1. Bureau of Gastroenterology, Infection
Adaptive Clinical Trial Designs: Health Canada’s Regulatory Perspective
Celia Lourenco, PhD
Bureau of Gastroenterology, Infection
And Viral Diseases

2. Health Canada - HPFB
Reviews and authorises clinical trial applications for pharmaceuticals, biologics, radiopharmaceuticals, medical devices, and natural health products
Reviews and authorises for sale pharmaceuticals, biologics, radiopharmaceuticals, medical devices, and natural health products
Carries out pharmacovigilance in clinical trials and post-market

3. Main regulatory concerns
Design should be appropriate to answer the scientific question of interest
Sponsor must demonstrate control of Power and Type I error rate over the entire clinical trial
Operational bias – appropriate pre-planning and measures are implemented to avoid operational bias (e.g., randomization, blinding, secure electronic systems, independent DSMBs, blinded steering committees, etc.)

4. Adaptive Designs
On Health Canada’s radar for several years (HC working group formed in 2008)
Many seen in clinical trial applications (CTAs)
Some in new drug submissions (NDSs)

5. HC WG definition of adaptive design
An adaptive clinical trial design is a study design planned prospectively that uses accumulating data to decide how to modify aspects of an ongoing study and that uses pre-specified, validated, methodological approaches to preserve the validity and integrity of the trial

6. Some examples in CTAs Adaptive randomization, drop or add arms
Mainly in phase 2 trials
Use of modeling and simulation
Sample size re-estimation: phase 2 or 3
Seamless design: phase 2/3, two-stage dose selection

9. Some examples in NDSs
Indacaterol: for treatment of COPD - Trial B2335S, a 26-week seamless adaptive design trial that included an initial 2 week dose-ranging phase
Gardasil 9: a vaccine indicated for the prevention of infection caused by the Human Papillomavirus (HPV) types 6, 11, 16, 18, 31, 33, 45, 52 and 58
A Randomized, International, Double-Blinded (With In-House Blinding), Controlled With GARDASIL™, Dose-Ranging, Tolerability, Immunogenicity, and Efficacy Study of a Multivalent Human Papillomavirus (HPV) L1 Virus-Like Particle (VLP) Vaccine Administered to 16- to 26-Year-Old Women

10. B2335s Trial Design

11. Gardasil 9 design From FDA’s review on FDA’s website:
Phase 2b/3, with two parts
Part A: ~1240 subjects were enrolled, equally randomized to 3 dose formulations of 9vHPV or qHPV
Part B: one dose formulation of 9vHPV was selected for Part B based on interim immunogenicity results, with ~13,380 subjects enrolled in Part B and equally randomized to the selected dose formulation of 9vHPV or qHPV

12. Conclusion from case-studies
Adaptive designs present increased complexity
May be difficult to interpret, and make use of new statistical tests/procedures
Increase in use of Bayesian statistics, which involves a different approach in statistical inference
Increase use of simulation – time consuming to validate and can be difficult to interpret what the results mean

13. Why and What of Simulation
Simulation provides the operating characteristics of the trial design
That is the description (a picture) of the likelihood (probabilities) of how the trial will progress down the different paths (planned possible adaptations) to eventual completion or termination of the trial

14. Seeing that Picture The sponsors should provide that picture
Usually in well designed and planned trials, yes
The question is should regulators look behind the picture and actually check that it was done right?
That means try to duplicate the simulation results
Ask to submit codes, and check/replicate

15. Conclusions & recommendations
Continue to monitor adaptive designs, expect that the topic will continue to evolve
Pre-submission meetings are encouraged
Optimize biostatistics and IT resources to deal with emerging trends such as use of Bayesian statistics
Provide support and encourage attendance of courses and seminars on adaptive design
Biostatistics consult sought (early) for pivotal Adaptive Design trials in submissions

16. THANK YOU!