Eleven health economic evaluations were included. Three biotechnology products were identified for which cell-derived wound care products for the treatment of chronic leg ulcers were economically assessed. All products are already available on the market: (1) Apligraf, a bilayered living human skin equivalent indicated for the treatment of diabetic foot and venous leg ulcers (five studies); (2) Dermagraft, a human fibroblast-derived dermal substitute, which is indicated only for use in the treatment of full-thickness diabetic foot ulcers of duration greater than 6 weeks that extend through the dermis, but without tendon, muscle, joint capsule, or bone exposure (one study); (3) REGRANEX Gel (becaplermin), a human platelet-derived growth factor for the treatment of deep neuropathic diabetic foot ulcers (five studies). Table
1 provides a brief overview of the products in the economic evaluations.
Table 1
Overview of human cell-derived wound care products for the management of chronic leg ulcers investigated by health economic evaluation
Apligraf®
| Bi-layered skin substitute: the epidermal layer is composed of human keratinocytes; the dermal layer is formed by human fibroblasts in a bovine type I collagen matrix | ▪ Non-infected partial and full-thickness venous leg ulcers ▪ Full-thickness neuropathic diabetic foot ulcers | Organogenesis, US |
Becaplermin (REGRANEX® Gel) | Clear colourless to straw-coloured gel, which contains 0.01% of the active substance becaplermin | ▪ Deep neuropathic diabetic foot ulcers | Systagenix Wound Management, US |
Dermagraft®
| Cryopreserved human fibroblast-derived dermal substitute composed of fibroblasts, extracellular matrix, and a bioabsorbable scaffold | ▪ Full-thickness diabetic foot ulcers | Advanced BioHealing, US |
Establishment of effectiveness
Many studies were based on randomised controlled clinical trials. In three of the studies considered here [
5‐
7], becaplermin efficacy was derived from a meta-analysis conducted by Smiell et al. [
8] of four randomised studies including 922 patients with diabetic foot ulcers. Kantor and Margolis [
9] took the becaplermin efficacy data from a review by Wieman [
10] of four multicentre, randomised, placebo-controlled, parallel group studies. These four studies included a total of 922 patients. Sibbald et al. [
11] used the multicentre double-blind placebo-controlled phase III trial of 382 patients by Wieman et al. [
12]. In the Apligraf study by AÉTMIS [
13], data were derived from the pivotal clinical trial by Falanga et al. [
14] including 293 venous ulcer patients to calculate the primary outcome measure. Steinberg et al. [
15] took effectiveness data from the randomised prospective trial by Veves et al. [
16] to evaluate the cost-effectiveness of Apligraf in the treatment of diabetic foot ulcers. Finally, in the Dermagraft study by Segal and John [
17], the US pivotal clinical trial by Naughton and colleagues [
18] of 235 patients was used to assess the mean cost per ulcer healed.
An overview of the sources for effectiveness data used in the evaluations is given in table S5 [see Additional file
5]. Table
2 provides an overview of the studies and systematic reviews used for the assessment of effectiveness.
Table 2
Characteristics of the randomised clinical trials for establishing effectiveness
Wound care product | Country | Study period | Number of patients/study design | Initial ulcer size (cm2) | Mean age | Dressings | Ulcers healed (%/duration) | Reference |
Apligraf | US | 12 w + 3 m (follow-up) | 112 (Apligraf), 96 (saline-moistened gauze), RCT | 2.97 intervention group (IG), 2.83 control group (CG) | 58 IG, 56 CG | Weekly application of Graftskin for a maximum of 4 weeks | 56/12 w IG, 38/12 w CG | Veves et al. 2001 |
Apligraf | US | 6 m + 6 m (follow-up) | 146 (Apligraf plus compression), 129 (compression alone), RCT | 1.33 IG, 1.05 CG | 60.2 IG, 60.4 CG | Maximum of 5 in weeks 0–3, (IG), 1 in weeks 0–8 (CG) | 63/6 m IG, 48.8/6 m CG | Falanga et al. 1998 |
Dermagraft | US | 32 w | 109 (Dermagraft plus conventional therapy, 126 (conventional therapy alone), RCT | ≥ 1 | Not stated | Weekly application of Dermagraft in weeks 0–7 | 38.5/12 w IG, 31.7/12 w CG | Naughton et al. 1997 |
Becaplermin | US | 20 w |
Study 1: 57 P, 61 B (30 μg/g); Study 2: *; Study 3: 68 GUC alone, 70 P, 34 B (100 μg/g); Study 4: 122 GUC, 128 B (100 μg/g); Total: 190 GUC, 254 P, 193 B (30 μg/g), 285 B (100 μg/g), 478 B (all doses), review of 4 RCTs |
Study 1: 7.2,
Study 2: 2.7,
Study 3: 2.2,
Study 4: 2.9
|
Study 1: 61,
Studies 2, 3: 58,
Study 4: 60
| Becaplermin or placebo gel was applied topically once daily and covered with saline-moistened gauze. |
Study 1: 48/20 w B (30 μg/g), 25/20 w P; Study 2: *; Study 3: 44/20 w B (100 μg/g), 36/20 w P, 22/20 w GUC; Study 4: 36/20 w B (100 μg/g), 32/20 w GUC | Wieman 1998 |
Becaplermin | US | 20 w | *, meta analysis of 4 RCTs |
Study 1: 9.0 P, 5.5 (30 μg/g); Study 2: *; Study 3: 2.5 GUC, 2.2 P, 1.6 B (100 μg/g); Study 4: 2.5 GUC, 3.2 B (100 μg/g) |
Study 1: 58 P, 63 (30 μg/g);
Study 2: *; Study 3: 60 GUC, 57 P, 59 B (100 μg/g); Study 4: 60 GUC, 59 B (100 μg/g) | ** | * for efficacy results of individual studies; combined analysis of treatment efficacy: 36/20 w (GUC/P), 42/20 B (30 μg/g), 50/20 B (100 μg/g) | Smiell et al. 1999 |
Becaplermin | US | 20 w | 127 P, 132 B (30 μg/g), 123 B (100 μg/g), RCT | 2.8 P, 2.6 B (30 μg/g), 2.6 B (100 μg/g) | 58 P, 58 B (30 μg/g), 57 B (100 μg/g) | ** | 50/20 w B (100 μg/g), 36/20 w B (30 μg/g), 35/20 w P | Wieman et al. 1998 |
Apligraf®
In our literature search, we identified 5 health economic evaluations that assessed the cost-effectiveness of Apligraf® in the management of venous leg or diabetic foot ulcers. All but one study were cost-effectiveness models and most economic evaluations were funded by manufactures/patentees of the products. Due to methodological weaknesses (i.e. only average cost-effectiveness ratios, small sample sizes, short time horizons, inadequate treatment of uncertainty), the quality of the evidence was considered limited.
An analytical prediction model was developed at AÉTMIS (2001) [
13] by assembling information for the following treatment options of venous leg ulcer patients: compression alone, compression and Apligraf simultaneously, compression and Apligraf for hard-to-heal ulcers which are unresponsive to conventional therapy. To assess the number of ulcer days averted, which was used as the benefit measure in the economic analysis, data from the pivotal study by Falanga et al. (1998) [
14] were obtained (further information on clinical trial characteristics are available in table
2). From both a health-care system perspective and a societal perspective the incremental cost for each ulcer day averted was calculated to amount to Can $26 when compression and Apligraf were used simultaneously, and Can $22 when compression and Apligraf were used for hard-to-heal ulcers.
Harding et al. (2000) [
19] combined a summary of published studies and expert opinion to compare the cost-effectiveness of saline gauze, the hydrocolloid dressing Granuflex
® (UK trade name for DuoDERM
®), and the human skin equivalent Apligraf for venous leg ulcer patients, over a 12-week treatment period. They identified 12 studies involving 843 ulcers, of which 205 were treated with saline gauze, 509 with Granuflex, and 278 with Apligraf. Due to heterogeneity across studies, only the percentage of ulcers healed was reported and used for the effectiveness estimate. The views of a European panel of four wound-care specialists on the issue of resource utilisation and costs were used to design protocols of care where data were not available from the literature. No summary measure of benefit was provided in the economic analysis. Cost-effectiveness was calculated from a health-care payer's perspective as the total medical cost of care of the cohort divided by the number of healed wounds, which yielded a cost per healed wound of £342 for Granuflex (nurse time £97, compression £121, dressing £124 and other £0), £541 for saline gauze (nurse time £327, compression £166, dressing £48 and other £0), and £6,741 for Apligraf (nurse time £70, compression £144, dressing £6,526 and other £1). An incremental cost-effectiveness ratio was not calculated.
Kerstein et al. (2001) [
20] undertook a study in the United States, similar to that by Harding et al. [
19], with a broader literature review to assess the cost-effectiveness of gauze dressings impregnated with saline, paraffin or zinc oxide, as compared with hydrocolloid dressings, and human skin construct (Apligraf) in venous leg ulcer patients. They included 18 studies and identified 223 patients on impregnated gauze dressings, 530 on hydrocolloid dressings, and 130 on Apligraf. The data on effectiveness were derived from a review of published studies. The benefit measure used in the economic analysis was the number of persons healed or not healed in a hypothetical managed-care plan with 100,000 covered lives. The average cost per patient healed was lowest with the hydrocolloid dressing DuoDERM (US $1,873), followed by impregnated gauze dressings at US $2,939, and then the human skin equivalent Apligraf at US $15,053 over a treatment period of 12 weeks.
Meaume and Gemmen (2002) [
21] also used a similar methodology to that adopted by Harding et al. [
19] to evaluate the cost-effectiveness of saline gauze, the hydrocolloid dressing DuoDERM (German trade name Varihesive
® and UK trade name Granuflex), and Apligraf in venous leg ulcer patients from a European and French perspective, respectively. The French perspective in this study was provided by a panel of five French wound-care experts. The European expert panel comprised four specialists from the UK, France, Germany, and Sweden. The evidence on effectiveness was derived from a literature review. The benefit measure used in the economic analysis was the number of patients healed at 6 and/or 12 weeks in a hypothetical cohort of 100,000. Although the treatment patterns are different between the United Kingdom and France, the pattern of cost-effectiveness per patient healed was consistent with the study conducted by Harding et al. [
19] with the hydrocolloid dressing DuoDERM being most cost-effective at £2,763/1,018, followed by saline gauze at £1,436/1,722 and Apligraf at £11,396/15,920 from a European and a French perspective, respectively.
In the economic analysis by Steinberg et al. (2002) [
15] the living skin equivalent Apligraf was compared to saline-moistened gauze to assess the cost-effectiveness of these two dressings in diabetic foot ulcer patients, on the basis of data from a six-month, multicentre, randomised trial [
16]. In this trial, there were 112 patients in the intervention group and 96 controls. The benefit measures used in the economic analysis were the number of ulcer-free months gained and the number of amputations or resections avoided. In comparison to controls, patients in the living skin equivalent group had a higher average number of ulcer-free months (2.3 in the intervention group vs. 1.5 in the control group) and a lower average number of amputations or resections (5.4% in the intervention group vs. 12.5% in the control group). With a follow-up of six months, the incremental cost-effectiveness ratio of Apligraf over saline-moistened gauze was US $6,683 when the benefit measure was based on the number of ulcer-free months gained, and US $86,226 when amputations or resections avoided were considered.
Becaplermin (REGRANEX®Gel)
In our literature search, we found 5 economic evaluation studies that assessed the cost-effectiveness of becaplermin in the management of diabetic foot ulcers. All studies were cost-effectiveness models. Most of these cost-effectiveness analyses were funded by pharmaceutical companies or coauthored by their employees, and reported results that favoured the sponsor's product. The quality of the evidence was considered high.
The following three studies [
5‐
7] used the same source of effectiveness evidence. However, country-specific patterns of resource usage and prices have a high impact on cost-effectiveness estimates. Therefore, to ensure that country-specific differences in treatment patterns and cost estimates are appropriately accounted for, the findings of these studies are reported here separately.
Persson et al. (2000) [
5] used a Markov model to evaluate the cost-effectiveness of using becaplermin gel in combination with good wound care, as opposed to good wound care alone, to treat diabetic patients in Sweden who presented neuropathic, lower extremity ulcers. As part of a recent study on the cost of illness, a Markov model was developed [
22]. With that as a starting point, the authors developed a more complete model of diabetic lower extremity ulcers. Data on resource usage were derived from a series of Swedish studies [
23‐
26]. The becaplermin efficacy was taken from a combined analysis of four randomised studies [
8]. The primary benefit measure used in the model was the number of ulcer-days averted. In comparison to controls, patients in the intervention group had a higher average number of ulcer-free months (4.22 in the intervention group vs. 3.41 in the control group) and a lower average number of amputations (5.91% in the intervention group vs. 6.50% in the control group). The average expected costs were US $12,078 for good wound care alone and US $11,708 for becaplermin.
In the economic analysis by Ghatnekar et al. (2000) [
6] a similar Markov model to that developed by Persson et al. [
5] was used to evaluate the cost-effectiveness in the UK of becaplermin gel as an adjunct therapy to good wound care in diabetic foot ulcer patients. Data on resource usage were taken primarily from a Swedish study [
25]. To ensure the generalisability of the study results to the UK setting, they were reviewed by an expert panel of UK physicians. Data on becaplermin efficacy were drawn from the analysis by Persson et al [
5]. The primary benefit measure used in the model was the number of ulcer-days averted. As in the analysis by Persson et al. [
5] the average number of months spent in the healed state rose by 24% from 3.41 to 4.22 and the average number of amputations fell from 6.50% to 5.91% – a decline of 9%. The average expected costs over a 12-month time horizon were £10,880 for good wound care alone and £10,403 for treatment with becaplermin.
Ghatnekar et al. (2001) [
7] used the same Markov model as the one developed by Persson et al. [
5] to assess cost-effectiveness in four European countries (France, Sweden, Switzerland, UK) of becaplermin as an adjunct treatment option to good wound care alone in patients with diabetic foot ulcers. Another objective was to address the issue of generalisability by analysing the effect of different resource use patterns on the economics of managing diabetic foot ulcers. Data on effectiveness evidence for becaplermin were drawn from a pooled analysis of four randomised trials [
8]. Resource data were primarily taken from a series of Swedish studies [
23‐
25]. The primary benefit measure used in the model was the number of ulcer-months avoided. The expected number of months in the healed state was higher in the becaplermin group, 4.22 months vs. 3.41 months – an increase by 24%. Furthermore it was assumed that the average number of amputations would decline by 9%, from 6.50 to 5.91 per 100 patients. The average expected costs over a 12-month time horizon in the becaplermin group and the control group respectively were US $11,977/11,993 for France, US $12,168/11,783 for Sweden, US $14,112/13,832 for Switzerland, and US $17,601/17,133 for the UK.
Kantor and Margolis (2001) [
9] used published literature and a database to assess the cost-effectiveness of various treatment options for diabetic neuropathic foot ulcers. The following treatment strategies were considered: standard care, standard treatment in a wound care centre, becaplermin, or platelet releasate. The becaplermin data were taken from a meta-analysis conducted by the authors on published studies of becaplermin gel 0.01% [
10]. The measure of benefit used in the economic analysis was the percentage of ulcers healed. At 20 weeks of care the percentages of ulcers healed were 30.9% for standard care, 43% for becaplermin, 36.8% for platelet releasate, and 35.6% for treatment in a wound care centre. The incremental cost per patient of increasing by 1% the chance of healing at 20 weeks was US $36.6 for standard care vs. becaplermin, and US $70.86 for becaplermin vs. treatment in a specialised wound care centre. At this time, becaplermin was superior to platelet releasate, as a more effective and less costly treatment.
In the economic analysis by Sibbald et al. (2003) [
11] a decision tree was used to assess the cost-effectiveness of becaplermin as an adjunct treatment option available to best clinical care in patients with nonhealing neuropathic diabetic foot ulcers. The effectiveness data were taken from a randomised controlled clinical trial of 251 diabetic patients [
12]. The benefit measure used in the economic analysis was the number of ulcer-days averted. The number of ulcer-days per patient was 237 in the intervention group and 211 in the control group over a one year time horizon. Based on the model, the incremental cost-effectiveness ratio was Can $6 per ulcer-day averted.
While the cost-effectiveness of tissue engineered skin was considered poor in three studies [
19‐
21], one study found it to be more cost-effective than compression alone [
13]. This difference could be explained by the assumptions made in each analysis, most importantly the frequency of tissue engineered skin application in each model. Table
3 provides an overview of the economic evaluations. As described in the methods section, the last column is based on an appraisal of studies by two independent reviewers according to two published quality checklists.
Comparison of the results to other studies
Ho et al. [
2] included in their review three cost-effectiveness analyses of Apligraf [
27‐
29], and one cost-effectiveness study of Dermagraft [
1]. Studies assessed by that review were excluded from the present analysis to avoid 'double counting' of evidence, thus enhancing the efficient use of resources. A summary can be found in Table
4.
Table 4
Overview of economic evaluations included in Ho et al. 2005
Wound care product | Source: author, country, year | Type of ulcers | Interventions | Perspective | Type of economic evaluation | Primary outcome measures/source of effectiveness evidence | Cost-effectiveness results (base case) | Sources of funding | Evidence |
Skin Substitutes | | | | | | | | |
Apligraf®
| Redekop et al., NL, 2003 | Diabetic foot | (1) GWC alone (2) GWC plus Apligraf®
| Societal | CEA | Number of ulcer-free months gained and amputations avoided/Veves et al. 2001 | Treatment with Apligraf (more effective and less costly) dominated over GWC alone. | Novartis | Limited |
| Schonfeld et al., US, 2000 | Venous leg | (1) Unna's boot (2) Apligraf®
| Health care payer | CEA | Number of healed months and total % healed at 12 months/Falanga et al. 1998 | Apligraf was the dominant strategy (more effective and less costly). | Novartis | |
| Sibbald et al., CA, 2001 | Venous leg | (1) 4-layer bandage system alone (2) 4-layer bandage system plus Apligraf®
| Societal/Health care payer | CEA | Number of ulcer days averted/Falanga et al. 1998 | Over a 3-month time horizon, the incremental cost per ulcer day averted with Apligraf plus 4-layer bandage system over 4-layer bandage system alone was Can $14 (US $12)* from both perspectives. | Novartis | |
Dermagraft®
| Allenet et al., FR, 2000 | Diabetic foot | (1) Standard treatment (2) Dermagraft®
| Societal | CEA | Number of additional ulcers healed/Naughton et al. 1997 | The incremental cost per additional ulcer healed of Dermagraft® over standard treatment was FF38,784 (US $41,260)*. | French Ministry of Health | Limited |
In the four health economic evaluations, univariate and multivariate sensitivity analyses respectively were conducted on probabilities and costs. The results of the sensitivity analyses showed that the models were generally robust to almost all variations in model inputs. The study results by Sibbald et al. [
29] were sensitive to changes in the time loss from usual daily activities, in which case Apligraf plus four-layer bandage became the dominant treatment modality. In the analysis by Schonfeld et al. [
28], when the cost of hospitalisation for patients in the Apligraf group was doubled, Apligraf was no longer the dominant strategy. In the economic evaluation by Redekop et al. [
27], the incremental cost-effectiveness ratio was seen to be sensitive to the required number of applications of Apligraf, to amputation costs and differences in infection rate. For all three parameters the results of the incremental cost-effectiveness ratios ranged from cost-effective to cost-saving.