I am just going to say it. The majority of prospective trials in wound healing have enrolled subjects whose wounds were more likely to heal than not. While more “generalizable” trials (meaning, actually relevant to real patients) are underway or in the planning stages, the pivotal studies of Cellular and/or Tissue based products (CTP) had a list of exclusion criteria as long as my arm. After the products were FDA cleared, those exclusion criteria were used to craft Medicare “coverage policies” that were actually non-coverage policies. My center was one of the sites for the original Apligraf trial (~1998) and if you want to know what the exclusion criteria were in the trial, you need look no further than the coverage policy that Trailblazer formulated after the product reached the market. Those exclusions (with little variation) have continued through the generations of coverage policies since then, for both Medicare and the private payers. Manufacturers perform EFFICACY (perfect world) trials (because that’s what the FDA asks for), and then payers deny coverage due to lack of data on real world EFFECTIVENESS. The scariest trend is the auditing of hospital based outpatient wound centers by their Medicare Administrative Carriers (MACs) which are demanding that much of the money paid for CTP applications be returned because the patients had exclusionary medical conditions.

Where does EFFECTIVENESS data come from? Since effectiveness is defined as the ability to work in the real world, it has to come from Real World Data (RWD). When that is analyzed, RWD turns into Real World Evidence (RWE). That’s why the US Wound Registry sponsors a CTP registry, a registry on Negative Pressure Wound Therapy (NPWT) and a Hyperbaric Oxygen Therapy registry (HBOTR), all described on Clinical Trials.gov, and all actively enrolling. The data are transmitted directly from the clinic electronic health records (EHRs) of over 100 hospital based outpatient departments. The primary value of EHR data (in addition to not having to perform manual data entry) is that there is no patient selection bias in registry enrollment. We know exactly how many patients/wounds were treated with a product. The challenge is how to get OUTCOMES on those wounds.

How do we get data on outcomes into an electronic registry? We leverage Quality Measures. We have been obtaining wound outcomes (including amputation rate and healing rate) by structuring the data as Quality Measures reportable through a Qualified Clinical Data Registry (QCDR), specifically, the US Wound Registry (USWR). That way the outcomes information does “double duty.” It can help physicians score well under the Merit Based Incentive Payment Plan (MIPS) while automating the collection of data needed to understand the value of interventions and devices. We’ve written a paper on the standards for EHR-derived registries and put them in an easy to use “Analysis of Bias Criteria (ABC)” checklist. We hope that the ABC Checklist will to impact the way studies from clinical data are evaluated for publication. Some “comparative effectiveness studies” published on CTPs did not describe the percentage of patients whose actual outcome was unknown! It’s no wonder the FDA is worried about trusting real word data.

There are limitations to the Quality Measure approach for collecting registry outcomes. For example, CMS rejected a USWR quality measure to obtain patient reported wound outcomes because they didn’t think that simply ASKING about wound outcomes was a quality activity. CMS argued that wound care physicians should report a specific percentage of improvement in wound-related quality of life. By the time that CMS rejected that quality measure (after approving it the first year) we had given the Wound QoL to 400 patients and transmitted the data from pre-programmed tablets directly to the USWR where the patient reported data was connected to the actual wound outcomes.

That’s a pretty amazing accomplishment for a project that had exactly zero funding. I might point out that a lot of money has gone to fund the very important Wound Care Endpoints project which recommended patient reported data as a surrogate endpoint, while the USWR had no funding for the project that actually collected patient reported outcome data on 400 patients and transmitted it to a CMS recognized quality registry! Since there was no funding to analyze the results, this valuable information has been relegated to the electronic junkyard. The USWR “built-it” thinking that CMS, manufacturers and clinical wound care associations would support obtaining patient reported data if doing so was automated. We were wrong. That’s the reason why, when a manufacturer asks me if the USWR has any patient reported data, they need to be wearing body armor.

The USWR sent the above letter to the FDA when it was reviewing its policy on Real World Evidence. It is worthy of a read. The USWR addressed the major concerns of the FDA as far as data derived from EHRs is concerned, including the issue of informed consent. I bring all this up because recently, the Bipartisan Policy Center (BPC) released a 54-page report on Real World Evidence. Three former FDA commissioners called on FDA, CMS and Congress to work with stakeholders to increase the use of real-world data. They cited the need to improve the evidence base for new drugs and biologics, refine regulatory decisions by FDA and promote value-based payment models. Former FDA chiefs Robert Califf, Andrew von Eschenbach and Mark McClellan say the recommendations in the BPC report would “clear barriers” to the use of RWD and advance new models of collaboration among stakeholders.

The first recommendation calls on Congress to fully fund a $60 million FDA request for a Medical Data Enterprise to advance RWE and expand CMS’ workforce so that it has the manpower to support value-based payment models for medical products. We need that help desperately in the area of CTPs. No one is funding the analytics of real world data to evaluate the proposed “Bundled payment” of CTPs. When the USWR did a very preliminary look at the impact of “package pricing,” it appears to have reduced access to CTPs for people of Color (at least for two years), who already are more likely to undergo amputations for conditions like diabetic foot ulcers. There’s been no discussion about the fact that patients without a “secondary insurance” are less likely to get CTPs, or the fact that access to CTPs is affected by high deductible plans. We are not analyzing the mountain of data available on the patients who get CTPs, and we are completely ignoring the patients who don’t even have the chance.

BPC suggests that the FDA accelerate its pilot projects focused on new data sources such as electronic health records (EHRs), registries and “initiatives focused on biologics and cell therapies,” and calls on the FDA and CMS to “improve their collaboration” on ways to foster more efficient evidence development on “high-impact, high cost medical products.” That seems like a great opportunity for the US Wound Registry and its vast repository of data on CTPs (“skin substitutes). Unfortunately, our experience is that these initiatives are focused on drugs and orthopedic implants. The multi-billion dollar burden of chronic wounds and the associated human suffering of the patients who have them is not on anyone’s radar screen. The FDA’s planned office of Drug Evaluation Science won’t help us get more generalizable trials in wound care. For all the talk about Real World Data, I can pretty much guarantee that chronic wounds and the data currently available to “Find What Works” for them won’t be represented when the stakeholders sit down. And that’s a crying shame for a problem that could cost Medicare $94 billion dollars a year.

Caroline Fife, M.D.

Dr. Fife is a world renowned wound care physician dedicated to improving patient outcomes through quality driven care. Please visit my blog at CarolineFifeMD.com and my Youtube channel at https://www.youtube.com/c/carolinefifemd/videos