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 How to Jump Start Sales? Inception A Approval TIME SALESSALES

4. Targeting Audience Decisions HCPs MCOs PATs Gatekeeper + + ++ Influencer++ + + Prescriber++ Buyer + + User/Monitor + ++

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

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

7. Role of the PI Roadmap for Drug Development License to Market PI 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. Cost Effectiveness Economists’ Standard Clinicians’ Standard Adequate and well controlled studies Disclosure The Law (Committee Report): FDA’s Previous Position (1995 Draft Guidance): Cost Effectiveness

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

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 - Reported Clinician - Reported For example, Functional status Symptoms HRQL….Satisfaction Evaluation Criteria Perceptions, Linkages Global Impression Well-being Treatment adherence For example, Global impressions Observation & tests of function Caregiver - Reported For example, Dependency Functional status Physiological For example, FEV 1 HbA1c Tumor size Patient Outcomes Assessment Sources and Examples

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

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 DeceptiveNot Deceptive True False AB C D

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