Regulatory Issues in Outcomes Labeling & Advertising

1. Regulatory Issues in Outcomes Labeling & Advertising Louis A. Morris, Ph.D. July 17, 2001

2. Objectives • Why are outcome claims becoming more important to drug development? • What types of outcome claims are relevant to pharmaceutical communications? • Health Economics • Quality of Life • PROs • How are these regulated by FDA?

3. Clinical and Marketing Testing Approval Product Adoption I II III Intro Growth Maturity Decline B A SALES Inception Approval TIME How to Jump Start Sales?

4. Targeting Audience Decisions HCPsMCOsPATs Gatekeeper + + ++ Influencer ++ + + Prescriber ++ Buyer + + User/Monitor + ++

5. Product Profile to Label • What label is desirable? • How will we get there? Think Forward Desired Product Label Target Product Profile Development Plan Phase I, II and III • Development plan to deliver label • Appropriate studies to support claims Plan Backwards Lawry 1999

6. Claims Development PI + HCP’s Audience: MCO’s Patients Clinical Trials Claim Planning Perceptual Analysis Scale Development Not just through the FDA, but through to the market

7. Role of the PI Roadmap for Drug Development PI License to Market Additional Substantiation Claims Basis HCP’s MCO’s Pat’s

8. Label or Advertising Claims • Label (approved claims) • Indications must be in label • Other information of clinical significance • Meet content and format requirements • Relevance for prescribing decision • Advertisements (permitted claims) • Meet advertising substantiation and disclosure requirements • Marketer decides, FDA reviews

9. Types of Outcomes Claims • Theoretically Any Endpoint • For Purposes of This discussion • Health Economic • Health Related Quality of Life (HRQL) • Patient Reported Outcomes (PROs) • Includes HRQL and other claims

10. Health Care Economic Information • Section 114 • 218 words, all confusing • effective Feb. 19, 1998 • Economic Information Not False or Misleading If: • only to formulary (and similar) committees • approved indication only • “competent and reliable scientific evidence”

11. What is Health Economic Information? • “… any analysis that identifies, measures, or compares the economic consequences, including the costs of the represented health outcomes, of the use of a drug to the use of another drug, to another health care intervention, or to no intervention.” • Substantiation to Upon FDA Request

12. Standards for Review • “Methods for establishing the economic costs and consequences used to construct the health economic information would be assessed using standards widely accepted by economic experts.” • “…clinical outcome assumptions … experts familiar with evaluating the merits of clinical assessments.”

13. The Law (Committee Report): Economists’ Standard Cost Effectiveness Clinicians’ Standard FDA’s Previous Position (1995 Draft Guidance): Disclosure Cost Effectiveness Adequate and well controlled studies

14. What is an Economic Claim? Side Effect Treatment QALYs Doctor Visits Hospital Room Charges Blood Pressure Laboratory Tests FEV1 Refills Drug Costs Hospital Room Days Economic Clincal

15. Overall Impact • Immediate • The door is opened • Deeper Look • What is really here? • Uncertainty in interpretation • some FDA submissions but not many • Self-implementing • FDA had promised Guidance but none came • Little industry interest

16. Quality of Life • Humanistic Data • represents patients’ perspective • HCP & MCO audiences • Rise in Disease-Specific Scales • sensitive; more likely to show differences • may need to develop/validate scale • Inclusion in Label or Advertising • support advertising claims • in clinical trials section (18)

20. Patient Outcomes Assessment Sources and Examples Clinician - Reported Patient - Reported Physiological Caregiver - Reported For example, Global impressions Observation & tests of function For example, FEV1 HbA1c Tumor size For example, Dependency Functional status For example, Functional status Symptoms HRQL….Satisfaction Evaluation Criteria Perceptions, Linkages Global Impression Well-being Treatment adherence

21. Source of Claim ADL QALYs QALYs Cost PROs Bother Discomfort HRQL Symptoms Satisfaction Productivity Meyer, Burke, 1999

22. Three Phases of Functional Claim Development • Specifying Desired Claims • meaningful to individual • positioning statement • Developing Meaningful &Validated Measures • importance, scale development • Obtaining Substantiating Evidence • substantial evidence, clinical trials

23. Phase I: Specifying the Claim • Needs Analysis • Focus group (phenomological, clinical, exploratory) • Projective Techniques • Fill in the blank (the thing I like best about my cholesterol-lowering medicine is _____) • Importance to Audience • HRQL (Disease) – is disease outcome important? • Benefit (treatment) – is treatment outcome important? • Means-End Chain – why is it important?

24. Phase 2: Measurement Determination • Examine Proposed Claim • Single or multiple items? • Scale Development • Single or multidimensional • Validity Study(ies) • Surveys or trials • Psychometric properties

25. Phase 3: Substantiation • Is the Claim truthful? • FC&C Act Prohibits Misbranding • Cannot be false or misleading “in any particular” • Express and Implied Claims • Description accurate, sufficient context • Risk disclosures • Confidence in Measurement • “All claims of clinical benefit require substantial evidence” Laurie Burke (5/00)

26. Express and Implied Claims Deceptive Not Deceptive True False A B D C

29. Absenteeism in productivity claims: Relenza

32. DDMAC Letters • Neoral (transplant rejection) (3/7/00) • Unsubstantiated Claims - “imply Neoral has an effect on physical, mental and social functioning that has not been demonstrated by substantial evidence” • Duragesic (serious pain) 3/20/00 • “Health related QoL claims such as these require substantial evidence in the form of adequate and well controlled studies designed specifically to address these issues”

33. Truthful Claims Substantiation • Substantial Evidence • Uses/Indications; comparative claims • Adequate and well controlled clinical investigations • Efficacy standard (redefined by FDAMA) • one AWC trial + cooborating evidence • Consistency with approved package label • Convincing Evidence (surveys, preferences) • Being reexamined by FDA

34. PROs: FDA Considerations • Claim specification • Instrument development • Instrument validation • Study design • Data analysis plan • Interpretation of results • Reporting of results in approved labeling or promotion

35. Psychometric Qualities • Evidence of validity, reliability, sensitivity, and responsiveness • Demonstrated validity in previous research • cannot change order, pick items • Clinical Meaningful Differences • Supporting documentation to FDA