Clinical trial IA % + Flashcards
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
- Generalizable Results?
- Subjects may not represent general patient population
- Tend to be better at complying
- 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
- Parallel
- Withdrawal
- Group/Cluster
- Randomized Consent
- Cross Over
- Factorial
- Large Sample
- Equivalence/Non-inferiority
- Sequential
Superiority vs.
Non-Inferiority Trials
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)
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
- 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
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
- Consent
- Ethics committee
- Placebos
- Children
- Study design
- MHRA/CSM/EU
- Insurance
- The Law
