Post-Market Surveillance

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Post-Market SurveillanceThird-Party Reporting
SystemsA presentation to the LSRO Panel on
Dietary Supplements and Adverse Event Reporting

• 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

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Talking 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

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Talking Points (cont.)

• PROSAR IPC- Data Collection- Severity
  Assessments- Surveillance, Analysis, and
  Benchmarking- Responding to a serious event
• Strengths and limitations of spontaneous
  reporting
• Implications for the Metabolife project
• Challenges related to Dietary Supplement
  Surveillance and Safety

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• Organizational Profile,
• Service Offerings,
• and Focus

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PROSAR

• 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
• gt100,000 cases per year
• private center serving gt200 clients

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PROSAR 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

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PROSAR International Poison Center

• Markets served
• Consumer Products Personal Care, Food,
  Household
• Industrial Chemical
• Drug/Pharmaceutical
• Ag-Chem-Pesticide-Herbicide
• Animal Health

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International Animal Poison Center Service

• Director, Lynn Hovda, R. Ph., D.V.M., M.S., CSPI,
  DACVIM
• Animal care provided by DVMs, CVTs, and
  Toxicologists
• Serving corporate clients and the general public
• EPA and FDA reporting

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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

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Experienced, 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

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Partial Client List
Commercial/Industrial Avecia Castrol Chemtrec
Dow Corning Dupont Ecolab Fuji USA Huntsman
Corporation ICI Americas Johnson Wax
Professional PRC - DeSoto Rohm Haas Spartan
Chemical Sysco Valspar Animal Health Bayer
Animal Health Fort Dodge Animal
Health Intervet Lambert Kay Merial Pharmacia
Animal Health Sargeants Wellmark
Agricultural/Pesticide Aventis Bayer
Advanced Bayer Crop Protection Bell Laboratories
Inc. Cargill Dow LLC Dow Agrosciences FMC MGK Scot
ts (Ortho) Syngenta Food Products Best
Foods Dole Food Company Inc. HJ Heinz Company
L.P. International Multifoods Kellogg
Company Land-O-Lakes Starbucks Unilever Pharmaceu
tical Bioglan HealthPoint LecTec
Corp. Medicis Zila Pharmaceutical
Household Products Amway Church
Dwight Dial Elmers 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
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Consumer Product Post-Market/In-Market
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.

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Post-Market/In-Market Surveillance

• Why is it necessary???? Your market
  population will likely be much larger than any of
  your pre-market test populations

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Post-Market/In-Market Surveillance

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

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Regulations and Safety

• The question to ask Are there systems or
  processes in place to identify safety issues
  through methods other than serendipitous
  discovery?
• and
• How do you acknowledge the varying levels of
  quality and integrity of typical spontaneous
  reports received regarding any consumer product

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Post-Market/In-Market Surveillance
What should it accomplish??

• 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

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Adverse Event Reporting Systems Utilized by
IndustryCPSC Monitoring Systems

• National Electronic Injury Surveillance System
  (NEISS)
• Surveys 100 ERs selected as a nationwide
  probability sample of all 5,300 U.S. Hospitals
  with ERs
• Designed to provide the Commission with evidence
  of need for - a product recall - a public
  awareness campaign - a product safety standard

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Adverse Event Reporting Systems Utilized by
IndustryCPSC 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

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Adverse Event Reporting Systems Utilized by
Industry FDA 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)

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Other External Surveillance Databases, Systems 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)

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Other External Surveillance Databases, Systems or
Services

• Media Clipping Service
• Surveys/reports of death or injury in the lay
  press that involves consumer products
• Product Liability Claims

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

• 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

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Toxic Exposure Surveillance SystemTESS

• Telephone based reporting Phone Calls ?
  Exposures ? Injury/Poisonings
  Hospitalization ? Injury/Poisonings

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Minnesota Poison Prevention FindingsY2K

• For all pediatric cases, 97.6 result in
  non-significant outcomes (ltminor 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.)

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Adverse Event Reporting Systems Utilized by
Industry EPA Monitoring Systems

• Environmental Protection Agency FIFRA 6(a)(2)
• Process maximally engages the Manufacturer in the
  process - Encouraged and supported Product
  Stewardship Efforts

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AER SystemsEPA Monitoring Systems

• 6(a)(2) Product Stewardship Identify,
  Manage, EvaluateAdverse incidents reportedly
  associated with products
• Previous 6(a)(2) RequirementsOnly serious or
  unexpected effects judged related to a product
  reported to EPA

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AER 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 reports a) Minor/more
  common effects aggregated b) More serious
  effects reported individually- New
  Penalties a) Civil b) Criminal

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Adverse Event Reporting Systems Utilized by
Industry EPA Monitoring Systems

• Industrys Response to the 6(a)(2) Challenge -
  Industrys Voluntary Report Forms (see
  www.fifra6a2.com)General Incident
  DataAddendums for specific eventsReport format
  for single reportable incidentsGuidance document
  for form completion

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Adverse Event Reporting Systems Utilized by
Industry EPA Monitoring Systems

• FOCUS AREAS1) General Incident Data Addendums
  for specific events Report format for single
  reportable incidents Guidance document for form
  completion2) Aggregate Reporting Form Guidance
  Document for form completion

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6(a)(2) Incident Reporting Process
Reported Event
Administrative Incident Data
Single Incident Report (Significant
Reportable Incident)
Fish Wildlife Plants, NonTarget Organisms Data
Domestic Animal Data
Human Data
Severity Classification
Property Damage Data
Surface Water Data
Ground Water Data
Aggregate Incident Report Minor and/or More
Common Reportable Incidents
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Classification 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)

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Classification of Incidents

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Challenges in Incident Classification

• Additional ConsiderationsDuration vs. In
  tensity of clinical effects

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Evolution 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)

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Product Stewardship

• CSPA ProductCare VisionTo 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.

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Product Stewardship(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

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Product Stewardship(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

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PROSAR 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

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PROSAR IPC Incident Monitoring Systems

• Data Collection
• Product Specific DetailsMultiple methods of
  product verificationEvaluating the role of
  labelingMarketing

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PROSAR IPC Incident Monitoring Systems

• 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

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PROSAR IPC Incident Monitoring Systems

• Surveillance, Analysis, and Benchmarking
• Benchmarking is provided through an automated
  data analysis system PSI (PROSAR Safety
  Index)

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PROSAR 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)

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Future Levels of Incident Evaluation

• Next level of Incident AssessmentRegistry
  approach to follow-up Product Surveillance
• The SAS Initiative (Safety Assurance
  Surveillance)

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Responding 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

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Telephone Based Incident DataStrengths/Limitati
ons of SpontaneousReported Data
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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

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Limitations

• 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

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Limitations continued

• Accuracy and Report Quality
• Voluntary vs. Mandatory
• Spontaneous Reports ? Rigorous Prospective
  Clinical Research
• Objective vs. Subjective Data
• Translation of laymans symptom descriptions into
  complex medical terminology (i.e. paresthesias,
  numbness, tingling, peripheral neuropathy)
• Second hand reporting
• Hidden agendas

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Implications for the LSRO Project

1. Metabolife Analysis -- Outstanding
   IssuesReport quality and integrityAbility to
   verify individual incidentsAbility to verify
   exact product(s) involvedLaboratory
   confirmationHidden AgendasCollection of data
   in a systematic formatNormalizing for product
   sales(eg. DEET)Independent verification of
   informationAbility to follow-up at this late date

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Implications for the LSRO Dietary Supplement AER
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