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Abstract

Actinic keratosis (AK) represents an emerging issue in the area of skin diseases which undergo high risk for developing squamous cell carcinoma (SCC). Recently, evidence has been accumulated that 3% diclofenac sodium and ingenol mubetate may efficiently counteract the development of progressive AK even if the pharmacoeconomic impact of such a treatment remains poorly defined. With the objective of assessing the efficacy of 3% diclofenac sodium versus ingenol mebutate, a comparative cost-efficacy analysis was performed between both pharmacological treatments. In the present analysis, data of efficacy of clinical studies were combined with information on the quality of life associated with AK lesions based on available literature data. Furthermore, the cost associated with the management of these lesions in Italy has been taken into account. To this purpose, we carried out a literature survey on the clinical and economic data among clinical reports available in Italy based on the assessment of related expenditure of public resources and their relationship with the subsequent health benefits.

Keywords

actinic keratosis cost-efficacy analysis diclofenac sodium ingenol mebutate

Introduction

Actinic keratosis (AK) represents a chronic skin disease associated with chronic exposure to ultraviolet (UV) radiation. The pathological pattern of AK is represented by erythematous papules or plaques and is considered the earliest clinically recognizable manifestation of squamous cell carcinoma (SCC) that is capable of transforming into squamous cell carcinoma in situ and invasive squamous cell carcinoma.^1–4 Fair skin, cumulative sun exposure, immunosuppression, and age increase the risk of AK.^5,6 AK is the second most common diagnosis seen by dermatologists in the United States, with the direct cost of therapy estimated at more than $1 billion per year with indirect costs nearing $300 million.⁷ The prevalence of AK was reported at 11–25% in 2008¹ with 5.2 million patient visits occurring annually for AK during the period from 2000 through 2003.⁸ The risk of progression of AK to SCC (invasive or in situ) is considered to be low, but highly variable.¹⁰ The risk of developing SCC increases with the number of AKs, with a relative risk of 1% in individuals with five or fewer AKs compared to 20% among patients with greater than 20 lesions.^1,9,11 Additionally, 60% of SCCs were shown to arise from prior AKs, with other estimates ranging from 25–80%. Thus, a small proportion of AKs will progress to SCC, but currently it is not possible to predict which lesions will progress and which will not. There are no distinct clinical boundaries between AK and invasive SCC, and in some reports AKs are considered SCCs.^1,11,12 Thus, it is accepted that the presence of AK is a biomarker of risk for SCC, and while histologically there is usually clear differentiation, AK must be treated to avoid possible morbidity and mortality associated with SCC.^1,3

Recently, evidence has been accumulated showing that ingenol mebutate, approved for the treatment of AK in January 2012, induces necrosis and produces a neutrophil-mediated, antibody-dependent cellular cytotoxicity (ADCC) of residual disease cells.^13,14

In particular, ingenol mebutate has been shown to produce significant improvement of AK multiple lesions when used alone or in combination with cryotherapy.

The dual mechanism of action which characterizes its activity in counteracting AK lesions, causes rapid lesion necrosis taking place over the course of hours, followed by ADCC, whose lasting effect allows for short duration of therapy.¹⁵ Perhaps most importantly, this short duration of treatment may not only decrease the burden of treatment, but also improve patient adherence. Ingenol mebutate offers patients field treatment in 2 or 3 days depending on distribution and was evaluated in four multicenter, randomized trials.¹⁶

In recent years, 3% diclofenac sodium given topically has been approved to treat multiple AK lesions. In particular, in AK, diclofenac is thought to act by blocking cyclooxygenase-2 in the arachidonic acid cascade, thereby reducing angiogenesis and cellular proliferation. Topical diclofenac has also been shown to induce apoptosis. The therapeutic effect of diclofenac may therefore relate to its activity in simultaneously “starving” dysplastic keratinocytes and promoting programmed cell death, resulting in lesion clearance with minimal inflammation.¹⁷

Due to their comparable efficacy in treating AK multiple lesions, pharmacoeconomic evaluation of cost-effectiveness of both treatments is required. For this purpose, here we performed a cost-efficacy analysis comparing 3% diclofenac sodium versus ingenol mebutate. In this analysis, data of efficacy of clinical studies were combined with information on the quality of life associated with lesions taken from literature and on the other side the costs associated to the management of these lesions in Italy. This analysis includes patients with AK that were exhibited in demographic and clinical features by the participants of the clinical studies performed for the determination of efficacy with the two comparative products.

Materials and methods

The following medications have been the considered in this analysis:

Solaraze®, gel 3%, diclofenac in 2.5% of hyaluronic acid.

Picato®, gel containing 150 μg/g of ingenol mebutate

A model of decisional tree is presented based on the results of the clinical studies performed with medicinal products evaluated and Italian costs. This type of model was chosen by developing an analysis in the time frame of 1 year evaluating the results obtained with the treatment of lesions, including relapses, without extrapolation of longer-term results. Other studies are available with economic evaluations using the same type of analysis. The model uses the clinical results of comparative medicinal products and data obtained from the literature to estimate the quality-adjusted life years (QALY), expressing the results as the incremental cost for QALY gained with Solaraze® versus Picato®.

Figure 1 shows the structure of the model which describes essentially the main clinical results associated with the comparative medicinal products both in the short period (20 weeks) and in the long period (52 weeks); these periods enable to evidence respectively the initial efficacy of the treatments (and the incidence of adverse effects) and any later recurrences.

Figure 1.

Model of decisional tree for the treatment of actinic keratoses.

The choice of the time frame of 1 year is based on the availability of data on the efficacy of comparative medicinal products supposing that the later lesions have similar prognosis and management.

This analysis is carried out in the prospect of the Italian National Health System (prospect of the public payer), including only the health costs.

Parameters of the model

To identify the efficacy data to be considered in the study, a review of the literature was carried out. Among the references various publications were found which describe the efficacy of diclofenac sodium^18–25 and one study¹⁶ for ingenol mebutate containing 150 μg/g of ingenol mebutate.

Data of efficacy and safety of diclofenac sodium and ingenol mebutate

For data of safety and efficacy of the two treatments we refer to chapters 4 and 5 of the “Master File to support the reimbursability and price.”

Summary of the comparison between efficacy and safety of diclofenac sodium and ingenol mebutate

Table 1 summarizes the available evidences, the probability of negative effects, the probability of a complete recovery, and the probability of partial outcomes of therapies are compared in the economic evaluation described in the next sections as well as the relevant sources of information. For diclofenac sodium, the probabilities are taken from publications and the results of important studies described in the “Master File to support the reimbursability and price.”^18,26

Table 1.

Comparison between efficacy and tolerability (Probability).

	Solaraze® (Nelson et al.¹⁸ and Nelson and Rigel²⁶)	Picato® (Lebwohl et al.¹⁶)
Probability of adverse effects during treatment	5%	37.2%
Probability of a complete cure at the end of the follow- up (week 20 for Solaraze® and day 57 for Picato®)	58%	42.2%
Probability of recurrence of the lesion at 12 months	21%	12.8%

In the instance of ingenol mebutate, the probabilities were taken from the publications which summarize the four cardinal studies, in particular the results of the studies carried out on the face and scalp.¹⁶

Moreover, in order to convert the rates of cure and the incidence of adverse effects for each QALY, the following utility values obtained from a recently published cost-utility analysis are applied.²⁷

Data on the costs

Costs which were included into the model refer to the drug treatments for each therapeutic option and the medical visits (specialist or of the primary physician), necessary for its administration both in the initial management of lesions and in the recurrences, assuming respectively one initial visit to the dermatologist and one follow-up visit. Concerning the visit to the dermatologist, the Health Ministry reference document “Nomenclatore tariffario dell’assistenza specialistica ambulatoriale,” published on the Ministry website and updated to 18 October 2012, does not specifically mention the visit to the dermatologist; for this reason, a general visit cost of €20.66, which is the same price for other specialist visits, is reported. In the sensitivity analysis, instead, the cost of a private dermatological visit of €70–85, as reported in the price list of Regione Veneto (the most updated available online), will be considered. Though in the analysis no cost is associated with the onset of adverse effects for the baseline analysis, as it was considered that they do not involve the use of resources specific for the treatments, the sensitivity analysis of result will include the incidence of adverse effects associated with a medical visit.

Other potential indirect costs were not taken into account due to the limited data available in the literature.

Sensitivity analysis

In order to evaluate the influence of the assumptions of analysis and the variability in some of data employed, various univariate sensitivity analyses were carried out to study the influence on results of the relevant parameters employed. The probability of a complete cure, the probability of adverse effects, or the risk of recurrence were taken into account. For most parameters, a +/– 50% variation was taken into account, which was considered to be significant and capable of reflecting large changes.

Results

This economic evaluation has estimated the costs and health results of diclofenac sodium versus ingenol mebutate in the treatment of actinic keratosis on a period of 52 weeks (12 months). The global number of patients was estimated as n = 1000. The assumption established one half of patients treated with diclofenac sodium and the other half with ingenol mebutate. The results of the incremental cost-efficacy relationship in the base scenario are shown here below (Table 2)

Table 2.

Results of the incremental cost-efficacy relationship diclofenac sodium vs. ingenol mebutate.

	Diclofenac sodium	Ingenol mebutate	Difference
Results for the series (n = 1000; 500 in each arm)
Costs (€)	82.594	95.416	−9.822
QALY	478	469.5	8.5
Results/patient
Costs (€)	165.19	190.83	−25.64
QALY	0.956	0.939	0.017
Reason for the incremental cost-efficacy
ICER		Inferior

During the 52 weeks (12 months) of observation, patients treated with diclofenac sodium reached a total cost of €82.594, which includes the cost of treatment and the direct costs of the first consultation with a dermatologist. In case of recurrence, the cost of a new visit to the dermatologist and the cost of the second cycle of treatment were added. For those patients who received ingenol mebutate, the total cost was of €95.416.

Patients included into the arm of economic model corresponding to the treatment with diclofenac sodium had a total of 478 QALY versus 469.5 QALY experimented in the arm treated with ingenol mebutate. When these results are calculated in QALY per patient, this translated into a gain of 0.956 for subjects treated with diclofenac sodium and of 0.939 for those subjects who were treated with ingenol mebutate. The difference of −0.017 per patient is considered to be clinically non-significant.

If we consider the results of QALY as equivalent, we could interpret this analysis as a cost minimization analysis. This translates into a higher cost to treat the patient with ingenol mebutate, additional cost of €19.65, to obtain a benefit similar to the treatment with diclofenac sodium. In conclusion, the test results show that the treatment with ingenol mebutate is associated with a higher cost of the treatment, having the same efficacy as diclofenac sodium treatment. This is visible in the cost-efficacy plan of Figure 2.

Figure 2.

Cost efficacy plan and bar diagram

As we are uncertain about the entry parameters of the economic model, it is common practice to use a sensitivity analysis to evaluate the impact of the variations of the values of these parameters on the results reported in the model (baseline scenario).

In this instance, a univariate sensitivity analysis was performed by changing the parameters listed in Table 3.

Table 3.

Parameters changed in the sensitivity analysis and changes on net cash benefit.

Base case (net benefit)	–€536	Min			Max
Parameter	Base value	Value (–50%)	Net benefit	Actualchange	Value (+50%)	Net benefit	Actualchange
Probabilities
(P) severe TEAEs (ingenol mebutate	0.370	−50%	−€500	€36	+50%	−€572	−€36
(P) severe TEAEs (diclofenac sodium	0.050	−50%	−€532	€5	+50%	−€503	€33
(P) complete lesion clearance (ingenol mebutate)	0.422	−50%	−€6.802	−€6266	+50%	€5730	€6266
(P) complete lesion clearance (diclofenac sodium)	0.580	−50%	€8.687	€9223	+50%	−€7409	−€6873
(P) recurrence (ingenol mebutate	0.128	−50%	−€530	€7	+50%	−€543	−€7
(P) recurrence (diclofenac sodium)	0.210	−50%	−€552	−€16	+50%	−€526	€10
Costs
Net price (ingenol mebutate)	€96	−50%	−€488	€48	+50%	−€584	−€48
Cost of specialist visit	€21	15,00	−€536	−€	85.00	−€536	−€
Cost of recurrence (dermatology consultation)	€21	15,00	−€536	€1	85.00	−€542	−€6
Utilities
Utility for complete lesion clearance (no recurrence)	0.997	−50%	€813	€1349	n/a	n/a	n/a
Utility for complete lesion clearance (recurrence)	0.993	−50%	€473	€1010	n/a	n/a	n/a
Utility for incomplete lesion clearance (recurrence)	0.901	−50%	−€2.470	−€1934	n/a	n/a	n/a
Disutility for TEAEs	0.085	−50%	−€505	€31	1000	−€568	−€31
Duration of TEAEs (weeks)	4	−50%	−€505	€31	+50%	−€599	−€63

All the results of the sensitivity analyses are shown with the profit net result. We can show how the value changes from positive to negative. A positive value shows that the health benefits overcome the additional costs, whereas a negative value shows that the costs are higher than the benefits for health.

To show a sensitivity example about the key parameters of the economic model, the bar diagram (Figure 2) evidences the variation of the net cash benefit at the variation of the tested parameters (for their majority +/– 25 %). The probability of a total clearance of the lesion for diclofenac sodium and ingenol mebutate, as well as the profit changes, are less influencing factors.

Discussion

The selection of treatment of AK reflects many considerations, including distribution, number, and thickness of lesions, as well as past history of treatment and recurrence. Patient preference with respect to convenience of therapy, tolerance of side effects, and treatment cost are indeed critical considerations.

AK can be considered invasive and therefore early treatment is very important according to various reports.^28–30

One important factor to take into account would be the short duration of treatment that may not only decrease the burden of treatment, but also improve patient adherence.

Ingenol mebutate offers patients field treatment in 2 or 3 days depending on distribution and was evaluated in four multicenter, randomized trials.¹⁶

In four multicenter, randomized, parallel-group, double-blind, vehicle-controlled studies, in patients with AK, ingenol mebutate gel was effective in treating AK as a 0.015% concentration applied once daily on 3 consecutive days to the face or scalp and as a 0.05% concentration applied once daily on 2 consecutive days to the trunk or extremities. In particular, two of these studies (total of 547 patients were enrolled in the two studies involving lesions on the face or scalp, with 277 randomly assigned to receive ingenol mebutate gel and 270 assigned to receive placebo) compared the 0.015% formulation of ingenol mebutate to vehicle gel when applied daily for 3 days to a 25 cm² area of face and scalp. Ingenol mebutate demonstrated higher complete (42.2% vs. 3.7%, P <0.001) and partial (63.9% vs. 7.4%, P <0.001) clearance rates compared to vehicle. The two studies (total of 458 patients, involving lesions on the trunk or extremities, were enrolled; 226 were assigned to receive ingenol mebutate and 232 to placebo) comparing 0.05% ingenol mebutate to vehicle applied for 2 days to a 25 cm² area of trunk and extremities showed higher complete (34.1% vs. 4.7%, P <0.001) and partial (49.1% vs. 6.9%, P <0.001) clearance rates in subjects treated with ingenol mebutate.¹⁶

Different studies from the literature shown the efficacy and safety of 3% diclofenac, known to be a safe and effective treatment of AK on both skin and mucosal lip, in both immunocompetent and immunosuppressed patients, with important impact on preventing field cancerization. In different clinical trials, the product is effective in significantly reducing lesions. However, the patients who achieve the complete clinical response should be adequately educated to continue their photoprotection in order to minimize recurrence of AK.

The analysis of the baseline case has demonstrated that when diclofenac sodium is used as a treatment for patients with AK, it is likewise effective but less expensive than ingenol mebutate. Data of efficacy which are the base of this analysis are taken from Phase III clinical trials recently carried out on patients from various centers. As it may be expected in such analysis, the main drivers of the results are the probabilities that the patient reaches a complete cure, the probabilities of having adverse effects, if the injury is recurrent, and the related values of utility. Tornado model views various values for these parameters in order to perform the sensitivity analysis.

Conclusions

The results of the cost-efficacy analysis of 3% diclofenac sodium versus ingenol mebutate, obtained from the combined efficacy data of clinical studies and information about the quality of life associated with the lesions taken from literature, together with the costs related to the treatment of these lesions in Italy, demonstrate that ingenol mebutate has a higher cost with the same efficacy. In many patients, various different treatment regiments must be employed in order to successfully manage AK, especially in widespread or resistant cases. As usual, the best way to manage AK is prevention, i.e. avoiding exposure to significant or unnecessary UV radiation may help prevent recurrence or limit the progression of AK.

Footnotes

Declaration of conflicting interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Pharmacoeconomy of drugs used in the treatment of actinic keratoses

Abstract

Keywords

Introduction

Materials and methods

Parameters of the model

Data of efficacy and safety of diclofenac sodium and ingenol mebutate

Summary of the comparison between efficacy and safety of diclofenac sodium and ingenol mebutate

Data on the costs

Sensitivity analysis

Results

Discussion

Conclusions

Footnotes

Declaration of conflicting interest

Funding

References