post-market surveillance & third-party reporting systems a presentation to the lsro panel on...

Post-Market SurveillancePost-Market Surveillance&&

Third-Party Reporting SystemsThird-Party Reporting Systems

A presentation to the LSRO Panel on Dietary Supplements and Adverse Event A presentation to the LSRO Panel on Dietary Supplements and Adverse Event

ReportingReporting Rick Kingston PharmD

Vice President & Senior Clinical Toxicologist PROSAR International Poison Center

&

Associate Professor

Department of Experimental and Clinical Pharmacology

College of Pharmacy, University of Minnesota

Talking PointsTalking Points

1. Introduction to PROSAR International Poison Center (IPC)

2. Brief overview of Post-Market Surveillance and sources of data relied upon by Companies

3. The EPA FIFRA 6(a)(2) model

4. Product Stewardship and evolution of the PROSAR IPC model

Talking Points (cont.)Talking Points (cont.)

6. PROSAR IPC- Data Collection- Severity Assessments- Surveillance, Analysis, and Benchmarking- Responding to a serious event

7. Strengths and limitations of “spontaneous reporting”

8. Implications for the Metabolife project

9. Challenges related to Dietary Supplement Surveillance and Safety

Organizational Profile,

Service Offerings,

and Focus

PROSARPROSAR

• Health & Safety Information Services

– Healthcare practice

– leverage technology extensively

•Case Manager

•Case Explorer

• PROSAR International Poison Center (IPC) serving clients with specialized post-market surveillance needs since 1997

– >100,000 cases per year

– private center serving >200 clients

PROSAR IPC ServicesPROSAR IPC Services

• PROSAR International Poison Center (Health & Safety Call Center focused on consumer product medical support and surveillance)

• International Animal Poison Center (Industry focused surveillance center for incidents involving animal health)

• Pet Poison Hotline (Public)

• Toxicology Consulting – Pre & Post Market Product Safety Assessments– Risk Assessments

PROSAR International Poison CenterPROSAR International Poison Center

• Markets served:

– Consumer Products: Personal Care, Food, Household

– Industrial Chemical

– Drug/Pharmaceutical

– Ag-Chem-Pesticide-Herbicide

– Animal Health

International Animal Poison Center ServiceInternational Animal Poison Center Service

• Director, Lynn Hovda, R. Ph., D.V.M., M.S., CSPI, DACVIM

• Animal care provided by DVM’s, CVT’s, and Toxicologists

• Serving corporate clients and the general public

• EPA and FDA reporting

Our Staff...Our Staff...

• Highly credentialed, healthcare professionals with over 150 years experience in clinical, academic, and research environments– Specific expertise in Toxicology, Pharmacology,

Infectious Disease Epidemiology, and Industrial Hygiene

– Physicians Board Certified in Internal Medicine, Emergency Medicine, Occupational Medicine, Veterinary Medicine, and Medical Toxicology

– Academic affiliation with University of Minnesota College of Pharmacy

Experienced, Multi-Disciplinary StaffExperienced, Multi-Disciplinary Staff

Name Years Experience

Leo Sioris, Pharm. D. 24

Richard Kingston, Pharm. D., CSPI 23

Steve Borron, M.D., M.S., FACEP, ABMT 15

Lynn Hovda, R. Ph., D.V.M., M.S., CSPI, DACVIM 16

Dean Filandrinos, Pharm. D., M.S. 9

John Gualtieri, Pharm. D. 7

John Shevlin, R. Ph., CSPI 21

Joele Richardson, R. Ph., CSPI 9

Ann Thompson, M.S., CIC 15

Lawrence Betts, M.D., Ph.D., CIH 27

Kurt Walstrom, Pharm. D. 6

Fred Oehme, D.V.M. 23

Jeanne Sutich, D.V.M. 3

Partial Client ListPartial Client List

Agricultural/Pesticide:Aventis Bayer AdvancedBayer Crop ProtectionBell Laboratories Inc.Cargill Dow LLCDow AgrosciencesFMCMGKScott’s (Ortho)Syngenta

Food Products:Best FoodsDole Food Company Inc.HJ Heinz Company L.P.International MultifoodsKellogg CompanyLand-O-LakesStarbucksUnilever

PharmaceuticalBioglanHealthPointLecTec Corp.MedicisZila Pharmaceutical

Commercial/Industrial:AveciaCastrolChemtrec Dow CorningDupontEcolabFuji USAHuntsman CorporationICI AmericasJohnson Wax ProfessionalPRC - DeSotoRohm & HaasSpartan ChemicalSyscoValspar

Animal Health:Bayer Animal HealthFort Dodge Animal HealthIntervetLambert KayMerialPharmacia Animal HealthSargeantsWellmark

Household Products:

Amway

Church & Dwight

Dial

Elmer’s

Iron Out Incorporated

WD-40 Company

Lime-O-Sol

Reckitt Benckiser

SC Johnson

Personal Care Products:

Amway

Bath & Body Works

Church & Dwight

Dial

Playtex

SC Johnson

Unilever

White Rain

Consumer Product Post-Market/In-Consumer Product Post-Market/In-Market SurveillanceMarket Surveillance

• What is it????

The processes whereby manufactures, regulators, health professionals, the public at large, and others monitor the performance and experience related to a given products life-cycle in the open market.

Post-Market/In-Market SurveillancePost-Market/In-Market Surveillance

• Why is it necessary????

“Your market population will likely be much larger than any of your pre-market test populations”

Study Population Size Necessary to IdentifyStudy Population Size Necessary to Identify1, 2, or 3 Cases of a Given Effect Based on its 1, 2, or 3 Cases of a Given Effect Based on its

Relative IncidenceRelative IncidenceADR Frequency Number of ADR Cases

1 2 3

1 out of 100 300 480 650

1 out of 200 600 960 1,300

1 out of 1,000 3,000 4,800 6,500

1 out of 2,000 6,000 9,600 13,000

1 out of 10,000 30,000 48,000 65,000


• “The absence of reliable evidence of risk should not be mistaken for reliable evidence of the absence of risk”

Regulations and SafetyRegulations and Safety

The question to ask:

Are there systems or processes in place to identify safety issues through methods other than serendipitous discovery?

andHow do you acknowledge the varying levels of

quality and integrity of typical “spontaneous reports” received regarding any consumer product


• Helps identify intended and unintended use patterns that may potentially contribute to Adverse Events

• Allows assessment of how the product performs by itself or in the presence of other products or substances

• Helps insure that “unique” populations are not adversely affected

• Should also help define a relative “Safety profile”

What should it accomplish??What should it accomplish??

Adverse Event Reporting Systems Utilized by Adverse Event Reporting Systems Utilized by Industry:Industry:

CPSC Monitoring SystemsCPSC Monitoring Systems

National Electronic Injury Surveillance System (NEISS):

• Surveys 100 ER’s selected as a nationwide probability sample of all 5,300+ U.S. Hospitals with ER’s

• Designed to provide the Commission with evidence of need for:

- a product recall- a public awareness campaign- a product safety standard

Adverse Event Reporting Systems Utilized by Adverse Event Reporting Systems Utilized by Industry:Industry:

CPSC Internal Monitoring SystemsCPSC Internal Monitoring Systems

Consumer Communications: Individual Reports Involving Death or Injury

• Results in CPSC investigation into injury allegations

• May include on-site, face-to-face interviews and analysis of the product involved as well as medical records related to the injury

Manufacturer Communications (CPSC): Individual Reports Involving Death or Injury

Adverse Event Reporting Systems Utilized Adverse Event Reporting Systems Utilized by Industry: :by Industry: :

FDA Monitoring SystemsFDA Monitoring Systems

• FDA MedWatch

- Depends on either the patient or a Healthcare Practitioner to identify an effect, identify a suspected cause, question a relationship and report it to a “governmental” body

- reporting is typically a “one-way” street (not designed to engage the caller and provide “clinical advice”)

Other External Surveillance Databases, Other External Surveillance Databases, Systems or ServicesSystems or Services

Medical Literature (human & animal)

• More in-depth reports with medical details on the injury

• Often lacking on “circumstance” info*** (focused on what was done after the exposure)

• Often serves as basis or support for “pro-active” regulation (animal or human data)

Other External Surveillance Databases, Other External Surveillance Databases, Systems or ServicesSystems or Services

• Media Clipping Service

• Surveys/reports of death or injury in the lay press that involves consumer products

• Product Liability Claims

23

American Assn. Poison Control Centers (AAPCC) American Assn. Poison Control Centers (AAPCC) Toxic Exposure Surveillance SystemToxic Exposure Surveillance System

“TESS”“TESS”

• Designed to allow documenting of all inquiries made to the poison center

• Basic set of data elements collected

• Provides a good overall picture of the “marketplace”

• Very “Sensitive” for certain types of reports but not necessarily “specific”

24

Toxic Exposure Surveillance SystemToxic Exposure Surveillance System“TESS”“TESS”

• Telephone based reporting:

Phone Calls Exposures Injury/Poisonings

“Hospitalization” Injury/Poisonings

Minnesota Poison Prevention FindingsMinnesota Poison Prevention FindingsY2KY2K

• For all pediatric cases, 97.6% result in non-significant outcomes (<=minor effects) and 91.1% of cases result in no reported adverse effects. These outcomes are achieved with fewer than 5 patients receiving specific therapies other than decontamination.

• Of all pediatric cases, 666(3.0%) received specific decontamination therapy other than simple dilution/irrigation such as syrup of ipecac or activated charcoal. (The lack of need for specific interventions may be the result of previously cited Minnesota data reporting that more than 55% of exposures from all routes including all reasons are “taste/touch” or mucous membrane types of exposures. These types of trivial exposures represent 71% of all “ingestions”.)

Adverse Event Reporting Systems Utilized by Adverse Event Reporting Systems Utilized by Industry: Industry:

EPA Monitoring SystemsEPA Monitoring Systems

• Environmental Protection Agency: FIFRA 6(a)(2)

• Process maximally engages the Manufacturer in the process

- Encouraged and supported Product Stewardship Efforts

AER Systems:AER Systems:EPA Monitoring SystemsEPA Monitoring Systems

• 6(a)(2) & Product Stewardship

Identify, Manage, Evaluate:Adverse incidents reportedly associated with products

• Previous 6(a)(2) Requirements:Only serious or unexpected effects judged related to a product reported to EPA

AER Systems:AER Systems:EPA Monitoring SystemsEPA Monitoring Systems

• 1998 Revisions

- All cases meeting minimum data elements must be reported to the Agency

- No cause and effect relationship need be established

- 2 types of reportsa) Minor/more common effects aggregatedb) More serious effects reported

individually

- New Penaltiesa) Civilb) Criminal



• Industry’s Response to the 6(a)(2) Challenge

- “Industry’s Voluntary Report Forms”(see: www.fifra6a2.com)

General Incident DataAddendum’s for specific eventsReport format for single reportable incidentsGuidance document for form completion



• FOCUS AREAS

1) General Incident DataAddendum’s for specific eventsReport format for single reportable incidentsGuidance document for form completion

2) Aggregate Reporting FormGuidance Document for form completion

PropertyDamage

Data

FishWildlifePlants,

NonTargetOrganisms

Data

DomesticAnimal

Data

SurfaceWaterData

GroundWaterData

HumanData

Administrative Incident Data

Aggregate Incident ReportMinor and/or More Common

Reportable Incidents

Reported Event

6(a)(2) Incident Reporting Process

SeverityClassification

Single Incident Report(Significant Reportable

Incident)

Classification of Incidents Involving HumansClassification of Incidents Involving Humans

• Aggregate Incident Report (Collect 3 months, report in 2)

Minor and/or More Common Reportable Incidents

H-D

• Single Incidents Reports: Significant Reportable Incident

H-B, H-C (Collect 1 month report following month)

H-A (Human Death: Report within 15 days of notification)

Classification of IncidentsClassification of Incidents

TESS FIFRA

No Effect (NA) Minor H-D Human Minor Moderate H-C Human Moderate Major H-B Human Major Death H-A Human Death Not Followed – Non tox & Pot. tox

(NA)

Challenges in Incident ClassificationChallenges in Incident Classification

• Additional Considerations

“Duration”vs.

“Intensity of clinical effects”

Evolution of the PROSAR ModelEvolution of the PROSAR Model

• Strongly influenced by national Product Stewardship efforts by Industry

- Responsible Care

- Responsible Distribution

- ProductCare

• Also influenced by evolution of “standard of care” as the model proliferated (consumer expectations)

Product StewardshipProduct Stewardship

• CSPA – ProductCare Vision

To promote the production and distribution of safe and effective formulated products that provide desirable benefits for household, commercial, institutional and industrial customers and consumers, and their families, pets and their environment.

Product StewardshipProduct Stewardship(eg. CSPA Product Care)(eg. CSPA Product Care)

• In-Market Support, Incident Evaluation and Follow-up

– Principle 5

• We will support dissemination of safety related product information regarding routine use of our products that is accurate, complete and in context to the inquiry or concern

• When product-related incidents occur, we will have systems in place to minimize adverse effects, assist our consumers/customers and provide needed information

Product StewardshipProduct Stewardship(eg. CSPA Product Care)(eg. CSPA Product Care)

• In-Market Support, Incident Evaluation and Follow-up

– Principle 5 (cont.)

• We will strive to influence product and label design as well as develop educational messages on safe and responsible product use based on information regarding unintended events and other types of exposures involving our products

PROSAR IPC Incident Monitoring SystemsPROSAR IPC Incident Monitoring Systems

Data Collection:• Information system and data collection tools based on basic

subset of information fields

• Basic subset captures both TESS data elements and EPA data elements.

• Proprietary “Case Manager” further individualizes data fields depending on the client and the Industry

• Heavily focused on documenting events surrounding the exposure, product specific details, other conditions affecting product use


Data Collection:• Product Specific Details

Multiple methods of product verification

Evaluating the role of labeling

Marketing


Case Analysis and Incident Severity Assessments:

• Not designed to determine “relatedness”

• Based on a “consistency” rating (eg. Likelihood that based on all available factors, exposure outcome and severity appears to be either consistent, inconsistent, or indeterminable, with the known toxicologic/safety profile

• Proprietary “Case Manager” further individualizes data fields depending on the client and the Industry


Surveillance, Analysis, and Benchmarking:

• Benchmarking is provided through an automated data analysis system:

PSI (PROSAR Safety Index)

PROSAR Safety IndexPROSAR Safety Index

• Designed to help identify when to “take a closer look”

• Analytical tool to aid in identifying products that fall outside of their normal safety profile

• Based on the total number of “significant outcomes” compared against all symptomatic incidents involving a given product or class of products for a given time period

• Initially calculated at the following levels:

– Individual product

– Company

– PROSAR(also allows normalizing with product sales

data)

Future Levels of Incident EvaluationFuture Levels of Incident Evaluation

• Next level of Incident Assessment:

“Registry” approach to follow-up Product Surveillance

The SAS Initiative (Safety Assurance Surveillance)

Responding to a “serious” eventResponding to a “serious” event

• Action is typically dictated by:

- type of incident

- supporting documentation

- existing regulatory reporting requirements

- ability to investigate, verify, and add definition

Telephone Based Incident Data:

Strengths/Limitations of SpontaneousStrengths/Limitations of SpontaneousReported DataReported Data

Strengths Strengths

• Monitoring for Sentinel Events:

– Critical Mass increases likelihood of discovery

• Hypothesis Generation:

– Background noise vs. emerging issue

– Aids in Design of Research?

• Generation of Safety Profile:

– Sufficient “Penetrance”?

– Insure representative sample relative intensity

LimitationsLimitations

• Outcome Severity Classifications– Some symptoms not amenable to clear-cut

classification– Indirect vs. Direct Effects– Physiologic vs. Psychologic S/S

• Assessment of Causation/Relatedness– Data does not lead to determination of “cause and

effect” relationship– At best may suggest an Epidemiological Association

• Under-reporting/Over-reporting– reporting of “real” vs. “perceived” threats– Media and promotion– Possible “link” not recognized

Limitations Limitations continuedcontinued

• Accuracy and Report Quality

– Voluntary vs. Mandatory

– Spontaneous Reports Rigorous Prospective Clinical Research

– Objective vs. Subjective Data

– Translation of layman’s symptom descriptions into complex medical terminology (i.e. paresthesias, numbness, tingling, peripheral neuropathy)

– Second hand reporting

– Hidden agenda’s

Implications for the LSRO ProjectImplications for the LSRO Project

I. Metabolife Analysis -- Outstanding Issues:

Report quality and integrityAbility to verify individual incidentsAbility to verify exact product(s) involvedLaboratory confirmationHidden Agenda’sCollection of data in a systematic formatNormalizing for product sales(eg. DEET)Independent verification of informationAbility to follow-up at this late date

Implications for the LSRO Dietary Supplement Implications for the LSRO Dietary Supplement AER ProjectAER Project

II. Advising on a appropriate model of Post-Market Surveillance for Dietary Supplements:

• Must differentiate between “ingredients” vs. “products”

• For AER/Surveillance…..No one system will suffice: All likely reporting avenues that patients, consumers, and healthcare professionals will use to request or report information must be cultivated for maximum input

• Mandatory vs. Voluntary Reporting for Manufacturers

post-market surveillance & third-party reporting systems a presentation to the lsro panel on...

Documents