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Presentation at a workshop on Research Methodology in Health Sciences held at the Northern Area Armed Forces Hospital on 29 December 2020 at 7:10pm. By Professor Omar Hasan Kasule MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Chairman, Institutional Review Board - KFMC
CLASSIFICATION OF TRIALS BY GRAND OBJECTIVES (Primary & Secondary):
} Therapeutic clinical trials are controlled experiments to compare the
effectiveness of different treatments by randomly allocating study
participants to treatment and control groups, observing the outcome of interest
(death, cure, and 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
}
Multi center 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 confounding and prognostic
factors.
} In cluster randomization =
it is the whole group such a hospital that is allocated.
} Fixed probability random
allocation vs variable probability allocation (adaptive).
CLASSIFICATION OF TRIALS BY TREATMENT OBJECTIVE:
} Comparative effective ness
research. = compare two treatments both considered standards of care. This
study is 2 sided.
} Superiority vs non-inferiority
trials = see of 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 the cases and controls simultaneously from time zero.
} Cross over a patient serves
as his 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 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
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 relation,
} 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
(detail enough for others to carry it out).
§ Study sample selection,
randomization, inclusion and exclusion,
§ Intervention, outcome,
adverse events reporting, safety monitoring,
§ 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.