Clinical Trial Design

Question 1

why are clinical trials important

Answer 1

they provide evidence which influences medical practice

Question 2

4 examples of drug treatments based on trial evidence

Answer 2

MI
stroke
cancers
rheumatoid arthritis

Question 3

investigating potential drugs (5)

Answer 3

• does it work
• what dose is therapeutic
• what dose is toxic
• is it safe
• is it necessary

Question 4

problems with observational studies (3)

Answer 4

correlation vs causation false + ves

replication is difficult

Question 5

why conduct robust clinical trials

Answer 5

what works in theory might not be best in practice

e. g. high [oxygen] in premature babies - found to be harmful tonsillectomy
- generally unnecessary bypass surgery vs coronary artery stenting

Question 6

Clinical trials are regulated by

Answer 6

MHRA- tests efficacy and safety

Question 7

stages in development (4)

Answer 7

drug discovery

preclinical development

clinical development

(volunteer studies, phase i)phase ii, phase iii, phase iv

Question 8

pre clinical development (3)

Answer 8

• Animal pharmacology (dose, adverse effects)

* Animal toxicology (teratogenicity, fertility, mutagenicity)- Tissue culture

Question 9

clinical development: phase i

Answer 9

• 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 e.g.

• TEGENERO DRUG: 8 paid volunteers
○ 6 given active drug IV, 2 given placebo
○ Regulated environment, according to protocol approved by MHRA

Developed multiple organ failure in an unpredicted biological action of the drug in humans

Question 10

phase ii

Answer 10

• Clinical investigation to confirm kinetics and dynamics in patients (who may have liver/renal/GI absorption problems)
• Provides some evidence of efficacy and identifies a likely dosage rangeInvolves up to 500 patients

Question 11

phase iii

Answer 11

• 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 patientsAt 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 12

phase iv

Answer 12

• Post-marketing surveillance to produce evidence of long term safety May involve tens or hundreds of thousands of patients world wide

Question 13

clinical trials

Answer 13

pilot studies

double blind/single blind

retrospective/prospective

Question 14

pilot studies

Answer 14

not to estimate outcome but to test study design

Question 15

double blind

Answer 15

patient and doctor blinded

Question 16

single blind

Answer 16

patient blinded

Question 17

prospective

Answer 17

protocol decided before hand

Question 18

retrospective

Answer 18

less good as open to bias

Question 19

placebo controlled study

Answer 19

100 patients
50 drug
50 placebo

compare outcome in the 2 groups

Question 20

comparison with other therapy

Answer 20

100 patients
50 study drug
50 comparative therapy

compare end pointsis one better than the other

Question 21

cross over design

Answer 21

100 patients
50 study drug
50

comparative therapy cross over at e.g. 8 wks (wash out period)compare outcomes A vs B in same patient

Question 22

randomised clinical trial

Answer 22

patients assigned at random to either treatment or control this is the ideal method

Question 23

disadvantages of randomised control clinical trials (4)

Answer 23

• Generalisable results?
  • Subjects may not represent general patient population
  • Tend to be better at complying - Recruitment
  • Twice as many new patients needed for the study
• Acceptability of randomisation process
  • Some physicians will refuse (PFO closure)
  • Some patients will refuse (want treatment)
  Administrative complexity (randomisation methods etc)

Question 24

commonly used phase iii designs (9)

Answer 24

• Parallel
• Withdrawal
• Group/cluster
• Randomised consent
• Cross over
• Factorial
• Large simple
• Equivalence/non-inferiority Sequential

Question 25

superiority vs non-inferiority trials

Answer 25

- SUPERIORITY: show that new treatment is better than the control or standard (maybe a placebo) - NON-INFERIORITY: show that the new treatment: A. Is'nt worse than the standard by more than some margin B. Would have beaten placebo is a placebo arm had been included (regulatory)

Question 26

how to design a study

Answer 26

- Randomised double blind comparison of angiotensin II antagonist vs atenolol in the treatment of hypertension - 12 wk comparison - End points (should be as simple as possible) • Death • Number of hospital admissions • Lowering of blood pressure • Compare with pain control or change in mood - Hypothesis - Number of subjects - Safety endpoints? - A good design will give robust results

Question 27

designing a study

Answer 27

- Choice of subjects: need enough to be able to detect/reject a difference between the 2 groups, statistical design is very important - Number of patients also depends on: frequency of outcome measurement (A v B in mild hypertensives, BP reduction: 200 patients over 12 wks; stroke reduction: thousands of patients over 5 yrs) - Choice of control drug: placebo, drug of known efficacy - Choice of patients: age and sex matched, race, other diseases and drugs, compliance - Exclusion and selection criteria: exclude pregnant women, children, seriously ill patients, elderly (?), patients at risk of side effects

Question 28

challenges in studies (2)

Answer 28

- Declining renal function Multiple morbidities: patients over 60 usually have multiple conditions

Question 29

analysis and interpretation

Answer 29

- Choose a stat test - Are differences due to chance - P<0.05 usually taken as significance- Interpreting an insignificant finding: • No difference or the study hasn’t found one Two treatments may be clinically effective

Question 30

ethical issues

Answer 30

- Consent - Ethics committee - Placebos - Children - Study design - Policing studies - MHRA/CSM/EU - InsuranceThe law

Question 31

all preclinical and clinical trial evidence is submitted to the ...

Answer 31

regulatory authority

Question 32

post marketing surveillance

Answer 32

- Medicines and healthcare devices regulatory authority (MHRA) • Committee of safety of medicines- Yellow card systemGP, hospital doctors and pharmacists

Question 33

why do we do clinical trials

Answer 33

- Patients may get better or worse despite drug therapy - There may be a placebo effect - Clinical practice needs to be evidence basedDrug companies have competing interests

Question 34

important clinical trials

Answer 34

4Scare trial

Question 35

scandinavian simvastatin survival trial

Answer 35

4444 patients with angina or post MI, serum cholesterol 5.5 -8.0mmol/L, simvastatin 20mg or placebodeath lower 4%, coronary events lower 9% in simvastatin

Question 36

cholesterol and recurrent events trial

Answer 36

does lowering normal cholesterol give benefit, 4000 patients, post MI, 'normal cholesterol', pravastatin 40mg or placeboStroke incidence reduced by 31%, p = 0.03