Introduction to Clinical Trials Flashcards
What are the three key features of an RCT broadly speaking?
Controlled
Unbiased
Adequately sized
List some different types of intervention that may be evaluated by a clinical trial
Drug therapy Medical procedures Educational intervention Screening Trial Vaccine trial Medical therapy Complex interventions (e.g effects of educational programmes)
What is the Declaration of Helsinki?
International recommendation on the conduct of medical research on human participants to which all clinical trials should comply
What is the national ethical committee responsible for reviewing of trial protocols in the UK to ensure safety of future participants?
IRAS (Integrated Research Application System)
What is the role of the MHRA in the UK and FDA in the USA
Regulatory authorities approve trials of investigational medicinal products and medical devises to ensure trials have been conducted with sufficient quality and standards and further to licence products which are effective and safety has been properly evaluated
Outline the role of an Observational Trial
Non-experimental study where the individuals are observed and data collected with nothing being done to influence either the exposure or the course of events.
What is the major flaw of observational trials?
Can be subject to considerable bias if not designed well. Often have very different outcomes to RCTs
Outline the different phases of clinical trials
Phase I - Testing effect(s) of novel therapy on healthy sample
Phase II - Dose-response curve
Phase III - large sample size
Phase IV - post-marketing (long-term safety and interactions)
What is the most common trial design?
Parallel trial - New vs standard therapy
List some other trial designs other than parallel
Cross-over Factorial Equivalence Bioequivalence Non-inferiority Superiority Exploratory Confirmatory Cluster
Outline the utility of single vs multi-centre trials
Single centre - used for Phase I and II trials
Multi-centre trials - good for large recruitment over short periods of time and increases generalisability of results
Outline three reasons why trial results may not represent the ‘truth’?
Biased in a predictable fashion
Contimainated with a confounding factor
Random chance
What are the most common sources of bias in trials?
Most commonly at selection and outcome measurement.
Also includes omission of data and loss to follow-up
How are confounding errors minimised?
Adequate planning and exploration of variables with sound scientific principles and reasoning.
Randomisation (e.g. stratified) to account for known dependent variables
Stratified analysis and regression analysis
How is the effect of random chance minimised in trials?
Large sample sizes, appropriate of results statistical analysis and meta-analysis
What are the advantages of uncontrolled trials?
Used to generate hypotheses and justifications of PIII trials
Can assess pharmacokinetic properties of novel agents
Might be the only study design possible due to ethical considerations
What are the disadvantages of uncontrolled trials?
Investigator bias
Susceptible to over-interpretation
Much less informative than RTCs
What is the purpose of the clinical trial protocol?
- Defines the clinical question
- Outlines how it is answered
- How will it be compliant to ICH-GCP, EUCTD, FDA/MHRA regulations
- What analyses should be reported
- How will results be interpreted?
What is the purpose of the clinical trial protocol?
- Defines the clinical question
- Outlines how it is answered
- How will it be compliant to ICH-GCP, EUCTD, FDA/MHRA regulations
- What analyses should be reported
- How will results be interpreted?
How are study objectives stated differently in a priori (proscpective) versus retrospective research?
Prospective (a priori) = stated as a hypothesis
Retrospective research = stated as a question
What are primary endpoints in a trial?
Measure outcomes that answer the primary question of the trial
What are secondary endpoints?
Ask other questions relevant to the study
What are the main type of endpoints investigated in RCTs?
Binary (e.g. death of any cause) Disease specific death Occurrence of symptoms QOL outcomes Utilisation of healthcare resources
What qualities must endpoints have to be clinical relevant?
Clinically meaningful
Answer the main question
Can be practically assessed
Occur frequently enough within the time frame of the study to be powerful enough
Death as an endpoint can be impractical for what reasons?
May be rare in the timeframe of the study
Death can results from factors other than those under scrutiny in the trial
What are composite endpoints?
Multiple outcomes measured
What stage of trials are composite endpoints more common?
Exploratory / Early-phase trials
How can composite endpoints be expressed in a trial?
Can be expressed as total numbers or in a hierarchical fashion (only counting the most serious endpoint)
What are the advantages of composite endpoints?
- Increases event rate therefore decreases participants required
- More comprehensive evaluation can be achieved including clinical, pathologic, radiographic and biochemical can be measured simultaneously
Limitations of composite endpoints are:
Assumption that avoidance of any one endpoint is as clinically significant as any other
Assumption that each outcome related to disease progress are equally important
Inconsistent results if some outcomes improve and some deteriorate.
What are surrogate endpoints?
A lab measurement / physical sign used as a substitute for a clinically meaningful endpoint that directly measures how a patient feels, functions or survives