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3C Patch for treating diabetic foot ulcers

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4 Committee discussion

Clinical-effectiveness overview

The committee recognised that there is an unmet need for new treatments for hard-to-heal diabetic foot ulcers and that 3C Patch is biologically plausible

4.1 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 there is an unmet need for new treatments for hard-to-heal diabetic foot ulcers (DFUs) and that not all treatments will work for all ulcers. The committee were 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.

Randomised controlled trial evidence shows improvements in ulcer healing proportion and time to healing but the clinical importance of the observed benefit is uncertain

4.2 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 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 it questioned the degree to which the statistically significant changes seen in the trial (12% more ulcers healing at 20 weeks and a 12-day reduction in ulcer healing time in the 3C Patch arm compared with standard care) were clinically meaningful. The committee also understood that it was not currently possible to identify a subgroup in which 3C Patch was more clinically effective compared with the overall trial population. 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 remains unclear whether the same impact would be observed if the treatment is used at the appropriate position in the current NHS treatment pathway. The committee were also uncertain of the clinical importance of the difference in healing time and healing rate shown in the evidence.

Other patient benefits or issues

3C Patch treatment should be halted whilst wounds have a moderate or severe infection

4.3 The committee recognised that there was a clinical rationale for discontinuing 3C Patch where 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. The committee concluded that 3C Patch should not be used in those with moderate or severe infections. It also noted that because this did not happen in the RCT, this adds uncertainty to the clinical evidence and company cost case.

Blood sampling and blood disorders could affect appropriateness of 3C Patch treatment

4.4 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 participants with platelet counts below 100 × 109/l and other clinically significant blood disorders. The committee were 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.

NHS considerations overview

3C Patch could have an impact on service organisation, depending on how they are currently structured

4.5 There is variation in the organisation of diabetic footcare services across the NHS. Some clinical experts stated that 3C Patch has a relatively limited impact on appointment times. This is 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 they have weekly appointments for other care options, especially for those with hard-to-heal ulcers. The committee heard from another expert that where 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 require some reorganisation of services and potentially an increase in NHS resource use in terms of time, space for equipment and staffing requirements.

Devices to accurately measure ulcer area are not available across the NHS

4.6 Clinical experts stated that digital devices for accurately measuring ulcer area are not consistently available across the NHS, with some centres using a ruler or visual inspection to assess wound healing progress. They stated that this is due to the current cost of these devices. The committee heard that access to digital ulcer-size measuring devices should increase following recommendations being made by the national wound care strategy.

Cost modelling overview

The stopping rule applied in the 3C Patch arm of the company model is not appropriate

4.7 The committee agreed with the EAC that the model structure was generally appropriate and modelling discontinuation for infection via 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

  • the stopping rule would not be easy to implement in practice due to a lack of accurate wound measuring tools

  • 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 where progress is being seen but the 50% threshold is not met, would 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 prior to 3C Patch use and stop treatment if there was no or limited progress. The company agreed with the clinical experts but 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. Overall, the committee acknowledged that a stopping rule would be needed in the economic model, but that there was no clarity on what the most appropriate rule would be.

Economic modelling is limited by the available clinical evidence and its relevance to the NHS clinical pathway

4.8 The committee recognised the uncertainty in the healing rates used in the company model as outlined by the EAC. This includes use of post-hoc analyses where 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 likely healing rates for those who would discontinue 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 published RCT, 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 EAC and company used different data sources in the cost modelling, which changed the direction of the cost case for 3C Patch

4.9 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. 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 DFUs to the NHS in England (Kerr et al. 2019). It was acknowledged that both sources of data had limitations but felt that Farr et al. (unpublished) was a reasonable alternative source of data given that it is appropriate to use direct trial evidence where possible. The committee were 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 company's base case is unstable and 3C Patch is unlikely to be cost saving

4.10 The committee acknowledged that the only way to off-set 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 due to an ulcer having a moderate or severe infection, the EAC's model B may be 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 making adjustments to 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.