1. Evidence Based Advertising “Don’t accept your dog’s admiration as conclusive evidence that you are wonderful” -Ann Landers

2. Guiding principles Code section 2.1 – Advertising must be accurate, complete and clear Code section 3.1 – Claims in advertising must be consistent with and within the limitations of the Terms of Market Authorization (TMA) (i.e. Product Monograph) or prescribing information for products with no TMA

3. The TMA (e.g. product monograph) is always an acceptable source of evidence. BUT Provided the advertising presentation reflects appropriate context & emphasis

4. What about other sources? When sources other than the TMA are used, we must pause to assess both: – Consistency with the product monograph – The “credibility” of the evidence

5. A Focus on Clinical Trials

6. PAAB s3.1

7. Message within the limitations of the TMA (s3.1) Indication TMA Dosing Regimen TMA Efficacy/Safety Information Outcome type Magnitude Direction Duration

8. A Focus on Clinical Trials

9. PAAB s3.1, 5.1, 5.3, 5.14

10. Trial Protocol consistent with TMA Indication TMA Dosing Regimen TMA Efficacy/Safety Information Duration

11. Takeaway…. Don’t forget to consider the comparator! Code section 5 relates to comparisons – Section 5.1: Authorized indication in common – Section 5.2: Comparable dosing range – Section 5.3: Consistent with comparator’s TMA – Section 5.14 : Non-Canadian products

12. A Focus on Clinical Trials PAAB s2.1, 3.1.1, 5.5, 5.7, 5.8, 5.9, 5.10,

13. What does “credible” mean? Appropriate steps are taken to ensure that the observation is not simply due to: – Chance – Methodological bias – Confounding This is concluded by assessing study protocol: – Design – Implementation – Reporting

14. How is this applied ? Published, peer-reviewed, well controlled and designed studies with statistical significance shown (Code s3.1.1) Comparative claims require support as above in a head-to-head study (Code s5.7) Validated, pre-defined endpoints (Code s5.8) To be considered evidence, claims must reach statistical significance (Code s5.9) – i.e. “no stats, no claim”

15. A Focus on Clinical Trials PAAB s2.3,4.1,4.2, 4.3

16. How to accurately interpret findings? Use the past tense (Code s2.1, 2.3, 5.11) – In order to reflect past study findings (not forecasts of future clinical experience) e.g. “Demonstrated”, “shown”, “In a study…” AND avoid generalizations – Better than one ACE Inhibitor does not mean better than all ACE Inhibitors (even if Key Opinion Leaders say that in medical practice all current opinions are similar)

17. How to accurately interpret findings? Interpreting statistics – Does the CI or p-value relate to that particular claim? – Was the CI or p-value interpreted correctly? e.g. Inability to attain statistical superiority is not proof of non-inferiority or “similarity” – Statistical significance ≠ clinically meaningful

18. How to accurately interpret findings? A study is designed and powered to assess the primary endpoint A failed study cannot be salvaged by a secondary endpoint

19. Secondary endpoints Example: Primary outcome: Bacterial eradication rates – Non-inferiority (NI) attained – Superiority NOT attained Secondary endpoints: Symptoms: – Sputum – NI – Fever – NI – Cough – NI and superiority – Headache – NI Secondary endpoints must be directionally consistent with the primary endpoint (see Guidance Document on Secondary Endpoints) Secondary endpoints should be identified as such within the claim copy NOT a footnote (Code section 3.1.10)

20. A Focus on Clinical Trials PAAB s2.3, 2.6, 5.6, 5.12

21. Context/Emphasis Keep non-clinical messages separate from clinical messages (Code s2.6.2 & 3.1.4) (e.g. Non-clinical experience and clinical efficacy/safety claims) Data presented in the TMA with a cautionary tone should not be presented as a product benefit (e.g. “Low” incidence of event which is a boxed warning) When TMA contains content which would otherwise not be accepted in drug advertising, restrict the presentation to the content, context, and emphasis in the TMA (e.g. “Special Study” data from part II of a product monograph)

22. A Focus on Clinical Trials PAAB s2.4 & 3.5, 4.4, 5.6, 5.11

23. When is additional information needed? Quantification (both implicit & explicit) Qualification Overly selective presentations (can’t systematically ignore negative findings) Present absolute data when claims are expressed in a relative way Balancing safety information

24. Is there a need to quantify or qualify the claim? Quantification = the presentation of magnitudes typically to answer one of the following questions (is the claim measureable?): How fast? How long? How short? How powerful? How low? How high? How much more? How much less? 24

25. Is there a need to quantify or qualify the claim? Qualification = insertion of text which limits/restricts the claim in some way For example: Claims relating to a study should be accompanied by the relevant study parameters (s5.11) Claims which are not clinically significant should be disclaimed accordingly (s2.6.2 & 3.1.4) e.g. “Clinical significance has not been established” 25

26. Overly Selective Presentations Code section 5.12 Not showing the whole story – various endpoints (at 2 weeks vs. 8 weeks) – context (overall score vs. selected sub scores, composite endpoint) 26

27. Exaggerated effect by omission of ARR (Code s4.2.3) Relative vs. Absolute Risk Reduction – 50% BP reduction may only correlate to a few mm Hg difference vs. comparator “Drug A shown more effective than Drug B with a 50% greater mean BP reduction”. Absolute BP reduction Difference (129 vs. 133) P<0.05 A vs. B p<0.001 A & B vs. placebo 27

28. FAQs What does PAAB consider acceptable references?

29. Answer Clinical/Therapeutic claims: Randomized controlled trials (RCTs) which are published & peer-reviewed (s3.1.1) Comparative clinical/therapeutic claims (e.g. efficacy/safety): – Must be a head-to-head RCT (s5.7) – Blinding required if subjective endpoint (not required if objective endpoint) – Statistical analysis required (e.g. p-value or CI) (s5.9) Place in therapy (e.g. first-line): Recognized Canadian consensus guidelines (s3.2)

30. Answer (Continued) Market Share: Authoritative recognized independent source (s4.2.2 & 5.10.2i) Non-clinical Product Claim (e.g. taste, packaging): Survey which is either published & peer reviewed OR Survey designed, conducted & analyzed without sponsor’s influence (s5.10.2ii) Non-clinical Comparisons of Product Properties Across TMAs: Complete comparison of Indications, Contraindications, Warnings, Interactions, Dosing, Pharmacokinetics, Mode of Action, NOT efficacy or adverse events (s5.10.2iii) Price Comparisons: Independent data. Must be the same source for all comparators (s5.10.2i)

31. What not to use as a reference Abstracts Symposia poster presentations Data on File references unless part of New Drug Submission (NDS) with proof of acceptance Review articles Opinions / Editorials Letters-to-editor Previous advertising Supplements Testimonials Adverse drug reaction reporting systems Pooled data See Code sections 3.1.1, 3.1.2 and 3.1.3

32. FAQs What type of reference do I use to support non- comparative statements about competitor’s products? E.g. Traditional NSAIDs have a high risk of GI ulcers

33. Answer “You don’t” Discussions of competing products should be limited to acceptable comparisons involving the sponsor’s product. Examples of acceptable comparisons: Efficacy/safety comparison from head-to-head clinical trial (s5.7) Product properties across TMAs (s5.10.2iii)

34. Disparaging Claims Cannot unfairly attack competitors (Code s5.6) Selective presentation of side effects Only showing other product’s data Only showing negative features of a competitor. “High risk of GI bleeds have been associated with the use of traditional NSAIDs” “Did you know that Drug X is derived from pig’s urine? Drug A is derived from a natural source” “ Had enough of needle injections? Consider Drug A, now in a convenient once a week patch”

35. PAAB Code update July 1, 2013 When surveyed, industry requested more guidelines Guidance documents can be found at http://www.paab.ca/advisories-guidance.htm

36. For more information http://www.paab.ca/advisories-guidance.htm

37. Questions??