Biosimilar uptake by British local formularies: a cross sectional study
Biosimilar uptake by British local formularies: a cross sectional study
Saja Alnahar 0 1 2 3
Rachel A. Elliott 0 1 2 3
Murray D. Smith 0 1 2 3
Great 0 1 2 3
0 Manchester Centre for Health Economics, Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester , Oxford Road, Manchester M13 9PL , UK
1 Division of Pharmacy Practice and Policy, School of Pharmacy, University of Nottingham , East Drive, University Park, Nottingham NG7 2RD , UK
2 & Saja Alnahar
3 Community and Health Research Unit, School of Health and Social Care, University of Lincoln , Lincoln , UK
Background Biological medicines are starting to lose their patent protection, so similar, inexact copies (biosimilars) are being developed and licensed. The high acquisition costs of biologics for healthcare providers could be reduced by switching to biosimilars, thus alleviating budgetary pressures and increasing patient access. Therefore, the acceptance of biosimilars by prescribers in Great Britain (GB; England, Scotland, Wales) needs to be described and understood. Objective To determine uptake of the first wave of biosimilars (somatropin, epoetin, filgrastim) by local formularies (lists of preferred medicines for prescribing in local healthcare settings). Settings This study targeted local formularies in GB. Method In November 2014, local formularies (medicines formularies of Acute Trusts and Health Boards in GB) were screened for their approach to listing of biologics and their biosimilars as well as recommendations on usage of these pharmaceuticals. Main Outcomes Measures Listing frequencies of biosimilars. Results One hundred and forty-six British local formularies were screened. Amongst the 80% of formularies in which brand names were specified, biosimilar filgrastim was the most frequently listed when compared to the other targeted biosimilars. Biosimilars were listed in preference to reference biologic medicine in 49% of local formularies for filgrastim, 11% for somatropin and in only 6% for epoetin. Conclusion Although the market for biosimilars can act in parallel to the generic market, their uptake measured using local British formularies was less than what is expected given that the British market for medicines has a strong focus on generics. Finally, geographical variability within GB requires further investigation.
Biosimilars; Biological medicines; Britain; Local formularies
Impacts on practice
As the use of brand names in prescribing and reporting
adverse drug reactions is part of active monitoring of
biological medicines safety, including the biosimilar
medicines, local formularies must actively list these
medicines using the brand name;
Specifying preferred brand for prescribing facilitates
and promotes local formularies in guiding cost effective
and rational medicines utilisation.
Biological medicines (BMPs) provide an innovative
method for treating chronic and life-threatening diseases
such as cancers, rheumatoid arthritis and multiple sclerosis.
Their rapid adoption into clinical practice has resulted in a
substantial share of the pharmaceutical market; for
example, in 2012–2013, 27% of total pharmaceutical sales
in Europe were BMPs [
]. Moreover, eight of the top ten
bestselling pharmaceuticals in 2013 in Europe were BMPs.
It is expected that BMPs will maintain the same market
share into 2016 [
] and likely beyond. BMPs have
significantly improved health and disease outcomes, but their
widespread utilisation is financially challenging to
healthcare providers worldwide .
In 2013–2014, in England, seven out of the top ten most
prescribed medicines in terms of cost to the National
Health Service (NHS) were BMPs [
]. Notable though is
that all seven will lose their patent protection by 2018 [
Patent expiry creates an opportunity for developing and
licensing similar copies of off-patent BMPs-called
biosimilar medicines (BSPs) [
]. Unlike conventional
generic medicines, BSPs are not identical but similar
copies of their reference BMP (R-BMP). The inability to
produce identical copies is related to the complex and
heterogenic molecular structure of these medicines, and
being produced by not fully controllable living systems
In their analysis of the European BSP market, Rovira
et al. reported that BSPs offer price reductions of between
10 and 35% [
]. Although this is a modest price reduction
in comparison to conventional generic medicines, the
overall cost saving to health service providers is expected
to be significant due to the high unit costs and extensive use
of BMPs [
]. The European Generic Medicines
Association reported that the European Union might save upwards
of €1.6 billion/year for the scenario in which a 20% price
reduction occurs on five off-patent BMPs [
Furthermore, it has been suggested that the availability of BSPs
might alter medical practice and increase compliance to
clinical guidelines [
In Europe, BSPs can be launched after being centrally
assessed and licensed by the European Medicines Agency
(EMA) for safety, quality and efficacy [
]. While the
EMA mandates full quality submission in order to license a
BSP, it does permit evidence based extrapolation of the
clinical outcomes from one tested indication to closely
related others [
In Great Britain (GB), the Medicines and Healthcare
products Regulatory Agency (MHRA) directs prescribers
to use brand name in prescribing any BMP and its BSPs
]. Brand name-based prescribing and reporting
facilitates capture of safety issues related to BMPs including
Despite being a generically-driven market [
uptake of BSPs in Britain seems to have been relatively
limited when compared to other European countries [
According to the British Generic Manufacturers
Association factors related to physicians’ lack of confidence in
prescribing BSPs, absence of encouraging national policies
and banned substitution at pharmacy level have resulted in
slow adoption of BSPs [
]. Lack of confidence might
relate to physicians questioning the safety and efficacy of
]. This might be at least partly explained by the
abridged approach the EMA follows in assessing clinical
efficacy of BSPs [
]. One exception is granulocyte-colony
stimulating factor (G-CSF)-filgrastim BSP, which is
achieving an uptake rate similar to that of conventional
generic medicinal products [
One approach to evaluating prescribers’ acceptance of
BSPs is through assessing uptake of BSPs in local
medicines formularies. The National Institute for Health
and Care Excellence (NICE) defines local formularies as
‘‘the output processes to support the managed introduction,
utilisation or withdrawal of healthcare treatments within a
health economy, service or organisation’’ [
formularies are working documents that are subject to regular
review and change. They tend to be robust on treatments
used frequently and weak on occasionally used ones (that
need to be available for a complete and comprehensive
service). Local formularies can act as prescribing guiding
tool at local settings [
]. Heal et al. (2004) reported that
more than 80% of their study participants were guided by
local formularies [
]. Accordingly, assessing BSP listing
in local formularies might reflect acceptance of these
products by prescribers.
Aim of the study
To determine uptake acceptance of first wave BSPs
licensed and marketed in GB prior to 2015 [somatropin
(HGH), epoetin (EPO) and filgrastim (G-CSF)] by local
Ethical approval was not needed as local formularies
throughout the UK are publically available documents
included in the freedom of information scheme.
During November–December 2014, a list of 157 Acute
Trusts (accountable organisations within NHS England that
manage and control the performance, services quality and
financial efficiency of clusters of hospitals in England) was
acquired from the NHS England website two Acute Trusts
were excluded as one was dissolved and the other one was
still in process of developing a formulary list. Details of the
14 Regional Health Boards in Scotland and 7 Local Health
Formulary list that is developed and/or used by more than one healthcare setting (primary and/or
BNF chapter 6.5.1*: somatropin (HGH)
BNF chapter 9.1.3**: epoetin alfa (EPO)
BNF chapter 9.1.6***: filgrastim (G-CSF)
Formulary Medicinal product that is routinely available for prescription
Non- Medicinal product that is not routinely available for prescription. However, if it is
formulary deemed needed, it will be made available for the patient
As per brands listed in BNF chapters 6.5.1, 9.1.3 and 9.1.6
If there are considerations related to patients’ age, medical history and/or life style factors that might
affect type/brand of preference (R-BMP or BSP)
If there are considerations related to indications that might affect type/brand of preference (R-BMP or
BNF British National Formulary 68th Edition; BMP biological medicinal product; BSP biosimilar medicinal product; INN international
nonproprietary name (molecular name); R-BMP reference biological medicinal product
* 6.5.1: drugs used in hypothalamic and anterior pituitary hormones and anti-oestrogen; 1 R-BMP and 1 BSP brand
** 9.1.3: drugs used in hypoplastic, haemolytic, and renal anaemias; 1 R-BMP and 2 BSP brands
*** 9.1.6: drugs used in neutropenia; 1 R-BMP and 3 BSP brands
Boards in Wales (accountable organisations within NHS
Scotland and NHS Wales that are responsible for the
delivery of healthcare services to the local population)
were acquired from Scottish Government and NHS Wales
websites. Northern Ireland was excluded as there was an
initiative underway to develop a joint formulary for the
whole country, and some of its chapters were still under
The most recent versions of local medicines formularies
were downloaded and examined for their listing of targeted
R-BMPs and BSPs according to the criteria given in Table 1.
These criteria enabled assessment of: (1) uptake of BSPs, (2)
compliance to the MHRA recommendation on brand name
prescribing of BMPs, and (3) the consideration given to
population or indication-specific recommendations.
The assessment process started by examining whether
the listing approach of R-BMP and BSPs was based on
using brand name, molecular name or both, as per the
British National Formulary (BNF) 68th edition. Then the
availability of prescribing guidance in terms of speciality
of the prescriber and/or the clinical settings was recorded.
Finally, formulary entries were classified and compared
according to preferred brand for prescribing. Formulary
uptake of targeted BMPs and BSPs was analysed using
descriptive statistics in an Excel 2010 spreadsheet.
One hundred and forty-six formularies were identified: 129
in England, 10 in Scotland and 7 in Wales. Forty-three
percent (63/146) of these were joint formularies (the term
given to a local formulary developed and/or used
simultaneously by more than one healthcare providing
Formulary uptake and listing approaches varied across
the three targeted groups. HGH was listed in 126
formularies achieving the highest percentage of medicine listing,
EPO achieved the highest brand name based listing with 60
formularies using brand names. Despite BSP G-CSF being
the last of the three groups to be authorised by the EMA, it
was most commonly listed in preference to the R-BMP.
Table 2 provides more details.
Variations between the countries of GB were seen, with
27% of English formularies listing BSP G-CSF in
preference to the R-BMP, versus 12.5% and 14.3% amongst
Scottish and Welsh formularies, respectively. In the cases
of HGH and EPO, 7% and 4% of English formularies
preferred BSP over R-BMP; respectively, but no Scottish
or Welsh formularies did so.
Only six formularies listed at least one BSP from all
three targeted groups. There were no instances of BSPs
being preferred to R-BMPs across all three targeted groups,
but at the opposite extreme there were only two formularies
in which R-BMPs were always preferred over BSPs.
In this study, formulary uptake of BSPs in three different
groups was employed as an indicator of clinical acceptance
of BSPs in GB. The uptake of BSPs by British local
formularies was less than what might be predicted from a
classical generically driven market for medicines, and there
appeared to be geographic variability in uptake which
requires further investigation.
Most frequently listed was HGH, the first licensed BSP
], however the maximum preference for BSPs over
R-BMP was achieved by G-CSF BSPs. On the other hand,
brand name-based listing was more frequent in the case of
EPO. Despite it not being possible to gain a complete
understanding of the variations between targeted groups, it
might be explained in large part by the molecular nature,
therapy duration and/or patients’ demographics,
preferences and life style.
Having several other medicinal products within the
same group where each has different dosing frequencies,
administration devices and storage conditions might affect
acceptance of BSPs. For example, one HGH product is a
needleless device making it more attractive to paediatric
and needle-phobic patients. Another HGH product can be
stored out of the refrigerator [
] which might make it the
brand of choice for frequent travellers.
G-CSF’s molecular structure and short duration of
therapy might increase the acceptance of its BSPs. It is a
small, easily characterised non-glycosylated molecule that
is indicated for short therapeutic periods [
However, special population considerations in terms of patient
age and therapeutic indications were flagged in those
instances when the R-BMP was listed in preference to
BSPs. Specifically, the R-BMP was listed as the preferred
product for paediatric patients and for stem cell
mobilisation. Reluctance to use BSPs in these settings may be
because of the lack of clinical trial evidence of their
efficacy and/or safety.
EPO achieved the highest percentage of brand
namebased listing. This is most likely due to EPO being a
glycosylated protein, in which case each brand has a different
glycosylation pattern and hence a different immunogenic
]. In addition, previously reported cases of the
life threatening pure red cell aplasia might encourage the
use of brand name based listing for EPO whether for the
R-BMP or the BSPs [
The MHRA has considered several measures in the
monitoring of BMPs, including BSPs, such as: demanding
brand name-based prescription, and requiring specification
of a product’s identifiers (brand name, batch number and
manufacturer) in reporting adverse drug reactions.
Furthermore, prescribers are directed to inform patients and/or
carers about a product’s brand name and batch number
]. However, more than one third of local formularies did
not specify brand names when listing BMPs in the groups
examined in this study. Unintentional switching between
brands might affect patients’ safety, if not carefully
monitored and managed. Such harm might be avoided in the
cases of G-CSF and EPO because of their short duration
prescription, but possibly not otherwise for HGH which is
typically used for prolonged periods.
The limited clinical evidence of BSPs’ efficacy has been
highlighted as a factor hindering BSPs’ acceptance in
clinical practice [
]. However, the BSP G-CSF brand that
was approved based on results of a pharmacokinetics/
pharmacodynamics trial in healthy volunteers instead of
patients, and in a non-comparative safety-focussed study in
] was recommended for use ahead of R-BMP
G-CSF in more local formularies than was any other
As there is a proposal to assign different international
non-proprietary name (INN) for BSPs, BSPs’
manufacturers argue that a differing INN might limit the uptake of
BSPs by giving suggestion to the view that BSPs are
completely different instead of being a highly similar
]. The effect of different INN was noted in the
case of epoetin zeta and epoetin alfa, where despite both
being EPO BSP the latter was more often listed than the
former. Moreover, 50% of formularies that preferred BSP
EPO over the R-BMP have not listed epoetin zeta, while
the remaining 50% listed it without brand specification. Of
the 27 formularies that did list EPO using its molecular
name none included epoetin zeta.
Variations in listing BSPs were observed between
England, Scotland and Wales. Although both the Scottish
Medicines Consortium and the All Wales Medicines
Strategy Group have been actively involved in evaluating
], Scottish and Welsh formularies were less
likely to list BSPs in preference to the R-BMP compared
with their English counterparts.
Research data and analysis indicate that some
formularies encourage BSP prescribing. However, variations and
lack of specificity in some formularies may suggest a vague
understanding of the concept and nature of BMPs in
general, and BSPs in particular, by the professionals involved
in developing local formularies.
The principal limitation of this study is that the uptake
of BSPs has been estimated using local medicines
formularies as a proxy for actual prescribing practice. This may
not necessarily provide a highly accurate reflection of BSP
prescribing, as it is not known to what degree these lists are
If equally safe and effective as the originator BMP,
lower prices for BSPs could potentially increase access to
treatment for more patients, or reduce drug spending in an
increasingly constrained financial environment.
Engagement is required with prescribers, formulary managers and
commissioners to understand the basis for formulary
decision-making, identify reasons for variation in
prescribing behaviour and develop strategies for more uniform
uptake of BSPs. Educational interventions are also needed
around adherence to standards of pharmacovigilance to
assure drug monitoring and patient safety.
The results of this study suggest that the uptake of BSPs in
Britain is highly variable, and generally less than what is
expected, given historically that its market for
pharmaceuticals is very much generically driven. Further work is
needed to understand why there is such low and variable
Funding This study is part of a Ph.D. project funded by Yarmouk
Conflicts of interest The authors declare no potential conflicts of
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