Identifying, Validating and Substantiating Claims for Labeling and Advertising

1. Identifying, Validating and Substantiating Claims for Labeling and Advertising Louis A. Morris, Ph.D. Outcomes Research Conference February 24, 2004

2. Objectives • Why is it important to prospective develop claims? • What claims should we develop? (Identification) • How do we know we are measuring the effect we want to measure? (Validation) • What information do we need so that FDA will not object to our claims? (Substantiation)

3. Claims Development PI + HCP’s Audience: MCO’s Patients Clinical Trials Claim Planning Perceptual Analysis Scale Development What is the starting point for claims development?

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

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

6. 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

7. PRO Interpretation Typology Self-Observation Emotional States Physical States Behavioral States Bodily Response SymptomGlobal ADL HRQLCriterion depression bother bathing asthma- Satisfaction anxiety pain walking HRQL Productivity Compliance indication --------clinical studies findings

8. FDA Claims Perspective • False – inconsistent with label • Lacks substantial evidence • Misleading - logical inferences • local coherence - “Avoid Colds, take X” • global implication - comparative claims • FTC Differences • What is the Claim? (audience interpretation) • External evidence for implied claims

9. Claims Planning:Working Backwards • What do you want to say? • Sufficient research/planning to understand positioning, specific claims • Specify the claim (envision headline) • What substantiation do you need? • Claims to be communicated • Scale development • Clinical trials • Risk information inclusion Limits on Claims: We can lead a horse to water, but can’t make him recite the pledge of allegiance

10. Three Phases of Claim Development • Identifying Desired Claims • meaningful to patient or prescriber • positioning statement • Developing Meaningful &Validated Measures • scale development • Obtaining Substantiating Evidence • substantial evidence, clinical trials

11. Phase I: Identifying the Claim • Product Attributes • Results from Using (benefits) • How it makes Patient/Prescriber Feel • What it helps Patient Achieve (Actual  Ideal State) • Fulfills Needs, Achieves Expectations, Produces Satisfaction, Sets New Norm • Persuasion Parameters • Instrumental to Achieving Valued Goal

12. Developing Meaningful Claims • Need to understand: • How do prescribers/patients conceive of products/features? • Why would prescribers/patients want to use product? • What are their product-related goals? • How does the product fit in with their goals? • What would motivate the patient to ask for or prescriber to use? • What do we communicate to the patient or prescriber? • Product features of value to the patient or prescriber? • Benefits of using the product? • Symbolic associations of significance?

13. Phase I: Research Approaches • Needs Analysis – Gaining Insights • Focus group (phenomological, clinical, exploratory) • Projective Techniques • Fill in the blank (the thing I like best about my cholesterol-lowering medicine is _____) • Systematic Quantitative Measures • Approaches • HRQL (Disease) – is disease outcome important? • Benefit (Treatment) – is treatment outcome important? • Means End Chain – why is it important? • How does product attribute link to patient or prescriber values? • How does product use fit with consumer goals?

14. Study Product – Value Linkages • Means-End Chain Analysis • Examine Product Attributes (distinctions) • Relate to Consequences • Link to Values • Process of Studying • Laddering • Generate ACV chains • Question Posed Repeatedly: Why is that important? • Compile into HVM

16. Hierarchical Value Map (HVM) More Time with Family Values Go More Places Person In Control No Fear Better Treatment Conseq. Easy to Remember Easy Use Product Easy to Breathe Attributes Opens Airways Take Once-Day Inhaler

17. Translating HVM to Meaningful Endpoints • What are the important concepts/claims? • Leverage points offer clues • no fear, do more things, in control • Showing linkages is important • How complex is the concept to be communicated? • concrete attribute vs abstract goals vs valued behavior • Face validity vs construct (validity) vs symbolic scenario • Once-a-day, Easy-to-use, Spend time with family • Further substantiation/research needed? • Laddering offers insights, not definitive outputs • Examine complexity, subjectivity, multidimensionality, consumer interpretability, existing substantiation

18. Phase 2: Measurement Determination • Examine Proposed Claim • Already in label/additional measures • Single (concrete attribute) or multiple items (abstract concept)? • Scale Development • Single or multidimensional • Validity Study(ies) • Surveys or trials • Psychometric properties

19. Hypothetical basis for PRO as a criteria of evaluation Desk research Study design Preliminary protocol Literature review Patient interviews Discussion of PRO concepts with clinical / marketing team Desktop evaluation of available instruments Selection of instrument(s Development of a new questionnaire Approval by authors of instruments Further validation work? Validation Translations & Psychometric validation Translations & Psychometric validation Integration in the trial protocol Stages for developing a PRO Claim Marquis, 2002

20. Scale Psychometrics • Validity • Reliability • Sensitivity • Responsiveness • Minimally Important Difference

21. Scale Development • Measures a complex concept • Fair sampling of items Amount Cognitive--------Physical

22. How do we know we are measuring what we want to measure? • Validity - process not a characteristic - Understanding what is measured • Face Validity - examine items • Content Validity - coverage • Construct Validity - any theory? • Concurrent Validity - positive correlation • Discriminative Validity - negative correlation

23. FACT-Fatigue Subscale • I feel fatigued – face validity • I feel weak - physical outcome • I feel listless (washed out) – logical outcome • I feel tired • I have trouble starting things because I am tired – (cognitive) • I have trouble finishing things because I am tired • I have energy – the opposite, negate yea saying, halo effect • I need sleep during the day - outcome • I am too tired to eat • I need help doing my usual activities – (social) • [Plus others] Correlate with Red Blood Cell Levels - Anemia

24. How do we know we are measuring a concept consistently? • Reliability • Within the same scale • inter-item • Chronbach’s alpha • Over time • test-retest

25. How do we know that our measures can pick up differences that actually exits? • Sensitivity • Type of scale items • I am not tired at all • I am so tired I must go to sleep right now • I am having trouble concentrating • I am feeling a little bit sleepy 2 items

26. How do we know that our measure corresponds to changes in the variable in question? • Responsiveness • Correlate changes in direct measure of clinical outcome (Red Blood Cell Count) with changes on scale (tiredness).

27. How do we know that an observed effect is clinically meaningful? • Minimally Important Difference • Smallest scale difference judged to be meaningful (e.g., where a change in therapy would be warranted) • Effect Size

28. Developing a Scale? Boredom Scale • Conceptual - what is boredom? • Other scales? – literature, experts • Boredom effects, validation methods • Operational - Item Generation/Reduction/Validation • modular, adaptation from general scales • focus groups • initial question design (scale measure type) • ratings: How important are each of these items? • Factors Analysis - how many dimensions? • Validation studies - psychometrics • Clinical Impact (substantiation studies)

29. Selecting a Scale • Apply all FDA considerations • Validity in my population? • May need a pilot to validate • Practical Aspects - will people fill it out? • Number, complexity of items • “Involvement” with scale • Bias - • Leading questions, socially desirability, yea-saying, etc. • Use in marketing • May require “as measured by” language as well as explanation of the scale

30. 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?, context sufficient? • Risk disclosures • Confidence in Measurement

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

32. Uh-Oh Homemade Sales Aid

33. DDMAC Letters • Duragesic (serious pain) “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”

35. DDMAC Letter Neuronton (seizures) Misleadingly claims improvement in QOL parameters based on the NEON study. The NEON study is not considered substantial evidence for claims of QOL improvements because it is not a controlled study.

36. Ad ran in Europe without objection

37. DDMAC Letter • Fosamax (prevention of osteoporosis) 6/20/01 • Fosamax web site: link to other web pages within site titled “Preserving Your Independent Lifestyle.” • Use of this phrase in the context of product-specific promotional materials misleadingly implies an outcome of Fosamax treatment that has not been demonstrated by substantial evidence. The claim is misleading because it overstates the potential benefit of Fosamax.

39. Zanaflex (Jan 2002) Secondary data must be consistent with label. Even if new data is found, the data must be based on convincing studies and must be consistent with label

41. Provigil (January, 2002) Must convey indication accurately, not expand the perceived usefulness of the drug

42. APLB Letter • AVONEX (MS) 10/24/02 AVONEX delivers the highest rate of satisfaction – 95%…are misleading because the misrepresent the results of the survey… • does not identify the number of patients (75 per group, three therapies identified) • represents (only) the those who responded to the question • Lumps together 60% very satisfied and 30% somewhat satisfied

43. FDA Letters • Need specifically designed studies • Need substantial evidence • Implied claims, avoid overstatement of benefit • Claims must be consistent with label • Claims must not promote for unapproved use • Must accurately (fully) present study results

44. Ran without FDA objection: 2 clinical trials

49. Conclusions • Pharmaceutical Marketing • Used to be a Biological Model (every product has a niche) • Now is a Warfare Model (competition) • Develop Claims/Messages to Communicate Benefits • Efficiency, rapid adoption • Plan A – get in Label • Need to Develop Substantiation (substantial evidence) • Even if not included in label • Plan B - Claims Dossier