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

FDA 7

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

FDA 11

FDA 12

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

FDA 20

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