46 terms

Randomized (Clinical) Trials

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Case Study or Case Series
-No randomization
-No comparison is made w/an untreated group or a group getting some other treatment
-Observations of clinical response
Studies w/a Comparison
-Historical controls
-Simultaneous non-randomized controls
-Randomization
-Stratified randomization
Historical Controls
-The use of a comparison group from the past
-Go back to records of patients w/the same disease w/the prior treatment used
Problems w/Historical controls
•Differences in:
-base population
-disease rates
-disease definition
-disease treatment
-quality of data collection
Simultaneous Non-randomized controls
•Can be a problem if the assignment system can be predicted
-for ex, if patients admitted on an even day got the new treatment and odd day admissions were the controls
•Can lead to selection bias--increased admissions on even days
Intervention Studies
•Used to test efficacy of preventive or therapeutic measures
•Two categories
-controlled clinical trials
-community interventions
•Multicenter trials--results from several researchers are pooled
Randomized Clinical Trials
•Subjects are enrolled in the study and exposure, the intervention, is manipulated by the investigator
•Subjects are randomized to the intervention or control (placebo) assignment
•Subjects are followed up for disease outcome
Design of a Randomized Trial
-Study Population--randomly assigned into current treatment and new treatment
-measure the people who improve and don't improve in each group
Characteristics of Clinical Trials
-assess the efficacy of a treatment
-carefully designed and rigidly enforced protocol
-random assignment of subjects to study groups (intervention and control)
Examples of Clinical Trials
•Medical Research Council Vitamin Study--studied role of folic acid in preventing neural tube defects
•South Bronx, NY, STD program--evaluated effectiveness of education efforts to prevent spread of STDs
Utility of Randomized Trials
-Evaluate new drugs and other treatments (nutritional supplements)
-Evaluate new medical technology
-Assess new screening programs
Randomized Clinical Trials Advantages
-No selection bias
-Certainty about exposure, although compliance should be monitored
-Gold standard of study designs
RCTs Limitations
-Expensive
-Can be lengthy
-Lack of generalizability
-Ethical issues
Important Concepts in RCT Design
•Concurrent controls
•Randomization
•Placebos
•Double blind technique
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
-Remember, this will impact on the generalizability or external validity
Why randomize?
-To prevent investigator/patient bias
-To establish balance at baseline in terms of potential confounders
-To create the basis for statistical testing, that may rely on prior randomization
Randomization Issues
•If some subjects leave the study based on certain characteristics (old age) to a greater extent in the intervention or control groups--the benefits of randomization are lost
•If one or both arms of the study are not compliant with the group assignment (intervention or control) it will lead to an underestimate of effectiveness
•For ex, intervention=exercise--they refuse to do so and placebo start to exercise b/c of press stating benefits of exercise
Randomization
Randomization increases the probability that there is an even distribution of observable and unobservable potential confounders b/t the intervention and control groups

-if age and sex strongly affect prognosis: use Stratified Randomization
Blinding
Blinding and placebo are used to ensure that neither study subjects or those assessing outcome are aware of group assignment--helps decrease bias
Blinding (Masking)
•To maintain the integrity of a study and reduce the potential for bias, the investigator may utilize one of two popular approaches:
-Single-blind design: subject unaware of group assignment
-Double-blind design: neither subject nor experimenter is aware of group assignment
Why use a placebo in the control group?
-The placebo effect exists and rates can vary (e.g. 0 to 35% in a study of soy and health)
-May help control crossover
-Even with a placebo, many guess treatment
-The placebo group can also be important to study side effects
Essential Data collection in Randomized Trials
•Treatment--what was the assignment and what was the compliance
•Outcome--measures of both drug efficacy and side effects. Need explicit criteria for evaluation and blinding is important
•Compare the entry characteristics to determine if randomization was successful
Outcomes of Clinical Trials
-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
Intention to treat analysis
•ITT is a conservative way of assessing the intervention b/c we know that the true intervention effect is diluted by crossovers
•If the data were not analyzed this way it would violate the randomization process and could introduce confounding
•For ex, in the exercise intervention you would end up comparing health conscious people to non-healthy individuals
Cumulative Incidence
•The proportion of subjects who develop the disease over the follow-up period of the study
•The average probability that an individual in the RCT will develop the disease over the follow-up period
•Also incidence rate is used as in cohort studies
Chi Square Test
X^2 = Sum of (observed-expected)^2/expected

-ex,, null hypothesis: one would expect that 37 total fractures would e distributed over 2 groups evenly
-expected calcium/vit D=17.7
-expected in placebo=19.2
-Test v. observed using chi-square
Similar statistics to cohort studies
•Survival analysis--Product limit analysis
=1-probability of not developing the disease in any of the time intervals
•Cox proportional Hazards model
•Kaplan Meier
To Measure Degree of Association
•Risk Ratio=cumulative incidence in intervention / cumulative incidence in control
•A risk ration of 0.5 says that the risk of disease in the intervention is half that of the controls
•RR=1 exposure does not increase risk of disease
•RR<1 exposure appears to be protective
•RR>1 exposure increases the risk of disease
•Risk ratio is a relative and not an absolute measure
Power and Sample size
•The larger the sample size of a study the more likely you are to see an intervention and disease association, given that the association really exists
•The power of a study is the probability of finding a statistically significant assoc in the data, given that the assoc really exists in the study population
What must be specified in order to estimate the sample size needed in a randomized trial?
1. the difference in response rates to be detected
2. an estimate of the response rate in one of the groups
3. level of statistical significance (alpha)
4. the value of the power desired (1-beta)
5. whether the test should one-sided or two-sided
alpha
=probability of making a type 1 error
=probability of conducting the treatments differ when in reality they do not differ
beta
=probability of making a type II error
=probability of concluding that the treatments do not differ when in reality they do differ
Power
Power = 1-Probability of making a type II error

=1-beta
=probability of correctly concluding that the treatments differ
=probability of detecting a difference b/t the treatments if the treatments do in fact differ
Crossover Designs
•Any change of treatment for a patient in a clinical trial involving a switch of study treatments
•In planned crossovers a protocol is developed in advance, and the patient may serve as his or her own control
•Unplanned crossovers exist for various reasons, such as patients request change treatment

•Planned crossover:
-each patient is his/her own control
-time for washout is important
-change order of two assignments

•ex, randomize population into surgical treatment and medical treatment--small portion of surgical treatment group refuse treatment and a portion of medical treatment require surgery--switch or cross these over
Factorial Design
Assuming that two drugs or 2 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
-ex. randomize into two groups--Aspirin and Placebo
--both of those groups are randomized into two other groups: beta-carotene and placebo
Non-compliance
Many patients will agree to randomization but do not comply with the assigned treatment
Efficacy
=[(Rate in those who received placebo)-(Rate in those who received the vaccine)] / Rate in those who received the placebo
Number Needed to Treat
NNT= 1/[(Rate in untreated group)-(Rate in treated group)]

-Thus, if for ex, the mortality rate in the untreated group is 17% and mortality in the treated group is 12%, we would need to treat 1/(17%-12%) = 1/0.05 = 20
MRFIT Study
•Special intervention
-hypertension treatments
-intensive counseling and education about lifestyle changes
•Usual care as comparison
FDA Required Clinical Trials
•Phase I - Clinical pharmacology studies of 20 to 80 people--look for toxicology and efficacy
•Phase II - Clinical investigations of 100-200 people for efficacy and relatives safety
•Phase III - Large scale RCT for effectiveness and safety
•Phase IV - post marketing surveillance
Ethical Considerations
•Is randomization ethical--yes if we don't know RX will work
•Is it ethical to randomize--yes or we may use ineffective treatments on patients
•Can patient really provide informed consent
•Should a trial be stopped earlier than originally planned
•Should a placebo be used
Ethical Aspects of Human Experimentation
•Benefits must outweigh risks
•Ethical issues:
-Informed consent
-Withholding treatment
--sequential designs are used as a solution
-Monitoring for side effects
--can be circumvented by using animals
-Deciding when to withdraw a patient
-Protecting the interests of patients
Summary of Clinical Trials
•Strengths:
-Provide the greatest control over:
--the amount of exposure
--the timing and frequency of exposure
--the period of observation
-Ability to randomize reduces the likelihood that groups will differ significantly

•Limitations:
-Artificial setting
-Limited scope of potential impact
-Adherence to protocol is difficult to enforce
-Ethical dilemmas
Community Trials
•Community intervention trials determine the potential benefit of new policies and programs
•Intervention: any program or other planned effort designed to produced changes in a target population
•Community refers to a defined unit, e.g. a country, state, or school district
•Start by determining eligible communities and their willingness to participate
•Collect baseline measures of the problem to be addressed in the intervention and control communities
•Use a variety of measures, e.g., disease rates, knowledge, attitudes, and practices
•Communities are randomized and followed over time
•Outcomes of interest are measured
Summary of Community Trials: Advantages
Represent the only way to estimate directly the impact of change in bx or modifiable exposure on the incidence of disease
Summary of Community Trials: Disadvantages
•Inferior to clinical trials with respect to ability to control entrance into study, delivery of the intervention, and monitoring of outcomes
•Fewer study units are capable of being randomized, which affects comparability
•Affected by population dynamics, secular trends, and nonintervention influences