L5: Randomised controlled trials Flashcards
what is a clinical trial?
“A clinical trial may be defined as a carefully
designed, prospective medical study which
attempts to answer a precisely defined set of
questions with respect to the effects of a particular
treatment or treatments.”
how to assess the benefit of a new treatment?
Assessing the benefit of a new treatment:
Expert opinion
Physiological concepts
Clinical experience
Retrospective studies
Clinical trials
These form sort of a hirearchy of level of evidence in treating a disease.
hirearchy of evidence?
Case report: a demonstration only that some event of clinical interest is possible.
Case series: a demonstration of certain possibly related clinical events but subject to large selection biases.
Database analysis: treatment is not determined by experimental design but by factors such as physician or patient reference.
Observational study: the investigator takes advantage of “natural” exposures or treatment selection and chooses a comparison group by design
Controlled clinical trials: the treatment is assigned by design. Endpoint ascertainment is actively performed and analyses are planned in advance
Lowest to highest level of evidence
But … there now is a need for Real World Evidence
Observational studies looking at pre existing data and forming analysis on it is really important these days.
RCT vs observational?
Patients in RCTs are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co-morbidities.
Supplementing RCT evidence with data from observational settings can also improve the external validity of oncology drug trials, such that physicians treating patients in real-world setting have the appropriate evidence on which to base their clinical decisions.
Rcts do not represent all social economic backgrounds and in diff regions access to clinical trials might be less. Many not representative to the normal population. People have to have a level of fitness cant be suffering from toher diseases e.g: another cancer for example so these people are excluded. In the real world- patients may have multiple illnesses. Greater need for real-world evidence.
The process of an RCT
RCT process?
Pharmaceutical development
Preclinical studies
Investigational New Drug Application
Phase I clinical trials
Phase II clinical trials
Phase III clinical trials
New Drug Registration
Phase IV clinical trials
preclinical and phase 0 studies?
Preclinical studies
Testing of drugs in non-human subjects (usually mice, cell lines)
Aim to gain information about:
Efficacy
Toxicity
Pharmacokinetic
How much is it absorbed, whats its half life, how is it metabolised, how is it excreted. Need to understand that to know what dose you want to give.
Phase 0: A recent designation for exploratory, first-in-human trials, usually involving microdosing, to accelerate drug development
phase 1?
Small number of subjects (20-100)
Focus on safety
Pharmacokinetics
Pharmacodynamics
Toxicity
For toxic drugs: maximum tolerated dose
Normally healthy volunteers - in oncology used in patients with cancer
First in human trial
Still figuring out pharmacodynamics, kinetics, toxicity- just because a compound is safe in mice doesnt mean it is in humans
phase 2?
Now have MTD- maximum tolerable dose
Phase 1- check how safe
Now checking effectiveness
Medium size – usually several hundred patients with the medical condition
Strict inclusion/exclusion criteria - of who can or cant be in the trial
Focus on safety and short-term efficacy
Clarify dose and dose regimen (is it best to give one a day, 4x etc. all determined by pharmacodynamics)
Basis for design of “pivotal” studies (i.e. needed to get drug registered 🡪 Phase III)
Generates a large amount of data to go ahead and make a submission for a phase 3 clinical trial
phase 3?
Compararing your new treatment against an existing treatment to see if its better
Pivotal for FDA submission
Strict inclusion/exclusion criteria
Large (hundreds – thousands of subjects)
Comparative (two or more treatment groups)
Focus on efficacy and cost benefits
planning a trial?
Organisation of a clinical trial
Planning the study
-Formulating the hypothesis
-Choosing the endpoint - the right outcome to demonstrate that hypothesis
-Choosing the design and sample size
Conduct of the study
-Patient accrual
-Data collection
-Data analysis
Data analysis
Publication of results
planning a trial: the hypothesis
Focus on a limited number of precisely formulated questions
The more questions, the more complicated the study and the higher chance of a failure
Title of trial normally crystalises the hypothesis for you
Planning a trial: the endpoint
Two main criteria for selecting the endpoint:
Sensitivity to detect treatment effects
Clinical relevance to goals of the study.
Evidence for biological activity of a drug (Phase II)
Definitive evaluation of clinical benefit (Phase III)
In life threatening diseases (AIDS, cancer, …) the endpoint relevant for definitive evaluation of at treatment is survival.
Sometimes the most sensitive and relevant endpoint may be difficult to use (eg. long follow-up for survival in early cancer)
One may want to use a surrogate endpoint – these should be validated (e.g Progression Free Survival instead of overall survival)
Clinical relevance and endpoint is diff for each phases. Phase 2 - safety + short term efficacy
Phase 3 - does it have clinical benefit
Other end points might be used: poteggresion free Survival cancer. Follow patients until patient changes treatment for cancer.
Planning a trial: the design
Depends on the goal of the trial
Time is important. If taking too long e.g: 25 yrs nobody will be interested.
It should be the most efficient for the question at hand
The sample size should provide enough power to detect a clinically relevant effect
Careful organisation is required: administrative office, data coordinating centre, clinical centres, committee structure (i.e. data safety and monitoring board, events committee, steering committee, subcommittees)
Committee (forgot which) check if harmful etc.
Collaborative effort: data-collecting staff, investigators, data managers, programmers, statisticians 🡪 should all be involved in the design and adequate flow of information needs to be secured.
