Cochrane Colloquium 2008 - Plenary 3

1. Non inferiority trials
EU regulator viewpoint
E.Abadie
CHMP chair

2. Disclaimer
• This presentation might not be the view of
CHMP or EMEA.
• This presentation is a personal viewpoint
and binds in no way the organisation
mentioned above.

3. Overview
• Rules of Marketing Authorizations in EU
• Components of B/R balance
• Design of non inferiority trials and caveats
• How to interpret the results of non
inferiority trials
• Ethical aspects of NI trials
• Conclusion

4. Rules of M.A in EU
• Article 26 Directive 2001/83/EC: MA
refused if R/B not favourable, or
therapeutic efficacy insufficiently
substantiated, or qualitative and
quantitative composition not as declared
• Conclusion: only based on QSE, no need
clause, even no mention B/R should not
be inferior to already existing products

5. Components of B/R balance
• B/R evaluation is a composite with following
components:
– Benefit: trials vs pbo, active controls
– Risk: pharmaceutical quality, non clinical, clinical
safety
• Annex 1 of Directive 2001/83/EC
(section5.2.5.1): in general..clinical
trials..controlled, randomised.. vs pbo AND vs
established MP of proven therapeutic value; any
other design to be justified
• B/R remains a value judgement

6. Design of non inferiority trials (1)
• E10, CHMP NfG choice of NI margin (2005),
CPMP PtC on switching (2000)
• Trials vs pbo (superiority) and vs active controls
(superiority or non inferiority)
• NI trial: to show that the new drug is not less
effective than the control by more than a defined
amount (margin)
• NI trials are frequent, since applicant not obliged
to show a superior B/R balance compared to
existing therapies. Don’t forget a superiority trial
which fails is useless (as far as 1st endpoint
concerned) !

7. Design of non inferiority trials (2)
• Caveats: assay sensitivity and delta margin
• Assay sensitivity: ability to distinguish an effective from a
less effective or ineffective treatment. If a trial lacks
assay sensitivity, risk is to conclude the test is « as
effective as » an ineffective active control.
• Assay sensitivity: evaluated before and after the end of
the trial
• Delta margin: degree of inferiority of the test treatment to
the control that the trial will try to exclude statistically,
based on statistical and medical judgements, depends
somewhat on the endpoint chosen. Danger: to chose a
margin which would render the test product
indistinguishable from the placebo.

8. Design of non inferiority trials (3)
• Four critical steps
– Historical evidence of sensitivity to drug
effects( HESDE): pts population, dose,
concomitant therapies, endpoints, etc…
– Designing a trial: to adhere closely to HESDE
– Setting a margin
– Conducting the trial: adhere closely to the
conduct of historical active controls, be of high
quality in order to mitigate the risk of not
observing the difference between groups

9. Interpretation of the results
• Three options: test product is 1) superior, 2) not
non inferior, 3) non inferior;
• Superior: planned in the statistical plan
• Not non inferior: need to see some form of
superiority (safety, tolerability, compliance)
• Non inferior:
– if mechanism of action is different, alternative for the
physician
– If mechanism of action is the same, « me too drug »,
to be handled through Health Technology Institutions

10. Ethical aspects of NI trials
• Generally active control trials perceived to pose
fewer ethical problems than pbo
• Equipoise, informed consent are paramount
• Difficulties:
– Not to conclude on efficacy of test product when no
placebo is involved (benign pathologies, assay
sensitivity), three arm trial advocated where
appropriate
– Many patients recruited with a test product being
ineffective (or lesss effective) at the end of the day….

11. Conclusion
• « Accepting to lose no more than » is different
from « not trying to prove any additional value to
the new drug »
• Superiority trial vs active control which fails
cannot be concluded as equivalent, can pose an
ethical problem
• Following the international rules, better than pbo
and (at least) non inferior to established active
control is the standard of approval of a new
medicine anywhere in the world.