ictw, cordoba, argentina clinical research design & methodology: phase iii trials ian tannock,...
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ICTW, Cordoba, Argentina
Clinical Research Design & Methodology: Phase III Trials
Ian Tannock, MD, PhD, DSc
Princess Margaret Cancer Centre & University of Toronto,
Toronto, Canada
ICTW, Cordoba, Argentina
To understand:• The sequence of clinical trials that is necessary to develop
an agent showing preclinical activity to become an approved anti-cancer drug
• The hierarchy of evidence from clinical trials• Basic principles underlying the design of Phase 3 clinical
trials• Common problems relating to the design, analysis and
interpretation of Phase 3 clinical trials• How the results of related clinical trials are combined in a
meta-analysis
Learning Objectives
Dr. Tannock
ICTW, Cordoba, Argentina
Anticancer Drug Development: Clinical Phases
Phase 1: Evaluate toxicity
Study drug disposition (pharmacokinetics)
Determine dose for Phase 2
Phase 2: Estimate antitumor efficacy
Further define toxicity
Phase 3: Compare outcomes with usual standard of care
Phase 4 (after registration):
Additional post-marketing safety assessment
Confirm results from fast-track approval trials
Dr. Tannock
ICTW, Cordoba, Argentina
Phase 3 Trials
Phase 3 trials have the goal of determining whether a new treatment provides sufficient benefit to patients that it should replace (or add to) current standard treatments.
Phase 3 trials generally include people with a single type of cancer, with randomization between the new treatment and an accepted “standard” treatment.
The new agent can be tested alone (i.e. standard vs. new treatment) or in combination with standard treatment (i.e. standard + new treatment vs. standard treatment).
They may be double-blind (e.g. standard + new treatment vs. standard treatment + placebo)
Dr. Tannock
ICTW, Cordoba, Argentina
Hierarchy of Evidence Used to Decide if Results of Clinical Trials Should Influence Clinical Practice
1. High quality randomized phase 3 trials, or meta-analyses
2. Small randomized trials
3. Non-randomized trials with concurrent controls
4. Non-randomized trials with historical controls
5. Expert committee review, case reports, retrospective studies
Dr. Tannock
Not included are large population-based outcome studies that can assess the influence of a new
strategy on a less selected population.
ICTW, Cordoba, Argentina
Asking a Good Question
Phase 3 trials require huge resources (collaborators, patients, $$$$)
It is therefore important that:– They address a clinically important question– There is substantial evidence for effectiveness of a new
treatment in preclinical models– There is evidence that the new treatment is safe and
tolerated (phase I)– There is good preliminary evidence of anti-tumor activity
(phase II)
Dr. Tannock
ICTW, Cordoba, Argentina
Phase 3 Trials
The primary endpoint (outcome measure) should be a measure of patient benefit (e.g. overall survival [OS] or QL)
If other endpoints are used they should be shown to be surrogates for OS or QL
Phase 3 trials are large (several hundred patients)
Entry criteria should be as broad as possible so that the results will apply to the general population of patients with the type of cancer under investigation
Dr. Tannock
ICTW, Cordoba, Argentina
DFS and PFS as Surrogate Endpoints in Phase 3 Trials
– When phase III trials show large early increases in PFS, and there are few alternative treatments, ethical considerations may require the new treatment be given to patients randomized to the control arm. This may make it difficult to detect an influence on survival.
– Examples include sunitinib for renal cell carcinoma and vemurafenib for BRAF-mutated melanoma
– This does not apply to treatments for (e.g.) metastatic breast or ovarian cancer
Dr. Tannock
ICTW, Cordoba, Argentina
Evaluation of Toxicity
Therapeutic benefit of a new treatment depends on a balance of efficacy and toxicity
All new agents add toxicity
Toxicity is usually reported and graded as per NCI CTC criteria, with rigid requirements for reporting serious (grade 3-4) toxicity
However toxicity is both under-recognized and under-reported in phase III trials – and chronic toxicity associated with many targeted agents may only become apparent after the trial is completed
Dr. Tannock
ICTW, Cordoba, Argentina
Principles of Design of Phase 3 Trials
Sample size depends on ....
The expected level of survival in the control arm
The difference in survival (δ) between arms that you wish to detect or rule out
α or type 1 error is the probability that a difference ≥ δ is a false positive result (usually α = 0.05)
β or type 2 error is the probability of failing to detect a real difference ≥ δ, i.e. of a false negative result (usually β = 0.1 or 0.2)
Dr. Tannock
The “power of the study” is then 1- β or 0.9 or 0.8
ICTW, Cordoba, Argentina
Phase 3 Trials: How to Determine Sample Size
Sample size for trials can be estimated from on-line calculators. e.g. http://www.openepi.com/v37/SampleSize/SSCohort.htm
Roughly 300 patients will be needed to detect or rule out a 15% absolute difference in survival & about 1,000 patients for a 10% difference!
Thus phase 3 trials require a large sample size to detect or rule out differences in outcome that might reasonably be expected
They require collaboration between multiple sites and are usually organized either by cooperative groups or companies
For company-organized trials it is essential that there be safeguards to ensure the validity of the data
Dr. Tannock
ICTW, Cordoba, Argentina
Phase 3 Trial: An ExampleA phase 1 trial indicates that a new drug, miraculin at 50mg/m2 IV every three weeks, can be added safely to standard gemcitabine/cisplatin
A phase 2 trial suggests that miraculin is active as second-line therapy for people with metastatic urothelial cancer (TCC)
MiraPharma agree to sponsor the following randomized phase 3 trial to determine if miraculin will become part of first-line treatment for this disease:
Gemcitabine + cisplatin + miraculin
Gemcitabine + cisplatin + matched placebo
Primary endpoint is
overall survival
Dr. Tannock
450 patients with metastatic TCC
and no prior chemotherapy
ICTW, Cordoba, Argentina
Survival Curves and Hazard Ratios
Patients are recruited to clinical trials at different times and have different length of follow up.
In actuarial survival curves patients alive at last follow-up are “censored”. The tail of the curve may depend on few patients (given as numbers under curves) and is subject to error.
Proportional hazards applies when the ratio of ‘events’ (e.g. deaths) in the experimental and control arms remains roughly the same over the time of observation.
Dr. Tannock
ICTW, Cordoba, Argentina
Survival Curves and Hazard Ratios
The Hazard Ratio (HR) is ratio of events in experimental to control arm in any given time interval.
HR < 1 with 95% confidence interval excluding 1.0 implies statistical benefit of experimental treatment.
Note that statistical significance is not the same as clinical significance
Dr. Tannock
ICTW, Cordoba, Argentina
Survival Curves and Hazard Ratios – An Example
Dr. Tannock
Baselga J, et al. N Engl J Med 2012; 366:109-119
ICTW, Cordoba, Argentina
Common Errors in Design, Analysis and Interpretation of Phase 3 Trials
Control arm is not an accepted standard treatment
The primary endpoint has not been shown to convey benefit to patients (i.e. not a surrogate for survival or its quality)
Sample size too small to detect or rule out a reasonable difference in outcome (failing to find a difference is not the same as proving no difference)
Sample size so large that difference in clinical outcome is statistically significant but not clinically meaningful
Making conclusions on the basis of secondary endpoints
Failure to provide detailed report of toxicity
Dr. Tannock
ICTW, Cordoba, Argentina
Post-marketing (Phase 4) Studies…
...evaluate a wider population of patients treated with a new therapy.
They can help to better define its tolerance and side effects in a wider population.
Often the unstated purpose of such studies is to encourage oncologists to become familiar with the new treatment (sometimes with financial reward) so that they will continue to use it when it is marketed.
Dr. Tannock
ICTW, Cordoba, Argentina
Meta-Analyses
Similar (but not necessarily identical) trials are combined (e.g. any adjuvant chemotherapy vs. none for women with primary breast cancer).
In a patient-based meta-analysis (preferred) the data are analyzed like one large trial to produce survival curves.
Date of randomization and death (or last follow-up alive) are known for all patients on multiple trials.
Data are displayed as a Forest plot: individual trials are represented by a square proportional to sample size, with whiskers showing confidence interval for Hazard or Odds Ratio.
Literature based meta-analysis combines published survival curves from reports of individual trials but is subject to error.
Dr. Tannock
ICTW, Cordoba, Argentina
Meta-Analyses: Example of a Forest Plot
Dr. Tannock
Dowsett M, et al. J Clin Oncol 2009; 28:509-518
Meta-Analysis of Aromatase Inhibitors vs. Tamoxifen
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