STUDY DESIGN FOR PHASE 3 RANDOMIZED CLINICAL
The study protocol describes objectives, the background, the sample, the treatments, data
collection and analysis, informed consent; regulatory regulations, and drug ordering. Trials may be single center or multi-center,
single-stage or multi-stage, factorial, or crossover. The aim of randomization in controlled clinical trials is to make sure
that there is no selection bias and that the two series are as alike as possible by randomly balancing confounding factors.
Equal allocation in randomization is the most efficient design. Methods of randomization include alternate cases and sealed
serially numbered envelopes. Stratified randomization is akin to block design of experimental studies. Randomization is not
successful with small samples and does not always ensure correct conclusions.
DATA COLLECTION IN RANDOMIZED CLINICAL TRIALS
Data collected is on patients (eg weight), tumors (eg TNM staging); tumor markers (eg AFP),
response to treatment (complete response, partial response, no response, disease progression, no evidence of disease, recurrence),
survival (disease-free survival, time to recurrence, survival until death), adverse effects (type of toxicity, severity, onset,
duration), and quality of life (clinical observation, clinical interview, self report by patient).
Case report forms design must have a logical order, be clear and not ambiguous, minimize text,
have self-explanatory questions, and ensure that every question must be answered.
In single blinding the diagnosis is known but the treatment is not. In double blinding both
the treatment and the diagnosis are unknown. The trial is stopped when there is evidence of a difference or when there is
risk to the treatment group.
Quality control involves measures to ensure that information is not lost. Institutional
differences in reporting, and patient management must be analyzed and eliminated if possible. A review panel or carry out
inter-observer rating to assure data consistence.
ANALYSIS and INTERPRETATION IN RANDOMIZED CLINICAL
Comparison of response proportions is by chi-square, exact test, chi-square for trend. Drawing
survival curves is by K-M & life-table methods. Comparing survival & remission is by the Wilcoxon and log-rank tests.
Prognostic factors of response, remission, duration, and survival times are investigated using Cox’s proportional hazards
data from several related clinical trials. Differences between the two treatment and control groups are due to sampling variation/chance,
inherent differences not controlled by randomization, unequal evaluation not controlled by double-blinding, true effects of
the treatment, and non compliance. Problems in trials are incomplete patient accounting, removing 'bad' cases from series,
failure to censor the dead, removing cases due to ‘competing causes of death’, analysis before study maturation,
misuse of the ‘p-value’, lack of proper statistical questions and conclusions, lack of proper substantive questions
and conclusions, use of partial of data; use of inappropriate formulas, errors in measuring response, and censoring of various