1. Temple University - 4/15/031 Practicing “Good Risk Management” Guidance Development Under PDUFA III Paul J. Seligman, MD, MPH Director Office of Pharmacoepidemiology & Statistical Science

2. Temple University - 4/15/032 Prescription Drug Users Fee Act (PDUFA 3) - October 1, 2002 Guidance DevelopmentGuidance Development –Good risk assessment –Good risk management –Good pharmacovigilance Develop interrelated documentsDevelop interrelated documents

3. Temple University - 4/15/033 Process Highlights Concept papersConcept papers –Public comments (through April 30, 2003) –[Docket 02N-0528] –Internet Address http://www.fda.gov/ohrms/dockets Draft guidancesDraft guidances –Fall 2003 –Public comment period on draft guidances Final guidancesFinal guidances –September 30, 2004

4. Temple University - 4/15/034 Objectives Key conceptsKey concepts –Premarketing Risk Assessment –Risk Management Programs –Risk Assessment of Observational Data: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Concept papers available atConcept papers available at –http://www.fda.gov/cder/meeting/riskmanagement.htm

5. Temple University - 4/15/035 Premarketing Risk Assessment

6. Temple University - 4/15/036 Premarketing Risk Assessment Generating Risk InformationGenerating Risk Information –General Considerations –Special Considerations Reporting Risk InformationReporting Risk Information –Analyzing and Presenting Risk Information

7. Temple University - 4/15/037 Premarketing Risk Assessment What is Risk Assessment?What is Risk Assessment? –Risk assessment is the process of identifying, estimating and evaluating the nature and severity of risk from a product –Good risk assessment underlies good risk management and pharmacovigilance

8. Temple University - 4/15/038 Premarketing Risk Assessment PremisePremise –Pre-marketing risk assessment relatively mature, but still evolving –Public health, industry and FDA would all benefit from optimizing risk assessment allowing for approval of safe drugs with fully informative labeling

9. Temple University - 4/15/039 Premarketing Risk Assessment General Considerations

10. Temple University - 4/15/0310 Key Issues Size of the safety data base Size of the safety data base –characteristics of the drug and its effects –proposed use –intended population Characteristics of an ideal safety data base Characteristics of an ideal safety data base –adequate duration –diverse population –better dose-response information particularly important for drugs with a high rate of drug- induced adverse effects or “biomarkers” of injury (CPK, TA, UA, K changes)particularly important for drugs with a high rate of drug- induced adverse effects or “biomarkers” of injury (CPK, TA, UA, K changes)

11. Temple University - 4/15/0311 Key Issues (cont.) “Individualization” factors“Individualization” factors drug-drug interactionsdrug-drug interactions drug-demographic relationshipsdrug-demographic relationships drug-disease relationships, including routine population PKdrug-disease relationships, including routine population PK Comparative data when it would be particularly importantComparative data when it would be particularly important

12. Temple University - 4/15/0312 Premarketing Risk Assessment Special Conditions

13. Temple University - 4/15/0313 Special Considerations Evaluation of safety –some general principles –doesn’t mean one size fits all –in planning and monitoring development needs to be constant attention to results of animal and human dataresults of animal and human data suggestions of problemssuggestions of problems population and drug-specific features that raise special concernspopulation and drug-specific features that raise special concerns

14. Temple University - 4/15/0314 Special Considerations DosingDosing – maintenance dose same as acute dose – titration Subtle adverse effectsSubtle adverse effects Pediatrics (dosing, AEs)Pediatrics (dosing, AEs) Database expansionDatabase expansion PharmacogeneticsPharmacogenetics –storing samples

15. Temple University - 4/15/0315 Always Evaluated Some matters always need assessment, notably QTc effectsQTc effects Evidence of hepatotoxicityEvidence of hepatotoxicity Polymorphic metabolismPolymorphic metabolism Drug-drug interactions, including new ones (inducers, inhibitors of glucuronidation, P-glycoprotein inhibitors)Drug-drug interactions, including new ones (inducers, inhibitors of glucuronidation, P-glycoprotein inhibitors) And, for biologics Immunogenicity, neutralizing antibodiesImmunogenicity, neutralizing antibodies For live agents - virulence, transmissibility, genetic stabilityFor live agents - virulence, transmissibility, genetic stability Transplantation therapies - survival, function, host immunocompetenceTransplantation therapies - survival, function, host immunocompetence

16. Temple University - 4/15/0316 Medication Error Prevention Analysis (MEPA) Pre-marketing assessmentPre-marketing assessment Increase “safe use” of products by:Increase “safe use” of products by: – minimizing medication errors related to namingnaming labeling, and/orlabeling, and/or packaging of the productpackaging of the product

17. Temple University - 4/15/0317 Premarketing Risk Assessment: Considerations for Data Analysis and Data Presentation

18. Temple University - 4/15/0318 Data analysis issues Grouping of adverse events Grouping of adverse events – coding/MedDRA Temporal relations between adverse events and Temporal relations between adverse events and product exposure product exposuretime-to-event Analyses of dose effects Analyses of dose effects Data pooling Data pooling Subgroup analysis Subgroup analysis Missing safety data Missing safety data Data presentation Data presentation

19. Temple University - 4/15/0319 Risk Management Programs

20. Temple University - 4/15/0320 Risk Management Programs Focuses on actions taken to reduce risks in drug product useFocuses on actions taken to reduce risks in drug product use –based on assessments described in other two concept papers

21. Temple University - 4/15/0321 Scope of Concept Paper Considerations for initiating and designing a risk management program - definitions and when appropriateConsiderations for initiating and designing a risk management program - definitions and when appropriate Selection of tools and levelsSelection of tools and levels Evaluation processes and methodsEvaluation processes and methods Elements of submissions to FDAElements of submissions to FDA

22. Temple University - 4/15/0322 Key elements (1) Definition of an RM Program (RMP)Definition of an RM Program (RMP) Clarity of RMP goals, objectivesClarity of RMP goals, objectives Determining when an RMP is needed and Sponsor/FDA roles in decision-makingDetermining when an RMP is needed and Sponsor/FDA roles in decision-making Best ways for tools to be in guidanceBest ways for tools to be in guidance Classification of RMP tools into LevelsClassification of RMP tools into Levels

23. Temple University - 4/15/0323 Key elements (2) Pretesting of RMP toolsPretesting of RMP tools Recommended evaluation of all RMPsRecommended evaluation of all RMPs Recommendation for 2 independent methods to evaluate key RMP goal(s)Recommendation for 2 independent methods to evaluate key RMP goal(s) Role of qualitative data in evaluationRole of qualitative data in evaluation Elements of RMP submissions & reportsElements of RMP submissions & reports

24. Temple University - 4/15/0324 Definition: Risk Management (RM) Methods used throughout a product’s lifecycle to: minimize risksminimize risks optimize benefit/risk balanceoptimize benefit/risk balance

25. Temple University - 4/15/0325 Risk Management Program (RMP) Strategic safety effort to reduce risk:Strategic safety effort to reduce risk: > 1 risk reduction goal > 1 intervention (tool) in addition to PI Tool examples: education, forms, processes, and other methods to influence or control a product’s:Tool examples: education, forms, processes, and other methods to influence or control a product’s: –prescribing –dispensing –use Note: the package insert (PI) is that portion of the approved product labeling described in 21 CFR 201.57, that is directed primarily to health professionals. The PI should not be confused with approved product labeling which my incorporate RMP materials such as Medication Guides and patient agreements in addition to the PI.

26. Temple University - 4/15/0326 When is an RM Program Appropriate? Whenever risk reduction needs emerge (throughout product lifecycle)Whenever risk reduction needs emerge (throughout product lifecycle) Sponsor may volunteer or FDA proposeSponsor may volunteer or FDA propose “When the number or severity of a product’s risks appears to undermine the magnitude of benefits in an important segment of actual or potential users.”“When the number or severity of a product’s risks appears to undermine the magnitude of benefits in an important segment of actual or potential users.”

27. Temple University - 4/15/0327 How to Assess Whether Risks Undermine Benefits? No simple formula compares risks to benefits.No simple formula compares risks to benefits. Risk and benefit numbers, types, measures vary.Risk and benefit numbers, types, measures vary. Case-by-case judgments required by sponsor and/or FDA on whether to develop, submit, and implement an RMPCase-by-case judgments required by sponsor and/or FDA on whether to develop, submit, and implement an RMP FDA expects:FDA expects: –Most products will be handled by PI. –PI revision will not automatically imply a need for RMP.

28. Temple University - 4/15/0328 Risk Management Tools

29. Temple University - 4/15/0329 Definitions Risk management intervention (tool): a process or system intended to enhance safe product use by reducing riskRisk management intervention (tool): a process or system intended to enhance safe product use by reducing risk Risk management programs use one or more toolsRisk management programs use one or more tools Choice of tools influenced by severity, reversibility and rate of riskChoice of tools influenced by severity, reversibility and rate of risk

30. Temple University - 4/15/0330 Types of Tools in Current Programs Education & outreachEducation & outreach Systems Guiding Prescribing, Dispensing, UseSystems Guiding Prescribing, Dispensing, Use Restricted Access SystemsRestricted Access Systems Suspension of MarketingSuspension of Marketing

31. Temple University - 4/15/0331 Selecting and Developing Tools Consider: Stakeholder input: feasibility, acceptanceStakeholder input: feasibility, acceptance Consistency: with existing/accepted toolsConsistency: with existing/accepted tools Evidence of success in achieving desired objective based on other RMPEvidence of success in achieving desired objective based on other RMP Evidence of success in ability of novel tool to achieve desired objectivesEvidence of success in ability of novel tool to achieve desired objectives –based on application in non-RMP settings Variability, validity, reproducibilityVariability, validity, reproducibility

32. Temple University - 4/15/0332 Proposed “Levels” for RMP Classification Level 1: Package insert only Level 2: Adds education and outreach tools Level 3: Level 2 plus systems guiding prescribing, dispensing and/or use Level 4: Access to product requires adherence to specific program elements

33. Temple University - 4/15/0333 Evaluation Processes and Methods

34. Temple University - 4/15/0334 Value of Risk Management Program (RMP) Evaluation Assess effectiveness of RMP & its toolsAssess effectiveness of RMP & its tools — Before implementation (pretesting) — Before implementation (pretesting) — Periodically after implementation — Periodically after implementation Ensure efforts are expended on effective interventionsEnsure efforts are expended on effective interventions Guide modifications of RMPGuide modifications of RMP

35. Temple University - 4/15/0335 Pretesting RMP Tools Allows : Stakeholder inputStakeholder input Comprehension testingComprehension testing Pilot testing of feasibility, acceptance, other factorsPilot testing of feasibility, acceptance, other factors

36. Temple University - 4/15/0336 Approaches To Evaluation Select what outcomes should be/can be measuredSelect what outcomes should be/can be measured Seek representative and quantitative dataSeek representative and quantitative data Use qualitative data as appropriate (e.g. risk communication)Use qualitative data as appropriate (e.g. risk communication)

37. Temple University - 4/15/0337 Approaches To Evaluation Consider using 2 complementary methods –especially for key goals or objectives –offset limitations of any single method

38. Temple University - 4/15/0338 Evaluation Methods Consider limitations Consider limitations  Validity  Accuracy  Timeliness  Representativeness  Biases  Social burdens  Costs

39. Temple University - 4/15/0339 Outcome Measures for Tools, Objectives, or Goals Changes in or absolute levels of: Patient health outcomesPatient health outcomes Surrogates of health outcomesSurrogates of health outcomes Process measures or behaviorsProcess measures or behaviors Behavioral components -Behavioral components - Comprehension, Knowledge, Attitudes Comprehension, Knowledge, Attitudes

40. Temple University - 4/15/0340 Limitations of Current Evaluation Methods Spontaneous adverse event reporting: – Decrease may reflect change in reporting, not change in frequency of event – Continuing reports may signal persistent safety problem – Continuing reports may signal persistent safety problem Administrative data: – May not be representative of general population – May not be representative of general population – Often exclude high risk populations – Often exclude high risk populations

41. Temple University - 4/15/0341 Limitations of Current Evaluation Methods Surveys or other active surveillance systems: – Reporting biases – Reporting biases – Sampling errors – Sampling errors

42. Temple University - 4/15/0342 Elements of RMP Submission to FDA Sections of RMP SubmissionSections of RMP Submission –Background –Goals, objectives, and level –Tools –Evaluation plan Reporting RMP to FDAReporting RMP to FDA

43. Temple University - 4/15/0343 Risk Assessment of Observational Data: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

44. Temple University - 4/15/0344 Scope of Concept Paper Important pharmacovigilance conceptsImportant pharmacovigilance concepts Safety signal identificationSafety signal identification Pharmacoepidemiologic assessment and interpretation of safety signalsPharmacoepidemiologic assessment and interpretation of safety signals Development of pharmacovigilance plansDevelopment of pharmacovigilance plans

45. Temple University - 4/15/0345 Scope of Concept Paper Focus solely on observational data sourcesFocus solely on observational data sources –Case Reports, Case Series –Pharmacoepidemiologic Studies RegistriesRegistries SurveysSurveys

46. Temple University - 4/15/0346 What is Pharmacovigilance? All post-approval scientific and data gathering activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other product- related problems This includes the use of pharmacoepidemiological studies

47. Temple University - 4/15/0347 Pharmacovigilance: Why? At the time of approval, clinical trial data are available on limited numbers of patients treated for relatively short periodsAt the time of approval, clinical trial data are available on limited numbers of patients treated for relatively short periods Once a product is marketed, large numbers of patients may be exposed, including:Once a product is marketed, large numbers of patients may be exposed, including: –Patients with co-morbid illnesses –Patients using concomitant medications –Patients with chronic exposure

48. Temple University - 4/15/0348 Pharmacovigilance: Why? After marketing, new safety information may become available:After marketing, new safety information may become available: –Through use of the product domestically or in other countries –Through use of other drugs in the same class –From preclinical studies –From pharmacologic studies –From controlled clinical trials

49. Temple University - 4/15/0349 What is a Pharmacovigilance Plan? A plan proposed by a sponsor for the ongoing evaluation of safety signals identified with the use of a productA plan proposed by a sponsor for the ongoing evaluation of safety signals identified with the use of a product May be developed at the time of product launch or after a signal is identifiedMay be developed at the time of product launch or after a signal is identified

50. Temple University - 4/15/0350 What is a Pharmacovigilance Plan? A sponsor’s plan may involve:A sponsor’s plan may involve: –Expedited reporting of certain serious adverse events –Implementation of active surveillance activities to identify as yet unreported adverse events –Conduct of additional observational studies or clinical trials A pharmacovigilance plan might be a component of a larger risk management programA pharmacovigilance plan might be a component of a larger risk management program

51. Temple University - 4/15/0351 Good Pharmacovigilance Practices

52. Temple University - 4/15/0352 Good Pharmacovigilance Practice starts by acquiring complete data from spontaneous adverse event reports.

53. Temple University - 4/15/0353 Characteristics of a Good Case Report Adverse event(s) detailsAdverse event(s) details Baseline patient characteristicsBaseline patient characteristics Therapy detailsTherapy details Time to onset of signs or symptomsTime to onset of signs or symptoms Diagnosis of the eventDiagnosis of the event Clinical course of the event and outcomesClinical course of the event and outcomes Laboratory dataLaboratory data Any other relevant informationAny other relevant information

54. Temple University - 4/15/0354 Good Medication Error Report ProductProduct Sequence of events leading to the errorSequence of events leading to the error Work environment in which the error occurredWork environment in which the error occurred Types of personnel involved with the errorTypes of personnel involved with the error Narratives- follow NCC MERP taxonomy (National Coordinating Council for Medication Error Reporting and Prevention)Narratives- follow NCC MERP taxonomy (National Coordinating Council for Medication Error Reporting and Prevention)

55. Temple University - 4/15/0355 Assessing Causality It is rarely certain whether the event was product induced.It is rarely certain whether the event was product induced. Features supportive of an associationFeatures supportive of an association –event occurred in the expected timeframe –absence of symptoms prior to exposure –absence of co-morbid conditions or use of concomitant medications –(+) dechallenge, (+) rechallenge –event consistent with the established mechanism of action of product Grouping case reports into “probable,” “possible,” and “unlikely” when appropriateGrouping case reports into “probable,” “possible,” and “unlikely” when appropriate

56. Temple University - 4/15/0356 Pharmacoepidemiologic Assessment

57. Temple University - 4/15/0357 When and why are pharmacoepidemiologic studies recommended? To further characterize potential safety signals from controlled clinical trialsTo further characterize potential safety signals from controlled clinical trials –chronic exposures –patients with comorbid conditions To further evaluate and quantify a safety signal identified after approvalTo further evaluate and quantify a safety signal identified after approval –incidence rate vs. reporting rate

58. Temple University - 4/15/0358 Minimal Requirements Pharmacoepidemiologic study protocolsPharmacoepidemiologic study protocols RegistriesRegistries SurveysSurveys Reporting and assessing safety signalsReporting and assessing safety signals

59. Temple University - 4/15/0359 Reporting Safety Signals to FDA Submit a synthesis of all available safety informationSubmit a synthesis of all available safety information Provide an assessment of the risk/benefit profile of the productProvide an assessment of the risk/benefit profile of the product Propose steps to further investigate through additional studiesPropose steps to further investigate through additional studies Propose risk management strategies as appropriatePropose risk management strategies as appropriate

60. Temple University - 4/15/0360 What is a Pharmacovigilance Plan? An enhanced pharmacovigilance plan proposed by a sponsor forAn enhanced pharmacovigilance plan proposed by a sponsor for –the ongoing evaluation of identified signals pre- or post-approval, or –to monitor at risk populations which have not been adequately studied FDA may request the plan at the time of launch or when a signal is identifiedFDA may request the plan at the time of launch or when a signal is identified Efforts may be above and beyond routine postmarketing spontaneous reportingEfforts may be above and beyond routine postmarketing spontaneous reporting

61. Temple University - 4/15/0361 Pharmacovigilance Plans May Involve... Expedited reporting of certain serious adverse eventsExpedited reporting of certain serious adverse events Periodic summary reporting at more frequent intervalsPeriodic summary reporting at more frequent intervals Perform active surveillance to identify unreported adverse eventsPerform active surveillance to identify unreported adverse events Conduct of additional observational studies or controlled clinical trials, registry, surveysConduct of additional observational studies or controlled clinical trials, registry, surveys

62. Temple University - 4/15/0362 Challenges Ahead How can the quality of adverse event reports be improved?How can the quality of adverse event reports be improved? What conclusions can be drawn from observational data sources given inherent limitations of such data?What conclusions can be drawn from observational data sources given inherent limitations of such data? What more can be done to enhance our knowledge about safety signals once they are identified?What more can be done to enhance our knowledge about safety signals once they are identified?

63. Temple University - 4/15/0363