Presentation on theme: "Discussionof Dynamic Treatment Regimens Dean Follmann NIAID."— Presentation transcript:
Discussionof Dynamic Treatment Regimens Dean Follmann NIAID
Thoughts Most clinical trials are 2 arms, maybe 2x2 factorial. – Simple, clear, familiar. Dynamic Treatment Regimens – Not DTRs efficiently address treatment strategies for settings where multiple sequential treatment decisions are made – More efficient than multiple separate clinical trials – Randomized design and analysis is best. Selling DTRs – Randomization quality inference where we efficiently address multiple questions
Collins R Medication BMOD Response Non-Response R Enhance (SG2) Augment (SG3) Response Non-Response R Enhance (SG5) Augment (SG6) Continue Med (SG1) Continue BMOD (SG4) Med=G1+SG2+SG3 versus BMOD=SG4+SG5+SG6 2 arm trial E=SG2+ SG5 versus A=SG3+SG6 Stratified clinical trial Two strata are 1) Medication NR 2)BMOD NR What is the best overall strategy? Med + E for NR, Med + A for NR BMOD + E for NR, BMOD + A for NR. An Uncovered 4 arm trial!
Farm Story Seed company interested in – Manure versus anhydrous fertilizer – Chemical versus mechanical weeding for weedy fields In March, randomize fields to 1 of the 4 strategies – March Manure + chemical if weedy in June – March Manure + mechanical if weedy in June – March Anhydrous + chemical if weedy in June – March Anhydrous + mechanical if weedy in June A standard 2 x 2 factorial clinical trial
DeKalb Seed Trial, sequentially R Manure Anhydrous few weeds weedy R Mechanical weeding Herbicide few weeds weedy R Mechanical weeding Herbicide No weeding March June October
Moral of the Story Factorial trials have a rich literature – Parsimony in analysis: Main effects, low order interactions – ``Two studies for the price of one” – Fractional factorials If randomize completely in March, factorial analysis of the 4 strategies is very clear.
Factorial Analysis Anhydrous Manure Herbicide Weeding Compare Anhydrous versus Manure using 2 strata: Herbicide & Weeding And vice versa Intended Action for Weedy Fields
Two Analyses Anhydrous Manure Herbicide Weeding Weedy Fields Compare Anhydrous versus Manure using 2 strata: Herbicide & Weeding Compare Herbicide to Weeding in the weedy fields using 2 strata: Anhydrous weedy fields & Manure weedy fields (it’s legit!)
Best Strategy? Four strategies – Med + Enhancement for Nonresponse – Med + Augment for Nonresponse – BMOD + Enhancement for Nonresponse – BMOD + Augment for Nonresponse Best way to pick the winner? – Pick the best of the 4 means. – Pick Med/BMOD then Pick Enhancement/Augment – Use factorial methods
Best Strategy? Four strategies – Med + Enhancement for Nonresponse – Med + Augment for Nonresponse – BMOD + Enhancement Method C for Nonresponse – BMOD + Augment Method D for Nonresponse Best way to pick the winner? – Pick the best of the 4 means. – Pick Med/BMOD then Pick Enhancement/Augment – Use factorial methods
DTRs Seem an exciting, rigorous, & efficient way to address multiple questions when we need to titrate a treatment strategy. When equivalent to factorial trial, sister literature may be somewhat helpful. – If on the fence fall to a factorial? Complication can be daunting to collaborators. – Emphasize efficiency of design – Find simple ways to convey results
,lwd=3) Responders Non-Responders & Augmented Non-Responders & Enhanced BMOD MED Post Randomization Subgroups for Responders. Strata for Non-responders
,lwd=3) Responders Non Responders & Augmented NonResponders & Enhanced BMODMED X Mean response For BMOD+AUGNR x
BMOD 1 st line treatment MED 1 st line treatment X Mean response For BMOD+AUGNR x
BMOD 1 st line treatment MED 1 st line treatment X x O O 2 nd line augmented 2 nd Line enhanced The uncovered 4 arm trial of strategies
Complexity DTRs can become complicated with multiple trajectories. Desirable to model mean structure with parsimony e.g. main effects. Unclear if conventional wisdom about interactions applies here. – But worth exploring Must fit separate means to uncovered trial if no common treatments.
Lynch Appealing design to efficiently ask several questions. Best initial therapy. Best 2 nd therapy for Responders & Non-responders. Initial analyses respect randomization. Subsequent analyses extracts randomized trials for 8 strategies. – (1) initial D2 if R then R1 if NR then NR1 – … – (8) initial D2 if R then R2 if NR then NR2 Can compare the 8 strategies
Above has D = +1,-1 5 day, not RespTx = +1, -1 NTX ONLY, not NRespTx = +1, -1 CBI+MM+PLA, not Just as we would for an old-school 2x2x2 factorial trial Does RespTX = -1 identify everyone else? i.e. Responders who got NTX+TDM and all Nonresponders?
Moodie Detailed development of strategies to optimize warfarin dosing. Comes up with suggested combinations that can be tested in clinical trials. Practicality of algorithms important
Dynamic Treatment Regimens Interested in efficiently answering many sequentially appropriate questions. Subsequent Randomizations can depend on previous responses. # possible Trajectories is large 2 x 2 x 2 Randomizations Early Randomizations Responses
Vanilla 2x2 Factorial Trial in would-be responders D2=R D5=? AND D2=? D5=R
2x2x2 DTR is like Two Old School 2x2 Randomized Trials Principal StratumDay 2Day 51 st 2x2 trial2 nd 2x2 trial 1No Response X 2ResponseNo ResponseXX 3 ResponseXX 4 X Vanilla 2x2 Factorial in would be D2 or D5 Responders D2 Responders are from Principal Stratum 2 & 4 D5 Responders are from Principal Stratum 3 & 4
2 by 2 Factorial D2 D5 R R R R = Randomization D2 + P D2 + T D5 + P D5 + T
Vanilla 2 by 2 Factorial in Would be D2 or D5 responders D2 D5 R R R R = Randomization D2 + P D2 + T D5 + P D5 + T
Factorial Studies How to analyze vanilla 2x2 trials? – Long history. Emphasis on parsimony & main effects – Y = b0 + b1 Z1 + b2 Z2 + b3 Z1 Z2 + e – Z1 = 1 if D2 (0 otherwise) – Z2 = 1 if TDM (0 otherwise) a