1. 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

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 pharmacodynamics of 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 clinical trial

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 development process

29. 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