What is Clinical Trial?
“A clinical trial is defi
Why we do clinical trials?
We do not fully understand the human body and the disease to accurately predict the efficacy and toxicities of a new therapy without a clinical trial
· Goal of typical drug trials: to find a dose (or dose range) of a drug that is safe and efficacious
Stages of Clinical Trials
Pre-clinical
Phases of Clinical Trials
Phase I: pharmacologically oriented, dose finding
Phase II: efficacy and safety
Phase III: comparing treatment efficacy
Phase IV: expanded safety study
Pre-clinical Studies
Drug candidate: new chemical compound or biologic
The efficacy and safety of drug candidates are first studied in cell cultures and animal experiments before in human
Pharmacology: study the selective biological activity, e.g. dose-response relationship
Toxicology/drug safety: observe adverse drug effects at different doses, duration (dose-toxicity relationship)
Formulation: tablets, capsules, solution, etc.
Decide if the drug candidate is promising enough to start clinical trials
Provide a starting dose for Phase I trials
Phase I Trials
Goal: dose finding, to estimate how large a dose (maximal tolerated dose, or MTD) can be given
without unacceptable toxicity
First in human, usually conducted in healthy volunteers or patients who have failed existing
standard interventions
Pharmacokinetics (PK): what does the body do to the drug
Quantify the drug exposure, e.g. AUC, C max
Identify PK profile that may lead to severe toxicity
Pharmacodynamics (PD): what does the drug do to the body
Do the pharmacological effects occur at the tolerable dose levels?
In cancer trials, usually start with a low dose and escalate until a pre-specified level of toxicity is observed
Ex: Phase I cancer trials (3+3 design)
Start at a very low dose base on preclinical studies
A cohort of 3 patients are enrolled at a dose level
Escalate to the next higher dose level if no unacceptable toxicity is observed
If unacceptable toxicity is observed in one of the three patients, enroll another cohort at the same dose level
De-escalate (or stop the trial) when two or more patients experience unacceptable toxicities at the current dose level
Phase II Trials
Goal: to evaluate the biologic activity of the drug and estimate the rate of adverse events
Response variables: efficacy, safety
Conducted in patients with the disease
Often with parallel treatment groups
Use the dose level (or dose range) suggested by
Phase I trials Usually short-term with a small or moderate sample size
Often use surrogate endpoint
Exploratory in nature
Ex: Phase II cancer trials (two-stage design)
Stage 1: enroll a small number (e.g. 10-20) of patients
If biological activity (response) is observed in more than a pre-specified number of patients, continue to stage 2
Otherwise, stop the trial and conclude the drug not promising at the tested dose
Stage 2: additional patients (e.g. 10-20) are enrolled
If the total number of response is larger than a pre-specified number, conclude the drug promising
Otherwise, conclude the drug not promising
Phase III Trials
Goal: to confirm findings (primarily efficacy, but also safety) from earlier phase studies
Conducted in patients with the disease
Comparative, usually randomized with parallel treatment groups
Use more clinically relevant endpoints
Usually long-term, large-scale
Can refine dose selection based on longer term data for efficacy and safety
Phase IV Trials
Goal: to establish a better safety profile
Post-marketing study, performed after the drug is approved
Long-term, large-scale drug safety surveillance of the intervention
Do not have control groups
Subject population less restricted than Phases I, II, III
Quality of Life (QoL) studies: to demonstrate improved QoL
Pharmaco-economic studies: to establish the economic value (cost) of the intervention
Phase I: Usually the first stage of testing per-formed in anticipation of an Investiga-tional New Drug Application (INDA); done to generate preliminary informa-tion on the chemical action and safety of the indicated drug and to find a safe dose; usually not randomized.
Phase II: Usually the second stage of testing; generally carried out on persons hav-ing the disease or condition of interest; done to provide preliminary informa-tion on efficacy of the drug and addi-tional information on safety; may be designed to include a control treatment and random assignment of patients to treatment.
Phase I/II: A trial having some of the features of Phase I and II trials; designed to pro-vide preliminary information on safety and efficacy.
Phase III: Usually the third and final stage in test-ing, prior to submission of an INDA; concerned with assessment of dosage effects, efficacy, and safety; usually designed to include a control treatment and random assignment to treatment. When the test is completed (or nearly completed), the drug manufacturer or sponsor may request permission to market the drug for the indication cov-ered in the testing by submission of an INDA.
Phase II/III: A trial having some of the features of Phase II and III trials; designed
to provide information on safety and efficacy.
Phase IV: A fourth stage of testing, sometimes carried out. Usually controlled and per-formed after approval of the INDA.Typically done under circumstances approximating real-world conditions;
usually has a clinical event as a basis for sample-size calculation and pro-vides for extended treatment (where appropriate) and long-term follow-up, with efficacy and safety of the drug being measured against a control treatment.
0 comments:
Post a Comment