Non-controlled studies (single-arm studies)

The simplest trial design, in which a sample of individuals with the targeted medical condition is given the experimental therapy and then followed over time to observe their response without a control group.

Responses could theoretically be due to the efficacy of the treatment, a placebo effect of an inefficacious therapy, or to a spontaneous or natural history improvement.

When to use non-controlled design

1. When the objective of the trial is to obtain preliminary evidence of the efficacy of the treatment.

2. To collect additional safety data.

3. When the available patient pool is limited and thus it is not optimal to randomize many participants to a control arm.

4. When the natural history of the disease is well understood, placebo effects are minimal or nonexistent, placebo control is not ethically desirable.

5. May be the only (or one of few) options for trials evaluating therapies for which placebos are not ethical and options for controlled trials are limited

6. Have been commonly implemented in oncology trials (Oncology trials often employ a dose at or near the maximum tolerated dose (MTD, known from Phase I trials) to deliver the maximum effect and thus frequently employ single dose trials.)

N.B

When designing single-arm trials, it is important to clearly define the goal or hypothesis of interest.

Limitations of Single-Arm Design

 NOT generally used as confirmation of efficacy.

 The interpretation of the trial results can be complicated despite the design simplicity.

 The inability to distinguish between the effect of the treatment, a placebo effect, and the effect of natural history.

 Would not be good choices for trials investigating treatments for chronic pain because of the large placebo effect in these trials.

It is also difficult to interpret the response without a frame of reference for comparison.

Controlled trials

Definition

Studies that contain more than one group (interventional group VS control group) to know what would have happened to patients if they had not received the test treatment or if they had received a different treatment known to be effective.

Major Purpose of Control Group

Allow discrimination of patient outcomes (for example, changes in symptoms, signs, or other morbidity) caused by the test treatment from outcomes caused by other factors, such as the natural progression of the disease, placebo effect, natural history, observer or patient expectations, or other treatment.

Types of control

1. placebo concurrent control

Placebo is considered as an inactive treatment that is similar to the form of intervention in route, color and shape, sometimes it‖s called a ―sugar pill‖, In fact, it may be in a pill or tablet form, or it may be an injection or a medical device.

2. No-treatment concurrent control

3. Dose-response concurrent control

Which the control is a different dose from the intervention

4. Active (positive) concurrent control

The control is an active treatment for comparison between the two treatments.

5. External control (including historical control)

In which the control group is from a population other than the interventional population (from another setting), it may be in the same time period of the study or earlier time period (historical control).

6. Multiple control groups

In this type, there are multiple types of control such as use of active control and placebo. This design may be useful for active drug comparisons where the relative potency of the two drugs is not well established, or where the purpose of the trial is to establish relative potency.

Types of Controlled Trials

1. According to randomization

Randomization:

Assurance that subject populations are similar in intervention and control groups is best attained by randomly dividing a single sample population into groups that receive the intervention or control treatments.

A. Randomized-controlled trials (The golden standard studies):

 A study design that randomly assigns participants into an experimental group or a control without following a “random” procedure.

 The only expected difference between the control and experimental groups in a randomized controlled trial (RCT) is the outcome variable being studied.

B.

Non - Randomized trials:

 In this design, participants are assigned to different intervention arms without following a “random” procedure but a quasi random manner.

 May be based on the investigator's convenience or whether the participant can afford a particular drug or not.

 Susceptible to bias with patients in the two groups being potentially dissimilar.

 The validity of the results obtained is low.

When to Use a Non-Randomized Trial

 When the act of random allocation may reduce the effectiveness of the intervention.

 Occurs when the effectiveness of the intervention depends on the participant‖s active participation which is influenced by their beliefs and preferences).

 When it would be unethical to do random allocation.

 When it is impractical to do random allocation (e.g. cost or convenience factors).

 When there are legal or political obstacles to random allocation.

2. According to blinding

Blinding:

A procedure in which one or more parties in a trial are kept unaware of which treatment arms participants have been assigned to, i.e. which treatment was received in order to avoid bias.

A. Unblinded or open label:

All are aware of the treatment the participant receives.

B. Single blind or single-masked:

Only the participant is unaware of the treatment they receive.

C. Double blind or double-masked:

The participant and the clinicians / data collectors are unaware of the treatment the participant receives.

D. Triple blind: Participants, clinicians / data collectors and outcome adjudicators / data analysts are all unaware of the treatment the participant receives.