Medical Devices: Evidence and Research
`
`Dove press
`
`open ac- 'ess t
`
`-.;c1er1trfi., :ind mEdical r
`
`'e1r h
`
`0 Open Access FullTextArticle
`An evaluation of prefilled insulin pens: a focus
`on the Next Generation FlexPen®
`
`REVIEW
`
`Estella M Davis
`Emily L Sexson
`Mikayla L Spangler
`Pamela A Foral
`
`Department of Pharmacy Practice,
`Creighton University School of
`Pharmacy and Health Professions,
`Omaha, Nebraska, USA
`
`Correspondence: Estella M Davis, PharmD
`Department of Pharmacy Practice,
`Creighton University School of Pharmacy
`and Health Professions, 2500 California
`Plaza, Omaha, Nebraska 68178, USA
`Tel + 1-402-398-5646
`Fax+ 1-402-398-5928
`Email edavis@creighton.edu
`
`Abstract: Insulin pen delivery systems are preferred by patients over the traditional vial and
`syringe method for insulin delivery because they are simple and easy to use, improve confidence
`in dosing insulin, and have less interference with activities and improved discretion with use.
`Insulin manufacturers have made numerous improvements to their first marketed pen devices
`and are now introducing their next generation of devices. Design modifications to the newest
`generation of pre filled insulin pen devices are intended to improve the ease of use and safety and
`continue to positively impact adherence to insulin. This review focuses on the Next Generation
`FlexPen® with regard to design considerations to reduce injection force, improve accuracy and
`ease of use, and evaluate the preference of patient and health-care provider compared with other
`disposable, prefilled insulin pen devices.
`Keywords: diabetes, dose accuracy, injection force, patient preference, insulin pen device
`
`Introduction
`Global estimates indicate the total number of individuals with diabetes will increase
`from 171 million in 2000 to a projected 366 million people by 2030, likely due to the
`population growth, aging, urbanization, and increasing prevalence of obesity and lack
`of physical activity. I Estimates from 2007 indicate the prevalence of undiagnosed and
`diagnosed patients with diabetes in the United States alone to be 23.6 million people
`or 7.8% of the population.2
`Studies show that maintaining glycosylated hemoglobin (HbA1c) goals close to
`the range ofnondiabetic patients reduces the risk ofmicrovascular complications.3
`---ll
`In order to achieve HbA1c goals and maintain glycemic control, insulin remains the
`cornerstone of therapy for patients with type 1 diabetes. 9 Furthermore, insulin admin(cid:173)
`istration is recommended as an additional method to intensify therapy when other
`antidiabetic agents and lifestyle modifications are insufficient to meet the HbA1c goals
`for patients with type 2 diabetes_ Io,II
`A treatment algorithm, formulated by a consensus panel of the American Diabetes
`Association (ADA) and European Association for the Study of Diabetes (EASD), to
`manage patients with type 2 diabetes recommends an option of additional therapy with
`insulin after monotherapy with metformin does not achieve the HbA1c goals_ Io
`The treatment algorithm, formulated by the American Association of Clinical
`Endocrinologists (AACE) and American College of Endocrinology (ACE), stratifies
`patients with type 2 diabetes based on their current HbA1c value with a goal of
`monitoring therapy every 2-3 months and intensifying therapy until the HbA1c goal
`
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`DOI: 10.2147/MDER.SI 1730
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`41
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`permits unrestricted noncommercial use, provided the original work is properly cited.
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`has been reached. It recommends that for patients with HbA1c
`values >9% and on antidiabetic medications or if medication
`naive and symptomatic, insulin therapy should be considered.
`For patients with HbA1c values <9% and combinations of
`dual or triple antidiabetic medications fail to achieve the
`HbA1, goal ofs6.5%, insulin therapy should be considered
`
`as an additional method of intensification. 11
`Despite these recommendations, it is estimated that
`only 27% of the adult American population diagnosed with
`diabetes are on some type of insulin treatment, whereas 73 %
`take either oral medication or no medication at all. 2 Further
`research is needed to assess the percentage of patients with
`type 2 diabetes who should have augmentation with insulin
`therapy according to these guidelines.
`Multiple patient factors and attitudes regarding insulin
`contribute to the overall reluctance to initiate therapy.
`Certain patient attitudes presenting a barrier to insulin use
`include: fear of hypoglycemic complications, increased
`complexity of managing diabetes, lifestyle restrictions,
`social unacceptability, and fear of self-injecting.12· 13 A
`survey validation study confirmed a positive correlation
`among three main pen product attributes that relate to the
`preference for insulin pens compared with vials and syringes
`including ease of use, less activity interference, and social
`acceptability. 14 Since the first introduction of insulin pens to
`the market, consideration of these three main attributes per(cid:173)
`meates throughout the design and evaluation of various pen
`devices in an effort to positively influence patient preference
`and ultimately adherence to insulin regimens.
`Although the traditional vial and syringe method is
`available for the delivery of insulin, this method requires
`extensive training and the patient must have the appropriate
`visual acuity, manual dexterity, and coordination to properly
`prepare and administer an insulin injection. 15 Studies have
`shown patients with diabetes prefer insulin pens over vials
`and syringes because of the improvements in the following
`features: ease of use, confidence in dosing, discretion with
`use, compliance, quality oflife, and independence of admin(cid:173)
`istration in patients with visual or motor disabilities. 15
`24
`-
`Furthermore, national health-care benefit studies revealed the
`transition from vials and syringes to insulin pens improves
`medication adherence and reduces overall health-care costs,
`emergency department and physician visits, and the likeli(cid:173)
`hood of experiencing a hypoglycemic event.25
`27
`-
`The purpose of this review is to present an evaluation
`of the Next Generation FlexPen® (NGFP) (Novo Nordisk,
`Bagsvaerd, Denmark) compared with other disposable,
`prefilled insulin pen devices. Emphasis will be placed on
`
`evaluating the utility of this device regarding the design
`considerations to improve accuracy, reduce injection force,
`and evaluate the preference of patient and health-care pro(cid:173)
`vider with NGFP compared with other disposable, prefilled
`insulin pen devices.
`A Pubmed search was conducted to identify studies
`published from 1985 to February 2010 using the search
`terms flexpen, next generation flexpen, pre.filled pen, insulin
`pen, and insulin delivery device. References of identified
`articles and pharmaceutical websites were also reviewed for
`additional pertinent articles.
`
`The evolution of new-generation
`prefilled insulin pens
`Insulin pen device delivery systems were created in 1985 with
`the intent to overcome barriers of the vial and syringe method.
`Insulin pen devices combine an insulin reservoir cartridge
`and syringe into a single component in an effort to overcome
`barriers to adherence with insulin self-administration and
`improve convenience and ease of use for patients.28 Insulin
`pen devices are typically classified as being either durable
`(reusable) or pre filled (disposable). Durable insulin pen
`devices use replaceable and disposable insulin cartridges that
`are loaded and removed from the insulin delivery pen by the
`patient. Prefilled insulin pen devices require no installation
`of an insulin reservoir cartridge by the patient. The entire
`device including the body of the pen and prefilled insulin
`cartridge can be discarded once it is empty. Both types of
`devices contain 3 mL of insulin (100 U/mL), for a total of
`300 U of insulin and require attachment of an insulin pen
`needle to administer a dose.29
`Dose preparation and insulin administration are simplified
`with prefilled insulin pens compared with the vial and syringe
`method. Pen device preparation and insulin administration
`with new-generation prefilled pens share broadly similar
`techniques. Patients would follow the following basic steps:
`correctly identifying the insulin analog for use, removing
`the pen cap, placing an insulin pen needle on the insulin end
`of the pen, and "dialing-up" or setting the insulin dose by
`twisting a dosage selector. At this point, patients can visualize
`their numerical insulin dose and concurrently hear audible
`clicks for each incremental dose increase from zero. Patients
`typically perform a 2 U safety airshot of insulin to verify
`whether the needle is working. Once this is confirmed and
`the patients have dialed up their insulin dose, they insert the
`pen at a 90° angle into subcutaneous tissue and depress the
`injection button on the end of the dosing knob of the pen.
`The dosing window returns to zero, resulting in delivery of
`
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`Next generation of insulin pen devices
`
`insulin. Patients should be instructed to wait for a few seconds
`to allow the absorption of the appropriate amount of insulin
`and withdraw the insulin pen from the subcutaneous tissue.
`Due to the ease of administration, patients can correctly dial
`up and administer their insulin with minimal instructions
`using pen devices. 30
`33
`-
`All three manufacturers of insulin dispensed in the United
`States. (Novo Nordisk; Eli Lilly and Company, Indianapo(cid:173)
`lis, Indiana, USA; sanofi-aventis, Bridgewater, New Jersey,
`USA) have disposable, prefilled insulin pens to facilitate the
`administration of their corresponding rapid- or long-acting
`insulin analogs and premixed insulin analog preparations
`from the devices (Table 1). Insulin manufacturers have made
`improvements to their first marketed pen devices and are
`now introducing their next generation of devices by making
`design modifications that are intended to improve the ease
`of use and safety and continue to positively impact adher(cid:173)
`ence to insulin.
`
`New-generation pen devices:
`product improvements
`Compared with the original FlexPen® (FP) (Novo Nordisk)
`design, the NGFP device has product modifications pro(cid:173)
`ducing a lower injection force, improved accuracy of dose
`delivery, and an easier pen needle interface requiring a
`single-luer lock type of twist to secure a NovoTwist® (Novo
`Nordisk) needle to the pen. These features were implemented
`to enhance convenience and ease of use. To improve patient
`safety, the NGFP imitated the color coding of the pen injec(cid:173)
`tion button found in the original FP, but the design has been
`modified to continue the color coding throughout the entire
`pen body (Figure 1). The color coding assigned to labeling
`and packaging ofinsulin aspart (NovoRapid®; Novo Nordisk)
`is orange, insulin detemir (Levemir®; Novo Nordisk) is green,
`
`and insulin aspart protamine/aspart 70/30 mix is blue with
`a clear cartridge.
`To enhance the ease of use, compared with the
`original durable OptiClik® (OC) pen (sanofi-aventis), the
`SoloSTAR® (SS) (sanofi-aventis) pen has been modified to
`a prefilled, disposable pen device (Figure 2). The OC and
`SS are the only pens that allow a maximum dose admin(cid:173)
`istration of 80 U. During development of the SS pens, the
`manufacturers wanted to maintain the ability to allow the
`maximum insulin dose, but retain a manageable "thumb
`reach" distance, defined as the dial extension distance from
`holding the pen in one hand to extending the thumb, and
`low injection force. 34 Compared with older-generation pre(cid:173)
`filled pens marketed at the time, the SS pen had the lowest
`mean injection force 35 and was preferred by patients with
`diabetes. 36 These changes were implemented to enhance
`convenience and ease of use. If a patient wants to mini(cid:173)
`mize the number of injections required for high doses that
`exceed 60 U but are less than 80 U, SS pen may be the ideal
`disposable pen device.
`In 2006, the Institute for Safe Medication Practices
`(ISMP) reported that the digital display for the insulin dose,
`which is near the dial used to set the dose on the OC pen for
`the injection of insulin glargine and insulin glulisine, had the
`potential for dosing errors and patient harm if the pen was
`oriented in the wrong direction. For example, if a left-handed
`practitioner or patient held the pen upside down, with the
`needle to the right, away from the hand, a dose that is actually
`52 U may appear as 25 U. ISMP believed that the design of the
`pen was potentially dangerous and could lead to a significant
`overdose or a subtherapeutic dose of insulin, and thus ISMP
`did not recommend clinical use of the device until safety
`issues were resolved. 37 Therefore, the SS pen was designed
`without the digital display. Additional improvements were
`
`Table I Prefilled disposable insulin pen devices available in the United States
`
`Manufacturer Pen
`devices
`
`Insulin
`aspart
`
`Insulin aspart
`protamine/
`aspart 70/30 mix
`
`Insulin
`detemir
`
`Insulin
`glulisine
`
`Insulin
`glargine
`
`Insulin
`lispro
`
`Insulin lispro
`protamine/lispro
`75/25 and
`50/50 mix
`
`Delivery
`range
`(units)
`
`✓
`
`✓
`
`✓
`
`✓
`
`✓
`
`✓
`
`Novo Nordisk
`
`sanofi-aventis
`Eli Lilly and
`Company
`
`FlexPen'
`Next
`Generation
`FlexPen
`SoloSTAR
`Humalog
`pen
`
`KwikPen
`
`✓
`
`✓
`
`✓
`
`✓
`
`✓
`
`✓
`
`1-60
`1-60
`
`1-80
`1-60
`
`1-60
`
`'Currently Novo Nordisk manufactures only the Next Generation FlexPen; however, it is possible that both the original FlexPen may still be available in some areas
`(depending on use).
`
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`I
`I I
`"Ill ii
`
`I
`ii
`
`I
`I
`~ il
`
`Levemir-• -
`_flex Pen!,
`
`0 _ .._
`'
`
`.,
`
`I I
`l!:
`;::
`
`I
`l!
`
`I
`ii
`
`I
`8 ~
`
`~ ),
`
`-
`
`N0v0Ra id•
`FlexPen
`
`Figure I View of FlexPen Levemir and FlexPen NovoRapid (left) and Next Generation FlexPen Levemir and Next Generation FlexPen NovoRapid (right).
`
`made utilizing a different coloring scheme of pen labeling
`to help distinguish between rapid- and long-acting insulin
`analogs. The rapid-acting analog, insulin glulisine, is dark
`navy blue, and the long-acting analog, insulin glargine, is
`gray. These color schemes were validated in studies includ(cid:173)
`ing patients with poor visual acuity or color blindness. 34
`An additional change to help differentiate between insulin
`glargine and glulisine is a raised ring on the dose button of
`the insulin glulisine pen to assist with tactile differentiation
`of the two insulin analogs. These design changes to the SS
`pen were implemented to improve patient safety.
`To enhance the ease of use, compared with the original
`Humalog®/Humulin® pen (HP) (Eli Lilly and Company), the
`KwikPen® (KP) (Eli Lilly and Company) device was modi(cid:173)
`fied to simplify dialing doses (Figure 3). The HP required
`the user to line up an arrow in the dosing window and pull
`out the dose knob to perform the priming step until a dia(cid:173)
`mond appeared. After the pen was properly primed, the user
`lined up the arrow in the dosing window again and had to
`pull out the dose knob to set the insulin dose. These steps
`were quite cumbersome and often led to poor satisfaction
`in comparison with other insulin pen devices. 36 Similar to
`the other new-generation insulin pens, now the KP only
`requires dialing the dose, which improves the convenience
`and ease of use. The KP is the shortest new-generation
`
`prefilled pen. Hence, the HP and KP devices have the shortest
`"thumb reach" distance overall. 35
`38 This device may be an
`•
`ideal choice for a patient with dexterity issues. The KP has
`been modified to have a lower injection force and is color
`coded to distinguish between rapid and long-acting analog
`mixes. The rapid-acting insulin lispro is burgundy, lispro
`protamine/lispro 75/25 mix is yellow, and lispro protamine/
`lispro 50/50 mix is red. Patients who are pen naive prefer
`the KP over vials and syringes and FP possibly due to these
`design modifications. 39
`Notably, Novo Nordisk and Eli Lilly and Company no
`longer manufacture human insulin in their new generation
`of disposable pen devices. The regular or Neutral protamine
`hagedom (NPH) human insulin alone or combined mixes
`were provided in disposable insulin pen models of the dis(cid:173)
`continued lnnoLet® (Novo Nordisk, or Princeton, New Jersey,
`USA) and Humulin pens. The AACE/ ACE guidelines do not
`recommend the use of short-acting regular human insulin or
`intermediate-acting NPH, if possible, for patients with type
`2 diabetes. II This recommendation is due to human insulin
`preparations' unpredictable time course, inability to mimic
`
`~~-----~@
`
`-
`-
`NI....,.,__.
`
`11 ·
`, -
`
`Figure 2 View of OptiClik (top) and SoloSTAR (bottom) pens.
`
`Figure 3 View of Humalog pen (top) and KwikPen (bottom).
`
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`Next generation of insulin pen devices
`
`the normal physiologic profile, and increased risk of hypogly(cid:173)
`cemia. 11 Similarly, the ADA standards recommend the use of
`rapid- and long-acting insulin analogs for patients with type 1
`diabetes since they are associated with less hypoglycemia and
`similar HbA1c lowering compared with human insulin.9.4°·41
`The ADA/EASD consensus statement and algorithm for
`patients with type 2 diabetes recognizes the use of insulin
`analogs results in lower risk of hypoglycemia. However, their
`recommendations include use of either intermediate- or long(cid:173)
`acting basal insulin and use of either short- or rapid-acting
`prandial insulin. Interestingly, the algorithm omits inclusion
`of short-acting human insulin for prandial coverage. Despite
`their recognition of insulin analogs in reducing the risk of
`hypoglycemia compared with human insulin, they do not
`conclude the analogs lower the HbA1c value more effectively
`than the human insulin. 10 Therefore, it can only be assumed
`that ceasing the production of human insulin preparations
`in prefilled pen devices was done in response to consensus
`statements discouraging their use and the shift toward the
`use of insulin analogs.
`
`Dose accuracy
`The accuracy of an insulin delivery system is of utmost
`importance in avoiding diabetes-related complications due to
`either hyperglycemia or hypoglycemia. The new-generation
`insulin pens available today have been shown to be exceed(cid:173)
`ingly accurate.
`Dosing accuracy for insulin pens is based on the regula(cid:173)
`tions set by the International Organization for Standardization
`(ISO). To define positive accuracy for insulin pen-injectors
`for medical use, the ISO standard allows for a deviation
`within 1 U of insulin when administering 20 U or less and no
`greater than 5% deviation for doses greater than 20 U.42
`Only three studies have evaluated the NGFP compared
`with the original FP or other new-generation pens.43
`5 The
`--4
`first study aimed to compare NGFP with FP using a total of
`180 delivered doses.43 It was found that neither of the pens
`delivered any doses outside the predefined ISO limits when
`tested at 1, 30, or 60 U. The NGFP was more accurate than
`FP atdelivering30 U (P < 0.05) and 60 Ubasedon the mean
`absolute deviation from the set doses. In addition, NGFP was
`more precise than FP at delivering 30 and 60 U (P < 0.05).
`Both NGFP and FP had similar accuracy in delivering 1 U
`ofinsulin.43
`The second study compared NGFP with SS using a total
`of66 delivered doses.44 NGFP was outside the predefined ISO
`limits for 1 dose (0.2%) at 10 U and 1 dose (0.6%) at 30 U.
`The SS pen was outside the predefined ISO limits for 2 doses
`
`(0.4%) at 10 U and 3 doses (1.8%) at 30 U. The NGFP was
`more accurate than SS at delivering 10 U, with an absolute
`deviationof 1.63% ± 0.84% and2.l l % ± 0.92%, respectively
`(P < 0.001). This was also seen at a dose of30 U, with an
`absolute deviation of 1.23% ± 0.76% and 1.54% ± 0.84%,
`respectively (P < 0.05).44
`The most comprehensive study to evaluate the accuracy
`of NGFP compared with the newer generation of prefilled,
`disposable insulin pens was conducted by Krzywon et al.45
`The accuracy of NGFP, FP, SS, and KP was evaluated at
`doses of 1, 10, 30, 40, and 60 U and SS alone at 80 U using
`a total of 1,260 delivered doses. All pens at every dose tested
`were within the predefined ISO limits, and absolute average
`deviation ofall insulin pens ranged between 0.09 and 0.81 U.
`The authors concluded that the dosing accuracy was excellent
`for all pens studied and there was no significant difference
`from one pen device to the next.45
`The aforementioned studies were conducted in controlled
`laboratory settings, by trained professionals. However, when
`patients with or without diabetes, not dependent on insulin
`therapy, and naive to pen device were instructed on FP and SS
`pen use, the results demonstrated that the participants were
`able to administer a 20 U dose accurately.46 A small amount
`of dosing errors occurred in this study, with less than 2%
`of doses from each pen delivered below the predefined ISO
`limits.46 Another study in patients with diabetes, with approxi(cid:173)
`mately 90% of patients reporting pen device experience,
`found that patients were able to accurately administer six
`different doses (range, 5-80 U) with the SS pen, with no mea(cid:173)
`surements outside the predefined ISO limits. 47 An interesting
`study evaluated the accuracy of administering injections with
`the SS pen under varying temperature conditions from 5°C
`to 40°C and found the SS pen dosed accurately according to
`ISO standards at 1, 40, and 80 U. 35
`All new-generation pens have excellent accuracy in a
`controlled laboratory setting45 and only the SS can claim its
`pen to be accurate under varying temperatures.35 No accuracy
`studies have been conducted using the NGFP or KP in
`patients with diabetes; however, studies show that patients
`can dose FP and SS accurately. Further studies are needed
`to determine if patient administration of insulin using other
`new-generation pens impacts their accuracy and/or clinical
`patient outcomes.
`
`Injection force
`Insulin pens have grown in favor amongst providers and
`patients for a number of reasons. One of the identified
`qualities affecting patient preference is the amount of force
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`necessary to inject insulin through a pen device (injection
`force ).48 It has been established that pen devices require less
`injection force to deliver an equivalent dose, in general, than
`insulin syringes because of the wide bore associated with
`the pen needles. 49 Injection force, measured in Newtons (N),
`is determined in clinical trials by mounting pens ready to
`deliver a set dose on a testing machine that is programmed
`to deliver the dose and depress the push button at a set speed.
`Injections are made into cushions designed to mimic adipose
`tissue in climate-controlled laboratories. 48 Injection force has
`been frequently validated with older insulin pens, and design
`modifications have been made that enable pens to require
`less injection force while maintaining accuracy. After the
`emergence of the SS insulin pen, a study comparing it with
`FP found that the FP required higher injection forces than SS
`to deliver equal amounts of insulin for numerous doses and
`speeds. 35 This validated survey data describing complaints
`from patients with manual dexterity problems in depressing
`the push button to deliver insulin doses with the FP.43•50
`Thus, the NGFP was developed with a goal of requir(cid:173)
`ing lower injection force for dose delivery to improve user
`satisfaction.48 Three studies have evaluated the injection
`force ofNGFP compared with FP and other new-generation
`pens.43.48.49
`A study comparing the injection force ofNGFP with its
`predecessor, the FP, evaluated 20 pens using a standard flow
`rate of 10 U/s with 1 standard needle size (30G). NGFP was
`superior to FP with a relative reduction in injection force
`by 29.8%.43
`The injection force of NGFP was also compared with
`SS in delivering a dose of60 U at3 constant injection speeds
`of 4, 6, and 8 mm/s. 49 Twenty-four pens were tested using
`the following combinations of pens and needle sizes: NGFP
`with a 32G needle, SS with a 32G needle, and SS with a 3 lG
`needle. Various injection speeds were evaluated to mimic the
`possible range of injection speeds at which a patient may
`perform self-administration of insulin, and two needle sizes
`were used to examine any influence of injection force from
`needle bore size. The NGFP with a 32G needle had signifi(cid:173)
`cantly lower mean injection force compared with SS with
`either a 32G or 31G needle (P < 0.0001). Over the range
`of injection speeds, the NGFP with 32G needle reduced the
`injection force by 18%-28% compared with the SS with
`32G needle and by 36%--45% compared with the SS with
`3 lG needle. Therefore, using a smaller-gauge (32G) needle
`reduced the injection force to the greatest extent and that
`increasing the injection speed required higher injection force
`using either pens.49
`
`The most comprehensive study to evaluate the injection
`force ofNGFP compared with the newer generation ofpre(cid:173)
`filled, disposable insulin pens was conducted by Asakura
`et al.48 A head-to-head comparison of NGFP, SS, and KP
`was conducted at 3 constant injection speeds with 2 needle
`sizes of 31 G and 32G. The set injection doses for this study
`were 20 U instead of 60 U doses delivered in the Rissler
`et al49 study. Results demonstrated similar findings showing
`superiority of NGFP over SS in requiring lower injection
`force by 12%-25% at both needle sizes and at all injection
`speeds (Tables 2 and 3). NGFP was also superior to KP
`requiring lower injection force by 35%--41 % at both needle
`sizes and at all injection speeds (Tables 2 and 3). This study
`also confirmed that increasing the injection speed and gauge
`size of the needle significantly increased the injection force
`with all pens tested.48
`Head-to-head comparisons of current insulin pen devices
`demonstrate clear superiority ofNGFP to either SS or KP in
`requiring lower injection force needed to deliver a set dose
`ofinsulin.48.49 Because injection force has been described in
`patient survey data as a factor affecting satisfaction, it may
`be inferred that improving this could result in improved
`patient preference. Further studies are needed to determine
`if improved injection force with the NGFP improves clinical
`patient outcomes.
`
`Patient-focused perspectives
`Patient perceptions of injection force, ease of use, product
`identification, and handling can influence pen preference.
`Only 2 studies evaluating patient preference ofNGFP com(cid:173)
`pared with other pen devices have been completed. Patient
`perceptions of injection force were evaluated in the study
`by Pfutzner et al.43 Fifty patients with type 2 diabetes who
`had insulin pen experience were asked to complete a survey
`after delivering 1 dose each of 20, 40, and 60 U with NGFP
`and FP devices into an injection pillow in a randomized
`
`Table 2 Comparative injection force (N) at various speeds using
`a 31 G pen needle and NGFP, SS, and KP insulin pens48
`
`Pen device
`
`Speeds of injection (mm/s)
`
`3.3
`
`5
`
`8.3
`
`Next Generation FlexPen'·'
`SoloSTAR'
`
`KwikPen'
`
`8.1 ±0.7
`9.2 ± 0.5
`12.5 ± 1.6
`
`10.7± 1.4
`13.3 ± 0.8
`
`15.6 ± 0.9
`20.7 ± 2.4
`
`16.9± 1.2
`
`24.5 ± 2.6
`
`Note: All values are given as mean± SD,
`Abbreviations: N, Newton; NGFP, Next Generation FlexPen; SS, SoloSTAR;
`KP, KwikPen,
`'P < 0.05 for all comparisons made between NGFP and KP; 'P < 0.05 for all
`comparisons made between NGFP and SS,
`
`46
`
`submit your manuscript I www.dovepress.com
`Dovepres,:;
`
`Medical Devices: Evidence and Research 20 I 0:3
`
`Sanofi Exhibit 2120.006
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Dovepress
`
`Next generation of insulin pen devices
`
`Next Generation FlexPen'·'
`SoloSTAR'
`KwikPen'
`
`the 20 U (91 % vs 67% respectively, P < 0.001), 40 U (72%
`Table 3 Comparative injection force (N) at various speeds using
`vs 22% respectively, p < 0.001), and 60 u doses of insulin
`a 32G pen needle and NGFP, SS, and KP insulin pens48
`(38% vs 2% respectively, P < 0.001). More patients rated
`Pen device
`Speeds of injection (mm/s)
`the NGFP as "very easy" for overall use (P < 0.001), the
`5
`3.3
`8.3
`12.7 ± 0.5 most convenient pen (P < 0.00 I), and the simplest pen to
`5.7 ± 0.4
`8.2 ± 0.7
`6.7 ± 0.3
`I 0.4 ± 2.1
`16.3 ± I. I
`use (P < 0.001) compared with the FP. Patients were more
`9.1 ± 1.3
`13.1 ± 0.8
`21.6 ± 2.0
`confident that the full dose of insulin was delivered using
`the NGFP than with the FP (P < 0.001). Accordingly, 83%
`of patients perceived that the NGFP was the safest to oper(cid:173)
`ate. Overwhelmingly more patients preferred the NGFP
`compared with the FP (95% vs 5% respectively, P < 0.00 I)
`if they had to use the pen on a daily basis. 50
`Unfortunately, there are no studies currently available
`that examine patient preference of NGFP compared with
`other new-generation prefilled pens, and further research is
`needed in this area.
`
`Note: All values are given as mean± SD,
`Abbreviations: N, Newton; NGFP, Next Generation FlexPen; SS, SoloSTAR; KP,
`KwikPen,
`'P < 0.05 for all comparisons made between NGFP and KP; 'P < 0.05 for all
`comparisons made between NGFP and SS,
`
`order. Significantly more patients rated the injection force as
`"good" or "very good" using the NGFP at all 3 tested doses
`of 20, 40, and 60 U compared with the FP (80%, 72%, and
`38% vs 48%, 32%, and 20%, respectively, P < 0.0001). In
`addition, significantly more patients found the NGFP to be
`"simpler and more comfortable to use" than the FP (76% vs
`24%, respectively, P = 0.0002).43
`Sixty-four patients with type 1 or type 2 diabetes were
`emolled in a survey study to evaluate the visual appearance
`and perceptions ofNGFP compared with FP. 50 All patients
`were shown the range of FPs and NGFPs prefilled with
`three types of analogs (insulin aspart, insulin detemir, or
`insulin aspart protamine/aspart mix) along with their packag(cid:173)
`ing and asked to answer nine survey questions corresponding
`to their ability to identify the type of insulin. Patients were
`also asked to attach a NovoFine® (Novo Nordisk) needle on
`the FP and NGFP, then attach a Novo Twist needle on NGFP
`(NovoTwist is not compatible with FP), and answer three
`survey questions about the ease of attaching the needle.
`Finally, the patients were asked to inject 1 dose of 20, 40,
`and 60 U of insulin detemir into an injection pillow and
`were randomized to inject either FP followed by NGFP or
`NGFP followed by FP. They then answered 22 additional
`survey questions relating to the injection force and device
`handling. Significantly more patients found the insulin ana(cid:173)
`log type with the NGFP was easier to identify with regard to
`labeling (P < 0.001), packaging (P < 0.001), and cartridge
`(P < 0.001) compared with the FP. Significantly more
`patients rated that attaching the Novo Twist needle on NGFP
`was easier than attaching a NovoFine needle on either FP or
`NGFP (P < 0.00 I), and significantly more patients preferred
`using the NovoTwist needle over the NovoFine needle with
`the NGFP (77% vs 6% respectively, P < 0.001). The NGFP
`was easier to inject than FP at all 3 doses of 20, 40, and 60
`U of insulin (P < 0.001). In addition, significantly more
`patients believed it was "easy" or "very easy" to push down
`the injection button on the NGFP compared with the FP for
`
`Health-care providers' perspectives
`Studies have shown that health-care providers' attitudes
`toward insulin pens are powerful predictors of pen u