Ravi Jandhyala

The Jandhyala Institute, Parnassus, Main Street, Great Bourton, Banbury, Oxfordshire, OX171QW, UK

Received 6 September 2011; accepted 1 December 2011

KEYWORDS

Botulinum toxintype A; Aesthetic; Glabellar lines; Cost-effectiveness

Summary Background: It is accepted that the three commercially available type A botulinum
toxins (BoNT-As) are different, their units of potency are not interchangeable and no
fixed dose conversion ratio exists between them. To date, there is no clear evidence demonstrating
the superiority of one toxin over another clinically.
Objective: The study aims to identify evidence confirming the equivocal efficacy of the formulations
and to justify that attention can therefore be reasonably turned to their differing costs as
a means of aiding choice of treatment. This is achieved via the development of the cost calculator
presented herein, to enable direct economic comparisons to be made between the three
commercially available BoNT-A formulations licensed for aesthetic indications in the UK.
Methods: An online literature search using PubMed was undertaken and the latest available information
on the cost for each BoNT-A treatment was accessed via the British National Formulary
(BNF). Predicated on the evidence review, a cost calculator was developed which takes into
account for the glabella: the number of treatments needed per patient with each product over
a year and the number of treatments available with differing dilutions of each vial of each product
over a year. A range of cost prices can also be introduced allowing a direct cost-comparison to be
made for treating the glabella of a set number of patients over a year between different products.
Results: Azzalure
(abobotulinumtoxinA) was the most cost-effective in almost all scenarios
tested, whilst Vistabel
(onabotulinumtoxinA) was the least cost-effective. Of the two products
with published non-inferiority with respect to each other, onabotulinumtoxinA and Bocouture

(incobotulinumtoxinA), incobotulinumtoxinA offered a lower overall cost to treat the glabella of
the same number of patients when compared with Vistabel.
Conclusion: In most scenarios, BoNT-A treatment with abobotulinumtoxinA will result in significant
annual cost savings when compared with treatment with onabotulinumtoxinA or incobotulinumtoxinA.
ª2011 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd.
All rights reserved.

In humans, botulinum toxin type A (BoNT-A), produced by the A serotype strain of Clostridium botulinum, has the biological action of cleaving a protein called synaptosomal membrane-associated protein 25 kDa (SNAP-25).¹ This action blocks the presynaptic release of acetylcholine at the neuromuscular junction and inhibits muscular contrac-tion.¹ As such, when administered intramuscularly in the glabellar region of the forehead, temporary muscle paral-ysis can effectively ameliorate the appearance of hyperki-netic glabellar frown lines.² As the appearance and exaggeration of these ‘wrinkle lines’ is associated with ageing and stress,³ requests for cosmetic treatment to reduce these facial lines have become common in devel-oped countries.⁴ Whilst traditional remedial surgical procedures (such as an upper face-lift) are associated with substantial patient risk, injection of BoNT-A is minimally invasive and associated with only minor, transient pain.² Consequently, BoNT-A treatment has become a mainstay of the modern treatment approach with applications extending from the smoothing of glabellar lines to a wide range of aesthetic facial treatments.⁵ Due to popularity and increasing consumer demand, a number of BoNT-A formu-lations are now commercially available for cosmetic procedures. These include Vistabel^_/BOTOX^_/BOTOX Cosmetic^_ (onabotulinumtoxinA) (Allergan Inc, Irvine, CA, USA),⁶ Azzalure^_ (abobotulinumtoxinA) (Galderma UK Ltd., Watford, Herts, UK)⁷ adapted from Dysport^_ (Ipsen UK Ltd., Slough, Berks, UK) and Bocouture^_ (incobotulinumtoxinA) (Merz Pharma UK Ltd., Elstree, Herts, UK)⁸ adapted from Xeomin^_ (Merz Pharma UK Ltd, Elstree, Herts, UK).

Currently, there is no clear evidence on any meaningful differences in the effectiveness of the three BoNT-A formulations.⁹ The situation is complicated by the hetero-geneity of the published studies, in terms of the area treated (predominantly glabellar lines), the study design chosen and primary efficacy ‘end’ points used.¹⁰ Further-more, the lack of a standardised conversion ratio between the formulations calls into question the validity of the results from the comparative trials published.¹¹

The rationale for this review is first to try and identify any distinguishing factors between the three commercially available BoNT-A formulations licensed for aesthetic indi-cations in the UK, including differences in efficacy, toler-ability and administration and, second, to develop an accurate cost calculator to enable direct economic comparisons to be made between the three BoNT-A formulations.

Literature review

To gain an up-to-date view of the three commercially available BoNT-A formulations and gather appropriate information to inform the development of a cost calculator, an online literature search was performed using PubMed (NCBI, U.S. National Library of Medicine). The following search terms/criteria were used: ‘botulinum toxin*’ and ‘cosmetic’ or ‘aesthetic’ or ‘glabellar’ or ‘wrinkle*’ or ‘crow’s feet’, limited by ‘humans’, ‘English’, ‘clinical trials’, ‘meta-analysis’ or ‘randomised controlled trial’ for citations from 1980 to 2011. In addition to the literature review, manual searching of key journals and bibliographies of pertinent reviews was undertaken. The Summary of Product Characteristics^6e8 for each formulation was also sourced, to critically assess dosing and administration guidance. The latest available information on the cost for each respective BoNT-A treatment was also sourced from the British National Formulary (BNF).¹²

Clinical effectiveness

Comparative efficacy

The literature searches identified 27 clinical studies/ meta-analyses of potential interest, the majority of which focus on the treatment of glabellar lines ( Tables 1  and 2). As expected, the ‘end’ points in the studies varied, including the use of quantitative or qualitative wrinkle severity scales assessed by clinicians and/or patients, as well as more general patient satisfaction scores. The studies also varied in duration, with most reporting ‘end’ points within 20 weeks. The studies clearly demonstrate the efficacy of the BoNT-A formulations at improving cosmetic outcome.

Six studies were identified that directly compared the efficacy and tolerability of the BoNT-A formulations: four comparing abobotulinumtoxinA to onabotulinumtoxinA^13,14 and two comparing incobotulinumtoxinA to onabotuli-numtoxinA ( Table 1).^15,16 No studies were identified that compared abobotulinumtoxinA to incobotulinumtoxinA. When compared at doses of w2.5:1 abobotulinumtoxinA: onabotulinumtoxinA, onabotulinumtoxinA appeared to demonstrate a trend for superior efficacy over abobotuli-numtoxinA in the treatment of glabellar lines.^13e15 In two of these studies, however, there was heterogeneity in the study populations, in both cases patients being significantly younger in the abobotulinumtoxinA arms than the onabo-tulinumtoxinA arms.^13,14 Conversely, at a dosage ratio of 3:1 abobotulinumtoxinA: onabotulinumtoxinA, abobotuli-numtoxinA appeared more efficacious than onabotuli-numtoxinA at treating forehead wrinkles.¹⁶ The other two studies showed incobotulinumtoxinA and onabotuli-numtoxinA to have similar efficacy in treating glabellar lines¹⁷ and crow’s feet.¹⁸ On the basis of these studies, the efficacy of the three formulations can be considered to be largely equivocal.

Since the studies were variable in terms of ‘end’ points and length, perhaps the simplest way of comparing dura-tion of benefit between the formulations is via what is stated in the respective Summary of Product Character-istics.^6e8 For onabotulinumtoxinA and incobotulinumtox-inA, efficacy is reported for up to 4 months,^6,8 whereas for abobotulinumtoxinA the benefits of treatment are stated to last up to 5 months in some patients.⁷ Thus, the dura-tion of response with abobotulinumtoxinA may in fact be sufficient to require only two to three treatments per year in some patients. By contrast, both onabotulinumtoxinA and incobotulinumtoxinA may require a minimum of three treatments per year, representing the potential for additional cost in comparison to abobotulinumtoxinA. Importantly, for each of these BoNT-A formulations, maximum dosing guidelines dictate that patients should not exceed a frequency of four treatments per year.^6e8

Comparative tolerability

All of the BoNT-A formulations appear similarly well tolerated, with no clear indication of any significant differences in adverse event rates.^13,14,17,18 There have been reports of a trend for greater patient rated pain with abobotuli-numtoxinA than with onabotulinumtoxinA, perhaps reflec-tive of the greater volume of solution injected,⁵ although this has not been definitively proven. The notion that novel formulations of BoNT-A without complexing proteins offer the benefit of a reduced risk of immunogenic reactions compared with onabotulinumtoxinA/Botox has also not been substantiated in the literature.⁵ For the majority of patients, minimal, transient pain is the most common side effect, with the overall rate of adverse events tending to diminish with repeated cycles.

Some researchers have theorised that there may be important differences in the diffusion rates of abobotuli-numtoxinA and onabotulinumtoxinA,³⁷ as the molecules of BoNT-A in abobotulinumtoxinA vary in molecular weight between 500 and 900 kDa, but are consistent at 900 kDa in onabotulinumtoxinA. Whilst some studies would cast doubt on this theory,³⁸ it does offer a potential explanation as to why local migration of BoNT-A appears to be more pronounced with abobotulinumtoxinA than with onabotuli-numtoxinA.³⁹ This would seem to intuitively suggest that the occurrence of migration-related adverse effects, such as ‘droopy eyelids’ and unwanted weakness/paraesthesia of nearby musculature, would be higher with abobotuli-numtoxinA than with onabotulinumtoxinA. A confounding factor in this is how patients are controlled and advised by their clinicians in the hours immediately after BoNT-A treatment, as behaving appropriately, by not exercising, lying down, manipulating the injection site, etc., may influence the risk of local BoNT-A migration. Taking these factors into consideration, evidence from the largest con-ducted safety trials for abobotulinumtoxinA,²⁷ onabotuli-numtoxinA⁴⁰ and incobotulinumtoxinA⁸ demonstrates that all formulations appear to be very well tolerated, with equivalent risk to injection with placebo solutions. In particular, the development of treatment-related eyelid ptosis appears to be similar, ranging from 1% to 4% with abobotulinumtoxinA in all studies reviewed by Rubin et al.²⁷ and 1.8e3.6% with onabotulinumtoxinA in studies reviewed by Brin et al.³⁷

Other considerations

The ability to titrate the doses of onabotulinumtoxinA and incobotulinumtoxinA over time, from 20 to 50 U and from 20 to 30 U, respectively, perhaps offers an added incentive to commence BoNT-A treatment with these formulations rather than with abobotulinumtoxinA, which is licensed only at 50 U. Indeed, the capacity to alter BoNT-A treat-ment doses with onabotulinumtoxinA and incobotuli-numtoxinA might enable clinicians to tailor their treatment approach to different individuals to a greater extent than is possible with abobotulinumtoxinA. It should never be forgotten that patient preference might also play a role in deciding the formulation administered.

Creating the cost calculator

The review of the evidence tends to indicate that the efficacy and tolerability of the BoNT-A formulations are largely equivocal, with only minor differences reported that are not currently substantiated.^9,10 Thus, to enable a more thorough comparison of available BoNT-A treat-ments in the aesthetic setting, it is becoming increasingly necessary for clinicians to consider additional factors, such as the economic cost of the formulations. This has led to the development of the Jandhyala Institute cost calculator and underlying model to permit quantitative and economic comparison of commercially available BoNT-A formulations for aesthetic treatments.

The calculator permits discussion of the potential cost impact of selecting a given BoNT-A formulation in comparison to alternatives. The cost-comparison calculator is based on BNF¹² prices and typical doses of onabotuli-numtoxinA, abobotulinumtoxinA and incobotulinumtoxinA, which can then be edited to suit local circumstances. Information is also included for the therapeutic formulations of each aesthetic BoNT-A treatment, abobotulinumtoxinA (therapeutic), onabotulinumtoxinA (therapeutic) and inco-boulinumtoxinA (therapeutic), so that comparisons with these ‘off-licence’ products are possible. This inherent flexibility of the calculator ensures that it is robust to potential revisions to the cost of these products or amend-ments to their respective Summary of Product Characteris-tics. Treatment characteristics, such as patient numbers, vial size, dosage, reconstituted volume (ml), number of treatments per year and the potential for vial sharing (including percentage of possible wastage) as well as acquisition and storage costs are considered in the economic analysis.

Using the cost calculator

The calculator displays the cost of onabotulinumtoxinA (aesthetic and therapeutic), abobotulinumtoxinA (aesthetic and therapeutic), and incobotulinumtoxinA (aesthetic and therapeutic) based on the number of patients and the frequency of treatments (per year) input by clinicians. The dosages of each formulation along with dosing characteris-tics can be altered to reflect local circumstance by adjust-ing the default base-case values ( Table 3).

The values entered for the treatment characteristics are used to calculate the cost per patient and the annual cost per patient for each BoNT-A formulation ( Table 4). The cost calculations are based on the standard list prices for each formulation, although local discounted prices can be added instead. The percentage cost disparity between any two of the formulations can be selected and displayed within the calculator (not shown herein).

A graphical representation of the comparative costs is also given, as well as the option to include vial sharing ( Figure 1). Even when vial sharing is selected, an option to include a certain percentage of wastage is included, to more accurately reflect clinical practice. Another function enables a quick review of any disparity in annual costs between any two selected formulations ‘side by side’ (not shown herein).

Additional factors to consider when using the cost calculator

The default base-case setting for the frequency of BoNT-A treatments per year is modifiable, and should be custom-ised based on clinicians’ experiences with each formulation and the perceived frequency of annual dosing. Please note, however, that a maximum frequency of four doses per year is allowed in the calculator, to reflect the advice of each of the BoNT-A treatment manufacturers, which warns against treatment occurring more than once every 3 months.^6e8

It is also important to consider other factors that might impact on the overall cost of treatment, and, therefore, the choice of BoNT-A treatment. OnabotulinumtoxinA (therapeutic and aesthetic) and abobotulinumtoxinA (therapeutic and aesthetic) formulations must be refriger-ated at 2e8 C prior to use.^6,7 IncobotulinumtoxinA (ther-apeutic and aesthetic), however, can be stored for up to 3 years (unopened, at <25 C),⁸ which adds an important element of convenience to the formulation and eliminates costs associated with refrigeration. Once reconstituted, however, immediate use of each solution is recommended (within 4 h) to minimise the risk of microbial con-tamination.^6e8 Thus, conditions for storage, preparation, administration and disposal of each BoNT-A treatment are broadly comparable, but incobotulinumtoxinA and incobo-tulinumtoxinA are slightly cheaper in this regard. The cost of refrigeration is included in the calculator.

Figure 1   Cost output based on maximum dosage (with vial sharing).

Results from the cost calculator

It is clear from the cost calculator that in most scenarios, BoNT-A treatment with abobotulinumtoxinA will result in significant annual cost savings when compared with treat-ment with onabotulinumtoxinA or incobotulinumtoxinA (based on current list prices). For example,  Figure 1 shows that when 100% vial sharing is assumed, treating 600 patients with abobotulinumtoxinA 50 U would result in an annual saving of £107 285.71 when compared with onabo-tulinumtoxinA 50 U at a frequency of one treatment every 4 months. If 20 U of onabotulinumtoxinA were used instead, there would still be a saving of £15 485.71 using abobotu-linumtoxinA. For abobotulinumtoxinA vs. incobotuli-numtoxinA, abobotulinumtoxinA was more cost-effective at the maximum dosage of incobotulinumtoxinA (50 vs. 30 U, respectively; £14 045.71 saving), but more expensive at the minimum dosage (50 vs. 20 U; £11 874.29 increment). IncobotulinumtoxinA was more cost-effective than onabo-tulinumtoxinA at maximum (30 vs. 50 U, respectively; £93 240.00 saving) and minimum dosages (20 vs. 20 U; £27 360.00 saving).

Whilst abobotulinumtoxinA offers seemingly attractive annual cost savings in most scenarios over onabotuli-numtoxinA and incobotulinumtoxinA, when administered in the conditions accounted for in the present cost calculator, these data should not be considered in isola-tion. As such, it remains important for clinicians to consider a wide range of different issues, in a patient-by-patient manner before choosing which of the commercially available BoNT-A treatment formulations is most appro-priate. It is also important to note that the use of ‘parent’ formulations of abobotulinumtoxinA (therapeutic), ona-botulinumtoxinA (therapeutic) and incobotulinumtoxinA (therapeutic) offers consistent savings over the use of their counterpart formulations that are licensed for aesthetic use.

Conclusions

The literature review confirmed that the clinical efficacy for the three BoNT-A formulations appears pretty much equivocal, and underlines the need for further studies to elucidate any potential differences in effectiveness. In the absence of any differentiating clinical data, the cost calculator was developed to gain a better understanding of the economic differences between formulations, as an aid to decision making. The cost calculator made it possible to identify that BoNT-A treatment with abobotulinumtoxinA typically results in significant annual cost savings when compared with treatment with onabotulinumtoxinA or abobotulinumtoxinA, based on current list prices. Clinicians may wish to consider using this cost calculator to aid choice of treatment for their patients.

Conflict of interest

RJ has received no sponsorship or research grants in the past.

Funding

There were no external funding sources for this study.

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