A cost-effectiveness analysis of sinecatechins in the treatment of external genital warts

Abstract

Abstract

Objective: To evaluate the cost-effectiveness and treatment-cost impact of sinecatechins (Veregen) as first-line therapy against its principal comparator, imiquimod (Aldara), in the treatment of external genital warts (EGWs).

Method: A two-stage decision model is proposed to compare sinecatechins with its principal comparator, imiquimod, as a first-line topical therapy in the treatment of EGWs. The model utilizes estimates of sustained clearance from two pivotal sinecatechins trials and from a systematic literature review for imiquimod. Resource inputs are: (1) trial-based estimates of average drug utilization and (2) CPT (Current Procedural Terminology) codes describing anticipated office visits and utilization of second-line ablative procedures.

The analysis considers: (1) comparative costs of achieving a successful outcome with sinecatechins versus imiquimod, and (2) comparative cost–consequences of sinecatechins versus imiquimod. As a modeled approach to evaluating comparative product effectiveness, the claims made reflect the structure of the model, which focuses on topical products as first-line therapy in EGW interventions and in its reliance on estimates of sustained clearance from pivotal randomized clinical trials (RCTs). Sustained clearance in this context being defined as the proportion of patients who report initial wart clearance over the RCT period corrected for subsequent recurrence.

Results: As first-line therapy, sinecatechins dominates imiquimod as a lower cost treatment with a higher sustained clearance rate (51.9 vs. 40.6%). First-line average cost of treatment with sinecatechins is $774 compared to imiquimod at $930. Cost per successful outcome with sinecatechins is $1,492, which is lower than $2,289 for imiquimod. Taking account of patients failing first-line therapy moving to a second-line ablative therapy yields an average cost of treatment for patients initiated to sinecatechins of $943 and $1,138 for those initiated to imiquimod. A sensitivity assessment confirmed the position of sinecatechins within the decision-model framework.

Conclusion: Sinecatechins yields a lower cost of treatment compared to imiquimod in the treatment of EGW. It also offers cost savings to healthcare systems. This conclusion should be qualified by the limitations of the decision framework within which the assessment has been made. The model focuses on topical preparations as first-line therapies, with estimates of sustained clearance taken from pivotal RCTs. Treatment cost estimates are generated independently, but reflect current product and ancillary costs.

Key words::

• cost
• cost-effectiveness
• external genital warts
• sinecatechins
• sustained clearance

Introduction

Although external genital warts (EGWs) are seen as the most common sexually transmitted infection, surprisingly little is known about their prevalence and treating prevalence in the US. As far as prevalence estimates are concerned, the most widely quoted estimate is based on the work of Koutsky which claims that 1000/10⁵ (1%) of the sexually active population (persons aged 15–49 years) present, in any year, with clinically identifiable EGWs¹. As such, EGWs present a significant public health problem in the US with approximately 20 million sexually active adults in the US believed to be infected.

Treatment regimens for EGWs are classified into patient-applied and physician-applied. The former are often preferred on privacy grounds, but they must be used effectively to reach all warts. Recommended regimens for EGWs are podofilox (0.5% solution or gel) or imiquimod 5% cream for patient-applied therapies, cryotherapy with liquid nitrogen or cryoprobe, podophyllin resin 10–20% in a compound tincture of benzoin, trichloroacetic acid (TCA) or bichloroacetic acid (BCA) 80–90% or surgical removal in the physician-applied category. A typical course of therapy could last up to 3 months or more with, in the case of the physician-applied therapies, visits weekly or bi-weekly.

In the case of the patient-applied therapies, podofilox 0.5% solution or gel, an antimiotic drug that destroys warts, and imiquimod 5% cream, a topically active immune enhancer, have been approved and have been available for some time. In common with the physician-applied therapies, neither of the patient-applied therapies report particularly high-sustained clearance rates. While evidence is limited for the physician-applied therapies with estimates of sustained wart clearance in the range 25–35%, pooled clinical data for the patient-applied therapies would suggest sustained clearance in the range of 15–40% for podofilox and a range of 35–40% for imiquimod^2–4. In 2006, however, sinecatechins 15% ointment was approved by the FDA for the topical treatment of external genital and perianal warts. Sinecatechins, the first FDA approved botanical drug in the US, is an important addition to the range of EGW treatment options because of a rate of sustained clearance substantially above those estimated for other EGW interventions, together with a tolerable side-effect profile.

Sinecatechins (Veregen) is a botanical product for topical use in treating EGW. The drug substance is derived from green tea leaves (Camellia sinensis) and consists of a proprietary quantified mixture of catechins (85–95% by weight), their derivatives and other green tea components. Catechins are the major polyphenol/flavonoids found in green tea leaves. They have been extensively studied for their anti-oxidative, immune-stimulatory and antiviral properties. They specifically inhibit the pathways which are activated by HPV oncogenes and have immune-stimulatory activities both resulting from the generation of an immune stimulatory cytokine environment and in lymphocyte activation. Each 15-g tube of the ointment contains 150 mg of sinecatechins in a water-free ointment base. The ointment is to be applied three times per day to all warts, and it is not necessary to wash it off. Application should be continued until complete clearance of the warts or up to 16 weeks.

Imiquimod (Aldara^†) is an immune response modifier. Imiquimod's biological activity is attributed to its ability to induce the production of interferon-α and other cytokines. These include interleukin 1, 1L-6, 1L-8 and tumor necrosis factor-α. This stimulates the cellular immunity of the skin. Imiquimod is supplied as a cream in 250-mg single-use packets. They are available as a box of 24 packets. The cream is to be applied three times per week, left on the skin for 6–10 hours and washed off. It should be continued until complete clearance of the warts or up to 16 weeks.

The objective of this study was to evaluate the cost-effectiveness and treatment-cost impact of sinecatechins as first-line therapy against its principal comparator, imiquimod in the treatment of EGWs.

Methods

The analysis presented here is based on a decision-model framework to represent the options present in the treatment of EGWs. A two-stage model is proposed where the first-line choice of treatment is assumed to be between two currently available topical or patient applied therapies: sinecatechins and imiquimod. The focus is on the cost consequences associated with differentially reported sustained clearance rates for the two products. These data are taken from published pivotal RCTs. The present analysis takes a similar approach to the earlier decision models in evaluating the cost-effectiveness case for sinecatechins against imiquimod in US managed care2. Imiquimod is considered the appropriate comparator because this is the topical application that sinecatechins is expected to be compared to in treating practice. Neither podofilox 0.5% solution nor gel are considered appropriate comparators for this modeled comparison because of the variability in reported sustained clearance rates.

Sustained clearance

In assessing the impact of EGW therapies, the focus is on claims for sustained clearance following one or more treatments, where sustained clearance (SC) is equal to the initial clearance (IC) multiplied by one minus the recurrence rate (RR); i.e. SC = IC (1 – RR). Clinical trial-based estimates of sustained clearance play a central role in modeling the comparative cost effectiveness of interventions for EGW. Typically, sustained clearance estimates are restricted to the 12 weeks following clearance with initial therapy. Given the latency period of HPV, it has been suggested that this period may be too short and hence understate recurrence rates. A recent analysis by Vexiau et al conclude that the follow-up period of 12 weeks is adequate and longer observation periods do not materially impact recurrence estimates⁵.

There have been only two systematic reviews published of clearance rates and adverse events in patient-applied therapies. The Moore et al review focuses on imiquimod while the Yan et al systematic review compares imiquimod to podophyllotoxin but does not detail recurrence patterns^4,6. In the Moore et al analysis the pooled assessment of initial clearance (based upon 454 patients from nine placebo controlled trials) was 49.1% (95% CI 44.5–53.7%). Seven of these trials provided estimates of recurrence (median duration of follow-up 12 weeks) with an estimated pooled recurrence rate of 28.5% (95% CI: 22.2–34.7%). These estimates yielded a pooled estimate for a sustained clearance rate for imiquimod of 40.6%^4,7.

Pooled data from the two pivotal trials of sinecatechins provide the estimates of sustained clearance⁸. The initial treatment period for sinecatechins and the recurrence observation period is the same for imiquimod. Summary data for initial clearance and recurrence for sinecatechins are presented in Table 1.

Table 1. Initial clearance and recurrence of baseline external genital warts with sinecatechins (Intention to treat results).

Clearance	Intention-to-treat (ITT) (%)	Standard deviation (%)
Complete clearance of baseline warts	55.4 (n=220)	2.49
Recurrence of baseline warts	6.4 (n=14)	1.65

Source: Veregen NDA 2005; combined trials CT1017 and CT1018 (n=397)

In assessing these results it is important to note that the sinecatechins trials differ from the imiquimod trials in capturing clearance rates for both the baseline warts and new warts that appeared since therapy initiation. Overall, for the intention-to-treat (ITT) population, 154/397 (38.8%) reported new EGWs. As far as initial clearance is concerned, 55.4% of subjects reported complete clearance of all baseline warts by week 16. Of these, 6.4% reported a recurrence within the succeeding 12 weeks, to yield a sustained clearance rate of baseline warts of 51.9%. This contrasts with a pooled sustained clearance rate for imiquimod of 40.6%.

It is important to note that in the pooled estimates for the two sinecatechins trials, 38.8% of patients reported new warts appearing within the 16-week study period. Only two imiquimod trials have, as far as can be ascertained, reported on the emergence of new warts and consequent complete wart clearance by the end of the study period. For patients treated with imiquimod, 30% of patients reported new warts with 39% of these clearing by the end of the study period. Estimates of sustained clearance for imiquimod do not appear to have taken the appearance or clearance of new warts into account.

In this context it is important to point out that the vehicle preparations used in the imiquimod and sinecatechins trials are quite different. Apart from the fact that imiquimod is a cream and sinecatechins an ointment, where ointment formulations provide an occlusive-type barrier that may accelerate healing compared to formulations such as creams and gels, the vehicle used in the sinecatechins trials was designed to bring out the independent and additive effect of sinecatechins. That is, the preparation used in the active arm involved sinecatechins added to the vehicle formulation. The inclusion of skin irritants in the vehicle formulation (e.g., isopropyl myristate and oleyl alcohol) may also have contributed to the low rate of EGW recurrence.

In short, because the vehicle used in sinecatechins served as the placebo for the sinecatechins studies, and some other vehicle or formulation served as the placebo for the imiquimod studies, the choice of vehicle formulation in these trials renders any placebo comparisons, and possible placebo adjustments, against imiquimod, impractical.

A further key input to developing a cost-effectiveness assessment is the quantity of the study medication required. In the case of imiquimod, the best estimate is 30 packets to achieve the estimated pooled sustained clearance of 40.6%⁷. For sinecatechins, one of the two pivotal clinical trials yields an estimate of 34.4 g (95% CI: 32.0–36.8 g) or 2.29 tubes⁸.

Cost and cost-effectiveness studies

The only study which has attempted to estimate both the prevalence of external genital warts and the average costs of treatment in fee-for-service US managed care has estimated the prevalence for EGWs at 0.17% and an average cost (year 2000 dollars) for an EGW episode of care of $436 (95% CI: $365–508)⁹. The average episode of care comprised 3.1 physician visits (95% CI: 2.9–3.3 visits) with nearly 40% of EGW treatments involving patient-applied therapies, which were often used in conjunction with physician-administered ablative therapies.

Only two cost-effectiveness studies have considered the claims for the competing patient-applied therapies in the US, and a single study that evaluated the combined direct medical costs of surgical and medical treatments^2,10,11. Outside of the US, there have been both cost-effectiveness studies that have considered the patient-applied therapies, together with studies that have evaluated treatment patterns and costs of treatment^12–15.

Model framework and inputs

Modeling the cost-effectiveness of competing EGW therapies focuses (1) on the therapies utilized as first-line interventions, as well as (2) on the therapies utilized as first-line therapy in a two-therapy sequence. In the former approach, the model emphasizes the impact of sustained clearance and compares the interventions in terms of the costs per successful outcome of first-line therapies. In the latter approach, account is taken of patients who fail to clear with an initial therapy and moving to a second-line treatment. Because of the absence of clinical-trial or even observational data to detail the success rate of second-line therapies (e.g., cryotherapy following failure on an initial patient-applied therapy) there are no estimates of sustained clearance in therapy sequencing for EGW interventions. The latter approach is limited to a cost-consequences analysis.

In both cases the analysis is from the perspective of a US managed-healthcare system where only direct costs of treatment are considered. The analysis is restricted to the approved indication for treatment duration for first-line topical treatment with either sinecatechins or imiquimod of 16 weeks. For patients who have failed to achieve sustained clearance in this time frame, the introduction of a second-line ablative therapy is assumed. There is no fixed timeframe within the model for second-line therapy because the analysis focuses on the costs of subsequent visits and procedures, not on their probability of success – for which there are no RCT estimates.

Drug utilization and costs

Drug costs are based upon the most recently published AWP (Average Wholesale Price) data and pivotal trial estimates of the average number of product units utilized: 2.29 15 g tubes in the case of sinecatechins and 1.25 boxes (@ 24 packets per box) in the case of imiquimod. The amount of drug utilized will depend upon the number and size of lesions. Total cost for the sinecatechins at an assumed $275.86 AWP per 15 g tube is $631.72; total imiquimod cost at $624.90 AWP per box is $781.13.

Physician visits and procedures

For both sinecatechins and imiquimod it is assumed that there is an initial physician visit, a follow-up visit at 8 weeks, for those patients where clearance has not been achieved, and a subsequent visit to evaluate clearance status at the end of 16 weeks, again for those who have not cleared. Estimates for imiquimod indicate that, at 8 weeks, 22.2% of patients achieve initial clearance. In the case of sinecatechins the situation is complicated by the potential appearance of new warts and the need to treat these, irrespective of the rate at which baseline warts are cleared. Focusing on baseline warts only, pooled estimates from the pivotal sinecatechins trials indicate that 20.9% of patients achieve wart clearance by 8 weeks. To simplify the analysis, the model assumes 20% clearance of baseline warts in both arms by week 8.

In modeling physician visits it is assumed that:

1.	The initial patient visit is an expanded (20 min) new patient visit (CPT 99202);
2.	All follow-up visits for patients who have not cleared at week 8, at week 16 and for those with a recurrence within 12 weeks are assumed to be an established patient extended visit (15 min) (CPT 99213);
3.	For patients who complete first-line therapy a final visit to assess clearance (CPT 99213); and
4.	For patients proceeding to second-line ablative treatment there is an expanded problem focused visit (CPT 99214) together with (a) for males either a simple destruction of lesion procedure with cryotherapy (CPT 54056) or an extensive destruction of lesion procedure for any method (CPT 54065) and (b) for females a simple destruction (any method) (CPT 56501) and extensive destruction (any method) (CPT 56515). In applying these procedures it is assumed that the distribution of treatments is 50:50 to give a simple weighted average procedure cost. Following the ablative treatment, patients are assumed to take one further office visit (CPT 99214)

Cost of physician visits and procedures are taken from the 2009 Medicare fee schedule. These are summarized in Table 2.

Table 2. Summary of model inputs for cost-effectiveness evaluation.

Cost-effectiveness model inputs	Input values
Initial clearance of baseline warts
At 8 weeks At 16 weeks Recurrence	Sinecatechins 20.9%/imiquimod 22.2%Sinecatechins 55.4%/imiquimod 52.3%Sinecatechins 6.4%Imiquimod 22.3%
Drug unit costs and average utilization
Sinecatechins Imiquimod	2.29 × 15 g tubes @ $275.86 (AWP Dec 2008)1.25 × 24-packet boxes @ $624.90 (AWP Jun 2009)
Drug costs (course of treatment)
Sinecatechins Imiquimod	$631.72$781.13
Physician visits
CPT99202 CPT99213 CPT99214	$63.48$61.31$92.33
Procedure costs (males)
CPT54056 CPT54065 Average/patient treated	$125.87$205.22$165.54
Procedure costs (females)
CPT56501 CPT56515 Average/patient treated	$122.99$209.91$166.45

Initial clearance, recurrence and sustained clearance

The model is estimated as a simple two-stage decision framework, where patients who fail first-line therapy with either sinecatechins or imiquimod move to cryotherapy as the second-stage treatment. The key inputs from the pivotal clinical trials are: (1) estimates of the number of patients who achieve clearance of baseline warts at 8 weeks; (2) estimates of the number of patients who achieve initial clearance of baseline warts at 16 weeks; and (3) estimates of the number of patients who experience a recurrence of baseline warts within 12 weeks of initial clearance.

Results

Modeled results are summarized in Table 3. At a unit AWP price of $275.86 for sinecatechins, the model results indicate that, compared to imiquimod, sinecatechins is the dominant therapy. That is, sinecatechins is clinically more effective in terms of long-term sustained clearance (51.9 vs. 40.6%) and at a lower cost. If the initial (or first-line) cost of treating EGWs with imiquimod or sinecatechins is considered, the average cost of treatment is $774 for sinecatechins compared to $930 for imiquimod. These cost estimates translate to $1,492 as the cost per successful outcome with sinecatechins compared to $2,289 for imiquimod.

Table 3. Modeled cost-effectiveness outcomes: sinecatechins and imiquimod.

Outcome	Sinecatechins	Imiquimod
Sustained clearance	51.9%	40.6%
Average cost of first-line therapy	$774	$930
Cost per successful outcome	$1,492	$2,289
Cost of first- and initial second-line therapy	$943	$1,138
First-line average cost advantage with sinecatechins	$156
First- and second-line cost advantage with sinecatechins	$196

If the numbers of patients who fail initial therapy and who are treated with an ablative therapy are also considered, then the average cost of treatment increases overall. However, as fewer sinecatechins patients progress to a second-line therapy, the overall cost of treatment with sinecatechins ($943) is lower than that for imiquimod ($1,138). Because there are no clinical data to provide estimates of the proportion of patients who achieve sustained clearance with ablative therapies applied as second-line, it is not possible to give corresponding estimates of costs per successful outcome of therapy.

Whether first-line treatment is considered or a combination of first- and second-line, the costs of treatment with sinecatechins is always less expensive than therapy involving imiquimod. The average cost saving as first-line is $156 in favor of sinecatechins and $196 for first- and second-line therapy.

To illustrate the potential budget impact of introducing sinecatechins as an option in EGW, consider the case of a 500,000-member healthcare system. Following Koutsky, if we assume the prevalence of EGWs is 1% of the sexually active population (persons 15–49 years of age), this equates to approximately 0.5% of a managed-care population or, in this example, 2,500 plan members. If, for example, 10% of these patients are treated with imiquimod, followed by an ablative therapy at an average cost of $1,138, switching these patients to sinecatechins at an average cost of $943 will result in a total cost saving of $48,750 (a 17.1% reduction in costs).

Sensitivity analysis

To illustrate the robustness of these results for sinecatechins, a sensitivity analysis was undertaken on the assumption that the sustained clearance for both products was 47.0% (approximately the upper and lower 95% CI for imiquimod and sinecatechins, respectively) but the same recurrence rates. Re-estimating the decision model yields an average cost of treatment as first-line therapy of $779 for sinecatechins and $934 for imiquimod. Cost per successful outcome is lower for sinecatechins ($1,770) than for imiquimod ($2,554). Overall, the total cost of both first and second-line treatment for sinecatechins ($975) is lower than for imiquimod ($1,155). If a patient is switched to sinecatechins from imiquimod, this results in an estimated cost saving of $180 for first- and second-line therapy.

Discussion

EGWs are difficult to treat. The available patient-applied and physician-administered therapies are limited in their ability to achieve satisfactory long-term outcomes. Imiquimod, which is the latest therapy, has been in the market for over 12 years but has only an estimated sustained clearance of 40.6%. This is equivalent to more expensive, and seldom used, laser therapy and only a few percentage points more successful than trichloroacetic acid. The new botanical product, sinecatechins, has a demonstrated greater trial-based sustained clearance to imiquimod – which represents a major improvement over existing therapy. Utilizing a decision-model framework, an indirect comparison of the treatment costs and cost-per-successful outcome for the two therapies points to the dominant position of sinecatechins as first-line therapy in EGWs. This is driven by both the more favorable sustained clearance rate for sinecatechins and the comparative product cost for up to 16 weeks of therapy.

Even so, the limitations implicit in claims based upon a modeled decision framework should be acknowledged. While estimates of sustained clearance, taken from well-conducted, placebo controlled RCTs, are the key input to this analysis, the results are only as robust as the choice of decision framework and the assumptions made as to the selection and cost of input parameters. Care has been taken to ensure that costs are representative of current treatment options, with a sensitivity analysis undertaken to assess the overall robustness of the claims made for comparative cost effectiveness. The model framework is designed to represent options that are open to physicians in the treatment of EGWs.

Conclusion

Given the RCT based clinical results in EGWs for sinecatechins and imiquimod, it is clear that the former yields a more favorable sustained clearance profile. Taking these results and utilizing an indirect comparison within a simple decision-model framework, at current product and procedure prices, sinecatechins is found to be the dominant therapy in the treatment of EGWs.

The model results, supported by the sensitivity analysis, provide a robust framework for assessing these two therapies. This points to the potential for cost savings within a US managed care environment. While one size does not fit all in EGW interventions, in situations where imiquimod might be indicated as a result of wart presentation, patient preferences and prior treatment experience with EGWs, consideration should be given to sinecatechins as an alternative therapy.

Acknowledgements

Declaration of interest: P.L. has disclosed that he is a consultant to PharmaDerm, Florham Park, NJ.

Notes

* Veregen is a registered trademark of MediGene AG, D 82152 Planegg/Martinsried, Germany

† Aldara is a registered trademark of Graceway Pharmaceuticals, LLC. Bristol, TN, USA