Critical Methological Issues in Recent Randomised Trials

MSO – ROMEa November 23, 2012 Critical Methological Issues in Recent Randomised Trials Paolo Bruzzi Epidemiologia Clinica IRCCS AUO San Martino IST

Topics • Changes in the methodology of the Phases of cancer trials • Efficacy: Do we still need (Large) Randomised Controlled Trials? • Perspectives ?

Conventional Methodology - Phase I: dose increases -> MTD • Phase II: Uncontrolled -> % Response in metastatic pts with a specific cancer • Phase III: Large RCT’s in relatively heterogeneous pts: OS (or EFS)

Conventional Methodology - Phase I: dose increases -> MTD The More the Better? DOSE –RESPONSE! PHASE I-II TRIALS

Conventional Methodology • Phase II: Uncontrolled -> % Response in metastatic pts with a specific cancer

Conventional Methodology • Phase II: Uncontrolled -> % Response in metastatic pts with a specific cancer • Response? Direct anticancer effect? • Metastatic pts? • Activity in pts with less disease burden • Need of repeated biopsies

Modern Methodology • Phase II trials: • Biological Endpoints • Window-of-opportunity studies- Neoadjuvant trials – Locally advanced dis. • Randomised Controls

Conventional Methodology - Phase I: dose increases -> MTD • Phase II: Uncontrolled -> % Response in metastatic pts with a specific cancer • Phase III: Large RCT’s in relatively heterogeneous pts: OS (or EFS)

Topics • Changes in the methodology of the Phases of cancer trials • Efficacy: Do we still need (Large) Randomised Controlled Trials? • Perspectives ?

Conventional Methodology - Phase III: Large RCT’s in relatively heterogeneous pts: OS (or EFS)

Conventional Methodology - Phase III: LargeRCT’s in relatively heterogeneous pts: OS (or EFS)

Conventional Methodology - Phase III: Large RCT’s in relatively heterogeneous pts: OS (or EFS)

Reasons for the need of Randomised Control groups • Inability to predict individual outcome • Inability to predict group outcome • Inability to predict effect of treatments based on mechanisms

Reasons for the need of Randomised Control groups • Inability to predict individual outcome • Inability to predict group outcome • Inability to predict effect of treatments based on mechanisms STILL TRUE!

On the other hand ...

if a new drug, • with a well-identified molecular target • which is present in subgroups of cancers in different sites • produces a strong benefit in one of these cancers, …it may become ETHICALLY unacceptable to run a randomised trial in other cancers with the same target

Example Mortality Tumor X Nil vs A 15% vs 12.5% N=12000 P = 0.0007 H0 Rejected: A is effective in X

Example Mortality Tumor X Nil vs A 15% vs 12.5% N=12000 P = 0.0007 Tumor Y Nil vs A 15% vs 7.5% N= 240 P=0.066 H0 not rejected: A not shown effective in y

Prior Information: Mortality Tumor X Nil vs A 15% vs 12.5% N=12000 P = 0.0007 Tumor Y Nil vs A 15% vs 7.5% N= 240 P=0.066

Prior Information: tumors X and Y are BRAF+ Mortality Tumor X Nil vs A 15% vs 12.5% N=12000 P = 0.0007 Tumor Y Nil vs A 15% vs 7.5% N= 240 P=0.066

Prior Information: tumors X and Y are BRAF+A = Anti BRAF Mortality Tumor X Nil vs A 15% vs 12.5% N=12000 P = 0.0007 Tumor Y Nil vs A 15% vs 7.5% N= 240 P=0.066 Interpretation?

Prior Information: tumors X and Y are BRAF+A = Anti BRAF I have to plan a trial in the rare tumor Z, which is usually BRAF+, and for which there is no effective treatment Do I need a randomised control group? Is it ethically acceptable?

GLEEVEC CML -> Large RCT GIST -> Large uncontrolled trial Chordomas -> Case Series

New paths to drug use Large RCT in a frequent cancer with the target - Proof of principle – Toxicity Uncontrolled (but formal) trial(s) in other cancers with the target Off label use in individual cases with the target

New paths to drug use Large RCT in a frequent cancer with the target - Proof of principle – Toxicity Uncontrolled (but formal) trial(s) in other cancers with the target Off label use in individual cases with the target Acceptable? Methodology?

Topics • Changes in the methodology of the Phases of cancer trials • Efficacy: Do we still need (Large) Randomised Controlled Trials? • Perspectives?

3. Perspectives • Adaptive trials • ‘Personalised’ Medicine • New Statistical Approaches

3. Perspectives Adaptive trials ‘Personalised’ Medicine New Statistical Approaches

3. Perspectives Radical changes in the way cancer trials are designed and analysed • Adaptive trials • ‘Personalised’ Medicine • New Statistical Approaches

Three modern revolutions 1950 RandomizedClinical Trial • EvidenceBased Medicine 1990 Molecular Medicine

Empirical Approach Preclinical work + Clinical observations Clinical rationale

Empirical Approach Preclinical work + Clinicalobservations Clinicalrationale CLINICAL STUDIES INTERPRETATION

Fondamenti della sperimentazione clinica randomizzata • Protezione da risultati falsamente positivi: • Randomizzazione • Protocolli rigidi/Piano statistico predeterminato • Intention to treat • (doppio cieco) • Protezione da risultati falsamente negativi • Dimensioni

RCT -> EBM in Oncology Golden Age • Rigid protocols • Drugs – Doses – Cycles • Modifications for toxicity or progression/relapse • Generic Selection Criteria • Site (e.g. Stomach) • Histology (ADK vs Lymphoma) • Stage (early vs late)

RCT -> EBM in Oncology Golden Age • Large and Simple Clinical Trials - Systematic Reviews – Meta-analyses • Clinical Guidelines/Recommendations – Generic • Flexibility in pt management not considered

Evidence Based Medicine ≈ Cookbook Medicine?

New Century • Technological advances – Discoveries • Cellular functions • Molecular mechanisms/pathways • Genes/Mutations /Gene Functions • Genomics/Proteomics/(Metabolomics) • Targeted Drugs Patients Heterogeneity New Approaches!

3. Perspectives • Adaptive trials • ‘Personalised’ Medicine • New Statistical Approaches

a) Adaptive design FDA’s draft guidance for industry on adaptive design clinical trials (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM201790.pdf).

Adaptive design clinical trial FDA’s Definition: “… a study that includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study”

Why adaptive designs are so attractive? • Early Responses • Effects in Subgroups of patients • Toxicity It is possible to obtain, during the trial, crucial information to improve some of its design features

Most conventional trials have an adaptive component Stopping rules based on interim analyses: • Toxicity • Rejection of null-hypothesis • Futility

Conventional Trials Few, if any, planned interim analyses • Change selection criteria ? • Change treatment protocol ? • NO Change of the Endpoint • NO Change of the Statistical Plan

Critical Methological Issues in Recent Randomised Trials