Clinical Trial Design Flashcards
What is the importance of clinical trials
Provide evidence (medicine is evidence based)
thing to consider about a drug before public distribution/clinical trials
basic considerations of trial design
- Does it work?
- What dose is therapeutic?
- What dose is toxic?
- Is it safe?
- Is it necessary?
Problems with observational studies
Correlation vs causation
False positives:
e.g. smoking and breast cancer, vasectomy and prostate cancer
why is replication of observational studies difficult
due to bias/different criteria
why must we conduct robust clinical trials
What works in therory may not work in practise
What are clinical trails regulated by and what do they test for?
MHRA
- Efficacy: compared with placebo, compared with another drug
- Safety
Stages in drug development
icnlude clinical development
- Drug discovery
- Pre-clinical development (animal pharmacology/toxicology, tissue culture)
- Clinical Development: Volunteer studies Phase 1 (clinical pharmacology in normal volunteers generating pharmacokinetic, metaboic and pharmacodynamic data) - about 100 subjects
- Phase 2: clinical investigations to confirm kinetics and dynamics in patients - provide evidence of efficact and identifies a likely dosage range - about 500 pateints
- Phase 3:formal therapeitic trials where efficacy wil be established and evidence of safety obtained - 1000 to 10000 patients
- All data submitted as application to regulatory authority for licence to sell drug
- Post-marketing surveillance to produce evidence of long term safety - loads of patients
What is done first before a clinical trial
Pilot study: not to estimate outcome but test study design
What 4 things could clinical trials be
- Double blind - doctor and patient blind
- Single blind - patient blind
- Prospective - protocol decided beforehand
- Retrospective - less good as open to bias
describe a placeo controlled study
100 patients with 50 active drugs and 50 placebo.
Compare outcome in 2 groups.
can do same but compare with other therapy (instead of placebo) –> compare end points
what is cross over design
- 100 patients and split into 50 study drug and 50 compared therapy
- take measurements
- wash out period
- switch treatments
- compare outcomes with A vs B in the same patient
randomised control clinical trial
patients assigned at random to either treatments or control
Disadvantages of randomised control clinical trial
- **Generalizable results **: subjects may not represent genetal patient population, tend to be better at complying
- Recruitment - twice as many new patients needed for the study
- Acceptability of randomization process (physicians or patients could refuse)
- Administative complexity (randomisation methods etc.)
commonly used phase 3 designs
- parallel
- withdrawal
- group/cluster
- randomized consent
- cross over
- factorial
- large simple
- 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 treatment is:
* a) not worse than the standard by more than some margin
* b) would have beaten placebo if a placebo arm had been included (regulatory)
uses of a clinical study
learn if a new treatment is more effective and/or has less harmful side effects than the standard treatment
ethics of clinical trials
- consent
- ethics committee
- placebos
- children
- study design
- “policing” studies
- Insurance
- the law
- MHRA/CSM/EU
yellow card
reporting of adverse drug reactions (ADRs) to MHRA/regulatory body. Can be done by GPs, hospital doctors or pharmacists (and patients to?)
why are good clinical trials necessary
- protect the public
- provide evidence to help rational prescribing
statistics: what is p < 0.05
taken as significant
What is parallel design in clinical trials
subjects are randomized to one or more study arms and each study arm will be allocated a different intervention
What is cross over design in clinical trials
two or more treatments (e.g., drugs, procedures) are provided to subjects at different time periods, and the sequence of treatments is randomized for each subject.
pros of crossover design
each subject acts as his or her own control, and that a smaller number of patients are required in comparison to parallel-group studies
disadvantages of crossover designs
Cross-over studies are often of longer duration than parallel-group studies. There may be difficulty in incorporating multiple dosage arms and in dealing with drop-outs; patients who only complete the first evaluation phase contribute little to the analysis. There is also potential for unblinding, when the effects of the active drug are more obvious to the participants than those of placebo, and for carry-over effects between evaluation phases, particularly for drugs with long elimination half-lives.
2 types of randomised trial
crossover or parallel
what is statistical power
(or sensitivity)
the likelihood of a significance test detecting an effect when there actually is one
importance of statistical power
to draw accurate conclusions about a population using sample data
clinical vs statistical significance
While statistical significance indicates the reliability of the study results, clinical significance reflects its impact on clinical practice.
In randomised controlled trials a non-significant result in a trial means…
may mean the trial was insufficiently powered to detect a significant result
