DIABETES TECHNOLOGY & THERAPEUTICS
`Volume 10, Number 5, 2008
`© Mary Ann Liebert, Inc.
`DOI: 10.1089/dia.2008.0082
`
`Dose Accuracy Comparison Between SoloSTAR
`and FlexPen at Three Different Dose Levels
`
`Alfred Penfornis, M.D., Ph.D. 1 and Kristian Horvat
`
`Abstract
`
`Background: The convenience and accuracy of insulin pens have led to their extensive use in patients with di(cid:173)
`abetes. Although all insulin pens go through extensive testing as part of the regulatory process, it is important
`that both the patient and clinician can be assured of the accuracy of the dose delivered. This study compared
`the dosing accuracy of two commonly available insulin pens, the SoloST AR® (sanofi-aventis Deutschland
`GmbH, Frankfurt, Germany) and FlexPen® (Novo Nordisk A/S, Bagsvaerd, Denmark) devices.
`Methods: Doses of 5, 10, and 30 units of insulin were investigated for SoloSTAR and FlexPen, and specific units
`of accuracy were based on International Organization of Standards for insulin injection pens ( ::+:: 1 unit for the
`5 and 10-unit doses, ::+::5% for the 30-unit dose). A total of 30 pens were tested for both the SoloSTAR and Flex(cid:173)
`Pen, and a total of 2,280 measurement values were taken for each pen type (5 units, 1,260; 10 units, 750; and
`30 units, 270 doses).
`Results: Both devices were shown to be accurate at all three doses, and all doses were delivered within the lim(cid:173)
`its proposed by the International Standard of Organization, which is used as part of the regulatory approval
`process when introducing an insulin injection device to the market.
`Conclusion: Our study shows that the SoloSTAR and FlexPen devices have comparable accuracy.
`
`Introduction
`
`SINCE THE LAUNCH of the first insulin pen in 1985, there are
`
`now numerous reusable or disposable pen devices offi(cid:173)
`cially approved for administering insulin; insulin pens cur(cid:173)
`rently account for just over 50% of insulin use worldwide.1
`With this widespread use, it is important that both the pa(cid:173)
`tient and clinician are confident regarding the accuracy of an
`insulin injection device, as the key to treatment management
`of diabetes is the consistent delivery of an accurate insulin
`dose. To this regard, it is important to note that all insulin
`pens undergo extensive evaluation as part of the regulatory
`process, which includes the demonstration of accuracy.
`The SoloSTAR® disposable pen (sanofi-aventis, Deutsch(cid:173)
`land GmbH) has been approved and is available on the mar(cid:173)
`ket to deliver insulin (either insulin glargine [Lantus®] or in(cid:173)
`sulin glulisine [Apidra®]; both sanofi-aventis, Paris, France).
`Dose delivery by SoloSTAR has been shown to be accurate
`in a previously published laboratory-based study,2 in addi(cid:173)
`tion to studies performed in a clinical setting. 3,4
`The aim of this study was to compare the dosing accuracy
`of two commonly used insulin injection pen devices, the
`
`SoloSTAR and FlexPen® (Novo Nordisk A/S Bagsvaerd,
`Denmark).
`
`Materials and Methods
`
`The method for generating the dose accuracy data is de(cid:173)
`tailed in the article of Asakura et al.5 Two batches of each of
`the SoloST AR and the FlexPen were tested: SoloST AR in(cid:173)
`sulin glargine pens (batch numbers U200 and U208) using
`Micro-Fine® needles (31 gauge, 0.25 X 5 mm; Becton, Dick(cid:173)
`inson and Co., Franklin Lakes, NJ) and FlexPen insulin de(cid:173)
`temir (Levemir®; Novo Nordisk A/S) pens (batch numbers
`VH70046 and VH70047) with Novo-Fine® needles (32 gauge,
`6 mm; Novo Nordisk A/S).
`The study sample size was based on the International Or(cid:173)
`ganization of Standards (ISO) 2000 regulation for insulin in(cid:173)
`jection pens (ISO 11608-1), which requires a minimum of 15
`pen devices to be tested in a laboratory setting repeatedly
`across three specified doses, for 60 single doses at each dose
`level.6 Therefore, a total of 15 pens from each batch (30 pens
`in total) were used to test doses of 5, 10, and 30 units, and
`each pen was tested 42, 25, and nine times, respectively. Dur-
`
`1Service d'Endocrinologie Metabolisme et Diabetologie Nutrition, H6pital Jean Minjoz, Besancon, France.
`2sanofi-aventis Deutschland GmbH, Frankfurt am Main, Germany.
`
`359
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`360
`
`PENFORNIS AND HORVAT
`
`ing the testing, the instructions for use of SoloST AR and Flex(cid:173)
`Pen devices were strictly followed. The pen injectors and
`needles were preconditioned for at least 4 h (standard atmo(cid:173)
`sphere at 18-28°C with relative humidity of 25-75%) and un(cid:173)
`derwent testing in these conditions. Before use, the pens
`were prepared for injection as stated in the instructional
`leaflet. Prior to each measurement, a new prescribed needle
`was mounted to the device. A safety shot (priming) as quoted
`in the instruction manuals was performed, and the subse(cid:173)
`quent units were dialled and dispensed. The mass of the in(cid:173)
`sulin delivered was weighed and recorded; measured mass
`was calculated to the subsequent volume by using the den(cid:173)
`sity of the relevant insulin (SoloSTAR insulin glargine, 1.004
`g/mL; FlexPen insulin detemir, 1.008 g/mL). After the dose
`was dispensed, the SoloST AR and FlexPen devices were held
`in place for 10 and 6 s, respectively, in accordance with the
`instruction manuals.
`The dose accuracy limits followed throughout this exam(cid:173)
`ination were based on the ISO regulation for insulin injec(cid:173)
`tion pens (ISO 11608-1).6 Specified accuracy ranges were 5 ±
`1 units (4.0-6.0 units), 10 ± 1 units (9.0-11.0 units), and 30 ±
`5% (28.5-31.5 units).
`
`Results
`
`All 2,280 measurement values (1,260 for 5 units, 750 for 10
`units, and 270 for 30 units) were within the accuracy limits
`for both SoloST AR and FlexPen.
`
`Figures 1-3 show the comparison of SoloSTAR and Flex(cid:173)
`Pen on the delivery of 5, 10, and 30 units, respectively.
`Table 1 summarizes the combined mean delivered doses
`of 5, 10, and 30 units of insulin with the SoloSTAR and Flex(cid:173)
`Pen for all batches tested.
`The overall variance of SoloSTAR for the 5-unit dose was
`lower compared with FlexPen; the variance for the 10- and
`30-unit doses was higher for SoloSTAR compared with Flex(cid:173)
`Pen.
`When comparing the ordinal view to the aberration from
`the target value, SoloSTAR had the majority of values closer
`to the target (at all dosing steps). A total of 47.9% of all 1,260
`detected dose accuracy values at the 5-unit dosing step of
`the SoloSTAR were within an area of 0.1 unit from target
`compared with 37.1 % of FlexPen values, and only 0.5% of
`all dose accuracy values of the SoloSTAR had an aberration
`of more than 0.5 unit from the target compared with 2.5%
`for FlexPen. For the 10-unit dose setting, 33.3% of all 750 de(cid:173)
`tected dose accuracy values for the SoloSTAR were within
`an area of 0.1 unit from target compared with 28.3% of Flex(cid:173)
`Pen values. No SoloSTAR dose accuracy values had an aber(cid:173)
`ration of more than 0.5 unit from the target compared with
`3.6% for FlexPen. At 30-unit testing, 28.5% of all 270 detected
`dose accuracy values with the SoloSTAR were within an area
`of 0.2 unit from target compared with 8.1 % of FlexPen val(cid:173)
`ues. A total of 9.3% of all SoloSTAR dose accuracy values
`had a deviation of more than 0.8 unit from the target com(cid:173)
`pared with 13.3% for FlexPen.
`
`Indivilklal Values of SoloStar SU Dose
`6,5~ - - - - - - - - - - - - - - - - - - - - ,
`
`Individual Values of FlexPen SU Dose
`6 ,5~ - - - - - - - - - - - - - - - - - - - - ,
`
`~ - - - - - - - - - - - - - - - 6
`
`6,0 - - - - - - - - - - - - - - 5
`
`5,5
`
`5,0
`
`4,5
`
`♦ I
`
`~ - - - - - - - - - - - - - - - 4
`
`5, 5
`
`5,0
`
`4,5
`
`4,0 --------------- 4
`
`3,5
`
`6,5
`
`Boxplot of SoloStar at SU
`Pen 1-15: batch U200 Pen 16-30: U200
`
`~ - - - - - - - - - - - - - - - 5
`
`3,5
`
`6,5
`
`6,0
`
`Boxplot of FlexPen at SU
`Pen 1-15: batch VH70046 Pen 16-30 : VH,1J047
`
`* t
`~ - - - - - - - - - - - - - - - 4
`
`3,5
`
`:: HiH!li~f 111 !iH!!Hlitl!II!
`
`*
`
`*
`
`4,5
`
`_ __ _ __ __ _ _.:J< ___ _ 4
`
`4,0
`
`3,5
`
`Pen no
`
`Pen no
`
`FIG. 1. Comparison of SoloSTAR and FlexPen at 5-unit dose. *Values outside the pen specific distribution, but still within
`the study limits.
`
`Sanofi Exhibit 2139.002
`Mylan v. Sanofi
`IPR2018-01675
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`

`

`Indivirual Values of SoloStar 10 U Dose
`11,5 - r - - - - - - - - - - - - - - - - - - - - - ,
`
`Indivicklal Values of FlexPen 10 U Dose
`u ,5 - r - - - - - - - - - - - - - - - - - - - - - ,
`
`~ - - - - - - - - - - - - - - - u
`
`~ - - - - - - - - - - - - - - - u
`
`10,5
`
`10,0
`
`9,5
`
`t
`
`10,5
`
`10,0
`
`9,5
`
`9,o -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`9
`
`9,0 t---
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`♦
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`9
`
`8,5~ - - - - - - - - - - - - - - - - -~
`
`8,5~ - - - - - - - - - - - - - - - - -~
`
`Boxplot of FlexPen at l0U
`Pen 1-15: IEtch VH,1JC>16 Pen 16-30: VH~ 47
`11,5 - r - - - - - - - - - - - - - - - - - - - - - ,
`
`Boxplot of SoloStar at l0U
`Pen 1-15: IEtc h U208 Pen 16-30 : U200
`u ,5 - r - - - - - - - - - - - - - - - - - - - - - ,
`
`~ - - - - - - - - - - - - - - - u
`
`~ - - - - - - - - - - - - - - - u
`
`10,5
`
`: l1[1i111,t,! 1f1j•!1f11•1111!1I
`*
`-
`
`9, □ - -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`9
`
`9,0 t---
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`9
`
`8,5
`
`8,5
`
`Pen no
`
`Pen no
`
`FIG. 2. Comparison of SoloSTAR and FlexPen at 10-unit dose. *Values outside the pen specific distribution, but still within
`the study limits.
`
`Indivirua I Va IIEs of SoloStar 30 U Dose
`32,0, - r - - - - - - - - - - - - - - - - - - - ,
`
`Indivicklal Values of FlexPen 30 U Dose
`32,0- r - - - - - - - - - - - - - - - - - - - - ,
`
`- - - - - - -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`31,5
`
`31,0
`
`30,5
`
`30,0
`
`29,5
`
`29,0
`
`28,5
`
`31,5
`
`31,5 -
`
`31,5
`
`31,0
`
`30,5
`
`30,0
`
`29,5
`
`29,0
`
`28,5
`
`28,5 -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`t
`
`•
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`28,5
`
`28,o,~ - - - - - - - - - - - - - - - - -~
`
`28,o~ - - - - - - - - - - - - - - - -~
`
`Boxplot of SoloStar at 30U
`Pen 1-15: batch U208 Pen 16-30: U200
`32,0, - r - - - - - - - - - - - - - - - - - - - ,
`
`Boxplot of FlexPen at 30U
`Pen 1-15: batch VH70046 Pen 16-30 : VH,1J047
`32,0- r - - - - - - - - - - - - - - - - - - - - ,
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`31,5
`
`31,5 - - - - - - - - - - - - - - 31,5
`
`31,5 -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`31,0
`
`-
`
`*
`
`I~ i,1!1l1''1t!lig!11j;,1;;11il
`
`31,0
`
`30,5
`
`1I
`
`28,5 -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`28,5
`
`28,5 -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`*
`
`-
`
`28,5
`
`28,0
`
`28,0
`
`Pen no
`
`Pen no
`
`FIG. 3. Comparison of SoloSTAR and FlexPen at 30-unit dose. *Values outside the pen specific distribution, but still within
`the study limits.
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`362
`
`PENFORNIS AND HORVAT
`
`TABLE 1. MEAN DELIVERED DOSES OF 5, 10, AND 30 UNITS
`OF INSULIN WITH SoLoST AR AND FLExPEN
`
`Intended dose (units)
`
`5
`10
`30
`
`n
`
`1,260
`750
`270
`
`Mean delivered dose (SD) ± 95% CI
`
`SoloSTAR
`
`FlexPen
`
`5.07 (0.15) ± 0.001
`9.87 (0.16) ± 0.01
`29.70 (0.38) ± 0.05
`
`5.03 (0.21) ± 0.01
`9.83 (0.14) ± 0.01
`29.45 (0.25) ± 0.03
`
`Data include the combined totals for the two batches of SoloSTAR (batches U200 and U208) and two
`batches of FlexPen (batches VH70046 and VH70047). SD, standard deviation; CI, confidence interval.
`
`Discussion
`
`Overall, the SoloSTAR and FlexPen devices had compa(cid:173)
`rable accuracy over the standard doses of 5, 10, and 30 units.
`Data from this study are in line with previous published
`studies, which demonstrate the accuracy of the SoloSTAR in
`laboratory- and clinical-based settings.2--4
`However, the findings from this study are different from
`those reported in a recently published study by Asakura et
`al.,5 which suggested that FlexPen was more accurate com(cid:173)
`pared with SoloSTAR at all doses tested. The methodology
`applied in our study was the same as that used in the study
`by these previous investigators. However, our findings are
`more robust compared to those in their study; 30 pens were
`tested compared with three pens in the previous study, and
`data from 2,280 doses versus 228 in the study by Asakura et
`al.5 were investigated for each pen type (5 units, 1,260 vs.
`126 doses; 10 units, 750 vs. 75 doses; and 30 units, 270 vs. 27
`doses, respectively).
`It should be noted that ISO 11608-1 describes the approach
`for determining the accuracy of dose delivery for injection
`devices. 6 However, the methodology of Asakura et al.5 did
`not follow the exact ISO methods; the minimum, medium,
`and maximum dose settings for each pen device were not
`tested, and there was no randomization in the order of dose
`settings (only one dose setting was tested for each pen).
`SoloSTAR accuracy evaluation studies are ongoing, which
`closely follow ISO testing; minimum, medium, and maxi(cid:173)
`mum dose settings for each pen device will be tested across
`a wider range of doses. Moreover, these studies are also de(cid:173)
`signed in such a way that will allow a robust statistical anal(cid:173)
`ysis for the comparison of the accuracy of SoloSTAR with
`FlexPen. Finally, further studies are being conducted that
`compare the dose accuracy of SoloSTAR with other com(cid:173)
`monly available insulin pens, such as Humalog® (Elly Lilly
`and Co., Indianapolis, IN).
`
`Conclusions
`
`Our results show that the SoloST AR has comparable ac(cid:173)
`curacy to that of the FlexPen. Both pens are accurate in dis(cid:173)
`pensing insulin, which was to be expected, considering reg(cid:173)
`ulatory review and acceptance. These data presented are of
`particular relevance for people with type 1 or type 2 diabetes
`
`who use SoloSTAR to inject insulin glargine or insulin gluli(cid:173)
`sine and who are reliant on the accuracy of the insulin in(cid:173)
`jection device they use.
`
`Acknowledgments
`
`This study was supported by sanofi-aventis. Editorial sup(cid:173)
`port for this manuscript was provided by the Global Publi(cid:173)
`cations Group of sanofi-aventis.
`
`Author Disclosure Statement
`
`A.P. has served as a consultant to Lilly and sanofi-aven(cid:173)
`tis, has lectured at a sanofi-aventis-sponsored symposium,
`and has served on an advisory board for Novo Nordisk and
`sanofi-aventis. K.H. is an employee of sanofi-aventis.
`
`References
`
`1. IMS Health: IMS MidasTM June 2006, quarterly insulin sales
`volume in units. 2006. Available at: http://wwwl.imshealth.
`com/ (accessed July 25, 2008).
`2. Clarke A, Spollett G: Dose accuracy and injection force dy(cid:173)
`namics of a novel disposable insulin pen. Expert Opin Drug
`Deliv 2007;4:165-174.
`3. Hermanns N, Kulzer B, Krichbaum M, Haak T: Hohe Dosier(cid:173)
`genauigkeit des LANTUS® SoloStar® und des APIDRA®
`SoloStar® Insulinfertigpens [abstract 286]. Diabetologie Stof(cid:173)
`fwechsel 2008;3(Suppl 1):S97.
`4. Schwartz SL, Vlajnic A: Validation of the SoloStar insulin pen
`[abstract]. J Diabetes Sci Technology 2008;1(Suppl 1):A159.
`5. Asakura T, Seino H, Kageyama M, Yohkoh N: Dosing accu(cid:173)
`racy of two insulin pre-filled pens. Curr Med Res Opin
`2008;24:1429-1434.
`6. International Organization for Standardization: Pen Injectors
`for Medical Use-Part 1: Pen Injectors-Requirements and
`Test Methods. ISO 11608-1. Geneva: International Organiza(cid:173)
`tion for Standardization, 2000.
`
`Address reprint requests to:
`Prof. Alfred Penfornis
`Service d'Endocrinologie Metabolisme et Diabetologie Nutrition
`H8pital Jean Minjoz
`25030 Besancon Cedex, France
`
`E-mail: Alfred.penfornis@univ-fcomte.fr
`
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`IPR2018-01675
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