How can the quality of spontaneously reported case reports be improved

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FDA Risk Management Public Workshop Risk
Assessment of Observational Data Good
Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment April 11, 2003

• How can the quality of spontaneously reported
  case reports be improved?
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• Stephen A. Goldman, M.D., FAPM, FAPA
• Managing Member
• Stephen A. Goldman Consulting Services, L.L.C.
• Morris Plains, New Jersey, USA
• Former Medical Director, MedWatch
• U.S. Food and Drug Administration
• sagcs_at_aol.com
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• In this bright future you cant forget your
  past...
• V. Ford, No Woman, No Cry Bob Marley and the
  Wailers
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Factors Affecting Spontaneous Reporting of
Adverse Drug Reactions (ADRs) 19691

• Assessment of factors impacting physician ADR
  reporting at Massachusetts General Hospital1
• Certainty of reaction
• Mechanism of reaction
• Morbidity of reaction
• Prolongation of hospitalization
• Onset of reaction
• 1Koch-Weser J, et al. NEJM 196928020-26
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Factors Affecting Spontaneous Reporting of ADRs
19691

• Marked increase in quantity/quality of physician
  ADR reporting since initiation of studies seen as
  due to
• Use of ADR definition
• Ease of applicability
• Meaningful operationally
• Exclusion of trivial side effects without true
  clinical significance
• Feedback clearly showed physicians reports were
  being carefully monitored and assessed
• Ongoing emphasis on ADRs likely heightened
  visibility of problem throughout institution1
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Factors Affecting Spontaneous Reporting of
ADRs 19882

• When asked about hesitation to report suspected
  ADR to FDA, Rhode Island physicians gave as
  reasons
• 38 didnt have form
• 28 unsure drug caused reaction
• 24 reaction expected
• 21 didnt know how to report
• 21 didnt occur to them
• 57 unfamiliar with FDA forms/guidelines for ADR
  reporting2
• 2Scott HD, et al. R I Med J 198871179-184
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Rhode Island ADR Reporting Project3

• Designed to increase physician reporting of
  suspected ADRs via sustained education utilizing
  several forms
• After 2 years, gt 17-fold increase in Rhode Island
  direct reports vs yearly average prior to project
  (similar increases not seen in overall U.S. rate)
  
• Similar trend seen regarding serious reports
• 1981 - 1985 0.4 of total serious reports to FDA
• 1988 3.6 of all serious direct reports to FDA3
• 31 reports on unlabeled reactions through 1988
• 3Scott HD, et al. JAMA 19902631785-1788
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Rhode Island ADR Reporting Project3

• Pre- and post-intervention surveys found
  significant gains in knowledge and attitude
  toward ADR reporting system
• Pre-intervention
• 55 familiar with FDA ADR reporting program
• 39 familiar with FDA forms/guidelines for
  reporting
• Post-intervention
• 85 familiar with FDA ADR reporting program
• 69 familiar with FDA forms/guidelines for
  reporting3
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Spontaneous Reporting of Adverse Events (AEs)
to FDA The MedWatch Factor4

• MedWatch launched June 1993 - trends in reporting
  of serious AEs from 1992-1994 and quality of
  reports before (4/93) and after (4/94) launch
  studied4
• Proportion of serious AE reports ? from 34
  (1992) to 49 (1994)
• Overall quality of 1994 reports gt 1993 reports
• Significantly greater percentage reported whether
  new molecular entity, indicated seriousness, and
  supplied lab/clinical data supporting event
  diagnosis
• Pharmacist reports ? in number and quality
• Physician reports of high quality in both years,
  but report numbers ?
• 4Piazza-Hepp TD, Kennedy DL. Am J Health Syst
  Pharm 1995521436-1439
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Impact of Physician Attitudes on Adverse Drug
Event (ADE) Reporting5

• Case-control study (ADE-reporting doctors vs
  randomly selected physicians) performed in Spain
• Probability of ADE reporting ? with increasing
  prescription volume, ? with increasing patient
  load
• Lower likelihood of reporting associated with
  attitudes
• Belief that truly serious ADEs well known by time
  of marketing
• Belief that determination of whether drug
  responsible for specific AE nearly impossible
• Reporting ADE only when sure of relation to use
  of specific drug
• Belief that isolated case possibly seen by one
  physician cant make contribution to medical
  knowledge
• 5Figueiras A, et al. Med Care 199937809-814
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Physician Knowledge/Attitudes on ADR
Reporting 20026

• ADR-reporting doctors and randomly sampled
  physicians surveyed in Germany6
• 75-85 never submitted ADR report to government
  or professional program
• Reporting much better to pharmaceutical companies
  
• 68.2 suspected ADR, but did not report
• Major reasons for lack of report
• 75.6 well-known ADR
• 71.1 trivial
• 66.3 uncertain causality
• 6Hasford J, et al. J Clin Epidemiol
  200255945-950
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Physician Knowledge/Attitudes on ADR
Spontaneous Reporting System (SRS) 20026

• Highest probability ADR reporting of
• Serious unknown ADRs to new drug (81.1) or older
  drug (72.9)
• Serious known ADRs to new drug (65.2)
• 20 acknowledged no awareness of SRS
• 30 didnt know how to report
• 54 would report if offered therapeutic advice6
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• We must use what tools we have.
• Abraham Lincoln, President of the United States,
  1862, quoted in David Herbert Donald, Lincoln.
  London Jonathan Cape Random House1995372
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Assessment of Interventions to Stimulate
Physician ADE Reporting7

• Noting health professionals voice dissatisfaction
  about not knowing disposition of ADE information
  they took time/effort to report, researchers
  found physician appreciation for such feedback
  provided (letter) by Mississippi ADE program7
• Good reception to newsletter summarizing
  number/types of reports and involved drugs
• Further enabled physician education about new
  drugs warranting careful observation
• Maintenance of awareness about ADE surveillance
  and concomitant effect on quality of care
  important
• Posters strategically placed and in-services at
  intervals effective
• 7Juergens JP, et al. Top Hosp Pharm Manage
  19921212-18
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Risk Education Drug-Induced Disease

• Designed conference on recognition and management
  of drug-induced disease8
• Multiple formats (didactics panels small group
  case discussions with faculty facilitators)
• Underlying clinical therapeutic approach
• Improved knowledge (global by professional
  discipline) demonstrated via pre-/post-testing
• Very well received by attendees
• 8Goldman SA, Lieberman R, Kausal DJ. J Clin
  Pharmacol 199636386-396
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Risk Education Drug-Induced Disease

• Mail-out MedWatch Continuing Education (CE)
  Article9
• Conference8 basis for Clinical Therapeutics and
  the Recognition of Drug-Induced Disease
• Distributed nationwide through Partners10
• Certified for physician pharmacist CE credit
• 9Goldman SA, Kennedy DL, Lieberman R (eds).
  Clinical therapeutics and the recognition of
  drug-induced disease. FDA, 1995. Available at
  http//www.fda.gov/ medwatch/articles/dig/ceart.pd
  f
• 10Goldman SA. J Clin Pharmacol 1999391126-1135
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Risk Education Drug-Induced Disease

• Results of Clinical Therapeutics and the
  Recognition of Drug-Induced Disease9,10
• 2.2 response rate
• 15,260 health professionals (55 physicians 37
  pharmacists) received CE credit
• 99 agreed learning objectives met and article
  relevant to clinical practice (assessed first 2/3
  of successfully completed exams)
• 150 spontaneous comments (great majority quite
  positive)
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Risk Education Drug-Induced Disease

• Preventable Adverse Drug Reactions
• A Focus on Drug Interactions
• Learning module
• Developed by Center for Education and Research on
  Therapeutics (CERT) while at Georgetown
  University (CERT now located at University of
  Arizona Health Sciences Center) in collaboration
  with CDER/FDA
• Based on needs survey sent to all 3rd year
  medicine clerkship and medicine residency program
  directors in US
• Sponsored by Agency for Healthcare Research and
  Quality (AHRQ)
• http//www.fda.gov/cder/drug/drugReactions
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Other Successful Interventions

• US Multidisciplinary ADR committee (pharmacists,
  nurses, physician) formed11
• Simplified ADR reporting hospital-wide via
• Development of ADR Reporting Form
• 24-hour Reporting Hotline
• Implemented
• ADR Newsletter
• Broad-range in-service educational program
• Pharmacist investigated suspected ADRs (from
  various health professionals), with formal report
  to committee forwarded on to P T Committee and
  clinical departments
• Generated 2.1 ADR reports/100 admissions
• 11Etzel JV, Brocavich JM, Rousseau M. Hosp Pharm
  1995301083-1087
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Other Successful Interventions

• Switzerland Clinical pharmacist
• Participated in daily rounds
• Solicited follow-up information from
  physicians/nurses
• Performed chart review
• with improved ADE identification and reporting12
  
• US Use of morning report to facilitate AE
  detection13 and as forum for ADR reporting14
• Both programs found strategy increased ADR
  reporting to appropriate hospital systems
• 12Schlienger RG, et al. Pharm World Sci
  199921110-115
• 13Welsh CH, Pedot R, Anderson RJ. J Gen Intern
  Med 199611454-460
• 14Sivaram CA, et al. Jt Comm J Qual Improv
  199622259-263 ?sagcs 2003

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Report Quality Completeness

• Completeness of AE report crucial - utilize
  appropriate measures to obtain full information
• Directed questioning/check-off list
• Instructions for Completing MedWatch FDA Form
  3500 and Instructions on How to Complete FDA Form
  3500A (www.fda.gov/medwatch)
• Consider drafting AE/AR-specific questions, e.g.,
  
• Focus on results of liver function parameters and
  other testing for hepatotoxicity, or
• Skin manifestations/biopsy results for serious
  dermatologic disorders like toxic epidermal
  necrolysis or Stevens-Johnson syndrome
• when particular serious AE/AR suspected to be
  associated with product
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Report Quality Completeness

• Ensure obtainment of such data as
• Medical product-specific information, such as
• Model and serial numbers for medical devices
• Confounding factors, such as
• Concomitant medical products, including
  prescription/OTC drugs, biologics, devices,
  dietary supplements (oral, topical)
• Medical history
• Alcohol/tobacco use
• Demographic data
• Temporal information
• Biopsy/autopsy results (as applicable)
• Dechallenge/rechallenge information (if
  available)
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Risk Education Areas of Focus

• Medication orders identified by teaching hospital
  pharmacists as potentially in error used to study
  factors related to prescribing errors15
• 30 of errors related to knowledge and
  application of knowledge as to drug therapy
• 29.2 of errors related to knowledge and use of
  knowledge regarding patient factors (history
  characteristics) that can impact drug therapy
• 17.5 involved errors in dose calculations,
  decimal point placement, and unit/rate expression
  
• 15Lesar TA, Briceland L, Stein DS. JAMA
  1997277312-317
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Lessons Learned

• Medical product safety/risk management education
  for health professionals should not be
  exclusively product-specific, and must be
  clinically oriented
• Goals should include
• Greater awareness of medical product-induced
  disease
• Enhanced knowledge and application of
  pharmacotherapy, and of the impact individual
  patient factors can have on pharmacotherapy
• Clear explanation of HOW and WHY to report
  AEs/ARs to FDA and/or manufacturer
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Lessons Learned

• Feedback to reporters crucial -- the more
  clinical, the better
• Education, education, education
• ALL levels
• Professional schools
• Training programs
• Post-graduate continuing education
• Based in clinical care setting (hospital clinic
  other facilities)
• ALL health professional disciplines
• MUST be ongoing
• One-shot programs not nearly enough
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Lessons Learned

• Demystify AE/AR reporting/assessment systems and
  processes in FDA and industry
• Explode myths
• All serious AEs/ARs NOT known by time of
  marketing
• Causality NOT requirement for reporting suspected
  AEs/ ARs
• Single case of suspected serious AE/AR CAN add to
  general medical knowledge
• Even if known, additional well-documented cases
  of serious AEs/ARs CAN add to general medical
  knowledge about product in question
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Lessons Learned

• Ongoing evaluation of methods used to solicit
  information from reporters
• Directed questioning/checklists
• Specialized questions for known AEs/ARs of
  interest
• 3/14/2003 Proposed Rules Always Expedited
  Reports
• No quick fix -- must be commitment of resources
• Financial
• Personnel
• Involvement of multiple sectors
• Partnerships
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Summary

• When evaluating interventions to improve report
  quality, try to make correct attribution between
  methods used and results
• I think the Union army had something to do with
  it.
• General George Pickett, Army of Northern
  Virginia, CSA, response to question regarding
  failure of his assault at the Battle of
  Gettysburg, in LaSalle Corbell Pickett, My
  Soldier, McClures Magazine, 1908569
• cited by Carol Reardon in The Gettysburg Nobody
  Knows, Gabor S. Borritt, ed. New York Oxford
  University Press, 1997122
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