DRUG DISCOVERY/DEVELOPMENT/DELIVERY

Topical drug development:
Clinical programmes in dermatology

Dr Betsy Hughes-Formella, bioskin GmbH

There are a number of unique aspects related to the clinical development of topical drugs for skin conditions. However, there are only a few current guidelines specific to the clinical development of these products. The most notable of these are the FDA Draft Guidance for Acne Vulgaris1, the EMEA Guideline for anti-psoriatic drugs2 and the FDA Guidance for topical corticosteroids3. This article presents a brief overview of some of the special considerations in clinical development of topical products for dermatological diseases.

Pharmacokinetics and systemic safety

The focus of dermatology – the skin – is directly accessible to therapy. However, the uppermost layer of the epidermis, the stratum corneum, is a formidable barrier to drug penetration and permeation. The main reason for giving a drug topically rather than systemically is to keep the drug restricted to the diseased area in the skin and avoid absorption into the systemic circulation.

Ideally there is no systemic absorption of topical drugs for skin diseases. However, with accumulation following repeated applications there is invariably systemic exposure, the extent of which is dependent on the body surface area treated. Safety pharmacokinetic studies should be designed to measure systemic levels following maximum exposure. Data should be collected in patients following repeated application of the highest concentration of the topical product to the maximal body surface area which will be allowed according to label. Because skin penetration is altered in diseased skin compared to healthy skin, pharmacokinetic data in patients are generally required for licensing purposes. These data may be collected within the framework of a therapeutic trial.

For NCEs with no prior exposure in man, a Phase I study for systemic absorption following topical application is usually necessary before moving forward with efficacy studies. This is usually done in healthy subjects before moving into patients. This may not be necessary in cases where Proof of Concept (POC) is planned using a model with only a minimal treatment area, eg the psoriasis plaque test. Many new topical formulations contain active substances which are already marketed as systemic or topical products or are being developed in parallel for systemic therapy. In these instances systemic safety can initially be derived by calculating the maximal exposure assuming 100% absorption of the applied dose.

Cutaneous safety

The local skin safety battery for topically applied products typically includes evaluation of the final formulation for dermal irritation, potential for cutaneous contact sensitisation, phototoxicity, and potential for photoallergic contact sensitisation. Photosafety testing is required if the final formulation absorbs light between the wavelengths 290 and 700 nm. Since dermal irritation data from humans is often required by Ethical Committees or Competent Authorities prior to conduct of Phase IIa efficacy studies, this is often the first clinical study. The classical design is a 21-day, vehicle-controlled, within-subject cumulative irritation study with occlusive application of test formulations in 30 to 35 subjects. In cases of known irritants, eg retinoids or excipients like alcohol, non-occlusive application may be justified. A known irritant such as sodium dodecyl sulfate is often included as a positive control.

The largest, and therefore most costly, dermal safety study is the Repeated Insult Patch Test to assess sensitisation potential. This Phase I study is often conducted at the end of Phase II or in parallel to Phase III, at a time when there is some certainty that the product is unlikely to fail for efficacy reasons. The study design requires application of test formulations three times weekly during a three-week induction phase, followed by a rest phase and challenge application, after which potential allergic dermal reactions are assessed. The panel size is 200 evaluable subjects.

If there is no evidence of phototoxic potential on the basis of preclinical studies, this study does not need to be included as one of the first clinical studies and is usually conducted in parallel to Phase II. However, if there is evidence that a formulation may be phototoxic this study should be performed as early as possible. It is vital to include precautions to protect against light exposure in all clinical protocols until the question of phototoxicity is clarified. To test phototoxic potential, formulations are applied occlusively for 24 hours prior to exposure to a standard dose of UV light. Dermal reactions are then recorded for a 48 hour period following light exposure. Twelve to 30 subjects are included in a panel for testing phototoxic potential.

The clinical study for photoallergic contact sensitisation potential is usually conducted in parallel to Phase II studies. Similar to testing of sensitisation potential, this study consists of a three-week induction phase followed by a rest and challenge phase. Following each application of the test formulations the test fields are exposed to UV light. Twenty-five to 50 subjects are usually included in a panel for testing photoallergic contact sensitisation potential. There are many variations in designs for cutaneous safety studies. Most notably, there is no harmonisation in accepted designs between national authorities, eg for sample sizes. Therefore, unless the most conservative test design is selected, approval of designs should be obtained from the respective authorities before study conduct.

Outcome measures

A well-designed clinical trial is dependent on valid, reliable and relevant outcome measures. Due to the lack of validated tests of clinical significance that measure skin function and are adequately standardised for multicentre use, the therapeutic response is generally monitored using lesion counts and scoring systems in pivotal trials. In indications such as acne and actinic keratosis, the percent reduction in lesions is the primary outcome measure usually preferred by authorities due to greater objectivity than possible with clinical scoring. Scoring is subjective and interobserver variation is likely to be a problem with all grading systems involving visual assessment by investigators. The use of inadequately standardised grading systems harbours the risk of erroneous and non-reproducible results. Therefore, the selection of the most suitable scoring system is paramount to trial success, especially if there is no alternative measure for the primary outcome. Descriptive grading scales, visual analogue scales and photographic grading scales all have their merits and disadvantages, depending on indication and investigator experience.

Bhor and Pande4 have compiled a fairly comprehensive listing of existing scores used for common skin diseases. In the case of psoriasis and atopic dermatitis, widely used grading systems such as the PASI (Psoriasis Area and Severity Index), Scorad (Scoring atopic dermatitis) or EASI (Erythema Area and Severity Index) have gained acceptance. However, high interobserver variability has been reported even for these well standardised grading systems. There is a need for validation of more objective outcome measures which can be used in dermatology. While there are a number of wellknown non-invasive bioengineering methods which are routinely used for the investigation of skin function, these methods are rarely used in drug development. At present their use is largely limited to POC studies which can be conducted in one or two centres specialised in these methods.

The first steps toward establishing validity of the use of noninvasive skin function tests to improve standardisation of disease grading have already been made for atopic dermatitis. A score called OSAAD (Objective Severity Assessment of Atopic Dermatitis) has been developed which is based on assessment of epidermal barrier function using TEWL, stratum corneum moisturisation using corneometry and computer-assisted estimates of disease extent. Grading of atopic dermatitis severity using OSAAD correlated well with independent observations using SCORAD in children and adults5,6. Interobserver variability was lower using OSAAD than SCORAD in a trial with three independent investigators6. Regardless of which outcome measure is chosen, in a confirmatory therapeutic trial reponders must be defined within the framework of a clinically relevant response using the selected primary outcome measure.

Photographic documentation

In pivotal efficacy studies it is advisable to document each patient’s therapeutic response by taking photographs at least at baseline and end of treatment. Regulatory agencies may use these photographs for auditing purposes. The degree of standardisation necessary for this documentation differs. For photographs which are only to be used as supporting documentation it may not be necessary to standardise the photographic equipment over all sites. Most dermatological clinics have experienced photographers and make high quality photographs. However, in some trials photographic methodology may be used to complement lesion counting or to measure the size of lesions. In these instances highly standardised photographs must be made and all investigators must be trained in the use of identical equipment, including cameras, lenses, flashes and backdrop. If photographs are part of the essential trial documentation, the integrity of the original must be ensured. Photographic documentation of unexpected adverse skin reactions can be extremely helpful. In multicentre trials it is necessary to instruct the investigators accordingly.

Development Strategy

The advantages of topical therapy can be optimally used in early clinical development. It may be possible to establish clinical efficacy for topical drugs before committing to a full clinical and safety program. Since a small treatment area can often be selected for dosing of topical therapies, potential side effects associated with systemic exposure can be eliminated. In many cases a POC study with a NCE may be conducted with only minimal human safety data, eg a five-day cumulative local irritation study.

Topical application to the skin offers a unique opportunity for simultaneous evaluation of multiple products in intra-individual or within-patient comparison. Parallel comparison of various formulations in one individual reduces inter-subject variability and consequently smaller panel sizes are needed to determine efficacy. The use of intra-individual comparisons is restricted to exploratory trials, evaluating short-term changes in skin disease. In a number of dermatological indications such as psoriasis, atopic dermatitis and other inflammatory conditions, established test designs or models using intra-individual comparison in “symptomatic” volunteers or healthy subjects may be used to evaluate efficacy before proceeding with therapeutic trials in large numbers of patients. In these models changes in skin function and structure measured using non-invasive biophysical methods can be used as endpoints.

As true for every therapeutic area, early efficacy and POC studies occupy a critical position in clinical development strategy. Since these studies lead to go/no go decisions in product development, it is important to critically evaluate every facet of study design. Results from these studies are often the basis for design of later therapeutic trials, eg sample size calculation, choice of outcome measures and response criteria, and dose selection. In most dermatological programs the Phase II dose-ranging trial is exploratory with parallel group comparisons. If instead a confirmatory design is chosen, the pros and cons of hierarchical testing procedures versus pair-wise comparisons with alpha-correction must be weighed. Ideally the grading and photographic systems which are planned for the Phase III studies are also used in the late Phase II trials.

In late clinical development therapeutic confirmatory trials must include adequate follow-ups in order to explore the duration of response as well as relapses or rebounds. Long-term safety, the length of which depends on the indication and drug under investigation, must also be documented in Phase III. In most dermatological programs two pivotal Phase III therapeutic confirmatory studies are conducted before submission for registration. However, it may be conceivable to design a dermatological program with only one very well designed Phase III trial if sufficient confirmatory trials are included in Phase II.

There is no single, clearly defined path to registration of topical products which can be used for every clinical program. There should be continual dialogue with the authorities about the specialties associated with each drug and indication. The challenge in dermatological development is to find the best and most efficient path for each new product.

Betsy Hughes-Formella, PhD

Betsy Hughes-Formella is Director of Business Development and Consulting at bioskin GmbH. She received her MS and PhD in Physiology from the University of Georgia, Athens, Georgia before moving to Germany to join a research team at the University Medical Center in Hamburg. Betsy’s research interests were in the areas of steroid biochemistry and the pathogenesis of melanoma. In 1993 Dr. Hughes-Formella joined bioskin. In her current function she is responsible for the co-ordination of the company’s business development activities and is a consultant and advisor for clinical development concepts and study designs.

Betsy.Hughes@bioskin.de
bioskin GmbH
Burchardstrasse 17
20095 Hamburg
Germany

Notes
1. Guidance for Industry. Acne Vulgaris: Developing Drugs for Treatment (Draft). U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). September 2005
2. Guideline on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriasis. Committee for Medicinal Products for Human Use (CHMP). European Medicines Agency Evaluation of Medicines for Human Use. 18 November 2004
3. Guidance: Topical Dermatologic Corticosteroids: In vivo Bioequivalence. Division of Bioequivalence. Office of Generic Drugs. Food and Drug Administration. June 1995
4. Bhor U, Pande S. Scoring systems in dermatology. Indian J Dermatol Venerol Leprol 2006; 72:315-321
5. Sugarman JL, Fluhr JW, Fowler AJ, Bruckner T, Diepgen TL, Williams ML. The Objective Severity Assessment of Atopic Dermatitis Score. Arch Dermatol. 2003; 139: 1417-1422
6. Angelova-Fischer I, Bauer A, Hipler UC, Petrov I, Kazandjieva J, Bruckner T, Diepgen T, Tsankov N, Williams M, Fischer TW, Elsner P, Fluhr JW. The Objective Severity Assessment of Atopic Dermatitis (OSAAD) score: validity, reliability and sensitivity in adult patients with atopic dermatitis. British Journal of Dermatology 2005; 153: 767-773

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