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FDA CBER:
Safety Assessment of 20- valent Pneumococcal Conjugate
Vaccine (PCV20)
ACIP February 2024
Richard Forshee, PhD
Office of Biostatistics and Pharmacovigilance
Center for Biologics Evaluation and Research
US Food and Drug Administration
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Disclaimer
•The BEST Initiative and its studies are funded by the U.S.
Food and Drug Administration (FDA)
•There are no potentially conflicting relationships to disclose
•The findings and conclusions in this presentation are those of the authors and do not necessarily represent the official position of FDA, the Centers for Medicare & Medicaid Services, or Acumen, LLC
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•Acute Myocardial Infarction
•Myocarditis/Pericarditis
•Anaphylaxis
•Atrial Fibrillation
•Bell’s Palsy
•Cardiomyopathy; Heart Failure
•Cellulitis and Infection
•Cholecystitis or Cholelithiasis
•Guillain -Barré syndrome
•Immune Thrombocytopenia
•Thrombocytopenia
•Transient Ischemic AttackIs there an elevated risk for the listed health outcomes*
following PCV20 vaccination?
* The list of health outcomes were identified via literature review
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Near Real -Time Monitoring: Medicare Fee -for-Service (FFS)
Population (Age ≥ 65 years)
DesignConcurrent Comparator Cohort Design1 for Near Real -Time Sequential Analysis
Self-controlled case series planned to verify detected signals
Data Sources Centers for Medicare & Medicaid Services (CMS) – Shared Systems Data (SSD)
Study PopulationMedicare FFS beneficiaries (age ≥ 65 years) receiving one dose of PCV 15 or PCV 20
on or after the licensing date for the product-Two product populations analyzed separately
Study PeriodLicensing date (PCV 15 = July 16, 2021 and PCV 20 = July 1, 2021) through the end of
each calendar month (most recent update through November 30, 2023)
Health OutcomesThe 12 pre-specified health outcomes identified by claims algorithms and monitored
within the follow -up window for each vaccinated beneficiary
1. Klein, N.P ., et al., Surveillance for Adverse Events After COVID -19 mRNA Vaccination. JAMA, 2021. 326(14): p. 1390- 1399.
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Near Real -Time Monitoring: Medicare Fee -for-Service (FFS)
Population (Age ≥ 65 years)
Statistical
Analyses•Descriptive and Sequential analyses were performed monthly
•Bayesian Poisson Regression was used to estimate the posterior distribution of incidence rate ratio (IRR) between pre-specified post -vaccination risk and comparison
windows for each outcome
•Age, Sex, Immunocompromised Conditions*, Concomitant Influenza Vaccination**, and Months Post -Surveillance Start Date were included as
adjustment covariates
•Adjustment for claims delay was made
•Safety signal was assessed by evaluating if:
•The 95% Credible Interval (CI) exceeds 1 –Weak Signal
•The 98% Credible Interval (CI) exceeds 1 – Strong Signal
* Immunocompromised conditions was identified using administrative codes indicating presence of immunocompromising conditions or use of immunosuppressive therapies2
** Concomitant influenza vaccination is defined as seasonal influenza vaccination events that happened on or within 42 days prio r to PCV 20 vaccination date
2. Greenberg JA, et al., Validation of a Method to Identify Immunocompromised Patients with Severe Sepsis in Administrative Data bases. Ann Am Thorac Soc. 2016;13(2):253- 258.
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Uptake of PCV15 or PCV20 Vaccines in the Medicare FFS 65+
years Population; Monthly (top) and Cumulative (bottom) Counts*
* Data cut: 11/30/2023Total PCV 15 uptake: 53,018
Total PCV 20 Uptake: 2,832,555
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Descriptive Characteristics of PCV 20 Vaccinees (N = 2,832,555)
Beneficiary Characteristics Number of
Vaccinees% of
Vaccinees
Race/Ethnicity
Asian 70,416 2.49%
Black 155,878 5.50%
Hispanic 41,611 1.47%
Alaska Native/American Indian 6,964 0.25%
White 2,410,290 85.09%
Other 57,163 2.02%
Missing/Unknown 90,233 3.19%
Age (years)
65-69 1,242,140 43.85%
70-74 599,077 21.15%
75-79 461,978 16.31%
80-84 291,753 10.30%
85-89 154,499 5.45%
90-94 64,176 2.27%
95+ 18,932 0.67%Beneficiary Characteristics Number of
Vaccinees% of
Vaccinees
Sex
Female 1,614,235 56.99%
Male 1,218,320 43.01%
Urban/Rural
Urban 2,375,807 83.88%
Rural 455,787 16.09%
Missing/Unknown 961 0.03%
Immunocompromised Status
Yes 144,510 5.10%
No 2,688,045 94.90%
Medicare -Medicaid Dual Eligibility Status**
Yes 264,266 9.33%
No 2,568,289 90.67%
Concomitant Influenza Vaccination***
Yes 496,007 17.51%
No 2,336,548 82.49%
* Data cut: 11/30/2023
** Medicare- Medicaid dual eligibility status is defined as ever being dual eligible within the 3 months prior to the vaccination date
*** Concomitant influenza vaccination is defined as seasonal influenza vaccination events that happened on or within 42 days prior to PCV 20 vaccination date
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Outcome Count and Incidence Rate (IR) among PCV20 vaccinated population*
Health Outcome Risk
Window**
(days)Comparison
Window
(days)Total
N (IR***)Risk Window
N (IR****)Comparison
Window
N (IR****)
Acute Myocardial Infraction 1-28 29-56 3,274 (970) 1,699 (965) 1,575 (975)
Myocarditis/Pericarditis 1-21 22-42 80 (31) 43 (32) 37 (29)
Anaphylaxis 0-1 3-16 25 (20) - (26) - (20)
Atrial Fibrillation 1-42 43-84 17,925 (3,879) 9,709 (3,908) 8,216 (3,845)
Bell’s Palsy 1-42 43-84 1,090 (207) 624 (220) 466 (191)
Cardiomyopathy; Heart
Failure1-42 43-84 16,263 (3,503) 8,778 (3,518) 7,485 (3,486)
Cellulitis and Infection 1-7 8-14 3,187 (3,548) 1,660 (3,685) 1,527 (3,410)
Cholecystitis or Cholelithiasis 1-28 29-56 665 (195) 323 (182) 342 (210)
Guillain -Barré Syndrome 1-42 43-84 29 (6) - (8) - (4)
Immune Thrombocytopenia 1-42 43-84 49 (10) 30 (11) 19 (8)
Thrombocytopenia 1-28 29-56 3,552 (1,053) 1,787 (1,015) 1,765 (1,093)
Transient Ischemic Attack 1-28 29-56 621 (182) 318 (179) 303 (186)
* Data cut: 11/30/2023, # of PCV 20 total uptake: 2,832,555
** Risk and comparison windows are defined as the number of days post vaccination *** All IRs expressed as IR per 100,000 person -years
**** For the health outcome that has risk or comparison windows count less than 11, the counts for both windows are masked by “-”
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IRR between Risk and Comparison Windows with 95% and 98% CI among
PCV20 Vaccinated Population*
Health Outcome IRR** 95% CI 98% CI
Acute Myocardial Infraction 0.95 (0.89, 1.02) (0.87, 1.03)
Myocarditis/Pericarditis 1.05 (0.69, 1.64) (0.64, 1.77)
Anaphylaxis 1.11 (0.31, 3.12) (0.22, 3.78)
Atrial Fibrillation 0.98 (0.95, 1.01) (0.95, 1.02)
Bell’s Palsy 1.13 (1.00, 1.29) (0.97, 1.32)
Cardiomyopathy; Heart Failure 0.96 (0.93, 0.99) (0.92, 1.00)
Cellulitis and Infection 1.06 (0.99, 1.14) (0.97, 1.15)
Cholecystitis or Cholelithiasis 0.85 (0.73, 1.00) (0.71, 1.03)
Guillain -Barré Syndrome 2.19 (0.97, 5.42) (0.82, 6.50)
Immune Thrombocytopenia 1.35 (0.75, 2.50) (0.67, 2.78)
Thrombocytopenia 0.89 (0.83, 0.95) (0.82, 0.97)
Transient Ischemic Attack 0.94 (0.80, 1.11) (0.78, 1.14)
* Data cut: 11/30/2023, # of PCV 20 total uptake: 2,832,555** IRR = Incidence rate ratioNo statistically
significant elevated
risk was detected
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Estimated Posterior Distributions of IRR from Sequential Analyses at
Different Data Cuts – Myocarditis/Pericarditis
Median of the Posterior Distribution
(IRR = 1.05)
IRR = 1, meaning no rate difference
in the health outcome between risk and comparison windows
IRR posterior distribution from Bayesian model using data through November 2023
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Estimated Posterior Distributions of IRR from Sequential
Analyses at Different Data Cuts – All Health Outcomes
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Summary
•Incidence rates post PCV 20
•Incidence rates for Myocarditis/Pericarditis, Anaphylaxis, Guillain -Barré
Syndrome and Immune Thrombocytopenia are less than 100 cases per 100,000
person -years
•Signal detection
•The estimated IRRs and CIs did not identify statistically significant risk
elevation following PCV 20 vaccination for any of the outcomes (no significant
evidence that IRR > 1)
•We continue to monitor and evaluate the health outcomes
Note: Summary based on results from data cut: 11/30/2023
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Limitations for Sequential Monitoring
•Statistically significant results may appear and disappear from
month to month due to use of Bayesian methods.
•Events were not chart- confirmed and the Positive Predictive
Value (PPV) for some outcomes are likely low, e.g. The PPV for
Bell’s Palsy was 12.66% and the PPV for ITP was 4.00% in a
recent study.
•Residual confounding may still exist given the limited number
of variables being adjusted in the regression model
•Large uncertainty of incidence rate ratios for certain outcomes
•Small number of events, wide credible intervals
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Future Planning
•Active monitoring to continue monthly
•End of surveillance analysis may be performed using the self- controlled
case series (SCCS) method for each outcome where there is sufficient
sample size for a powered analysis
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Summary of Evidence
•No GBS signal in clinical trials
•GBS signal for PCV20 in VAERS
•Currently no GBS signal in Medicare sequential
monitoring. Monitoring is ongoing.
•Significant uncertainty because of the small number of cases observed
•Limitations in VAERS and Medicare studies
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Acknowledgements
FDA CBER
Xinyi Ng
Richard ForsheeWhitney SteeleBarbee Whitaker
www.bestinitiative.orgAcumenYue WuMao HuJing WangNatalie SistoYoganand ChillarigeBing LyuJianfeng ZhuangPurva ShahWenxuan ZhouHolin ChenSamikshya SiwakotiYenlin LaiCenters for Medicare
and Medicaid Services (CMS)