# Presentation: 656628

## Adverse Events

*The FDA Perspective **— *
*Where We Are Now, Where We Hope to Go*
*Rachel E. Behrman, M.D. M.P.H.*

## FDA Mission — Ensure That...

**Foods** are safe, wholesome, and properly labeled
**Human drugs** and **vaccines **are safe and effective
**Blood** used for transfusions and **blood products **are safe, pure, and potent
**Medical devices** are safe & effective
**Transplanted tissues** are safe
**Animal drugs and medicated feeds** are safe and effective, and food from treated animals is safe for human consumption
**Radiation-emitting electronic products **are safe
**Cosmetics** are safe and properly labeled

**Notes:**
Protect and promote public health by ensuring the safety, effectiveness, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and radiation emitting products....
Surveillance of adverse events associated with regulated products directly serves this mission.

Every day, every American comes in contact with a host of FDA-regulated products.
Varied products
- Everything from the most common food ingredients to complex medical and surgical devices, lifesaving drugs, and radiation-emitting consumer and medical products.
$ 1.5 trillion a year 
- In fact, FDA-regulated products account for about 25 cents of every consumer dollar spent.
FDA's regulatory approaches are as varied as the products it regulates: 
* Some products -- such as new drugs and complex medical devices must be proven safe and effective before companies can put them on the market.  
* Other products -- such as x-ray machines, airport scanners, and microwave ovens must measure up to performance standards.
* And some products -- such as cosmetics and dietary supplements can be marketed with no prior approval.
These differences are dictated by the laws we enforce and the relative risks that the products pose to consumers.

## Definitions

***Adverse Experience*** – any adverse event associated with the use of the medical product whether or not related to the use of the product
***Adverse Reaction*** – an undesirable effect, reasonably associated with the use of the medical product, that may occur as part of the pharmacological action...or may be unpredictable in its occurrence....

**Notes:**
Can occur in the course of use in professional practice; accidental or intentional; any failure of expected pharmacological action

## Adverse Experience Can Be

- Life-threatening — patient placed at immediate risk of death from the AE
- Serious
- Death; Life-threatening; Inpatient hospitalization or prolongation of hospitalization; Persistent/ significant disability/ incapacity; Congenital anomaly/ birth defect, or
- Permanent impairment to body function or permanent damage to a body structure; Necessitates medical/ surgical intervention to preclude permanent impairment/ damage (Medical Devices)
- Unexpected
- Premarket (investigational) product
- Not listed in the investigator’s brochure or general investigational plan
- Not previously observed or not anticipated based on the pharmacological properties of the product
- Postmarket product  - not listed in the current product labeling

## What FDA Receives

**Preapproval AE reports** required from sponsors monitoring clinical trials
- Investigators must report to sponsor
- Sponsors must report to FDA
- Reports critical to FDA’s approvable or not approvable decision
- Limited exposure
- Expedited and periodic
**Postmarketing AE reports** (*today’s topic*)
- Required from industry
- Voluntary from healthcare professionals, patients, others
- Broad exposure
- Expedited and periodic
**Postmarketing information is (after appropriate redaction) publicly available**

## Postmarketing (Drugs/Biologics) 

**Mandatory**
**15-day Alert Reports** (MedWatch Form 3500A) - written reports for serious and unexpected, foreign and domestic, submitted within 15 days of manufacturers’ receipt of the information
**Expedited (immediate) fatality reports** on blood components
**Periodic Report** - manufacturer reports each ADE (not reported above) quarterly for 3 years from the date of approval and annually thereafter
**Voluntary **from healthcare professionals, consumers, patients, etc.
**Medical errors** included in both categories

**Notes:**
15-day Alert Follow-up Reports
Manufacturer completes a full investigation and submits a follow-up report within 15-days of receipt of new information

## VAERS

- National vaccine safety surveillance program, co-sponsored with CDC
- Created in response to the National Childhood Vaccine Injury Act of 1986
- Manufacturers must report serious events
- Healthcare professionals must report certain events (e.g., those labeled as contraindications to subsequent doses)

**Notes:**
Any event listed in the reportable events list that occurs after the specified time frames
Manufac report about 42% of all reports

## Medical Device AE Reports

**Mandatory (**MedWatch Form 3500A)
**User Facilities – r**eport within 10 days, death or serious injury
**Manufacturers** report within
- 30 days, death, serious injury, or information that suggests a device malfunction could cause a death or serious injury
- 5 days, a reportable MDR necessitates remedial action to prevent an unreasonable risk of substantial harm to public health
**Voluntary **– (MedWatch 3500) from the public

## Consumer Complaint Reports

- Office of Crisis Management
- 24/7 Operation Center
- Voluntary reporting: consumers/healthcare professionals
- 5-6 thousand complaint reports annually
- 9% reports are eventually classified as AE reports
- Majority are product quality reports
- Majority received by telephone; Require manual entry
- Complaints are referred to the appropriate Center/ Office in FDA for follow-up

## Individual Case Safety Report

- Messaging standard for exchanging adverse event reports for all FDA regulated products
- Release 1 is ANSI accredited HL7 standard for human pharmaceuticals and devices
- Release 2 is a draft HL7 standard that adds animal products and foods
- Will enable interoperability/sophisticated analyses of data

## Improving Ease of Reporting

- Modifying FDA Web site to create a single user-friendly portal for electronically submitting AE information
- Partnering with NIH in developing rational questionnaire
- Goals of ICSR + New Portal:
- Increase efficiency from electronic submission: saves $14 – 17 per report
- Rapid detection of safety problems from FDA regulated products
- Allow patients, consumers, and healthcare professionals to file safety reports easily over the Internet
- Does not affect existing Gateway used for bulk reports

## Federal Medication Terminology Standard

- Interagency collaboration to standardize terminology used in HIT initiatives
- Includes:
- FDA: Unique Ingredient Identifiers (UNIIs)
- NLM: RxNorm for clinical drugs
- VA: NDF-RT for pharmacological class

## Federal Collaborators

- National Library of Medicine
- Department of Veterans Affairs
- Centers for Medicaid & Medicare Services
- National Cancer Institute  — NCI Enterprise Vocabulary Services (manages terminology, e.g. thesaurus, browser)
- Agency for Healthcare Research and Quality

## Substance Registration System/UNIIs 

- FDA-managed process that generates a UNII for substances used in foods, drugs, biologics, and cosmetics. Includes
- Dietary supplements
- Both active and inactive ingredients
- Components of certain devices (e.g., silicon for implants, enzymes, and chemical reagents)
- In collaboration with USP
- Will collaborate with EPA (environmental ingredients)

## Structured Product Labeling(SPL)

- HL7 standard for computer-readable product information will support HIT efforts such as clinical decision support
- Distributed free of charge through *DailyMed* in collaboration with NLM
- Includes
- Content of labeling for prescription drugs
- Detailed product information (e.g., ingredients, appearance, strength)
- Packaging information (e.g., NDC)
- Will include clinical data elements (e.g., drug interactions, adverse reactions)
- Will expand to active ingredients for non-prescription drugs and inactive ingredients

**Notes:**
More than 2K at daily med – over 5k marketed packaged products
Content of labeling — Narrative text describing how and when to use
Drug listing data elements — Structured format for describing the product, including ingredients and packaging
Highlights data elements — Structured format for describing:
Indications and limitations of use
Class (mechanisms of action, physiologic effect)
Key interactions with foods and drugs
Adverse reactions (most common and severe)

## Collaborations with Standards Development Organizations

- ISO, ANSI, HL7, NCPDP, CDISC, international regulatory standards organizations, global regulatory standards groups (ICH, VICH, GHTF)
- Member of HITSP, participated in Consumer Empowerment Technical Committee last summer (re medication terminology)

## Limitations of Current System

- Information too often in paper
- Cannot retrieve
- Cannot analyze
- Inefficient and very expensive
- Emphasis on passive surveillance
- We cannot know how biased or incomplete the information is
- Little information on risk factors or patterns of use
- No “Denominator” – we don’t know total usage, so can’t determine incidence

**Notes:**
Problems with quality, quantity, and timeliness of information

Limitations in FDA capacity to rapidly conduct post-market surveillance studies when needed

Additional limitations:
-- Low likelihood of detection for long latency events
-- Absence of controls

## Path Forward

- We want to receive all information in a standardized electronic format so we can automate our processes.  This will allow us to:
- Effectively analyze in a timely manner the wealth of information we receive
- Provide up-to-date information to practitioners, patients, and consumers about how to use medical products in an optimally safe and effective manner
- Expand the data available to use, such as active surveillance of unbiased and complete health records
- Novel techniques, such as data mining, appear promising

**Notes:**
Systems have not been subject to rigorous testing for this purpose.  Need to test:
Best statistical methods
What to look for (e.g., rare events? common events?)
Records system itself: can only ascertain outcomes that are identifiable by the clinical/coding system used.
What benchmarks? There is no “gold standard” for signal identification.
Barriers: human and $$ resources (work is labor intensive)

## Conclusions

- We know what we have to do
- Standardize
- Automate
- Inter-operate
- We will continue to work with the broader healthcare community (e.g., to get the EHR)
- Federal agencies
- Healthcare professionals
- Providers
- Information vendors
- Patients, other consumers
- Active surveillance is part of science safety at FDA
- We are on our way!

**Notes:**
The move from the kind of epi studies done today to true prospective surveillance is bigger than you might think.

Today’s epi studies use data bases to look at emerging safety signals suggested by other sources.  True prospective surveillance means relying on those data bases to identify the emerging signal itself. Must be prospective, to allow assessment of signal detection in real time

True active surveillance means looking for events that no one, including the treating physician, recognized as possibly product related.

Not just the algorithms but also the records systems must be validate – the outcomes ascertainable are only those identifiable by whatever clinical or billing coding system is in use.

Calculating the sensitivity, specificity, and positive predictive value of each approach is not a straightforward task.

Prospective validation allows assessment of signal detection in real time, to determine the validity of signals as they emerge from the available data.  Published descriptions of systems available for drug safety active surveillance have not included a prospective demonstration of performance of the active surveillance systems in identifying real signals in real time, but rather have shown retrospective demonstrations.  (Start at present time and goes back to see if signals detected in the past through passive surveillance can be detected in the studied system in the same timeframes.)

Need prospective tests to inform resource allocation and degree of confidence in the system.  Encouraging the community to develop innovative strategies for validating these systems is part of the goal with our Sentinel public meeting. 

Lets discuss RFI and CERTS... procurement issues to be aware of during Q&A.

## FDA’s Core Business Functions — Three Key Areas

_**Premarket Review**_

_**Product Safety & Compliance**_

_**Consumer & Patient Safety**_

*Assessment of safety and effectiveness of new medical technology & *
*safety of new food ingredients*

*Inspection of manufacturing facilities and products to ensure safety, quality & compliance with FDA regulations*

*Postmarketing surveillance to ensure the safety of consumers & patients who use FDA-regulated products*

## FDA — Organized by Regulatory Center

**O**ffice of the
**C**ommissioner

**O**ffice of
**R**egulatory
**A**ffairs

**C**enter for
**F**ood
**S**afety &
**A**pplied
**N**utrition

**C**enter for
**D**rug
**E**valuation &
**R**esearch

**C**enter for
**B**iologics
**E**valuation &
**R**esearch

**C**enter for
**D**evices &
**R**adiological
**H**ealth

**C**enter for
**V**eterinary
**M**edicine

**N**ational
**C**enter for
**T**oxicological
**R**esearch