Topic 8: clinical trials

Question 1

Phase 1: part 1 purpose

Answer 1

• Part 1 trials are designed to determine safety and tolerability over the dose range and characterize the pharmacokinetic properties of the molecule. That is:
• Cl, T1/2, Fe, Volume, Bioavailability, Fraction unbound
• Linearity over the dosage range

Question 2

Design of a phase 1 clinical trial: part 1

Answer 2

• Based heavily on pre-clinical data, includes calculated human dose. This is calculated from the NOAEL in animals
• HED = Animal dose (mg/kg) * (Animal weight(kg)/Human Weight (kg)) or Via allometry
• First subject cohort is administered a very low dose. The dose increment then increases progressively from one cohort to the next i.e. 10, 15, 25, 40, 60, 80 (mg/kg)
• Independent review board analyses data. The board has predetermined “stopping criteria” based on efficacy and toxicity.

Question 3

Phase 1: subject selection

Answer 3

Subject Selection:

• Healthy volunteers with tight age and gender requirements
• If the drug has benefits over potential toxicities (i.e. cancer) sometimes the patient population will be used
• Subjects are tightly monitored in terms of kidney and liver function. 10-15 blood samples will be taken.

Question 4

Phase 1: part 2

Answer 4

-Purpose: selection of routes of administration

• Use routes of administration that will be used in the final product
• Pharmacokinetic parameters must be accurately defined so they can be compared with pre-clinical study
• If an oral and IV formulation are available, both will be administered in a series of dosing days to calculate F
• Should use the final oral formulation that will go into phase 1 and 2, if this is not possible a further bioequivalence study will be required.
• Placebo will be included

Question 5

Parallel and cross over studies

Answer 5

Parallel studies:

• Two or more groups are followed concurrently
• Require larger numbers (40+) than cross over as subject are not able to act as their own controls
• Do not have to take into account washouts and drop outs do not affect the outcome
• Safety and Efficacy trials

Question 6

Cross over studies

Answer 6

Cross over studies:

• Bioequivalence and Bioavailability trials
• Subjects randomized in treatment order (AB or BA)
• Subjects act as their own control
• Makes big assumption there are no time dependent changes
• 20 or so patients
• Greater than 5 half life washout period (limitation)
• Analysis is greatly affected by drop outs

Question 7

Phase 2: Purpose, design,

Answer 7

Purpose: Support the dose response relationship

Design:

• Initial dose is lower than the highest dose evaluated in phase
• High level of supervision, regularly report back to the clinical trial unit to provide blood samples
• If placebo group is included they will continue to take their current medication

Question 8

Phase 2 subject selection

Answer 8

Subject Selection:

• Very narrow (weight, renal function, age etc)
• N = 50-500

Question 9

Phase 3: Purpose

Answer 9

• Understand safety and efficacy in large population and differences between populations
• If the medicine confers economic benefit
• If it is therapeutically effective

Question 10

Phase 3: design

Answer 10

• Specific objectives
• Defined endpoint
• Appropriate randomization to allocated treatment
• Appropriate blinding
• Significant statistical power
• Control group is key as it provides quantitation of the effects on disease progression

Question 11

Phase 3: Subject selection

Answer 11

• General population for which use is intended. I.e. high blood pressure
• N > 1000s
• Also include special populations i.e. hepatic failure