1. This is a platform alteration: A Trial Management Perspective on the operational aspects of adaptive platform trials
Francesca Schiavone & Riya Bathia
MRC Clinical Trials Unit at UCL
ICTMC 09-May-2017
Who we are
Where we’re from
We are here to bring a slightly diff perspective in this session as we’re going to be focussing on the operational aspects of running adaptive platform trials

2. Adding new research comparisons
Widely recognised efficiencies of trial design§¥
Identify operational challenges
Share our experience in trial conduct
STAMPEDE
FOCUS4
The efficiencies of adaptive platform trials are widely recognised and these are described in several publications
However little information is available on the operational aspects and the challenges of running these trials
We will be sharing our experience from 2 leading adaptive platform design trials run by the MRC CTU at UCL
STAMPEDE and F4
And in particular we will be focusing on the operational aspects of adding new research comparison, a key feature of adaptive platform designs
§Kaplan R, Maughan T, Crook A, Fisher D, Wilson R, Brown L, et al. Evaluating many treatments and biomarkers in oncology: a new design. Journal of Clinical Oncology : official journal of the American Society of Clinical Oncology. 2013;31(36): Epub 2013/11/20.
¥ Sydes MR, Parmar MKB, Mason MD, Clarke NW, Amos C, Anderson J, de Bono JS, Dearnaley DP, Dwyer J, Green C, Jovic G, Ritchie AWS, Russell JM, Sanders K, Thalmann G, James ND. Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials. 2012;13(1):168. PubMed PMID:
MRC Clinical Trials Unit at UCL

3. STAMPEDE STAMPEDE MAMS design Locally advanced and metastatic PCa
Opened in 2005, 5 contemporaneously recruiting research comparisons and one shared control arm
Since 2011, 4 new research comparisons have been added to the existing trial platform and 2 more are in pipeline for activation in the next 6-12 months
MRC Clinical Trials Unit at UCL

4. FOCUS4 Restart first line chemo on progression Primary endpoint:
MRC Clinical Trials Unit at UCL
REGISTER
Biomarker analysis during first-line treatment
RANDOMISE
STRATIFY
BRAF
mutation
PIK3CA
RAS + p53 mutation
All Wild type
Non-stratified
Restart first line chemo on progression
Primary endpoint:
PFS in the interval
MSI/MMR
def
H3K36me3
loss
Synthetic lethality cohort N D E C A
Novel Agent P B
Aspirin
WEE1 inhibitor
No Rx
CAP
FOLLOW-UP
Advanced or Metastatic Colorectal cancer
First-line treatment ~ 16 wks
-> Stable/Responding disease
FOCUS4 is a molecularly stratified, multi-comparison randomised trial programme for patients with colorectal cancer 
The trial opened in Jan 2014 with one molecular cohort comparison and one non stratified comparisons.
Since opening, one additional molecular cohort comparison has been opened, a further one will be opening this summer and several others are in development for activation in the near future

5. Operational steps for addition of new comparisons
 Operational Components
 Project Timeline
Criteria for inclusion of new comparison
Grant application/Scientific peer review
Funding & Biomarker development
Protocol development
Regulatory application
Contracts and drug supply
CRFs and DB development
Site Implementation
We have distilled the key operational components required for the activation of a new research comparison
What some of you might find striking is that these steps don’t differ greatly to setting up a trial form scratch
During this presentation we will focusing on the challenges encountered specifically when adding a new research comparison and some of the strategies and solutions we have found throughout the years
Note: biomarker development constitutes a significant piece of work within these steps but we are not being focusing on this here
Time
MRC Clinical Trials Unit at UCL

6. Scientific peer-review and funding
Challenge
Multiple funders
Cancer Research UK (CRUK)
MRC/NIHR EME Programme
Industry
Strategy
Trial-specific review committees
Dialogue with funders
Processes changed for adaptive platform trials
Scale of funding
Scientific peer review and funding is one of the first steps required when considering the addition of a new research comparison to a platform trial
Due to scale of platform trials like STAMPEDE and F4 we typically see several founders and peer-review bodies round the table
The key strategy we identify for a more streamlined approach to peer review is a constant dialogue with funders from the outset
A trial-specific review committee was put in place for F4 by the NIHR EMA Programme to ensure Continuity of review system and meaningful review of the trial platform
In STAMPEDE, a continuous dialogue with CRUK has lead to the peer-review process to be adapted to allow selective review of new research proposals for platform trials
The scale of the funding has also been changed over the years to allow more adequate support to large platform projects

7. Protocol development Challenge Continuous adaptations and amendments
Strategy
Futureproofing
Modular vs single protocol
Terminology
Understanding by all stakeholders
When adding new research comparisons in an adaptive platform trial, continuous adaptations and amendments pose a challenge to protocol development
We have therefore found very important to futureproof the protocol and reflect on the protocol structure as this is such a key trial document. Include plan to add comparisons
In F4, the younger of the two trials presented here, a modular structure has been adopted with a master protocol and self-contained comparison-specific sections –this allows a more flexible implementation across sites as not all centres might be participating to all res comparisons
STAMPEDE on the other hand is following a more traditional protocol structure with the protocol being a single document.
There are merit and benefits in using both models but we emphasise the importance of thinking about the protocol structure
Terminology = ppl understand it’s ONE trial
Stakeholders = sites and regulators

8. Regulatory & governance review
Challenge
Approval of original platform and amendments
Strategy
Engagement with regulators from the outset
Benefit and Efficiency of adding new research comparisons to an existing platforms become more apparent when it comes to the regulatory approval
In the UK, the addition of a new res comparison can be implemented via a substantial amendment which requires 35 days approval window a much shorter timelines compared to starting a trial from scratch
A word of caution still needs to mentioned about the magnitude of changes required to the trial documentation to activate a new res comparison even if timelines for approval are shorter
Approval Relies on understanding of design by regulators
Chat with MHRA prior to adding each comparisons
F4 chat with MHRA EMA informal advisory discussion on trial design

9. Agreements Challenge Negotiation timelines EU Tender Strategy
Identify step in critical path
Negotiations often time consuming, can be rate limiting step. Particularly is EU tender required
Be aware and factor into project plan
Drug supply may depend on contract sign off and EU tender –see STAMPEDE abi+enza comparison

10. Case Report Forms and database development
Key for addition of new comparison
Poster board #:381
Lead by Dominic Hague
Specific challenges to the data management aspects of adding new comparison – described in poster.
Including effect on timelines, time to develop and test, timelines to implement new comparison are depends on this work.

11. Site Implementation Challenge
Activating research comparisons to an ongoing platform
Strategy
Early engagement with sites
Intensive site training programme
Consideration on existing platform
Stop vs Continue randomisations
Key area of efficiency is a site implementation where a new comparison is implemented as an amendment.
Challenge is activating across a large number of sites which platform ongoing – intense period of activity at sites and CTU
Survey to sites to involve them at early stages of development of a new comparison cont though to intensive site training programme
Risk based approach to relation to site set-up process and set an activation date which acts as a deadline for the activation steps to be completed deadline both trials
Stop rando to other comparisons?
Shared control arm in STAMPEDE therefore can close all
FOCUS4 allow reg and rando to other comparison if delays in implementation
CTU workload – intense period

12. Example of when the design pays off
Example of when the design pays off. This shows the time to 1st pt recruited by site for the original comparisons (opened in 2005) and the first new research comparisons added to the original platform (the abiraterone comparison opened in 2011)
It takes 9 years for 120 centres to recruit their first patient whereas the abiraterone comparison achieves that in 24 months. Faster accrual is due to sites being activated more quickly after a new comparison is launched

13. Reiterated when looking at the subsequently added comparisons (time to 3rd pt) with the majority of sites recruiting 3 patient between 6 to 12 months from the launch of a new research comparison.
M1|RT comparison
Enzalutamide + Abiraterone comparison
Metformin comparison

14. Trial Management Team Challenge TMT workload and resourcing
Conflicting tasks
Changes to original platform
Interim analyses
Strategy
Team structure
Resource planning and task prioritisation
Stepping back form focusing on the addition of new comparisons, some specific challenges to the TMT at CTU in running adaptive platform trials
Intense Workload at time resulting in higher resource requirements
Conflicting tasks and the balance between existing trial and changes to platform
Both trials have large teams with multiple TM and DM to address the needs. Traditional model, consider how work is split e.g by comparison, or specific tasks. Balancing the development needs of staff and progress of the trials
Proactive oversight, careful resource planning and constant review tasks and prioritisation of task is required to ensure successful delivery and ensure quality
STAMPEDE
SOC changes following primary analysis –protocol change had to take priority and delayed slightly activation to metformin comparison
Closing research arms leaving only arms opened to a sub-set of pts  abi+enza comparisons closed in Apr and metformin open in Sept 2016 leaving only the M1|RT comparison open (only to a sub-set of pts)
FOCUS4
Stopping recruitment to FOCUS4-D following Activity Stage analyses few weeks after the opening of F4-B

15. Open questions What do sites think of these types of trials?
What is the best resourcing model?
How do we measure operational efficiency in conduct?
There are still many other unanswered question around running these types of trials.
Site perspective on operational issue? large numbers of centres suggests interest and engagement, recruitment to stampede is successful
Resourcing and team structure within CTU – both trials similar approach
Measuring operational efficiency? design known for its efficiencies in relation to trial results however how do we measure the operational efficiencies compared to setting up new trials?

16. Trial design has efficiencies Operational complexities
Conclusion
Trial design has efficiencies
Operational complexities
Complexities can be overcome
Publication on trial conduct in progress
Make it positive!
Known efficiencies
Not without some operational complexities
S & F shown that these can be overcome but don’t underestimate the time and resource implications. to successfully deliver adaptive platform trials
Full publication on this topic in progress

17. Acknowledgments
Co-authors: K. Letchemanan, L. Masters, L. Brown, CL. Amos, A. Bara, MKB. Parmar, MR. Sydes
STAMPEDE Trial Management Group
FOCUS4 Trial Management Group
Trial Management Teams at MRC Clinical Trials Unit at UCL
Sponsor: MRC
Funders
CRUK
MRC/NIHR EME Programme
Industry partners
The FOCUS4 Trial Programme is jointly funded by the MRC-NIHR Efficacy and Mechanism Evaluation Programme (11/100/50) and Cancer Research UK (A13363).

18. This is a platform alteration: A Trial Management Perspective on the operational aspects of adaptive platform trials
Francesca Schiavone & Riya Bathia
MRC Clinical Trials Unit at UCL
ICTMC 09-May-2017