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Pre-clinical development

•Animal pharmacology (dose, adverse effects)

•Animal toxicology (teratogenicity, fertility, mutagenicity)

Tissue culture


Clinical development 1

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


Clinical development 2

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


Clinical development 3

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


Clinical development 4

Phase IV

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

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


Clinical trials

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


Placebo controlled study pic


Cross over design pic

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


Randomised Control Clinical Trial (pic)


Disadvantages of randomised control clinical trial

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)


Commonly Used Phase III Designs




•Randomized Consent

•Cross Over


•Large Sample




Superiority vs.
Non-Inferiority Trials

Superiority Design

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


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)


How to desing a study

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


•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


•Seriously ill patients

•Elderly patients?

•Patients at risk of side effects



Analysis and interpretation

•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




•Ethics committee



•Study design



•The Law


Parallel study

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"