# Presentation: 106753

## Risk Management:  The FDA Role

- Paul J. Seligman, MD, MPH
- Director, Office of Pharmacoepidemiology and Statistical Science
- Center for Drug Evaluation and Research
- January 17, 2002

## Outline

- Risk Management
- why now, what does it mean
- systems approach
- FDA role
- where we are today
- what is working, what is not
- Vision for the Future
- where we’re going

## Recent CDER Reorganization

## OPaSS

- Office of Drug Safety
- surveillance, AERS, epidemiology, MedWatch, labeling, MedGuides, medication errors, trade name review, post-marketing research
- Office of Biostatistics
- datamining, patient profiles, methods research

## Risk Management Drivers

- Focus on health care quality, patient safety, prevention of medical errors
- Withdrawal of valuable drugs due to poor or ineffective management of known risks
- interactions/co-prescribing
- failure to monitor
- inappropriate use

## What is the Drug Safety Profile in the U.S. Today?

**David Laurence (CEO, Kaiser Health plans): 180,000 deaths per year in hospitalized patients**
**GAO (Jan., 2000):  Magnitude uncertain**
**Hospitals****	****1.9-19 ADEs/100 admissions**
**Nursing Homes  .4-.7 ADE/resident/month**
**Deaths****	********100,000/year in hospitals**
**                   ****(not reliable)**

## Post-Marketing Adverse Event ReportsManufacturer 15-day Reports & Direct Reports

- <date/time>

**Post-Marketing Adverse Event Reports****Manufacturer 15-day Reports & Direct Reports**

**1989**

**1990**

**1991**

**1992**

**1993**

**1994**

**1995**

**1996**

**1997**

**1998**

***1999**

-                                 **Calendar Year ( * as of 11/10/99 )**

## Anticipating Serious Adverse EventsLimitations of Premarketing Database

- Too few subjects
- Too homogenous population
- age
- disease
- concomitant drugs
- Too brief duration
- Not how it’s used in practice

## Increasing Importance of Post-marketing Surveillance

- Increased role of pharmacotherapy
- More rapid uptake of drug use post launch
- Healthcare systems in general manage risk poorly
- Must customize approach
- Passive surveillance vs active surveillance
- Observational vs Prospective studies

## Managing the Risks From Medical Product Use & Creating a Risk Management Framework May 1999

- http://www.fda.gov/oc/tfrm/1999report.html
- FDA Task Force
- Frames FDA’s Role in Medical Product Risk Management
- Pre-market and Post-market

## Task Force Findings

- time is right to apply systems framework to medical product risk management
- FDA plays only a part in complex system of RM
- involves numerous other groups
- systems approach leads to better integration of efforts of all involved parties

## Components of RM System

- Risk Assessment - estimation & evaluation of risk
- Risk Confrontation - determination of acceptable levels of risk in societal context
- Risk Intervention - actions to control risk
- Risk Communication - interactive process of exchanging risk information
- Risk Management Evaluation - measurement of effectiveness of aforementioned activities

## Slide 13

**Notes:**
This is a rm model taken from the 1999 FDA report ......

This very general graphic represents how most organizations view risk management.  It expresses rm as a continuum in perpetual revision.

Is this how cder works? Well sort of. The focus of most of our effort is up at 2 o’clock as we assess premarket safety and efficacy. We are truly engaged with only a fraction of stakeholders involved in drug prescribing, dispensing, and funding.  Input other than from our advisory commitees, input that may greatly influence how drugs are actually is not universally sought. 

Some review divisions - such as anti-virals, have developed exceptional relationships with their stakeholders.

To actually take advantage of this framework - and maximize our opportunities to reduce risks of pharmaceutical use - we need to focus more on our stakeholders and more on what happens after drugs are approved.

Missions in post-marketing, compliance, stakeholder partnerships, labeling & other communication efforts can be unified under risk management principles

## Risk Management?

- Not a commodity or ‘off the shelf’ solution
- Not applied equally to all issues/drugs
- What is it attempting to address?
- Preventable adverse events due to the use/misuse of the product

## Benefit:risk management

- Maximizing the benefits
- Maximizing the safe use
- Minimizing the risks
- drug “safety” equated with latter two

## Safety Central to Mission

- Food, Drug, and Cosmetic Act (Sec. 505)
- “include all tests reasonably applicable to show.... Drug is safe...under...proposed labeling”
- results of such tests show...drug is safe under such conditions”

## What is “Drug Safety”?

**No drug is 100% “Safe”**
**FDA Definition:  Benefits outweigh foreseeable risks for:**
**Specific Indication**
**Specific Population**

## A Drug is Less “Safe” if:

**Used in a way that decreases foreseeable benefit**
**Used in a way that increases the risk**
**If the actual risks are greater than the predicted risk**

**In addition, for most drugs....**
**	****	****Benefit to **_**many**_
_**	**__**	**_**Severe harm to tiny minority**

**Example ****	****	****Acetaminophen**
**	**_**Minor**_**  benefit to vast numbers**
**	****#1 cause of drug-induced liver failure in the U.S.**

## Risk Perception

**High risk - when newly approved drug develops safety problem**
**Lower risk - severe known side effects of older drug (e.g. NSAIDS)**

## Conceptual Framework

## Preventable Errors

- Poor Communication
- Product Name Confusion
- Directions for Use
- Abbreviations
- Stress

- Poor Techniques
- Knowledge Deficit
- Staffing
- Labeling
- Packaging

## FDA Risk Management

- Maximize Benefit

- Minimize Risk

**Reduce**
**Preventable**
** ****Risks**

**Reduce Quality**
** ****Risks**

## Risk Management Model

**Premarket Risk Assessment must include anticipated conditions of use**

**FDA approval **_**may**_** require risk**
**management steps**

**Assess adequacy of risk management**

**Iteration**

## Features of Risk Management Model

**Explicitly acknowledges RISKS**
**Focuses on roles of manufacturer, regulator, prescriber, patient, healthcare system in  mitigating risk and maximizing benefit**
**Shift from “blame” model to constructive model**

## What Can the FDA Control?

- Marketing status
- Approval decision
- Withdrawal from market
- Labeling
- Accuracy, completeness and new information
- Availability of patient information
- Trade names and packaging

## Lessons Learned

*“**Risk management of marketed drugs:  FDA & the interface with the practice of medicine” (Pharmacoepidemiology & Drug Safety 2001;10:205-208)*
- Labeling & ‘Dear Dr’ letters relatively ineffective risk management tools
- Most common systems failure - getting knowledge to physicians
- Labeling and labeling changes  knowledge
- Knowledge does not necessarily drive behavior

## What Can the FDA Control?

- Marketing status
- Approval decision
- Withdrawal from market
- Labeling
- Availability of patient information
- Trade names and packaging
- Application of risk management strategies

## What Can the FDA Control?

- Restricted access
- Subpart H (21 CFR 314.520)
- FDA ‘concludes that a drug product shown to be effective can be safely used only if distribution or use is restricted’
- ‘Distribution restricted to certain facilities or physicians with special training’
- ‘Distribution conditioned on the performance of specified medical procedures’
- Serious or life threatening

## FDA Risk Communication Initiatives

- Proposed professional labeling changes
- Medication guides
- Risk communication research

## Proposed Professional Labeling Rule

- Published December 22, 2000
- Based on research/focus groups
- Usefulness of current label
- Information they want to know
- Three sections
- ‘Highlights’
- Index
- Comprehensive (reorganized) section

## Involving the Patient Medication Guides

- Regulations published 12/1/98 (eff. 6/1/99)
- Triggering criteria
- When it poses a “significant public health concern...”
- Translation:
- when patient needs to know of serious risks, relative to benefits, that might affect decision to use or continue use
- could help prevent serious adverse events
- when a drug is important to health, patient adherence to directions is critical to effectiveness
- On average, to apply to 5-10 products annually
- Not to be used indiscriminately

## Improving Risk CommunicationHealthcare Provider

- Learn from others
- Risk Communication Workshop:  sponsored by the Centers for Education and Research on Therapeutics (CERTS)
- Programmatic Research
- Understanding how best to communicate appropriate drug usage to HCPs
- Understanding how to communicate to change ‘risky’ HCP behavior once identified
- Quantifying the effects of our efforts; how to measure message penetration, what are the outcomes of interest
- CERTs:  “Practice change interventions” as focus of one of the new evidence-based practice centers

## Improving Risk CommunicationThe Patient

- Efforts should be guided by a ‘diagnostic analysis’ of factors/barriers/ perceptions likely to influence the effectiveness of the message.
- Choice of strategy should be guided by this analysis and informed by knowledge of relevant research.
- Consumer involvement has been shown to be variably effective:  we need to learn from these experiences.

## 	Risk Management in CDER	Current Initiatives

- Patient Safety Task Force - reduce patient risks in partnership with federal agencies, private-sector organizations and states
- Continued research collaboration with AHRQ/CERTS
- Adopting RM approach to drug quality surveillance
- GMP Inspection Compliance Program Pilot

## Risk Management in CDER	Current Initiatives	

- White Paper and Action Plan
- Enhanced use of data to target compliance
- Advisory Committee
- Patient Safety Initiative
- Broadening partnership discussions
- Reorganization/staffing changes

**Notes:**
(Janet - need guidance on this..don’t want to worry folks)

## Drug Safety & Risk Management Subcommittee (DSaRM)

- Nationally recognized experts in
- risk perception
- risk management
- pharmacoepidemiology
- clinical pharmacology
- clinical research
- medication errors

## DSaRM MembershipChair - Peter Gross, MD

- Brian Strom, MD
- Michael Cohen
- Ruth Day, PhD
- Jacqueline Gardner, PhD
- Eric Holmboe, MD

- William Campbell, PhD
- Curt Furberg, MD
- Stephanie Crawford, PhD
- Kenneth Melmon, MD

## DSaRM

- First meeting - April 22-23
- Tentative dates - July 25-26, Sept 26-27
- Plan to change DSaRM status to full agency committee

## Visions for the future

- More rigorous, quantitative, analytic approach to making RM decisions
- at all phases of drug review and marketing process
- how to appropriately, independently assess risks and benefits
- how to compare/evaluate the benefit:risk ratio
- when do the risks outweigh the benefits?

## Visions for the future

- Development of a hierarchy of RM interventions
- to be applied as indicated
- involves stakeholders in new ways

## Visions for the future

- Guidance for the FDA
- ensure consistency and transparency in applying RM
- Proactive vs. reactive
- anticipates problems
- active surveillance of drug utilization
- close monitoring of known safety concerns

## Visions for the future

- New Age of Drug Information
- for the consumer
- for the healthcare provider