Clinical trial design is an important aspect of interventional trials that serves to optimise, ergonomise and economise the clinical trial conduct. The goals of a clinical trial, whether medtech or pharma, can encompass assessment of safety, dosage optimisation, evaluation of efficacy or accuracy and comparison to existing treatments or diagnostics. This of course varies with the phase of the trial. For phase III or IV trials the goal is most often to determine superiority, non-inferiority, or equivalence of the novel therapeutic or device to one in standard use. A well-conducted study that achieves regulatory approval for the asset in an efficient way depends upon the design that informs it. An optimal design, from a statistical and data collection perspective, ensures accurate evaluation efficacy and safety, as well as getting the product to market sooner. Knowing which study designs best suit your research will improve the chances of success, enable the best method for sample size estimation and re-estimation, save time and reduce unnecessary costs (Evans, 2010). While many clinical study designs exist this article focuses on perhaps the most rudimentary and frequently used designs
- Parallel group design
- Crossover design
- Factorial design
- Randomised withdrawal design
1. Parallel group study design
A commonly used study design is a parallel arm design. When using this as a study design, subjects are randomised and allocated to one or more study arms. In a parallel group study design, each study arm is allocated a different intervention. After study subjects have been randomised and allocated to a study arms they can not be allocated to another arm throughout the study.
Advantages of parallel group trial study design
A key advantage of parallel group trial design is that it can be applied to many different diseases as well as allows for conducting multiple experiments simultaneously between many groups. A further advantage is that these different groups need not be sourced from the same site.
Note: Once patients have been randomised and assigned to a specific arm, these arms are mutually exclusive. This means that unplanned co- interventions or cross-overs between different treatments cannot be introduced.
Steps involved in a parallel arm trial design:
1. Eligibility of study subject assessed
2. Recruitment into study after consent
3. Randomisation
4. Allocation to either treatment or control arm
2. Cross-over study design
There are some ethical limitations to the use of placebo controls that can be partially overcome by using a cross over design. This means that every patient taking part in the clinical trial will receive both treatment and placebo being given in a randomised order (Evans, 2010). Cross-over study design can also be used in the absence of placebo where the intention is to compare the new treatment to the standard one.
Advantages of cross-over design
One of the advantages of cross over design is the fact that each patient acts as their own control results in order to balance the covariates in treatment and control arm. Another major advantage of cross over design is the fact that it requires a smaller sample size (Nair, 2019).
Note: When cross over design is applicable and chosen for the study, some of the patients will start the trial with using intervention A and then switch to intervention B which is known as a AB sequence, whereas other patients will start with using intervention B and later switch to intervention A which is known as BA sequence.
! There needs to be an adequate washout period before the crossover in order to eliminate the effects from initially assigned and administrated intervention. After all data has been collected the results are then compared within the same subject assessing the effect of intervention A vs. effect of intervention B (Nair, 2019).
Variations of cross-over design
(i) Switch back design (ABA vs BAB arms) –
1. Drug A -> Drug B-> Drug A
2.Drug B -> Drug A -> Drug B
The switch back and multiple switchback designs are of emerging relevance with the advent of biosimilars where switchability and interchangeability of a biosimilar to a bio-originator molecule can only be confirmed by such trial designs.
(ii) N of 1 design – N of 1 trials or “single-subject” or “structured within-patient randomized controlled multi-crossover trial design”
This type of cross over design is used for evaluating all interventions in a single patient. A typical N of 1 design clinical trial consists of repeating experimental/ control treatment periods number of times. The interventions being tested are assigned randomly within each period pair. This design has gained a lot of popularity, because in most cases the aim of using this type of design is to determine which treatment works best for the individual patient.
3. Factorial design
Factorial design is most suited when the study is looking at two or more interventions in various combinations within one study setting. This design helps in the study of interactive effects that have resulted from a combination of different interventions (Nair, 2019).
Advantages of Factorial design
A key advantage of factorial design is that it can help answer multiple research questions in a clinical trial instead of conducting multiple trials. This helps to optimise resources, thereby reducing costs and speeding up research pipelines.
2 × 2 factorial design with placebo
In a 2 × 2 factorial design with placebo, patients are randomized into four groups:
i) treatment A plus placebo
ii) treatment B plus placebo
iii) both treatments A and B
iv) neither of them, placebo only.
Limitations of the factorial design
The main limitations of using factorial design for clinical trials is the fact that:
○ Increased complexity of the trial overall
○ Makes it more difficult to meet inclusion criteria
○ Inability to combine multiple incompatible interventions
○ The protocols are complex
○ High complexity of statistical analysis
4. Randomised withdrawal design (EERW)
The aim of randomised withdrawal design is to evaluate the optimal duration of the treatment for patients that are responsive to the intervention.
After the initial enrichment period (open label period) which main purpose is to assign the subjects to intervention, the subjects that are not responding are removed (dropped) from the study and the subjects that did respond are randomised into receiving the intervention or placebo during the second phase of the clinical trial (Nair, 2019).
Note: This means that only subjects that have responded are carried forward to the second stage of the study and randomised.
Statistical analysis of randomised withdrawal design
When using randomised withdrawal design the analysis of the study is conducted using only data from the withdrawal phase. Outcome is usually set to relapse of symptoms. The aim of the enrichment phase is to increase the statistical power for the estimated sample size.
Advantages of EERW
A main advantage of a randomised withdrawal design is that it can reduce the time patients receive placebo. Only patients that are responsive to the intervention are randomised to placebo, hence an increased ethical advantage. A further advantage of this study design is that it can help to determine if the treatment should be stopped or continued (Nair,2019).
Conclusion
One of the key stages of planning a clinical trial involves deciding on the appropriate study design to ensure the success of the research and help to choose the right method for sample size estimation and re-estimation, save time and reduce unnecessary costs.
The most commonly used study designs are :
- Parallel group study design
- Cross over study design
- Factorial study design
- Randomised withdrawal study design (EERW )
A well-conducted study with optimal design, that encorporates a robust hypothesis evolved from clinical practice, goes a long way in facilitating the regulatory approval process – evaluating efficacy and safety, and getting the product to market. Therefore when undertaking a clinical trial close attention should be paid to ensure that a study design forms a solid foundation upon which to conduct the trial phases.
References
Evans, S., 2010. Fundamentals of clinical trial design. [online] PubMed Central (PMC). Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3083073/>.
Expert, T., 2022. Clinical Trial Designs & Clinical Trial Phases | Credevo Articles. [online] Credevo Articles. Available at: <https://credevo.com/articles/2021/02/05/the-phase-of- study-clinical-trial-design/>.
Nair, B., 2019. Clinical Trial Designs. [online] PubMed Central (PMC). Available at: <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434767/>.
The BMJ | The BMJ: leading general medical journal. Research. Education. Comment. n.d. 13. Study design and choosing a statistical test | The BMJ. [online] Available at: <https://www.bmj.com/about-bmj/resources-readers/publications/statistics-square-one/ 13-study-design-and-choosing-statisti>.