Evidence Based Advertising Part II

Beyond the TMA: From clinical trials to real world evidence

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

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

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?

A Focus on Clinical TrialsPAAB 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?

Message within the limitations of the TMA (s3.1)

Indication

TMA Dosing Regimen

TMA Efficacy/Safety Information• Outcome type• Magnitude• Direction• Duration

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?

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?

Trial Protocol consistent with TMA

Indication

TMA Dosing Regimen

TMA Efficacy/Safety Information• Duration

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

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?

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

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

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.

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”

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?

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?

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?

So what does PAAB consider acceptable references?

AnswerClinical/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)

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)

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

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

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)

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”

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?

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)

PAAB Code updateJuly 1, 2013

• When surveyed, industry requested more guidelines

• Guidance documents can be found at http://www.paab.ca/advisories-guidance.htm

PAAB Code updateJuly 1, 2013

• Review tips can be found at http://www.paab.ca/reviewer-tips.htm

Case Study

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

p-values? Other quantification/qualification?

PPG ?

The End