Topics in Clinical Trials (1) - 2012
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Transcript of Topics in Clinical Trials (1) - 2012
Topics in Clinical Trials (1) - 2012
J. Jack Lee, Ph.D.Department of BiostatisticsUniversity of Texas M. D. Anderson Cancer Center
1: Introduction to Clinical Trials• Why do we need them?• What is a clinical trial?• History of clinical trials• Clinical trial phases• Major aspects of clinical trials• Ethics of clinical trials• Study protocol• Examples
Why do we need clinical trials?
A researcher tried jalapenos on a stomach ulcer patient, and the ulcer went away.
The researcher published an article:
“Jalapenos Cure Stomach Ulcers.”
The next patient subjected to the same treatment died. The researcher published a follow-up article:
“More Detailed Study Reveals That Jalapenos Cures 50% of Stomach Ulcers.”
Is erlotinib (an EGFR inhibitors) effective in treating lung cancer?
Overall response rate: Chemo – 30% Erlotinib – 25%
Response rate by EGFR mutation (a predictive marker)
EGFR Mutation
No (90%) Yes (10%)
Chemo 30% 30%
Erlotinib 20% 70%
Data: Signal + Noise
Data Analysis:
Extract the signal and filter out the noise
Statistics:
Find a needle in a haystack
Finding A Needle In A Haystack
Data Tsunami
Statistics and Medical Research
Premise: Advance in medical practice is based on researchResearch validity is based on scientific credibilityScientific Method:
QuestionDesignStudyDataAnalysisConclusion New Question
Good design + Good analysis Valid Inference
Statistics is needed in every stepSound statistics is the basis of evidence based medicine (EBM) Statistician is a guardian of science
Triumph of Medical Research and Clinical TrialsDiscovery and Approval of STI571/Gleevec (Glivec)
1960-1980s: Identify chronic myelogenous leukemia (CML) is associated with chromosome
translocation of the abl proto-oncogene, on chromosome 9 in non-CML patients and translocated to the chromosome 22 in patients with CML.
abl oncogene is activated by this translocation, which leads to the formation of an altered protein containing a piece of the Abl protein joined to a piece of a second protein, BCR. It is this fused protein product, called BCR-ABL, which is abnormally expressed in about 95 percent of CML patients.
1990: Several labs showed that bcr-abl alone causes leukemia in mice. STI571 was formulated and shown to inhibit the growth of BCR-ABL-expressing cells. The preliminary results of this early study showed that 31 out of 31 patients who
received at least 300 milligrams daily had their blood counts return to normal. In nine of the 20 patients who were treated for five months or longer, no cells with the Philadelphia chromosome could be found.
2001: February: Novartis submitted the New Drug Application for STI571, now known as
Gleevec, to FDA for the treatment of the late phases of CML. April: Results of a larger study of STI571 in 83 patients were reported in New
England Journal of Medicine. In the 54 chronic-phrase CML patients who were treated with doses of 300 milligrams or more, normal blood counts were restored in 53, and in 29 of the 54 patients, the Philadelphia chromosome disappeared. Most side effects were mild.
May: U.S. Food and Drug Administration approved the sale of STI571/Gleevec for CML.
Capdeville, Nature Review 2002
FDA Approval August, 2011
Crizotinib for lung cancer with EML4-ALK translocation
Vemurafenib for melanoma with BRAF V600E mutation
FDA Approval August, 2011
What is a clinical trial?A clinical trial is a prospective study evaluating the effect and value of intervention(s) in human beings under pre-specified conditions.A controlled clinical trial is a prospective study comparing the effect and value of intervention(s) against a control in human beings.The clinical trial is the most definitive tool for evaluation of the applicability of clinical research.It represents a key research activity with the potential to improve the quality of health care and control costs through careful comparison of alternative treatments.
A properly planned and executed clinical trials is a powerful experimental technique for assessing the effectiveness of an intervention.
Type of Research
Case ReportObservational Study Retrospective Cross-sectional Prospective
Clinical Trial Single arm vs. multi-arm trials Controlled clinical trials
Historical control Concurrent control
Randomization Blinding
Single center vs. multi-center trials
History of Clinical TrialsDaniel 1:12-16. A diet experiment (Royal food and wine versus vegetables and water) for 10 days
17th century: Lancaster (captain of a ship of East Indian Shipping Co.) conducted an experiment to examine the effect of lemon juice on scurvy for sailors. Ships with lemons were free of scurvy compared to ships without lemons having scurvy.
Lind (1753) – Study of 5 tx for scurvy in 10 pts (2/tx) plus 2 pts without tx (control).
First two pts given orange and lemons recovered quickly and was fit for duty after 6 days, compared favorably with all other patients.
Smallpox experiment (1721) at the Newgate prison in Great Britain. Voluntary inmates were inoculated and were free from smallpox.
Modern Clinical Trials (post WWII)
Medical Research Council (UK): treatment for common cold (1944), tuberculosis (1948)
National Institutes of Health (US): Cancer trials (1960’s), Coronary Drug Project (1965)
Observational studies lead to clinical trials Cholesterol:
Framingham Heart Study (1951): high cholesterol, high blood pressure, smoking, and diabetes correlated with cardiovascular disease
Scandinavian Simvistatin Survival Study (1994): statin reduced mortality
Hormone Replacement Therapy (HRT) Observation studies show that HRT reduced cardiovascular mortality and
morbidity HERS trial: HRT has no benefit but a risk for thrombosis (Grady, 1998) WHI: HRT has no CV benefit but has a harmful effect due to blood
clotting Beta-carotene
Numerous epidemiology study showed benefit for protecting against cancers
ATBC trial and CARET trial showed a harmful effect among current smokers. Both trials stopped early.
PHS showed that beta-carotene has no effect on mostly non-smokers
Clinical Trial Phases
Phase I: clinical pharmacology and toxicityPhase II: Initial Assessment of EfficacyPhase III: Full-scale Evaluation of Treatment EfficacyPhase IV: Postmarking Surveillance
Ref:
1. Nottage M and Siu LL. Principles of clinical trial design. Journal of Clinical Oncology 20:42s-46s, 2002.
2. Lee JJ. Clinical trial design for anticancer therapies. In: The Cancer Handbook, 2nd Ed. Ed(s) Alison M. Wiley: London, UK, 1330-44, 2007.
Phase I: clinical pharmacology and toxicity
1st experiment in human for new drug, schedule, or combination
Primary concern: Safety Goal: define the maximum tolerated
dose (MTD) in a dose-escalation study Typically required 15-30 patients Algorithm-based design: 3+3 Model-based design: continual
reassessment method (CRM)
Phase II: Initial Assessment of Efficacy
At MTD or recommended phase II dose, examine the efficacy and refine the toxicity profile of the agent
Goal: IIA – screen out ineffective drugsIIB – sending promising agents to
Phase III Typically, require 30-100 patients in a
multi-stage design Commonly used design: Gehan’s design,
Simon’s two-stage design, randomized phase II design
Phase III: Full-scale Evaluation of Treatment Efficacy
Compare new treatment with standard treatment in a rigorous manner, e.g. a double-blind randomized placebo-controlled study
Goal: define the ‘best’ treatment, which has an implication of changing the current practice in treating patients.
Typically required hundreds or even tens of thousands patients in primary cancer prevention trials.
Long-term, expensive
Phase IV: Postmarking Surveillance
Goal: monitoring the adverse effects, long-term morbidity and mortality after the treatment being used in a large number of patients and patients being followed up for a long period of time
Examples
Pilot study (feasibility): N 18Phase I (toxicity): 20 N 40Phase II (efficacy): 30 N 100Phase III (confirmatory): N > 100Primary Prevention Trials: N > 10,000
e.g. BCPT (Tamoxifen): N=16,000 (13,388)
PHS (aspirin, -carotene): N=22,071
Phase I Phase II Phase III
Pt. Characteristics sicker healthier
heavily pre-treated/ Untreated
failed std. tx
poor prognosis good prognosis
heterogeneous homogeneous
Treatment 2nd, 3rd, or 4th line front-line therapy
therapy
Drug Development
Treatment of Choice
Two Big Enemies Against Finding the Truth and Effective Weapons to Fight Against Them
BiasVariation
To tackle bias Randomization Blinding Intent to treat principle
To tackle variation Control or reduce variation Increase sample size
Randomized Control Trials
Advantages of randomization Remove the potential bias in treatment
assignment - conscious or subconscious Randomization tends to produce
comparable groups - known or unknown prognostic variables
Validity of statistical tests of significance is guaranteed
Randomization
1st introduced by Fisher in 1926 in agriculture research1st clinical trial used randomization – Amberson et al. (1931) Matching 24 pts with pulmonary tuberculosis
into 2 comparable groups of 12 each Flip a coin to decide which group received
sanocrysin, a gold compound
Streptomycin trial by British Medical Research Council (1948) 1st to use random numbers in allocation pt to
experimental or control groups
Random Number Table20
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Blindness
Amberson et al. (1931) Pts were not aware of whether they received IV
injection of sanocrysin or distilled water
Single-blinded study Either pts or physicians are blinded to the tx
allocation
Double-blinded study Both pts and physicians are blinded to the tx
allocation
Key: In general, it will be desirable that whosoever evaluates the outcome should be blinded to the treatment assignment
Controlled TrialsNo treatment control e.g.: standard practice is observation after surgery Observation versus ‘adjuvant’ therapy
Different types of controls Placebo Active control
use standard therapy use another new therapy
‘sham’ treatment control sham surgery or accupuncture
Reciprocal control Tx A: smoking cessation counseling, no dietary
intervention Tx B: dietary intervention, no smoking cessation
counseling Two endpoints: Smoking cessation and weight loss
Primary Hypothesis and Endpoint
Each clinical trial must have a primary question. The primary question, as well as any secondary or subsidiary questions, should be carefully selected, clearly defined, and stated in advance.Hypothesis generation versus hypothesis testingDefinition of primary endpoint(s)Definition of secondary endpoints
Primary Objective
Define one question the investigators are most interested in answering and is capable of being adequately answered.Define the primary endpoint Toxicity, efficacy (response/survival), QOL
Define the type of study: Hypothesis testing or estimation, Superiority or equivalence trials
The sample size is based on.
Secondary Objectives
Different endpointsSubgroup hypotheses Prospectively defined Based on reasonable expectations Limited in number
Hypothesis testing vs. hypothesis generatingHunting expedition vs. fishing expeditionMultiplicity Issues
Examples of post-hoc subset analyses
In the International Study of Infarct Survival-2 (ISIS-2), the treatment effect seemed to differ by astrological sign:
More adverse effect of aspirin on mortality for patients born under Gemini (5/21-6/21) or Libra (9/23-10/23) than others (P < 0.00001).
Is the data convincing? Do you believe it? What is the one question you may ask to discern
whether the claim is true or not?
Response Variables
Dose limiting toxicities (DLT), complicationsResponse, incidence of a disease, total mortality, death from a specific cause Overall survival, time to progression, time to cancerBlood pressure, biomarkers, PSA, CD4 countQuality of lifeCost and ease of administrating the interventionIn general, a single response variable should be identified to answer the primary question.
General rules for response variable
Define the questions prospectively and specifically Gleevec can increase the response rate from 50% to
80% in patients with chronic CML
The primary response variable can be assessed in all participants and as completely as possible Informative drop-out or lost to f/u due to toxicity
Participation generally ends when the primary response variable occurs Off-drug, off-study, extended f/u
Response variables should be unbiased assessed Hard, objective endpoints vs. soft, subjective
endpoints
Intent-to-treat (ITT) Principle
Unlike animal studies, investigator cannot dictate what a participant should do in a clinical trial.A participant may forget to take the pills, receive dose reduction due to toxicity, drop out from the study at any point or lost to f/u.Use only full compliers in the analysis? Use all subjects?ITT compares ‘intervention strategies’ and not ‘interventions.’
Ethics of Clinical Trials
Do no harm. Clinical trials must be reasonably safe to participants and have a favorable risk-benefit ratio.Proper informed consent is essential.Rationale for randomization (clinical equipoise) must be sufficiently justified.Finder fee for recruitment can result in bias. Unreasonable compensation to participants can also cause problems.Equal opportunities to be recruited and treated, e.g.: race and gender.Individual ethics and group ethics must be balanced.
Protect Human Subjects
Nuremburg Code (1947): In response to Nazi atrocities of using concentration camp prisoners for human experiments. voluntary consent, avoid unnecessary suffering,
subject/scientist free to end experiment
Declaration of Helsinki (1964, 1989) informed consent
Belmont Report (1979) risk/benefit assessment, fair selection of
subjects
Human Subject Committee (HSC), Institutional Review Board (IRB), Ethics Committee, Surveillance Committee
STATISTICAL PRINCIPLES FOR CLINICAL TRIALS (ICH E9)
International Conference on Harmonisation encompassing three main ICH regions: Europe, Japan and the U.S.A.An effort to establish clinical trial standards by integrating inputs from government (regulatory authority), industry, and academia. A comprehensive guideline was developed in
1998 and published in Lewis, Statistics in Medicine 18:1903-1942,1999.
E10: Choice of Control Group in Clinical Trials E9: Statistical Principles for Clinical Trials E8: General Considerations for Clinical Trials http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/200
9/09/WC500002928.pdf http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/statistical-
principles-for-clinical-trials.html
1. Introduction . .1.1 Background and Purpose 1.2 Scope and Direction
2. Considerations for overall clinical development 2.1 Trial Context
2.1.1 Development Plan 2.1.2 Confirmatory Trial 2.1.3 Exploratory Trial
2.2 Scope of Trials 2.2.1 Population 2.2.2 Primary and Secondary Variables 2.2.3 Composite Variables 2.2.4 Global Assessment Variables 2.2.5 Multiple Primary Variables 2.2.6 Surrogate Variables 2.2.7 Categorized Variables
2.3 Design Techniques to Avoid Bias 2.3.1 Blinding 2.3.2 Randomization
3. Trial design considerations 3.1 Design Configuration
3.1.1 Parallel Group Design 3.1.2 Cross-over Design 3.1.3 Factorial Designs
3.2 Multi-centre Trials 3.3 Type of Comparison
3.3.1 Trials to Show Superiority 3.3.2 Trials to Show Equivalence or Non-
inferiority 3.3.3 Trials to Show Dose-response Relationship
3.4 Group Sequential Designs 3.5 Sample Size 3.6 Data Capture and Processing
CONTENTS
4. Trial conduct considerations 4.1 Trial Monitoring and Interim Analysis 4.2 Changes in Inclusion and Exclusion Criteria 4.3 Accrual Rates 4.4 Sample Size Adjustment 4.5 Interim Analysis and Early Stopping 4.6 Role of Independent Data Monitoring Committee (IDMC)
5. Data analysis considerations 5.1 Prespecification of the Analysis 5.2 Analysis Sets
5.2.1 Full Analysis Set 5.2.2 Per Protocol Set 5.2.3 Roles of the Different Analysis Sets
5.3 Missing Values and Outliers 5.4 Data Transformation 5.5 Estimation, Confidence Intervals and Hypothesis Testing 5.6 Adjustment of Significance and Confidence Levels 5.7 Subgroups, Interactions and Covariates 5.8 Integrity of Data and Computer Software Validity
6. Evaluation of safety and tolerability 6.1 Scope of Evaluation 6.2 Choice of Variables and Data Collection 6.3 Set of Subjects to be Evaluated and Presentation of Data 6.4 Statistical Evaluation 6.5 Integrated Summary
7. Reporting .7.1 Evaluation and Reporting 7.2 Summarizing the Clinical Database
7.2.1 Efficacy Data 7.2.2 Safety Data
Glossary
CONTENTS (cont.)
Study Protocol
Every well-designed study required a protocol.Protocol is a written agreement between investigators, participants, and the scientific community.Protocol is a comprehensive operational manual. It specifies the standard operation procedure (SOP).Examples
Intergroup Lung StudyIntergroup Lung StudyStudy ObjectivesStudy Objectives
To evaluate the efficacy of 13cRA in reducing the incidence of second primary tumors (SPTs)To evaluate quantitative and qualitative toxicity of 13cRA 30 mg/dayTo compare overall survival of patients treated with 13cRA vs. patients treated with placebo
Intergroup Lung StudyIntergroup Lung StudyPatient EligibilityPatient Eligibility
Stage I non-small lung cancer, currently free of disease, between 6 wks and 36 mos from resectionNo prior or concurrent therapy for lung cancer other than surgeryNormal hepatic, renal and bone marrow functionFasting triglycerides < 320 mg/dLLife expectancy > 12 mos & Zubrod 0-2No cancer history within last 5 yearsNo synchronous lesionsNo history of high dose Vitamin A or beta-carotene
Intergroup Lung StudyIntergroup Lung Study
8 8 Week Week
Run-inRun-in
13cRA
Placebo
3 Years3 Years
4 Years4 Years
RREEGGIISSTTRRAATTIIOONN
RREEGGIISSTTRRAATTIIOONN
RRAANNDDOOMMIIZZAATTIIOONN
RRAANNDDOOMMIIZZAATTIIOONN
TTRREEAATTMMEENNTT
TTRREEAATTMMEENNTT
FFOOLLLLOOWWUUPP
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OOFFFF SSTTUUDDYY
OOFFFF SSTTUUDDYY
Study Design
Randomized, placebo controlled trial to compare the efficacy of 13cRA vs. placebo in reducing SPTN=1,379 registered; 1,242 randomizedAnnual SPT rate: 3% in the placebo groupSPT rate reduced by 50% in the 13cRA group3 years of accrual + 4 years of f/u or 4 years accrual + 3 years of f/u Total study duration = 7 years from 1st patient randomized
Planned Interim Analyses based on the O’Brien-Fleming Boundary
Primary endpoint: Time to SPTEarly stopping if Ho: No difference between arms is rejectedNo early stopping based on futility
1st Analysis:
2nd Analysis:
Final Analysis:
Level of Significance
0.0005
0.014
0.045
Time since 1st pt randomized*
3 years
5 years
7 years
* The 1st patient was randomized on 2/5/93.
Trial History
1,486 pts were enrolled from 12/8/92 to 4/9/971,304 were randomized from 2/5/93 to 6/23/97Among them, 1,265 were randomized and eligibleMajor Analyses 3/96: 1st interim analysis 7/97: 2nd interim analysis 7/98: 3rd interim analysis 2/00: 4th and final analysis
Y ears 3-533 deaths + 159 censored 110
Y ears 1-383 deaths + 152 censored 302
Y ear 0-114 deaths + 26 censored 537
PlaceboN = 577
Y ears 3-528 deaths + 174 censored 104
Y ears 1-376 deaths + 140 censored 306
Y ear 0-132 deaths + 35 censored 522
Isotre tinoinN = 589
1 ,1 6 6 P r o p e r ly r a n d o m iz e d a n d e l ig ib le
1,265 R andom ized and e ligible
1,304 C om pleted run-in and random ized (planned 1,241)
1,444 R egistered and eligible (planned 1,379)
1 ,4 8 6 R e g is te r e dE C O G , 23.8% ; C A LG B , 22.2% ; SW O G , 15.1% ; R T O G, 14.4% ;
N C C T G , 12.5% ; M DA C C -C C O P, 6.3% ; M D A C C /AFFILIA T E S, 5 .7 %
Consort Diagram: Colin et al., JAMA 276: 637-639 1996.Lung Intergroup Trial: Lippman et al. JNCI 93:605-618, 2001.
Table 1. Characteristics of randomized, eligible patients by study arm*
Characteristics Placebo (N = 577) Isotretinoin (N = 589) Total (N = 1166)
AgeMedian (Range)Mean (S.D.)
66.0 (34-81)64.1 (8.9)
65.0 (31-86)64.3 (8.6)
65 (31-86)64.2 (8.8)
N (%) N (%) N (%)Gender
FemaleMale
251 (43.5%)326 (56.5%)
248 (42.1%)341 (57.9%)
499 (42.8%)667 (57.2%)
RaceWhiteBlackOther
525 (91.0%)41 (7.1%)11 (1.9%)
552 (93.7%)31 (5.3%)6 (1.0%)
1077 (92.4%)72 (6.2%)17 (1.5%)
HistologySquamousNon-Squamous
191 (33.1%)386 (66.9%)
187 (31.8%)402 (68.2%)
378 (32.4%)788 (67.6%)
T-StageT1
T2
315 (54.6%)262 (45.4%)
316 (53.7%)273 (46.4%)
631 (54.1%)535 (45.9%)
Smoking StatusCurrentFormerNever
231 (40.0%)301 (52.2%)45 (7.8%)
225 (38.2%)319 (54.2%)45 (7.6%)
456 (39.1%)620 (53.2%)90 (7.7%)
*S.D. = standard deviation.
Event Charts
Calendar event chart, Interval event chart, Goldman’s event chartGraphical tools to track and plot multiple timed event data at the individual levelHighly effective in monitoring clinical trialVery useful for assessing covariate effectComplementary to survival plots
(Lee, Hess, and Dubin: Extension and application of
event charts. The American Statistician, 54: 63-70, 2000)
Study Date
05
00
10
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15
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12/8/92 10/18/94 8/27/96 7/8/98 5/17/00
Calendar Event Chart for ID91-025
Follow-up Time
05
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10
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15
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0 2 4 6
Interval Event Chart for ID91-025