Recommendations for Adverse Event Monitoring Programs for ... · Adverse Event Monitoring Programs...

LSRO Life Sciences Research OfficeLife Sciences Research Office

RecommendationsRecommendationsfor for

Adverse EventAdverse EventMonitoring Programs Monitoring Programs

for for Dietary SupplementsDietary Supplements

Catherine J. Klein, PhD, RD, CNSDCatherine J. Klein, PhD, RD, CNSDNovember 2, 2004November 2, 2004

Life Sciences Research OfficeLife Sciences Research Office

NonNon--profit 501(c)(3) scientific organizationprofit 501(c)(3) scientific organizationAffiliated with scientific societies Affiliated with scientific societies ((e.ge.g., ASNS, ASPET, ISRTP, APS, ASIP, ASCN)., ASNS, ASPET, ISRTP, APS, ASIP, ASCN)

Independent, objectiveIndependent, objectiveComprehensive reviews by expert panels, Comprehensive reviews by expert panels, authoritative reportsauthoritative reports

LSRO

SponsorSponsor

Metabolife International, Inc. Metabolife International, Inc. (San Diego, CA),(San Diego, CA),

through its counsel,through its counsel,Patton Boggs, L.L.P. Patton Boggs, L.L.P.

(Washington, DC)(Washington, DC)

TerminologyTerminology

Adverse Event (AE)Adverse Event (AE)Individual Data Record of AEIndividual Data Record of AESignal (pairing of product with AE )Signal (pairing of product with AE )Postmarket SurveillancePostmarket Surveillance

Potential Sources of Risk Potential Sources of Risk from Dietary Supplementsfrom Dietary Supplements

Unexpected product effectsUnexpected product effectsReactions to product/ingredientsReactions to product/ingredientsSupplement interactions with drugs, disease, and Supplement interactions with drugs, disease, and lifestyle factors lifestyle factors

Contaminated/mislabeled raw materialsContaminated/mislabeled raw materialsProblems introduced during manufacture, Problems introduced during manufacture, distribution, storagedistribution, storageTamperingTamperingMisuse by consumerMisuse by consumer

Challenges to MonitoringChallenges to MonitoringDietary SupplementsDietary Supplements

No federal guidanceNo federal guidanceHeterogeneous dietary supplementsHeterogeneous dietary supplementsManufacturer experiences differManufacturer experiences differTraditional and alternative distributionTraditional and alternative distributionConsumer complaints Consumer complaints vsvs. medical reports. medical reports

Recommendations for Recommendations for Adverse Event Monitoring Programs Adverse Event Monitoring Programs

for Dietary Supplementsfor Dietary Supplements

PurposePurposeTo provide scientific advice on how To provide scientific advice on how surveillance programs can be tailored surveillance programs can be tailored to monitor the safety of dietary supplementsto monitor the safety of dietary supplements

Expert PanelExpert Panel

Catherine St. Hilaire, Ph.D. Catherine St. Hilaire, Ph.D. (Chair)(Chair)John A. Clark, M.D., MSPH John A. Clark, M.D., MSPH Barbara Crouch, Pharm.D., MSPH Barbara Crouch, Pharm.D., MSPH Janet Greger, Ph.D. Janet Greger, Ph.D. Robert Hoerr, M.D., Ph.D.Robert Hoerr, M.D., Ph.D.Valen Johnson, Ph.D.Valen Johnson, Ph.D.D. Warner North, Ph.D. D. Warner North, Ph.D.

ProcessProcess

Review and compare federal and industry Review and compare federal and industry data recordsdata recordsEvaluate the usefulness of records for Evaluate the usefulness of records for generating signalsgenerating signalsReview other surveillance programsReview other surveillance programsRecommend monitoring system for dietary Recommend monitoring system for dietary supplementssupplements

Sample Databases of Ephedrine Sample Databases of Ephedrine AlkaloidAlkaloid--Containing SupplementsContaining Supplements

FDA MET 356

MedWatchMedWatch-- calls, calls, letters, FAX, emailletters, FAX, emailAE & ephedrineAE & ephedrine--alkaloid supplementalkaloid supplementStandardized formsStandardized formsLSRO sample: n=200 LSRO sample: n=200 of 1800 records

Customer service Customer service telephone linetelephone lineAE & ephedraAE & ephedra--supplementsupplementStandardized formStandardized formLSRO sample: n=200 LSRO sample: n=200 of 14,000+ recordsof 1800 records of 14,000+ records

FDA Database RecordsFDA Database Records

Incoming ReportIncoming ReportAffidavitsAffidavitsLabel Sample Label Sample Outpatient Medical ReportsOutpatient Medical ReportsER/Urgent Care RecordsER/Urgent Care RecordsHospital Record SummariesHospital Record SummariesHospital Medical NotesHospital Medical NotesHospital Surgical ReportsHospital Surgical ReportsOther (Other (e.g.,e.g., Autopsy Report)Autopsy Report)

MET Database Record FormMET Database Record Form

Caller contact info & date

Product user age, height, weight

Daily dose & duration

Intake of water, caffeine, diet

Check-list of health complaints

Check-list of recommendations

Additional comments

Functional Steps Functional Steps in Postmarket Surveillancein Postmarket Surveillance

Recognize & report AERecognize & report AECreate individual data recordsCreate individual data recordsBuild a relational databaseBuild a relational databaseSignal from databases & other sourcesSignal from databases & other sourcesInvestigate signalInvestigate signalResolve issues & formulate risk management Resolve issues & formulate risk management interventionsinterventions

Only a fraction of AE Only a fraction of AE are recognized and reportedare recognized and reported

AEreported

AE recognizedReport

of non-event

AE occurs after exposure

Dietary supplement use

Adverse reactionto dietary

supplement

Adverse reactionAdverse reactionto dietaryto dietary

supplementsupplement

AE due to chanceAE due to chanceAE due to chance

(Modified from Siev, Adv Vet Med, 1999)

Signaling from a DatabaseSignaling from a Database

Signal EvaluationSignal Evaluation

Individual Data Records

“Interesting”AE-product

relationships

Reliableand

Accurate

Serious

Detected Signals

Signal PrioritizationSignal Prioritization Case-Series

Signal DetectionSignal Detection




relationships

““Interesting” Interesting” productproduct--AE relationshipsAE relationships

••New, unexpected relationshipNew, unexpected relationship••Change in relationship over timeChange in relationship over time

••Volume/rateVolume/rate•• intensity of AEintensity of AE

••Comparison to other productsComparison to other products

MethodsMethods••CaseCase--byby--case inspectioncase inspection••Automated detectionAutomated detection

Information for Signal DetectionInformation for Signal Detection**

FDA MET 356FDA MET 356(n=200) (n=200)(n=200) (n=200)

98% 96%1. Identifier for product

user

2. Determine if AE

3. Determine if supplement use was prior to AE

4. Dated

98% 96%



relationships

*Records meeting all four criteria

Signal PrioritizationSignal Prioritization




relationships

Reliableand

Accurate

Serious

Detected Signals



Serious (FDA)

Disability

Hospitalization

Life-threatening

Fatal

Reproductive AE




relationships

Reliableand

Accurate

Serious

Detected Signals


Information for Signal PrioritizationInformation for Signal Prioritization**

Reliability & Reliability & AccuracyAccuracy

FDAFDA(n=200) 98 %(n=200) 98 %

MET 356MET 356(n=200) 15 %

Reliableand

Accurate

Serious

Detected Signals

SeriousSerious

FDAFDA(n=200) 79 %(n=200) 79 %

MET 356MET 356(n=200) 7 %(n=200) 7 %(n=200) 15 %

*Records having sufficient information to determine reliability,accuracy and whether or not event was serious.





relationships

Reliableand

Accurate

Serious

Detected Signals

Signal PrioritizationSignal Prioritization Case-Series


Information for Signal EvaluationInformation for Signal Evaluation

FDA MET 356

Medication + +

Time to onset + +

Gender & Age + -

Medical history + -

Reason for use + -

Daily dose - +

Batch/lot # - -

Other supplement - -

Rechallenge - -


Case-Series

Principal Findings Principal Findings from Industry and Federal Examplefrom Industry and Federal Example

FDA & MET records adequate for detectionFDA & MET records adequate for detectionFDA records were more informative than FDA records were more informative than MET records for prioritization and evaluation MET records for prioritization and evaluation (MET not designed to generate signals) (MET not designed to generate signals) Because databases contained information of Because databases contained information of value for signal generation it is likely that signals value for signal generation it is likely that signals (hypotheses) worthy of investigation would arise (hypotheses) worthy of investigation would arise if developed in context of surveillance system if developed in context of surveillance system having LSRO recommended featureshaving LSRO recommended features

Surveillance ProgramsSurveillance Programs

NutraSweetNutraSweetAspartameAspartame

Procter & Gamble, FritoProcter & Gamble, Frito--LayLayOlestraOlestra

FDA MedWatchFDA MedWatchDrugs, Dietary supplementsDrugs, Dietary supplements

Poison Control CentersPoison Control CentersDietary supplementsDietary supplements

World Health OrganizationWorld Health OrganizationHerbal productsHerbal products

Anecdotal aspartame complaints Anecdotal aspartame complaints

after introduction into marketafter introduction into market

*

*

*

**

*

*

*#

#

##

#

## #

# # ##

#

(Butchko (Butchko et alet al. Reg Tox Pharmacol, 1994). Reg Tox Pharmacol, 1994)

Effect of negative news reports on Effect of negative news reports on anecdotal aspartame complaintsanecdotal aspartame complaints

0

20

40

60

80

100

120

Janua

ryFeb

ruar

yMar

ch

April

May

June

July

August

Septem

ber

October

Novem

berDec

ember Medical

ComplaintTotals

(Butchko (Butchko et alet al. . Reg Tox Pharmacol,Reg Tox Pharmacol, 2002)2002)

Gender difference in AE reportingGender difference in AE reportingrates rates (per 100,000 population) (per 100,000 population) to FDA for to FDA for

consumerconsumer--reported events reported events (1998(1998--2001)2001)

0

10

20

30

40

50<5 5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

90-94

95-99

>100

Age Range

Rep

ortin

g R

ate

MALESFEMALES

0

10

20

30

40

50<5 5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

90-94

95-99

>100

Age Range

Rep

ortin

g R

ate

MALESFEMALES*

*

**

*

*

*

*

(Clark J.A. Galt Associates, Inc., Sterling, VA, 2003)(Clark J.A. Galt Associates, Inc., Sterling, VA, 2003)

Human Exposures

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

8000

1/1/2000 7/1/2000 12/30/2000 6/30/2001 12/29/2001 6/29/2002 12/28/2002

Cas

es/D

ay

WeekdaysWeekends

Poisonous Substances (reports/day)Poisonous Substances (reports/day)

(Watson (Watson et al.,et al., Am J Emergency Med, 2003)Am J Emergency Med, 2003)

Pesticides (reports/day)Pesticides (reports/day)

Pesticide Exposures

0

100

200

300

400

500

600

6/15/1994 10/28/1995 3/11/1997 7/24/1998 12/6/1999 4/19/2001 9/1/2002 1/14/2004

Cas

es p

er d

ay, a

ll ag

es, a

ll ro

utes

(American Assoc. Poison Control Centers, 2003)(American Assoc. Poison Control Centers, 2003)

Recommendations for Recommendations for Adverse Event Monitoring Programs Adverse Event Monitoring Programs

for Dietary Supplementsfor Dietary Supplements

LSRO recommends how AE can be collected, LSRO recommends how AE can be collected, documented, organized, and analyzeddocumented, organized, and analyzed

LSRO specifies the minimal requirements of an LSRO specifies the minimal requirements of an effective AE monitoring program for dietary effective AE monitoring program for dietary supplementssupplements

(Handout notes(Handout notes--not in slides)not in slides)

Recommended Reporting & Intake ProcessesRecommended Reporting & Intake Processes

Collect via common transmissionsCollect via common transmissionsUserUser--friendly, simple, and concise for all friendly, simple, and concise for all geographic areasgeographic areasSafeguard confidential dataSafeguard confidential dataTrained customer service representatives Trained customer service representatives

Available 24Available 24--hr, 365 days/yearhr, 365 days/year

(Handout notes(Handout notes--not in slides)not in slides)

Recommendations for CreationRecommendations for Creationof Individual Data Recordsof Individual Data Records

Standardized questionnaire form Standardized questionnaire form Collect data useful for detecting, prioritizing, and Collect data useful for detecting, prioritizing, and evaluating signalsevaluating signalsFollow up missing relevant dataFollow up missing relevant dataSkilled data coding and entrySkilled data coding and entryTrack status of recordTrack status of recordSupervision of medical evaluationSupervision of medical evaluationSecure & accessible source materials Secure & accessible source materials

Recommended Reporting ProcessRecommended Reporting Process& Creation of Data Records& Creation of Data Records

Paper Based ProcessPaper Based Process

CodeLog

Write Up Report

Incoming Call, Facsimile, Mail, or Electronic Form Enter Data

Verify

Review

Electronic ProcessElectronic ProcessIncoming Call, Facsimile, Mail, or Electronic Form

Verify ReviewAutomated logging

and notification of receipt

Computer-assisted write-up, coding, and data entry

(Graphic modified from (Graphic modified from FaichFaich, 2003), 2003)

Minimal Data for Signal DetectionMinimal Data for Signal Detectionfor Dietary Supplementsfor Dietary Supplements

Purpose of complaint Purpose of complaint (AE (AE vs.vs. product quality only)product quality only)

Date of AE complaintDate of AE complaintProduct exposure prior to AEProduct exposure prior to AEVerbatim description of AEVerbatim description of AEProduct identifierProduct identifierContact info for individual reporting AEContact info for individual reporting AEIdentifier for product userIdentifier for product user

Additional Data for Signal PrioritizationAdditional Data for Signal Prioritizationand Signal Evaluationand Signal Evaluation

Relationship of caller to userRelationship of caller to userContact info for product userContact info for product userAdditional product infoAdditional product infoWhy and how product usedWhy and how product usedDate of first exposureDate of first exposureFollow up with health care providerFollow up with health care provider**

Follow up clinical course Follow up clinical course Etiological dataEtiological dataReproductive statusReproductive statusDemographic and confounding factorsDemographic and confounding factors

*Patient consent required

Recommendations for DatabaseRecommendations for Databaseand Signaling Processand Signaling Process

Secure data exchange between internal and Secure data exchange between internal and external databasesexternal databasesSignaling process should be designed and Signaling process should be designed and managed by professionalsmanaged by professionalsTimely reviews and analysesTimely reviews and analysesFurther investigationsFurther investigations

Recommendations for Recommendations for Issues Resolution & Risk ManagementIssues Resolution & Risk Management

Formulate signal that can be assessed for public Formulate signal that can be assessed for public health impacthealth impactTake action to protect public healthTake action to protect public healthInform FDA of new, serious AEInform FDA of new, serious AE--product product relationshipsrelationshipsInform product users about new findingsInform product users about new findings

Recommendations for Recommendations for Quality Assurance & OversightQuality Assurance & Oversight

Ensure high quality data Ensure high quality data are collected, secured, are collected, secured, & processed expediently & processed expediently without errorwithout error

Evaluate objective Evaluate objective performance measures of performance measures of programprogram

Recommended EnhancementsRecommended Enhancements

Determine barriers to submission of AEDetermine barriers to submission of AEDirect electronic data entry with logicDirect electronic data entry with logicReference databases Reference databases (ingredient, product)(ingredient, product)

IndustryIndustry--wide relational database of records for wide relational database of records for interinter--product signalingproduct signalingCollaborate with surveillance expertsCollaborate with surveillance expertsOversight by independent expertsOversight by independent experts

Findings EmphasizedFindings Emphasized

Evidence of causality is not required for Evidence of causality is not required for signal detectionsignal detectionQualified operators are needed to implement Qualified operators are needed to implement quality systemsquality systemsProspective studies help understand the Prospective studies help understand the productproduct--event relationshipevent relationshipSurveillance programs by industry can Surveillance programs by industry can complement federal programscomplement federal programs

Citations for GraphicsCitations for Graphics

American Association of Poison Control Centers, Inc. (2003) (UnPub).Butchko, H. H., Tschanz, C. & Kotsonis, F. N. (1994) Postmarketing surveillance of food additives. Regul. Toxicol. Pharmacol. 20: 105-118. Butchko, H. H., Stargel, W. W., Comer, C. P., Mayhew, D. A., Benninger, C., Blackburn, G. L., de Sonneville, L. M., Geha, R. S., Hertelendy, Z., Koestner, A., Leon, A. S., Liepa, G. U., McMartin, K. E., Mendenhall, C. L., Munro, I. C., Novotny, E. J., Renwick, A. G., Schiffman, S. S., Schomer, D. L., Shaywitz, B. A., Spiers, P. A., Tephly, T. R., Thomas, J. A. & Trefz, F. K. (2002) Aspartame: review of safety. Regul. Toxicol. Pharmacol. 35: S1-93.Clark, J. A. (2003) Signaling methods and signaling program design. Galt Associates, Inc. Sterling, VA (UnPub).Faich, G. (2003) Comments on FDA's pharmacovigilance and pharmacoepidemiologic assessment concepts. Available at http://www.fda.gov/cder/meeting/RMtranscript3.doc. Accessed 7-18-2003.Siev, D. (1999) An introduction to analytical methods for the postmarketingsurveillance of veterinary vaccines. Adv. Vet. Med. 41: 749-774. Watson, W. A., Litovitz, T. L., Rodgers, G. C., Jr., Klein-Schwartz, W., Youniss, J., Rose, S. R., Borys, D. & May, M. E. (2003) 2002 annual report of the American association of poison control centers toxic exposure surveillance system. Am. J. Emerg. Med. 21: 353-421.

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www.LSRO.org www.LSRO.org

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