Clinical trials can be classified by design. This classification is more descriptive in terms of how patients are randomized to treatment.
There are several types of trial designs which are as follows:
· Non-randomised controlled trials – is a trial where the participants are assigned to the treatment by a method that is not random. The investigator defines and manages the alternatives.
In a non-randomised study, participants are allocated into control or treatment arms by a method that is not random. The investigator defines and manages the alternatives.
It is appropriate to use a non-randomised controlled trial design when randomisation may be unethical, not suitable due to legal or political challenges or when it is impractical in terms of cost and convenience.
There are many possible types of non-randomised controlled trials that do not use appropriate randomisation strategies (sometimes called quasi-randomised studies).
Non-randomised controlled trials have the potential to study two groups that are not strictly comparable. However, there are different types of controls that can be used in non-randomised trials:
a) Concurrent controls: the treatment and control group participants are matched based on demographic and other characteristics. They receive different treatments at the same time.
b) Historical controls: the investigators compare outcomes among a group of participants who are receiving a new treatment (experimental group) with outcomes among participants who received standard treatment in a previous period (control group).
All participants receive the medicine being studied; the results are either compared to the patient's history (for example a patient living with a chronic illness) or a previous study control group.
c)
· Randomised controlled trials - is a trial where the participants are randomly allocated to one or another of the different treatments under study. They can be:
o Parallel group
o Cross-over
Randomization in clinical trial:
Randomisation is the process of making something random, by chance. This can be applied in:
• Selecting a random sample of a population.
• Allocating units to different conditions with no order
In clinical trials, randomisation refers to the process of assigning a trial participant into treatment or control groups (or arms) using an element of chance to determine the assignments. This procedure is made in order to reduce bias.
The assignment can be done using different tools, such as closed envelopes, random numbers, scratch sheets, computer generated sequences and contacting interactive voice recognition systems (IVRSs).
There are two components to randomisation:
a) the generation of a random sequence
b) Implementation of the random sequence, ideally in a way so that participants are not aware of the sequence.
RCT:
- Participants are randomly allocated between treatment and control groups.
- Randomisation removes potential for bias.
- There are different types of randomised trial designs:
1. Factorial design trials
2. Withdrawal trials
3. Parallel group trials
4. Cross-over trials
• Randomisation is the process of making something random, by chance. This can be applied in: Selecting a random sample of a population; or allocating units to different conditions with no order. In clinical trials, randomisation refers to the process of assigning a trial participant into treatment or control groups (or arms) using an element of chance to determine the assignments. This procedure is made in order to reduce bias. The assignment can be done using different tools, such as envelopes, random numbers, scratch sheets, computer generated sequences and contacting interactive voice recognition systems (IVRSs).
• From trial inclusion criteria, there is equal allocation with regard to gender, age and health status. It removes the potential of bias in the allocation of participants and tends to produce comparable groups, however it cannot eliminate accidental bias.
There are different types of randomised trial designs:
• Factorial design attempts to evaluate two interventions compared to a control in one trial. Each participant receives two different medicines: x and y; x and control; y and control; control and control.
• In withdrawal trials, participant receives a test treatment for a specified time and are then randomised to continue the test treatment or placebo (withdrawal of the active therapy).
• In parallel group trials each participant is randomly assigned to a group, and all the participants in the group receive (or do not receive) an intervention.
• In cross-over trials, over time each participant receives (or does not receive) an intervention in a random sequence.
· Single blind - a study in which one party, either the investigator or participant, is unaware of what medication the participant is taking; also called single-masked study.
· Double blind - a clinical trial design in which neither the participating individuals nor the study staff knows which participants are receiving the experimental treatment and which are receiving a placebo or comparator. Double-blind trials produce objective results, since the expectations of the doctor and the participant about the experimental medicine do not affect the outcome; also called double-masked study.
· Superiority Trial
· Non-inferiority Trial
In a clinical trial design, there are a number of different types of comparisons that can be included:
1. Superiority comparison trials demonstrate that the investigational medicine is better than the control.
2. Equivalence comparison trials demonstrate that the endpoint measure is similar (no worse, no better) to the control.
3. Non-inferiority comparison trials demonstrate that the investigational medicine is not worse than the control.
4. Dose-response relationship trials demonstrate various dose parameters including starting dose and maximum dose.
When the aim of a randomised controlled study is to demonstrate that one treatment is superior to another, a statistical test is employed and the trial is called a superiority trial. Often a non-significant superiority test is wrongly interpreted as proof of no difference between the two treatments. With statistical tools, at most one can show that they are equivalent. This type of study design is often used to test the effectiveness of a treatment compared to placebo.
In an equivalence trial, the statistical test aims at showing that two treatments are not too different in characteristics. These trials are designed to demonstrate that one treatment is as effective as another.
Finally, a non-inferiority trial is designed to demonstrate that a treatment is at least not (much) worse than a standard treatment. Non-inferiority comparison trials are often used for efficacy studies and the control is a medicine already on the market.
Dose-response relationship trials are a class of trials that determine an optimal dose of a specific medicine. The dose response of a medicine is important in pharmacology, pharmacokinetics, toxicology and clinical research. Dose response studies may be part of larger research to develop new treatments or to supplement existing knowledge of a medicine whose benefits may have already been established.
Dose-response relationship comparison studies investigate:
• The shape and location of the dose-response curve
• The appropriate starting dose
• The optimal strategies for individual dose adjustments
• The maximal dose beyond which additional benefit would be unlikely
A parallel design is where two groups of treatments, A and B, are given so that one group receives only A, while another group receives only B throughout the trial. Participants are randomised into different study arms, but there is approximately an equal number in each group.
The statistical mean of each group is then compared, and unexplained variability is attributed to between patient differences (age, weight, disease severity)
The parallel design is the most common design for clinical trials. However, when participants are randomised, there are practical considerations to take into account. For example, missing data over time may lead to some participants not being included in the final analysis.
| Advantages | Challenges |
| Can be applied to almost any disease | Homogenisation of the groups (Especially where different geographical locations are used) |
| Any number of groups can be run simultaneously |
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| Groups can be in separate locations |
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A parallel study is a type of clinical study where two groups of treatments, A and B, are given so that one group receives only A while another group receives only B. Other names for this type of study include "between patient" and "non-crossover".
This is unlike a crossover study where at first one group receives treatment A and later followed by treatment B while the other group receives treatment B followed by treatment A. There are, however, certain characteristics that allow for differentiation between these two types of trials. For example, a parallel study would be more appropriate if any concerns about carryover effects were present. This type of study might also be more beneficial if the disease or disorder being studied has a likely chance of progression during the time in which the study takes place. One significant issue with parallel studies, though, is the concept of intra subject variability, which is defined as variability in response occurring within the same patient.
The two treatment groups in a parallel study can either consist of two completely separate treatments (i.e. different drugs), or simply different doses of a common drug. One major aspect of a parallel study is randomization – this ensures that the results are accurate and have a lower risk of being biased. Control groups utilizing a placebo, or active control, are often used in this type of study.
The most common design is the parallel-group trial. Patients are randomized to the new treatment or to the standard treatment and followed-up to determine the effect of each treatment in parallel groups. Other trial designs include, amongst others, crossover trials, factorial trials, and cluster randomized trials.
· Crossover trials randomize patients to different sequences of treatments, but all patients eventually get all treatments in varying order, ie, the patient is his/her own control.
In a cross-over clinical trial design, participants receive a sequence of different treatments. For instance: Patient X and Y are randomised into two different treatment groups. Patient X receives Treatment A during the first period of the study; Patient Y receives Treatment B. After the first period is over, there is a washout period. Patient X then receives Treatment B for the second period of the study while Patient Y receives Treatment A.
Each treatment starts at an equivalent point, and each individual (with a stable and chronic disease) serves as his/her own control.
Single-patient response to different treatments is compared, normally the variability of response is less than the variability from parallel group designs. It also allows fewer patients, but the study must run for a longer period of time.
| Advantages | Challenges |
| Low variance due to treatment and control being the same | Can only be applied to chronic illnesses as treatments are applied one after the other one |
| Can include a number of treatments |
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· Factorial trials assign patients to more than one treatment-comparison group. These are randomized in one trial at the same time, ie, while drug A is being tested against placebo, patients are re-randomized to drug B or placebo, making four possible treatment combinations in total.
· Matched-pair design:
Randomisation is not always a practical nor ethical method of assigning a participant to a comparison group. For obvious reasons, for example, we cannot assign individuals to wear a seat-belt or not to use it in an attempt to assess the effect of seat-belts in car accidents. In such situations, the method of matched-pair clinical trial design is widely used.
This design can be used when the experiment has only two treatment conditions and participants can be grouped into pairs – matched up to be as similar as possible in order to reduce variability in results.
Matching is typically used in comparative observational studies, in which individuals are either self-selected into identifiable groups (for example, seat-belt wearers and not) or individuals have fixed, pre-determined characteristics that dictate their group membership (for example, males and females). The primary advantage of matching is that biases due to baseline group differences are minimized, thereby reducing the variability, and increasing the precision, of the group comparisons.
Advantages: There is less variability found in results, and it can be applied to most diseases.
Challenges: Based on similarity within the selected groups, the researcher needs awareness of factors that could influence results
Randomisation using stratification
1. Stratification ensures balanced allocation within each combination.
2. Studies can be stratified for more than one factor, for example, age and gender.
3. Common stratification factors include by site, age groups, and previous exposure, gender, and lifestyle factors.
Smokers
|
Non-smokers
|
Participant No
|
Random arm/group
|
Participant No
|
Random arm/group
|
001
|
A
|
003
|
B
|
002
|
B
|
005
|
A
|
004
|
B
|
006
|
B
|
Normally patients would be allocated to a treatment group randomly, and while this maintains a good overall balance, it can lead to imbalances within sub-groups. For example if a majority of the patients who were receiving the medicine happened to be male, or smokers, the statistical usefulness of the study would be reduced.
The traditional method to avoid this problem is to stratify participants according to a number of factors (e.g. age or smokers and non-smokers) and to use a separate randomisation list for each group. Each randomisation list would be created such that after every block of a number of patients, there would be an equal number in each treatment group.
Randomisation using cluster sampling
Cluster randomized trials are performed when larger groups (eg, patients of a single practitioner or hospital) are randomized instead of individual patients.
§ Find suitable geographical areas (e.g. catchment area, city, country, etc.).
§ Randomly choose a number of these geographical areas
§ For each of these chosen geographical areas, choose a proportional subsample from the members of the study population in that area.
§ Combine these subsamples to get a sample group.
Blinding/Masking:
A blind experiment is one in which the subjects who are participating in the study are not aware of whether they’re in the treatment group or the control group. In the zinc example, the vitamin C tablets and the zinc tablets would be made to look exactly alike and patients would not be told which type of pill they were taking. A blind experiment attempts to control for bias on the part of the participants and to ensure that a placebo effect will not affect only the treatment group. (If the example study was not blind, those not taking zinc may not bother to take their pills or may believe they won’t get better because they know they’re not taking the good stuff.)
A double-blind experiment controls for potential bias on the part of both the patients and the researchers. Neither the patients nor the researchers collecting the data know which subjects received the treatment and which didn’t. So who does know what’s going on as far as who gets what treatment? Typically a third party (someone not otherwise involved in the experiment) puts together the pieces independently, and only he knows which subjects received the treatment and which did not. A double-blind study is best, because even though researchers may claim to be unbiased, they often have a special interest in the results — otherwise they wouldn’t be doing the study!
Blinding is a procedure in which one or more parties in a trial are kept unaware of which treatment arms participants have been assigned to, in other words, which treatment was received. Blinding is an important aspect of any trial done in order to avoid and prevent conscious or unconscious bias in the design and execution of a clinical trial.
Blinding to avoid bias
The different parties involved in a clinical trial are all possible sources of bias, including:
- The patient being treated,
- The clinical staff administering the treatment,
- The physician assessing the treatment,
- The team interpreting the results.
All these parties can be blinded to ensure objectivity.
Types of blinding
A clinical trial is called single blind when only one party is blinded, usually the participants. If both participants and study staff are blinded, it is called a double blind study. Triple blinded studies also extend blinding to the data analysts. A trial in which no blinding is used and all parties are aware of the treatment groups is called open label or unblinded.
Table listing the different types of blinding
Type
|
Description
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Unblinded or open label
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All parties are aware of the treatment the participant receives
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Single blind or single-masked
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Only the participant is unaware of the treatment they receive
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Double blind or double-masked
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The participant and the clinicians / data collectors are unaware of the treatment the participant receives
|
Triple blind
|
Participant, clinicians / data collectors and outcome adjudicators / data analysts are all unaware of the treatment the participant receives
|
Unblinding is the disclosure to the participant and/or study team of which treatment the participant received during the trial. The process of unblinding is planned and included in the study protocol. Unblinding a trial is a necessary process to protect participants in the event of medical or safety reasons. There is also a defined process to ‘break the blind’ of a single participant when required.
Difference between Randomized clinical trial and controlled clinical trial:
A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial.
Controlled clinical trial is a clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all.
Difference between treatment group and controlled group:
A control group is used as a baseline measure. The control group is identical to all other items or subjects that you are examining with the exception that it does not receive the treatment or the experimental manipulation that the treatment group receives. For example, when examining test tubes for catalytic reactions of enzymes when added to a specific substrate, the control test tube would be identical to all other test tubes with the exception of lacking the enzyme. The treatment group is the item or subject that is manipulated. In our example, all other test tubes containing enzyme would be part of the treatment group.
Statistical studies often involve several kinds of experiments:
· treatment groups
· control groups
· placebos
· blind and
· Double-blind tests.
An experiment is a study that imposes a treatment (or control) to the subjects (participants), controls their environment (for example, restricting their diets, giving them certain dosage levels of a drug or placebo, or asking them to stay awake for a prescribed period of time), and records the responses.
The purpose of most experiments is to pinpoint a cause-and-effect relationship between two factors (such as alcohol consumption and impaired vision; or dosage level of a drug and intensity of side effects). Here are some typical questions that experiments try to answer:
· Does taking zinc help reduce the duration of a cold? Some studies show that it does.
· Does the shape and position of your pillow affect how well you sleep at night? The Emory Spine Center in Atlanta says yes.
· Does shoe heel height affect foot comfort? A study done at UCLA says up to one-inch heels are better than flat soles.
Most experiments try to determine whether some type of experimental treatment (or important factor) has a significant effect on an outcome. For example, does zinc help to reduce the length of a cold? Subjects who are chosen to participate in the experiment are typically divided into two groups: a treatment group and a control group. (More than one treatment group is possible.)
· The treatment group consists of participants who receive the experimental treatment whose effect is being studied (in this case, zinc tablets).
· The control group consists of participants who do not receive the experimental treatment being studied. Instead, they get a placebo (a fake treatment; for example, a sugar pill); a standard, non experimental treatment (such as vitamin C, in the zinc study); or no treatment at all, depending on the situation.
In the end, the responses of those in the treatment group are compared with the responses from the control group to look for differences that are statistically significant (unlikely to have occurred just by chance).
Placebo controlled trial:
A placebo is a fake treatment, such as a sugar pill. Placebos are given to the control group to account for a psychological phenomenon called the placebo effect, in which patients receiving a fake treatment still report having a response, as if it were the real treatment. For example, after taking a sugar pill a patient experiencing the placebo effect might say, “Yes, I feel better already,” or “Wow, I am starting to feel a bit dizzy.” By measuring the placebo effect in the control group, you can tease out what portion of the reports from the treatment group were due to a real physical effect and what portion were likely due to the placebo effect. (Experimenters assume that the placebo effect affects both the treatment and control groups similarly.)
A term used to describe a method of research in which an inactive substance (a placebo) is given to one group of participants, while the treatment (usually a drug or vaccine) being tested is given to another group. The results obtained in the two groups are then compared to see if the investigational treatment is more effective than the placebo.
