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FDA 1
Overview of Postmarketing Safety Surveillance in FDA
(For Drugs and Biologics)
Min Chen, M.S., R.Ph. Min Chen, M.S., R.Ph.
Associate DirectorAssociate Director
Division of Drug Risk Evaluation Division of Drug Risk Evaluation
Office of Drug SafetyOffice of Drug Safety
CDERCDER
FDA 2
Outline
Office of Drug Safety OrganizationOffice of Drug Safety Organization Postmarketing Reporting RegulationsPostmarketing Reporting Regulations Adverse Event Reporting System (AERS)Adverse Event Reporting System (AERS) Evaluation of Reports and Assessment of Evaluation of Reports and Assessment of
Safety IssuesSafety Issues Regulatory Actions and Risk Management Regulatory Actions and Risk Management
for Safety Issues for Safety Issues
FDA 3
Office of Drug Safety in CDER
O ffic e o f N e w D r ug sJ o hn J e nk ins , M .D .
O ffic e o f P ha r m a c e utic a l S c ie nc e sH e le n W ink le
O ffic e o f T r a in ing & C o m m unic a t io nN a nc y S m ith , P h .D .
O ffic e o f Info r m a tio n T e c hno lo g y
O ffic e o f M a na g e m e ntR uss A b b o tt
O ffic e o f M e d ic a l P o lic yR o b e r t T e m p le , M D
O ffic e o f C o m p lia nc eD a v id H o r o w itz
O ffic e o f D r ug S a fe tyV ic to r R a c zk o w sk i, M D
R o b er t O 'N e ill, P hDO ffice o f B io sta tis tic s
O ffic e o f P ha r m a c o e p id e m io lo g y & S ta t is t ic a l S c ie nc eP a ul S e lig m a n, M D
O ffic e o f R e g ula to r y P o lic yJ a ne A xe lr a d
C D E R D irec to rJ a n e t W o o d co ck , M .D .
FDA 4
Office of Drug Safety
D iv is io n o f D r u g R is k E v a lu a t io n (D D R E )D ir e c to r : J u lie B e itz , M D
D iv is io n o f M e d ic a t io n E r r o r s &T e c h n ic a l S u p p o r t (D M E T S )
A c t in g D ir e c to r : J e r r y P h illip s
D iv is io n o f S u r v e illa n c e , R e s e a r c h , &C o m m u n ic a t io n S u p p o r t (D S R C S )
D ir e c to r : A n n e T r o n te ll, M D
O ff ic e o f D r u g S a fe ty (O D S )D ir e c to r : V ic to r R a c z k o w s k i, M D
FDA 5
Overall ODS Organization Supports 15 OND Review DivisionsSupports 15 OND Review Divisions Currently 95 Staff membersCurrently 95 Staff members Safety EvaluatorsSafety Evaluators
Clinical Pharmacists, PhysiciansClinical Pharmacists, Physicians EpidemiologistsEpidemiologists
Clinical Epidemiologists (MD, MPHs), PhDsClinical Epidemiologists (MD, MPHs), PhDs Functional pool with specialty expertiseFunctional pool with specialty expertise
Social scientistsSocial scientists Project ManagersProject Managers IT supportIT support
FDA 6
Why Postmarketing?Limitations of Premarketing Clinical Trials
Size of the patient population studiedSize of the patient population studied Narrow population - often not providing for Narrow population - often not providing for
special groupsspecial groups Elderly, children, womenElderly, children, women
Narrow indications studied Narrow indications studied Exclusion of certain disease statesExclusion of certain disease states
Short durationShort duration Not reflective of a drug’s potential chronic useNot reflective of a drug’s potential chronic use
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Beyond Approval-Postmarketing Monitoring Low frequency reactions (not identified in Low frequency reactions (not identified in
clinical trials)clinical trials) High risk groupsHigh risk groups Long-term effectsLong-term effects Drug-drug/food interactionsDrug-drug/food interactions Increased severity and / or frequency of Increased severity and / or frequency of
known reactionsknown reactions
FDA 8
1962 Harris-Kefauver Amendments to FD&C Act
Adverse Event ReportingAdverse Event Reporting Proof of EfficacyProof of Efficacy
FDA 9
Current Regulations on Safety Reporting 21 CFR 312.32 - IND safety reports21 CFR 312.32 - IND safety reports 310.304 - “Grandfathered” drugs (pre-1938)310.304 - “Grandfathered” drugs (pre-1938) 314.80 - Postmarketing Rx drugs - NDA314.80 - Postmarketing Rx drugs - NDA 314.98 - Generic drugs - ANDA314.98 - Generic drugs - ANDA 600.80 - Biologics600.80 - Biologics OTC drugs - No reporting requirement OTC drugs - No reporting requirement
unless drug was approved under NDAunless drug was approved under NDA Dietary supplement and food - voluntary Dietary supplement and food - voluntary
reporting reporting
FDA 10
Source of Reports Voluntary/spontaneous reportingVoluntary/spontaneous reporting Health care professionals, consumers/ Health care professionals, consumers/
patients, or otherspatients, or others Manufacturers: Required for postmarketing Manufacturers: Required for postmarketing
reporting (>90%)reporting (>90%) All adverse drug experience information All adverse drug experience information
obtained or otherwise received from any obtained or otherwise received from any source, foreign or domestic source, foreign or domestic
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What Manufacturers Must Report (21CFR 314.80) Commercial marketing experienceCommercial marketing experience Postmarketing studiesPostmarketing studies Scientific literatureScientific literature
All All domestic spontaneousdomestic spontaneous reports reports Foreign and literatureForeign and literature reports - Serious, reports - Serious,
UnlabeledUnlabeled StudyStudy reports - Serious, Unlabeled, "Reasonable reports - Serious, Unlabeled, "Reasonable
Possibility" that event is related to drugPossibility" that event is related to drug
FDA 13
Regulatory Definition of Serious(21 CFR 314.80) DeathDeath Life-threateningLife-threatening Hospitalization (initial or prolonged)Hospitalization (initial or prolonged) Persistent or significant disabilityPersistent or significant disability Congenital anomalyCongenital anomaly Important medical events that may jeopardize Important medical events that may jeopardize
the patient and may require medical or surgical the patient and may require medical or surgical intervention to prevent one of the above intervention to prevent one of the above outcomesoutcomes
FDA 14
Factors Affecting Reporting
Nature of the Adverse eventNature of the Adverse event Type of drug product and indicationType of drug product and indication Rx or OTC drug statusRx or OTC drug status Length of time on marketLength of time on market Public or media attentionPublic or media attention Extent and quality of manufacturer’s Extent and quality of manufacturer’s
surveillance systemsurveillance system
FDA 15
Limitations of Spontaneous Reports Passive surveillance Passive surveillance
Underreporting occurs and is variable from drug Underreporting occurs and is variable from drug to drug and over timeto drug and over time
Reporting bias existsReporting bias exists Quality of the reports is variable and often Quality of the reports is variable and often
incomplete incomplete Cannot reliably estimate rates of events Cannot reliably estimate rates of events
Numerator uncertainNumerator uncertain Denominator can only be projected Denominator can only be projected
FDA 16
AERS Report Counts by Type: 1990 through 2001
0
50000
100000
150000
200000
250000
300000
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
Direct
15-day
Periodic
FDA 17
Adverse Event Reporting System (AERS) Database of spontaneous reports established in Database of spontaneous reports established in
1969 and restructured in 1997 with greater 1969 and restructured in 1997 with greater capacity to:capacity to: Accommodate internationally accepted E2B data Accommodate internationally accepted E2B data
formatformat Adopt internationally accepted MedDRA coding Adopt internationally accepted MedDRA coding
terminology for adverse events and indicationsterminology for adverse events and indications Allow electronic transmission using international Allow electronic transmission using international
standardstandard
FDA 18
AERS Process Flow Contractors:Contractors:
All MedWatch reports scanned into imagesAll MedWatch reports scanned into images Full text data entered (E2B format)Full text data entered (E2B format) AEs and indications coded in MedDRA at Preferred Term AEs and indications coded in MedDRA at Preferred Term
levellevel
Safety Evaluators:Safety Evaluators: Receive and review reports in “Inbox” for 15-day & direct Receive and review reports in “Inbox” for 15-day & direct
reports reports Screen and monitor potential signals Screen and monitor potential signals
Review division: Review division: Access thru AERS DatamartAccess thru AERS Datamart
Electronic submission: Electronic submission: MFR reports directly via MFR reports directly via gateway gateway
FDA 19
ODS Safety Evaluators Main mission: To identify and assess Main mission: To identify and assess
previously unrecognized (unlabeled) and previously unrecognized (unlabeled) and serious adverse drug eventsserious adverse drug events
Hands-on daily review of all 15-day and Hands-on daily review of all 15-day and direct reports, monitor any safety issues direct reports, monitor any safety issues including known adverse eventsincluding known adverse events
Most intensive monitoring over first several Most intensive monitoring over first several years but continued over the drug's lifetimeyears but continued over the drug's lifetime
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FDA 21
FDA 22
Elements of a "Good" Report: Contains complete dataContains complete data
Suspect drug therapy datesSuspect drug therapy dates Concomitant drug(s) therapy datesConcomitant drug(s) therapy dates Patient medical historyPatient medical history Patient's baseline status documentedPatient's baseline status documented Confirmed diagnosis of the event/diseaseConfirmed diagnosis of the event/disease
Temporal relationship to drug may be Temporal relationship to drug may be establishedestablished Including dechallenge / rechallengeIncluding dechallenge / rechallenge
FDA 23
Signal Generation One or more good case reports from AERS, One or more good case reports from AERS,
literature publication or other sources can literature publication or other sources can trigger further evaluation of a potential trigger further evaluation of a potential safety signalsafety signal
Monitoring of AERS crude data from the Monitoring of AERS crude data from the frequency of PT and other higher level frequency of PT and other higher level grouping case counts may indicate grouping case counts may indicate emerging signalsemerging signals
FDA 24
Evaluation of Reports One very good case or case series reviewed One very good case or case series reviewed
collectively - follow up if neededcollectively - follow up if needed Establish temporal relationship at case levelEstablish temporal relationship at case level Establish case definition whenever feasibleEstablish case definition whenever feasible Look for trends and patterns of events - age, sex, Look for trends and patterns of events - age, sex,
time to onset, dose, severity, outcometime to onset, dose, severity, outcome Identify risk factorsIdentify risk factors Evaluate strength of evidence for causal Evaluate strength of evidence for causal
relationship between drug and eventrelationship between drug and event Assess clinical significance of the issueAssess clinical significance of the issue
FDA 25
Epidemiologic Assessment of Selected Safety Issues Reporting rates vs. background incidence rates- Reporting rates vs. background incidence rates-
Drug utilization data and literatureDrug utilization data and literature Query large databases Query large databases
Cooperative agreementsCooperative agreements Medicaid, large health plans, etc.Medicaid, large health plans, etc.
Active surveillance methods under evaluation- Active surveillance methods under evaluation- looking for drug-related adverse events in a looking for drug-related adverse events in a prospective fashionprospective fashion
FDA 26
Drug Safety Assessment
In addition to signal generation, the office In addition to signal generation, the office responds to consult requests from OND responds to consult requests from OND review divisions, CDER, FDA, outside: review divisions, CDER, FDA, outside: Congress, GAO, DHHS, FBI, CPSC, foreign Congress, GAO, DHHS, FBI, CPSC, foreign
regulatory authoritiesregulatory authorities Develop risk management programsDevelop risk management programs Advisory committee involvement:Advisory committee involvement:
e.g., PPA, COX-2, non-sedating antihistaminese.g., PPA, COX-2, non-sedating antihistamines
FDA 27
Communicating Safety Information Within the FDA Maintain informal communication and Maintain informal communication and
collaborative efforts with Review Divisionscollaborative efforts with Review Divisions Pre-approval Safety Conferences (PSC)Pre-approval Safety Conferences (PSC) Regular Safety Conferences Regular Safety Conferences Written communication Written communication
Summary analysis and assessment of specific Summary analysis and assessment of specific safety issue or overall safety review of a drugsafety issue or overall safety review of a drug
Advisory Committee MeetingsAdvisory Committee Meetings
FDA 28
Regulatory Actions/Risk Management Labeling changes- ADR, Precautions, Labeling changes- ADR, Precautions,
Warnings sectionsWarnings sections Restricted use, registry, special monitoringRestricted use, registry, special monitoring Evaluate the effectiveness of the risk Evaluate the effectiveness of the risk
management programmanagement program Withdrawal from marketWithdrawal from market
FDA 29
Risk Communication
Physician and patient labeling, MedGuidePhysician and patient labeling, MedGuide "Dear Doctor" letter (for specific warnings), "Dear Doctor" letter (for specific warnings),
FDA Talk Papers and Public Health FDA Talk Papers and Public Health Advisories, publicationsAdvisories, publications
FDA MedWatch website postingFDA MedWatch website posting
FDA 30