1
2	Phases of Clinical Trials When testing a new treatment or disease preventive regimen, phase III confirmatory studies are typically preceded by several phase I and II screening studies Phase I: Initial safety / dose finding Phase II: Preliminary efficacy / further safety Phase III: Establishment of efficacy Phase IV: Therapeutics: Post-marketing surveillance Prevention: Effectiveness
3	Phase I Clinical Trials Phase I: Initial safety / dose finding in humans Goals: Pharmacokinetics / pharmacodynamics Incidence of major adverse effects Decide whether it is ethical to continue testing in humans Methods Relatively small number of participants Participants often not true target population Sometimes dose escalation Sometimes no comparison group
4	Phase II Clinical Trials Phase II: Preliminary evidence of efficacy Goals: Screening trial to look for any evidence of treatment efficacy Incidence of major adverse effects Decide if treatment is worth studying in larger samples Methods Relatively small number of participants Participants closer to true target population Outcome often a surrogate Sometimes no comparison group (especially in cancer)
5	Phase III Clinical Trials Phase III: Establishment of efficacy Goals: Obtain measure of treatment’s efficacy on disease process Incidence of major adverse effects Therapeutic index Modify clinical practice (obtain regulatory approval) Methods Relatively large number of participants from true target population (almost) Clinically relevant outcome
6	Phase III Clinical Trials: Settings Phase III: Common scenarios Establish efficacy of new treatment superiority over no intervention superiority over existing treatment Establish equivalence with current treatment Two-sided equivalence: bioequivalence One-sided equivalence: noninferiority perhaps superior on secondary endpoint Establish harm of existing treatment
7	Phase IV Clinical Trials Therapeutic Phase IV: Post-marketing surveillance Goals: Monitor for rare serious events (Some “Phase IV” trials are of more interest for marketing than for science) Prevention Phase IV: Effectiveness
8	Impact on Study Design The stage of clinical investigation is a major factor to consider in choosing a particular clinical trial design Scientific issues Strength of evidence required at the end of the trial Ethical issues Potential for benefit (or harm) to patients