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

17

42

28

23

17

59

66

38

61

02

10

86

10

51

55

92

52

44

25

74

49

04

19

03

04

10

33

53

70

11

54

48

63

94

60

94

49

57

38

94

70

49

31

38

67

23

42

29

65

40

88

78

71

37

18

48

64

06

57

22

15

78

15

69

84

32

52

32

54

15

12

54

02

01

37

38

37

12

93

93

29

12

18

27

30

30

55

91

87

50

57

58

51

49

36

12

53

96

40

45

04

77

97

36

14

99

45

52

95

69

85

03

83

51

87

85

56

22

37

44

91

99

49

89

39

94

60

48

49

06

77

64

72

59

26

08

51

25

57

16

23

91

02

19

96

47

59

89

65

27

84

30

92

63

37

26

24

23

66

04

50

65

04

65

65

82

42

70

51

55

04

61

47

88

83

99

34

82

37

32

70

17

72

03

61

66

26

24

71

22

77

88

33

17

78

08

92

73

49

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

FFOOLLLLOOWWUUPP

OOFFFF SSTTUUDDYY

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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

00

15

00

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

00

10

00

15

00

0 2 4 6

Interval Event Chart for ID91-025