Non inferiority trials
EU regulator viewpoint
        E.Abadie
       CHMP chair
Disclaimer
• This presentation might not be the view of
  CHMP or EMEA.
• This presentation is a personal viewpoint
  and ...
Overview
• Rules of Marketing Authorizations in EU
• Components of B/R balance
• Design of non inferiority trials and cave...
Rules of M.A in EU
• Article 26 Directive 2001/83/EC: MA
  refused if R/B not favourable, or
  therapeutic efficacy insuff...
Components of B/R balance
• B/R evaluation is a composite with following
  components:
  – Benefit: trials vs pbo, active ...
Design of non inferiority trials (1)
• E10, CHMP NfG choice of NI margin (2005),
  CPMP PtC on switching (2000)
• Trials v...
Design of non inferiority trials (2)
• Caveats: assay sensitivity and delta margin
• Assay sensitivity: ability to disting...
Design of non inferiority trials (3)
• Four critical steps
  – Historical evidence of sensitivity to drug
    effects( HES...
Interpretation of the results
• Three options: test product is 1) superior, 2) not
  non inferior, 3) non inferior;
• Supe...
Ethical aspects of NI trials
• Generally active control trials perceived to pose
  fewer ethical problems than pbo
• Equip...
Conclusion
• « Accepting to lose no more than » is different
  from « not trying to prove any additional value to
  the ne...
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What is the EU-regulatory point of view on non-inferiority trials?

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Cochrane Colloquium 2008 - Plenary 3

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What is the EU-regulatory point of view on non-inferiority trials?

  1. 1. Non inferiority trials EU regulator viewpoint E.Abadie CHMP chair
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.

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