Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community.

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.

End points in dermatologic clinical trials: A review for clinicians.

Clinical trials are critical for the development of new therapies in dermatology, and their results help determine US Food and Drug Administration (FDA) approval and guide care. Of special relevance is the clinical trial efficacy end point, the metric from which statistically significant outcome is derived. Clinicians' understanding of a clinical trial's end point is necessary for critical analysis of the trial results and for applying those results to daily practice. This review provides practical knowledge and critical evaluation of end points used in treatment approvals by the FDA. The end points for actinic keratosis, acne vulgaris, atopic dermatitis, onychomycosis, and cutaneous ulcer serve as examples.

Food and Drug Administration (FDA) drug approval end points for chronic cutaneous ulcer studies.

The rising costs of caring for chronic cutaneous ulcers (CCUs) and recent appreciation of the mortality of CCUs have led to consideration of the reasons for the failure to have new drug therapies. No new chemical entities to heal CCUs have been approved by the Food and Drug Administration (FDA) in over a decade, in part due to an inability to reach the FDA accepted end point of "complete wound closure." The frequent failure to reach the complete closure end point brings forward the question of the relevance of other healing end points such as improved quality of life, or partial healing. Because CCUs carry a prognosis and mortality rate worse than many cancers, it is reasonable to compare the FDA trial end points for cancer drug approval with those for CCUs. And the difference is quite striking. While there is only one end point for CCUs, there are five surrogate and three direct end points for cancers. In contrast to cancer, surrogate end points and partial healing are not acceptable for therapies aimed at CCUs. For example, making tumors smaller is an acceptable end point, but making CCUs smaller is not and improvement in the signs and symptoms of cancer is an acceptable end point for cancers but not CCUs. As CCUs carry a prognosis and mortality rate worse than many cancers, we believe a reconsideration of end points for CCUs is highly warranted.

The FDA and designing clinical trials for chronic cutaneous ulcers.

Treatment of chronic wounds can present a challenge, with many patients remaining refractory to available advanced therapies. As such, there is a strong need for the development of new products. Unfortunately, despite this demand, few new wound-related drugs have been approved over the past decade. This is in part due to unsuccessful clinical trials and subsequent lack of Food and Drug Administration (FDA) approval. In this article, we discuss the FDA approval process, how it relates to chronic wound trials, common issues that arise, and how best to manage them. Additionally, problems encountered specific to diabetic foot ulcers (DFU) and venous leg ulcers (VLU) are addressed. Careful construction of a clinical trial is necessary in order to achieve the best possible efficacy outcomes and thereby, gain FDA approval. How to design an optimal trial is outlined.

New drugs and new molecular entities in dermatology.

OBJECTIVE: To identify and analyze the possible reasons that so few drugs with new molecular entities (NMEs) are first developed for "dermatologic diseases," especially diseases treated primarily by dermatologists. DESIGN: Systematic review and analysis. IMS Health (the pharmaceutical industry worldwide product database) was searched using the terms first launch, topical, and skin/dermatological for the preceding decade. These terms were used for inclusion but not exclusion so that intravenous and oral agents were also identified if they were for skin or dermatologic use. The US Food and Drug Administration (FDA) New Molecular Entities Drug and New Biologic Approvals Web site for the 10 years from 1999 to 2009 was examined for approval of dermatologic agents. To determine the frequency of drug development for dermatologic drugs compared with other fields, the total number of NMEs by therapeutic category for the 5-year period 2005 to 2009 was assessed. RESULTS: Worldwide, the total number of NMEs for diseases treated primarily by dermatologists for almost a decade was 13. Using the FDA Web site, 5 NMEs for diseases treated primarily by dermatologists were approved in 10 years. CONCLUSIONS: The major factors precluding NME development for dermatologic diseases seem to be (1) the economic potential of dermatologic drugs, (2) the benefit-to-risk relationship, (3) the limited number of surrogate end points and "soft" semiquantitative end points, and (4) the limited or inadequate basic knowledge of the pathophysiologic characteristics of skin diseases.

Evidence-based medicine, the research-practice gap, and biases in medical and surgical decision making in dermatology.

The objectives of this article are to promote a better understanding of a group of biases that influence therapeutic decision making by physicians/dermatologists and to raise the awareness that these biases contribute to a research-practice gap that has an impact on physicians and treatment solutions. The literature included a wide range of peer-reviewed articles dealing with biases in decision making, evidence-based medicine, randomized controlled clinical trials, and the research-practice gap. Bias against new therapies, bias in favor of indirect harm or omission, and bias against change when multiple new choices are offered may unconsciously affect therapeutic decision making. Although there is no comprehensive understanding or theory as to how choices are made by physicians, recognition of certain cognition patterns and their associated biases will help narrow the research-practice gap and optimize decision making regarding therapeutic choices.

A gene signature of nonhealing venous ulcers: potential diagnostic markers.

BACKGROUND: Venous leg ulcers are responsible for more than half of all lower extremity ulcerations. Significant interest has been focused on understanding the physiologic basis on which patients fail to heal with standard therapy. OBJECTIVE: This study uses complementary DNA microarray analysis of tissue samples from healing and nonhealing venous leg ulcers to identify the genetic expression profiles from these dichotomous populations. METHODS: Ulcer size and chronicity, factors that have been identified as prognostic indicators for healing, were used to distribute venous leg ulcers as healing versus nonhealing. Punch biopsy samples were obtained from the wound edge and wound bed of all venous leg ulcers. The top 15 genes with differential expression greater than 2-fold between the two populations of wounds (P < .05) were reported. RESULTS: Significant differences were demonstrated in the expression of a diverse collection of genes, with particular differences demonstrated by genes coding for structural epidermal proteins, genes associated with hyperproliferation and tissue injury, and transcription factors. LIMITATIONS: Small sample size may mitigate potential clinical implications of findings. CONCLUSIONS: The genetic expression profiles displayed here may have implications for the development of novel therapies for chronic venous leg ulcers, and may also serve as prognostic indicators for wound healing.

Microscopic and physiologic evidence for biofilm-associated wound colonization in vivo.

A biofilm is a collection of microbial cells that are attached to a surface and embedded in a self-produced extrapolymeric substance. The understanding of the biofilm phenotype is important in the understanding of bacteria in vitro but it has been difficult to translate biofilm science to the clinical setting. More recently, preliminary criteria for defining biofilm associated diseases have been proposed and the purpose of this study was to create a biofilm-associated wound model based on these criteria. Using a porcine model, partial thickness wounds were inoculated with a wound isolate Staphylococcus aureus strain. Wounds were then treated with either one of two topical antimicrobial agents (mupriocin cream or triple antibiotic ointment) within 15 minutes to represent planktonic bacteria or 48 hours after initial inoculation to represent biofilm-associated wound infection. Using light microscopy, scanning electron microscopy and epifluorescence microscopy, we were able to observe biofilm-like structures in wounds after 48 hours of inoculation and occlusion. The in vivo antimicrobial assay was used to demonstrate that both mupirocin cream and the triple antibiotic ointment were effective in reducing planktonic S. aureus but had reduced efficacy against biofilm-embedded S. aureus. Our results demonstrated that S. aureus form firmly attached microcolonies and colonies of bacteria encased in an extracellular matrix on the surface of the wounds. These biofilm-like communities also demonstrated increased antimicrobial resistance when compared with their planktonic phenotype in vivo. The structural and physiological results support the hypothesis that bacterial biofilms play a role in wound colonization and infection.

Topical oxygen emulsion: a novel wound therapy.

OBJECTIVE: To investigate the use of a topical oxygen emulsion (TOE), consisting of a supersaturated oxygen suspension using perfluorocarbon components, on second-degree burns and partial-thickness wounds. DESIGN: Oxygen is a required substance for various aspects of wound repair, and increased oxygen tension in a wound has been shown to stimulate phagocytosis and to reduce the incidence of wound infection. Second-degree burns and partial-thickness wounds were created on the backs of specific pathogen-free pigs. Wounds were then randomly assigned to 1 of the following treatment groups: TOE, TOE vehicle, or air-exposed control. MAIN OUTCOME MEASURE: Wounds were assessed for complete epithelialization using a salt-split technique. RESULTS: The TOE was able to significantly (P = .001) enhance the rate of epithelialization compared with both vehicle and untreated control. These data suggest that topical oxygen may be beneficial for acute and burn wounds. CONCLUSIONS: The results obtained from this double-blind, control, in vivo study demonstrate that TOE can significantly enhance the rate of epithelialization of partial-thickness excisional wounds and second-degree burns. These findings could have considerable clinical implications for patients with surgical and burn wounds by providing functional skin at an earlier date to act as a barrier against environmental factors, such as bacteria invasion. Other types of wounds may also benefit from this therapy (eg, chronic wounds and surgical incisions). Additional studies, including clinical studies, are warranted.

Evaluation of Apligraf persistence and basement membrane restoration in donor site wounds: a pilot study.

Apligraf is a bilayered tissue-engineered product consisting of a bovine collagen matrix with neonatal fibroblasts, overlaid by a stratified epithelium containing living keratinocytes. The United States Food and Drug Administration has approved its use for venous leg ulcers and neuropathic diabetic foot ulcers. Apligraf provides a dermal matrix and produces cytokines similar to the human skin. However, its mechanism of action and ultimate fate in host wounds are unclear. The aim of this study was to evaluate the persistence of Apligraf fibroblasts and keratinocytes in human acute partial-thickness wounds (split-thickness donor sites) treated with Apligraf. In an open-label, within-patient, three-centered, controlled pilot study, 10 patients were treated with Apligraf, Apligraf dermis only (without epidermis), and a polyurethane film for donor site wounds of the same size, depth, and anatomical location. Apligraf DNA persistence was the primary outcome measure. Basement membrane components, cosmetic outcome, time to wound healing, and safety parameters were secondary outcome measures. One week after the initial treatment, reverse transcription polymerase chain reaction analysis found that two Apligraf and two Apligraf dermis-only-treated sites had Apligraf DNA present. Four weeks posttreatment, only one Apligraf and one Apligraf dermis-only sites showed the presence of Apligraf DNA. There was no difference between the three treatment modalities in establishing basement membrane in donor site wounds. No differences in other secondary outcomes were found. Apligraf DNA persisted in a minority of patients at 4 weeks in acute partial-thickness wounds. Apligraf's success in speeding healing of acute wounds appears to be related to factors other than the persistence of donor DNA or effect on basement membrane restoration.