US Food and Drug Administration: 2005-4180s 02 iyasu

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Overview of Pediatric Safety Reporting andOverview of Pediatric Safety Reporting and

Role of the CommitteeRole of the Committee

Pediatric Advisory Committee MeetingPediatric Advisory Committee Meeting

November 18, 2005November 18, 2005

Solomon Iyasu, M.D., M.P.H.Solomon Iyasu, M.D., M.P.H.Acting Deputy DirectorActing Deputy Director

Division of Pediatric Drug DevelopmentDivision of Pediatric Drug Development

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Food and Drug AdministrationFood and Drug Administration



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Best Pharmaceuticals for ChildrenBest Pharmaceuticals for Children

Act: Legislative MandateAct: Legislative Mandate

• Section 17 of the BPCA mandates the Office of Section 17 of the BPCA mandates the Office of

Pediatric Therapeutics (OPT) to:Pediatric Therapeutics (OPT) to:

– Review post-marketing adverse event reportsReview post-marketing adverse event reportsduring the one-year period after a drug receivesduring the one-year period after a drug receives

market exclusivitymarket exclusivity

– Refer such reports to the Pediatric AdvisoryRefer such reports to the Pediatric AdvisoryCommittee for review and obtaining anyCommittee for review and obtaining any

recommendations for actionrecommendations for action



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FDA Adverse Event ReportingFDA Adverse Event Reporting

System (AERS)System (AERS) • Database of all AERS and manufacturer Database of all AERS and manufacturer

reportsreports

• Origin 1969 (SRS until 1997)Origin 1969 (SRS until 1997)

• ~ 2 million reports~ 2 million reports

• Contains drug and "therapeutic" biologicContains drug and "therapeutic" biologic

reportsreports

• Exception = vaccinesException = vaccines

VAERS 1-800-822-VAERS 1-800-822-

79677967



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Source of ReportsSource of Reports

• Voluntary/spontaneous reportingVoluntary/spontaneous reporting• Health care professionals, consumers/Health care professionals, consumers/

patients, or others patients, or others

• Manufacturers: Required for post-Manufacturers: Required for post-marketing reporting (>90%)marketing reporting (>90%)

– All adverse drug experience informationAll adverse drug experience information

obtained or otherwise received from anyobtained or otherwise received from anysource, foreign or domesticsource, foreign or domestic



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FDA post-marketing DefinitionsFDA post-marketing Definitions

(21 CFR 314.80 )(21 CFR 314.80 )

• Adverse Drug Experience (ADE): anyAdverse Drug Experience (ADE): any

adverse event associated with the use of aadverse event associated with the use of adrug,drug, whether or not considered drugwhether or not considered dru

g

relatedrelated, including

, including

– Accidental or intentional overdoseAccidental or intentional overdose

– Occurring from abuse or drug withdrawalOccurring from abuse or drug withdrawal

– Failure of expected pharmacological actionFailure of expected pharmacological action



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FDA post-marketing DefinitionsFDA post-marketing Definitions

(21 CFR 314.80)(21 CFR 314.80)• Serious Adverse Event (SAE): any event

occurring at any dose that results in any of the

following outcomes:

• Death

• Life-threatening ADE (immediate risk)

• Hospitalization or prolongation of hospitalization

• Persistent/significant disability/incapacity

• Congenital anomaly/birth defect

• Other/requiring intervention (e.g. bronchospasm)



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Causality Assessment of AE reportsCausality Assessment of AE reports

• Temporal relationshipTemporal relationship• De-challenge - ADR subsides when drug is discontinuedDe-challenge - ADR subsides when drug is discontinued

• Re-challenge - ADR returns when drug is re-administeredRe-challenge - ADR returns when drug is re-administered

• Dose-responseDose-response• Biologic plausibility (knowledge of PK and PD)Biologic plausibility (knowledge of PK and PD)

• Animal preclinical studiesAnimal preclinical studies

• Laboratory evidenceLaboratory evidence

• Known class effectKnown class effect

• Underlying diseaseUnderlying disease

• Concomitant drugsConcomitant drugs



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AERS: StrengthsAERS: Strengths

• Includes all U.S. marketed drugsIncludes all U.S. marketed drugs

• Simple, inexpensive reporting systemSimple, inexpensive reporting system

• Provides for early detection of safetyProvides for early detection of safety

signalssignals

– Especially good for rare Adverse DrugEspecially good for rare Adverse Drug

Reactions (anaphylaxis, liver failure, aplasticReactions (anaphylaxis, liver failure, aplastic

anemia, serious skin reactions etc.)anemia, serious skin reactions etc.)



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AERS: LimitationsAERS: Limitations

• UnderreportingUnderreporting: varies from drug to drug: varies from drug to drug

and over timeand over time

•Quality and completeness of reportsQuality and completeness of reports

::

variable, often poor variable, often poor

• Can estimate rates of events only grossly:Can estimate rates of events only grossly: – Numerator uncertain (event counts) Numerator uncertain (event counts)

– Denominator (number of patient exposed) must beDenominator (number of patient exposed) must be

estimated, virtually impossible for inpatient, hospitalestimated, virtually impossible for inpatient, hospital

outpatient clinics, and OTC drugsoutpatient clinics, and OTC drugs



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Role of the Committee:Role of the Committee:

Primary Materials for ReviewPrimary Materials for Review

• One-year post-exclusivity adverse eventOne-year post-exclusivity adverse event

reportsreports

– Focus on pediatric AE reportsFocus on pediatric AE reports

• Pediatric drug use data (denominator)Pediatric drug use data (denominator)

– Outpatient use can be projected nationallyOutpatient use can be projected nationally

• Dispensed prescriptions from retail pharmaciesDispensed prescriptions from retail pharmacies

• Drug mentions in office based practiceDrug mentions in office based practice

– Inpatient useInpatient use cannotcannot be projected nationally be projected nationally



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Role of the Committee:Role of the Committee:

Additional Materials for ReviewAdditional Materials for Review

• Summaries of clinical, and pharmacology &Summaries of clinical, and pharmacology &

toxicology reviews of exclusivity studiestoxicology reviews of exclusivity studies

• Drug product labelDrug product label

• Published literaturePublished literature

• Sponsor materials/presentationsSponsor materials/presentations



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Types of Safety ReviewTypes of Safety Review

PresentationsPresentations

• Abbreviated:Abbreviated:

– No safety signal of concern No safety signal of concern

• StandardStandard

– No unlabeled safety signal No unlabeled safety signal

• Drug product has reports of labeled SAEs that are of interest (Cipro)Drug product has reports of labeled SAEs that are of interest (Cipro)

• Drug Product with safety concern of recent public interest (Vioxx)Drug Product with safety concern of recent public interest (Vioxx)

• In-depthIn-depth

– New possible safety concern New possible safety concern

• Entire AC meeting or session dedicated to drug or class-Entire AC meeting or session dedicated to drug or class-

specific safety concern ( SSRI’s, ADHD drugs)specific safety concern ( SSRI’s, ADHD drugs)



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Overview of Today’s PresentationsOverview of Today’s Presentations

• Abbreviated Presentations:Abbreviated Presentations:

– Sumatriptan (IMITREXSumatriptan (IMITREX®®))

– Irinotecan (CAMPTOSAR Irinotecan (CAMPTOSAR ®®))

– Carboplatin (PARAPLATINCarboplatin (PARAPLATIN®®))

– Rofecoxib (VIOXXRofecoxib (VIOXX®®))

– Anagrelide (AGRYLINAnagrelide (AGRYLIN®®))

– Sodium Ferric Gluconate (FERRLECITSodium Ferric Gluconate (FERRLECIT®®))



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Overview of Today’s PresentationsOverview of Today’s Presentations

(cont’d)(cont’d)

• Standard Presentation:Standard Presentation:

– Fluconazole (DIFLUCANFluconazole (DIFLUCAN®®))

• In-depth Presentation:In-depth Presentation:

– Oseltamivir (TAMIFLUOseltamivir (TAMIFLU®®))

– Presentations include:Presentations include:

• One-year post-exclusivity AEs, drug use review and summaryOne-year post-exclusivity AEs, drug use review and summary

of materials from the Japanese Regulatory Authoritiesof materials from the Japanese Regulatory Authorities

• Literature and pediatric clinical trial reviewLiterature and pediatric clinical trial review

• Influenza surveillance in the USInfluenza surveillance in the US

• Sponsor presentationSponsor presentation

– Committee Discussion of QuestionsCommittee Discussion of Questions



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AcknowledgmentsAcknowledgments

• Division of Pediatric Drug Development,Division of Pediatric Drug Development,

OCTAPOCTAP

• Office of Drug Safety (DDRE, DSRCS)Office of Drug Safety (DDRE, DSRCS)

• Office of New DrugsOffice of New Drugs

• Office of Pediatric TherapeuticsOffice of Pediatric Therapeutics

US Food and Drug Administration: 2005-4180s 02 iyasu

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