The FDA has been presented the robust evidence to support new primary wound care endpoints in clinical trials for approvals of new devices and drugs. This author details the new proposed endpoints and the collaborative approach that went into identifying them.
After years of hard work and research by countless dedicated wound care clinicians and advocates, the Food and Drug Administration (FDA) noted in a statement in September that it is “open to discussing each endpoint with sponsors, but each endpoint needs to be validated with a specific measurement tool that has validation data behind it.” The FDA also noted that for a qualified clinical outcome measure, more information on the context of use should be provided.
It all began with the groundbreaking work of Robert Kirsner, MD, PhD, William Eaglstein, MD, and Martin Robson, MD, who researched and published data on the enormous impact of wounds to the health system with an incidence larger than some types of cancers, and the lack of sufficient primary endpoints for new device and drug approvals by the FDA.1
This vital work was shared by a core group of wound care experts with the FDA’s newly formed Inter-Center Wound Healing Work Group (ICWHWG). Following these meetings and discussions in June 2015, the Association for the Advancement of Wound Care (AAWC) initiated the Wound Experts/FDA Clinical Endpoints Project (WEF-CEP). Under the leadership of Vickie Driver, DPM, then President of AAWC, funding was solicited and attained. Soon thereafter, the Wound Healing Society, under the leadership of Lisa Gould, MD, PhD, joined the initiative as a co-host. Collaboratively these clinician-based organizations embraced the goal to identify, research, and validate clinically meaningful and patient-centered primary endpoints for new device or drug development and approvals.
This was the first true collaborative approach in which the wound care community worked hand in hand with the FDA to define a pathway, set goals and determine the data needed to recommend changes in the way clinical trials are conducted for wound care device and drug approvals.
But it wasn’t easy and it was no small feat.
How the Endpoints Were Identified
First, the WEF-CEP had to identify the endpoints that wound care experts thought were clinically meaningful and relevant to research trials and then evaluate this list with a broader range of multispecialty wound care clinicians (628) through surveys for 28 endpoints (phase 1). A biostatistician analyzed the results and calculated the content validity indexes (CVI) for each of the 28 endpoints. Utilizing the endpoints with the highest CVI scores (>0.85), 15 endpoints were identified for inclusion in the research phase. Teams of volunteer researchers and clinicians were identified and trained in the FDA Clinical Outcome Assessment (COA) Qualification Process for development of tools before beginning their work. Six teams reviewed the literature to validate the top 15 endpoints using criteria set by the FDA (construct validity, reliability, ability to detect change, and responder analysis) (phase 2).
Throughout all that effort, the WEF-CEP team continued to share progress and results with the FDA and conducted an educational seminar in 2017 on the methodology and results of the clinician survey and an update session on the research results in 2018. Additionally, WEF-CEP published the clinician survey results and the research validation results.2,3 But we still needed the patient’s perspective.
Between 2017–2018, an institutional review board (IRB) approved survey was developed and conducted with patients (438), again by all volunteer clinicians and facilities, using the patient-centered endpoints from the clinicians’ survey. This was done to determine what is important for both the clinical outcome and the patient regarding new wound care devices and drugs (phase 3). The preliminary results were shared with the FDA in the fall of 2018 and the final data have been accepted for publication.
In August 2019, the final WEF-CEP Research and Recommendations Packet (60 pages) was submitted to the FDA Inter-Center Wound Healing Work Group (ICWHWG) and a flurry of actions followed. By November 2019, WEF-CEP submitted an application to the FDA’s Critical Path Innovation Meeting (CPIM) Committee, managed by the Office of Translational Sciences requesting a meeting review. Approval from the FDA was received in January 2020 and the required presentation and data materials submitted in February with a scheduled meeting at FDA on March 25. And then COVID-19 restrictions hit.
Undeterred, the WEF-CEP rescheduled the CPIM and on June 1 conducted an exploratory meeting with Michelle Tarver, MD, PhD, and Laurie Marqualt, MD, from the FDA Patient Science and Engagement group in the Office of Strategic Partnerships & Technology Innovation to explore the Collaborative Community model.
On June 29, 2020, the FDA CPIM was conducted (virtually) with WEF-CEP, industry representatives and the CPIM participants from the ICWHWG, the Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER), and the Center for Drug Evaluation and Research (CDER). In July, following the CPIM, the WEF-CEP developed and provided FDA with “context” charts to relate each endpoint to applicable wound types and preliminary summary charts with known measurement methods/tools to evaluate outcomes for each endpoint as requested by the FDA.
In August, the FDA shared with the WEF-CEP that in an effort to consolidate and coordinate efforts by CDER, CDRH and CBER, the CDER Office of New Drugs (OND), Division of Dermatology and Dentistry (DDD) has agreed to participate in a strategic planning pilot on wound healing and will coordinate further communication between the FDA and WEF-CEP. A meeting will be scheduled by FDA to review the next steps for such an initiative and pilot.
In early September, in large part based on the robust new evidence, the FDA confirmed it was open to discussing the below listed proposed primary endpoints with industry for use in clinical trials for new devices and drug approval:
1. Percent area reduction (PAR)
2. Reduced infection
3. Reduced pain/reduced analgesia use
4. Increased physical function and ambulation
5. Quality of life
Desmond Bell, DPM, CWS, notes the work on the endpoints is “really important.” For the second proposed endpoint of reduced infection, he wonders if that is measurable versus “incidence of infection.”
“Unless there is some way to compare overall occurrence of wound infections, I don’t see how measurement of such a reduction is achievable whereas measuring the incidence of infection in a study is,” says Dr. Bell.
Cost-effectiveness has been discussed as a useful endpoint but the FDA has made it clear that at this time, cost is not a factor that they can include in their deliberations and presumably this includes cost-effectiveness.
Over the years, the FDA has recognized the value of collaboration with stakeholders and formalized a process for multi-stakeholder groups to apply to FDA to work together to achieve goals that impact large patient populations and clinical practice to improve care and outcomes. Drs. Driver and Gould are now in the process of applying to FDA to form a “Wound Care Collaborative Community” to engage industry, patients, wound care specialists, associations and societies, payers, advocates, and FDA in addressing broad wound care issues, identifying methods, tools and future approaches to measure wound care outcomes, setting standards for wound care evidence and evaluating processes to improve the adoption of new evidence for devices and drugs by FDA and payers (phase 4).
So hats off to the WEF-CEP leaders Dr. Vickie Driver (Chair) and Dr. Lisa Gould (Co-chair), and their support team (Gary Gibbons, MD, Marissa Carter, PhD, Laura Bolton, PhD, and Peggy Dotson, RN, BS), who have been unwavering in their persistence to get this done for patients and the wound care community and to the AAWC and WHS, along with industry for their ongoing support to achieve this milestone.
Peggy Dotson, RN, BS, is President of Healthcare Reimbursement Strategy, a consultancy focused on coverage and payment issues for new devices and technologies. She has served as the volunteer WEF-CEP project coordinator since 2014 and was Chair of the AAWC Public Policy Committee from 2009-2019.
1. Eaglstein WH, Kirsner RS, Robson MC. Food and Drug Administration (FDA) drug approval endpoints for chronic cutaneous ulcer studies. Wound Rep Regen. 2012;20(6):793–796.
2. Driver VR, Gould LJ, Dotson P, Gibbons G, Li WW, Ennis WJ, Kirsner RS, Eaglstein WH, Bolton LL, Carter MJ. Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Wound Rep Regen. 2017;25 (3):454–465.
3. Driver VR, Gould LJ, Dotson P, Allen LL, Carter MJ, Bolton LL. Evidence supporting wound care endpoints relevant to clinical practice and patients’ lives. Part 2. Wound Rep Regen. 2019; 27(1):80–89.
4. Liu J, Driver VR, Carter MJ, Dotson M, Wan R, Gould LJ. Evidence supporting wound care end points relevant to clinical practice and patients’ lives. Part 3: the patient survey. Accepted for publication to Wound Rep Regen in September 2020.