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The Stages of a Clinical Trial
MPN Horizons 2016, November 2016, Belgrade, Serbia Nicolaus Kröger Department of Stem Cell Transplantation University Medical Center Hamburg/Germany
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Introduction Clinical trial is a systemic investigation in human subjects for evaluating the safety & efficacy of any new drug Clinical trials are a set of tests in medical research and drug development that generate safety and efficacy data for health interventions in human beings
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Introduction Clinical trials are conducted only when - satisfactory information has been gathered on the quality of the nonclinical safety - health authority/ethic committee approval is granted in the country where approval of the drug is sought Clinical trial is the mainstay for bringing out new drugs to the market and to improve clinical outcome in patients
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Stages of Clinical Trial
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Preclinical evaluation phase (animal studies)
Major areas are: Pharmacodynamics studies in vivo in animals, in vitro preparation Absorption, distribution, elimination studies (pharmacokinetics) Acute, subacute, chronic toxicity studies (toxicity profile) Therapeutic index (safety & efficacy evaluation)
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Drug review Before one can initiate testing in human beings extensive preclinical or laboratory research is required Research usually involves years of experiments in animal and human cells If this stage of testing is successful the sponsor then provides this data to the FDA or EMA requesting approval to begin testing in humans. This is called an Investigational New Drug (IND) Application. If approved by the FDA or EMA testing in humans begins
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Phase 0 study / microdosing
Study of new drug in microdoses to derive pharmacokinetic information in human before undertaking phase I studies is called Phase 0 Microdose: less than 1/100 of the dose of a test substance calculated to produce pharmacolo- gical effect with a max dose ≤ 100 micrograms Objective: to obtain preliminary pharmacokinetic data Preclinical data: subacute toxicity study in one species by two routes of administration
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Microdosing / Phase 0 study
These are very early studies of the pharmacodynamics and pharmacokinetic properties of a potential drug in humans Microdosing approach could ‘accelerate’ drug development without compromising clinical safety Microdosing helps researchers select better drug candidates for clinical trials by providing early human PK and bioavailability data
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Stages of Clinical Trial
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Phase I First stage of testing in human subjects
Designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of drug 20 – 25 healthy volunteers Patients: anticancer drug Duration: 6 – 12 months No blinding / open labelled
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Phase I studies: Subjects
Healthy human volunteers: most commonly used (non-therapeutic research) - Subjects receive no therapeutic benefit by participation - Ethical issue Patient volunteers: cytotoxic drugs, AIDS therapy - Patients in advanced stage of disease
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Phase I study: Objectives
Primary - tolerability and safety - pharmacokinetics Secondary - pharmacodynamics
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Phase I study / clinical trial
The aim of a phase I trial is to determine the maximum tolerated dose (MTD) of the new treatment The MTD is found by escalating the treatment dose until the dose-limiting toxicity (DLT) is reached
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Stages of Clinical Trial
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Phase II Therapeutic exploratory trial 20 – 300 subjects
To confirm effectiveness, monitor side effects, & further evaluate safety First in patients (who have the disease that the drug is expected to treat) Duration: 6 months to several years
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Phase II: Objectives Efficacy in patients (primary objective)
Safety issue (secondary objective) Optimum dose finding - Dose efficacy relationship - Therapeutic dose regimen - Duration of therapy - Frequency of administration - Therapeutic window
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Phase II study / clinical trial
Phase II types Phase IIA: designed to assess dosing requirements Phase IIB: designed to study efficacy
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Stages of Clinical Trial
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Phase III Therapeutic confirmatory trials
Large scale, multicenter, randomized, controlled trials Target population: several 100’s to 3000 patients Takes a long time: up to 5 years To establish efficacy of the drug against existing therapy in larger number of patients, method of usage, & to collect safety data etc.
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Phase III: Objectives To assess overall and relative therapeutic value of the new drug efficacy, safety, and special properties To determine optimal dosage schedule for use in general The dosage schedule in C.T.’s should be as close as possible to its anticipated clinical use
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Stages of Clinical Trial
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Stages of clinical trial
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Phase IV Done after drug has been marketed
Post marketing surveillance (PMS) No fixed duration / patient population Studies continue to collect data about effects in various populations & side effects from Long-term use These are primarily observational or non- experimental in nature
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Phase IV: Objectives Evaluation in different age groups / types of patients Comparative benefit-risk assessment Benefit-cost assessment (pharmacoeconomics) Drug usage in the community Quality of life assessment
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Phase IV: Objectives Confirm the efficacy and safety profile in large populations during practice Detect the unknown/rare adverse drug reaction/s Evaluation of over-dosage Identifications of new indications Dose refinement: evaluation of new formulations, dosage, durations of treatment
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Phase IV study / clinical trial
Harmful effects discovered may result in a drug being no longer sold, or restricted to certain use On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high- dosage use
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Phases of clinical trials
Phase 0: from bench to human: is the agent hitting its target? Phase I: Deciding on dose (DLT/MTD) Phase II: Efficacy and safety Phase III: Clinical outcome Phase IV: long-term outcome (post marketing surveillance
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Drug development process
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Conclusion There is an unmet need for new effective drugs for treatment of malignant diseases including MPNs Because of the long duration from early clinical testing to approval, new ways of acceleration have been implemented in Europe by EMA such as : Accelerated Assessment, Conditional Marketing Authorisation and Compassionate Use Programme and new projects are curently under discussion such as: Adaptive Pathways (Adaptive Licening) however saftey issues should be taken into consideration
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