STUDY DESIGN FOR PHASE 3 RANDOMIZED CLINICAL TRIALS
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 TRIALS
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 regression model. Meta-analysis combines 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 types.