just how flexible can a prospective clinical trial be? donald a. berry dberry@mdanderson.org donald...
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Just How Flexible Can a Prospective Clinical Trial Be?
Just How Flexible Can a Prospective Clinical Trial Be?
Donald A. Berrydberry@mdanderson.org
Donald A. Berrydberry@mdanderson.org
BERRY
STATISTICAL INNOVATION
CONSULTANTS
22
Definition of “flexible”Definition of “flexible”
Pliant Characterized by a ready
capability to adapt to new, different, or changing requirements
Pliant Characterized by a ready
capability to adapt to new, different, or changing requirements
33
With thanks to Mike Krams & Vlad DragalinWith thanks to Mike Krams & Vlad Dragalin
44
Original question is not helpful
Original question is not helpful
Two kinds of flexibility: Ad hoc (improvised) Planned (prospective)
Two kinds of flexibility: Ad hoc (improvised) Planned (prospective)
55
Original question is not helpful
Original question is not helpful
Two kinds of flexibility: Ad hoc: okay for personal or
internal company decisions Planned: essential for
external buy-in
Two kinds of flexibility: Ad hoc: okay for personal or
internal company decisions Planned: essential for
external buy-in
66
New question 1: How to deal with ad hoc flexibility
in a clinical trial?
New question 1: How to deal with ad hoc flexibility
in a clinical trial?
You can’t!You can’t!
77
New question 2: How to deal with planned flexibility
in a clinical trial?
New question 2: How to deal with planned flexibility
in a clinical trial?
Design
The team on board?
Logistics
Regulatory
Design
The team on board?
Logistics
Regulatory
88
DesignDesign
Modeling--arbitrarily complicated Efficacy and safety Computation OCs & comparisons
Type I error Power Sample size Alternative designs
Modeling--arbitrarily complicated Efficacy and safety Computation OCs & comparisons
Type I error Power Sample size Alternative designs
99
The team on board?The team on board? You have to teach them
And you have to keep teaching them!
“I don’t want the DSMB making decisions such as whether to go to phase III.”
DSMB as automaton
You have to teach them
And you have to keep teaching them!
“I don’t want the DSMB making decisions such as whether to go to phase III.”
DSMB as automaton
1010
LogisticsLogistics Data flow: Updating database Clean data? (no, but model)
QA Auxiliary variables Central review
Missing data--same as above What CRO? Information leakage--who
knows what and when?
Data flow: Updating database Clean data? (no, but model)
QA Auxiliary variables Central review
Missing data--same as above What CRO? Information leakage--who
knows what and when?
1111
Logistics (cont’d)Logistics (cont’d)
“Adaptive design is a whole new ball game. If you don’t know what you are doing, you can do some very bad things and damage the integrity of the trial, and of the whole process.”
“Adaptive design is a whole new ball game. If you don’t know what you are doing, you can do some very bad things and damage the integrity of the trial, and of the whole process.”
1212
Who knows what & when?Who knows what & when? Phase I or II vs Phase III Dose-finding (“The Pharmacist Knows”) Dropping arms or adaptive
randomization (blinded vs open) Seamless phase II/III
Simple line in the sand (Publish but continue to accrue?)
“End of phase II meeting” Expanding accrual One study or two?
Phase I or II vs Phase III Dose-finding (“The Pharmacist Knows”) Dropping arms or adaptive
randomization (blinded vs open) Seamless phase II/III
Simple line in the sand (Publish but continue to accrue?)
“End of phase II meeting” Expanding accrual One study or two?
1313
RegulatoryRegulatory
CRCs and IRBs
“Please explain in lay terms” (Examples, examples, examples)
Informed consent?
FDA, EMEA
Meet early & as often as possible
CRCs and IRBs
“Please explain in lay terms” (Examples, examples, examples)
Informed consent?
FDA, EMEA
Meet early & as often as possible
1414
The Bottom LineThe Bottom Line
Clinical trials will continue to become more complicated (such as I-SPY2)
This is good and bad Trials must begin to address
interactions between treatments and patient covariates
Clinical trials will continue to become more complicated (such as I-SPY2)
This is good and bad Trials must begin to address
interactions between treatments and patient covariates
1515
The Bottom LineThe Bottom Line Traditional trials are poorly suited
for identifying treatments that benefit patients who have hetero-geneous diseases such as cancer
The adaptive path is treacherous, with mines every step of the way
Avoiding mines is challenging, but enormously rewarding ... and fun!
Traditional trials are poorly suited for identifying treatments that benefit patients who have hetero-geneous diseases such as cancer
The adaptive path is treacherous, with mines every step of the way
Avoiding mines is challenging, but enormously rewarding ... and fun!
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