3 Evidence

NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.

Clinical evidence

The main clinical evidence comprises 18 studies

3.1 The evidence assessed by the EAC included 18 studies. Seventeen were full-text peer-reviewed publications and 1 was an unpublished study. Of the included studies, 9 were comparative studies (7 randomised controlled trials and 2 observational studies) and 9 were non-comparative observational studies. The comparative evidence included a total of 792 people, of which 415 had Prontosan, 281 had saline, 53 had saline or Ringer's solution, 23 had silver sulfadiazine, and 20 had sterile water. For full details of the clinical evidence, see section 4 of the assessment report in the supporting documentation for this guidance.

There are weaknesses in the evidence with only 1 study at low risk of bias

3.2 The EAC considered the strength of the evidence to be limited, with only 1 randomised controlled trial at low risk of bias. Five randomised controlled trials had some methodological concerns. The remaining studies were considered to be at high risk of bias. Further limitations of the evidence base included the following points:

  • Most of the included studies had small sample sizes and some of the larger randomised controlled trials were underpowered (meaning they do not have enough people in them to draw meaningful conclusions). However, the EAC noted that larger sample sizes might not be achievable.

  • Prontosan use varied across the studies. For example, in 3 studies Prontosan solution was used only once, to irrigate the wound. In 4 studies only the gel was used. It was not always used in a way that reflects NHS practice, or in line with the company's instructions for use.

  • Outcomes were not always clearly reported and similar outcomes were reported differently across different studies. This made it difficult to make comparisons and draw conclusions across the evidence base.

The evidence for different types of chronic wounds was varied with 3 comparative and 7 non-comparative studies

3.3 Ten studies included different subgroups of chronic wounds, for example, venous leg ulcers, vascular ulcers, pressure ulcers, arterial leg ulcers, diabetic foot ulcers, burns, trauma wounds and surgical wounds). These included 2 randomised controlled trials (Bellingeri 2016; Valenzuela 2008), 1 comparative cohort study (Assadian 2018) and 7 non-comparative studies (Atkin 2020; Ricci 2018; Moore 2016; Durante 2014; Moller 2008; Horrocks 2006; Oropallo, 2021). Bellingeri 2016 was at low risk of bias, but the study was underpowered based on its own statistical analysis plan. It was also potentially at risk of selective reporting. Clinical experts advised that Prontosan gel may not be used at every dressing change and depends on the clinical assessment of the wound (For full details of the cost evidence, see section 4.2 of the assessment report in the supporting documentation for this guidance). Valenzuela 2008 used the gel only. Assadian 2018 had a small sample size and had limited applicability to the NHS because only a single application of Prontosan was used. Reported outcomes included wound healing, wound bed condition, wound infection, pain, dressing changes and quality of life.

There are 4 comparative studies for venous leg ulcers

3.4 Four studies were included for venous leg ulcers: 3 randomised controlled trials (Borges 2018; Harding 2012, unpublished; Romanelli 2010) and 1 comparative retrospective analysis (Andriessen 2008). All 3 randomised controlled trials had a small sample size and may have been underpowered. The control group in Andriessen 2008 had either saline or Ringer's solution. The clinical experts advised the EAC that Ringer's solution is not routinely used in the NHS to cleanse venous leg ulcers. Reported outcomes included rate of wound healing, time to wound healing, wound size, wound infection and factors associated with wound infection (bacterial burden and number of microorganisms) and pain.

There is limited evidence for burn wounds with no NHS comparators

3.5 Only 3 studies were included for burns: 1 randomised controlled trial (Wattanaploy 2017) and 2 non-comparative studies (Ciprandi 2018; Kiefer 2018). The sample size in the randomised controlled trial was small, saline was used in both arms, and the comparator was silver sulfadiazine. This was not considered to be standard care in the NHS so was not included in the scope for this guidance as a comparator for Prontosan. However, silver sulfadiazine is indicated for prevention and treatment of infection in burns. Reported outcomes included wound healing, wound infection, pain and treatment satisfaction. No significant differences were found for healing burn wounds and improving wound infection with Prontosan compared with silver sulfadiazine (Wattanaploy 2017).

There is limited evidence for surgical site wounds

3.6 Only 1 study, a randomised controlled trial, was included for surgical site wounds (Saleh 2016). This study had a small sample size, and the comparator was sterile water. The EAC included this study because surgical site wounds were considered relevant to the decision problem. The EAC noted that although the study compared Prontosan with dressings soaked with sterile water, only one dressing was applied after surgery. This treatment approach may have limited applicability to the NHS. The study outcomes included wound infection but not wound healing. The study reported a statistically significant higher rate of infection in the Prontosan group compared with the sterile water group.

It is not certain if Prontosan has better outcomes than saline

3.7 In total, 6 randomised controlled trials and 1 comparative retrospective analysis compared Prontosan with saline. Wound healing was reported in 2 studies (Harding 2012, unpublished; Andriessen 2008), wound size in 3 studies (Romanelli 2010; Valenzuela 2008; Harding 2012, unpublished) and wound condition improvement in 2 studies (Bellingeri 2016; Valenzuela 2008). Of these 4 studies, 2 showed statistical significance in wound improvement (Bellingeri 2016; Valenzuela 2008). Infection rate was reported in 2 studies (Harding 2012, unpublished; Andriessen 2008), bacterial burden in 2 studies (Assadian 2018; Romanelli 2010), bacterial load in 1 study (Borges 2018), inflammation score in 1 study (Bellingeri 2016), and microbiological cultures and redness around the skin (a clinical sign of infection) in 1 study (Valenzuela 2008). Of these 6 studies reporting on wound infection and associated factors, only 3 showed a statistically significant reduction in:

  • bacterial burden (Romanelli 2010)

  • inflammation score (change in inflammatory signs; Bellingeri 2016)

  • microbiological cultures and redness around the skin (Valenzuela 2008).

    Pain was reported in 4 studies (Bellingeri 2016; Harding 2012, unpublished; Romanelli 2010; Valenzuela 2008). Only 1 study found a significant reduction in pain when using Prontosan (Romanelli 2010). The EAC concluded that Prontosan appeared to be effective for some clinical parameters in chronic wounds, but there is not enough good quality comparative evidence with saline.

Prontosan is safe and easy to use

3.8 Prontosan is safe, provided clinical staff are aware of the contraindications outlined in the instructions for use. Adverse events are rare and easily managed. The products are easy to use and the clinical experts said that minimal training is needed. Training resources are available from the company.

Cost evidence

The company's cost modelling finds Prontosan to be cost saving

3.9 The company submitted 2 de novo cost analyses with different model structures. One used a Markov model (wound closure model) that compared costs for Prontosan with saline to treat venous leg ulcers until full wound closure. The time horizon was 1 year. The clinical experts advised the EAC that when using Prontosan, wounds healed within a year. The company provided 2 alternative data sets for rate of wound healing for this model (Andriessen 2008 and Harding 2012, unpublished). The other model was a simple cost model (wound bed preparation model) that compared costs for Prontosan with saline to treat chronic wounds (for example, leg ulcers and pressure ulcers) until the wound bed is fully granulated. This means that there are visible signs that the wound is healing. The time horizon used was the time to reach a Bates-Jensen wound assessment tool (BWAT) score of 14. The BWAT score is a clinical tool used for scoring wound healing. The time taken to reach a score of 14 was 4.1 weeks for Prontosan and 11.3 weeks for saline (Bellingeri 2016). The company reported base-case cost savings per person with Prontosan of £1,118.26 and £1,188.47 for the wound closure model (with data from Andriessen 2008 and Harding 2012, unpublished, respectively) and £1,134.40 for the wound bed preparation model. The key drivers for cost savings in both models included reduced:

The EAC agrees with the company's cost models but the key limitation is that the clinical evidence is uncertain

3.10 The EAC agreed with the structure of both of the company's models and its assumptions and made minor alterations to the costs and resource use. This had little impact on the cost savings (for full details see section 9 of the assessment report in the supporting documentation for this guidance). The EAC noted that the inputs for wound healing and infection rates in the wound closure model were uncertain, as were the inputs for wound bed improvement in the wound bed preparation model. The EAC acknowledged uncertainty in the cost modelling but noted that the approach was conservative. It made the following comments:

  • Andriessen (2008) is a retrospective comparative case series of 112 patients with venous leg ulcers with a follow-up time of 6 months. The EAC considered that Andriessen 2008 was a suitable data source because of the larger number of patients and longer follow up. However, the study was at high risk of bias because of potential selection and reporting bias.

  • Harding (2012) is a small, unpublished, UK pilot randomised controlled trial with 34 patients. The shorter follow-up period of 12 weeks meant that there was greater reliance on extrapolation for the calculation of transition probabilities for wound healing. There were some concerns about the randomisation process.

  • Bellingeri (2016) is a randomised controlled trial of 289 patients with pressure ulcers or vascular leg ulcers at low risk of bias. The follow up was 28 days, and wounds were assessed using the BWAT score. The company used an Excel trendline to extend the graphs to reach a mean BWAT score for both arms. However, there were concerns about the data. The study seemed to use only 8 out of the 13 dimensions of the BWAT. This meant the overall score was not on a scale of 13 to 65, but on a scale of 8 to 40. As a result, the EAC could not be confident that a reported BWAT score of 13 or 14 in Bellingeri (2018) accurately corresponded to a wound approaching healing or one that has healed. However, no improved data source has been identified.

The EAC base case uses the wound closure model with inputs from Andriessen 2008 and estimates a cost saving of £951 per person

3.11 The EAC considered that the wound closure model with clinical inputs from Andriessen 2008 was the most appropriate base case. It concluded that Andriessen 2008 was the most suitable data source and provided the most robust estimates for wound improvement, deterioration and recurrence that reflected the clinical reality of treating chronic wounds. This model estimated a cost saving from the use of Prontosan compared with saline of £951 per patient over a time horizon of 1 year.

  • National Institute for Health and Care Excellence (NICE)