HLTH 207 Week 4 - Randomized Controlled Trials

How is the sample population of a controlled trial selected?

Selected from source population

Requirement for sample population of controlled trial

Sample populations must be individuals who are at-risk of the outcome of interest

General process of controlled trial

• Same population is assigned to an exposure, either an intervention group or control group

• Then, they are followed forward in time to observe who develops the given outcome of interest

2 measures of outcome frequency used in randomized controlled trials

Risk and/or rate

2 measures of association used in randomized controlled trials

Risk and/or rate ratios and differences

4 basic steps in designing and conducting a randomized controlled trial

1. State the research question

2. Design the trial

3. Conduct the trial

4. Analyze and report data

2 aspects of stating the research question

1. State the trial study hypothesis

2. Define the exposure condition (both exposed and unexposed and define outcome(s) with case definitions

Aspect of designing a randomized controlled trial

Determine the randomization strategy, select the type of trial, and decide whether there will be masking

3 aspects of conducting a randomized controlled trial

1. Select subjects from an at-risk source population and obtain informed consent

2. Allocate subjects to exposure groups with concealment

3. Follow subjects and collect data on incident outcome as well as key covariates

3 aspects of analyzing and reporting the data from a randomized controlled trial

1. Calculate measures of frequency and association from an intention-to-treat analysis and/or a per-protocol

2. Report findings using the CONSORT reporting guidance

3. Consider the strengths and limitations of the study

What is the exposure condition comprised of

The arms of the trial (there can be more than 2)

2 common arms of a study

1. Exposed group(s): intervention or treatment group(s)

2. Unexposed group: control

2 types of exposure that may be evaluated in a trial

1. Preventative exposure

2. Therapeutic exposure

Preventative exposure

administered to those who are at-risk of health outcome(s) to assess whether the exposure can reduce the frequency of incident negative health outcomes

3 examples of preventive exposure

1. Vaccines

2. Exercise programs

3. PrEP

Therapeutic exposure

administered to those who have health outcome(s) to assess whether the exposure can improve their health status

3 examples of therapeutic exposure

1. Chemotherapy

2. Beta blockers

3. Antibiotics

Control group

either receives a placebo or standard of care option

Standard of care

standard therapeutic or preventive option, if one exists

Placebo

inert or fake control group (sugar pill, saline injection, etc.)

In a randomized controlled trial, should a placebo or standard of care (if it exists). Why?

• Standard of care

• Participants in a trial should not be denied an existing, effective preventive or therapeutic option

1985 randomized controlled trial that did not utilize standard of care

A 1985 randomized controlled trial of ivermectin to treat onchocerciasis (river blindness) used a placebo control arm even though the drug diethylcarbamazine had been used as a standard of care for several decades

1992 randomized controlled trial that did not utilize standard of care

Another trial in 1992 evaluated the antidepressant drug paroxetine in patients with severe depression, and the control group was given a placebo over other antidepressants

What piece of legislature required that a standard of care be used as a control if it exists?

1996 revisions of Declaration of Helsinki specified that control groups in clinical research should be offered the best standard of care, if one exists

How does using a placebo instead of a standard of care for the control group affect data analysis?

Association will be stronger when compared to the placebo than to the standard of care

Placebo effect

participants report benefit from just receiving an intervention (regardless of whether the intervention itself truly has a clinical benefit)

Example of placebo effect

IBS patients were told they were receiving placebo, but still reported improvement due to their beliefs around mind-body self-healing process

Function of placebo arm

the use of a placebo control arm allows investigators to estimate the effect of an intervention above and beyond any benefits derived from the act of receiving an intervention

3 types of trial hypotheses

1. Superiority trial

2. Non-inferiority trial

3. Equivalence trial

Superiority trial question

Is the intervention better than the control?

Function of superiority trial

If no standard of care exists, or the current standard of care is not very effective, we may want to demonstrate that the new intervention is better than control

What data indicates that the intervention is better than the control?

• The frequency of negative health outcomes in the intervention group is meaningfully lower than the control group

• Measures of association fall below the null

Non inferiority trial question

Is the intervention at least as beneficial as the control?

Function of non-inferiority trial

If a new intervention could conserve resources or was less invasive relative to control, we may want to demonstrate that it is not worse than control

What data indicates that the intervention is at least as beneficial as the control?

• Frequency of negative health outcomes in the intervention group is not meaningfully higher than the control group

• Measures of association fall slightly above or below the null

Equivalence trial question

Is the intervention similar to the control?

Function of equivalence trial

Compares two or more options (therapeutic or preventive) when some patients, providers, or other stakeholders may prefer one over another

What data indicates that the intervention is similar to the control?

• Frequency of negative health outcomes in the intervention group is similar to that of the control group

• Measures of association are not meaningfully different from the null

How are exposures assigned in controlled trials? Why?

randomization, which makes it so that no individual is more (or less) likely to be allocated to a given exposure condition than anyone else

Goal of randomization

yield exposed and unexposed groups that are comparable on all factors except for the exposure status

Confounding error

 systemic error when one or more external factors can explain the observed association between an exposure and health outcome

How does randomization correct for confounding error>

On average, randomization creates comparison groups that are balanced for all confounders

2 randomization techniques

1. Simple randomization

2. Stratified randomization

Simple randomization

study participants are randomly assigned to an exposure condition

Strength of simple randomization

relatively straightforward process (analogous to assignment by flipping a fair coin)

Weakness of simple randomization

may still produce imbalances in confounding factors between study arms if the sample size is small

Stratified randomization

study participants are first grouped by important potential confounders, then assigned to exposure conditions within those groups

Strength of stratified randomization

potential confounders that are stratified on are balanced across trial arms

Weakness of stratified randomization

 stratification by other important confounders (those not stratified on) may not be possible if sample sizes are small

2 possible units of randomization

1. Individual randomization

2. Cluster randomization

Individual randomization

each participants is individually randomized to an exposure condition

Cluster randomization

groups of individual are randomized to an exposure condition

When is cluster randomization useful?

Useful when individual level exposure is not possible (i.e. school or household-based interventions)

Risk (exposed) calculation based on 2×2 table

 A/N1 = number of incident cases in an exposed at-risk population during a follow-up period/number of individuals in the exposed at-risk population at the beginning of the follow-up period

Risk (unexposed) calculation based on 2×2 table

B/N0 = number of incident cases in an unexposed at-risk population during a follow-up period/number of individuals in the unexposed at-risk population at the beginning of the follow-up period

Risk ratio calculation

risk in the exposed/risk in the unexposed = (A/N1)/(B/N0)

Risk ratio interpretation structure

The [length of follow-up] risk of the outcome in the exposed is RR times the risk of the outcome in the unexposed

Risk difference calculation

risk in the exposed - risk in the unexposed = (A/N1) - (B/N0)

Risk difference interpretation structure

The difference in the  [length of follow-up] risk of the outcome in the exposed versus the unexposed is RD

Positive risk difference interpretation

the risk is higher among those who are exposed (the additional/excess risk of an outcome due to exposure)

Negative risk difference interpretation

the risk is lower among those who are exposed (the reduction in risk of an outcome due to exposure)

Rate (exposed) calculation

A/PT1 = number of incident cases in an exposed at-risk population during a follow-up period/person-time contributed by those in the exposed at-risk population during the follow-up period

Rate (unexposed) calculation

B/PT0= number of incident cases in an unexposed at-risk population during a follow-up period/person-time contributed by those in the unexposed at-risk population during the follow-up period

Rate ratio (IDR) calculation

 rate in the exposed/rate in the unexposed = (A/PT1)/(B/PT0)

Rate ratio interpretation structure

The rate of the outcome in the exposed is IDR times the rate of the outcome in the unexposed

Rate difference (IDD) calculation

rate in the exposed - rate in the unexposed = (A/PT1) - (B/PT0)

Rate difference interpretation structure

The difference in the rate of the outcome in the exposed versus the unexposed is IDD

2 types of analysis

1. Intention to treat

2. Per protocol

Effectiveness

measures the ability of an intervention to prevent or treat the outcome among those randomized, whether or not they actually adhere to the assigned trial arm

What does effectiveness esimtae?

Estimates the benefit of an intervention closer to a real-world setting

Analysis type used when assessing effectiveness

Intention-to-treat - includes all randomized individuals, regardless of their adherence to their assigned trial arm

Efficacy

measures the ability of an intervention to prevent or treat the outcome only among those who adhere to their assigned trial arm

What does efficacy estimate?

Estimates the true etiologic benefit of an intervention

Analysis type used when assessing efficacy

Per-protocol - only includes individuals with perfect adherence to their assigned trial arm

An intervention that is not efficacious ________ (can/cannot) be effective

cannot

What 2 substances does the FDA regulate?

1. Prescription drugs

2. OTC drugs

When/at what stage does the drug testing process begin

The process begins at the preclinical phase with in vitro or in vivo animal model studies

Phase 0 of clinical phase of drug testing

evaluate pharmacokinetics and pharmacodynamics among smaller numbers of healthy participants

Phases I, II, and III of clinical phase of drug testing

evaluate safety, side effects, efficacy, and effectiveness among progressively larger number of healthy participant and progressing to larger groups including those who may have the condition or be at risk for the outcome

Phase IV of clinical phase of drug testing

occur after FDA approval and can include an even larger number of participants, find new markets, and assess longer-term outcomes

Randomization ethics principle

It is not ethical to randomize participants to receive exposures known to be harmful

Epiquoise definition and should a trial have it?

• the interventions tested should not already be known to be inferior or superior relative to control prior to the trial

• Yes, a study should have this

Protocol for a controlled trial in relation to harm vs. benefit principle

The protocol for a controlled trial should include stopping rules to halt the trial when risks outweigh benefits, there is not enough statistical power, and/or when the benefit or inferiority of the intervention is established

What 2 issues should be considered when conducting trials in underserved population?

1. Literacy

2. Coercion

There is a debate about whether trial participants should be receive _________________________ after the trial

guarenteed access to beneficial interventions

What type of reporting guidance is an accepted standard way to report clinical trials?

CONSORT reporting guidance

4 strengths of controlled trials

1. Temporarily between exposure and outcome is established by design because participants are assigned an exposure and followed forward in time to see whether the outcome develops (i.e. the exposure is known to precede the outcome in time)

2. Masking can minimize bias in how study procedures are conducted and/or how outcomes are ascertained or analyzed]

3. Randomization (with allocation concealment) can minimize bias due to confounding

4. Well-suited for studying rare exposures since the investigators assign the exposure conditions

4 limitations of controlled trials

1. Potential for loss to follow-up which could lead to selection bias

2. May not be well-suited to the study of rare outcomes and outcomes that take a long time to occur

3. Expensive, time-consuming, resource intensive, and require specific ethical considerations

4. May have limited generalizability to other populations or non-trial settings