Abbreviations:RCT (randomized controlled trial)
- •Trials of topical drugs require a detailed description of all application modalities such as the amount of drug to apply, how to apply treatments, and the delay between drug application and use of hygiene products.
- •Three main designs can be used when assessing topical drugs: (i) designs allowing for comparison between parallel groups, including the classical individual parallel randomized controlled trial (RCT), in which patients are randomized and one assessment is available per patient, and the individual parallel RCT with clustering, in which patients are randomized and allocated to one treatment, but several lesions from the patient are separately assessed; (ii) the cluster design, in which clusters of patients are randomized and allocated to one treatment; and (iii) designs allowing for a within-individual comparison RCT, including the cross-over design, in which individuals switch from one treatment to another after a wash-out period, and the within-person design, in which lesions are separately randomized and concomitantly treated and assessed.
- •In the within-person RCT, also called split-body RCT, left and right comparisons RCT, or intraindividual comparison RCT, patients simultaneously receive topical experimental drugs and controls on different lesions or body sites, which reduces interobservation variability.
- •As compared with the individual parallel RCT design, the within-person design allows for reducing the number of patients to be included in the trial; thus, the design is well-adapted for rare diseases.
- •The main constraint of the within-person design is the need to control the risk of the carry-across effect, that is, leakage of the treatment effect from one site to another for a patient simultaneously receiving different drugs on different lesions.
- •The choice of design depends on the drug (systemic passage, etc.) and the disease (number and extension of lesions, prevalence, etc.).
|Carry-across effect||The potential leakage of the treatment effect from one site to another in a patient receiving two or more topical treatments.|
|Cluster RCT||Trials in which clusters of patients, such as wards, practices, schools, or villages, are randomized rather than the patients themselves. They are usually used for evaluating health service organization and health policy, often with complex interventions targeted at the level of the cluster, the individual, or both.|
|Cross-over RCT||Patients are randomized to sequences of interventions and receive multiple interventions. Each patient receives each intervention in a separate period of time. There is usually a wash-out period between sequences. Each patient is in his or her own control.|
|Individual parallel RCT||Patients are randomized to intervention A (experimental treatment) or intervention B (control treatment).|
The objective of a superiority individual parallel RCT is to reveal that intervention A is superior to intervention B.
The objective of a noninferiority individual RCT is to reveal that intervention A is at least as good as intervention B in terms of efficacy.
|Individual parallel RCT with clustering||Patients with one or several lesions are randomized, but the treatment effect is assessed for each lesion treated with the topical drug. Because each patient may have one or more lesions, the design is similar to a cluster RCT, in which patients are clusters, and cutaneous lesions are assessment units within clusters. These units are correlated, as in any cluster RCT.|
|Within-person RCT||Patients receive two or more treatments to different body sites. The unit of randomization is not the patient but an organ or a lesion (cutaneous lesions, eye, teeth, etc.) or body area (arms, legs, etc.). The within-person design is also called the split-body design or intraindividual comparison design.|
Specificities of Trials of Topical Drugs
- ✓Description of the characteristics of the topical drug
- -Galenic formulation
- -Drug components
- -Frequency of application
- -Duration of treatment
- ✓Definition of quantity of topical drug to apply
- ✓Description of allowed concomitant topical drugs and cosmetics/hygiene care products
- ✓Description of the delay between drug applications and cleaning products
- ✓Description of potential systemic passage of the drug
- ✓Description of the topical control and justification for the choice
Which Designs to Be Used When Assessing a Topical Drug
- 1.The classic individual parallel RCT. Patients are randomized, and assessment involves the whole patient (Papp et al., 2016) or a single lesion on the patient.
- 2.The individual parallel group with clustering RCT. Patients are also randomized, but the treatment effect is assessed for each lesion treated with the topical drug. For example, the study byCavalié et al., 2015, which evaluated 0.1% topical tacrolimus for vitiligo, included 35 randomized patients and 72 assessed lesions. Because each patient may have one or more lesions, the design is similar to a classical cluster RCT, in which patients are clusters, and vitiligo lesions are assessment units within the clusters. These units are correlated, as in cluster RCT.
- 3.The classical cluster RCT. Groups (clusters) of patients are randomized and allocated to one topical treatment. For example,Madan et al., 2019performed a cluster RCT to evaluate the efficacy of a behavior change package, including regular use of moisturizing cream to prevent hand dermatitis in nurses working in healthcare. In this trial, clusters were hospitals, and nurses, who corresponded to assessment units, were embedded within clusters.
- 4.The cross-over RCT. Patients are randomized to a sequence of interventions and switch from one topical treatment to another after a wash-out period. Therefore, patients act as their own control. This design is appropriate for chronic stable disease (e.g., recurrent aphthous stomatitis), in which topical treatments will have transient effects without carry-over effects between the two periods of treatment (Gorsky et al., 2007).
- 5.The within-person design. The lesions or body sites are randomized but the patient is not, and lesions or sites are further assessed. The patient concomitantly receives the topical intervention and the topical control. The within-person design is close to the cross-over design, but treatments are administered at the same time rather than consecutively. As for the cross-over design, the within-person RCT benefits from patients being compared with themselves. Thus, because each patient contributes to both groups and because it reduces interobservation variability, the required sample size greatly decreases. This design has been used in studies of topical drugs for acne vulgaris, in which patients applied the experimental drug to the right or left side of the face and the control to the contralateral side, then each side was assessed. In such designs, assessment units within patients are correlated (Pandis et al., 2017).
Methodological Issues That Must Be Considered When Planning a Within-Person RCT
Eligibility criteria—for both patients and lesions
Interventions—the carry-across effect
- Leducq S.
- Caille A.
- Barbarot S.
- Bénéton N.
- Bessis D.
- Boccara O.
- et al.
Compliance—the use of a care provider optimizes the protocol
Outcomes and estimation
Recruitment—patient must accept to receive both treatments
Blinding is more challenging
When to Use a Within-Person RCT
Scenario 1—an RCT of a dermatological condition that involves a single lesion (e.g., a wide patch of alopecia areata)
Scenario 2—an RCT of a dermatological condition involving several countable lesions (e.g., vitiligo)
Scenario 3—an RCT of a dermatological condition involving multiple diffuse lesions (e.g., guttate psoriasis)
Conflict of Interest
Multiple Choice Questions
- 1.In a trial evaluating a topical drug, dermatological departments are randomly allocated to the experimental or control group (all patients from a department receive the same treatment). What is the randomized control trial (RCT) design?
- A.Within-person RCT
- B.Cluster RCT
- C.Classical individual parallel RCT
- D.Cross-over RCT
- 2.For a within-person RCT, what are the correct answers?
- A.The unit of randomization is the patient
- B.The unit of randomization is the lesion
- C.The unit of assessment is the patient
- D.The unit of assessment is the lesion
- 3.The carry-across effect depends on
- A.The skin condition
- B.The drug properties
- C.Molecular weight of the drug
- D.All of the above
- 4.When should a within-person RCT be avoided?
- A.For rare diseases
- B.If the relevant primary outcome is QOL
- C.If the best control is another active topical drug and not a placebo
- D.Dermatological conditions with facial involvement
- 5.For which dermatological condition should a within-person RCT not be used?
- A.Acne vulgaris
- B.Acral melanoma
- C.Plaque of vitiligo
- D.None of the above
- 1.In a trial evaluating a topical drug, dermatological departments are randomly allocated to the experimental or control group (all patients from a department receive the same treatment). What is the randomized controlled trial (RCT) design?
- CORRECT ANSWER: B. Cluster RCT
- In cluster RCTs, groups (clusters) of patients are randomized and allocated to one topical treatment. For example,Madan et al., 2019performed a cluster RCT to evaluate the efficacy of a behavior change package, including regular use of moisturizing cream to prevent hand dermatitis in nurses working in healthcare. In this trial, hospitals were clusters, and nurses constituted the assessment units within clusters.
- 2.In a within-person RCT, what are the correct answers?
- CORRECT ANSWER: B. The unit of randomization is the lesion; D. The unit of assessment is the lesion.
- In a within-person RCT, the lesions or body sites but not the patient are randomized, and these randomization units are further assessed.
- 3.The carry-across effect depends on
- CORRECT ANSWER: D. All of the above
- The carry-across effect depends on numerous variables, including the molecular weight of the drug and its afterglow in the dermis (depends on systemic passage of the drug), the drug properties (anti-inflammatory properties can have local extension), and the skin where the drug is applied (more systemic passage with wide area of application or severe alteration of the cutaneous barrier).
- 4.When should a within-person RCT be avoided?
- CORRECT ANSWER: B. If the relevant primary outcome is QOL
- Patient-reported outcomes such as QOL cannot be assessed in a within-person RCT because the patient receives both topical drugs simultaneously. For pathologies with facial involvement (acne for example), a within-person RCT could be used, although the investigator should keep in mind that aesthetic consequences are possible and could cause inconvenience to the patient.
- 5.In which dermatological condition should a within-person RCT not be used?
- CORRECT ANSWER: B. Acral melanoma
- A within-person design could be chosen for acne vulgaris (split-face design), and for plaque of vitiligo (several lesions can be randomized and included in different groups of treatment).
- Surgery is the recommended treatment of acral melanoma and not topical treatments.
- Teaching Slides
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- A behaviour change package to prevent hand dermatitis in nurses working in health care: the SCIN cluster RCT.Health Technol Assess. 2019; 23: 1-92
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- Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a phase 2b randomized clinical trial.BMC Dermatol. 2016; 16: 15
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- Interventions for vitiligo.Cochrane Database Syst Rev. 2015; : CD003263
- How clinically relevant are treatment comparisons of topical calcineurin inhibitor trials for atopic eczema?.J Invest Dermatol. 2016; 136: 1944-1949
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