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ā | Phase I | Phase II | Phase III | Phase IV |
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Objectives | (1) General safety evaluation (2) PICO specification | Pilot testing on efficacy and on acute, common side effects and harms | Full-scale testing on efficacy and on acute, common side effects | (1) Surveillance on rare chronic harms (2) Investigation on mechanisms and active substances |
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Study designs | (1) Case series, n of 1 trials (2) Analysis of routine data (3) Observational studies (4) Non-/quasi-RCTs, cross-over trials sequential trials, and so forth | (1) Analysis of routine data, observational studies (2) Non-/quasi-, open-labeled, cross-over trials, sequential trials, small-scale RCTs, and so forth | Rigorously-designed RCTs, large multicentre RCTs | (1) Analysis of routine data (2) Observational studies (cohort studies and case control studies) (3) Laboratory studies on mechanisms and active substances |
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Patients | (1) People with or without the target WM disease (2) Sample size: dozens | (1) Patients with the target WM disease and specific characteristics (2) Sample size: dozens to hundreds | (1) More representative patients (2) Sample size: hundreds to thousands | (1) Usually those who have received the treatment and those who have not (2) Sample size: thousands and often more |
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Interventions | CHMs with varying herb components, doses, routes, therapeutic durations, and so forth | CHM of relatively fixed combination of herbs, dose, route, and so forth, which are determined in phase I | CHM similar to that in phase II or more fixed | CHM similar to that in phase II and III possibly with minor modifications in real practice |
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Controls | No control, or no treatment, standard proven effective treatments or placebo as control | No treatment, or different doses or delivery routes, standard proven effective treatments, or placebo as control | Standard proven effective treatment or placebo | Usually those patients who have not taken the treatment |
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Outcomes | Routine laboratory tests (e.g., blood counts, renal and liver functions, and ECG) for detecting side effects and harms, and surrogate outcomes defined in WM/TCM for detecting benefits | Surrogate outcomes for beneficial effects and appropriate outcomes for acute common harms | Endpoint outcomes for benefits and appropriate outcomes for acute common harms | Endpoint outcomes for rare chronic harms such as deaths |
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