W Taylor & Francis
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`Current Medical Research and Opinion
`
`ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20
`
`Prefilled insulin device with reduced injection
`force: patient perception and accuracy
`
`A. Pfutzner, T. Reimer, C. Hoh berg, L. P. F. Fr0kjrer & C. J0rgensen
`
`To cite this article: A. PfUtzner, T. Reimer, C. Hohberg, L. P. F. Fr0kja:ir & C. J0rgensen (2008)
`Prefilled insulin device with reduced injection force: patient perception and accuracy, Current
`Medical Research and Opinion, 24:9, 2545-2549, DOI: 10.1185/03007990802329264
`
`To link to this article: https://doi.org/10.1185/03007990802329264
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`la Published on line: 29 Jul 2008.
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`CURRENT MEDICAL RESEARCH AND OPINION®
`VOL.24,NO.9,2008,2545-2549
`
`© 2008 lnforma UK Ltd.
`
`0300-7995
`doi:10.1185/03007990802329264
`
`All rights reserved: reproduction in whole or part not permitted
`
`ORIGINAL ARTICLE
`Prefilled insulin device with
`reduced injection force: patient
`perception and accuracy
`A. PfUtznera, T. Reimera, C. Hohberga,
`L. P. F. Fr0kjffirb and C. J0rgensenc
`a Institute for Clinical Research and Development (ikfe) GmbH, Parcusstr. 8,
`
`55116 Mainz, Germany
`
`bNovo Nordisk A/S, Brennum Park, DK-3400 Hillerod, Denmark
`
`0 Novo Nordisk A/S, Hummeltoftevej 49, 2830 Virum, Denmark
`
`Address for correspondence: Christina Jorgensen, Hummeltoftevej 49, 2830 Virum, Denmark.
`Tel.: +45 4443 2884; Fax: +45 4442 1848; cjrg@novonordisk.com
`
`Key words: Dose accuracy - FlexPen - Injection force
`
`ABSTRACT
`
`Objective: The injection force and the patient perception of
`the Next Generation FlexPen* (NGFP) with design modifi(cid:173)
`cations aimed at reducing injection force was assessed.
`The accuracy and precision of the NGFP was also tested
`under standard conditions.
`Research design and methods: Dosing accuracy was
`tested (according to ISO 11608 requirements) at 1 IU, 30 IU
`and 60 IU doses (acceptable limits were 1 ± 1 IU (0-2 IU),
`30 ± 1.5 IU (28.5-31.5 IU), and 60 ± 3 IU (57-63 IU)). Pens
`were tested at reference conditions (18-28°C and relative
`humidity 25-75%). Delivered doses were measured on
`a sensitive balance and corrected for the specific density
`of the insulin aspart used (according to ISO 11608-1).
`Precision was calculated from the variance around the
`mean delivered dose. The injection force of NGFP was
`measured, and user-preference of NGFP and FlexPen
`(FP) were compared in 50 patients with type 2 diabetes.
`
`Results: The mean injection force with NGFP and FP
`was 12.57±1.81 N and 17.90±1.51 N (p<0.001),
`respectively. Almost twice as many patients rated the
`injection force as 'good' or 'very good' with NGFP (80%,
`72% and 38% when delivering 20 IU, 40 IU and 60 IU,
`respectively) compared with FP (48%, 32% and 20% when
`delivering 20 IU, 40 IU and 60 IU, respectively) and 76% of
`patients rated NGFP as superior, in terms of simplicity and
`comfort, to FP. NGFP accurately delivered the set doses
`(means [SD] were 0.98 [0.06] IU, 29.98 [0.18] IU, and
`59.93 [0.24] IU for the 1 IU, 30 IU and 60 IU doses,
`respectively).
`Conclusions: These results show that NGFP has a 30%
`reduction in injection force compared with FP and was
`rated as 'more simple and comfortable to use' by patients.
`Furthermore, NGFP was as accurate and as precise as FP.
`
`Introduction
`
`The use of insulin injections for the management of
`diabetes can be perceived as inconvenient and trau(cid:173)
`matic by patients. Many patients fear injections, find
`traditional vial and syringes inconvenient, and lack
`confidence in delivering accurate doses of insulin;
`these factors limit patients' overall confidence to self(cid:173)
`2
`manage their diabetes with insulin 1
`,
`.
`
`Partly because of injection fears and partly because
`the use of vial and syringe can lead to inaccurate
`dosing3
`,4, injection pens are now the predominant
`devices for insulin delivery, especially in Europe. Pens
`overcome the patient's fear of injection, are convenient
`to use and increase confidence in dose delivery, and
`therefore, potentially improve the quality of life of
`10
`the user 5
`. Because it can have consequences for gly(cid:173)
`-
`caemic control, the improved accuracy and precision of
`
`*FlexPen is a registered trade name of Novo Nordisk A/S, Bagsva:rd, Denmark
`
`Article 4634/333093
`
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`insulin pens compared with vials and syringes is very
`13
`important11
`. The ability of pens to deliver more
`-
`accurate insulin doses than syringes is particularly
`obvious when low doses (1-5 IU) have to be adminis(cid:173)
`tered 11· 12, but the impact this may have on the
`frequency of hypoglycaemia or even more serious long(cid:173)
`term consequences of poor glycaemic control has not
`been demonstrated.
`FlexPen* (FP) is a prefilled insulin pen that is used by
`4
`more than 3 million people with diabetes 1
`. The dosing
`accuracy and consistency of FP has been confirmed in
`18
`several studies 15
`. It is known that some insulin pens
`-
`can, on rare occasions, block if the push button is
`pushed at an oblique angle, and the manufacturer has
`received occasional reports that patients found the
`push-button hard to push down. To overcome these
`issues and to reduce the injection force, a Next
`Generation FP (NGFP) has been designed. The NGFP
`has changes to the ratchet, the clutch and the push(cid:173)
`button to reduce the injection force and to eliminate
`blocking with FP. The other features of NGFP are
`exactly the same as FP. As with any new insulin pen,
`existing pens that undergo design changes must be
`shown to deliver accurate and reliable insulin doses
`during rigorous testing. Here we report on the dosing
`accuracy of NGFP compared with FP. The injection
`force of NGFP and FP was also tested in our study. In
`addition, we present the results of a questionnaire
`survey of user preference between NGFP and FP.
`
`qualified and experienced in conducting such tests
`according to ISO standards, and standard methodology
`was used for the measurement of dose accuracy as
`9
`described in the ISO standards for insulin pen devices 1
`.
`All doses were delivered in a random order. The accuracy
`of dosing was measured by delivering 1 IU, 30 IU or 60 IU
`60 times (180 doses in all) with each pen (according to
`ISO 11608-1). Each test was carried out with a new and
`unused pen, and before delivering each dose the pen was
`prepared according to ISO 11608-1 instructions. Doses
`were delivered onto a precision balance and weighed.
`Weights were corrected for the specific density of insulin
`aspart (1.008 g/ml at S°C, 1.005 g/ml at 20°C and
`0.999 g/ml at 40°C). Dose accuracy was measured at
`reference conditions: pens were exposed to 18-28°C
`and relative humidity (RH) 25-75% for at least 4
`hours before measuring dose accuracy.
`Acceptable limits for dose accuracy were based on
`ISO regulations (ISO 11608-1): 1 ± 1 IU (0-2 IU),
`30±1.SIU (28.5-31.SIU), and 60±3IU (57-631U).
`The mean value and standard deviations of the 60 doses
`delivered at each of the three settings (1 IU, 30 IU and
`60 IU) were calculated. In addition, minimum, maxi(cid:173)
`mum and inter-quartile range values were recorded.
`The difference between mean absolute deviation in
`the delivered dose of each pen was calculated using
`Stigma Stat v3.5. and the Levenes test was used to
`test for homogeneity of variance as a measure of pen
`precision.
`
`Methods
`
`All dose accuracy test methods were conducted in an
`identical manner with both NGFP and FP.
`
`Materials
`
`The NGFPs tested for injection force and performance
`were all drawn from the same batch (lot TG 70313/ A)
`and were filled with NovoRapidt (insulin aspart) (batch
`TZ60322). For the tests on FP, pens were drawn from
`batch SPS0497 and filled with NovoRapid (insulin
`aspart) (batch RQ50794). Pens were picked randomly
`from these lots to perform each test. The same batches
`of pens were used for the user preference study.
`
`Calculation of dose accuracy
`
`Accuracy was measured in the Novo Nordisk NS
`Quality Assurance laboratory, all testers were suitably
`
`Injection force measurements
`
`Injection force was measured under standard condi(cid:173)
`tions with 20 previously unused pens with the cartridge
`and NovoFinei 30G 8 mm needle attached and at
`a flow rate of 10 IU/s.
`
`User preference questionnaire
`
`In this part of the study NG FP and FP were com pared for
`injection force perception by users. The survey recruited
`50 patients with type 2 diabetes. The study was handled
`in accordance with local legal and ethical requirements
`and each patient signed an informed consent form before
`taking part in the study. All participants were receiving
`insulin at the time and used an insulin pen at least once
`per day. Test injections with insulin aspart (NovoRapid)
`were made into an injection pillow. Pens were fitted with
`30G 8 mm needles, and each patient used a previously
`unused pen of each type.
`
`*FlexPen is a registered trade name of Novo Nordisk A/S, Bagsva:rd, Denmark
`tNovoRapid is a registered trade name of Novo Nordisk NS, Bagsva:rd, Denmark
`tNovoFine is a registered trade name of Novo Nordisk NS, Bagsva:rd, Denmark
`
`2546 Preti/led insulin device with reduced injection force
`
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`Each patient delivered one dose of 20 IU, 40 IU and
`60 IU with each pen into the injection pillow, in
`a randomised order. After delivering each dose with
`both pens, each patient answered Questions 1, 2 and 3,
`respectively (see Appendix). After delivering all doses
`and answering Questions 1-3, each patient answered
`Question 4 on pen 'simplicity and comfort' of use.
`For the answers to Questions 1-3, data were mod(cid:173)
`elled by logistic regression for ordinal response with
`pen and patient as fixed effects. A likelihood-ratio
`Chi-square test was used to test if pen type had a sig(cid:173)
`nificant effect on answers. The responses to Question 4
`were tested for equal 'simplicity and comfort' using
`a two-sided chi-square test. JMP version 7 .0.1 was
`used for these analyses.
`
`Results
`Dose accuracy
`
`Dose accuracy was well within the acceptable limits for
`NGFP and FP (Table 1 ). No single dose delivered by any
`pen (at 1 IU, 30 IU or 60 IU) was below or above the
`pre-specified acceptable ranges. The mean absolute
`deviation from the set doses for FP were 0.06 IU (6% ),
`0.23 IU (0.8%) and 0.36 IU (0.6%) for 1 IU, 30 IU and
`60 IU, respectively. The corresponding values for NGFP
`were 0.05 IU (5% ), 0.14 IU (0.5%; p < 0.05 compared
`with FP) and 0.19IU (0.3%; p<0.01 compared with
`FP) for 1 IU, 30 IU and 60 IU, respectively. The analysis
`of precision also showed that NGFP was significantly
`more precise when delivering doses of 30 IU (p < 0.05)
`and 60IU (p<0.05) than FP. Stress tests of NGFP at
`different
`temperatures and humidity
`( conducted
`according to ISO methodology) showed that there
`was no significant change in the dose accuracy under
`various environmental conditions (results not shown).
`
`Injection force
`
`The mean injection force with NGFP was 12.57 N and
`this is considerably lower than the injection force with
`
`FP (17 .90 N measured with the same methodology).
`This equated to a 29 .8% relative reduction in the
`injection force of NGFP compared with FP (p<0.001;
`t-test assuming normally distributed measurements).
`The range of injection force measured with FP was
`15.35-19.99N, so all FPs had injection force higher
`than the mean injection force with NGFP.
`
`User preference survey
`
`After delivering three doses with each pen, more
`patients rated the injection force with NGFP as 'good'
`or 'very good' than with FP (Figure 1). The difference
`in responses after using each pen was significant
`(p < 0.0001) for all three doses. An injection force
`rating of 'very good' or 'good' was given to NGFP
`by 80% of patients when delivering 20 IU, 72% when
`delivering 40 IU and 38% when delivering 60 IU - the
`corresponding proportions for FP were 48, 32 and 20%,
`respectively.
`In response to Question 4, 7 6% of the patients stated
`that NGFP was 'simpler and more comfortable' to use
`than FP, and only 24% stated that FP was 'simpler and
`more comfortable' to use than NGFP. The hypothesis
`of equal
`'simplicity and comfort' is rejected and
`shows that a significantly greater proportion of patients
`found NGFP more 'simple and comfortable' to use
`(p=0.0002).
`
`Discussion
`
`This study demonstrated that NGFP delivers insulin in
`an accurate and precise manner and is more 'simple and
`comfortable' to use than FP. The design modifications
`to NGFP have not adversely affected any of the pre(cid:173)
`18 but have
`viously demonstrated attributes of FP 15
`-
`reduced the injection force by 30% compared with
`FP. NGFP delivered doses were more accurate and pre(cid:173)
`cise (significantly for 1 IU) than FP delivered doses.
`
`Table 1. Accuracy and precision of NGFP and FP under standard conditions*
`
`Dose of insulin delivered with NGFP
`
`Dose of insulin delivered with FP
`
`Value
`
`Set to 1 IU
`
`Set to 30IU
`
`Set to 60IU
`
`Set to 1 IU
`
`Set to 30IU
`
`Set to 60IU
`
`Mean
`Standard deviation
`Min
`25th percentile
`50th percentile
`75th percentile
`Max
`Range
`
`0.98
`0.06
`0.83
`0.95
`0.97
`1.02
`1.10
`0.27
`
`*60 tests for each set dose
`
`29.98
`0.18
`29.65
`29.89
`29.98
`30.09
`30.78
`1.13
`
`59.93
`0.24
`59.43
`59.80
`59.94
`60.10
`60.43
`1.00
`
`1.04
`0.06
`0.91
`1.00
`1.03
`1.08
`1.23
`0.32
`
`29.93
`0.31
`29.06
`29.71
`29.99
`30.10
`30.52
`1.46
`
`59.90
`0.45
`59.00
`59.59
`59.96
`60.21
`60.82
`1.82
`
`© 2008 lnforma UK - Curr Med Res Opin 2008; 24(09)
`
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`FP 20 IU
`
`FP 40 IU
`
`5
`::::.,
`Q) NGFP 20 IU
`U)
`0
`"lJ
`.!:
`::i
`U) NGFP 40 IU
`.!:
`"lJ
`C:
`Ctl
`C:
`Q)
`
`FP 60 IU
`
`D.. NGFP 60 IU
`
`22%
`
`6%
`
`24%
`
`22%
`
`4%
`
`46%
`
`2%
`
`14%
`
`1•
`
`..
`
`48%
`
`22%
`
`10%
`
`32%
`
`24%
`
`■ . . ■ = . ■
`
`36%
`
`12%
`
`, ..
`
`- 48%
`
`14% 6%
`
`....
`
`30%
`
`8%
`
`100
`
`50
`0
`50
`Percentage of patients rating as postive or negative
`
`100
`
`*p<0.0001; tdata missing for one patient
`
`Figure 1. Patient perception of FP and NG FP injection force when injecting 20 JU, 40 JU and 60 JU of insulin aspart.
`*p < 0.0001 between pens; responses compared using likelihood ratio chi-square test
`
`One aim of this study was to confirm that the design
`changes had reduced the injection force of NGFP .
`The mean injection force for all NGFPs was 30%
`lower than the mean value for FPs. The maximum
`and minimum injection forces measured with 20
`NGFPs (10.63-18.57 N) were consistently lower than
`the maximum and minimum injection forces measured
`with 20 FPs (15.35-19.99 N), therefore NGFP does
`have the desired reduced injection force. A lower injec(cid:173)
`tion force is generally preferred by patients simply
`because the lower the force required for injection, the
`easier it is to inject the insulin dose. This is particularly
`important in patients with impaired manual dexter(cid:173)
`ity20-22. To test if the reduction in injection force
`with NGFP had an actual benefit to the end-user, the
`results from the user-preference study were included
`here. In this user-preference study, patients had
`a better perception of the injection force of NGFP
`than FP at all doses tested ( nearly twice as many patients
`rated the injection force as 'good' or 'very good' with
`NGFP compared to FP). Not only does this suggest that
`the reduced injection force is perceived as an improve(cid:173)
`ment by patients, but it also contributed to three out of
`four patients finding NGFP 'simpler and more comfor(cid:173)
`table' to use. However, a limitation of this study is the
`fact that NGFP has not been tested in routine clinical
`practice, and whether this preference is maintained in
`everyday use will need to be investigated.
`With the increased use of insulin pens23, a wider vari(cid:173)
`ety of patients will gain more experience with a range of
`pens. Different patient populations will have different
`specific demands and the importance of various pen
`features will vary from patient to patient. Several stu(cid:173)
`dies have investigated the reasons for patient preference
`• l
`d
`.
`l
`.
`s-10 24-27 F
`wr pens over via an syringe
`'
`. or examp e, m
`1:
`a study of insulin users and non-users, social acceptabil(cid:173)
`ity and ease of use were the most important factors for
`preference for pens10. In a study of FP versus vial and
`
`syringe, patients preferred FP due to improvements in
`convenience, flexibility, perceived clinical efficacy and
`quality of life26. The changes to NGFP are designed to
`enhance the preferred features of FP further and this
`report suggests that NGFP is rated as 'simpler and
`more comfortable' to use than FP, because it delivers
`the same accurate and reliable doses of insulin at high
`and low doses under a variety of everyday conditions,
`but with a considerably lower dose force.
`
`Conclusion
`
`The modifications made to NGFP have resulted in
`a significant 30% reduction in injection force compared
`with FP. These changes have contributed to NGFP
`being considered more 'simple and comfortable' to
`use by patients. Importantly, the dose accuracy of
`NGFP is at least as good as FP, and our study suggests
`that NGFP may actually be significantly more accurate
`and precise than FP - deviation from set doses and the
`variance in the delivered dose were small with both
`pens but smallest with NGFP. Although the NGFP
`has not been tested in everyday use, this study suggests
`that the changes made are likely to enhance patient
`comfort and aid accurate insulin dosing.
`
`Acknowledgements
`
`Declaration of interest: The preference study was sup(cid:173)
`ported by Novo Nordisk and performed by the Institute
`for Clinical Research and Development (ikfe) GmbH,
`Mainz, Germany. Publication was supported by Novo
`Nordisk NS (Bagsv~rd, Denmark) with editorial assis(cid:173)
`tance from ESP Bioscience (Sandhurst, UK).
`Dr Andreas Pfiitzner is a part of the advisory board of
`Novo Nordisk A/S. C. forgensen and L. P. F. Frokj~r
`are employees of Novo Nordisk A/S. T. Reimer and
`C. Hohberg are employees of ikfe and assisted in the
`
`2548 Preti/led insulin device with reduced injection force
`
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`practical performance of the study. The authors have
`approved the final draft of this manuscript and take full
`responsibility for its contents.
`
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`
`Question 1. How do you perceive the injection force at 20 IU?
`Possible answers: 'very bad', 'bad', 'neutral', 'good', and 'very good'
`Question 2. How do you perceive the injection force at 40 IU?
`Possible answers: 'very bad', 'bad', 'neutral', 'good', and 'very good'
`Question 3. How do you perceive the injection force at 60 IU?
`Possible answers: 'very bad', 'bad', 'neutral', 'good', and 'very good'
`Question 4. Which pen, in your opinion, is simpler and more comfortable to use?
`
`CrossRef links are available in the online published version of this paper:
`http://www.cmrojournal.com
`Paper CMRO-4634_ 4, Accepted for publication: 8 July 2008
`Published Online: 29 July 2008
`doi: 1 O. l l 85/03007990802329264
`
`© 2008 lnforma UK - Curr Med Res Opin 2008; 24(09)
`
`Preti/led insulin device with reduced injection force Prntzner et al. 2549
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`Sanofi Exhibit 2175.006
`Mylan v. Sanofi
`IPR2018-01676
`
`