Chapter 7

Meet predetermined eligibility rules

-Inclusion criteria -Exclusion criteria

NATURE OF COMPARISON GROUP

-Usual care -Other doses of same treatment -Other treatments -Placebo (inert agent that looks indistinguishable from active agent)

Size of block:

2 treatments--4 or 6

What is randomization?

A process by which the investigator assigns subjects to treatment and comparison groups. Subjects have and equal chance of being assigned to ethier the treatment or comparison group

Penalty of non-uniform ascertainment of outcome is

BIAS

Randomization & Comparability Randomization assures that groups are balanced

Balances both measured and unmeasured variables Balances groups only at baseline

Assure relatively equal number of patients to each treatment

Blocking

arranging experimental units in groups (blocks) that are similar to one another, controls for nuisance factors

Blocking

Ensures balance in the mix of treatment groups with regard to the time of enrollment & reduces the effect of secular trends

Blocking:

what do we need for an trial to demonstrate a true effect

Compliance

Should be random assignment

DEFINITION: Each individual has the same chance of receiving each possible treatment

Types of admissibility criteria

Demographic (e.g., age, sex, race) Prior condition (e.g., free of disease) Risk factor restriction (e.g., non-smokers)

Sample Size

Determine if there is a true difference between treatment & comparison group -Sufficient sample size to detect a difference if one is truly present -Expected difference -Baseline rate of the outcome -Probability of type 1 and type 2 errors

Neither subjects nor investigators know who is receiving treatment or placebo

Double blind

balanced doubt

Equipoise

Ethical issues in experimental studies

Equipoise: Must be genuine doubt about efficacy of treatment yet sufficient belief that it may work

Called trials (from the French trier - to try)

Experimental Studies

What are the gold standard of epidemiological research. They have high status and validity, and can pick up small and modest effects

Experimental Studies

Subjects improve an aspect of their behavior being experimentally measured simply in response to the fact that they are being studied, not in response to any particular experimental manipulation.

Hawthorne effect

Consider the Multiple Risk Factor Intervention Trial (1982) -- MRFIT

Health education and interventions vs. no special intervention in prevention of CVD Treatment group experienced dramatic declines in CVD, but so did the control group Rates were declining in all groups over time in all groups Effect of the intervention was negligible

Characteristics of volunteers -

How does study population differ from total experimental population?

Would this be considered indivisidual or community Do women with stage I breast cancer given a lumpectomy alone survive as long without recurrence of disease as women given a lumpectomy plus radiation?

Individual

what is the Unit of treatment assignment

Individual Trials: treatment is allocated to the individual Community Trials: treatment is allocated to a community, not an individual

how can you categorize experimental studies

Individual versus community (treatment allocated to individual OR entire community)

Type of prospective cohort study in which exposure is allocated by investigator

Intervention Study:

The physiologic, behavioral and cultural characteristics of the study population

Limitations to generalizability

Simple randomization

Low tech High tech

Assure equal distribution of both..

Measured/known confounders Unmeasured/unknown confounders

bias relative risk towards the null value

Noncompliance

makes the compared groups more alike with respect to treatment, which reduces the ability of the investigator to detect a difference between the group

Noncompliance

Allocation of Study Regimens

Optimal way is randomization (treatment group allocated at random, by computer or table of random numbers)

Treatment groups must not differ in ways other than the exposure being studied

Otherwise, effects of the exposure will get mixed up (confounded) with these unbalanced factors

What is the method of treatment in experimental studies

Parallel: Two or groups, each with different treatment Cross-over: Treatment groups change treatment mid-study

An inactive substance otherwise identical to the experimental compound

Placebo

Permits blinding (masking) of health care providers, investigators, participants

Placebo

Useful when ascertainment of outcome is subjective

Placebo

are used to make the groups as comparable as possible (recall laboratory experiment).

Placebo

When a beneficial effect is produced by an inactive control treatment, thought to arise from the power of suggestion

Placebo effect

What is the purpose of Experimental studies

Prevention: To prevent the occurrence of disease Therapeutic: To treat disease or illness

Does tamoxifen lower the incidence of breast cancer in women with high risk profile compared to high risk women not given tamoxifen?

Preventive (prophylactic agent given to healthy)

what is the difference between preventive and therapeutic trials

Preventive trials investigate measures that stop or delay the onset of disease ; therapeutic trial investigate measures that treat exisiting disease.

Monitor groups for occurrence of outcomes

Primary outcome - Main condition trial is evaluating, used for sample size calculations Secondary outcomes - Less important

To avoid or minimize bias in ascertainment of outcome (particularly important if outcome assessment is subjective)

Purpose of blinding:

Toss a coin for each subject: heads=A, tails=B But cannot assure equal numbers per group or balance

Random Allocation

As each subject enrolled, assigned a number from the random number table Assign even numbers to treatment A and odd to treatment

Random allocation

How can you avoid lack of baseline comparibility

Randomize a large number of study subjects

RCTs are optimal to detect effects of drugs or interventions that are statistically small to moderate in size, but clinically worthwhile. Every design feature is to minimize bias and confounding.

Randomized Clinical Trial (RCT)

Type of cohort study in which the participants are allocated by the investigator to receive one of the exposures or treatments under study.

Randomized Clinical Trial (RCT)

Selection of Study Population

Reference population - general group to whom results of a trial should be applicable (all humans, or some restrictions may apply) Study or experimental population - people who are considered for enrollment in a trial, potential participants

eligibility criteria

Restriction of study to individuals with certain characteristics Facilitates comparability via homogeneity

what is the number of treatments to be tested within an experimental study

Simple: One treatment Factorial: Two or more treatments

Subjects do not know if they are receiving treatment or placebo

Single blinding

How many endpoints (outcome under study) are expected

Size, size, size - not just number of people in the trial, but...

participants are grouped into "strata" of some confounding factor prior to randomization

Stratification:

Restrictions on who is eligible (eligibility criteria)

Substantive: What group are you interested in? Logistics: What group is accessible? Who will comply with study protocol? How feasible is complete and accurate follow-up on the subjects?

Must provide a proper baseline for comparison

The control group

may receive no intervention, an inert intervention (placebo), or an alternative treatment

The control group

provides a baseline by which to gauge the effects of the treatment

The control group

Reference population

The group os people to whom the study results may be applied or generalized

what is the only difference in an labortory experiment?

The only difference is the test agent

How are the results assesed within an experimental study?

The results are assessed by rigorous comparison of rates of disease, death, recovery, or other appropriate outcome in the study and control groups, respectively.

Run-in period

The run in period occurs before enrollment and randomization to determine which participants are able to comply with the study regimen. Pitencial participants are able to comply with the study regimen. Potencial participants are placed on the test control treatment for a certain period of time to asses their tolerance to acceptance of the treatment and to obtain info on compliance.

Single-masked study

The study subject does'nt know whether he or she is in the treatment or comparison group

Why are experimental studies difficult to conduct?

They are expensive to conduct, physician and patients may be reluctant to participate and a state of equipoise must exist.

what distintive features of experimental studies enhance their ability to produce scientifically rigorous results?

They are unique feature includeing random assignment of subjects to treatmetn and comparison groups to control for confounding and to reduce biased allocation, and the use of placebo controls to permit masked assessment of the outcomes

what is the intent to treat analysis?

This includes all people who were randomly allocated to the treatment and comparison groups, reguardless of whether they completed or even recieved their assigned regimen. This type of analysis preserves the baseline comparibility and gives information on the effectivness of the treatment under real life conditions.

How many types pf trials are there?

Three: 1) Clinical-apply therapeutic interventions to sick individuals (e.g., chemotherapy trial) 2) Felid -apply preventive interventions to healthy individuals (e.g., vaccine trial) 3) community-apply interventions to aggregate units (e.g., fluoridation of public water)

Neither subjects nor investigators nor individuals assessing the outcome know who is receiving treatment or placebo

Triple blind

Shifts in equipoise over the course of the trial

What if it becomes apparent, before the trial is over, that the new treatment is beneficial (and should not be withheld from the placebo group) or is toxic (and treatment should be withdrawn)?

Widest possible generalizability Sufficiently high event rate (for power to be adequate) Population in whom intervention likely to be effective and safe Ease of recruitment Likelihood of compliance with treatment and F/U

Who to Study: Factors to Consider for Inclusion/exclusion

What is an sham procedure

a bogus procedure that is designed to resemble a legitimate one

what is an placebo

an inactive substance , sugar coated pill that is given as a substitute for an active substance.

Ascertainment of outcome must

be standard, uniform, reproducible and valid.

How are the placebo and sham the same

both placebo and sham procedures permit the study participants and caregivers to be masked

Would this be considered indivisidual or community Does fluoride in the water supply decrease the frequency of dental caries in a community compared to a similar community without such water treatment?

community

Study requires active participation and cooperation of participants, but what will occur related to side effects, illness, level of interest, and length of follow-up.

deviations from the protocol

Are these good or bad controls: Concurrent Independent

good

Are these good or bad controls: Have same baseline risk as the treatment group Are observed in same way as the treatment group

good

what is the difference between individual and community trials

individual= the treatment is allocated to a particular people, in community trials they are allocated to the entire community

what is an Equipoise

is a state of mind characterized by genuine uncertainty about the appropiate course of action, to give or withhold a particular treatment

what are the Disadvantages of blocking

is that participant allocation may be predictable (in unblinded trials)

does randomiszation work better with larger or smaller groups?

larger groups

Biased information on the outcome

mask investigators to group assignment

Alternate assignment of treatments

non-random allocation

Assignment by day of the week

non-random allocation

Experimental population

population in whom study is done

REFERENCE POPULATION

population to whom results generalizable

Known and unknown confounders are on average distributed equally among the study groups

randomization

Minimizes selection bias and confounding

randomization

Other assignment schemes, or use of historical comparison group, have potential problems

randomization

Strength is unpredictability

randomization

Works "on average" - so if going to do a trial, do it big

randomization

An experiment in which subjects are randomly allocated into groups, usually called :

study and control groups, to receive or not to receive an experimental preventive or therapeutic procedure, maneuver, or intervention.

what randomization can accomplish:

the equal distribution of known and unknown factors (confounders) that are relevant to response to the treatment.

Do combinations of two or three antiretroviral drugs prolong survival of AIDS patients as well as regimens of single drugs?

therapeutic( treatment given to diseased individual to reduce risk of recurrence, improve survival, quality of life )

"How many of your pills did you take?" "Did you watch the program?" "How much of the manual did you read?"

what we should ask when conducting and compliance

PARTICIPANTS

willing and eligible

How can you avoid Low compliance

you would have to exclude subjects who might have a hard time complying, and present a realistic picture of the required task at enrollment, maintain frequent contact with study subjects, and use item such as pill packs to make it easier to comply with the treatment regimen