39 terms

Lecture 5: Randomized Clinical Trial

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Case study/case series
- no randomization
- no comparison is made with an untreated group or a group getting some other treatment
- observations of clinical response
What do studies with a comparison involve?
- historical controls
- simultaneous nonrandomized controls
- randomization
- stratified randomization
Historical Control
- use of comparison group from the past
- go back to records of patients with the same disease with the prior treatment used. E.g) length of stay
Problems with historical control
Differences in:
- base population
- diseases rates
- disease definition
- disease treatment
- quality of data collection
Simultaneous non-randomized control
- problem if the assignment system can be predicted (e.g. if patients admitted on an even day got the new treatment and odd day admissions were the controls)
- can lead to selection bias (increased admission on even days)
Intervention study
- used to test efficacy of preventitive or therapeutic measures
- 2 categories:
- controlled clinical trial
- community interventions
- multicenter trial - results from several researchers are pooled
Clinical trial definition
- a planned experiment that assesses the efficacy of a treatment
- outcomes in treated group are compared with outcomes in an equivalent control group
- participants in both groups are enrolled, treated, and followed over the same period
Randomized clinical trials
- subjects are enrolled in the study and exposure, the intervention, is manipulated by the investigator
- most rigorous design, greatest control over the research center
- subjects randomized
- blinded investigators and subjects
Characteristics of clinical trial
- assess the efficacy of a treatment
- carefully designed and rigidly enforced protocol
- random assignments of subjects
- placebo to control
Outcomes of clinical trial
- referred to as clinical end points
- may include rates of disease, death, or recovery
- outcomes must be measured in a comparable manner in the intervention and control conditions
- outcomes similar to cohort study (RR, HR)
Advantages to randomized clinical trial
- no selection bias
- certainty about exposure, although compliance should be monitored
- gold standard of study design.
Limitations to randomized clinical trial
- expensive
- can be lengthy
- lack of generalizability
- ethical issue
Selection of subjects
- investigators must have clear criteria for who will be in the study
- criteria must be written in advance for both inclusion and exclusion
- impact on the generalizability or external validity
Why randomize?
- prevent investigator/patient bias
- establish balance at baseline in terms of potential confounder
- create the basis for statistical testing, that may rely on prior randomization
Randomization issues
- if some subjects leave the study based on certain characteristics to a greater extent in the intervention or control, the benefits of randomization are lost
- if one or both arms of the study are not compliant, lead to underestimate of effectiveness
Stratified randomization
if any characteristics affect prognosis (e.g. sex, age); can randomize by sex first then age
blinding
ensure neither study subjects are aware
- reduce potential for bias
- single-blind: subjects unaware of group assignment
Why use placebo?
- may help control crossover (e.g. people who know what they are taking would switch themselves)
- even with a placebo, many guess treatment
Treatment
what was the assignment and what was compliance
outcome
measure both drug efficacy and side effects; need explicit criteria for evaluation and blinding important
- compare entry characteristics (table 1) to see if randomization was successful
Intention to treat analysis
- conservative way of assessing the intervention because we know that the true intervention effect is diluted by crossovers
- if the data were not analyzed this way, it would violate randomization process and introduce confounding
Cumulative incidence
- proportion of subjects who develop the disease over the follow up period of the study
- incident rate also used
Measure degree of association
- risk ratio = cumlative incidence/cumulative incidence in control
- RR= 1 exposure does not increase risk of disease
RR <1 exposure appears to be protective
Power and sample size
- the larger the sample size, the more likely you are to see an intervention and disease association
- power of study is the probability of finding a statistically significant association in the data
alpha outcome
- probability of making a type I error
- probability of concluding the treatments differ when in reality they do not differ
beta outcome
- probability of making a type II error
- probability of concluding the treatments do not differ when in reality they do differ
Power (1-beta)
probability of detecting a difference between the treatments if the treatments do in fact differ
What must be specified in order to estimate the sample size needed in a randomized trial?
1. difference in response rates to be detected
2. estimate of the response rate in one of the groups
3. level of statistical significance (alpha)
4. the value of the power desired = 80-90%
5. whether the test should be one sided or two sided
Crossover design
- any change of treatment for a patient in a clinical trial involving a switch of study treatments
Planned crossover
protocol is developed in advance, and the patient may serve as his or her own control
- time for washout is important
- change order of two assignments
- each patient is his/her control
Unplanned crossovers
exist for various reasons, such as patient's request to change treatment
Factorial design
assume that two drugs/nutrients are to be tested and the outcomes for the two are different, and modes of action are independent: use the same population for testing both drugs
non-compliance
many patients agree to randomization but not comply
Efficacy
[(rate in placebo group)-(rate in vaccine group)]/rate in those who received placebo
Number needed to treat
1/[(rate in untreated)-(rate in treated)]
MRFIT study
- special intervention: hypertension treatments, intensive counseling and education about lifestyle changes
Phases of Clinical trial, why need?
- before treatment can be liscensed, must go through several stages
- lengthy process protects the public but delay access to needed pharmaceutical agents for critically ill patient
3 phases of clinical trial for vaccines
Phase I: test a new vaccine in volunteer (<100 volunteer)

Phase II: expand testing to a group of 100-200 subjects

Phase III- assess the efficacy of the vaccine in the target population; main test
4 FDA required clinical trials for new medicine
Phase I: clinical pharmacology studies of 20-80 people, look for toxicology and efficacy

Phase II: clinical investigations of 10-200 people for efficacy and relative safety

Phase III: large scale RCT for effectiveness and safety

Phase IV: post marketing surveillance; side effect not anticipate