Transcript A Focus on Clinical Trials

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?
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?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
A Focus on Clinical Trials
Is the message within the limitations of the TMA?
Message sourced from TMA
PAAB s3.1
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?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
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?
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?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
A Focus on Clinical Trials
Is the message within the limitations of the TMA?
Message sourced from evidence other than the TMA
PAAB s3.1,
5.1, 5.3, 5.14
Is the protocol, endpoint, & outcome consistent with the TMA for
sponsor’s product (and comparator where relevant)?
Is the protocol & endpoint valid/credible?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
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
Is the message within the limitations of the TMA?
Message sourced from evidence other than the TMA
PAAB s2.1, 3.1.1, 5.5,
5.7, 5.8, 5.9, 5.10,
Is the protocol, endpoint, & outcome consistent with the TMA for
sponsor’s product (and comparator where relevant)?
Is the protocol & endpoint valid/credible?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
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
Is the message within the limitations of the 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?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
PAAB
s2.3,4.1,4.2,
4.3
A Focus on Clinical Trials
Is the message within the limitations of the 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?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
PAAB s2.3,
2.6, 5.6, 5.12
A Focus on Clinical Trials
Is the message within the limitations of the 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?
Does the message accurately interpret the findings?
Is message context & emphasis appropriate?
Should other messages be added from the source of TMA?
PAAB s2.4,
3.5, 4.4, 5.6,
5.11
So what does PAAB consider
acceptable references?
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)
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 noncomparative 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 update
July 1, 2013
• When surveyed, industry requested more
guidelines
• Guidance documents can be found at
http://www.paab.ca/advisories-guidance.htm
PAAB Code update
July 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 noninferiority (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
PPG ?
The End