Clinical Trials Flashcards
1) What is the purpose of preclinical development? What needs to be considered before human trials?
•To determine:
Safety - if the compound can be safely entered into human trials, and
Efficacy - if the compound exhibits anticipated pharmacological activity
•Considerations (for human use):
–Target organ/disease
–Dosage form
– Oral/Intravenous/Subcutaneous/Topical
–Expected therapeutic dose
–Anticipated/Unanticipated toxicities
2) What is the definition of a clinical trial?
A clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes. (prospective not retrospective)
3) What happens during a phase 1 Trial (predicates, goals, characteristics, subjects)?
Predicates:
Biological Validity, Drug Discovery, Chemistry, Safety First studies of compound in humans:
Establishes tolerability and initial indication of safety;
Establishes Pharmacokinetics (Exposure, Dose Linearity, Interactions);
Some initial indication of Pharmacodynamics (Glucose, Tumor Size, Viral Load, Biomarkers)
Next Steps
•Inform Phase 2 with regards to
–Doses, Safety issues, Population, PD, Biomarkers Characteristics
- Number of subjects/patients: 20-80
- Duration: 3-12 months
- Highly intensive monitoring
- Conducted in specialised units
–Specialized laboratory tests
–Monitoring
–Explore biomarkers
•Can be divided into Ph 1a and Ph 1b Can involve healthy volunteers or patients:
-Healthy patients: homogenous population; limited confounding factors; easily studied under controlled conditions; able to comply with complex procedures/restrictions; paid for participation Patients: they have the disease; pharmacology may be disease dependent; AE may be population dependent; closer to real life
4) What is the purpose of a control group?
- To allow discrimination of patient outcomes caused by test treatment from those caused by other factors
1. Natural progression of disease
2. Observer/patient expectations
3. Other treatment -fair comparisons for study to be informative
5) How does placebo controls work and why is it necessary?
The placebo effect is well documented. Usually use
1) no treatment + placebo or
2) standard of care + placebo. Matched placebos are necessary so patients and investigators cannot decode the treatment assignment.
6) How does randomization and blinding work? Why is this necessary?
- Principle: Groups must be alike in all important aspects and only differ in the treatment each group receives. In practical terms, “comparable treatment groups” means “alike on the average”.
- Randomization: Each patient has the same chance of receiving any of the treatments under study. Allocation of treatments to participation is carried out using a chance mechanism so that neither the patient or physician know in advance which therapy will be assigned.
- Blinding: The process used in clinical trials in which the participants, investigators and/or assessors do not know which treatments the participants are receiving. The aim is to minimise observer bias, in which the assessor, the person making a measurement, have a prior interest or belief that one treatment is better than another, and therefore scores one better than another just because of that.
- In a single blind study it is may be the participants who are blind to their allocations, or those who are making measurements of interest, the assessors.
- In a double blind study, at a minimum both participants and assessors are blind to their allocations.
7) How are subjects dosed?
Single ascending dose: A small group of subjects/healthy volunteers receive a single dose of study drug while being observed and tested for a period of time to confirm safety and characterize the PK of the study drug, where safety and PK assessments are done for a predefined time.
Multiple ascending dose: Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics (PK and PD) of multiple doses of the drug, looking at safety and tolerability. (in nutshell Mad studies check for safety/tolerability and PK/PD)
8) What is the purpose of a phase II trial?
Phase II trials are also referred to as therapeutic exploratory studies:
- Determine safety in target population
- Identifying the patient population that can benefit from the drug
- To estimate and verify dosing regimen
- Patient volunteers with the disease to be treated:
- Otherwise free of hematologic, hepatic, renal, cardiac or other serious diseases*
- Not receiving concomitant therapy, if feasible
9) What are the characteristics of a phase II trial?
- Number of patients: 100-300
- Duration: 6 months - 3 years
- At the end of Phase 2
–Defined patient group/disease state
–Established safe and efficacious dose, dosing regimen, dose response
–Established likely toxicities and side effects
Further validation of biomarkers and end points
10) What is the purpose of a phase III trial?
May be referred as Therapeutic Confirmatory studies.
- Pivotal Studies
–Intended to provide adequate basis for marketing approval
–Primary objective is to demonstrate or confirm therapeutic benefit shown in previous phase II studies
- Purpose
–Confirming safety
–Confirming efficacy
–Confirming drug dosage and formulation
- Population
–A well-defined population of patients with the disease to be treated
11) What are the characteristics of a phase III trial?
- Randomised, blinded, controlled (standard/placebo) studies
- Number of patients: 1000-3000 •Duration: 2-5 years
- Can include other studies to support registration, such as bioavailability/bioequivalence and PK in special populations.
12) What are the characteristics of phase IV trials?
- Conducted after the drug is marketed
- May be required by regulatory authorities as a condition of market approval
- Focused on two key issues:
–Keeping track on how safe the drug is in a large population and especially in the groups not involved in the pre-marketing trials
–Long-term morbidity and mortality profile of the drug
•To find new indications for the drug
