Wound Healing Research- The Paradigm Shift by woundmasterclass

Wound Healing Research: The Paradigm Shift

Editorial Summary

Wound healing research is undergoing a transformative shift from single-endpoint clinical studies to patient-centered, multifaceted evaluations. Regulatory changes in both the US and Europe are driving this evolution, demanding more rigorous clinical evidence and broader outcome measures. In the US, the FDA is revising its 2006 guidelines to include additional endpoints beyond complete wound closure, such as Percent Area Reduction, Limb Preservation, and Pain Reduction. Meanwhile, Europe’s Medical Device Regulation (MDR) and Clinical Trials Regulation (CTR) are raising clinical evidence standards and mandating continuous post-market surveillance. Reimbursement challenges further complicate market access. CMS has tightened coverage criteria in the US, recently delisting over 130 wound care products due to insu cient evidence. In Europe, fragmented national healthcare systems require tailored market entry strategies. To navigate this evolving landscape, companies must adopt innovative clinical trial designs, leveraging AI-driven assessments and transatlantic studies. Partnering with specialized wound care CROs will be critical to accelerating regulatory approval and securing reimbursement, ensuring innovative therapies reach patients e ciently.

Introduction

The Wound Care industry stands at the precipice of a fundamental paradigm shift in how clinical evidence is generated and valued, marking a departure from traditional single-endpoint studies to comprehensive, patient-centric clinical trial designs. This transformation is being catalyzed by evolving regulatory frameworks on both sides of the Atlantic, with the FDA’s consideration of expanding its 2006 guidelines to beyond the conventional endpoint of complete wound closure to embrace a spectrum of clinically relevant outcomes, and simultaneously, Europe’s implementation of the Medical Device Regulation (MDR) and Clinical Trials Regulation (CTR) elevating the standards for clinical evidence generation while creating a more uni ed approval pathway across EU member states. This synchronous evolution in regulatory requirements, combined with the increased scrutiny of wound care reimbursement in the US and the heterogenous reimbursement landscape in Europe, is driving a commercial need for companies bringing innovative therapies to market, to substantially increase their investment in clinical trials to meet these diverse regulatory and reimbursement needs. To meet the challenge of this coming paradigm shift, there is a growing requirement for specialized clinical research organizations (CROs) that possess sophisticated wound care expertise across trial design, clinical practice, and regulatory/reimbursement landscapes to help expedite the adoption of these innovative products and meet the urgent patient need for these therapies.

Clinical Data and Regulatory Status

UpdatingtheFDAGuidelines:CreatingopportunitiesforaParadigmShiftin WoundCareResearchintheUSA

In 2006, the United States Food and Drug Administration (FDA) published comprehensive guidance delineating clinical endpoints for validating the e cacy of novel wound care interventions. The guidance established several key, critical methodological and evaluative parameters for clinical trials:

• Standardized wound assessment is essential, requiring precise measurements of wound dimensions at baseline and consistent, predetermined intervals throughout the study duration. This approach ensures objective and reproducible evaluation of wound healing progression.

• The population chosen should optimize the study’s ability to detect

Mark D. Cregan

Global Clinical Research Institute

Copenhagen, Denmark

Morgan Zelen

Global Clinical Research Institute

Copenhagen, Denmark

Bent von Eitzen

Global Clinical Research Institute

Copenhagen, Denmark

David G Armstrong

University of Southern California, Los Angeles California, USA

Marissa J Carter

Strategic Solutions Inc., Bozeman Montana, USA

treatment e ect.

• Standard of care is not de ned by the FDA but should optimize conditions for healing and be prospectively de ned in the protocol.

• Improved wound healing was the only endpoint formally accepted by the FDA to validate wound healing e cacy for new products to market. Wound healing is de ned as the incidence of complete wound closure with full skin re-epithelialization and no drainage being present, which needed to be con rmed at two consecutive study visits 2 weeks apart.

Following the initial guidance publication, an extensive array of wound care clinical trials were conducted adhering to the established single endpoint. However, in contrast to therapeutic interventions targeting other disease states, which routinely leverage multiple endpoints to secure FDA approval, wound care product development remained constrained by a focus on complete wound healing. This precluded the recognition of potentially transformative interventions that o er substantive clinical or patient-centered bene ts that were not captured by the traditional healing-only assessment. Indeed, this was noted by researchers in the eld with some calling the need for intermediate endpoints to be recognized1,2. To this end, in 2014 a comprehensive, cross-disciplinary consortium of wound care specialists collaborated directly with the FDA to systematically develop alternative endpoint criteria. The outcome of this initiative was a recommendation to broaden the accepted endpoint criteria to include both clinical practice relevance and patientcentered outcomes, ensuring a more expansive assessment of potential value of clinical trial interventions3,4,5. These recommended new endpoints are; Percent Area Reduction (PAR), Limb Preservation, Reduced Pain, Reduced Infection, Time to Heal, Time to Recurrence, Improved Ambulation, Increased Patient Activity, Reduced Social Isolation, and Increased Independence6,7. The next step in the process

is for the inclusion of these modi ed endpoints into the o cial FDA guidelines for wound care clinical trials. A process is currently underway, with the Wound Care Collaborative Community (WCCC) being invited by the FDA to suggest updates to the 2006 Guidelines to re$ect these new endpoints (amongst other areas of interest)—a process that is expected to remain ongoing for the remainder of 2025. If implemented, the updated guidelines, could simplify the pathway for wound care companies to address both pre-market regulatory and post-market, market access needs concurrently.

Europe:

A Changing Regulatory Landscape Creating Opportunty for Innovative Clinical Trials

In Europe, for Medical Devices, the Medical Device Regulation (MDR Regulation 2017/745) has strengthened the requirements for obtaining a CE mark compared to the previous Medical Device Directive (MDD) by introducing more stringent standards across all aspects of medical device certi cation. This has had a particular impact on clinical evidence requirements. Manufacturers must now provide more robust clinical data for all device classes that demonstrates clinical bene t, safety, and performance throughout the entire lifecycle of the device. In short, this imposes a need for not only pre-clinical data, but also post- market

Figure 1: Lower leg wound

clinical follow-up is now mandatory, with companies obligated to continuously monitor and validate their devices’ safety and performance in real-world conditions. This data will now be tracked and monitored through a centralized platform for clinical investigation information, called EUDAMED, a database that stores outcomes and safety reports from clinical investigations providing a transparent system where competent authorities and noti ed bodies can access relevant device information.

Meanwhile for Investigational Medical Products, the Clinical Trials Regulation (CTR - EU No 536/2014) and the Clinical Trials Information System (CTIS) harmonized the assessment and supervision processes for clinical trials across the EU. Under this regulation, sponsors can submit a single application through CTIS for conducting clinical trials in multiple EU member states, replacing the previous system that required separate submissions to each national competent authority. This streamlined approach has signi cantly reduced administrative burden and improved e ciency in the drug approval process, enabling collaboration between sponsors, member states, and the European Medicines Agency (EMA), while promoting transparency through public access to trial information. This increased transparency helps prevent duplicate trials and allows better access to trial results for healthcare professionals and patients.

Together, the implementation of the MDR/ EUDAMED and CTR/CTIS has created resource challenges for wound care companies in Europe as they must now invest heavily in clinical studies, strengthen their clinical evidence generation capabilities, and establish comprehensive post-market clinical followup programs. Nonetheless, with forward planning and a creative approach to clinical trials, much like in the USA with the impending implementation of new clinical trial endpoints, the burden of creating this additional evidence can be mitigated by utlizing the opportunity to create innovative clinical trial design to support market access initiatives.

Clinical Data for Market Access

For a new product to successfully enter the market, regulatory clearance is only the rst step, with the next hurdle being to secure reimbursement from payers. In the US this process usually commences with a submission to CMS (Centers for Medicare and Medicaid), followed by the private payers. For some products, an existing CPT or HCPCS code already exists. In these cases, evidence must be generated to demonstrate the product is substantially equivalent to existing, covered technologies - with substantial equivalence de ned as (1) shares mechanism of action with existing technology; (2) falls within the same MSDRG category; and (3) treats similar diseases and patient populations8. However, for innovative new products, clinical data to help identify and communicate the product’s value proposition needs to be generated to demonstrate that this product is not substantially equivalent to existing reimbursement codes. In stark contrast to the US, one of the most challenging aspects of the European market is its diversity, with each country maintaining its own distinct healthcare system, with unique processes for evaluating and approving new treatments. This fragmentation means that companies must carefully plan their market entry strategies, as decisions made in one country can signi cantly impact opportunities in others. As a consequence of

Figure 2: Skin substitute

While wound care technology has advanced considerably over the past three decades, coding language has not kept pace, creating systemic barriers for the integration of cutting-edge solutions—even those with FDA clearance. A notable example is the emerging Micro Water Jet technology for wound bed preparation, which has demonstrated promising clinical outcomes10,11. Despite its potential, this technology faces substantial reimbursement challenges under existing codes.

each European country operating independently, the structure of healthcare decision-making varies dramatically across Europe. Some countries have adopted streamlined, national-level systems where a single authority makes decisions that apply countrywide. The Netherlands exempli es this approach, with its straightforward centralized process. In contrast, countries like Italy maintain more complex regional systems, where local authorities have considerable independence in healthcare decisions, often leading to varying levels of treatment access within the same nation. Di erent European nations also take distinct approaches to assessing a treatment’s worth. The German system, for instance, places primary importance on robust clinical evidence and appropriate comparison to existing treatments. British authorities focus heavily on cost-e ectiveness, using sophisticated analyses to determine whether a treatment’s bene ts justify its cost. Southern European nations like Spain tend to emphasize overall healthcare budget considerations, scrutinizing expensive treatments that might strain healthcare resources. Despite, this heterogeneity, one common theme prevails; European payers wield considerable in$uence over healthcare providers and patients, and their requirements for robust, high quality, innovative and creative clinical data to address di ering national priorities are fundamental to achieving reimbursement in European markets.

Case Studies: Clinical Data and Coverage.

A case study in point is the importance of clinical data for achieving lasting coverage. Recently, Medicare’s monthly expenditure on cellular and tissue-based products (CTPs) reached $1 billion, triggering a Local Coverage Determination (LCD) review where they used the GRADE system to assess the e cacy of these products and evaluate the quality of each CTP’s supporting clinical evidence. Following this substantive review, Medicare approved only 15 CTPs for ongoing coverage and removed an additional 130, citing insu cient clinical evidence

of quality demonstrating their e cacy9. An important observation of this ruling is that of the 15 CTPs which retained their coverage, eight generated their clinical data through a specialized wound care CRO with detailed knowledge of data generation in the eld, emphasizing the importance of working with a specialist and experience clinical trial partner with detailed knowledge of the disease. Current CPT and HCPCS codes often present signi cant challenges for the adoption and reimbursement of innovative wound care products due to outdated terminology and descriptors. While wound care technology has advanced considerably over the past three decades, coding language has not kept pace, creating systemic barriers for the integration of cutting-edge solutions—even those with FDA clearance. A notable example is the emerging Micro Water Jet technology for wound bed preparation, which has demonstrated promising clinical outcomes10,11. Despite its potential, this technology faces substantial reimbursement challenges under existing codes. The currently available CPT codes, 97597 and 97598, were originally written to describe “high-pressure” wound irrigation techniques, speci cally pulse lavage systems operating at pressures of 5-10 psi. However, these codes fail to capture the capabilities of modern technologies like Micro Water Jet systems, which operate at signi cantly higher pressures (2,000-3,000 psi) and require more advanced, cost-intensive manufacturing processes.

This misalignment between coding language and technological advancements creates nancial disincentives for adopting newer solutions. Manufacturers are compelled to undertake extensive and costly clinical research to justify the di erentiation of their innovative products from procedures inadequately described by outdated codes. This burden delays market entry and widespread adoption of e ective technologies, ultimately impacting patient access to optimal wound care. A reevaluation and update of CPT and HCPCS code descriptors to re$ect

modern wound care techniques are essential. Doing so would not only foster innovation in wound care but also ensure that reimbursement pathways align with current clinical practices and technological advancements, reducing barriers to access for patients and providers alike.

On the European side, several systematic reviews conducted by health technology assessment (HTA) organizations and other independent bodies expressed concerns about the quality of evidence to support the clinical bene ts of negative pressure wound therapy (NPWT). These criticisms highlighted various methodological issues, including problematic outcome measures, insu cient sample sizes, and inappropriate control groups - particularly the comparison with traditional gauze dressings rather than contemporary wound care products12. Similarly, Germany’s Institute for Quality and E ciency in Health Care (IQWiG) concluded that the clinical trial quality for NPWT remained substandard13, while France’s High Authority of Health (HAS) has issued an equally inconclusive assessment regarding NPWT’s therapeutic value due to poor quality clinical evidence14.

Innovative Clinical Trials Driving a Paradigm Shift in Wound Care Research

The landscape of wound care has evolved dramatically since the introduction of negative pressure wound therapy three decades ago, which marked a pivotal shift from basic wound management to active wound healing. Today, innovation in wound care continues at an unprecedented pace, encompassing various breakthrough technologies including precision digital wound measurement, advanced cellular and tissue-based products, antimicrobial cold-plasma applications, re ned wound bed preparation techniques, real-time digital monitoring systems, and promising pharmaceutical interventions. Among these

innovations, Arti cial Intelligence (AI) stands out as a particularly transformative technology, o ering sophisticated solutions for wound assessment, prediction, and treatment planning. AI systems leverage deep learning, machine learning algorithms, and computer vision to analyze wound images and patient data with remarkable accuracy, enabling capabilities ranging from automated tissue segmentation to healing prediction. These systems have proven especially valuable in facilitating remote care through smartphone-based assessments and thermal imaging analysis, capabilities that became crucial during the COVID-19 pandemic.

Despite its proven advantages in improving diagnostic accuracy and enabling standardized assessment methods, the implementation of AI in wound care faces several important challenges. These include the need to develop more comprehensive and diverse training datasets, ensure robust data privacy protections, and establish standardized protocols for image capture across di erent clinical settings. Nevertheless, research consistently demonstrates that AI-supported wound care has the potential to signi cantly reduce healthcare costs while improving patient outcomes through more personalized,

Figure 3: Thermal Imaging

Wound Healing Research: The Paradigm Shift

data-driven approaches. The technology shows particular promise in accelerating wound assessment and enhancing prediction accuracy, potentially transforming how clinicians manage wound care. Moving forward, the key to realizing AI’s full potential in wound care lies in validating these systems through rigorous clinical trials to ensure their e ectiveness and reliability in realworld healthcare settings.

With chronic wounds a ecting over 10 million people and costing $67B annually in the US15, and costing $70B (ie. 4% of total healthcare expenditure) in Europe16,17, the impact of these innovations on the healthcare sector globally will be profound.

To successfully bring these products to market, these innovations will need substantive clinical data, generated to the highest standard.

However, given the paradigm shift in the clinical evidence landscape created by the new FDA–proposed endpoints, and the MDR/ CTR in Europe, a fantastic opportunity exists for these companies to generate high impact, transatlantic clinical evidence that serves both regulatory and market access needs. Indeed, with the implementation of the MDR/CTR in Europe standardising how clinical trials are conducted in Europe, and utilizing the FDAproposed endpoints, it is now realistic for wound care clinical trials to take a transatlantic approach, generating data simultaneously in Europe and the USA supporting both regulatory and market access submissions through the creation of innovative clinical trial designs. However with the design for such clinical trials becoming more expansive and complex, the depth of wound care knowledge required to drive these clinical trials to success will become a major challenge and barrier to success. To this end, having a specialised wound care CRO bringing detailed know-how of wound care trial design, clinical practice, and the regulatory/ reimbursement landscape will become a key asset to companies aiming to bring their product to market with reimbursement in the shorest timeframe possible.

Conclusion

Medicare’s recent LCD review of CTPs demonstrated that products supported by specialized wound care CROs were twenty times

More likely to maintain coverage, highlighting the critical importance of partnering with CROs that possess deep wound care expertise. The convergence of regulatory changes in both the US and Europe, combined with increased market access scrutiny, will drive a shift from single-endpoint studies to comprehensive, patient-centered clinical trial designs. This transition creates both signi cant challenges and unprecedented opportunities to transform wound care research through innovative clinical trial approaches.

As innovations in wound care therapies continue to enter pre- and post-market clinical trial phases, the expertise required to meet these diverse needs will become increasingly specialized. To maximize opportunities, clinical trial sponsors with innovative products should aim to partner with a CRO that possess a sophisticated understanding of wound care clinical trial design, strong clinical knowledge of wound pathophysiology and the practical challenges in wound care in clinical settings, and a deep understanding of the wound care regulatory and reimbursement landscape. Perhaps even more important than those critical characteristics is that the group should have site management expertise speci c to studies in tissue repair and wound healing. Bringing all these converging factors together will drive a paradigm shift in wound care research over the coming years, empowering new therapies to reach more patients, across more countries, in a shorter period of time be investigated in future clinical studies.

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Wound Healing Research: The Paradigm

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