3C Patch for treating diabetic foot ulcers

The committee acknowledged that there is biological plausibility in the device's mechanism of action. This is because the device separates and concentrates autologous blood components associated with tissue healing, including platelets, growth factors and immune cells involved in the inflammatory response. It is feasible that the components forming the biological patch could promote ulcer healing. The committee also acknowledged that hard-to-heal diabetic foot ulcers (DFUs) can reduce quality of life. It stated that there is an unmet need for new treatments for these ulcers and recognised that not all treatments will work for all ulcers. The committee was concerned that the treatment program, with weekly appointments and blood draws, would be difficult to follow for some people. Clinical and patient experts stated that the 3C Patch treatment program would likely be adhered to if progress is seen. This is because those who are likely to be considered for 3C Patch already have ulcers that are not healing despite standard care and have become chronic. However, it was still appreciated that weekly visits to secondary care could be challenging for some people because of difficulties with transportation or regularly taking time off work. The committee acknowledged that for some people, 3C Patch might fulfil an unmet need in DFU care.

The main evidence presented was from a well-conducted randomised controlled trial (RCT) done mostly in the UK. The committee acknowledged the strengths and limitations noted by the external assessment centre (EAC; see sections 3.1 to 3.3). Clinical experts confirmed that the trial population was broadly in keeping with the population of interest. However, they were unsure if the results of the current study would have been different if UrgoStart (see NICE's medical technologies guidance on UrgoStart for treating diabetic foot ulcers and leg ulcers) had been used by everyone in the run-in period. The committee considered the lack of data in an UrgoStart-experienced population to be an important evidence gap. The committee also noted that a sizeable group of people healed with standard care (22% in the RCT at 20 weeks), and clinical experts were not able to identify a subgroup of people who would be unable to heal with standard care but likely to heal with 3C Patch. Overall, the committee accepted that 3C Patch had some beneficial impact relative to other dressings for a proportion of people in the trial population. However, it is not possible to further identify those people most likely to benefit and it remains unclear whether the same impact would be observed if the treatment is used after UrgoStart.

The committee recognised that there was a clinical rationale for discontinuing 3C Patch when infection was present. The company acknowledged that it may be clinically appropriate to stop 3C Patch treatment if there was a moderate or severe infection, but that treatment could continue if the infection was mild. Clinical experts agreed that clinical judgement around 3C Patch treatment continuation is needed when an ulcer becomes infected. The committee concluded that 3C Patch should not be used in those with moderate or severe infections. It also noted that this did not happen in most cases in the RCT, which added uncertainty to the clinical evidence and company cost case.

Clinical experts stated that some people with diabetes may struggle to have weekly blood draws, making 3C Patch challenging and potentially distressing. The committee also questioned the suitability of the patch for people with certain blood conditions. The Game et al. (2018) RCT excluded people with platelet counts below 100×10⁹/litre and other clinically significant blood disorders. The committee was concerned that there was no evidence on the impact these conditions could have on patch coagulation, efficacy and the ability to have weekly blood sampling. It also noted that for people on anticoagulation therapy, patch formation may take longer, leading to longer appointment times. Clinical experts stated that weekly blood draws did not seem to lead to anaemia and that patch coagulation could vary independently of blood disorders. The committee concluded that blood sampling and blood disorders should be considered when selecting treatment options, but this should not prevent 3C Patch usage.

There is variation in the organisation of diabetic footcare services across the NHS. Some clinical experts stated that 3C Patch use could make up a relatively small proportion of their foot clinic referrals. The use of 3C Patch would also have a limited impact on appointment times because the appointments have been structured to accommodate blood taking and centrifugation time. Some centres also have podiatrists and nurses trained in blood taking or have phlebotomists available to help with 3C Patch preparation. Although 3C Patch needs weekly appointments, some clinical experts noted that there are weekly appointments for other care options, especially for those with hard-to-heal ulcers. The committee heard from another expert that when 3C Patch is not currently being used, there may not be the resources available to introduce the service. The committee concluded that in some settings, 3C Patch use may need some reorganisation of services and potentially an increase in use of NHS resources including time, space for equipment and staffing requirements.

The committee agreed with the EAC that the model structure was generally appropriate, and modelling discontinuation for infection by the inclusion of a moderate or severe infection state was justified based on clinical opinion. It also agreed with the concerns raised by the EAC around the stopping rule used in the 3C Patch arm. The committee recognised that the key concerns were that:

• The stopping rule was not used in the Game et al. (2018) RCT and there was no evidence on how this rule would work in practice.

• A lack of access to digital wound-measuring tools may make wound area changes more difficult to track.

• Clinical experts felt that any notable improvement in healing would justify continuation of the patch and that the 50% rule was difficult to follow in practice.

• The use of a strict stopping rule, when progress is being seen but the 50% threshold is not met, could have a negative effect on the physical and mental wellbeing of the patient.
  
  Clinical experts stated that they would review ulcer healing at 4 to 6 weeks of treatment and regularly thereafter. They would measure any improvement relative to the rate of healing before 3C Patch use and stop treatment if there was no or limited progress. The company clarified that the 5‑week stopping rule was used as a proxy for discontinuation of 3C Patch at any point within the 20‑week period. It also stated that healing at 5 weeks was a good predictor of healing at 20 weeks, based on analysis of patient-level data. The company suggested that further research could be done, using a Delphi Panel or a Sheffield Elicitation Framework (SHELF) methodology, to inform what stopping rule to use in clinical practice and how long 3C Patch treatment would continue. The EAC confirmed that further clinical evidence collection would be needed alongside this to reduce uncertainty in the economic model after the implementation of the proposed stopping rule. Overall, the committee acknowledged that a stopping rule would be needed in the economic model, but that there was currently no clarity on what the most appropriate rule would be.

The committee recognised the uncertainty in the healing rates used in the company model as outlined by the EAC. This includes the use of unplanned post-hoc analyses when data used was based on 42% of people in the 3C Patch arm (for weeks 6 to 20). It also acknowledged that there was no clinical evidence on the healing rates for those who would stop 3C Patch treatment if a stopping rule had been used in the trial. The committee recognised that the EAC's modelling, based on healing rates in the intention-to-treat population, resulted in very different cost estimates. This highlighted the impact of the uncertainty in the healing rate parameters. It also noted that because the EAC analysis included no discontinuation of treatment at all, it was unlikely to provide a true estimate of the cost impacts of 3C Patch. The committee concluded that the lack of direct clinical trial evidence for the company's proposed treatment pathway is a major limitation of the economic analysis.

The committee heard that EAC changes to the data sources used in the cost modelling meant that the overall cost of 3C Patch was increased by around £800 in the EAC's model A (a model without a separate infection state). The EAC confirmed that although the Farr et al. report was unpublished, it was based on direct trial evidence rather than a more general published study on the cost of DFUs to the NHS in England (Kerr et al. 2019). It was acknowledged that both sources of data had limitations but the EAC's approach using costs from Kerr et al. (2019) with resource use data from Farr et al. (unpublished) was preferred given that it uses direct trial evidence that is most relevant to the population. The committee was concerned that changing the source of the costs for the economic model was sufficient to make 3C Patch cost incurring. It concluded that the EAC changes to the costs further highlighted the uncertainty in the company base case for 3C Patch.

The committee acknowledged that the only way to offset the higher upfront costs of 3C Patch treatment was to reduce the resources needed later in the pathway for managing unhealed ulcers and their complications. It acknowledged that the company had presented results that indicated that such savings were possible. But the committee noted that these results were based on a model populated with uncertain clinical and cost inputs that had been questioned by the EAC. The committee also noted that varying the model inputs for treatment discontinuation, healing rates and inpatient and outpatient care costs, within ranges that reflected the uncertainty in the underlying data, led to a change in direction of the cost case for 3C Patch. Further to this, the committee noted that if 3C Patch is discontinued because of an ulcer having a moderate or severe infection, the EAC's model B (which included an additional state to capture moderate or severe infections) may be the most appropriate model structure. It acknowledged that this model led to 3C Patch being more cost incurring. The committee considered that the EAC's 2‑way sensitivity analysis was helpful in demonstrating that there are few combinations of discontinuation and healing rates that can lead to 3C Patch becoming cost saving, with the combinations that were associated with cost savings being less clinically plausible. It also noted that the company model was sensitive to changes in the cost parameters and that using the EAC's costs alone (without adjusting the company's healing and discontinuation rates) also led to 3C Patch becoming cost incurring. The committee concluded that the case for adoption was not supported because the estimated cost-saving case presented by the company was not robust. Large savings in care costs would be needed to offset the cost of 3C Patch and there was insufficient evidence presented to show that care needs would be significantly reduced after 3C Patch treatment.

Although the committee acknowledged that the Game et al. (2018) RCT was well conducted, it felt that additional research could help resolve some uncertainties around the cost and clinical case for 3C Patch. Specifically, research identifying the most appropriate stopping rule, and the associated clinical outcomes of implementing the rule, would help address key uncertainties within the cost case. Additional collection of resource use data on unhealed hard-to-heal ulcers could also reduce uncertainty in the cost case. Further to this, evidence could be collected on an UrgoStart-experienced population, as this would be reflective of current NHS care. Clinical experts thought a trial on this population would be feasible. The committee concluded that although further research could be done, on balance it was unlikely to result in a cost-saving case for 3C Patch based on the decision problem evaluated in this guidance.