How can the quality of spontaneously reported case reports be improved? sagcs 2003

1. 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? sagcs 2003

2. 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@aol.com sagcs 2003

3. “In this bright future you can’t forget your past...” • V. Ford, No Woman, No Cry [Bob Marley and the Wailers] sagcs 2003

4. 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 1969;280:20-26 sagcs 2003

5. 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 sagcs 2003

6. Factors Affecting Spontaneous Reporting of ADRs: 19882 • When asked about hesitation to report suspected ADR to FDA, Rhode Island physicians gave as reasons: • 38%: didn’t have form • 28%: unsure drug caused reaction • 24%: reaction expected • 21%: didn’t know how to report • 21%: didn’t occur to them • 57% unfamiliar with FDA forms/guidelines for ADR reporting2 2Scott HD, et al. R I Med J 1988;71:179-184 sagcs 2003

7. Rhode Island ADR Reporting Project3 • Designed to increase physician reporting of suspected ADRs via sustained education utilizing several forms • After 2 years, > 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 1990;263:1785-1788 sagcs 2003

8. 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 sagcs 2003

9. 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 > 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 1995;52:1436-1439 sagcs 2003

10. 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 can’t make contribution to medical knowledge 5Figueiras A, et al. Med Care 1999;37:809-814 sagcs 2003

11. 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 2002;55:945-950 sagcs 2003

12. 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% didn’t know how to report • 54% would report if offered therapeutic advice6 sagcs 2003

13. “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 House;1995:372 sagcs 2003

14. 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 1992;12:12-18 sagcs 2003

15. 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 1996;36:386-396 sagcs 2003

16. 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.pdf 10Goldman SA. J Clin Pharmacol 1999;39:1126-1135 sagcs 2003

17. Risk Education: Drug-Induced Disease • Results of “Clinical Therapeutics and the Recognition of Drug-Induced Disease”9,10 • 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) sagcs 2003

18. 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 sagcs 2003

19. 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 1995;30:1083-1087 sagcs 2003

20. 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 1999;21:110-115 13Welsh CH, Pedot R, Anderson RJ. J Gen Intern Med 1996;11:454-460 14Sivaram CA, et al. Jt Comm J Qual Improv 1996;22:259-263 sagcs 2003

21. 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 sagcs 2003

22. 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) sagcs 2003

23. 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 1997;277:312-317 sagcs 2003

24. 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 sagcs 2003

25. 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 sagcs 2003

26. 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 sagcs 2003

27. 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 Rule’s “Always Expedited Reports” • No quick fix -- must be commitment of resources • Financial • Personnel • Involvement of multiple sectors • Partnerships sagcs 2003

28. 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, McClure’s Magazine, 1908:569 [cited by Carol Reardon in The Gettysburg Nobody Knows, Gabor S. Borritt, ed. New York: Oxford University Press, 1997:122] sagcs 2003