December 2nd, 2022

Statistical and logistical issues of platform trials- summary introduction Shogo NOMURA
Department of Biostatistics and Bioinformatics
Graduate School of Medicine
The University of Tokyo

Woodcock J and LaVange LM, N Engl J Med 2017. /Renfro LA and Mandrekar SJ. J Biopharm Stat 2017.
/ Renfro LA, et al. Cancer Letters 2017.

Master protocol

One overarching protocol designed to answer multiple questions:– Multiple treatments– Multiple diseases– Multiple subgroups (e.g., defined by biomarkers)

Three types of master protocol– Umbrella trial: multiple enriched sub-trials for one disease– Basket trial: one treatment for multiple diseases with specific biomarker status– Platform trial: sub-trials continually enter and exit

3Park JJH, et al. Trials 2019.

Number of platform trials

4Park JJH, et al. J Clin Epidemiol 2020. revised Fig1

Why are platform trials needed?
Sometimes, there is urgent medical needs for developing multiple
experimental candidate treatments at the same time.
– Infectious diseases (rescue treatments for Ebola disease, Covid-19, and so on)– Oncology (e.g., neoadjuvant chemotherapies for high-risk breast cancer patients)

Platform trial applies shared-controlled designs (SCDs) which can assess
multiple experimental groups in a single RCT.

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Angus DC and Alexander BM, et al. Nat Rev Drug Discovery 2019.

Existing platform trials (selected)

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SCDs versus 2-armed RCTs
Multiplicity adjustments due to multiple control-test comparisons:– 2-armed RCTs: not needed– SCDs• inferentially dependent (e.g., various dose levels of the same drug) → needed;• inferentially independent → adjustments may not be needed.

SCDs can be a more efficient approach than multiple 2-armed RCTs.
– #patients in the control arm in SCDs is smaller than that in multiple 2-armed RCTs.
– Power of SCDs can be higher than that of multiple 2-armed RCTs
even with multiplicity adjustments (Drs. Uemura and Lori will explain later).

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Park JJH, et al. J Clin Epidemiol 2020. revised Fig1

Plausible adaptive features in SCDs
A trial would be more efficient and/or ethical if …
(1) New arm introduction is allowed.
(2) Dropping existing arm(s) due to futility or efficacy.

8Sridhara R. et al. Stat Biopharm Res 2021.

Open platform trials
New arm(s) introduction (arms C-E) is allowed.

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Sridhara R. et al. Stat Biopharm Res 2021.

Different analytic strategies to use control data
Concurrent control

Non-concurrent control– Some control pts are discarded
from control-trt A comparison.
– Valid inferences due torandomization.

– Efficient use of existing data.
– Invalid inference due to nonrandomized controlled pts.

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Other modifications of platform trials
More complex and adaptive!!
– A Bayesian modeling approach which enables the followings.
• Response adaptive randomization;• Borrowing strengths from internal or external data;• Hierarchical modeling between multiple disease subtypes or biomarker-defined subsets;• Modeling surrogate and true endpoints for imputing missing data.

– Time machine for comparing non-concurrent control and test arm• A modeling technique used to estimate how a control arm has evolved over time.
• Incorporation of time trends in non-concurrent control

Embedding– Collecting data in a more routine clinical practice (e.g., electrical health records)

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How to assess statistical complexities?
Statistical OCs of clinical trials– Type-I error rate, power, bias and variance of estimated treatment effects– Average sample size if interim analyses are planned.

For simple closed platform trials, evaluation of OCs can be easy.
For complex open platform trials, evaluation may be difficult.
– Extensive simulation is needed.
– Simulation reports should be assessed by regulatory bodies, if needed.
– Education of statistically complex issues for non-statistical experts is also important.

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Fig: Lavange L, et al. Annals Intern Med 2021.

Logistical issues
The use of common organizations and procedures in one master
protocol can be a less redundant approach.
• Teams for protocol development and selection of therapeutic candidates;• DMCs and other related organizations.

Who holds leadership positions of many collaborators?
– Multiple pharma, CROs, research organizations, committees for clinical trials, funders– A case example of ACTIV trial• NIH & CDC sponsored• ACTIV partnership– U.S. government (incl. FDA)
– academia– 18 pharma, and so on14

Level of confirmatory natureConfirmatory
Closed platform with conventional analysis methods/ open platform using concurrent control only
– Suitable for the primary analysis in the pivotal trials– Highly likely to gain a regulatory approval

Open platform using several complex ideas– Not suitable due to the exploratory nature– Less likely to gain a regulatory approval

Exploratory15

Price D and Scott J. Clin Trials 2021.

Complex innovative trial design (CID) @FDA
CIDs: no fixed definitions– CIDs referred to as complex adaptive, Bayesian, and other novel clinical trial designs inPDUFA VI commitment letter.
– Designs that have rarely or never been used.

Recently, there are great expectations for CIDs, but …
– Limited use;
– Lack of clarity regarding regulatory acceptance and guidance;– Lack of experience and understanding;– No chance to publicly discuss CID proposals.

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Price D and Scott J. Clin Trials 2021.

CID paired meeting program
Prescription drug user fee act VI (PDUFA VI; 2018-2022)– CID pilot meeting program (5 yrs)
– FDA selected 2 submissions from sponsors per quarter.
• Sponsors had the opportunity to discuss with regulatory team.

PDUFDA VII (2023-2027)– Continuation of CID paired meeting program• FDA will select up to 8 proposals per year.

– For promotion purposes, CIDs through the program may be presented by FDA (e.g., in aguidance or public workshop).

https://www.fda.gov/drugs/development-resources/complex-innovative-trial-design-meeting-program17

Price D and Scott J. Clin Trials 2021.

Case studies of CIDs
#1: Duchenne muscular dystrophy デュシーヌ型筋ジストロフィー症– Placebo versus low/high doses RCT– Bayesian MMRM, sample size re-estimation, treatment selection,response adaptive randomization, hybrid control approach#2: Pediatric multiple sclerosis 小児多発性硬化症– 2-armed RCT (non-inferiority)– Bayesian negative-binomial model, meta-analytic predictive prior from adult data

#3: Multiple interventions across multiple pain conditions 慢性疼痛
– Multiple placebo-controlled RCTs（sub-study）

https://www.fda.gov/media/155403/download– Bayesian hierarchical model to leverage placebo and treatment effect information.
https://www.fda.gov/drugs/development-resources/complex-innovative-trial-design-meeting-program18

Price D and Scott J. Clin Trials 2021.

Case studies of CIDs
#4: Systemic lupus erythematosus 全身性エリテマトーデス– Placebo versus 3-doses RCT– Response adaptive randomization, futility monitoring and dose selection

https://www.fda.gov/media/155404/download#5: Population: Diffuse large B cell lymphoma びまん性大細胞リンパ腫

https://www.fda.gov/media/155405/download– Hybrid control approach (2-armed RCT, 2:1 ratio)– Assess secondary endpoint of OS by using propensity score matching
and Bayesian survival analysis methods.

https://www.fda.gov/drugs/development-resources/complex-innovative-trial-design-meeting-program

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High hurdle for Japanese platform trials
Limited governmental leadership and funding
Limited experiences for CIDs
– Statisticians and clinical teams in academia and pharma– Regulatory may have few experiences

Several difficulties for global expansions
These do hinder ambitious and challenging Japanese platform trials.

20Please enjoy our symposium!!
Dr. Lori will come back to Japan on March 2023.
@ 日本臨床腫瘍学会 https://site2.convention.co.jp/jsmo2023/

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