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Presented at a lecture for Clinical Research Coordinators held at King Fahad Medical City on Sunday May 31, 2020 11.00am - 12.00pm By Professor Omar Hasan Kasule MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Chairman of the Institutional Review Board
CLASSIFICATION OF TRIALS BY GRAND OBJECTIVES (primary and 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 PHASE (recheck definitions)
• In vitro: laboratory research for example to observe the effect of the drug on a cancer cell
• In vivo: observing the effect of the drug on an animal disease model
• Phase 1: study pharmacokinetics and pharmacodynamics in healthy volunteers: maximum tolerated dose, distribution in the body, excretion, etc
• Phase 2: study efficacy and safety in a small number of patients with disease
• Phase 3: a randomized study of efficacy and safety in a large number of patients with the disease
• Phase 4: Postmarketing observational study of long-term efficacy and safety
CLASSIFICATION OF TRIALS BY GEOGRAPHY
• Single-center
• Multicenter 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 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 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 trial 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.
• 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,
• 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.