Discussion
The panel have made a series of recommendations which define a group of
patients in whom the use of biologics is considered appropriate in the
treatment of CRSwNP, and a group where use would be considered
inappropriate, considering the current evidence base, costs and capacity
in the setting of the NHS.
The RAND/UCLA appropriateness methodology is well described and has
previously been utilised defining appropriateness criteria for ESS
during management of uncomplicated adult CRS and adult recurrent acute
rhinosinusitis (1, 11, 12). We have used a similar process to develop
BRS guidance on the management of incidental findings in the maxillary
sinuses with regard to dental implantation(13), and to develop guidance
on the treatment of COVID-19 related loss of smell(14). This exercise or
process aims to detect and achieve consensus amongst a group of experts,
and is ideally suited to evaluating the appropriateness of use of
medical interventions where the evidence base is limited, which consume
significant resources or where use remains controversial. Defining
appropriate use of biologics in CRSwNP would therefore seem to be well
suited to the methodology.
Biologic therapy using Mabs that block the action of interleukins or
other targets central to type 2 inflammation now play an important role
in the management of difficult-to-treat asthma and many of these
treatments have also been shown to be effective in the management of
severe CRSwNP. Dupilumab, an anti IL4/13 receptor mab, and omalizumab,
an anti-IgE mab, have been shown to achieve significant reductions in
polyp size and nasal congestion in large phase 3 studies(15, 16). Both
have now been granted FDA and EMA approval for use in patients with
CRSwNP, and are currently available for use in the US and selected
European countries. Other drugs will likely soon follow, specifically
with phase 3 trials completed for mepolizumab(17) and benralizumab,
which target IL5.
Although biologicals have been shown to reduce the need for surgical
intervention for CRSwNP(17), their high costs and the need for long term
treatment mean that this is unlikely to be the most cost-effective
treatment across the whole population with CRSwNP, even if superior in
terms of long-term symptom control in the difficult-to-treat group.
Scangas et al undertook a Markov decision tree cost-effectiveness model
over 20 years(18), and found, based on US costs (which may not be
applicable in all healthcare setting), that a strategy of sinus surgery
cost circa $50,000 producing 9.80 QALYs while dupilumab treatment costs
$535,000 but produced 8.95 QALYS. Surgery was more cost-effective
regardless of the frequency of revision surgery. Similarly, in asthma,
although the efficacy of biologic therapy is well established, none of
the currently available drugs have been found to be cost-effective(19).
Currently, no biologic treatments have been approved by NICE for the
treatment of patients with CRSwNP. NICE considers evidence of
effectiveness of new interventions, but applies a standard threshold
range with an upper limit of £20-30,000 per QALY and a budget impact
test, where drugs that cost more than £20million in any one of their
first three years of use trigger commercial discussions to mitigate the
impact on the wider NHS, or further restrictions on usage
(www.nice.org.uk). Using the data from Scangas et al, with a £43,500
cost per QALY at current currency conversion rates, it is unlikely that
the NICE threshold could be met if biologics were prescribed to all
patients with CRSwNP.
However, the panel’s recommendations identify a group who are more
likely to fail to achieve long term benefit from conventional treatment
pathways and to undergo repeated interventions with higher associated
healthcare resource utilisation. A recent study has shown that patients
with a history of previous surgery are twice as likely to need further
revision surgery, or those with a history of N-ERD five times more
likely to require further revision when undergoing endoscopic sinus
surgery(20). Therefore, as the patients identified by the panel have
higher direct costs over their lifetime than other patients with CRSwNP,
use of biologics in this subgroup are more likely to be cost-effective.
Patients with higher rates of revision surgery also likely derive less
symptomatic benefit from conventional treatment pathways; indeed a
recent study found that 43% of patients’ symptoms were uncontrolled
after sinus surgery and this again was more common after revision
surgery and in the setting of N-ERD(21). Our criteria will also,
therefore, help to identify patients for who current treatments are
likely unsuccessful in achieving adequate disease control, and where
biologics may offer the only option that may achieve long term disease
control. We, therefore, hope that NICE and other organisations will
consider our criteria to define a group for whom biologics should be
approved even if the usual threshold limit per QALY cannot be met, and
not seek to impose further restrictions on usage over and above those
defined by the panel (Fig 1).
The criteria used by the panel in reaching consensus where biologics are
considered appropriate define a smaller group of eligible patients than
either the EPOS(8) or EUFOREA(9) criteria for patient selection for
biologic therapy. The scenarios where the panel felt that use of a
biologic was uncertain included patients with at least one previous
surgery, many of whom would meet the EPOS criteria for biologics,
although it should be noted that the BRS set a lower threshold of
symptom severity at baseline, measured using the SNOT-22 or VAS. Many of
the scenarios where use of biologics in the NHS is currently considered
’uncertain’ by the BRS panel represent patients who would have been
eligible for recruitment to published trials demonstrating the
effectiveness of biologics, and within the trials achieved significant
improvements in nasal polyp score and quality of life on
biologics. Therefore, it is important to state that the BRS
recommendations are not intended to predict response to treatment to
biologics, but only to define a group where the panel felt use was
appropriate given the financial restrictions within the NHS at the
current time. It is very likely that recommendations for the scenarios
rated ‘uncertain’ will change if the relative cost of treatment is
reduced in the future.
Panellists recommended that biologic treatments for CRSwNP, if approved
for use within the NHS, should be delivered within centres of excellence
co-located with difficult to treat asthma, where there is pre-existing
experience of treatment with biologics. Centres should also be able to
offer a range of other treatments. This will also have the likely impact
that patients with difficult to treat CRSwNP, for example those with
N-ERD, are directed to specialist centres that can ensure that surgery
is performed optimally and that patients are considered for adjunctive
treatments such as post-operative desensitisation, thus reducing the
need for biologics. Indeed, a recent paper has shown that more extensive
surgery in patients with CRSwNP was associated with lower rates of
revision surgery(20); creation of specialist centres will, therefore,
likely improve outcomes from other interventions such as sinus surgery.
Panellists commented that in future, the extent of previous surgery and
the interval between previous surgery may also be considered in the
decision making process, and perhaps patients who have only had more
limited surgery be considered for revision surgery before biological
therapies.
While the panel made recommendations for use in AFRS, it was noted that
clear evidence of efficacy on trials was needed before these should be
implemented. The panel also agreed that there was no indication for use
in patients with CRS without nasal polyps in the absence of evidence in
this group
Once biologic therapies are initiated, the response to treatment must be
assessed to determine if a patient should continue treatment; how this
should be determined is beyond the remit of the current study. Further
limitations of these current recommendations are that biomarkers, such
as eosinophil levels in blood or tissue, were not considered in the
clinical scenarios, as the panel felt that there is insufficient
evidence to determine how these aid selection or predict response to
treatment. Biologics were considered as a collective intervention but in
reality different biologics, defined by their inflammatory target,
differ in terms of costs and effectiveness. The impact of COVID-19 on
healthcare delivery in the NHS at the current time was not considered –
this may favour biologics over surgery, for example, if demand for
surgery greatly exceeds capacity. Finally, we have not included patient
preferences for different treatments into our recommendation but these
of course play an important role in the final decision making with
regards to use if biologics become available within the UK.