Study design in clinical trial

Placebo must only be used if no permanent harm death or irreversible morbidity accrues by delaying available active treatment for the duration of the trial and is preferable for a minimal risk, short-term study. Study end points must be objective in this design. The downsides are potential for observer bias and difficulty in blinding in this design. Active treatment concurrent control — This design involves comparison of a new drug to a standard drug or compare combination of new and standard therapies vis a vis standard therapy alone.

A therapeutic modality that should preferably be the current standard of care against which the active drug to be studied is compared with. This design can be used to demonstrate equivalence, non-inferiority, and superiority. This design is most ethical whenever approved drugs are available for the disease under study. The Declaration of Helsinki mandates the use of standard treatment as controls. Dose-comparison concurrent control — Different doses or regimens of same treatment are used as active arm and control arm in this design.

This design may include active and placebo groups also in addition to the different dose groups. This design may be inefficient if the therapeutic range of the drug is not known. Historical control external and non-concurrent — Source of controls are external to the present study and were treated at an earlier time earlier therapeutic gold standard or in a different setting.

The advantage of historical controls is in studying rare conditions where sample size generation is difficult. The downside is that no randomization or blinding is possible in this design.

A disadvantage is that the co-interventions evolve in due course of time thereby reducing the comparability of the present intervention versus historic control. Another deficiency of this design is the difference between baseline characteristics of subjects in trial arm versus historical arm. For example, toxic epidermal necrolysis, where clinical outcomes in cyclosporine treated patients can be compared with historical controls treated in the same center with IVIg in the past.

Add-on design — This design denotes a placebo-controlled comparison on top of a standard treatment given to all patients. If the improvement that is achievable in addition to that obtained from the standard treatment is small, the size of such trial may need to be very large. Early escape design — The early escape design using a placebo control allows a patient to be withdrawn from the study as soon as a predefined negative efficacy criterion has been attained.

This reduces the time on placebo or in treatment failure. This design analyses failure rate, so minimizes exposure to ineffective treatment. The time for withdrawal is then used as the primary outcome variable. The patient could then be switched over to another therapy, including the test treatment if appropriate.

If the drug has a slow and deliberate effect on long-term use then that might be missed in this design. Unbalanced assignment of patients to placebo and test treatment.

By this design it is implied that a smaller number of patients could be assigned to the placebo group compared to the test treatment group e. Double-dummy design [ Figure 3 ] — This design is of great utility if the comparator interventions are of different nature. Illustrative example — Comparison of oral acitretin versus injection purified protein derivative PPD in extensive verruca vulgaris. So, blinding of patients is not feasible in this scenario. But this issue can be circumvented by administering acitretin orally with a dummy injection like normal saline to one study group and injection PPD along with placebo capsule identical in size and appearance to the acitretin capsule to the comparator arm.

Placebo run-in design — Placebo run-in period is a period before a clinical trial is commenced, when placebo is administered for all study subjects. The clinical data from this stage of a trial are only occasionally of value but can serve a valuable role in screening out ineligible or non-compliant participants, in ensuring that participants are in a stable condition, and also helps in providing baseline observations.

After the run-in phase, randomisation is done, patients are randomized into study arms where different active interventions are added to the placebo in each study arm [ Figure 4 ].

In randomized controlled trials, trial participants are randomly assigned to either treatment or control arms. Different tools can be used to randomize closed envelopes, computer generated sequences, random numbers. There are two components to randomization: the generation of a random sequence and the implementation of that random sequence, ideally in a way that keeps participants unaware of the sequence allocation concealment.

Randomization removes potential for systematic error or bias. The biggest upside of an RCT is the balancing of both the known and unknown confounding factors which leads to wrong conclusions.

Stratified randomization — This refers to the situation in which strata are constructed based on values of prognostic variables and a randomization scheme is implemented separately within each stratum.

The objective of stratified randomization is to ensure balance of the treatment groups with respect to the various combinations of the prognostic variables. This method can be used to achieve balance among groups in terms of subjects' baseline characteristics covariates.

Specific covariates must be identified by the researcher who understands the potential influence each covariate has on the dependent variable. To avoid strata with very less patients, the number of strata should be kept minimum.

After all the subjects have been identified and assigned into strata, simple randomization is performed within each stratum to assign subjects to either case or control groups.

Block randomization — Blocking is the arranging of experimental units in groups blocks that are similar to one another. Typically, a blocking factor is a source of variability that is not of primary interest to the experimenter. An example of a blocking factor might be the sex of a patient; by blocking on sex, this source of variability is controlled for, thus leading to greater accuracy. The block randomization method is designed to randomize subjects into groups that result in equal sample sizes.

This method is used to ensure a balance in sample size across groups over time. Blocks are small and balanced with predetermined group assignments, which keeps the numbers of subjects in each group similar at all times.

Randomization by body halves or paired organs Split Body trials — This is a scenario most often used in dermatology and ophthalmic practice where one intervention is administered to one half of the body and the comparator intervention is assigned to other half of the body.

This can be implemented only if experimental treatment acts locally. Randomization is used to select which side of the body receives which drug.

The upside is the elimination of confounding factors between trial arms, as the baseline characteristics of both arms are the same. The downside is difficulty in blinding the investigator, statistical analysis, and influence of therapy administered in one half of the body influencing disease on the other side as the halves of the human body is a continuum and not entirely independent entities carryover of the experimental treatment to control half.

Paired data statistical analytic tests need to be done in this scenario. Cluster randomization — Study patients and treating interventionists do not exist in isolation.

Sometimes interventions need to be applied at ward level, village level, hospital level, or group practice level. Hence intervention is administered to clusters by randomization to prevent contamination.

Each cluster forms a unit of the trial and either active or comparator intervention is administered for each cluster.

Allocation by randomized consent Zelen trials — Eligible patients are allocated to one of the two trial arms prior to informed consent. This is utilized when informed consent process acts as an impediment to study subject accrual. However, this design raises serious ethical uncertainties and must only be used in severely flagging trials in terms of insufficient sample size of great public health importance and is not recommended in routine clinical trial design.

Minimization — Stratification based on multiple co-variates age, sex, gender, baseline severity of disease, personal habits, co-morbidities, treatment naivety, etc. Hence, an alternate strategy to control for prognostic variables to avoid such small strata is minimization. After identification of these variables, they are dichotomized at some break point in case of continuous variables or based on presence or absence of a categorical variable.

Then each dichotomized half is given a value of 0 or 1 e. For example, patient number 1 with score 2 is randomized to control arm. Patient no. So now the control arm total score is 2 and case arm score is 1.

Patient 3 is a female with score 1 and will be allocated to case arm and thus the cumulative score in both groups will be balanced at 2 points. Once the running scores in both arms are tied, the next recruited subject is again randomly allocated and the whole cycle repeats. Thus, minimization is a viable alternative to randomization for known prognostic factors, but does not factor in the unknown prognostic confounding variables.

Hence, it can be considered a platinum standard to the gold standard of random allocation. Parallel arm design is the most commonly used study design.

In this design, subjects are randomized to one or more study arms and each study arm will be allocated a different intervention. After randomization each participant will stay in their assigned treatment arm for the duration of the study [ Figure 5 ].

Parallel group design can be applied to many diseases and allows running experiments simultaneously in a number of groups, and groups can be in separate locations.

The randomized patients in parallel groups should not inadvertently contaminate the other group by unplanned co-interventions or cross-overs. Illustrative example — A comparative trial of Acitretin and Apremilast in palmoplantar psoriasis, where there exits clinical equipoise as regarding efficacy can be conducted as a randomized controlled acitretin as active control parallel arm trial design.

Another advantage is requirement of a smaller sample size [ Figure 6 ]. The ethical limitations of a placebo control are partially overcome by a cross over design in which each patient receives both interventions but in a different order. The order in which patient receives interventions is randomized. View our Terms and Privacy Policy. Researchers ask questions from participants to observe the effect of a risk factor, diagnostic test or treatment.

This is done to collect information on prevalence, incidence or experience such as data collection using existing medical records. Sometimes an observational study is conducted before an experimental study to gain insight before testing a hypothesis. Have you got any tips or useful ideas to remember different clinical trial designs? Dinethra Menon is a medical and science writer with over a decade of experience communicating and writing medical education for doctors.

She has a Bachelor of Science from the University of Melbourne and a postgraduate diploma in genetic counseling. These include the use of screening platforms to allow potential participants to be screened for multiple studies at the same time.

Further, the centralization of study governance committees and institutional review board oversight enables more efficient study conduct and streamlined communication and decision-making pathways. These are especially important factors when the studies may include adaptive elements that require real-time assessment of incoming information and rapid responses to those data.

However, despite the operational advances in some areas, master protocols may still be challenging to conduct. In most institutions, clinical divisions and administrative infrastructure are designed based on disease type or location: the breast oncology department, the gastrointestinal oncology department, etc. Research administration is often parallel to this, so that research team staffing, facilities, budgets, and other considerations are allocated and managed by disease-based divisions.

In disease-location agnostic study, this structure needs to be re-invented. Study coordinators may have to work together or to work across departments. As therapeutic agents evolve and our understanding and ability to utilize precision medicine grows, the study designs that we use to test the safety and efficacy of these novel therapies must evolve as well.

While there is still a place for the standard randomized, parallel-group clinical trial, designs such as for basket trials allow the enrichment of study populations for specific markers to which therapies are targeted. Taking advantage of both study design and operational advances in the way we conduct clinical research will help us to answer research questions with efficacy and scientific rigor, allowing us to identify promising therapies more quickly and to move them forward toward the clinic.

Apply by March 31, to earn your certification online, on-demand from February 15 to April 15, Understanding Clinical Trial Protocols. Building Quality Management Systems. Site Quality Management Tools. View More Free Courses. Separate from primary study designs is the meta-analysis. A meta-analysis is a systematic review of other studies. The strength of the meta-analysis is dependent on the strengths of the studies included in the analysis.

Even if all of the studies included in a meta-analysis are randomized, a meta-analysis cannot be considered randomized. Experimental In Experimental studies, researchers assign patients to an experimental or control group.

Level 1 Study: Randomized, Prospective, Control Group Participants are randomly assigned to an intervention and followed prospectively Provides most compelling evidence that a treatment causes an observed outcome.

Level 2 or 3 Study: Not Randomized, Prospective or Retrospective, Control Group Participants are non-randomly separated based on exposure or treatment. Example: HCRN tested a new shunt surgical protocol.