Regulation of Pharmacovigilance Activities by the FDA

Amarilys Vega, MD, MPH

The Center for Drug Evaluation and Research p gy Office of Surveillance and Epidemiology

August 22, 2011

Outline
Background S f t Surveillance i th Lif Safety S ill in the Lifecycle of l f CDER-regulated Products Postmarketing Safety Surveillance
Postmarketing Safety Regulations

Possible Regulatory Actions Based on Postmarketing Safety Data

2

Pharmacovigilance1
The science and activities relating to the g detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems.

The Importance of Pharmacovigilance, World Health Organization 2002

3

Center for Drug Evaluation and Research (CDER) dR h

Center for Drug Evaluation and Research

Janet Woodcock, MD

Approved 5/9/2011, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OrganizationCharts/UCM254312.pdf, accessed 8/1/2011

CDERs Core Functions

Oversight of
Drug Development Postmarketing Safety Product Quality Product Advertising ( g (Promotion) )

Everything someone in CDER does is linked to one of these activities

6

Safety in the Lifecycle of FDA-regulated Products

PreApproval

A P P R O V A L

PostMarketing

Safety in the Lifecycle of FDA-regulated Products

Pre-clinical
Safety & Biological Activity

Phase 1
Safety & Dosage

Phase 2
Safety & Efficacy

Phase 3
Safety & Efficacy

A P P R O V A L

PostMarketing
Safety Surveillance

Safety Concerns S f t C

Strategies and Actions to Minimize Risk

Strategies and Actions to Minimize Risk at Time of Approval

All Products have: P d t labeling Product l b li Routine pharmacovigilance Some products also have: Postmarketing requirements
Cli i l t i l Clinical trials Observational studies

Ri k Evaluation and Miti ti St t Risk E l ti d Mitigation Strategy (REMS)

CDER Forum for International Drug Regulatory Authorities

October 17-21, 2011, College Park, MD Point of Contact , , Justina A. Molzon, MS Pharm, JD
CDERForum@fda.hhs.gov

For meeting information

http://www.fda.gov/Drugs/NewsEvents/ucm167011.htm
10

Office of Surveillance and Epidemiology ( p gy (OSE) ) Overview

11

Office of Surveillance & Epidemiology

Gerald Dal Pan, MD, MHS

Approved 4/29/2011, http://www.fda.gov/downloads/AboutFDA/CentersOffices/OrganizationCharts/UCM254438.pdf, accessed 8/1/2011

12

OSE Mission
The Office of Surveillance and Epidemiology evaluates drug risks and promotes the safe use of drugs by the American People To carry out its mission, OSE works y , together with other offices in CDER
13

OSEs Core Areas

Pharmacovigilance Pharamcoepidemiology Risk Management Medication Error Prevention Everything someone in OSE does is tied to these areas
14

Many Disciplines Carry Out OSE s OSEs Mission

Safety Evaluators Drug Use Analysts Epidemiologists Social Science Analysts s a age e t a ysts Risk Management Analysts Safety Project Managers AERS and IT specialists Contracts specialists Administrative Staff
15

OSEs Roles
Most of OSEs work = Postmarketing Safety OSE always reviews new product proprietary names from a medication error perspective OSE is sometimes involved with evaluation of p premarketing safety of new p g y products
Examples: risk management, epidemiology studies, specific safety issues f f
16

Office of Surveillance and Epidemiology p gy

Premarketing Safety

17

Medication Error Prevention

Division of Medication Error Prevention Analysis (DMEPA) has reg lator a thorit for proprietary name regulatory authority proprietar review
Approach from a safety perspective to minimize medication errors Incorporates input from Office of New Drugs ( p p g (OND), Division of ), Drug Marketing, Advertising, and Communications (DDMAC), others

Identifies error-prone aspects of labels, labeling, & packaging of drug products & provides recommendations t minimize user error d ti to i i i
18

Office of Surveillance and Epidemiology p gy

Postmarketing Safety

19

OSE Role Postmarketing

Reviews and Evaluates Spontaneous Reports Medication error prevention analysis Pharmacoepidemiology Drug utilization data Risk management Regulatory research
20

Postmarketing Safety Laws, Regulations and Guidances

21

Laws
The Federal Food, Drug, and Cosmetic Act (including amendments)
includes the basis for most regulatory activities for human drug products, including postmarketing drug safety Recently amended by the Food and Drug Administration Amendments A t (FDAAA) of 2007 Ad i i t ti A d t Act f

Complete list of the laws

http://www.fda.gov/RegulatoryInformation /Legislation/default.htm /Legislation/default htm

22

Food and Drug Administration Amendments Act (FDAAA)

Public Law 110-85 in September 27, 2007 Content
Title I: Prescription Drug User Fee Amendments of 2007 Title II: Medical Device User Fee Amendments of 2007 Title III: Pediatric Medical Device Safety and Improvement Act of 2007 Title IV: Pediatric Research Equity Act of 2007 Title V: Best Pharmaceuticals for Children Act of 2007 Title VI: Reagan-Udall Foundation Title VII: Conflicts of Interest Title VIII Cli i l Trial Databases Titl VIII: Clinical T i l D t b Title IX: Enhanced Authorities Regarding Postmarket Safety of Drugs Title X: Food Safety Title XI: Other Provisions
23

FDAAA
Title IX Postmarket Safety of Drugs
Subtitle A Postmarket Studies and Surveillance A, contains new FDA authorities to:
Require postmarketing studies and clinical trials Require sponsors to make safety related labeling changes Require sponsors to develop and comply with risk evaluation and mitigation strategies (REMS)

Subtitle A took effect March 25, 2008 FDAAA mandated FDA to develop an enhanced ability d t d t d l h d bilit to monitor the safety of drugs after these products reach the market (Sentinel Initiative)
24

Requirements for Post-Marketing Reporting of Adverse Experiences

21 Code of Federal Regulations (CFR)
310.305 Prescription drugs without Approved Application 314 80 - Drugs New Drug Applications (NDA) 314.80 314.98- Generic drugs Abbreviated NDA (ANDA) 600 80 Biologics Biologics License Application (BLA) 600.80-

Section 760 of Food Drug and Cosmetic Act

Dietary Supplement and Nonprescription Drug Consumer Protection Act Self-implementing law
25

Highlights of Required Adverse Experience Reporting

Serious adverse experience - Results in any of these outcomes:
Death Life-threatening adverse experience Inpatient hospitalization new or prolonged Persistent/significant disability/incapacity Congenital birth defect Others medical judgment jeopardize the patient and require intervention to prevent serious outcome

Nonserious: Not serious Unexpected: Not in the current labeling E Expected: I the current labeling t d In th t l b li
26

Highlights of Required Adverse Experience Reporting

All marketed drugs have reporting requirements to submit expedited reports (15 day)
serious, unexpected adverse events f some OTC products, expedited reports of ALL serious for d t dit d t f i adverse events

Drugs with approved applications also have requirements to submit Periodic reports of other q p adverse events, including other safety-related info (actions taken due to adverse events)
Every 3 months or every year
27

Laws & Regulations Are Enforceable

Work with CDERs Office of Compliance When can FDA take action?
If the company introduces a drug into interstate commerce in violation of provisions If a drug is found to be misbranded If company fails to comply with REMS, postmarket study/clinical trial, or safety labeling c a ges equ e e s changes requirements
28

Laws & Regulations Are Enforceable

What can FDA do?
Issue an untitled letter Issue a Warning Letter Initiate a seizure, injunction, or other proceeding seizure injunction FDA can impose civil penalties for certain violations of the Act
29

Guidances
Guidances further describe FDAs current thinking on a particular topic
External audience Non-binding on the industry http://www.fda.gov/Drugs/GuidanceComplianceR egulatoryInformation/Guidances/default.htm

30

Postmarketing Safety Reporting Guidances (1)

1992 Guideline for Postmarketing Reporting of Adverse Drug Experiences 1997 G idance Postmarketing Ad erse Guidance: Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification of What to Report 2001 Draft Guidance: Postmarketing Safety Reporting for Human Drug and Biological Products Including Vaccines.
31

Postmarketing Safety Reporting Guidances (2)

2008 Draft Guidance: Providing Regulatory Submissions in Electronic Format--Postmarketing Format Postmarketing Individual Case Safety Reports 2009 Guidance: Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed without an Approved pp Application g 2011 Draft Guidance: Postmarketing Adverse Event Reporting for Medical Products and Dietary Supplements During Pandemic Influenza
32

Review and Evaluation of Spontaneous Adverse Event Reports

33

How does post-marketing adverse event & medication error reports get to FDA?
Patients, consumer, Patients consumer and healthcare professionals
Voluntary V l t Voluntary V l t

FDA MedWatch

Manufacturer
regulatory requirements

FDA
AERS Database

5% of all reports

95% of all reports

AERS
Adverse Event Reporting System Database

35

 AERS is a computerized information database designed to support the FDA's postmarketing safety surveillance program for all approved drugs and therapeutic biologic products. The FDA uses AERS to monitor for new adverse events and medication errors that might occur with these marketed products.
36

What is in AERS ?
Individual Case Safety Reports (ICSRs)
Adverse Events Medication Errors Product Problems with adverse events

FOR:
D Drugs and therapeutic bi l i (R + OTC) d h i biologics (Rx Homeopathic Products Tissue products, therapeutic blood products

37

37

What is in AERS ?

5.5 million reports in AERS

Data since 1969 Over 700,000 reports in 2010

Paper submissions
3500 (voluntary) and 3500A (mandatory) forms

Electronic submissions of mandatory ICSRs

International ICH* E2B(R2) standards Majority of submissions today are submitted electronically

Medical Dictionary for Regulatory Activities (MedDRA) coding

events and indications for use

For more information: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/S urveillance/AdverseDrugEffects/default.htm

*I t International C f ti l Conference on H Harmonisation of T h i l Requirements for i ti f Technical R i t f Registration of Pharmaceuticals for Human Use

38

38

Safety Evaluators
Postmarketing Adverse Events Medication Errors Events,
Signal Identification g
Trigger could be AERS or other originating source Review/analyze event reports using AERS

Signal Evaluation
Provide evaluation of safety issues (adverse events and medication errors)

C ll b t with other OSE disciplines Collaborate ith th di i li Collaborate with OND and other CDER offices as appropriate for safety issue Provide recommendations regarding potential regulatory actions
39

mmt6

Diapositiva 39 mmt6 suggest moving this bullet point follow under the Signal Identification bullet above
TRUFFAM; 08/08/2011

When a Serious AE is Rare in the Population Spontaneous Reports are M S t R t More U f l Useful
Rare b t serious adverse event R but i d t
Market Introduction Pre-marketing Safety Data

Intensive case evaluation i l i

Post-marketing Period

Look back at pre-marketing safety database

Example: Felbamate and Aplastic Anemia

Twenty cases of patients with aplastic anemia developing while on felbamate About 100 000 ti t Ab t 100,000 patients exposed t d to felbamate Reporting rate in felbamateexposed: 200/million Incidence in general population: 2/million/year
Source: Nightingale SL. JAMA 1994;272:995
41

When a Serious AE is Common in the Population Spontaneous Reports are Less Useful
AE common in the population OR is a manifestation of the underlying disease
Market Introduction Pre-marketing Safety Data

Intensive case evaluation

Post-marketing Period

Look back at pre-marketing pre marketing safety database

Still hard to establish and quantify risk q y

Spontaneous Reports: The Challenge

Rates (estimates) of adverse drug events can be calculated, but... calculated but
Numerators (exact number and extent of adverse events) impossible to know
Reporting by public not required

Denominators (drug exposure) impossible to know

Number of prescriptions filled is not an absolute measure of exposure due to non-compliance, misuse, abuse, etc.

Event Rate is not the same as Incidence in the Population

43

Drug Utilization Analysts

Analyze data from drug utilization databases A Access t outpatient, inpatient, medical to t ti t i ti t di l claims data # prescriptions, # patients, concomitant use, d ti of use and more duration f d
44

Epidemiologists
Risk identification
Provide context for potential signals p g
Drug use data (denominator) Background rates of adverse events (medical literature)

Risk quantification
Review studies/protocols submitted by sponsors for epidemiologic studies to quantify risks Review published studies Conduct population-based epidemiologic studies to quantify risk and identify risk factors
Through direct access to population-based data population based Through collaborations with outside investigators

Develop new surveillance capabilities

Active surveillance programs
Sentinel initiative
45

Passive vs. Active Surveillance

Passive Surveillance Only cases are reported cases Spontaneous reporting Denominators estimated (drug use data); actual rates of events cannot be determined Active Surveillance Both cases and non-cases are observed Cases are defined by objective criteria Denominators and baseline rates of adverse events are determined P Population b l ti based d
46

Sentinel Initiative - Goals

Develop a national electronic safety monitoring system Leverage multiple sources of electronic data by partnering with data holders
Healthcare systems, insurance companies, etc. 100,000,000 patients by July 1, 2012

Enhance active post-market monitoring of medical product safety

M More effectively l k at common outcomes ( ff i l look (e.g. MI f MI, fractures) ) Increase population basis, sample size Improved access to subgroups, special populations

Use lid t d U validated methods th d Near real-time monitoring

Common data model

Integrate active surveillance with current post-market safety I i ill ih k f monitoring systems

Sentinel will augment, not replace, existing safety monitoring systems

47

Sentinel Initiative Components

Mini-Sentinel Pilot Federal Partners Working Group OMOP Observational Medical Outcomes Partnership http://omop.fnih.org http //omop fnih org

48

Risk Management
Risk management is an iterative process of
Assessing a products benefit-risk balance product s balance, Developing and implementing strategies to minimize its risks while preserving its benefits, Evaluating tool effectiveness and reassessing the benefit-risk balance, and , Making adjustments, as appropriate, to the risk minimization strategies to further improve the benefit-risk balance 49

What is a REMS* ?
Risk Evaluation and Mitigation Strategy (REMS) may require to include:
Medication Guide (patient labeling) C Communication plan (h lth i ti l (healthcare providers) id ) Elements to assure safe use (ETASU) Implementation system

Must include a timetable for submission of assessments of the REMS

*section 505 1 of FDCA 505-1
50

What are ETASUs?

A. B. C. D. E. F. Health care providers who prescribe the drug have particular training or experience, or are specially certified; experience Pharmacies, practitioners, or health care settings that dispense the drug are specially certified; The drug is dispensed to patients only in certain health care settings, such as hospitals; The drug is dispensed to patients with evidence or other g documentation of safe use conditions, such as laboratory test results; Each patient using the drug is subject to certain monitoring; p g g j g; or Each patient using the drug is enrolled in a registry
51

Risk Management Analysts

Leads OSE review of
Proposed risk management programs, such as Risk Evaluation and Mitigation Strategies (REMS) Ri k management program assessment Risk t t Often OSE multidisciplinary team reviews

Premarketing and Postmarketing

52

Health Communications Analysts & Social Scientists

Health Communications Analysts
Review risk communication components of risk management programs (such as REMS)

Social Scientists
Review behavioral or comprehension studies/protocols submitted by sponsors
Often relates to risk management program assessment
53

What Actions Can FDA Take Based on Postmarketing Safety D t ? S f t Data?

54

Safety in the Lifecycle of FDA-regulated Products

A P P R O V A L
PostMarketing g
Safety Surveillance (Passive & Active) Clinical Trials Observational Studies Drug Use Patterns Drug Other

New Safety Concerns

Strategies & Actions to Minimize Risk

55

Post-marketing surveillance: Potential FDA regulatory action(s)

Ch Changes t safety sections of labeling to f t ti f l b li
Contraindications, Boxed Warning, Warnings/Precautions, Adverse Reactions Can require (FDAAA) or request labeling changes

Post-marketing requirement (PMR) studies Risk evaluation and mitigation strategies (REMS) Removal of product from market
56

Communicating New y Safety Information to the Public

FDA might: Ask manufacturer to issue a Dear Health Care Professional Letter Issue an FDA Drug Safety Communications g y
MedWatch email Safety Alerts www.fda.gov/medwatch

Publish an FDA analysis in a medical journal Postmarket Drug Safety Information for Patients and Providers website
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationf p g g g y g y orPatientsandProviders/default.htm
57

Questions

58