CLINICAL STUDIES

Clinical Trials

Simply put, clinical trials are experimental studies on humans. Their purpose is to determine how effective a certain treatment is in patients with a certain diagnosis. Results from a sample of patients are used to draw conclusions on a population of present and future patients.

Most clinical trials are conducted by pharmaceutical companies to investigate the effects of certain drugs. However, clinical trials may also be used to investigate other modes of treatment, like surgery, counseling, or radiation therapy.

Blinding Definition

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.

Types of Blinding and their Effects on Results

The focus of conducting a randomized controlled trial (RCT) is the elimination of bias. Unconscious information bias may be introduced if the investigators or participants are aware of who is getting the intervention and who is not.

 Unblinded or open label: All are aware of the treatment the participant receives.

 Single blinded: A single stakeholder is blinded i.e. they do not know which group the participants have been assigned to or what treatment they are receiving. Usually, the participant is blinded, and only the data collectors and the researchers know which group they’ve been assigned to.

 Double-blinded: Two stakeholders are blinded, usually the participants plus the data collectors OR the researchers. Neither of the two blinded parties knows which group the participant falls in.

 Triple blinded: The participant, the researchers, and the data collectors are all blinded. None of the parties know which group the participant falls in.

Who can be blinded in clinical trials

 Participants in a trial: Awareness of group assignment will influence their behavior in the trial and their responses to subjective outcome measures if participants are not blinded. A participant who is conscious of not receiving active therapy, for example, maybe less likely to conform with the trial procedure, more likely to pursue further treatment beyond the trial, and more likely to exit the trial without presenting outcome results

 Clinicians: Blinded clinicians are far less inclined than unblinded clinicians to shift their behaviors to participants or have preferential care for the active and placebo classes.

 Data collectors and Outcome adjudicators: To ensure unbiased ascertainment of outcomes, blinding of data collectors and outcome adjudicators (sometimes the same individuals) is crucial.

For example, in a randomized controlled study of cyclophosphamide and plasma exchange in multiple sclerosis patients, when examined by blinded neurologists, no successful therapy regimen was superior to placebo, however, there was an obvious advantage from cyclophosphamide, plasma exchange, and prednisone treatment when evaluated by unblinded neurologists

 Data analysts: By selective use and reporting of statistical measures, bias can also be added during the statistical study of the trial. This may be a subconscious process motivated by researchers willing to see a good outcome, but there are profound implications.

Methods to implement blinding

 Placebo: intervention indistinguishable from the experimental intervention

 “Double‐dummy” : design (i.e., comparing active A + placebo B with active B + placebo A)

 Sham surgery: which is a fake surgery that omits the step, is thought to be therapeutically necessary. But, it is ethically controversial in some surgeries where control group patients might be at risk when exposed to operations.

N.B

- Experiments are sometimes simply defined as 'blind' or 'double-blind' and do not indicate who was blinded, which suggests that one or more patients, healthcare professionals, result evaluators, and observers were blinded. Thus, it

Is Far Preferable For Researchers To Explicitly State Which Individuals In The Trial Were Blinded

- As part of the technique, all blinding techniques should be clarified and gain ethical consent from scientific ethics committees.

Importance of blinding

Blinding is used to prevent conscious or unconscious bias in the design of a clinical trial and how it is carried out. It is used to ensure the objectivity of trial results. Lack of blinding has been found to be consistent with more exaggerated predicted intervention results in randomized controlled trials (RCTs), by 9 percent on average. (In a systematic analysis of 250 RCTs found from 33 meta-analyses, researchers noticed a substantial gap in the magnitude of the predicted treatment effect between studies that reported double-blinding relative to nonblinding studies (p = 0.01), with an average odds ratio of 17 percent greater in studies that did not mention blinding.)

The placebo effect is often addressed or regulated by blinding (placebo effect: a mechanism in which a virtual -and ineffective- therapy will often improve the health of a patient, merely because the individual believes it to be helpful. In the placebo effect, anticipation is central.)

In some cases, blinding is not possible such as some surgeries or due to unethical considerations.

Differences Between Allocation Concealment and Blinding

Allocation Concealment Blinding

 Conceals randomization sequences.

 Eliminate selection bias during the process of recruitment and randomization.

 Done when participants enter trials (during the recruitment).

 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.

 Seeks to reduce performance and ascertainment bias after randomization.

 Done after the participants entered the trail (after recruitment)

Allocation of the groups

Differences between sampling and allocation into groups

Random Sampling Random Allocation (Randomization)

The method by which the participants were selected for the trial

Random allocation is how participants were allocated to treatment.

Randomization eliminates accidental bias, including selection bias, and provides a base for allowing the use of probability theory.

It promotes the comparability of the sample groups and provides the basis for statistical inference for the quantitative evaluation of the impact of medication as it is used to create similarity of groups.

Random Allocation Techniques

Simple randomization

It is a process that guarantees Participants in the trial have a fair probability of being allocated to a group of therapies. The techniques of sequence generation by simple randomization procedure include:

 Tossing of a coin

 Die throwing

 Card shuffling

 Using table of random numbers

The major disadvantage of simple randomization is that the treatment groups can, by chance, end up being dissimilar both in size and in prognostic factors; these imbalances might be substantial in small sample trials.

Blocking allocation (random permuted blocks)

It operates by randomizing participants inside blocks such that each therapy is given an equal number.

For example,

With a block size of 4, there is an assurance that the group is balanced each time the 4th patient is enrolled. With a block of size 4, there are six ways in which we can allocate treatments so that two subjects get A and two get B:

Advantages

Treatment groups will be equal in size and tend to be distributed uniformly according to key characteristics related to the results. In time, smaller block sizes will result in more balanced groups than larger block sizes.

Disadvantages

That when the research groups are unmasked, the allocation of participants can be predictable and result in selection bias. That is, the care assignment that has happened so far the least often in the block is likely to be the next one selected.

N.B: By using random block sizes and holding the investigator oblivious to the scale of each block, selection bias can be minimized.

Stratified random allocation

This is a procedure that splits the trial Participants into strata according to meaningful Prognostic factors linked to results; follow-up The classification and distribution process takes place. The participants are inside each stratum by which they are assigned to treatment groups using separate treatment groups Schedules of randomization. Importance:

 Simple randomization sometimes fails to establish equilibrium in baseline prognostic variables between therapies groups, especially when the sample size is low; The first stratified random allocation constitutes the first effort to correct the template for this.

 Stratification reduces variance, Both power and precision are inversely related to the variance.

 It has been suggested that the drug effect estimation can be more reliable and has more strength in a limited sample size study following a stratified random allocation process.

 Increased efficiency, facilitation of subgroup analysis, and protection against type I error.

Adaptive allocation (adaptive randomization)

It is a way of changing the probability of allocation according to the study's progress and position. It can be used both to minimize the imbalance between treatment groups, and to alter the probability of allocation based on the therapeutic effect.

To minimize the disparity, covariate adaptive randomization changes the distribution of a subject, taking into consideration the imbalance of the prognostic variables.

One example is the minimization randomization (minimization) strategy to establish metrics that jointly assess and distribute the distributional imbalance of different prognostic variables to mitigate the imbalance.

Minimization

To balance the prognostic factors, minimization was first adopted as a covariate adaptive process.

By simple randomization, the first subject is allocated, and the following ones are allocated to match the prognostic factors. In other words, to assign the newly recruited subjects and reduce the imbalance of the prognostic variables, the data of the subjects that have already participated in the analysis is used to. One of drawbacks From a statistical point of view, it does not satisfy randomness, which is the underlying hypothesis of statistical inference.

How to Assign Groups in Clinical Research

In order to select participants, certain eligibility criteria are used. Eligibility criteria describe the specific parameters of the population to be studied, including the age range, the diagnosis, prior therapy allowed, and organ function requirements.

Each of the eligible participants should have an equal chance to be allocated the intervention or not. One way of achieving this is by the parallel-group design. Here, each group of participants is exposed to only one of the study interventions.

Another way of achieving this is by using a crossover design. In a crossover design, all the trial participants sequentially receive both interventions. The only component being assigned here is the order of intervention. A participant can receive the experimental treatment followed by the placebo, or the other way around.

Clinical Trials Registration

The protocol should be reviewed and approved by an independent ethics committee before starting the trial. For clinical trials, it is now obligatory that protocols are registered with a publicly available trial registry before recruiting any participants to the trial.

The patient is registered using a procedure that is described in the protocol. In order to register, the patient has to go to the central registration office of the trial, usually in a healthcare setting. Eligibility will be checked by conducting laboratory tests, weighing the patient, etc. This data is documented prior to the start of the trial. Informed consent, usually through a written form, is also obtained to ensure that the study proceeds in an ethical manner. Each participant is assigned a unique identification number.

Randomized Controlled Trials (RCTs) and their Phases

What are Randomized Controlled Trials?

A randomized controlled trial (RCT) is a study design in which participants are randomly assigned to an experimental group or a control group. It is the most commonly used clinical study, because it measures the efficacy of a certain treatment or intervention on a group of patients with the same diagnosis.

The experimental group receives the new intervention or drug that is being tested. On the other hand, the control group receives the conventional intervention or drug or receives no treatment at all (i.e. a placebo).

The two groups are then followed up to see if there are any differences between them in the outcome. If the experimental group shows a greater improvement in their health condition, then the new intervention or drug is said to be effective. The results and subsequent analysis of the trial are used to assess the effectiveness of the intervention.

Because the outcomes are measured, randomized controlled trials are considered quantitative studies. They are one of the simplest, yet most effective study designs. They also provide high-quality evidence with low levels of bias. On the pyramid of evidence, RCTs fall near the very top, or apex, right below systematic reviews and meta-analyses of RCTs.

Phases and their Purposes

Pre-clinical phase: In this phase, researchers test the drug on non-human subjects, usually animals. The effects of the drug on the animal are studied. Rodent and non-rodent mammalian models are used to determine the drug’s pharmacokinetic profile, safety, and adverse effects. One or more species may be used. This phase can last for several months.

Phase 0: This is the very first phase of the trial that involves human subjects. In this phase, researchers aim to learn how a drug is metabolized in the body and the effects it exerts. A very small dose of a drug is given to about 10 to 15 healthy people. This phase lasts several months.

Phase I: In this phase, a trial is conducted on a small group of patients with the same disease or condition. Its purpose is to study the toxicity and side-effects of the drug. Typically, there are 10-30 participants, but some phase I trials can include up to 100 participants. Like phase 0, phase I also lasts several months.

Phase II: Small groups of patients are used to study the effects of various doses of a drug. When a drug is believed to have shown promising effects in these early phases of its development, it is desirable to test the new treatment against the standard treatment. Like Phase I, Phase II also uses patients with the same disease or condition. Phase II can involve up to several hundred people. The length of this phase ranges from several months to two years.

Phase III: Phase III comprises larger clinical trials that compare the effects of the experimental (new) drug with a placebo or a conventional drug typically used for treatment. These trials are used to document the effects of a new drug and compare its efficacy to a standard drug. This is the last phase before the manufacturer applies for marketing authorization, or for the drug to be licensed for selling. Phase III trials are those that most often come to mind when clinical trials are mentioned; because they use the RCT study design. Phase III can involve anywhere from 300 to 3,000 participants, and usually lasts from one to four years. There are some exceptions as regards to the duration, like the Covid-19 vaccine, whose phase III trials lasted only six months due to the urgent state of the pandemic.

Phase IV: This is the postmarketing phase. It covers both long-term studies of safety and pure marketing studies. Phase IV trials test new drugs after they’ve been approved. The drug is tested in several thousand patients. The advantage of using a large group of participants is that it increases the probability of discovering rare side effects. This allows for better research on short-lived and long-lasting side effects and safety. Doctors can also learn more about the efficacy of the drug and its effect when used with other treatments.