Sponsor's response to Independent Review Report'
The following page outlines the sponsor response to the Independent Review Report for Imiquimod
Page last updated: 03 July 2009
Imiquimod 5% Cream Sachets - ALDARATM – iNova Pharmaceuticals (Aust) Pty Ltd
This response is to clarify and resolve matters raised in the
Independent Review Report on the March 2008 submission to extend
the PBS listing of imiquimod (Aldara™) cream sachets as a
field therapy for multiple solar keratosis (SK) lesions on the face
Should SK Be Treated?
“It is important to recognise that SK can spontaneously
regress without pharmacologic or ablative therapy.”[Review Pg 4]
The clinical rationale and value of treating SK lesions is widely recognised in the literature and in clinical practice. Therefore, a prima facie case for conclusively establishing the value of treatment already exists, especially for patients described by the requested listing. While some SK lesions do regress, the requested listing for imiquimod concerns high risk patients who represent a minority subpopulation with more extensive SK that is not limited to single clinically visible lesions. Their condition indicates field cancerisation within an anatomical skin area, characterised by subclinical i.e. non-visible disease that becomes apparent during imiquimod therapy, multiple primary tumours, local recurrences and premalignant change. The regression of significant amounts of disease in these patients who have an area of multiple lesions resulting from field cancerisation is highly unlikely and would be most unusual.
iNova agrees with the Independent Review Report that reduction of UV light exposure should be the cornerstone in managing SK, and sun protective measures are fundamental to managing patients with SK and preventing further disease. However, successful management requires both prevention and treatment measures. Sensible sun protection alone is highly unlikely to reverse the condition of patients requiring field therapy who have a persistent SK disease burden. Imiquimod is not a substitute for sensible sun protection, instead, it a field therapy treating active disease, which complements protective measures.
The Australian Government for many years has been paying for cryotherapy and other non-drug SK treatments via the Medical Benefits Schedule. Government expenditure on cryotherapy to treat 10 or more SK lesions under MBS Item Code 30192 alone cost $16.6 Million in 2008, although there is scant RCT efficacy data on such use.
SK is treated for two reasons.
- Symptoms. In patients with multiple lesions needing field therapy, SK is typically not asymptomatic. The lesions may be painful, itchy, red and crusty, creating an unsightly appearance, and the standard approach in clinical practice is to treat (Cancer Council 2008; NHMRC 2002);
- Disease spectrum. It is widely recognised that SK is ‘pre-malignant’ or has ‘malignant potential’, and is part of a continuum of disease ranging from less specific solar damage of various forms through to SK, then Bowen’s Disease (intra-epithelial squamous cell cancer [SCC]), and SCC (NHMRC 2002; Marks 2006).
Recent literature, however, now considers SK to be early in situ SCC, noting cancer-related molecular alterations are found in both SK and SCC and that “This genetic link supports the malignant nature of SKs from their inception”(Stockfleth et al 2006; Rowert-Huber et al 2007).
Although there are no studies of QALYs in relation to SKs, clinical practice guidelines indicate there is value in treating SK (Cancer Council 2008; Stockfleth 2006; NHMRC 2002). Moreover, while the imiquimod studies presented in the submission provide duration of treatment effect to 16 months, the body of evidence for long term beneficial effects includes a two year SK sustained clearance rate of 80% for imiquimod used three times weekly for 12 weeks (Stockfleth et al 2004) and no SCC developed. In the same double-blind randomised trial (n=36), 90% of placebo patients developed new SK lesions in only one year and one patient developed SCC. The Review references Vatve et al 2007, which includes this study for initial and sustained clearance to show imiquimod is effective in treating SK field change. This study is also important is showing that, longer term, most SK lesions do not spontaneously regress – only one placebo patient experienced spontaneous remission.
Field cancerisation is well established in various areas of
medicine, and has gained increasing clinical relevance in SK, as
recognised by Vatve et al 2007, Krawtchenko et al 2007, in clinical
management guidelines by Stockfleth et al 2006, and the Expert
Report by Professsor Wilkinson (Submission Attachment 3). It is
therefore more than “an interesting concept”
described in the Review [pg 7]. Indeed, field
cancerisation has evolved to include a clinically occult area with
multifocal preneoplastic changes related to genetic mutations that
precede the development of second primary tumours and local
recurrences (Vatve et al 2007).
Field Therapy [pg 5, 15 & 22]
Field therapy applies the well established ‘field
cancerisation’ concept, and is defined as treating beyond the
visible lesion whereby malignant changes seen in an individual SK
lesion also extend beyond it in a variety of forms. In terms of an
area of sun damaged skin with multiple visible lesions, this will
be in various stages of malignant potential. This is why there are
some patients with the whole spectrum of damage in one area
(non-specific solar damage, SK, Bowen’s Disease, SCC).
The term “field therapy” in the requested PBS listing addresses the histopathological changes associated with a more severe form of SK, and is necessary to identify the target patient population eligible for imiquimod.
The aim of field therapy in SK is to treat an area of field change in clearing visible and non-visible lesions, thereby reducing the risk of developing new lesions or delaying progression. Transformed keratinocytes have the potential to progress and the more there are the greater the risk of progression, given they show a high mutation rate of the tumour-suppressor gene p53, as well as other genetic aberrations (Stockfleth et al 2006). Patients requiring field therapy typically present with multiple visible SK lesions against a background of moderate to severe solar damaged skin, which suggests field cancerisation. The Krawtchenko study, several placebo controlled randomised trials and approved Product Information, collectively represent solid evidence that subclinical lesions not visible at the start of imiquimod therapy subsequently appear during treatment and resolve. No other SK treatment has the amount of evidence imiquimod has in clearing SK, as recognised in clinical practice guidelines (Cancer Council 2008, Stockfleth et al 2006).
H2H Study - Imiquimod vs 5-FU vs Cryotherapy Comparison: Krawtchenko et al 2007
This comparative study, in addition to numerous randomised double
blind placebo controlled studies, represents more evidence than
what was available to list imiquimod on the PBS for superficial
BCC. Although a small study that was open label for reasons shown
on pg 10 of the Review, the following should be recognised:
1) Assessment time point [pg 12]: The appropriate time to initially assess clearance with imiquimod is 8 weeks post treatment, not 4 weeks, as explained in the H2H study report, which found that 5-FU clears lesions more quickly than imiquimod. However, in a study focused on 12 month total field clearance of initial and subsequent lesions, topical 5-FU did not display further clearance after the 4 week post treatment assessment. On the contrary, in the 5-FU and cryotherapy groups the percentage of completely cleared patients decreased with time, signalling new lesions and recurrences. Whether patients were initially assessed at 4 or 8 weeks is therefore irrelevant in assessing total field clearance longer term which is the main goal of field therapy.
2) Exclusion criteria [pg 12]: The exclusion criteria follow those of other imiquimod studies in SK and sBCC, among which were co-morbidities that represent clinically significant unstable conditions. Patients with clinically stable medical conditions were allowed to participate in the study.
3) Histological assessment [pg 13]: The methodology is appropriate and follows standard clinical procedures.
4) Field Clearance [pg 40, 41]: The Review acknowledges the statistically significant differences between imiquimod and 5-FU, which favoured the former, were sustained clearance of the total treatment field and skin quality “cosmetic” outcomes. Given the aim of field therapy is to clear a field of visible and non-visible lesions longer term, field clearance is the most important trial result. Very few, if any, SK studies for other treatments have measured this key outcome, focusing only on initial clearance of treated lesions and sometimes their recurrence.
5) Clearance as a Surrogate Marker [pg 14]: iNova is not aware of any literature to support the unreferenced Review statement that “Complete clearance is a surrogate marker of the cosmetic result and does not reflect the propensity to develop SCC”. This appears to be at odds with the plethora of literature on the related pathophysiology of SK and SCC. Complete SK clearance is also an accepted health outcome in its own right by clinicians and regulatory agencies TGA, FDA and EMEA.
6) Publication: The H2H study was published in the British Journal of Dermatology by Krawtchenko et al 2007. This is a credible journal with stringent publication requirements, focused on original research and implications for clinical practice. It is one of the top dermatology journals in the world and is regarded for the high quality original research it publishes.
H2H Study Sample Size & Statistical Assessment [pg 13]:
Sample size was determined with reference to clearance or reduction
of two specific oncogene mutations. While this cannot be used to
assess efficacy or conduct economic analysis, sustained field
clearance and the incidence of new lesions are highly relevant to
the requested listing. Total sustained field clearance is
the most important endpoint that matters, for which there was
adequate power to detect a difference between treatments in the
In planning a sustained field clearance study, the required sample size for adequate power is based on various assumptions of what size difference between treatment groups is likely and clinically relevant. A typical study aims to have 80% power to detect such a difference using a two-sided test at the 5% level.
For sustained field clearance at 12 months, trial experience suggests a 70% rate for imiquimod might be expected versus 30% for 5-FU which is known to have a high recurrence rate (Stockfleth et al 2006). Cryotherapy is not a field treatment and so it is expected this therapy will have little impact on the incidence of new SK lesions as shown in the H2H study. For 80% power and a two-sided test at the 5% level, the required number of patients per treatment group is 24 (Table 3.1 in Machin et al., 1997).
The required sample size is unchanged if the assumed rates for imiquimod and 5-FU under the alternative hypothesis are 75% and 35%. If these rates were 5% and 40%, 22 is the required number of patients per treatment group to have 80% power of a two-sided test at the 5% level for finding a difference in rates.
Importantly, these endpoints reflect the underlying action of these treatments. In particular, imiquimod has an effect of making more lesions evident during treatment, which later resolve so there are few recurrent or new lesions over the longer term. This is why assessment of initial efficacy for imiquimod should be at 8 weeks post treatment and not 4 weeks, i.e. well after the period during which sub-clinical lesions become evident and are resolved.
Given the highly significant differences for 12 month sustained clearance shown in Table 1 of this response, it is likely the results would retain statistical significance if adjusted for multiple comparisons.
The H2H study had 26 and 24 patients randomised to imiquimod and 5-FU treatment groups. Given the likely and clinically relevant differences in efficacy between the two treatments, this sample size would have at least 80% power for a two-sided test at the 5% level to detect differences between the two groups. The sample size is modest because these large differences are expected from the literature.
The Review is unclear as to how 19 and not 13 imiquimod patients had no SK lesion at the post treatment visit and at 6 and 12 month follow-up [pg 15]. Total clearance was histologically confirmed for 19 of 22 imiquimod patients who completely cleared their lesions based on clinical (visual) inspection 8 weeks post treatment. This is the appropriate ”test of cure’ time point for imiquimod which appears in the Krawtchenko publication, not 4 weeks post treatment, as previously discussed.
Imiquimod Safety as Field Therapy [Review pg 22, 35 & 36]
The Review arbitrarily assumes “field therapy” for SK
means treating an area 10 to 20 times greater than
25cm2. The Review later presumes this term means
treatment application to sun-exposed areas of the face and/or scalp
representing a treatment field of 300 to 500cm2.
However, there is no basis for either assumption, other than the
Review observation that Efudix® can be applied up to a 500cm2
maximum area from the Product Information, although this
therapy’s approved use for SK is not limited to face/scalp.
Field therapy does not assume size of the affected area
being treated, which is up to the individual prescribing
doctor’s clinical judgement.
The Review claims one imiquimod cream sachet can cover up to a 386cm2 skin area, based on a non-efficacy study conducted on the disease free skin of two pigs and one human arm. This is not valid as iNova has previously stated and clinical practice guidelines have since confirmed, advising that two sachets would be required to treat several fields, i.e. both cheeks, both temples and the forehead (Cancer Council 2008).
Study 1402 [pg 22]: The Review refers to this Phase 1 study (n=58), misnaming it as a Phase II study, in concluding imiquimod’s safety in use is limited to a 25cm2 application due to local and systemic effects. Yet the Review agrees no major safety concerns have been raised by the submission literature review or Phase III studies including Study H2H (Krawtchenko et al 2007). In study 1402, all patients applied imiquimod three times weekly continuously for 16 weeks, and up to six sachets were used. One sachet was applied to a 25cm2 facial area, two sachets were applied to the entire balding scalp and six sachets were applied to two entire forearms (three each forearm) continuously for 16 weeks and even if SKs cleared so that patients received a total of 49 doses (3 x 16 + 1 initiation dose). This is twice the maximum number of doses in the requested PBS listing. Multiple sachets per application and forearms are also off label uses which are not part of the requested listing. The Review claims that study 1402 shows increased systematic bioavailability of imiquimod for treatment of a surface area greater than 25cm2. However, this is inconsistent with the TGA Clinical Evaluation Report summary of study 1402 results which states: “Systemic imiquimod serum concentrations were generally low, providing a large safety margin”.
The Review erroneously claims the H2H study is the only trial where a larger surface area than 25cm2 was treated for SK and hence there is no proper safety data for areas exceeding this size. It is unfortunate the Review did not identify the large multi-centre Phase IIIb efficacy and safety study of 829 patients from 180 dermatology clinics and practices who applied one or two sachets, depending on the treatment area size, three times per week for one or two 4 week cycles to SK lesions located anywhere on the head, excluding upper/lower eye lids, nostrils, lip vermilion and inside ears (Stockfleth et al 2007). The size of the treatment area was not restricted. Importantly, this study was the basis for there being no application area restriction for imiquimod’s use in SK based on the European Product Information (named Summary of Product Characteristics). This study was not previously available for TGA evaluation in obtaining registration approval for the SK indication in Australia.
iNova is concerned this study evidence was not identified during the PBAC evaluation process nor the Review process during their search of the literature in addressing safety. Instead, both processes conclude there are safety issues based on a Netherlands Pharmacovigilance Centre reporting four patients with severe local skin reactions (effects all in the Product Information), only one of whom used imiquimod for SK.
The Review also misinterprets iNova’s quoted statement about transposing safety issues from Europe to Australia [pg 28]. On the contrary, we believe safety issues, if they arise in one country, are usually relevant to other countries, and so we consider the 829 patient German study to be highly relevant to resolving the PBAC’s concern about imiquimod’s safety. The data upon which the PBAC and Review processes conclude there are safety issues, however, appears to be somewhat selective, i.e. a relatively small report from the Netherlands Pharmacovigilance Centre versus the PSUR cumulative data over several years, the large 829 Phase IIIb study (Stockfleth et al 2007), numerous Phase III studies and Krawtchenko et al 2007.
Tanghetti et al 2007 study [pg 20]:High quality double blind randomised controlled studies confirmed three times weekly dosing with imiquimod is the optimal dosing regimen for treating SK since complete clearance rates are appreciably higher than those achieved with twice weekly dosing. This is why the TGA approved dosing regimen is three times and not two times per week. The dose frequency is therefore absolutely critical to maximising efficacy. By contrast, one or two 4 week treatment cycles produce similar acute clearance results to those for 16 weeks continuous therapy, as shown in Submission Attachment 10. In addition to the suboptimal imiqiuimod dosing in the Tanghetti study for which longer treatment duration cannot compensate, this initial clearance study does not assess longer term outcomes nor confirms short term efficacy by histological assessment. For these reasons alone this study cannot be compared with the Krawtchenko study and, due to various other weaknesses, is correctly described by the Review as “flawed”.
There is a large body of efficacy and safety evidence for imiquimod as a true field therapy in clearing clinical and subclinical SK lesions. Field therapy is not defined by surface area size, and any serious adverse event, if it occurs, is the exception, not the rule. Of further relevance is the RPBS listing of imiquimod cream as a field therapy for SK, effective 1 February 2009, for which dermatologist expertise was sought during the RPRC evaluation process. There are no major limitations of imiquimod as a treatment for SK. If there was, imiquimod would not be now registered for over three years in Australia for SK on the face and scalp, and it would not have achieved RPBS reimbursement for the treatment of SK in war veterans and war widow(er)s.
Table 1: H2H Study (Krawtchenko et al 2007) Short term Clearance at Test of Cure (TOC) and sustained clearance (ITT analysis)
|IMIQ||5-FU||CRYO||p-value among all treatments||p-value IMIQ vs 5-FU||p-value IMIQ vs CRYO||p-value 5-FU vs CRYO|
|Clinical clearance at TOC [95% CI]||22/26 (85%) [0.65, 0.94]||23/24 (96%) [0.76, 0.99]||17/25 (68%) [0.48, 0.83]||0.030||0.351||0.199||0.023|
|Sustained clearance at M12 [95% CI]||19/26 (73%) [0.53, 0.87]||8/24 (33%) [0.18, 0.54]||1/25 (4%) [0.01, 0.24]||<0.0005||0.010||<0.0005||0.011|
Note: - 95% CI calculated using logistic transform, with exact formula used for 0/n and n/n.
- Figures in bold are statistically significant different.
Source: H2H Study - Statistical report (Submission Attachment 7)
Table 2, Stockfleth CSR Table 22
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