# Presentation: 212694

## Update from the Office of Postmarketing Drug Risk Assessment

- 36th Annual Meeting of the DIA
- San Diego, CA
- June 12, 2000

## Agenda

- Organizational and procedural initiatives in OPDRA
- Patrick Guinn
- Status update on AERS and electronic ADR submissions
- Greg Brolund
- Scientific and QA/QC safety evaluation initiatives
- Min Chen
- Tradename analysis and medication error surveillance
- Carol Pamer

## Slide 3

## Office of Postmarketing Drug Risk Assessment

- Organizational and Procedural Initiatives
- Patrick F. Guinn
- Project Manager, DDRE I

**Notes:**
Good Morning. 
As part of this session’s presentation today, I will be going over some of the Organizational and Procedural Initiatives in OPDRA. 

## Organizational Changes Since June 1999

- Permanent Office Director Selected
- Establishment of Second Associate Office Director Position
- Establishment of Deputy Division Director Positions
- Establishment of Project Management Positions in the Office and Divisions
- Increase in Personnel

**Notes:**
The following is a list of some of the most significant organizational changes that have taken place within OPDRA since June 1999.

[READ THROUGH  LIST]

These changes have allowed a greater stability within OPDRA and  the ability to work more closely with the ORM Review Divisions.  

## CDER Organization

**Notes:**
This is a basic organizational chart that shows where OPDRA fits into the overall CDER structure. OPDRA has been placed within the Office of Review Management because we interact very closely with the ORM Review Divisions. As you can see, OPDRA is made up of the Immediate Office as well as 5 additional areas.

## Immediate Office

- Office Director: Peter Honig
- Associate Office Director: Jerry Phillips
- Associate Director for Science and Medicine: David Graham
- Project Manager: Linda Brophy
- AERS Group (4 Staff Members)
- Administrative Staff (4 Staff Members)

**Notes:**
I will briefly describe the different areas within OPDRA, starting with the Immediate Office.

Dr. Peter Honig was selected to lead OPDRA in overseeing the safety of marketed drug  products. 

Jerry Phillips is the Associate Office Director. He primarily oversees the Medication Errors and Tradename Review areas in addition to representing the Office in many other capacities.

Dr. David Graham was selected  for the second Associate Office Director position within OPDRA. In this position, he will be working with and developing the scientific capabilities of the Office. (This will entail all aspects of the scientific program, including pharmacovigilance, epidemiology, database development, and Staff development. The goal is to further develop OPDRA’s capabilities to study important safety issues using population based resources to move us beyond sole reliance on spontaneous case reports.)  

## Medication Errors Staff

- Associate Office Director: Jerry Phillips
- Project Manager: Sammie Beam
- 4 Safety Evaluators
- Activities:
- - Tradename Evaluation (Pre-marketing)
- - Assess Medication Errors (Post-marketing)

**Notes:**
[Read Slide]

Carol Pamer will discuss these activities more in depth, in her presentation for this session. 

## Extramural Program Staff

- Acting Staff Director: Jerry Phillips
- 2 Administrative Staff Members
- Activities:
- Management of the Cooperative Agreement Program

**Notes:**
Through the Cooperative Agreement Program, OPDRA has the ability to leverage its internal expertise and surveillance data with formalized access to extensive databases and epidemiologists experienced with the use of each database.

## Current agreement holders for the CO-OP AG Program

- United Health Care (Shatin, Peterson, Gardner)
- Harvard Pilgrim Health Care (Platt, Chan)
- Vanderbilt University (Ray)
- Boston Collaborative Drug Surveillance Program (H.Jick, S.Jick)
- Johns Hopkins University (Moore)

**Notes:**
UHC - Drs. Deborah Shatin, Eileen Peterson, and Jacqueline Gardner
Serves more than 40 million individuals through a broad continuum of health care products and specialty services. Current and historical medical and pharmaceutical data from 12 health plans are included in this research database.
Harvard Pilgrim - Drs. Richard Platt and Arnold ChanCombines populations and resources from 3 HMO (Harvard Pilgrim Health Care, HealthPartners, and Fallon Community Health Plan. Each HMO maintains automated record linkage systems including drug dispensing information, coded diagnoses for ambulatory and in-patient care, and access to medical records.
Vanderbilt - Dr. Wayne RayContains computerized files of the Medicaid program - which include enrollment, pharmacy, hospital, outpatient, and nursing home files - define the population and person-time, provide a measure of drug exposure, facilitate rapid disease ascertainment and provide some information on confounders.
Boston Collaborative - Drs. Herschel Jick and Susan JickThe General Practice Research Database (GPRD) provides information derived from computerized general practices in the UK and Group Health Cooperative of Puget Sound.
JHU - Dr. Richard MooreThe Johns Hopkins AIDS service is the largest care provider for HIV-AIDS infected persons in Maryland.

## Information Technology Staff

- Acting Staff Director: George Armstrong, Jr.
- 8 IT Specialists
- 1 Epidemiologist
- 2 Administrative Staff Members
- Activities:
- AERS and Med Errs Troubleshooting, validation
- Database Support and Searches
- Customized Data Presentations
- Database Acquisition

**Notes:**
[Read Slide]

This only a sample list of the extensive work and support that this group provides to the Office. 

## Division of Drug Risk Evaluation I

- Director: Julie Beitz
- Deputy: Anne Trontell
- Project Manager: Patrick Guinn
- 10 Safety Evaluators
- 5 Epidemiologists
- 2 Administrative Staff Members
- Program Management Officer (IMS Data)
- Supports: ODE I, ODE V, and HFD-570

**Notes:**
Within OPDRA, there are two Divisions of Drug Risk Evaluation which work closely with the Office of Review Management Review Divisions.  
These Divisions are structured with the following positions.
[Read slide]
The Safety Evaluators and Epidemiologists are responsible for post-marketing safety surveillance. Min Chen will discuss the Safety Evaluator portion more in depth, later in this session. In addition, OPDRA is becoming  more involved at an earlier stage in drug development, including some pre-marketing support.

ODE I: 
HFD-110 Cardio-Renal Drug Products
HFD-120 Neuropharmacological Drug Products
HFD-150 Oncology Drug ProductsODE V:
HFD-540 Dermatologicic and Dental Drug Products
HFD-550 Anti-Inflammatory, Analgesic, and OphthalmicDP
HFD-560 Over-The-Counter Drug ProductsODE II:
HFD-570 Pulmonary and Allergy Drug Products

## Division of Drug Risk Evaluation II

- Director: Evelyn Rodriguez
- Deputy: Kathleen Uhl
- Project Manager: Mary Dempsey
- 10 Safety Evaluators
- 5 Epidemiologists
- 2 Administrative Staff Members
- Program Management Officer (IMS data)
- Supports: ODE II, ODE III, and ODE IV

**Notes:**
ODE  II: 
HFD-510 Metabolic and Endocrine Drug Products
HFD-580 Reproductive and Urologic Drug ProductsODE III:
HFD-160 Medical Imaging and Radiopharmaceutical DP
HFD-170 Anesthetic, Critical Care, and Addiction DP
HFD-180 Gastro-Intestinal and Coagulation DP
ODE  IV:
HFD-520 Anti-Infective Drug Products
HFD-530 Anti-viral Drug Products
HFD-590 Special Pathogen and Immunologic Drug Products 

## Postmarketing Surveillance Procedures within OPDRA

- AERS
- Datamining Initiatives
- MARS
- Database Resource Procurement

- Consult Tracking System
- SE Forum
- Epi Forum

**Notes:**
This is a list of some of the resources or activities that we use within OPDRA to aid us in postmarketing surveillance.
AERS - Adverse Reporting System
MARS - Internally generated surveillance signals
Database Resource Procurement - Drug utilization and Population based data resources
SE Forum and Epi Forum are weekly meeting in which emerging signals or safety issues are discussed

## Postmarketing Surveillance Procedures within FDA

- Pre-Approval Safety Conferences
- Participation in ORM Review Division Administrative Rounds
- Monthly Safety Meetings with ORM Review Divisions
- Consult Requests/Processing

- Support for FDA Advisory Committee Presentations
- DataMart
- Electronic submission of ADRs  starting October 2000
- Collaboration with CFSAN on Dietary Supplements

**Notes:**
These are some examples of the collaborative effort within the FDA pertaining to Postmarketing Surveillance.

[Read Slide]

Greg Brolund will discuss DataMart and the Electronic Submission of ADRs more in depth in his presentation for this session.

## Goals of Pre-Approval Safety Conferences

- Ensuring that OPDRA is aware of potential postmarketing safety problems in drugs about to be approved
- Considering, jointly, the need for any special postmarketing analyses, or postmarketing safety studies, or other evaluations to be implemented by or agreed to by the sponsor prior to the approval of a drug product
- Determining if there is any special information or feedback that the ODE review division would like from the OPDRA risk evaluation division during the immediate postlaunch life of the soon-to-be-approved drug product

**Notes:**
Pre-Approval Safety Conferences between the ORM Review Divisions and OPDRA take place for all New Molecular Entity Drugs that are about to be approved. The main objective is to detect suspected serious reactions as quickly as possible so that the newly detected risk can be communicated promptly and necessary adjustments to the labeling or marketing status can be made promptly.

## Postmarketing Surveillance External Collaboration

- IMS Health Data (NDTI, NPA, PP, RP)
- Cooperative Agreements
-         “Hot Topics”
-         Feasibility Studies
-         Full Epi Studies

**Notes:**
NDTI - National Disease and therapeutic Index
provides statistical information on the patterns and treatment of disease encountered in office-based medical practicesNPA - National Prescription Audit
can be used to track dispensing trends over specific periods of time and for calculation of Adverse Drug Report (ADR) reporting ratesPP - Provider Prospective
monitors pharmaceutical purchases (prescription, OTC and select diagnostic products) to the non-retail market (non-federal hospitals, federal facilities, clinics, long-term care facilities and HMOs.RP - Retail Perspective
monitors pharmaceutical purchases by independent, chain, and food stores with pharmaciesSafety issues at different stages are discussed with the cooperative agreements. 

## Postmarketing Surveillance External Collaboration (cont.)

- Monthly Video Conferences
- Health Canada
- EMEA (European Medicines Evaluation Agency)
- TGA (Therapeutic Goods Agency)
- CERTS (Centers for Education & Research in Therapeutics)

**Notes:**
Discussion of safety issues or emerging signals in the International Community.

A more in depth discussion on the CERTS Program will be presented this afternoon by Dr. Honig. However, I will provide brief information on how this relates to OPDRA.

## CERTs 

- Coordinating Center:  Duke University
- Duke University (Califf)
- University of North Carolina (Campbell)
- Vanderbilt University (Ray)
- Georgetown University (Woosley)
- More to come
- All to share 7.7 million dollars/3 years
- Public-private partnership

**Notes:**
The Coordinating Center for the Centers for Education and Research in Therapeutics is [Read Slide]

## Sampling of OPDRA initiatives underway with CERTs

- Active surveillance in UNC Emergency Rooms
- Drug Induced Prolonged QT registry (Georgetown)
- Assessment of effectiveness of dofetilide risk management measures (Duke)
- Pediatric medication errors classification and analysis (UNC)
- Survey of training program directors of prevalence of the teaching of rationale therapeutics, prescribing, ADR recognition and reporting (Georgetown)

**Notes:**
These are some of the OPDRA initiatives underway with CERTS
[Read slide]

## Upcoming OPDRA Organizational Initiatives

- Paul Stolley, MD (former Chief of the Department of Epidemiology at University of Maryland)
- Joining OPDRA in July 2000
- Senior Scientific Advisor
- Didactics, core competencies, development plans
- Strategic planning (e.g. active surveillance)
- Fellowship training program (with CERTs as shared experience).

**Notes:**
In July of this year, Dr. Paul Stolley will joining OPDRA to serve as a Senior Scientific Advisor.

His activities will include [Read Slide]

## Slide 22

## OPDRA Update - Adverse Event Reporting System (AERS)

- Greg Brolund
- Associate Director, Office of Information Technology, CDER/FDA

## Agenda

- Adverse Event Reporting System
- DataMart
- Electronic Submissions

## Post Marketing Surveillance at the Center for Drug Evaluation and Research 

- 300,000+ reports received each year
- Expedited; Periodic; Spontaneous
- Reviewed by about 36 safety evaluators, epidemiologists and medical error reviewers
- Of interest to about 300 medical reviewers of pre-approval applications

## AERS and the Data Mart

## Adverse Event Reporting System

- AERS Application
- Core application for data entry and safety evaluation
- In use since November 1997
- Database schema is ICH E2B compliant with additional elements for regional needs
- Supports multiple report types and sources.
- Periodic and Serious Reports
- Spontaneous and Medication Errors

## AERS 2.0

- Major new release of AERS implemented May 2000
- New functionality
- Improved leveraging of product data to accelerate data entry process
- Enhanced searching capability
- Integration to electronic submissions

## Agenda

- Adverse Event Reporting System
- DataMart
- Electronic Submissions

## AERS DataMart

- For NDA reviewers and safety evaluators
- Fast access to large amounts of data based on complex query criteria
- Intuitive, reliable application built for low cost and high benefit
- Individual report display - 3500A format
- “Line listing” display for groups of reports
- Export data to other desktop tools e.g. Excel
- First release of datamart developed and deployed in 90 days

## DataMart Benefit

- Datamart application will allow NDA reviewers to access reports without using paper copies
- Will eliminate the need for industry to submit paper copies - Electronic submissions.

## Agenda

- Adverse Event Reporting System
- DataMart
- Electronic Submissions

## AERS Electronic Submissions

- FDA has prioritized the implementation of electronic submissions as a top program goal.
- Electronic submissions will support:
- ICH E2B and M2 Step 4 documents
- Efficient and effective safety reporting
- “Paperless office” requirements
- Reduced costs for FDA and industry
- Electronic submissions software has been available since October 1999 for “perfect submissions”.
- Full production is scheduled for October 31, 2000.

## Expedited Report Working Group

- Approximately 15 PhRMA companies are in the working group
- Goal is to identify and solve technical and process problems associated with electronic submission of expedited reports
- At least 9 companies are submitting reports via physical media

## Software Version 1.1

*Software Version 1.1*

- Nine manufacturers have submitted DTD 2.0 files since November 1, 1999.

**For files that have passed Parsing and M2 Validation*

**Notes:**
Note: Numbers in chart reflect test files received through 2/2/00.

Were any of these reports actual reports?  Did they contain most of the fields that we would expect to be filled in for a complete report?  Or were the reports mocked up, sparsely populated test data?

[I do not know whether any of these reports were actual reports, although the reports have been fairly complete.  My guess is the use of actual reports has varied somewhat from one manufacturer to the next, and that the further along the manufacturer is with their software, the less likely the report is to be real (i.e., some manufacturers use the same report over and over, changing slightly each time for testing purposes.)]  
The test files submitted by manufacturers varied somewhat in terms of which data elements were populated, however, most files contained all of the data fields that would be expected for a complete report, with a few exceptions (e.g., missing drugs, missing patient information).  Most ICSRs were not sparsely populated.  

## October 2000 Implementation

- Submissions via Gateway or physical media
- Automated acknowledgement for Gateway submissions
- Acceptance of a subset of information contained within the submission
- Acceptance of reports with the minimum data set

## Pre-marketing Application

- Industry Generates an e-IND, e-NDA Original, Amending and Supplemental Submission

- FDA parses e-IND into EDR, Scientific Databases, and tracking databases

**Pre-marketing Application**

- Exchange between FDA and Industry via secure e-mail

- Formal reviews archived in E-Doc Check-in

**Review Process**** **

**AERS**

- Adverse event reports submitted to FDA

- Adverse event reports received through Gateway

- Databases populated, submissions archived in EDR and available to reviewers at desktop

- Field Inspectors access information electronically and enter inspection data

**Post-marketing**

**INDUSTRY**

**FDA**

**EDR**

**SURVEILLANCE**

**REVIEW**

- Databases populated, submissions archived in EDR and available to reviewers at desktop

**RESEARCH**
**REG AFFAIRS**

**RESEARCH**
**REG AFFAIRS**

**PUBLIC**

**E Reading Room**

- Internet Access to Reviews,
-  Current Labeling

**MEDWATCH**

## Slide 38

## Scientific and QA/QC Safety Evaluation Initiatives in OPDRA

- By
- Min Chen, M.S., R.Ph.
- Team Leader, DDRE I
- June 12, 2000

## Count of Total Reports Received by Report Type and Year

## OPDRADrug Safety Monitoring

- Hands-on review all 15-day and direct MedWatch reports
- Follow-up on selected reports
- Evaluate case series retrieved from AERS & literature
- Identify signals
- Risk assessment
- Documentation and recommendation

## Slide 42

## Points to Consider for QA/QC in Drug Safety 

- Report sources
- Data retrieval methods
- Report evaluation principles
- Risk assessment of a signal
- Regulatory actions

## Report Sources

- FDA
- U.S. (all*)
- Foreign (serious, unlabeled)
- Study, Literature (serious, unlabeled, causally related)
- Direct MedWatch

- MFR
- U.S. (all)
- Foreign (all)
- Study, literature (all)
- Direct MedWatch**

## Data Retrieval (FDA)(Good Searching Practice) 

- Databases
- Data entry timelag of non-serious periodic reports
- Adverse event terms coding principles
- Search strategy- PT, HLT, HLGT, SOC

## MedDRA Structure

## Report Evaluation Principles(Good Evaluation Practice)

- How to decide there is a drug association?
- What causality assessment rules to use?
- Case definitions
- Temporal relationship between drug and event in each case report
- Concomitant drug(s)
- Underlying medical history
- Suspect drug dechallenge/rechallenge

## Report Evaluation Principles(Good Evaluation Practice)

- Many other factors considered-
- pharmacology, pharmacokinetics /pharmacodynamics of a drug or class
- animal testing findings
- clinical study findings
- population risk characteristics
- quality of data

## What constitutes a signal?

- Any previously unrecognized serious, unlabeled event possibly related to drug administration?
- Specificity? Severity?
- How many good cases should constitute a signal?
- NME vs older drug
- Datamining tool utility- detection of “higher than expected” rare and serious events

## Risk Assessment of a Signal 

- Population exposure data
- Background incidence rate references
- Calculation of the risk, relative risk or absolute risk
- How big should the risk be to recommend different regulatory actions?
- When are Epi studies needed?

## Regulatory Actions

- Revise the labeling-
- Adverse Reactions
- Precautions
- Warnings, Box Warning
- Dear Health Care Practitioner letter
- Restriction in use (e.g., second line)
- Withdrawal from market
- Time line of the actions
- Post-action monitoring

## Good Pharmacovigilance Practice Initiatives in OPDRA

- Quality assurance in data
- Good searching practice
- Good evaluation/assessment practice
- Good communication practice
- written reviews
- labeling recommendations
- regulatory actions
- SOP’s/MAPP’s/Guidances- FDA’s GRP

## Summary

- FDA  and Industry are partners in drug safety
- More interactions needed to assure consistent quality of data, evaluation principles, risk assessment, and regulatory actions

## Slide 54

## Office of Postmarketing Drug Risk Assessment

- Medication Errors Prevention Staff
- Carol Pamer, R.Ph.
- Safety Evaluator

## Previous FDA Processes

- Labeling and Nomenclature Committee (LNC)
- FDA review chemists, pharmacists, MDs as well as representation from Division of Drug Marketing and Advertising and Communication (DDMAC)
- Reviewed proposed tradenames and established names collectively on a monthly basis

## Previous FDA Processes

- Medication Error Committee
- Consisted of FDA health professional staff
- Reviewed FDA MedWatch/Spontaneous Reporting System postmarketing safety reports of medication errors
- Determine action(s) required by FDA to prevent further errors, such as public notices, repackaging, product recalls

## Current Process

- Proprietary name review and postmarketing safety error report reviews under OPDRA as of 10/1/99
- Consulting role to FDA Reviewing Divisions
- Full-time staff for CDER (4 Safety Evaluators, Project Manager, 2 Data Entry Technicians, Data Classifier, Secretary)
- LNC responsible for established name, new dosage form names. Consults w/USP&USAN
- DDMAC participates in OPDRA review process

## Published FDA Policy, Procedures

- Imminent release of MAPP for “Medication Error Prevention” drafted, reviewed by FDA reviewing divisions
- Imminent release of FDA Guidance for Industry “Evaluating Proprietary Drug Names”
- FDA proposed regulations regarding reporting of medication errors, serious ADRs by manufacturers drafted

## Pre-marketing Proprietary Name Review

- Expert Panel Review
- Simulation of prescription ordering process
- Review of packaging and labeling for error-prone qualities
- Perform risk-benefit analysis

## Pre-marketing Proprietary Name Review

- Submit as early as end of IND Phase 2 but minimum data needed: recommended dose, dosage form, route, strength(s), indication(s), proposed packaging format
- First-in-First-Out Policy, but primary consideration given to PDUFA/Goal date
- Accepted names re-reviewed 90 days prior to NDA action date, for products approved in the interim

## Expert Panel Review

- OPDRA Medication Errors Prevention Staff, DDMAC representative
- Group consensus formed based on extensive review of number of drug reference texts, FDA internal databases (INDs & NDAs)
- Clinical practice experience
- Primary focus is to identify potential sound-alike, look-alike names

## Expert Panel Review

- Look for overlapping strengths, similarity in dosage regimens which increase potential for error
- Levoxine 0.125mg q.d. and Lanoxin 0.125mg q.d.
- Norvasc 10mg and Navane 10mg
- Celebrex, Celexa, Cerebyx

## Simulated Rx Ordering: Written

- Inpatient orders, Outpatient Rxs handwritten, optically scanned, and sent to  approx. 100 health professionals in FDA
- Specific dosing included
- Marketed products included
- Reviewers provide written interpretation of name via email and comments on related products that could increase chance of error

## Simulated Rx Ordering: Verbal

- Verbal inpatient and outpatient orders recorded via voicemail and sent out to another set of FDA reviewers
- Similar format
- Reviewers provide written interpretation of name via email, as well as comment on related names or products that could increase chance of error

## Other resources

- Adverse Event Reporting System (AERS) database
- Drug Quality Reporting System (DQRS) database
- National Library of Medicine’s MEDLINE database
- Look for similar naming structure for already approved products & if errors already occurring or if in foreign market

## Packaging, labeling review

- Review at earliest possible time, often close to NDA action date at second review
- Identify error-prone packaging or labeling prior to entry into marketplace
- Multiple strengths distinguishable?
- Potential packaging confusion? (pre-mixed Flagyl/Mivacron IVPB solutions)
- Would an error with the product be likely to have serious outcome? (e.g., KCl injection)

## Overall Assessment

- Summary document to Reviewing Division
- Information conveyed by Reviewing Division to sponsor regarding suitability of chosen proprietary name
- Submit additional name(s) if necessary
- Phase 4 commitment(s)

## Postmarketing Safety Reviews

- Monitor MedWatch reports in AERS database for errors with all FDA-approved products
- Summarize nature and extent of identified problems
- Provide summary of cases and recommendations to FDA Reviewing Divisions