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Presentation at a workshop on Clinical Trials – Clinical Research Program held at the King Fahad Medical City, Riyadh on 27 June 2021 at 11.00 am. By: Professor Omar Hasan Kasule MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics, King Fahad Medical City
CLASSIFICATION
OF TRIALS BY GRAND OBJECTIVES (Primary & Secondary)
▪Therapeutic clinical trials are controlled experiments to
compare the effectiveness of different treatments by random allocation of study
participants to treatment and control groups, observing the outcome of interest
(death, cure, tumor size), adverse events, quality of life, etc.
▪ Preventive trials are controlled experiments to study the effect of an
intervention on preventing the outcome of interest.
CLASSIFICATION
OF TRIALS BY GEOGRAPHY
▪ Single center
▪ Multi-center national
▪ Multicenter
International
CLASSIFICATION
OF TRIALS BY RANDOMIZATION
▪ Random
allocation vs non-random allocation.
▪Simple
randomization vs blocked/stratified/cluster randomization. Simple randomization
requires a large sample size. Stratified randomization balances are confounding and
prognostic factors.
▪ In cluster
randomization = it is the whole group such as a hospital that is allocated.
▪ Fixed
probability random allocation vs variable probability allocation (adaptive).
CLASSIFICATION
OF TRIALS BY TREATMENT OBJECTIVE
▪Comparative
effectiveness research. = compare two treatments both considered standards of
care. This study is 2 sided.
▪ Superiority vs
noninferiority trials = see if a new treatment is equal to or not worse than the
approved treatment. This study is one-sided.
▪ Equivalence
trial.
CLASSIFICATION
OF TRIALS BY TYPE OF CONTROL (We learn by comparing)
▪ Parallel study
= We follow simultaneously the cases and controls from time zero.
▪ Cross over a
patient serves as his own control with a washout period between the two
interventions. Because of the pairing, we use a smaller sample size.
▪ Withdrawal you
start all on the intervention and after a time withdraw some.
▪ Before and
after/pre-post.
▪ Factorial tests
2 interventions in the same study.
▪ Uncontrolled/quasi-experimental.
▪ Pragmatic
trials follow usual practice and are more generalizable.
CLASSIFICATION
OF TRIALS BY SIZE
▪ Large
multi-center trials with extensive.
▪ Simple small
trials (can be combined by meta-analysis).
CLASSIFICATION
OF TRIALS BY BLINDING
▪ Non-blinded.
▪ Single
blinding: participant does not know.
▪ Double
blinding: participant and investigator do not know. Blind can be broken if the drug
and placebo look different?
▪ Triple
blinding: participant, investigator, and data monitoring committee/statistician
do not know.
CLASSIFICATION
OF TRIALS BY TYPE OF COMPARISON / CONTROL GROUP
▪ Historical,
▪ Concurrent,
▪ Self,
▪ Untreated,
▪ Placebo,
▪ Negative,
▪ Positive
controls.
CLASSIFICATION
OF TRIALS BY PHASE
▪ Clinical trials
are preceded by screening in vivo in animals and in vitro in human tissues.
▪Phase 1 trials
study maximum tolerated doses, drug administration schedules, drug toxicity,
and evidence of anti-tumor activity.
▪ Phase 2 studies
assess the therapeutic activity of a drug in advanced disease on a small number of
patients.
CLASSIFICATION
OF TRIALS BY PHASE con’t.
▪ Phase 3 trials
are used to compare a drug to a placebo or a new drug to an existing drug.
Comparability is assured by randomization and equal handling of the 2 groups.
The sample size is larger than in Phase 2.
▪ Phase 4 studies
involve post-marketing surveillance by collecting data on short-term and long-term effects.
ETHICAL
ISSUES IN CLINICAL TRIALS
▪ Justification: Search
for better treatment justifies clinical trials.
▪ Withholding a
potentially beneficial treatment from the controls,
▪ Unknown risks
of new agents,
▪ Lack of
informed consent or consent under stress,
▪ Trials if an
effective treatment exists,
ETHICAL
ISSUES IN CLINICAL TRIALS con’t.
▪ Trial when one
treatment is known to be better,
▪ Testing with no
evidence of usefulness,
▪ Unscientific
research,
▪ Violation of
the normal doctor-patient relationship,
▪ Randomization
when there is prior knowledge that one treatment is the better one,
▪ Failure to stop
the study when harmful/beneficial effects appear.
HOW
TO CONDUCT A CLINICAL TRIAL
▪ Find a sponsor
because it is very expensive.
▪ Find (a)
hospital (s) to carry out the study.
▪ Write an
extensive protocol (detailed enough for others to carry it out).
o Study sample
selection, randomization, inclusion, and exclusion,
o Intervention,
outcome, adverse events reporting, safety monitoring
o statistical
analysis, stopping rules, etc.
HOW
TO CONDUCT A CLINICAL TRIAL, con’t.
▪ Consent:
disclosure and signatures.
▪ Case report
form (CFR) for data collection.
▪ Apply to IRB.
▪ Apply to SFDA.
▪ Register in the
clinical trials register.