 13-valent conjugate vaccine
Advertisements

CBER Isolagen Therapy (IT) BLA FDA Clinical Review Agnes Lim, MD Yao-Yao Zhu, MD, PhD DCEPT/OCTGT/CBER, FDA October 9, 2009 Advisory Committee Meeting.
Telithromycin Integrated Summary of Safety Anti-Infective Drugs Advisory Committee January 8, 2003 Charles Cooper, M.D. Medical Officer Division of Anti-Infective.
Chapter 2: Healthy People A NNUAL D ATA R EPORT V OLUME 2: E ND -S TAGE R ENAL D ISEASE.
Pneumococcal Disease and Pneumococcal Vaccines Epidemiology and Prevention of Vaccine- Preventable Diseases National Immunization Program Centers for Disease.
Pneumococcal Disease and Pneumococcal Vaccines Epidemiology and Prevention of Vaccine- Preventable Diseases National Immunization Program Centers for Disease.
TMC125 Safety and Tolerability: 24-week Results of the Pooled DUET-1 and -2 Trials R Haubrich, M Schechter, S Walmsley, M Peeters, M Janssens, G De Smedt.
RACIAL DISPARITIES IN PRESCRIPTION DRUG UTILIZATION AN ANALYSIS OF BETA-BLOCKER AND STATIN USE FOLLOWING HOSPITALIZATION FOR ACUTE MYOCARDIAL INFARCTION.
National Vaccine Advisory Committee November 29, 2005 Update on NIH H5N1 Vaccine Trials Linda C. Lambert Chief, Respiratory Diseases Branch Division of.
Adult Immunization 2010 Influenza Segment This material is in the public domain This information is valid as of May 25, 2010.
Adult Vaccination Update Walter W. Williams, M.D., M.P.H. Medical Epidemiologist, NCIRD National Adult and Influenza Immunization Summit Provider Work.
Vaccines and Related Biological Products Advisory Committee Meeting
Treating to New Targets Study TNT Trial Presented at The American College of Cardiology Scientific Sessions 2005 Presented by Dr. John C. LaRosa.
VITAL STATISTICS ANALYSIS RESULTS FENGQING (ZOE) ZHANG COMMUNITY HEALTH INTERN 2012.
Vaccines and Related Biological Products Advisory Committee Presentation on Sanofi Pasteur’s H5N1 Vaccine Andrea N. James, M.D. Senior Medical Officer.
Greenview Hepatitis C Fund Deborah Green Home: Cell: /31/2008.
Abatacept (ORENCIA) for Rheumatoid Arthritis Biological License Application Arthritis Advisory Committee September 6, 2005.
Vascular issues associated with bevacizumab Stuart M. Lichtman, MD, FACP 65+ Clinical Geriatric Program Associate Attending Memorial Sloan-Kettering Cancer.
Clinical implications. Burden of coronary disease 56 millions deaths worldwide in millions deaths worldwide in % due to CV disease (~ 16.
Cardiovascular Disease in Women Module I: Epidemiology.
Use of 12 weekly doses of isoniazid and rifapentine for the treatment of latent tuberculosis − Connecticut , Kelley Bemis, MPH CDC/CSTE Applied.
Arthritis Advisory Committee August 16, 2001
A-50 Table 7.1: U.S. Population Trends and Projections (1) by Age, 1980 – 2050 Source: U.S. Department of Commerce, Bureau of the Census. U.S. Interim.
Chris Knefelkamp, PharmD PGY2 Internal Medicine Resident Richard L. Roudebush VA Medical Center September 17, 2015 A SHOT IN THE DARK: PNEUMOCOCCAL PNEUMONIA.
Laura Mucci, Pharm.D. Candidate Mercer University 2012 Preceptor: Dr. Rahimi February 2012.
Adult Immunization 2010 Pneumococcal Segment This material is in the public domain This information is valid as of May 25, 2010.
Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) Trial IDEAL Trial Presented at The American Heart Association Scientific.
1 Agenda  Overview –Burt Adelman MD  Efficacy and Pharmacodynamics –Akshay Vaishnaw MD, PhD  Safety –Gloria Vigliani MD  Alefacept Risk Benefit Profile.
1 ENTEREG ® (Alvimopan) Special Safety Section Marjorie Dannis, M.D. Division of Gastroenterology Products Office of Drug Evaluation III CDER, FDA The.
Meningococcal A,C,Y,W135 Conjugate Vaccine (Menactra TM ) Lucia H. Lee CBER, FDA Vaccines and Related Biological Products Advisory Committee Meeting September.
VIOXX ™ Gastrointestinal Outcome Research (VIGOR) Arthritis Advisory Committee Meeting February 8, 2001 Lourdes Villalba, M.D. DAAODP, CDER, FDA.
EAE Training EAE Reporting and Assessment Overview DAIDS Regional Training Event, Regulatory Compliance Center Kampala, Uganda, September 2009 DAIDS Regional.
1 Vaccines and Related Biological Products Advisory Committee Meeting November 18, 2009 Questions for the Committee Prevnar 13 Pneumococcal 13-valent Conjugate.
1 Vaccines and Related Biologic Products Advisory Committee (VRBPAC) May 16, 2007 FluMist ® Influenza Virus Vaccine Live, Intranasal Safety and Effectiveness.
Focus Area 17: Medical Product Safety Progress Review November 5, 2003.
Community Outreach to Reduce Disparities in Cardiovascular & Diabetes Morbidity & Mortality in the South Bronx Michael Alderman, MD Michelle Johnson, MD,
A-50 Table 7.1: U.S. Population Trends and Projections (1) by Age, 1980 – 2050 Source: U.S. Department of Commerce, Bureau of the Census. Projections.
1 FluMist® age extension Five years & younger May 16, 2007.
Risk factors for severe disease from pandemic (H1N1) 2009 virus infection reported to date are considered similar to those risk factors identified for.
Angelo L Gaffo Kenneth G Saag Core Evidence 2009:4 25–36
2015 ANNUAL DATA REPORT V OLUME 2: E ND -S TAGE R ENAL D ISEASE Chapter 2: Healthy People 2020.
Preoperative Hemoglobin A1c and the Occurrence of Atrial Fibrillation Following On-pump Coronary Artery Bypass surgery in Type-2 Diabetic Patients Akbar.
Oxypurinol for Symptomatic Gout in Allopurinol Intolerant Patients Lourdes Villalba, M.D. DAAODP, CDER, FDA Arthritis Advisory Committee Meeting June 2,
Clinical Outcomes with Newer Antihyperglycemic Agents FDA-Mandated CV Safety Trials 1.
FDA Review of Clinical Safety Data Omalizumab for treatment of Allergic Asthma Genentech, Inc. FDA/Center for Biologics Evaluation and Research.
Review Update: QT Prolongation with Citalopram and Escitalopram Pediatric Advisory Committee Meeting November 16, 2006 Prepared by M. Lisa Jones, MD Division.
C-SAF- 1 Raptiva ™ (efalizumab) Safety Richard Chin, MD Director of Clinical Research, Specialty Biotherapeutics Genentech, Inc.
RAD Immunosuppression in Heart Transplant Recipients Duke Heart Failure Research Pager:
C-1 Safety Results S. aureus Bacteremia and Endocarditis Study Gloria Vigliani, M.D. Vice President, Medical Strategy Cubist Pharmaceuticals.
A-52 Table 7.1: U.S. Population Trends and Projections by Age, 1980 – 2060 (1) Source: U.S. Department of Commerce, Bureau of the Census. Projections.
LSU Journal Club Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD WISDOM study H. Magnussen MD, et al. Nisha Loganantharaj, PGY1 April 21,
1 13-valent pneumococcal conjugate vaccine (PCV13) – new ACIP recommendations 44 th National Immunization Conference April 21, 2010 Pekka Nuorti, MD, DSc.
The JUPITER Trial Reference Ridker PM. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
Anemia in CKD The TREAT Trial Reference Pfeiffer MA. A trial of Darbepoetin alpha in type II diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–2032.
CHEST 2013; 144(3): R3 김유진 / Prof. 장나은. Introduction 2  Cardiovascular diseases  common, serious comorbid conditions in patients with COPD cardiac.
TM Influenza Vaccine Safety in Children: Data from VAERS John Iskander MD MPH Gina Mootrey DO MPH Penina Haber MPH Roseanne English-Bullard BS.
Pneumococcal Disease and Pneumococcal Vaccines Epidemiology and Prevention of Vaccine- Preventable Diseases National Center for Immunization and Respiratory.
Statins The AURORA Trial Reference Fellstrom BC. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360. A.
Guidelines for Vaccinating Dialysis Patients BY: DR. JONAIDI ASSOCIATE PROF. OF INFECTIOUS DISEASES.
Date of download: 9/17/2016 From: Advisory Committee on Immunization Practices Recommended Immunization Schedule for Adults Aged 19 Years or Older: United.
Supplementary Data Tables Community Health Indicators APPENDIX 7.
Burden of acute otitis media, recurrent otitis media and tympanostomy tube insertion in urban, minority children less than 7 years of age in Boston: Comparison.
Pneumococcal Vaccination Small group cases:Facilitator’s Guide
Pneumococcal vaccination in adults: PCV13?.. PPSV23?.. both??
Dr. Iram Shad PGT-Medicine MU-1, HFH,RWP
Table 1. Baseline Characteristics of the 36,636 Study Subjects
Vaccines and Related Biological Products Advisory Committee Meeting
Volume 2: End-Stage Renal Disease Chapter 4: Hospitalization
The following slides highlight a presentation at the Late-Breaking Clinical Trials session of the American Heart Association Scientific Sessions, November.
ARISE Trial Aggressive Reduction of Inflammation Stops Events
Presentation transcript:

1 Prevnar 13 for Adult Use (Age >50 Years) (Pneumococcal 13-valent Conjugate Vaccine (Diphtheria CRM 197 Protein) Applicant: Wyeth Pharmaceuticals, Inc. Rosemary Tiernan, MD, MPH Division of Vaccines and Related Products Applications CBER/FDA Vaccines and Related Biological Products Advisory Committee Meeting November 16, 2011

2 Overview of Safety Presentation Studies Supporting Safety in Adults Age > 50 yrs Safety Population Safety Monitoring and Data Collection Adverse Reactions Summary/Conclusions

3 Six Phase 3 Studies Supported Safety of PCV13 in Adults StudySite Age (Yrs ) Schedule and ( # Vaccinated) 004 Naive USA Initial Study: Extension (3-4.5yrs): Cohort 1 PCV13 (417) PCV13/PCV13 (108) PCV13/23vPS (108) Cohort 1 23vPS (414) 23vPS/23vPS (189) Cohort 2 PCV13 (404) PCV13/PCV13 (214) 3000 >1 dose 23vPS > 3 yrs prior USA, GER Sweden > 68 1 dose of PCV13 (1049) 3001 Naive USA50-59 Group 1 PCV13 + TIV / Placebo ( ) Group 2 Placebo + TIV / PCV13 ( ) dose 23vPS > 5 yrs prior USA, Sweden > 70 Group 1 PCV13 (463) Year 0 Group 2 23vPS (473) Group 1.1 PCV13 / PCV13 (391) Year 1 Group vPS / PCV13 (404) 3008 Naive GER, NETH BELG, HUNG > 65 Group 1 PCV13 + TIV / Placebo ( ) Group 2 Placebo + TIV / PCV13 ( ) 3010 Naive USA60-64 Group 1 PCV13 (478 ) Year 0 Group 2 23vPS (237) Group 1.1 PCV 13 / PCV 13 (161) Year 1 Group 1.2 PCV13 / 23vPS (266) Group vPS/ PCV13 (223)

4 Six Phase 3 Studies Supported Safety of PCV13 in Adults Description of the Six Phase 3 Studies that Supported the Safety of Prevnar13 in Adults: –History of Prior PNEUMOVAX23 Vaccination –Study Site –Subject Age –Vaccine Schedule and –Number Vaccinated

5 Safety Population

6 Demographics Demographic Factors (N = 6198)PCV13 (N = 5667) Age (Years) (46.2) (11.4) (20.1) (13.4) > (8.9) Gender Female %* Race/Ethnicity White> 91% Black or African American % Hispanic or Latino % Asian % Native Hawaiian or other Pacific Islander <1% American Indian<1% Alaskan Native<1% Other<1.4% *Study 3005 Males ( %)

7 Demographics Demographics of Subjects (Across 6 Studies) and Specific Age Strata for Prevnar13 Recipients

8 Study Populations Pre-existing underlying diseases included if condition was “stable”: Disease not requiring significant change in therapy or hospitalization for worsening disease for 12 weeks before receipt of study vaccine Change to new therapy allowed if not caused by worsening disease Change in dose or therapy within category allowed Key Exclusion Criteria included: Receipt of diphtheria-tetanus toxoid containing vaccines within 6 months of study vaccine Streptococcus pneumoniae infection documented w/in past 5 years Impairment of immunological function: –Immunoglobulin deficiencies, hematological malignancies, known HIV infection, collagen vascular disorders and subjects receiving immunosuppressive therapy –If systemic corticosteroids administered short term for treatment of acute illness, subjects excluded from vaccination until corticosteroid therapy had been discontinued for at least 30 days. Serious chronic disorders: –Metastatic malignancy, severe chronic obstructive pulmonary disease, end-stage renal disease, clinically unstable cardiac disease, or any other disorder that in investigator’s opinion precluded subject from participating in study.

9 Underlying Medical Conditions in PCV13 Recipients (at 1 st Dose) Medical Conditions Vaccine NaïvePre-immunized Study Age (Yrs) > 65> 68>70 N=1094 % N=403 % N=417 % N=478 % N=1134 % N=1049 % N=463 % Cardiac Pulmonary Diabetes Renal Liver Asthma

10 Underlying Medical Conditions in PCV13 Recipients (at 1 st Dose) Underlying Medical Conditions in Prevnar13 Recipients at Initial Dose Evaluated by –Pneumococcal Vaccine Naïve and –Pre-immunized Status and by –Study

11 Safety Data Collection and Monitoring

12 Solicited Adverse Events Local and systemic reactions monitored daily for 14 days: –Electronic diary cards used to record information –Local events included Redness, swelling, pain, limitation of motion (LOM) –Systemic events included: Fever measured using oral digital thermometer daily (at bedtime and whenever fever suspected) Fatigue, headache, chills, rash, vomiting, decreased appetite, new generalized muscle pain, aggravated generalized muscle pain, new generalized joint pain and aggravated generalized joint pain –Data regarding medications to treat pain and fever collected in all studies, except study 004.

13 Analysis of Adverse Events (AEs) Solicited Local and Systemic AEs –Vaccine Naïve –Pre-immunized Unsolicited Adverse Events Deaths Discontinuations due to Adverse Event Serious Adverse Events (SAES)

14 Vaccine Naïve Subjects Studies 004 and 3010 Solicited Local Adverse Reactions Solicited Systemic Adverse Reactions

15 Local Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Local Reactions STUDY 004STUDY 3010 PCV13 23vPSPCV1323vPS yrs60-64 yrs N= % N= % N= % N= % N= % Redness Any Severe Swelling Any Severe Pain Any Severe Limitation of Motion Any Severe

16 Local Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Local Reactogenicity within 14 days of Vaccination in a Pneumococcal Vaccine Naïve Population (Study 004 and Study 3010) with –Prevnar13 or –PNEUMOVAX23

17 Systemic Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Systemic Reactions STUDY 004STUDY 3010 PCV13 23vPSPCV1323vPS yrs60-64 yrs N= % N= % N= % N= % N= % Any Fever (>38C) Fatigue Headache Chills Rash Vomiting Decreased Appetite New Myalgia Aggravated Myalgia New Joint Pain Aggravated Joint Pain Pain Meds N/A Fever Meds N/A

18 Systemic Reactogenicity Within 14 Days of PCV13 or 23vPS (Naïve) Systemic Reactogenicity within 14 days of Vaccination in a Pneumococcal Vaccine Naïve Population (Study 004 and Study 3010) with –Prevnar13 or –PNEUMOVAX23

19 Summary on Reactogenicity in Naïve Subjects Local Reactogenicity –Study 004 PCV 13 >23vPS for “any” redness/swelling/pain 23vPS >PCV13 for “severe” pain (8.6% > %) –Study 3010 PCV13 >23vPS for “any” pain (69.2 % vs 58.3%) Systemic Reactogenicity –Study 004 PCV13 vs 23vPS similar incidences of systemic reactions –Study vPS>PCV13 for decreased appetite, aggravated muscle pain, new joint pain, use of medication to treat fever

20 Pre-Immunized Subjects Studies 3000 and 3005 Solicited Local Reactions Solicited Systemic Reactions

21 Local Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Local Reactions Study 3000 ( > 68 yrs. )Study 3005 ( > 70 yrs) > 1 dose 23vPS > 3 yrs prior1 dose 23vPS > 5 yrs prior PCV13 23vPS N= % N= % N= % Redness Any Severe Swelling Any Severe Pain Any Severe Limitation of Motion Any Severe

22 Local Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Local Reactogenicity within 14 days of Vaccination in a Pre-Immunized Population (Prior receipt of PNEUMOVAX23) with –Prevnar13 or –PNEUMOVAX23

23 Systemic Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Systemic Reactions Study 3000 ( > 68 yrs. ) > 1 dose 23vPS > 3 yrs prior Study 3005 ( > 70 yrs) 1 dose of 23vPS > 5 yrs prior PCV13 23vPS N= % N= % N= % Any Fever(>38C) >40C Fatigue Headache Chills Rash Vomiting Appetite Decreased New Myalgia Aggravated Myalgia New Joint Pain Aggravated Joint Pain Pain Meds Fever Meds

24 Systemic Reactogenicity Within 14 days of PCV13 or 23vPS (Pre-Immunized) Systemic Reactogenicity within 14 days of Vaccination in a Pre-Immunized Population (Prior receipt of PNEUMOVAX23) with Prevnar13 or PNEUMOVAX23

25 Summary of Reactogenicity: Pre-Immunized Subjects Local Reactogenicity –Study vPS > PCV13 for all local reactions Systemic Reactogenicity –Study vPS >PCV13 for fatigue, rash, new muscle pain (myalgia), aggravated muscle pain

26 Reactogenicity of Sequential Vaccine Administration (Studies 004 and 3010) Single dose 23vPS (naïve) compared to: –PCV13 /23vPS 1 year interval (study 3010) 3-4 year interval (extension study 004) –23vPS / 23vPS administered at 3-4 year interval (extension study 004)

27 Local Reactogenicity within 14 days Post Dose Local Reactions Yrs STUDY 004STUDY 3010 Year 0Year Year lYear 0 23vPS*PCV13 / 23vPS23vPS/ 23vPSPCV13 / 23vPS23vPS* N= % N=41-87 % N= % N= % N= % Redness Any Severe Swelling Any Severe Pain Any Severe Limitation of Motion Any Severe vPS* administered at Year 0 was years prior in Study 004 and was 1 year prior in Study 3010.

28 Local Reactogenicity within 14 days Post Dose Local Reactogenicity within 14 days of a Single Dose of PNEUMOVAX23 at Year 0 compared to a Subsequent Dose of PNEUMOVAX23 using a Dosing Interval of 1 Year and Years

29 Systemic Reactogenicity within 14 days Post Dose Systemic Reactions Age Yrs STUDY 004STUDY 3010 Year 0Year 3.5-4Year 1Year 0 23vPS*PCV13 / 23vPS23vPS/ 23vPSPCV13 / 23vPS23vPS* N= (%) N=43-68 (%) N= (%) N= (%) N= (%) Any Fever(>38C) Fatigue Headache Chills Rash Vomiting Decreased Appetite New Myalgia Aggravated Myalgia New Joint Pain Aggravated Joint Pain Pain MedsN/A Fever MedsN/A vPS* administered at Year 0 was years prior for Study 004 and was 1 year prior for Study 3010.

30 Systemic Reactogenicity within 14 days Post Dose Systemic Reactogenicity within 14 days of a Single Dose of PNEUMOVAX23 at Year 0 compared to a Subsequent Dose of PNEUMOVAX23 using a Dosing Interval of 1 Year and Years

31 Summary on Reactogenicity: Sequential Doses Solicited Local –Using a dosing interval of 3-4 yrs (extension study 004): 23vPS/23vPS is more reactogenic than PCV13/23vPS for redness, swelling and limitation of motion –Using a dosing interval of 1 year (study 3010): PCV13/23vPS is more reactogenic than 23vPS alone Solicited Systemic –Using a dosing interval of 3-4 yrs, 23vPS/23vPS is more reactogenic for rash when compared to 23vPS alone –Using a dosing interval of 1 yr, PCV13/23vPS is more reactogenic for rash and use of pain medications when compared to 23vPS alone

32 Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) Studies 3001 and 3008 Solicited Adverse Reactions for PCV13 + TIV compared to PCV13: –Local –Systemic Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population: Design for Studies 3001 and 3008 Study ArmsConcomitant Dose 1Dose 2 (1 month later) Group 1PCV13 + TIVPlacebo Group 2Placebo + TIVPCV13

33 Local Reactogenicity (PCV13+TIV vs PCV13) within 14 Days (Naïve) Study 3001 (age yrs)Study 3008 ( age > 65 yrs) Local Reactions PCV13 +TIV / Placebo Concomitant Dose 1 Placebo +TIV / PCV13 Dose 2 PCV13 +TIV/ Placebo Concomitant Dose 1 Placebo +TIV/ PCV13 Dose 2 N= % N= % N= % N= % Redness Any Severe Swelling Any Severe Pain Any Severe Limitation of Motion Any Severe

34 Local Reactogenicity (PCV13+TIV vs PCV13) within 14 Days (Naïve) Local Reactogenicity within 14 days of PCV13 Administered Concomitantly with TIV compared to PCV13 alone in a Pneumococcal Vaccine Naïve Population

35 Systemic Reactogenicity (PCV13 + TIV vs PCV13) within 14 Days (Naive) Systemic Reactions Study 3001 (Age yrs) Study 3008 (Age > 65 yrs) PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Dose 2 PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Dose 2 N = % N= % N= % N= % Any Fever(>38C) Fatigue Headache Chills Rash Vomiting Appetite Decreased New Myalgia Aggravated Myalgia New Joint Pain Aggravated Joint Pain Pain Meds N/A Fever Meds N/A

36 Systemic Reactogenicity (PCV13 + TIV vs PCV13) within 14 Days (Naive) Systemic Reactogenicity within 14 days of PCV13 Administered Concomitantly with TIV compared to PCV13 alone in a Pneumococcal Vaccine Naïve Population

37 Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) Studies 3001 and 3008 (Naïve) Solicited Adverse Reactions for PCV13 + TIV compared to Placebo +TIV: –Local –Systemic Reactogenicity of Concomitant Administration of PCV13 with Trivalent Influenza Vaccine (TIV) in a Pneumococcal Vaccine Naïve Population: Design for Studies 3001 and 3008 Study ArmsConcomitant Dose 1Dose 2 (1 month later) Group 1PCV13 + TIVPlacebo Group 2Placebo + TIVPCV13

38 Local Reactogenicity (PCV13+TIV vs TIV+ Placebo) within 14 Days (Naïve) Local Reactions Study 3001 (Age yrs) Study 3008 (Age > 65 yrs) PCV13 +TIV / Placebo Concomitant Dose 1 Placebo +TIV / PCV13 Concomitant Dose 1 PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV / PCV13 Concomitant Dose 1 N= % N= % N= % N= % Redness Any Severe Swelling Any Severe Pain Any Severe Limitation of Motion Any Severe

39 Local Reactogenicity (PCV13+TIV vs TIV+ Placebo) within 14 Days (Naïve) Local Reactogenicity within 14 days of PCV13 Administered Concomitantly with TIV compared to PCV13 alone in a Pneumococcal Vaccine Naïve Population

40 Systemic Reactogenicity (PCV13 + TIV vs TIV+ Placebo) within 14 Days (Naive) Systemic Reactions Study 3001 (Age yrs) Study 3008 (Age > 65 yrs) PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Concomitant Dose 1 PCV13 +TIV /Placebo Concomitant Dose 1 Placebo +TIV /PCV13 Concomitant Dose 1 N = % N= % N= % N= % Any Fever(>38C) Fatigue Headache Chills Rash Vomiting Appetite Decreased New Myalgia Aggravated Myalgia New Joint Pain Aggravated Joint Pain Pain Meds Fever Meds

41 Systemic Reactogenicity (PCV13 + TIV vs TIV+ Placebo) within 14 Days (Naive) Systemic Reatogenicity within 14 days of PCV13 administered concomitantly with TIV compared to TIV given with Placebo in a Pneumococcal Vaccine Naïve Population

42 Summary of Reactogenicity for Concomitant Administration of PCV13 +TIV compared to PCV13 and TIV+ Placebo: Studies 3001 and 3008 (Naïve) Solicited Local Reactogenicity –Study 3001 (age yrs) PCV13 (42%) > PCV13+TIV (35.6%) for “any” limitation of motion PCV13 +TIV > TIV for all local reactions Solicited Systemic Reactogenicity –Incidence of “any” fever (>38C) not increased with concomitant administration of PCV13+TIV compared to PCV13 or TIV + placebo in studies 3001 and –In study 3001 and 3008, when compared to PCV 13 or TIV+ placebo, PCV13+ TIV study arm had a higher incidence of these AEs: Fatigue Headache Chills Rash Decreased appetite New and aggravated muscle pain New joint pain Aggravated joint pain

43 Unsolicited Adverse Events within 1 Month Incidence across 6 studies for PCV13 was % Similar incidence in naïve and pre-immunized subjects Similar incidence for initial dose of PCV13 when compared to 23vPS in naïve and pre-immunized subjects: –Naïve subjects Study 004 (60-64 yrs) –PCV 13 (17.0%) vs 23vPS (16.7 %) Study 3010 (60-64 yrs) –PCV 13 (19.2%) vs 23vPS (20.7 %) –Pre-immunized subjects Study 3005 –PCV13 (14.9 % ) vs 23vPS (18.6%) Most frequent AEs reported for PCV13: –Infections and Infestations ( %) –Musculoskeletal ( %) –Gastrointestinal ( %) –General disorders and administration site conditions ( %)

44 Summary of 16 Deaths Across 6 Studies StudyVaccine AdministeredLast Dose Days Post-Dose Age at Death (Yrs) MedDRA Term 3008PCV13 +TIV / Placebo2372Cardiac Failure 3008Placebo +TIV / PCV Peritonitis 3001PCV13 +TIV / Placebo27155Hemoptysis vPS17285 Post-Procedure Pulmonary Embolus 3005PCV13 / PCV Atherosclerotic coronary artery disease 3005PCV Myocardial Infarction 3005PCV Cardiac Arrest vPS114175Cardiac Failure Congestive 3000PCV Metastatic Neoplasm 3000PCV Septic Shock 3000PCV Lung Neoplasm Malignant 3005PCV Colon Cancer 004PCV Hepatic neoplasm Malignant, Pancreatic carcinoma, Thrombosis vPS125677Acute Myocardial Infarction VPS126286Cardiac Arrest 3005PCV Atherosclerotic coronary artery disease

45 Summary of 16 Deaths Across 6 Studies Summay of 16 Deaths (Across 6 Studies) by: –Study –Vaccine Administered –Dose Number –Days Post-Dose –Age at Death –Cause of Death (MedDRA)

46 Deaths (Across 6 Studies) 16 subjects died: 2/16 deaths occurred within 30 days of vaccination –Cardiac Failure at 3 days after PCV13+TIV / Placebo –Peritonitis at 20 days after Placebo+TIV / PCV13 9/16 in study 3005 –Subjects ≥70 years of age 12/5667 (0.21%) received PCV13 or PCV13+TIV 4/1391 (0.29%) subjects received 23vPS

47 Summary of 16 Adverse Events leading to Discontinuation (6 Studies) StudyVaccine Administered Last Dose Days Post-Dose SeverityMedDRA Term 3001Placebo +TIV11ModerateFatigue and Headache 3005PCV13 / PCV1329SevereWorsening of COPD 3008PCC13 +TIV/ Placebo 210Life-threateningAngina pectoris, ECG ST segment elevation vPS123SevereProstate cancer vPS128SevereUnstable Angina vPS139Life-threateningMalignant Melanoma vPS1135ModerateHyperthyroidism, Mental Status Changes vPS1154SevereProstate cancer 3005PCV131174SevereMetastatic prostate cancer/bone vPS1235ModeratePolymyalgia 3005PCV131274Life-threateningCerebral Infarction vPS1284/297Severe / Moderate Atrial Flutter, Congestive Heart Failure / Pneumonia and Pericardial/pleural effusion status post drainage 00423vPS1290SevereLung cancer metastatic 3005PCV131323ModerateAbdominal Pain Upper 3005PCV131329ModerateBladder Neoplasm vPS1365SevereAdenocarcinoma

48 Summary of 16 Adverse Events leading to Discontinuation (6 Studies) Summary of 16 Adverse Events Leading to Discontinuation (Across 6 Studies) by: –Study –Vaccine Administered –Dose Number –Days Post-Dose –Severity and Cause (MedDRA)

49 Adverse Events leading to Discontinuation (Across 6 Studies) 16 subjects discontinued due to adverse events –7 of 16 subjects discontinued due to cancer 6 of 16 subjects received PCV13 9 of 16 subjects received 23vPS 1 of 16 subjects received TIV +placebo

50 Incidence of Serious Adverse Events after Initial Dose (6 Studies) Subjects with SAEsWithin 1 month n (%)Within 6 months n (%) Naïve Subjects: Study 004 Initial Dose PCV13 ( N= 417) (60-64 yrs)1 (0.2)12 (2.9) 23vPS (N= 414) 2 (0.5)10 (2.4) PCV13 (N= 403) (50-59yrs)2 (0.5)5 (1.2) Study 3010 (60-64 yrs) Initial Dose PCV13 (N= 478)2 (0.4)15 (3.1) 23vPS (N= 237)1 (0.4)6 (2.5) Study 3001 (50-59 yrs) PCV13+TIV / Placebo (N=551 / 538)4 (0.7) / 3 (0.6)18 (3.3) Placebo+TIV / PCV13 (N= 560 / 543)5 (0.9) / 6 (1.1)10 (1.8) Study 3008 (>65 yrs) PCV13+TIV / Placebo (N= 576) 4 (0.7) / 5 (0.9)No 6 month follow-up Placebo+TIV / PCV13 (N=575)0 (0) / 8 (1.4)No 6 month follow-up Pre-Immunized Subjects: Study 3000 ( > 68 yrs) PCV13 (N = 1049)10 (1.0)41 (3.9) Study 3005 ( >70 yrs) (Initial Dose) PCV13 (N= 463)3 (0.6)27 (5.8) 23vPS (N= 473)8 (1.7)26 (5.5)

51 Incidence of Serious Adverse Events after Initial Dose (6 Studies) Incidence of Serious Adverse Events after Initial Dose (Across 6 Studies) Within 1 Month and Within 6 Months by –Pneumococcal vaccine naïve status –Pre-immunized status –Study –Treatment arm

52 Serious Adverse Events (Initial Dose, 6 Studies) SAE range within 1 month of vaccination: –0.2% to 1.4% of PCV13 recipients –0.4% to 1.7% of 23vPS recipients. SAE range within 6 months of vaccination: –1.2% to 5.8% of PCV13 recipients –2.4% to 5.5% of 23vPS recipients Categories of SAE: –Age > 65 years Cardiac disorders, cerebrovascular events, neoplasms, respiratory disorders and injuries occurred more frequently than in younger subjects

53 Incidence of Serious Adverse Events after Subsequent Dose (3 Studies) Subjects with SAEsWithin 1 month n (%)Within 6 months n (%) Naïve Subjects: Study 004 Extension Study (Year 3-4) PCV13/ PCV13 (N =108) (60-64 yrs) 1(.01)*N/A PCV13/ 23vPS (N=108)1(.01)N/A 23vPS/ 23vPS (N=189) 0 (0)N/A PCV13 / PCV13 (N=214 ) (50-59yrs) 0 (0)N/A Study 3010 (Year 1) PCV13/ PCV13 (161) (60-64 yrs)0 (0)5 (3.1) PCV13/ 23vPS (266)2 (0.7)6 (2.2) 23vPS / PCV13 (223)1 (0.4)3 (1.3) Pre-Immunized Subjects: Study 3005 (Year 1) PCV13/ PCV13 (N= 391) (>70 yrs)4 (1.0)17 (4.3) 23vPS/ PCV13 (N= 404)7(1.7)21 (5.2) *Erythema multiforme at day 34.

54 Incidence of Serious Adverse Events after Subsequent Dose (3 Studies) Incidence of Serious Adverse Events after Subsequent Dose (Across 3 Studies: 004, 3010 and 3005) Within 1 Month and Within 6 Months by: Pneumococcal vaccine naïve status Pre-immunized status Study Vaccine schedule

55 Conclusions Regarding Safety In 6 clinical studies, which included vaccine naïve and adult subjects with prior receipt of PNEUMOVAX23, no imbalances in deaths or serious adverse events were detected in subjects who received Prevnar13 when compared to PNEUMOVAX23. No safety issues were identified for administration of Prevnar13, as a single dose, to vaccine naïve or pre-immunized adults aged > 50 years –the safety database is not large enough to detect rare events that could occur at a frequency lower than 0.1%. When Prevnar13 was concomitantly administered with TIV, systemic reactogenicity was increased in subjects aged yrs and subjects > 65 yrs when compared to administration of TIV or Prevnar13 alone. No data available for concomitant administration of Prevnar13 with adult vaccines other than TIV. No data available for use of Prevnar13 in immunocompromised adults. Safety data will be submitted from the randomized, placebo-controlled CAPITA trial of PCV13 for the prevention of vaccine type pneumococcal pneumonia conducted in 85,000 subjects aged > 65 years in the Netherlands. Safety data will include: –SAEs in the 28 days post-vaccination for subjects not in the immunogenicity cohort –SAEs for 6 months post-vaccination for the 2000 subjects in the immunogenicity cohort –Incidence rates of local, systemic and adverse events for all subjects in the immunogenicity cohort.