Clinical trial IA % +

Question 1

Pre-clinical development

Answer 1

• Animal pharmacology (dose, adverse effects)
• Animal toxicology (teratogenicity, fertility, mutagenicity)
• Tissue culture

Question 2

Clinical development 1

Answer 2

Volunteer studies (phase I)

–Clinical pharmacology in normal volunteers generating pharmacokinetic, metabolic and pharmacodynamic data.

–Usually involves around 100 subjects

–Certain drugs e.g. cytotoxics will bypass this phase

Question 3

Clinical development 2

Answer 3

Phase II

–Clinical investigation to confirm kinetics and dynamics in patients (who may have renal/liver/GI absorption problems)

–Provides some evidence of efficacy and identifies a likely dosage range

–Involves up to 500 patients

Question 4

Clinical development 3

Answer 4

Phase III

–Formal therapeutic trials where efficacy will be established and evidence of safety obtained

–i.e. does it work for the condition we are testing?

–Involves 1000 - 3000 patients

–At completion, all data (pre-clinical, pharmaceutical and clinical data) is submitted as an application to the regulatory authority for a license to sell the drug

Question 5

Clinical development 4

Answer 5

Phase IV

–Post-marketing surveillance to produce evidence of long term safety

–May involve tens or hundreds of thousands of patients world wide

Question 6

Clinical trials

Answer 6

Pilot studies

–Not to estimate outcome, but to test study design

Trials may be:

–Double blind ⇒ patient/doctor blinded

–Single blind ⇒ patient blinded e.g. stent study

–Prospective ⇒ protocol decided before hand

–Retrospective ⇒ Data is collected after treatment. less good as open to bias

Question 7

Placebo controlled study pic

Answer 7

Question 8

Cross over design pic

Answer 8

• Patients take both treatments being test,one after the other

Question 9

Randomised Control Clinical Trial (pic)

Answer 9

Question 10

Disadvantages of randomised control clinical trial

Answer 10

1. Generalizable Results?

• Subjects may not represent general patient population
• Tend to be better at complying

2. Recruitment
   * 2X as many new patients needed for the study

¨3. Acceptability of Randomization Process

• Some physicians will refuse (PFO closure)
• Some patients will refuse (want treatment)

¨4. Administrative Complexity (randomisation methods etc)

Question 11

Commonly Used Phase III Designs

Answer 11

• Parallel
• Withdrawal
• Group/Cluster
• Randomized Consent
• Cross Over
• Factorial
• Large Sample
• Equivalence/Non-inferiority
• Sequential

Question 12

Superiority vs.
Non-Inferiority Trials

Answer 12

Superiority Design

• Show that new treatment is better than the control or standard (maybe a placebo)

Non-inferiority:

Show that the new treatment:

• a) Is not worse that the standard by more than some margin
• b) Would have beaten placebo if a placebo had been included (regulatory)

Question 13

How to desing a study

Answer 13

Choice of subjects

• Need enough to be able to detect or reject a difference between the groups
• Statistical design is very important

No of patients also depends on

• Frequency of outcome measurement
• e.g Smarties vs atenolol in mild hypertensives

Choice of patients

• Age and sex matched
• Race
• Other diseases and drugs etc
• Are they going to comply?
• BP reduction: 200 patients over 12 weeks
• Stroke reduction: thousands of patients over five years

Choice of ‘control’ drug

• Placebo (50% effective in anxiety!)
• Drug of known efficacy (eg atenolol)

Exclusion and selection criteria

• Exclude pregnant women
• Children
• Seriously ill patients
• Elderly patients?
• Patients at risk of side effects

Question 14

Analysis and interpretation

Answer 14

• Choose a statistical test
• Are differences due to chance?
• p<0.05 (probability that the results where due to chance is less than 5%) usually taken as significance

Question 15

Ethics

Answer 15

• Consent
• Ethics committee
• Placebos
• Children
• Study design
• MHRA/CSM/EU
• Insurance
• The Law

Question 16

Parallel study

Answer 16

A parallel study is a type of clinical study where 2 groups of treatments, A and B, are given so that one group receives only A while another group receives only B.

Other names for this type of study include “between patient” and “non-crossover”