# Presentation: 318155

##  LYMErix® Safety Data Reported to the Vaccine Adverse Event Reporting System (VAERS)

- Robert Ball, M.D., M.P.H., Sc.M.
- Division of Epidemiology
- Office of Biostatistics and Epidemiology
- Center for Biologics Evaluation and Research
- Food and Drug Administration (FDA), Rockville, MD
- January 31, 2001

## What is the Vaccine Adverse Event Reporting System (VAERS)?

- National system for surveillance of adverse events after vaccination
- Jointly managed by FDA and CDC
- Reports received from health professionals, vaccine manufacturers, and the public
- All death and serious (hospitalization, prolongation of hospitalization, life-threatening illness, or permanent disability ) reports receive follow-up
- Death and serious reports are reviewed by FDA medical officers

## Uses of VAERS

- Detecting  unrecognized adverse events
- Monitoring known reactions
- Identifying possible risk factors
- Vaccine lot surveillance

## Limitations of VAERS

- Reported diagnoses are not verified
- Lack of consistent diagnostic criteria
- Wide range in data quality
- Underreporting
- Inadequate denominator data
- No unvaccinated control group
**Usually not possible to assess whether a vaccine caused the reported adverse event**

## Analysis of VAERS Data

- Describe characteristics and look for patterns to detect signals of adverse events plausibly linked to a vaccine
- Age, gender, time to onset, dose, “positive rechallenge” reports, symptom codes, and clinical characteristics
- Biological plausibility, pre-existing conditions, and concomitant illness and medication usage
- Signals detected through analysis of VAERS data almost always require confirmation through a traditional epidemiological or other (e.g. laboratory) study

## Coding of VAERS Reports

- No standardized case definitions
- Processed by non-physician nosologists
- Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART)
- Report coding depends on the use of certain words or phrases
- rheumatoid arthritis if report mentions “rheumatoid arthritis”
- arthritis if report mentions “arthritis” or “arthritic”
- arthrosis if report mentions “joint swelling”
- Reports with different degrees of diagnostic precision may have the same coding term
- Coding terms must be interpreted very cautiously

## LYMErix® Safety Surveillance Through VAERS

- Purpose:  describe characteristics and look for patterns to detect adverse events plausibly linked to **LYMErix® **
- Review from licensure (12/21/98) to 10/31/00
- Selected adverse events
- Death and Serious
- Hypersensitivity
- Facial paralysis, arthritis, arthrosis, and rheumatoid arthritis
- Lyme disease
- Selected potential risk factors
- Self-reported HLA DR4
- Self-reported history of Lyme disease

## LYMErix® Safety Surveillance Through VAERSResults Overview

- 1,048 reports and ~ 1.44 million doses distributed
- 1,026 (98%) reports after Lyme vaccine alone
- 4 (0.4%) deaths
- 85 (8%) serious
- Selected adverse events
- Hypersensitivity (22)
- Arthritis (74), arthrosis (46), rheumatoid arthritis (13)
- Facial Paralysis (13)
- Lyme Disease (16)
- Selected potential risk factors
- HLA DR4 (19)
- History of Lyme disease (76)

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Number of VAERS LYMErix® 

**Number of VAERS LYMErix® **
**Reports  by State**
**December 21, 1998 to October 31, 2000**

- State not available for 55 reports

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of All VAERS LYMErix® Reports (n=878) by Calendar Quarter

- Date vaccinated  not available for 165 of 1,048 reports (16%),
- 5 reports prior to 1999

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of All VAERS LYMErix® Reports (n=877) by Age at Onset of Adverse Event 

- Age not available for 171 of 1,048 (16%) reports

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of All VAERS LYMErix® Reports (n=739) by Time to Onset of Adverse Event

- Time to onset not available for 309 of 1,048 (29%) reports

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of All VAERS LYMErix® Reports (n=1,007) by Dose

- Dose not available for 41 of 1,048 (3.9%) reports

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Ten Most Common VAERS LYMErix® Adverse Event Coding Terms

***Arthralgia**** (322)*
***Myalgia ****(227)*
- Pain (196)
- Asthenia (167)
- Headache (151)
***Fever (126)***
***Flu syndrome (124)***
***Injection site pain (117)***
***Rash (85)****** ***
**	****	****         ***** ******Italicized***** = event associated with vaccine in pre-licensure trial**
- 		Interpretation of VAERS data is subject to important limitations - see methods for details

## Summary of Deaths (n=4) after LYMErix® Reported to VAERS

- Deaths
- 54 y/o man died of autopsy proven **“hypertensive cardiovascular disease”** 1 day after 2nd dose
- 63 y/o man died of autopsy proven **“hypertensive and arteriosclerotic cardiovascular disease”** 3 days after 1st dose
- 43 y/o man developed **arthritic and neurologic symptoms** attributed by the reporter to LYMErix® and committed **suicide** 7 months after 2nd dose
- 69 y/o woman developed illness, including anemia and thrombocytopenia, 7 months after 1st dose and died 6 months later an unknown time after 3rd dose with diagnosis of **myelofibrosis**
- 		Interpretation of VAERS data is subject to important limitations - see methods  for details

## Summary of Serious Reports (n=85) Following LYMErix® Reported to VAERS

- 44 reports of musculoskeletal events
- 12 arthritis or arthrosis
- 6 rheumatoid arthritis
- 24 reports of  a variety of neurological events
- 5 reports of cerebral ischemia
- 5 reports of demyelinating disease
- 3 reports of hypersensitivity events
- 	Interpretation of VAERS data is subject to important limitations - see methods for details

## Summary of Serious Reports Following LYMErix® (n=85) Reported to VAERS (cont)

- 13 miscellaneous events
- 5 multiple systemic complaints including dizziness, nausea, fever, photophobia, headache, fatigue, sore throat
- 2 chest pain (1 pericarditis)
- 2 syncope
- 2 chronic or recurrent sinusitis (1 with depression)
- 1 aseptic meningitis
- 1 Lyme disease
- 	Interpretation of VAERS data is subject to important limitations - see methods for details

##  Frequency Distribution of VAERS LYMErix® Reports (n=21) of Hypersensitivity by Time to Onset

- Time to onset  not available for 3 of 24 (13%) reports

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of Reports of Arthritis, Arthrosis, and Rheumatoid Arthritis (n=132)by Calendar Quarter

- Vaccination date not available for 1 of 133  reports (1%)

- Interpretation of VAERS data is subject to important limitations - see methods for details

##  Reports of Arthritis (n=74), Arthrosis (n=46), and Rheumatoid Arthritis (RA) (n=13) Following LYMErix®

- Gender
- Arthritis:  39 women, 34 men
**Arthrosis: 15 women, 24 men**
- RA: 9 women, 4 men
- Total: 63 women, 62 men

- Dose (1st, 2nd, 3rd, 4th)
**Arthritis (25, 32, 12, 0)**
- Arthrosis (19, 15, 8, 1)
**RA (3, 8, 0, 0)**
**Total (47, 55, 20, 1)**

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of VAERS LYMErix® Rheumatoid Arthritis Reports (n=8) by Time to Onset and Dose 

- Time to onset or dose not available for 5 of 13 (38%) reports

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of VAERS LYMErix® Arthritis  Reports (n=40) by Time to Onset and Dose

- Time to onset or dose not available for 34 of 74 (46%) reports

- Interpretation of adverse event reports is subject to limitations - see methods for details

## Clinical Characteristics of VAERS LYMErix® Reports Coded Arthritis, Arthrosis, and Rheumatoid Arthritis (RA)

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Frequency Distribution of VAERS LYMErix® “Arthritis” Reports Indicating Joint Swelling (n=30) by Time to Onset and Dose

- Time to onset or dose not available for 28 of 58 reports (48%) of joint swelling

- Interpretation of VAERS data is subject to important limitations - see methods for details

##  Reports of Facial Paralysis Following LYMErix® 

- 13 reports (2 serious)
- Median age 53 years (range: 18 - 73)
**10 men, 2 women**
- Dose:  9 after 1st , 4 after 2nd
- Follow-up survey (October 2000)
- 7/12 contacted
- 4/7 had concomitant illness
- 5/7 completely recovered

- Interpretation of VAERS data is subject to important limitations - see methods for details

##  Frequency Distribution of VAERS LYMErix® Reports of Facial Paralysis (n=11) by Time to Onset

- Time to onset  not available for 2 of 13 (15%) reports

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Reports of Adverse Events Following LYMErix® for People with a Self-Reported HLA Type

- 19 reports of HLA DR4 and 17 reports of other HLA types
- Coding terms “arthritis” and “arthrosis” were more common in people who reported **any** HLA type than for all reports following LYMErix®
- Clinical characteristics and coding terms similar in both groups
- no predominance of arthritic conditions in DR4 group
- More reports after second dose for both groups
- Time to onset reported to occur over a wide range

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Ten Most Common VAERS Coding Terms Following LYMErix® for People with a Self-Reported History of Lyme Disease (n=76)

- Arthralgia			25
- Asthenia			19
- Myalgia			19
- Headache			18
- Pain				16
- Injection Site Pain		12
- Fever			10
- Injection Site Hypersensitivity  	  8
- Chills			  7
- Rash				  7

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Ten Most Common VAERS Coding Terms Following LYMErix® for People with a Self-Reported History of Lyme Disease

- Arthralgia			25 (33%)		322 (31%)
- Asthenia			19 (25%)		167 (16%)
- Myalgia			19 (25%)		227 (22%)
- Headache			18 (24%)		151 (14%)
- Pain				16 (21%)		196 (19%)
- Injection Site Pain		12 (16%)		117 (11%)
- Fever			10 (13%)		126 (12%)
- Injection Site Hypersensitivity	  8 (11%)		  76 (  7%)
- Chills			  7 (  9%)		  78 (  7%)
- Rash				  7 (  9%)		  85 (  8%)

- Interpretation of VAERS data is subject to important limitations - see methods for details

- Self-Reported History of Lyme Disease (n=76)       All Reports (n=1,048)

## Self-Reported Lyme Disease Following LYMErix® 

- 16 reports
- Clinical characteristics and coding terms consistent with Lyme Disease
- 14 after first or second dose before completion of series
- may not have achieved adequate immune response
- A few reports of “reactivation” of Lyme disease

- Interpretation of VAERS data is subject to important limitations - see methods for details

## Summary of VAERS Analysis

- VAERS has limited ability to assess the causal relationship of adverse events and vaccines
- Hypersensitivity reactions reported to VAERS are uncommon, but can be plausibly linked to LYMErix® because of their specific timing and clinical features
- Question of the association of arthritis with LYMErix® cannot be resolved with VAERS data alone, although reports of arthritic events reported to date do not provide clear evidence of a causal association

## Follow-up Study

- Telephone survey to evaluate joint problems reported following LYMErix®
- events coded arthritis, arthrosis, rheumatoid arthritis, joint disease, or arthralgia
- Purpose:
- obtain detailed information about the events including medical records
- look for patterns of unusual disease or laboratory values
- confirm diagnoses of arthritis for case-control study
- 35 of ~200 planned interviews completed as of 1/25/01

## Planned Follow-up Study

- Case-control study planned to examine the hypothesis that LYMErix® is associated with arthritis
- arthritis cases confirmed by survey
- two control groups identified from VAERS
- arthritis cases reported following other vaccines
- events other than arthritis reported following LYMErix®
- conduct high resolution HLA typing and test for   T-cell reactivity to OspA and LFA-1
- probably only a very strong risk will be detectable

## Plans for Continued Safety Evaluation of LYMErix® 

- We continue to monitor VAERS reports of adverse events following LYMErix®
- We are conducting a VAERS-based telephone survey and a case-control study is planned to further evaluate joint problems following LYMErix®
- Results of LYMErix® manufacturer sponsored phase IV study will be important to help evaluate safety concerns

## Collaborators in Analysis of VAERS Data

- M. Miles Braun, M.D., M.P.H. , Sean Shadomy D.V.M., M.P.H.,
- Chester Clarke, M.D., M.P.H., Brad K. Robison, M.D., M.P.H.
- Division of Epidemiology, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration (FDA), Rockville, MD;
- Sarah Lathrop, D.V.M., Ph.D., Ned Hayes, M.D.
- National Center for Infectious Disease, Centers for Disease Control and Prevention (CDC), Fort Collins CO;
- Penina Haber, M.P.H. , Gina T. Mootrey, D.O., M.P.H.
- Vaccine Safety and Development Activity, Epidemiology and Surveillance Division, National Immunization Program, CDC, Atlanta, GA, USA
- and
-  the VAERS Working Group