Evidence Based Advertising Part I Using the TMA as evidence in HCP advertising

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

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

Thought process for evaluating APS’s* *APS: Advertising promotions system

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

A Thought Process 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 PAAB s3.1

A Thought Process 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 TMA

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)

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

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

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 )

A Thought Process 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 TMA

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)

A Thought Process 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 TMA

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

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? 17

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” 18

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) 19

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 20

PAAB Code update July 1, 2013 When surveyed, industry requested more guidelines Guidance documents can be found at

PAAB Code update July 1, 2013 Review tips can be found at

Case Study

TMA Summary Indication: JENSULIN [sublingual basal insulin praspart] is indicated for the treatment of Type 1 or Type 2 diabetes in patients over 17 years of age who require basal insulin for the control of hyperglycemia Caution in elderly patients (≥65 years of age) as they are more likely to have impaired renal function Dosing: Once daily sublingual tablet Cardiovascular safety outcome: Demonstrated comparable risk in the composite endpoint of time to the first occurrence of CV death, non-fatal MI or non-fatal ischemic stroke (secondary outcome). Caution is recommended in patients with cardiovascular comorbidities. Efficacy: A total of 1262 patients with type 2 diabetes participated in two double-blind, active- controlled studies, one of 18-week and another of 24-week duration, to evaluate the efficacy and safety of JENSULIN® monotherapy vs insulin passad. Patients with inadequate glycemic control (HbA1c 7% to 10%) were randomized to receive a 100-mg dose of JENSULIN® OD or insulin passad twice daily. Baseline A1C was 7.6% for both groups. Treatment with JENSULIN® at 100 mg daily provided significant improvements in HbA1c, FPG, and 2-hour PPG compared to insulin passad (Table 11). JENSULIN patients had a mean reduction of 0.7% vs 0.3% with comparator (p=0.01) The improvement in HbA1c compared to comparator was not affected by gender, age, race, prior antihyperglycemic therapy or baseline BMI. The effect of JENSULIN® on lipid endpoints was similar to placebo. Body weight did not increase from the baseline with JENSULIN® (mean weight loss of 0.6 kg in the 18-week study and 0.2 kg in the 24-week study).

1 JENSULIN Product Monograph. PAABPharma Inc. January Insulin passad Product Monograph. CROpharms Inc. December 2013.

Summary: Indication presented upfront with/prior to 1 st marketing benefit claim Avoid the absolute Identify comparator Quantify and qualify Clinical and non-clinical stay separate Balance

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