Getting the help of SAS in Getting the help of SAS in Clinical Trial setting: Clinical Trial setting: Monitoring Monitoring

and Simulationsand Simulations

Presented By:Presented By:Mehmet KocakMehmet Kocak

Phase I Clinical TrialsPhase I Clinical Trials

Objective is to find a maximum tolerated dose Objective is to find a maximum tolerated dose (MTD) of a new cytotoxic drug(MTD) of a new cytotoxic drug– MTD is not really the “maximum” tolerated dose MTD is not really the “maximum” tolerated dose

but rather the highest dose that yields manageable but rather the highest dose that yields manageable side effects.side effects.

– This dose is called the “target” dose.This dose is called the “target” dose.– Think of MTD as the target dose which is the dose Think of MTD as the target dose which is the dose

that yields a specified probability of toxicity, e.g. that yields a specified probability of toxicity, e.g. 25%.25%.

Continual Reassesment Method(CRM)Continual Reassesment Method(CRM)

Bayesian dose-finding method developed by Bayesian dose-finding method developed by O’Quigley et al (Biometrics, 1990)O’Quigley et al (Biometrics, 1990)Statistical model is used to estimate the Statistical model is used to estimate the relationship between dose and probability of relationship between dose and probability of toxicity (dose-toxicity)toxicity (dose-toxicity)After study opens, the model is fit to the actual After study opens, the model is fit to the actual data and used to estimate the target dose.data and used to estimate the target dose.

Continual Reassesment Method(CRM)Continual Reassesment Method(CRM)

Go to Next Dose

Add More

Go to Previous Dose

Decision

Start with the first Dose

First Dose is too toxic.

Continual Reassesment Method(CRM)Continual Reassesment Method(CRM)Obs Dose n r MTD MidDose Decision

1 120 2 0 1216.67 180 GOTONEXT

2 240 2 0 1165.46 360 GOTONEXT

3 480 3 0 1243.45 600 GOTONEXT

4 720 3 2 539.85 960 GOTOPREV

5 480 1 0 560.85 600 ADDMORE

6 480 1 0 578.19 600 ADDMORE

7 480 1 0 592.62 600 ADDMORE

8 480 1 0 604.67 600 GOTONEXT

9 720 1 0 654.01 960 ADDMORE

10 720 1 0 703.34 960 ADDMORE

11 720 1 0 753.23 960 ADDMORE

12 720 1 0 803.51 960 ADDMORE

13 720 1 1 679.89 960 ADDMORE

CRM – Statistical ModelCRM – Statistical ModelLogistic function is used frequently to model Logistic function is used frequently to model the dose-toxicity relationship.the dose-toxicity relationship.

Don’t know the true relationship between dose Don’t know the true relationship between dose and the probability of toxicity.and the probability of toxicity.

Here are three sample logistic curves:Here are three sample logistic curves:

100 300 500 700 900

Dose

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bilit

y o

f T

ox

icit

y

Relationship Between Dose and Toxicity Based on the Logistic Function

Curve 1

Curve 2

Curve 3

CRM – Statistical ModelCRM – Statistical Model

DoseDose Prob. Tox. Prob. Tox. Curve Curve 11

Prob. Tox. Prob. Tox.

Curve 2Curve 2

Prob. Tox. Prob. Tox.

Curve 3Curve 3

100100 2%2% 25%25% 1%1%

235235 6%6% 95%95% 3%3%

472472 44%44% 100%100% 16%16%

628628 78%78% 100%100% 35%35%

If you don’t know the true relationship between dose If you don’t know the true relationship between dose and toxicity, how do you estimate the MTD?and toxicity, how do you estimate the MTD?– Use the actual data from the study to estimate the Use the actual data from the study to estimate the

dose-toxicity curvedose-toxicity curve– Borrow data from other experiencesBorrow data from other experiences

What is the target dose of interest?What is the target dose of interest?– Dose that has 25% toxicityDose that has 25% toxicity

What is the proposed dose-toxicity relationship?What is the proposed dose-toxicity relationship?– Don’t have actual data when the study opensDon’t have actual data when the study opens– Need idea about the relationship between dose and Need idea about the relationship between dose and

toxicity to initiate the model fitting (priors)toxicity to initiate the model fitting (priors)

CRM – Statistical ModelCRM – Statistical Model

CRM – PriorsCRM – Priors

Other StudiesOther Studies– Adult studyAdult study– Study in different populationStudy in different population

GuessGuess– Quantify clinical intuition about drug behavior at Quantify clinical intuition about drug behavior at

high and low doseshigh and low doses

What dose would you guess has 90% toxicity?What dose would you guess has 90% toxicity?

What dose would you guess has 10% toxicity?What dose would you guess has 10% toxicity?

CRM - ExampleCRM - Example

Investigator wants to open a phase I study with 4 dose levelsInvestigator wants to open a phase I study with 4 dose levels– 100 mg/m2, 235 mg/m2, 472 mg/m2, and 628 mg/m2100 mg/m2, 235 mg/m2, 472 mg/m2, and 628 mg/m2

Need priors to initiate modelNeed priors to initiate model– Prior studiesPrior studies

Has there been a previous phase I study using this drug?Has there been a previous phase I study using this drug?– Investigator’s clinical intuition about high and low dosesInvestigator’s clinical intuition about high and low doses

What dose would you expect 90% toxicity?What dose would you expect 90% toxicity?What dose would you expect 10% toxicity?What dose would you expect 10% toxicity?

– Reduce the lowest dose by half for the low prior and increase Reduce the lowest dose by half for the low prior and increase the highest dose by half for the high priorthe highest dose by half for the high prior

50 for low prior and about 950 (628 + 314) for high prior50 for low prior and about 950 (628 + 314) for high prior

Modified Continual Reassesment Modified Continual Reassesment (CRM) Software (CRM) Software

Programmed by Dr. Steve PiantadosiProgrammed by Dr. Steve Piantadosi– Nice interfaceNice interface– Has problemsHas problems

Required data for the model to run:Required data for the model to run:– DoseDose– N (number of patients treated)N (number of patients treated)– r (number of responses (DLTs))r (number of responses (DLTs))

Probability of toxicityProbability of toxicity

– WeightWeight

Depending on the priors, our initial curve changes tremendously.

Actual Patient DataActual Patient Data

PatientPatient DoseDose Date on TreatmentDate on Treatment End of Dose Finding End of Dose Finding PeriodPeriod

DLT?DLT?

11 100100 2/14/032/14/03 3/14/033/14/03 NoNo

22 100100 2/23/032/23/03 3/23/033/23/03 NoNo

First two patients at Dose 100 mg/m2 did not have

DLTs.

DECISION: ESCALATE TO THE NEXT DOSE LEVEL

Sample Patient Data (Cont.)Sample Patient Data (Cont.)

PatientPatient DoseDose Date on TreatmentDate on Treatment End of Dose Finding End of Dose Finding PeriodPeriod

DLT?DLT?

11 100100 2/14/032/14/03 3/14/033/14/03 NoNo

22 100100 2/23/032/23/03 3/23/033/23/03 NoNo

33 235235 3/19/033/19/03 4/19/034/19/03 NoNo

44 235235 4/05/034/05/03 5/05/035/05/03 NoNo

Note: Next two patients treated at Dose 235 mg/m2 did not have DLTs, either.

DECISION: ESCALATE TO THE NEXT DOSE LEVEL

Sample Patient Data (Cont.)Sample Patient Data (Cont.)PatientPatient DoseDose Date on TreatmentDate on Treatment End of Dose Finding End of Dose Finding

PeriodPeriodDLT?DLT?

11 100100 2/14/032/14/03 3/14/033/14/03 NoNo

22 100100 2/23/032/23/03 3/23/033/23/03 NoNo

33 235235 3/19/033/19/03 4/19/034/19/03 NoNo

44 235235 4/05/034/05/03 5/05/035/05/03 NoNo

55 472472 4/21/034/21/03 5/12/035/12/03 YesYes

Note: Patient-5 had a DLT. We will immediately re-estimate the MTD based on the current toxicity information.

DECISION: GO BACK TO Dose Level 235.

History of CRM DecisionHistory of CRM Decision

Two Step SimulationTwo Step SimulationRemember that we decided to

de-escalate from Dose 472 mg/m2 to 235

mg/m2.

What can we say about the

future decisions?

Not the actual doses under investigation!

Two Step Simulation with SASTwo Step Simulation with SAS

Thanks to SAS ANNOTATE Facility

Function=

“move”

Function=

“draw”

Simulation Study with SAS: Simulation Study with SAS: Does CRM really Works?Does CRM really Works?

Go to Next Dose

Add More

Go to Previous Dose

Decision

Start with the first Dose

First Dose is too toxic.

Simulation Study in SASSimulation Study in SAS

Various Dose-toxicity relationshipsVarious Dose-toxicity relationships

Iterative Procedure, which is most likely Iterative Procedure, which is most likely different for each simulation run;different for each simulation run;

You cannot sample the whole data at once;You cannot sample the whole data at once;

10,000 simulations in each setting10,000 simulations in each setting

Preserving all necessary components of runs Preserving all necessary components of runs for summarizationfor summarization

Huge data sets, complicated algorithm.Huge data sets, complicated algorithm.

The Brain of the Simulation in SASThe Brain of the Simulation in SASIf the current dose is safe

%next:

If you need more data

%addmore:

If the current dose is not safe,

%prev:

%Decision:Processes…

%goto…

Start with the first Dose

If First Dose is too toxicOr you find the MTD,

%exit:

Simulation Study in SASSimulation Study in SAS%decision:--- DATA STEPS ------ SEVERAL %IF AND % GOTO STATEMENTS---

%if &maxcount>=6 and &decision=GOTONEXT and &dose<&nofdl %then %goto next;%else %if &maxcount>=6 and &decision=GOTOPREV and &dose^=1 %then %goto prev;%else %if &decision=GOTONEXT and &dose=&nofdl %then %goto addmore;%else %if &decision=GOTOPREV and &dose=1 %then %goto exit;%else %if &decision=GOTONEXT %then %goto next;%else %if &decision=ADDMORE %then %goto addmore;%else %if &decision=GOTOPREV %then %goto prev;%next: %let dose=%sysevalf(&dose+1); %let ctr=%sysevalf(&ctr+1); %goto decision;%addmore: %let ctr=%sysevalf(&ctr+1); %goto decision;%prev: %let dose=%sysevalf(&dose-1); %let ctr=%sysevalf(&ctr+1); %goto decision;%exit:

A paper submitted for publicationA paper submitted for publicationModified Continual Reassessment Method versus the Traditional Empirically-Based Design for Phase I Trials in Pediatric Oncology: Experiences of the Pediatric Brain

Tumor Consortium

Arzu Onar, Mehmet Kocak, James M. BoyettBiostatistics Department, St. Jude Children’s Research Hospital, 332 North Lauderdale St.

Mail Stop 768 Memphis TN 38105

Corresponding author: Arzu Onar Biostatistics Department, St. Jude Children’s Research Hospital, 332 North Lauderdale St. Mail Stop 768 Memphis TN 38105. Email:

arzu.onar@stjude.org. Tel: 901 495 5499. Fax: 901 544 8843.

ReferencesReferencesPiantadosi S, Fisher JD, Grossman S. Piantadosi S, Fisher JD, Grossman S. Practical implementation of a modified Practical implementation of a modified continual reassessment method. continual reassessment method. CancerCancer Chemother Pharmacol,Chemother Pharmacol, 41:29-436, 1998. 41:29-436, 1998.Goodman SN, Zahurak ML, Piantadosi, S. Goodman SN, Zahurak ML, Piantadosi, S. Some practical improvements in the continual Some practical improvements in the continual reassessment method for phase I studies. reassessment method for phase I studies. Statistics In Medicine,Statistics In Medicine, 14:1149-1161, 1995. 14:1149-1161, 1995.