To make a clinical trial faster, less costly, and more successful it all starts with strategically designing a clinical trial. The sturdy trial design is essential to ensure a successful clinical outcome.

A proper study design determines the fate of the clinical trials and their likeliness to be successful as it involves many deciding parameters such as the number of patients to be recruited, the length or duration of the trial, the comparator arm, using the information on current treatments, the anticipated effect of the therapeutic intervention and applying biostatistics methods, etc.

So let’s first understand what is a clinical trial design

What is a clinical study design?

The clinical study design is the formulation of clinical trials and experiments, as well as observational studies in medical, clinical, and other types of research (e.g., epidemiological) involving human beings.

The goal of any clinical study or research is to assess the safety, efficacy, and/or the mechanism of action for an investigational medicinal product (IMP) or procedure, or new drug or device that is in development or to assess the bioequivalence (BE) of similar drugs in case of generic drugs.

The study designs vary with the goal and expected outcome from a clinical trial. Strategic experts design clinical trials to answer specific research questions related to a medical product which include

  • Selection criteria
  • How many people will be part of the study
  • How long the study will last
  • How the drug is given to the patients (formulation & dosage)
  • Whether there will be a control group and other ways to limit research bias
  • How the drug will be given to patients and at what dosage
  • What assessments will be conducted, when, and what data will be collected
  • How the data will be reviewed and analyzed

In this article, we will be discussing the two major trial designs Randomized controlled trials (RCT) and Adaptive trials which are commonly used in most of the clinical trials.

Randomized controlled trials (RCT)

A Randomized Controlled Trial (RCT) is a type of scientific experiment that aims to reduce certain sources of bias when testing the effectiveness of new treatments and is accomplished by randomly allocating subjects to two or more groups, treating them differently, and then comparing them with respect to a measured response.

For example, one group of the experiment receives the intervention being assessed, while the other usually called the control group receives an alternative treatment, such as a placebo or no intervention. These RCT trials are either conducted as

  • A well-blended RCT is often considered the gold standard for clinical trials.
  • Blinded RCTs are commonly used to test the efficacy of medical interventions and may additionally provide information about adverse effects, such as drug reactions.

Based on allocation these are further divided into

  • Simple randomization: This method is similar to flipping a coin. This method provides an even distribution of subjects to each of the interventions.
  • Block Randomization: This method is used if there is concern that subjects may change over time. In block randomization, the number of subjects in a block is defined. Within the block, subjects are equally and randomly assigned to the interventions. 
  • Stratified Randomization: This method is used when there is concern that subjects may not be balanced based on baseline characteristics, such as age, length of time of disease, or disease control. 
  • Unequal Randomization: This method does not allocate subjects equally to study interventions. Instead, subjects are randomized in greater proportions to a defined intervention. 

Advantages of RCT

  • RCTs are considered to be the most reliable form of scientific evidence in the hierarchy of evidence
  • RCTs reduce spurious causality and bias
  • Results of RCTs may be combined in systematic reviews which are increasingly being used in the conduct of evidence-based practice. 

Disadvantages

  • RCTs can be expensive
  • The conduct of an RCT takes several years and It is costly to maintain RCTs for the years
  • Some trials using this design require extremely large sample sizes which may be difficult for recruitment

Types of RCT

  • Blinded studies meaning that information which may influence the participants is withheld until after the experiment is complete. A blind can be imposed on any participant of an experiment, including subjects, researchers, technicians, data analysts, and evaluators. Effective blinding may reduce or eliminate some sources of experimental bias.
    • These blinded studies are further divided as
      • Single Blind: Persons who collect outcome variable (observers) do not know treatment assignment
      • Double-Blind: Study participants and observers do not know treatment assignments
      • Triple Blind: Data interpreters, study participants, and observers do not know treatment assignments
  • Non-Blinded studies (Open-label trial, or open trial) are the type of clinical trial where the information is not withheld from trial participants. Both the researchers and participants know which treatment is being administered and this contrasts with blinded studies 
  • Placebo-Controlled studies: In placebo-controlled studies, subjects are randomized to receive either placebo (sugar-pill, or any other palatable substance with inactive excipients) or the active intervention. Placebo-Controlled trials may be challenging to perform, particularly if the intervention involves injection or use of a device. 
  • Active Comparator: In some RCTs, subjects are randomized to an active comparator arm which is compared against an experimental intervention arm. Active comparator trials are powerful methods to determine if a new therapy is non-inferior or superior to the current standard of care treatments.
  • Cross-Over Design: In this design, all subjects randomized to the active comparator may be crossed-over to receive the experimental agent after a set time period, while all subjects receiving the experimental agent will cross-over to the active comparator. The advantages of this design are that each subject serves as his/her own control, and the number of subjects needed to answer a clinical question may be less.
  • Parallel group trial design: In parallel group randomization, after randomization, each participant will stay in their assigned treatment arm for the duration of the study. Parallel group design can be applied to many diseases, allows running experiments simultaneously in a number of groups, and groups can be in separate locations.
  • Matched pair trial design: In the matched-pair design, participants are first matched in pairs according to certain characteristics. Then, each member of a pair is randomly assigned to one of the two different study subgroups. This allows a comparison between similar study participants who undergo different study procedures.

Some other type of trial designs in RCT

  • Stratification also allows for a comparison between similar study participants who undergo different study procedures. All study participants are grouped according to one or more factors (such as age, gender, lifestyle factors, concomitant medication, etc) before being randomized. This ensures a balanced allocation within each combination.
  • Cluster sampling: In cluster sampling, suitable geographical areas are found (for instance, city, region, etc.). A number of these geographical areas are then randomly chosen. For each of these chosen geographical areas, a proportionate subsample from the members of the study sample in that area are chosen, and these subsamples are then combined into a sample group.
  • Withdrawal trials: In a withdrawal trial, the participant receives a test treatment for a specified time and are then randomized to continue either with the test treatment or a placebo (withdrawal of active therapy).

Adaptive clinical trials

Adaptive clinical trials are the trials that evaluate treatment or medical devices by observing participant outcomes and possibly other measures, such as side-effects on a prescribed schedule and modifying parameters of the trial protocol in accordance with those observations. 

An adaptive design consists of multiple stages and at each stage, data analyses are conducted and adaptations take place based on updated information to maximize the probability of success of a trial.

  • Modifications may include dosage, sample size, drug undergoing trial, patient selection criteria, and “cocktail” mix.
  • The trial protocol is set before the trial begins; the protocol pre-specified the adaptation schedule and processes.

Common Types of Adaptive Designs Used in Clinical Trials

  • Group sequential design
  • Error-spending approach
  • Sample-size re-estimation design
  • Pick the winner design
  • Adaptive randomization designs
  • Adaptive dose-escalation designs
  • Biomarker-adaptive designs

Example of adaptive trials

  • An adaptive trial design enabled two experimental breast cancer drugs to deliver promising results after just six months of testing, far shorter than usual. 
  • Researchers assessed the results while the trial was in process and found that cancer had been eradicated in more than half of one group of patients. The trial, known as I-Spy 2, tested 12 experimental drugs.
  • Another example of adaptive design exists in early-phase dose escalation studies. These studies often employ prospectively planned interim reviews of pharmacokinetic and safety data by a review committee,

Advantages

  • The aim of an adaptive trial is to more quickly identify drugs or devices that have a therapeutic effect and to zero in on patient populations for whom the drug is appropriate.
  • Adaptive design can reduce the number of patients in a trial and the number of trials overall. 
  • Adaptive design is particularly useful for adequately controlled clinical safety and efficacy trials. 
  • Adaptive design can also be quite beneficial in early-phase studies and exploratory trials, as well as later trials, conducted to satisfy post-marketing commitments
  • FDA considers adaptive guidelines and provides guidance documents on
    • When to interact with the FDA while planning and conducting adaptive design studies
    • What information to include in the adaptive design for FDA review, and
    • issues to consider in the evaluation of a completed adaptive design study.

Disadvantages and challenges of adaptive trials

  • The adaptive design may not be the best option for all clinical trials such as short-duration studies (e.g., 2-8 weeks) in populations that can be recruited very quickly (in a few months), since recruitment needs to be halted while interim analyses are conducted.
  • Critical insights may be missed during a rapid interim analysis that might have been captured by more thoughtful analyses following an exploratory study and Such oversights can be costly and may extend overall development timelines.

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In the next article, we will be discussing the new trial designs such as the umbrella trial design, platform trial designs, bucket trial designs, etc, along with their advantages and disadvantages.

References

  1. https://toolbox.eupati.eu/resources/clinical-trial-designs/
  2. https://www.pedsendo.org/assets/education_training/residents_fellows/research_opportunities/Clinical_Trials_and_Study_Design.pdf
  3. https://www.nuventra.com/resources/blog/adaptive-design-clinical-trials/
  4. https://www.scientific-european-federation-osteopaths.org/different-types-of-clinical-trials/
  5. https://www.veristat.com/blog/what-are-the-major-common-types-of-adaptive-designs-used-in-clinical-trials-today
  6. https://www.fda.gov/media/78495/download
  7. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/master-protocols-efficient-clinical-trial-design-strategies-expedite-development-oncology-drugs-and