1. Evidence Based Advertising Part II Beyond the TMA: From clinical trials to real world evidence

2. This morning we learned that…. 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. 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

4. A Focus on Clinical Trials Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from TMA Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

5. A Focus on Clinical Trials PAAB s3.1 Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from TMA Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

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

7. A Focus on Clinical Trials Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from TMA Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

8. A Focus on Clinical Trials PAAB s3.1, 5.1, 5.3, 5.14 Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

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

10. 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

11. A Focus on Clinical Trials PAAB s2.1, 3.1.1, 5.5, 5.7, 5.8, 5.9, 5.10, Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

12. 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

13. Study protocol Control Arm Randomization for therapeutic claims Blinding for subjective endpoints (e.g. pain, questionnaires) a priori (e.g. endpoint, subgroup, stats) No stats = no claim Valid endpoint/instrument

14. Endpoint Valid & Credible The instrument should be widely accepted as a measurement of drug outcomes in that specific patient group and condition. As evidenced by discussion of the endpoint/instrument in at least one of the following: a TMA within the therapeutic area (not required to be the sponsor’s TMA) consensus guidelines an authoritative medical text multiple peer-reviewed trials including at least one competitor’s trial.

15. 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”

16. A Focus on Clinical Trials PAAB s2.3,4.1,4.2, 4.3 Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

17. A Focus on Clinical Trials PAAB s2.3, 2.6, 5.6, 5.12 Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

18. A Focus on Clinical Trials PAAB s2.4, 3.5, 4.4, 5.6, 5.11 Is the message within the limitations of the TMA? Does the message accurately interpret the findings? Is message context & emphasis appropriate? Should other messages be added from the source of TMA? Message sourced from evidence other than the TMA Is the protocol, endpoint, & outcome consistent with the TMA for sponsor’s product (and comparator where relevant)? Is the protocol & endpoint valid/credible?

19. So what does PAAB consider acceptable references?

20. 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)

21. 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)

22. 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

23. 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

24. 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)

25. 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”

26. FAQs My client wants to show real world data, clinical trial aren’t representative of what patients are really doing. Can I use observational trials?

27. Answer See PAAB’s Guidance document on Observational studies: – May be considered for claims relating to adherence or preference and as additional support for efficacy/safety claims established by randomized clinical trials – Insufficient alone for efficacy/ safety claims (s3.1.1) – See Observational claims checklist Adapted from STROBRE checklist (16 items)

28. 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 http://www.paab.ca/advisories-guidance.htm

29. PAAB Code update July 1, 2013 Review tips can be found at http://www.paab.ca/reviewer-tips.htm http://www.paab.ca/reviewer-tips.htm

30. Case Study

32. Study designs Study 1: – multicenter, randomized, open-label non-inferiority trial in patients with Type 2 diabetes Dosing: – JENSULIN once daily or insulin passad twice daily Primary outcomes: HbA1c – demonstrated non- inferiority (NI) – failed superiority (SUP) test Secondary outcomes: PPG – failed NI and SUP FPG – NI Weight – NI and SUP Hypoglycemia – symptomatic and confirmed – NI Study 2: – multicenter, randomized, double blinded trial in patients with Type 2 diabetes Dosing: – JENSULIN twice daily or insulin passad twice daily Primary outcomes: Change in HbA1c vs baseline – JENSULIN – p=0.01 – Insulin passad – p=ns Secondary outcomes: Weight – JENSULIN – p=0.001 – Insulin passad – p=0.01 Hypoglycemia – descriptive findings

34. PPG ?

36. The End