Assessing Vaccine Safety Post Licensure

Neal A. Halsey Johns Hopkins University Inactivated Respiratory Syncytial Virus Vaccine: 1960’s • Formalin inactivated • Administered to infants • Minimal reactions • Induced neutralizing antibody

Kapikian AZ. Amer. J. Epid., 1969, 89:405-21 Kim HW et al 1969 Enhanced RSV Disease 9-10 Months Following Inactivated RSV Vaccine RSV Vaccine No Vaccine

Pneumonia 9/13 (69%) 4/47(9%) p< .001 RSV Vaccine Paraflu Vac.

Hospitalization 80% 5% p< .001

Kapikian AZ. Amer. J. Epid., 1969, 89:405-21 Kim HW et al 1969 Randomized Placebo

Controlled Trials Double blind

evaluations

Recruit Vaccine Outcomes Enroll

Partici- Randomize Population pants Placebo Outcomes Selected: healthy, age, gender? Investigating Causal Relationships Randomized Placebo-Controlled Double Blind Trials

Disorder Rel Risk

yes no Risk

a b a a yes a+b a+b

c c Vaccine

no c d c+d c+d

a+c b+d Sample sizes required for identification of relative risks.

Ellenberg S S Clin Infect Dis. 2001;33:S319-S322 © 2001 by the Infectious Diseases Society of America Intussusception after Rotavirus Vaccines Pathogenesis unknown

Intussusception/100,000: Rhesus(Rotashield): 10-20 ILEO-ILEOCOLIC INTUSSUSCEPTION RV1 (Rotarix) and RV5 (Rotateq) No increased risk in trials of ~30,000)

*1-2/100,000 in some populations

US: RV1 > RV5 ILEOCOLIC INTUSSUSCEPTION

Weintraub NEJM 2014 Shaw Annu. Rev. Med. 2013. 64:165–74 Patel. Expert Rev Vaccines. Source: Netter. The CIBA Collection of 2009 Nov;8(11):1555-64. Medical Illustrations, Vol 3, 1962. pg134. Post-licensure Safety Studies

1. Surveillance for AEFI in all countries 2. Individual case investigation of SAEs 3. Signal detection 4. Special studies Individual AEFI

Disorder Risk Risk

yes no Ratio

a b a a yes a+b a+b

c c Vaccine

no c d c+d c+d

a+c b+d False Assumptions of Causal Relationships based on Temporal Association

Post hoc, ergo propter hoc After this, therefore because of this Unexpected reports of serious adverse events have resulted in stoppage of national programs to introduce hepatitis B, Hib, pneumococcal, MMR and HPV vaccines. Global Vaccine Safety Blueprint Vision

“Effective vaccine pharmacovigilance systems are established in all countries”

. Vaccine pharmacovigilance is the science and activities relating to the detection, assessment, understanding, prevention and communication of adverse events following immunization

WHO/IVB/12.07 Courtesy C. Vellozzi 16 Global Vaccine Safety Blueprint: Minimal Capacity for Vaccine Safety Surveillance

• National dedicated vaccine pharmacovigilance capacity

• Encourage reporting of vaccine safety issues

• Reporting form for individual case safety reports

• National database or system for collating, managing and retrieving AEFI reports

• Harmonized methods and tools for the monitoring and investigation of AEFI

Courtesy C. Vellozzi WHO/IVB/12.07; *www.Brightoncollarboration.org 17 Global Vaccine Safety Blueprint: Enhanced Capacity for Vaccine Safety Surveillance

. The ability to carry out active surveillance rather than relying solely on spontaneous reporting of AEFI alone for the purpose of signal detection

. The ability to carry out epidemiological studies to test hypotheses

WHO/IVB/12.07 Courtesy C. Vellozzi 18 Vaccine Safety Signal: Definition

The Council for International Organizations of Medical Sciences (CIOMS) definition:

Information…from one or multiple sources …, which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.

Courtesy C. Vellozzi Source: Report of CIOMS Working Group VIII, Practical Aspects of Signal Detection in Pharmacovigilance. Geneva 2010. 19 Vaccine Safety Signal Management Guidance

Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) March 2005 Clinical Medical

http://www.fda.gov/cder/guidance/index.htm Courtesy C. Vellozzi 20 Vaccine Safety Signal Management Framework

Signal detection

Interim signal assessment Decision to end Prioritization and Decision Decision to end Final signal assessment

Verified Ruled Out

Courtesy C. Vellozzi 21 Causality Assessment What do we mean when we say a vaccine “causes” an adverse event?

• Population: The vaccine increases the risk of the event. • Individual: The vaccine was a factor in the patient developing the adverse event.

Coggan and Martyn Lancet 2005; 365: 1434–37 Usual criteria for determining a causal relationship between vaccines and adverse events

Epidemiologic Studies: Evidence of increased risk in vaccine recipients vs controls, or Definitive laboratory tests linking disease to vaccine component A few exceptions Bradford Hill Causality Criteria

1. Strength 6. Plausibility 2. Consistency 7. Coherence 3. Specificity 8. Experimental 4. Temporality evidence 5. Biologic gradient 9. Analogy

K. Rothman. Causation and Causal Inference. In: Rothman KR and Greenland S, Modern Epidemiology. Lippincott; 1998 Causality Assessment from Individual Case Reports • Causality established (usually): – Isolation of live vaccine agent in normally sterile body fluid. • Yellow fever vaccine virus in liver. • Polio vaccine (OPV) virus in CSF. • Measles vaccine virus in lung of child with leukemia. –

Sem in Ped Infect Dis 2002 July;13(3):205-14 Causality Assessment from Individual Case Reports • Causality established (usually): – Isolation of live vaccine agent in normally sterile body fluid. • Yellow fever vaccine virus in liver. • Polio vaccine (OPV) virus in CSF. • Measles vaccine virus in lung of child with leukemia. – Rule out wild type virus (genetic sequencing)

Sem in Ped Infect Dis 2002 July;13(3):205-14 Causality Assessment from Individual Case Reports • Causality not established: – Antigen detection or PCR without sequencing. • False positives • Contamination • Coincidental infection

Causal Associations Usually Cannot by Determined from Passive Reports of Individual Cases Without Isolation of Vaccine Agent Possible exceptions: 1. Injection site reactions 2. Immediate hypersensitivity reactions 3. Repeat challenge(no clear criteria) 4. Disorders where general causality has already been established and alternative causes ruled out Immediate Hypersensitivity Reactions • Hives, angioedema, anaphylaxis • Pathogenesis known • Short interval from vaccine to reaction • Unlikely for other exposures • Skin testing with vaccine components Post-licensure Investigation of Individual Case Reports of AEFI CISA Review of Case Reports of Adverse Events Following Immunizations Causality Work Group of CISA

AEFI Case Report

Indeterminate, Other diagnosis 1. Is the diagnosis correct? No Uncertain diagnosis uncertain Yes

2a. Is the evidence 2. Is there evidence for definitive? Yes other causes? If continue, include statement regarding Not uncertain diagnosis in conclusion available No Yes No

3. Is there a known 3a. Was the event within the causal association with Yes Indeterminate time window of increased risk? the vaccine? If continue, include statement regarding evidence for other cause in No No conclusion 3b. Are there Yes Inconsistent with 4. Is there strong qualifying causal association, Not evidence against a factors? other cause definitive causal association? identified No No or Yes Yes Uncertain Consistent Inconsistent with with causal causal association association 5. Is the AEFI an Infection? Halsey et al. Vaccine 2012:30(39):5791-8. Review of Case Reports of Adverse Events Following Immunizations Febrile seizure Causality Work Group of CISA 12 month old 7 days after MMR AEFI Case Report

Indeterminate, Other diagnosis 1. Is the diagnosis correct? No Uncertain diagnosis uncertain Yes

2a. Is the evidence 2. Is there evidence for definitive? Yes other causes? If continue, include statement regarding Not uncertain diagnosis in conclusion availabl No Yes No e

3. Is there a known 3a. Was the event within the causal association with Yes Indeterminate time window of increased risk? the vaccine? If continue, include statement regarding evidence for other cause in No No conclusion 3b. Are there Yes Inconsistent with 4. Is there strong qualifying causal association, Not evidence against a factors? other cause definitive causal association? identified No No or Yes Yes Uncertain Consistent Inconsistent with with causal causal association association 5. Is the AEFI an Infection? Vaccine 2012: 30(39):5791-8. Algorithm Advantages

1. Visual 2. Standardized 3. Transparent 4. Tracking assessments 5. Revise assessments as new data become available WHO Causality Assessment Tool http://www.who.int/iris/bitstream/10665/80670/1/9789241505338_eng.pdf

Tozzi et al. Vaccine 2013;31(44):5041-6

3. Algorithm

No No No 4. Classification Investigating Individual Case Reports

• No Known Causal Association

• No Specific Laboratory Test Case Reports and Temporal Associations for Diseases of Unknown Etiology • The number of cases reported can serve as a signal, but not for determining causal relationship. – 1, 10, 100, or 1,000 • Need epidemiologic studies to determine increased risk in vaccinated or in risk window after vaccination Post-licensure Population Based Studies Retrospective or Non-concurrent Cohort Studies • Defined population. • Identify vaccinated and unvaccinated prior to risk period. • Identify all cases in defined time period. • Compare rates of disease in vaccinated and unvaccinated. Investigating Causal Relationships Retrospective or Non-concurrent Cohort Studies

Disorder Rel Risk

yes no Risk

a b a a yes a+b a+b

c c Vaccine

no c d c+d c+d

a+c b+d Potential Problem: Self selection for vaccine? Relative Risk of Sudden Infant Death Syndrome by Day after DTP: Tennessee

10

1

Relative Risk 0.1

0.01 0-3 4-7 8-14 15-30 >30 Days after DTP Healthy Vaccinee Effect: children with illnesses not vaccinated DTP does not increase the risk of SIDS Griffin et al. NEJM 1988;319:618-23. Investigating Causal Relationships Case-Control Studies

Disorder

case control Odds Ratio

a b a/b ad

yes c/d bc

Vaccine

no c d

Potential Problems: • Not randomized • Selection bias? • Matching? Bell’s Palsy

www.elib.gov.ph/edatabase Switzerland: Odds Ratios for Receipt of Vaccines <91 Days Prior to Bell’s Palsy

Case Patients Controls Adjusted Odds (N=250) (N=722) Ratio Vaccine (95%CI)

Intranasal 63 7 84.0 inactivated (25.2%) (1.0%) (20.1-351.9) influenza Parenteral 10 41 1.1 inactivated (4.0%) (5.7%) (0.6 - 2.0) influenza

Mutsch M, et al. NEJM 2004;350:896. Vaccine Only Studies

Disorder

yes no

Potential Problems: a b • Selection bias?

yes • Need to include all cases

Vaccine

no c d

a+c b+d

Vaccine Only Studies

Risk Control Vaccination window window

0 7 30 60 Days after vaccination

Compare the incidence of disease In risk window with control window after receiving vaccine Risk of febrile seizures on days 0-1 vs 14-15 after TIV alone, PCV13 alone, and simultaneous TIV and PCV13

Increased Risk of Febrile Seizures With Simultaneous TIV and PCV13 MenAfriVac™ Rollout in Mali Campaigns 2010 and 2011 – ~6 million vaccinated

K. Vannice risk control Risk Washout Control window window SeasonalityDepicts of other individual diseases- e.g. malarialevel and respiratory disease assessment in vaccinated areas

K. Vannice, in preparation Case Only Studies

Disorder

yes no

Potential Problems: a b • Selection bias?

yes • Need to include all cases

Vaccine

no c d

a+c b+d Self Controlled Case Series Case Only Studies

Vaccination Vaccin- Disease ation Onset

90 60 30 7 Days prior to onset

Compare the incidence of receiving vaccines in different time periods prior to onset of disease Conclusions

1. Post-licensure monitoring for safety is essential in all countries 2. Poor understanding of causality assessment is a problem 3. Expect the unexpected 4. Plan for objective investigations 5. Demand good science