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The Stages of a Clinical Trial

The Stages of a Clinical Trial. MPN Horizons 2016, 11-13 November 2016, Belgrade , Serbia. Nicolaus Kröger Department of Stem Cell Transplantation University Medical Center Hamburg/Germany. Introduction.

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The Stages of a Clinical Trial

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  1. The Stages of a Clinical Trial MPN Horizons 2016, 11-13 November 2016, Belgrade, Serbia Nicolaus Kröger Department of Stem Cell Transplantation University Medical Center Hamburg/Germany

  2. 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

  3. 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

  4. Stages of Clinical Trial

  5. 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)

  6. 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

  7. 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

  8. 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

  9. Stages of Clinical Trial

  10. Phase I • First stage of testing in human subjects • Designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamicsof drug • 20 – 25 healthy volunteers • Patients: anticancer drug • Duration: 6 – 12 months • No blinding / open labelled

  11. 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

  12. Phase I study: Objectives • Primary- tolerability and safety • - pharmacokinetics • Secondary- pharmacodynamics

  13. 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

  14. Stages of Clinical Trial

  15. 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

  16. 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

  17. Phase II study / clinical trial Phase II types • Phase IIA: designed to assess dosing requirements • Phase IIB: designed to study efficacy

  18. Stages of Clinical Trial

  19. 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.

  20. 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

  21. Stages of Clinical Trial

  22. Stages of clinicaltrial

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. Drug developmentprocess

  29. Conclusion Thereis an unmetneedforneweffectivedrugsfortreatment of malignantdiseasesincluding MPNs Because of thelongdurationfromearlyclinicaltestingtoapproval, newways of accelerationhavebeenimplemented in Europe by EMA such as : Accelerated Assessment, Conditional Marketing AuthorisationandCompassionateUse Programme and newprojectsarecurentlyunderdiscussion such as:Adaptive Pathways (Adaptive Licening) howeversafteyissuesshouldbetakenintoconsideration

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