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principles of disease > clinical trial design > Flashcards

clinical trial design Flashcards

1
Q

why are clinical trials important

A

they provide evidence which influences medical practice

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2
Q

4 examples of drug treatments based on trial evidence

A

MI
stroke
cancers
rheumatoid arthritis

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3
Q

investigating potential drugs (5)

A
  • does it work
  • what dose is therapeutic
  • what dose is toxic
  • is it safe
  • is it necessary
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4
Q

problems with observational studies (3)

A

correlation vs causation
false +ves
replication is difficult

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5
Q

why conduct robust clinical trials

A

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

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6
Q

Clinical trials are regulated by

A

MHRA

- tests efficacy and safety

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7
Q

stages in development (4)

A

drug discovery
preclinical development
clinical development (volunteer studies, phase i)
phase ii, phase iii, phase iv

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8
Q

pre clinical development (3)

A

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

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9
Q

clinical development: phase i

A
  • 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

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10
Q

phase ii

A

• 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 range
Involves up to 500 patients

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11
Q

phase iii

A

• 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

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12
Q

phase iv

A

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

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13
Q

clinical treials

A

pilot studies

double blind/single blind/retrospective/prospective

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14
Q

pilot studies

A

not to estimate outcome but to test study design

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15
Q

double blind

A

patient and doctor blinded

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16
Q

single blind

A

patient blinded

17
Q

prospective

A

protocol decided before hand

18
Q

retrospective

A

less good as open to bias

19
Q

placebo controlled study

A

100 patients
50 drug, 50 placebo
compare outcome in the 2 groups

20
Q

comparison with other therapy

A

100 patients
50 study drug, 50 comparative therapy
compare end points
is one better than the other

21
Q

cross over design

A

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

22
Q

randomised clinical trial

A

patients assigned at random to either treatment or control

this is the ideal method

23
Q

disadvantages of randomised control clinical trials (4)

A
  • 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)
24
Q

commonly used phase iii designs (9)

A
  • Parallel
  • Withdrawal
  • Group/cluster
  • Randomised consent
  • Cross over
  • Factorial
  • Large simple
  • Equivalence/non-inferiority
    Sequential
25
Q

superiority vs non-inferiority trials

A
  • SUPERIORITY: show that new treatment is better than the control or standard (maybe a placebo)
  • NON-INFERIORITY: show that the new treatment:
    A. Isnt worse than the standard by more than some margin
    B. Would have beaten placebo is a placebo arm had been included (regulatory)
26
Q

how to design a study

A
  • 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
27
Q

designing a study

A
  • 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
28
Q

challenges in studies (2)

A
  • Declining renal function

Multiple morbidities: patients over 60 usually have multiple conditions

29
Q

analysis and interpretation

A
  • 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
30
Q

ethical issues

A
  • Consent
  • Ethics committee
  • Placebos
  • Children
  • Study design
  • Policing studies
  • MHRA/CSM/EU
  • Insurance
    The law
31
Q

all preclinical and clinical trial evidence is submitted to the …

A

regulatory authority

32
Q

post marketing surveillance

A
  • Medicines and healthcare devices regulatory authority (MHRA)
    • Committee of safety of medicines
  • Yellow card system
    GP, hospital doctors and pharmacists
33
Q

why do we do clinical trials

A
  • Patients may get better or worse despite drug therapy
  • There may be a placebo effect
  • Clinical practice needs to be evidence based
    Drug companies have competing interests
34
Q

important clinical trials

A

4S

care trial

35
Q

scandinavian simvastatin survival trial

A

4444 patients with angina or post MI, serum cholesterol 5.5 -8.0mmol/L, simvastatin 20mg or placebo

death lower 4%, coronary events lower 9% in simvastatin

36
Q

cholesterol and recurrent events trial

A

does lowering normal cholesterol give benefit, 4000 patients, post MI, ‘normal cholesterol’, pravastatin 40mg or placebo
Stroke incidence reduced by 31%, p = 0.03

principles of disease (40 decks)

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