Skin Diseases Clinical Trials Roundtable Summary

Friday, December 11, 2009

NIH Campus, Building 31, Room 6C10
Bethesda, Maryland

Co-chairs
Stephen I. Katz, M.D., Ph.D., NIAMS
Robert H. Carter, M.D., NIAMS
Susana A. Serrate-Sztein, M.D., NIAMS

Introduction

This roundtable was convened as part of a larger NIAMS effort to assess its support of clinical trials across the Institute’s mission areas. Goals include defining needs and opportunities, as well as identifying key steps for evaluating trials and the significance of individual studies in the broader context of future clinical needs. There were prior discussions on the subject at the 2009 NIAMS Scientific Retreat and with the NIAMS Advisory Council. A Council subcommittee is being created for further developments. Roundtable attendees canvassed their relevant communities in advance, to bring more than their own opinions to the meeting.

Current needs

The treatments for most skin diseases vary across clinical settings, generally according to practitioner training or habits. The empirical use of drugs, such as systemic and topical corticosteroids, is often a balance between clinical responses and adverse events. There is a need for data-driven therapies for many specific conditions, such as prevention of ulcers and wound recurrence, non-melanoma skin cancer (including "watchful waiting" of biopsied lesions before launching more treatment), pediatric atopic dermatitis (AD), and alopecia areata. Wound healing, in particular, involves numerous disciplines (surgery, geriatrics, endocrinology), which adds complexity to the development of evidence-based medicine. Comparative effectiveness research (CER) is another critical need for the range of dermatological disorders; however, CER requires consensus on standardized treatments, and only the most common skin diseases, such as acne and psoriasis, are managed similarly across clinical practices.

The variation in presentation and progression in skin diseases and symptoms, such as psoriasis, allergic contact dermatitis, urticaria, and itch, hamper treatments, as well as research efforts. Skin conditions are often sequellae of other diseases. In turn, there are potential comorbidities for skin disorders, such as cardiovascular disease (CVD) in psoriasis patients, as well as systemic effects of skin disease treat-ments. Better characterization and subtyping of skin diseases, surrogate markers (e.g., for CVD), and uniform, validated outcome measures would enhance the design and conclusions of clinical trials and, ultimately, effective treatments. Initially, head-to-head comparisons of current outcome tools could be conducted.

Future efforts in personalized medicine will rely on knowledge of pathogenic mechanisms, molecular characterization of disease subtypes, and understanding the genetic basis of individual responses and adverse reactions to drugs, in children and adults. Recent research has revealed common mechanistic pathways between skin diseases and disorders in other organ systems, such as basal cell carcinoma and some visceral cancers, and psoriasis and several pro-inflammatory conditions, including Crohn’s disease. Some of these pathways involved in the pathogenesis of disease are the targets of existing drugs, including biologics for rheumatic diseases and other disorders, which could be evaluated and tested for skin disease therapies. Studies in mechanisms of action of biologics and other therapeutic compounds in systemic and skin diseases will provide further insights. Delivery of therapeutics, particularly nucleic acids, is another challenge, for skin diseases. Advances in skin may also inform drug delivery strategies for systemic treatments.

Rigorous research on prevention strategies is needed, for skin cancer, the subsequent development of asthma in pediatric AD, and relapses that may follow some treatments. There may be primary findings from large, observational research projects, such as data from the Women’s Health Initiative, that may provide insights into low-fat diets and skin cancer, but they must be validated in larger, controlled studies.

Different patient populations, such as children, minorities, and seniors, require specific disease management strategies. Patient needs, preferences, and quality-of-life issues for many diseases and symptoms, including keloids, scarring, and itch, must also be addressed. Behavioral research related to prevention (e.g., sun exposure and skin cancer risk) and treatment (e.g., for leg ulcers) needs to be included.

Future needs: obtaining input for important questions

The NIAMS seeks methods for receiving continuous information concerning the needs of the clinical research, clinician, and patient communities. Face-to-face roundtables and consensus conferences with stakeholders, such as clinical investigators, professional groups, clinicians, and patient groups, are useful approaches. It is particularly important to include practicing physicians and patients, because of their awareness of the daily clinical problems and essential participation in future clinical trials. Focused workshops, drawn from topics proposed by the community, such as CVD in psoriasis, could clarify clinical needs and opportunities. Web forms and social networking strategies, which have already been used to involve the skin disease patient community, can be employed to solicit concepts for funding initiatives from the broader research community, practicing physicians, and patient groups.

Professional society conferences are good venues for satellite meetings that focus on potential future clinical trials. Scientific sessions could conclude with brief discussions of translational research opportunities, and clinical needs and applications related to the session topics. Grant recipients could be encouraged to identify similar possibilities in progress reports. Formal literature reviews could also be used to identify concepts for future clinical trials.

Opportunities

Multi-site clinical trials can be very effective for attaining sufficient participant enrollment for clinical trials of relatively rare diseases. Many skin disorders may be classified as rare; however, the multi-site approach has not been used much in dermatology research. There are existing examples of cooperative groups in other disciplines, such as oncology and pediatric rheumatology (the Childhood Arthritis and Rheumatology Research Alliance, http://www.carragroup.org/) that could be models for skin clinical trial networks. Community physicians and physician assistants can be included in clinical research teams, to expand participation and recruitment efforts beyond the traditional limits of academic medicine.

Private foundations and professional societies are important resources for the formation, development, and funding of clinical trials networks, and can leverage support from federal and private sources, for subgroups of investigators pursuing individual diseases and specific projects. Fostering communications and collaborations with other disciplines is also important for reaching dermatology research and treatment goals. Disease registries and existing databases, particularly those from larger medical systems that are linked with genetic information and medical records, such as the Utah Population Database (http://www.hci.utah.edu/groups/ppr/), the U.S. Veterans Health Administration, and the United Kingdom’s National Health Service, would be valuable resources for long-term care studies and generating new questions for testing in clinical trials.

The Clinical and Translational Science Awards (CTSAs, funded by the NIH National Center for Research Resources) provide essential clinical research services to grantee institutions, such as regulatory document preparation, research nursing, and pilot study support, including manufacture of small quantities of clinical-grade therapeutic agents. Incorporating dermatology-oriented services, such as relevant expertise in nursing and regulatory staff, and topical agent preparation and skin therapeutic delivery systems, would enhance the utility of CTSAs for skin disease clinical trials. CTSAs, the NIAMS, and the rest of NIH offer many training initiatives for the next generation of clinical researchers, including a fellowship co-sponsored by the NIAMS and the American Skin Association for post-graduate training in epidemiology, clinical trials, and outcomes research in skin diseases. However, relatively few new dermatology investigators have pursued these funding opportunities.

Tools for measuring patient-reported outcomes (PROs) would be very useful for addressing quality-of-life issues in skin disease clinical trials, such as pain, itch, and fatigue. The NIH Roadmap for Medical Research’s Patient-Reported Outcomes Measurement Information System (PROMIS, http://www.nihpromis.org) initiative aims to assess PROs more precisely and efficiently, for a broad array of chronic diseases. The processes used by the international working group, Outcome Measures in Rheumatoid Arthritis in Clinical Trials (OMERACT), may provide a model for the dermatology research community’s development of standardized evaluation tools.

Prioritization

Limited resources encourage the development of predictors (biomarkers) of successful trials. The NIAMS will be requiring completion of a grant-supported planning phase, followed by a cooperative grant mechanism, for all clinical trials it funds.

A survey of a variety of stakeholders, such as researchers, providers, and patients, could be employed to systematically incorporate multiple factors into a conceptual framework for evaluating clinical trial priorities. Considerations could include:

  • economic and social burdens of the condition (e.g., healthcare costs, disability-adjusted life years, quality-of-life impact)
  • gaps in current evidence to justify the trial
  • biological plausibility of hypotheses
  • realistic clinical benefits
  • contribution to knowledge about mechanisms of action
  • project cost and feasibility

The NIAMS’s assessment of disease burden, which is one aspect of decisions about clinical trial support, considers the range of common and rare diseases. Disease prevalence is not included, so that many more disorders and patient populations receive due attention.

Meeting Participants

BAKER, Carl C., M.D., Ph.D.
Director, Keratinocyte Biology and Diseases Program
Division of Skin and Rheumatic Diseases
NIAMS

BECK, Lisa, M.D.
Director, Translational Research
Department of Dermatology
University of Rochester

BROWN, Patricia, M.D.
Medical Staff Member, Division of Dermatology and Dental Products
Center for Drug Evaluation and Research
Food and Drug Administration

CHREN, Mary-Margaret, M.D.
Director, Health Services Research Enhancement Award Program
Veterans Affairs Medical Center, San Francisco

CIBOTTI, Ricardo, Ph.D.
Director, Immunobiology and Immune Diseases of Skin Program
Division of Skin and Rheumatic Diseases
NIAMS

COOPER, Kevin, M.D.
Chairman, Department of Dermatology
Case Western Reserve University

EPSTEIN, Ervin, M.D.
Clinical Professor
Children’s Hospital Oakland Research Institute

FALANGA, Vincent, M.D.
Chairman, Department of Dermatology and Skin Surgery
Roger Williams Medical Center

GELFAND, Joel, M.D.
Medical Director, Clinical Studies Unit
Department of Dermatology
University of Pennsylvania

GOLDSMITH, Lowell, M.D.
Professor Emeritus, Department of Dermatology
University of North Carolina—Chapel Hill

HALL, Russell, M.D.
Interim Chair, Department of Dermatology
Duke University Medical Center

JACOBE, Heidi, M.D.
Assistant Professor, Department of Dermatology
University of Texas Southwestern Medical Center

KONG, Heidi, M.D.
Assistant Clinical Investigator, Intramural Research Program
National Cancer Institute, NIH

LEACHMAN, Sancy A, M.D., Ph.D.
Director, Melanoma and Cutaneous Oncology Program
University of Utah

PALLER, Amy, M.D.
Chair, Department of Dermatology
Northwestern University

PICKFORD, Jean
Executive Director
Foundation for Ichthyosis and Related Skin Types

TANG, Jean, M.D., Ph.D.
Assistant Professor, Department of Dermatology
Stanford University School of Medicine

TSENG, Hung, Ph.D.
Director, Extracellular Matrix Biology and Diseases Program
Division of Skin and Rheumatic Diseases
NIAMS