Randomized Control Trial

What is a RCT?

- A type of epidemiological study in which individuals are allocated randomly to receive one of many interventions/treatments (>= 2 treatments). - The intervention is controlled by the investigator. Thus, RCT's are experimental. - RCT's are comparative studies.

What is randomization?

- An approach of allocating subjects, such that each individual has an equal chance of receiving each possible treatment. - Assignment is NOT determined by the investigator, clinicians, or participants. - Assignment is not predictable based on pattern.

Assessing compliance

- Assess compliance if possible through: - Self-report - Pill counts - Biological measures (blood, urine)

When is it ethical to randomize?

- At least two answers to this question: - Uncertainty Principle - Clinical Equipoise - Which is the preferred moral basis of the RCT?

Examples that are not randomized designs

- Dates of birth (odd to group 1; even to group 2) - Hospital record number (last digit; odd to group 1, even to group 2) - Day of enrollment (Monday=Rx; Tuesday=Placebo) -Alternating (first person=Rx, second person=placebo)

Sometimes groups are cluster randomized

- Example: families, schools, towns, hospitals, communities. - Need to worry about contamination in cluster randomization. - Special statistical techniques needed to cope wit the loss of independence of the individual units.

Why blind/mask?

- Exposure status is unknown. - Minimizes bias in assessing outcomes. - Single-blind: subjects unaware of treatment group. - Double-blind: subjects ans investigators unaware. MORE ON SLIDES

Benefits of randomization

- Factors are distributed equally across the groups at baseline. - Not always (especially if N is small)! - Balances both measured and more importantly, non-measured, variables. - Note than risk of imbalance remains event after properly executed randomization. - Note that if randomization has been performed correctly, chance is the only explanation for any observed difference between groups, in which case statistical tests are considered unnecessary.

Importance of compliance and follow-up

- Following assigned protocol for the duration of the study is crucial to demonstrating a true effect. - Noncompliance makes the groups more alike & reduces the ability to detect a difference (bias towards the null). **Noncompliance tends to bias towards the "null" (i.e., minimizes any difference)

What purpose is served by randomization?

- If large and carefully performed, RCT's are particularly useful for assessing moderate or small effects, which may be clinically important. - Random assignment of a sufficiently large number of subjects provides exquisite control over both known and unsuspected confounding factors. - A large sample size increases the ability to identify modest, but significant differences.

Concealment of allocation

- If those making the decision about patient eligibility are aware of the arm of the study to which the patient will be allocated --if randomization is unconcealed-- they may systematically enroll sicker-- or less sick-- patients to either treatment or control groups. - This will defeat the purpose of randomization and the study will yield a biased result.

Stratified randomization

- Individuals are identified based on important covariates (sex, age, etc.) and then randomization occurs within the strata.

IRB Approval

- Institutional Review Board approval is required for ALL research involving human subjects (not just clinical trials). - "Human Research" means a systematic investigation involving living humans, designed to develop or contribute to generalizable knowledge.

How is randomization achieved?

- Involves two steps: 1. Generating the allocation sequence. 2. Implementing the allocation. - Although both are important, there is evidence that concealment of allocation is more critical.

Why use a placebo?

- It minimizes bias in assessing outcomes. - It makes groups as comparable regarding the perception of treatment. - It allows "blinding." (not always possible).

Informed Consent

- Obtained informed consent PRIOR to randomization. - Informed about: 1. Treatments 2. Potential outcomes; risks/benefits 3. Randomization (i.e. treatment is not their choice). 4. What is required of them

Types of randomization

- Simple randomization - Restricted randomization - Stratified randomization

Clinical Equipoise

...

The Uncertainty Principle

...

Simple randomization

Analogous to a repeated fair coin tossing.

The purpose of a double blind study is to....

Avoid observer and subject bias

The major purpose of a random allocation in a clinical trial is to...

Ensure that the study groups have comparable baseline characteristics.

Restricted randomization

Example: blocking - Done to ensure equal balance of arms throughout all portion of the study. - For example, blocks of six would have 3 active/3 controls. - Block size itself can/should vary.

An advertisement in a medical journal stated that "2000 subjects with sore throats were treated with our new medicine. Withing 4 days, 94% were asymptomatic." The advertisement claims that the medicine was effective. Based on the evidence given above, the claim may be correct or incorrect. Why?

Maybe incorrect because no control or comparison group was involved.

What elements of a trial can be randomized?

Most common unit is individual patient.

Blinding vs. concealment of allocation

READ SLIDES

How many to invite?

Read slides

Tips for ensuring compliance and follow-up

Read slides

Single-blind

The participants (usually) or the investigators assessing outcome (alternately) do not know the assignments.

Triple or quadruple blinding

Three or four of the relevant groups (prior slide) are not aware of the treatment assignment.

Double-blind

Two groups do not know- usually it is the participants and the outcome assessors/investigators