For reprint orders, please contact:
`reprints@future-drugs.com
`
`I
`EXPERT
`I REVIEWS
`
`Insulin glargine and glulisine
`SoloSTAR® pens for the
`treatment of diabetes
`
`Expert Rev. Med. Devices 5(2), 113-123 (2008)
`
`Samita Garg,
`William Charles Kelly
`and Satish Gargt
`t Author for correspondence
`Barbara Davis Center for
`Childhood Diabetes, University
`of Colorado at Denver and
`Health Sciences Center,
`1775 North Ursula, Room
`M20-1323, Aurora,
`CO 80045, USA
`Tel.: +1 303 724 6713 I 6770
`Fax: + 1 303 724 6784
`satish.garg@uchsc.edu
`
`Insulin is an effective medication for lowering hemoglobin A 1c values and can be used for both
`basal and prandial coverage of hyperglycemia in Type 1 and Type 2 diabetes. Despite its
`effectiveness there is still reluctance by patients and physicians to add insulin into the
`treatment regimen for Type 2 diabetes when needed. One of the key barriers to initiating
`insulin therapy is the method of delivery. Insulin delivery pens are continually developed as a
`means to improve upon the vial and syringe and to make it easier for patients to incorporate
`insulin therapy into their lifestyles. The SoloSTAR® pen (Sanofi-Aventis, Paris, France) was
`developed to make insulin delivery easier and to help eliminate barriers to the initiation of
`insulin therapy. In this article, we discuss the features and characteristics of SoloSTAR that
`overcome existing unmet needs.
`
`KEYWORDS: diabetes • hypoglycemia • injection force • insulin • insulin dose • SoloSTAR® pen
`
`The increasing prevalence of diabetes in most
`populations has had a major impact on healthcare
`systems worldwide [I]. Global projections for dia(cid:173)
`betes are increasing at an alarming rate, with the
`total number of people with diabetes projected to
`rise from 171 million in 2000 to 366 million in
`2030 [2]. In the USA for example, crude preva(cid:173)
`lence in 1999-2002 of total diabetes was 6.3%
`(19.3 million, 2002 US population), consisting
`of 3.5% diagnosed and 2.8% undiagnosed [3].
`Currently, the prevalence of diabetes in the USA
`is approximately 7.0% (21 million people with
`diagnosed or undiagnosed diabetes) [IOI]. This
`rise in prevalence of diabetes is closely associated
`with an increasing prevalence of obesity across
`the globe (FIGURE I) [2,4,5,102,103].
`In healthy individuals, pancreatic ~ cells
`respond to changes in blood glucose by secreting
`insulin and increasing insulin synthesis. Diabe(cid:173)
`tes is characterized by progressive ~-cell failure,
`resulting in a decline in insulin secretion and
`hyperglycemia [6]. The therapeutic approach to
`diabetes commonly involves intensive insulin
`management (basal/bolus) to maintain normal
`glycemic levels, by replacing insulin as close to
`the physiological insulin secretion profile of
`healthy individuals as possible [6]. For patients
`with Type 1 or Type 2 diabetes, maintaining
`glycemic levels as close to the nondiabetic range
`
`as possible has been demonstrated to reduce the
`risk of developing diabetes-specific complica(cid:173)
`tions, including retinopathy, nephropathy and
`neuropathy [7-9]. Insulin is the most effective
`diabetes medication in lowering glycemia and,
`when used in adequate doses, can decrease any
`level of elevated hemoglobin (Hb)A1c [IO].
`The recently published American Diabetes
`Association (ADA) and European Association
`for the Study of Diabetes (EASD) consensus
`statement guidelines recommend the early addi(cid:173)
`tion of insulin therapy in patients who do not
`meet target goals (Box I) [IO].
`Previous data from intermittent self-monitor(cid:173)
`ing of blood glucose (SMBG) in Type 2 diabe(cid:173)
`tes indicated higher contributions to elevated
`HbA1c from fasting blood glucoses at higher
`levels (>9%), and significantly higher contribu(cid:173)
`tions to rise in HbA1c from postprandial blood
`glucose (PPBG) at lower HbA1c levels (<8%).
`More recent data from continuous glucose
`monitoring (CGM) systems indicate an inabil(cid:173)
`ity for patients to achieve normal fasting blood
`glucose, even amongst those with near normal
`HbA1c values (i.e., <6%; FrGuRE 2) [II]. In addi(cid:173)
`tion, a significant contribution to rises in HbA1c
`levels also comes from post-dinner elevations in
`blood glucose at higher HbA1c values, which in
`turn might contribute to higher fasting blood
`
`www.future-drugs.com
`
`10.2217/17434440.5.2. l 13
`
`© 2008 Future Drugs Ltd
`
`ISSN 1743-4440
`
`113
`
`Sanofi Exhibit 2128.001
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Garg, Kelly & Garg
`
`glucose levels. Glucose variability, in part due to postprandial
`hyperglycemia, has been demonstrated to correlate with oxida(cid:173)
`tive stress markers [12]. Recent data from CGM also indicates
`loss of postprandial glucose control preceding fasting hyper(cid:173)
`glycemia with increasing duration of diabetes (FIGURE 3)
`[13].
`Thus, early focus on postprandial hyperglycemia may need to
`be considered (across all HbA1c levels), especially when
`attempting to achieve normal fasting glucose.
`
`Overview of the market: the impact of glucose control
`Tight blood glucose control has been shown to prevent, or delay,
`the development of diabetes-related microvascular and macro(cid:173)
`vascular complications. An epidemiologic analysis of data from
`the United Kingdom Prospective Diabetes Study (UKPDS)
`patient population demonstrated that for each 1 % reduction in
`mean HbA1c, there was a 37% reduction in risk for microvascu(cid:173)
`lar complications alongside a 14% reduction in macrovascular
`complications [14]. Similar data from the Diabetes Control and
`Complication Trial (DCCT) in Type 1 diabetes shows the bene(cid:173)
`fits of intensive insulin therapy resulting in significant reductions
`in both microvascular and macrovascular complications. Despite
`all of the available data, only approximately 30% of patients
`with Type 2 diabetes are on some sort of insulin treatment in the
`USA [15,IOl]. While this is, in part, due to some patients being
`well controlled with lifestyle management and oral antidiabetic
`drugs (OADs), patient and physician reluctance to start insulin
`therapy is also thought to be a contributor [16,17]. In order to
`achieve and maintain tight blood glucose control, insulin use in
`patients diagnosed with diabetes should be an integral compo(cid:173)
`nent of their management strategy. Most patients with Type 1
`diabetes, and increasingly more patients with Type 2 diabetes,
`use two different types of insulins to provide basal and prandial
`coverage for hyperglycemia; however, many still use premixed
`formulations. Indeed, it has been estimated that premixed insu(cid:173)
`lins account for 22% of the total volume of insulin sold world(cid:173)
`wide [15]. Premixed insulin usually contains a rapid-acting insu(cid:173)
`lin and an intermediate-acting insulin with an aim to mimic
`endogenous insulin secretion patterns [18]. However, the use of
`premixed insulins is declining as the use of basal and prandial
`insulin increases [15], which is in line with the ADA/EASD con(cid:173)
`sensus guidelines that only recommend the use of premixed
`insulin after a patient is stabilized on insulin and if their mix
`ratio is close to one of the available premixed insulin ratios [IO].
`A basal insulin supply, such as insulin glargine (Lantus®;
`Sanofi-Aventis, Paris, France), which has a relatively constant
`and peakless delivery over 24 h [19], can provide the steady,
`low-level insulin that is constantly present in the circulation to
`cover preprandial and overnight fasting periods. This is sup(cid:173)
`plemented with multiple preprandial injections of regular
`human insulin or rapid-acting insulin analogs, such as insulin
`glulisine (Apidra®; Sanofi-Aventis, Paris, France), which aim
`to normalize and maintain good glycemic control, reduced
`glucose variability and better HbA1c values.
`
`Box 1. Summary of the American Diabetes
`Association/European Association for the Study of
`Diabetes consensus algorithm for the
`management of Type 2 diabetes.
`
`• Step 1. Lifestyle modification and meformin
`- Lifestyle modification and metformin at diagnosis
`- Titrate metformin to maximum effective dose over
`1-2 months
`- Check HbA1 c every 3 months until <7%, and every 6 months
`thereafter
`• Step 2. Intensify therapy
`- Add further medications within 2-3 months if HbA1c remains
`>7%:
`- Insulin
`- Sulfonylureas
`- Glitazones
`- Choice of agent depends on HbA 1c level
`- Insulin is recommended if HbA1c remains >8.5%
`
`HbA1i Hemoglobin A1c
`From [IO]
`
`Insulin administration
`An important aspect of diabetes care and glycemic control is
`the delivery of insulin. The method by which insulin is
`administered has been shown to impact patient acceptability
`of insulin therapy and quality of life, and may serve as a key
`barrier to insulin initiation [20]. Previously, the predominant
`route of insulin administration for patients with diabetes was
`the syringe and vial. However, this method of administration
`has many disadvantages, including fear of injections [21,22],
`poor dose accuracy [23], lack of social acceptance [24], inaccu(cid:173)
`racy when self-mixing insulins [25] and possibly changing
`pharmacokinetics of both long- and rapid-acting insulins.
`While still an injection device, insulin pens help to overcome
`many of these barriers.
`Since the introduction of the first insulin pen, NovoPen®
`(Novo Nordisk, AS Bagsvaerd, Denmark) in 1985, insulin pens
`have continued to improve in design and usability features and
`address many of the barriers associated with administering
`insulin using a syringe and vial. Precision and accurate dosing is
`crucial for patients with diabetes, particularly for those on com(cid:173)
`plex treatment regimens. Previous studies have indicated that
`up to 80% of people with diabetes incorrectly administer their
`insulin when using a syringe [26,27]. Santiago et al. conducted a
`precision, accuracy and durability study of an insulin pen
`(NovoPen) that tested the pen at three preset doses under stress
`conditions (multiple thermal and vibration stress tests), which
`were intended to replicate daily use by patients [28]. The accu(cid:173)
`racy of the insulin pen was within 1 % of the preset dose after
`the stress and endurance tests, and the precision of the pen
`devices were likewise high (delivery-dose relative error was at
`most 0.8% of the intended dose) after thermal stress, vibration
`stress, free-fall testing or 5-year endurance testing.
`
`114
`
`Expert Rev. Med Devices 5(2), (2008)
`
`Sanofi Exhibit 2128.002
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`SoloSTAR® pen
`
`Device Profile
`
`--
`
`-
`
`-
`
`-
`
`-
`
`IB
`
`Male
`Female
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`w
`w
`0
`
`-a.
`<I: -,
`
`a:
`u..
`<I:
`
`I
`
`<I: w
`
`(/)
`
`®
`
`-
`
`---
`
`-
`
`-
`
`- - - - - - -
`
`2025: 333 milliom
`Increase 72%
`
`®
`
`Figure 1. (A) Global projections for the diabetes epidemic; 2003-2025 (millions) and (B) increasing prevalence of obesity.
`AFR: Africa; CAV: China and Vietnam; CEE: Central and Eastern Europe; JAPI: Japan, Australia and Pacific Islands; LAC: Latin
`America/Caribbean; ME: Middle East; NAC: North America/Cuba; SEA: South-East Asia; WE: Western Europe.
`Part (A): Reprinted with permission from Macmillan Publishers Ltd [lJ.
`Part (B): Information from [2,4,5,101,102].
`
`Korytkowski et al. demonstrated
`that 82% of patients
`(n = 105) indicated greater confidence with dose setting using
`FlexPen ® (Novo Nordisk) versus 11 % of patients who preferred
`the syringe and vial method [29]. In addition, it was also demon(cid:173)
`strated that 73% of patients reported more confidence in the
`accuracy of the dose delivered with FlexPen compared with 19%
`of patients using a syringe and vial. Insulin pens are now the pre(cid:173)
`dominant form of insulin administration in many countries,
`accounting for over 50% of insulin use worldwide, especially in
`Europe and Asia. In the USA uptake of insulin pens is steadily
`increasing, but it lags behind that seen in Europe and Asia [30].
`
`Unmet needs
`While insulin pen devices have made it easier for users to adminis(cid:173)
`ter insulin, there remains scope for further development of insulin
`pens in response to unmet patient needs in relation to the develop(cid:173)
`ment ofSoloSTAR® (Sanofi-Aventis). Type 2 diabetes is character(cid:173)
`ized by obesity and insulin resistance and, coupled with the pro(cid:173)
`gressive nature of the disease, increasing doses of insulin are
`required over time. Accordingly, many patients need to administer
`doses of insulin exceeding 60 units, the maximum dose of many
`insulin pens, thus necessitating multiple injections. Limited joint
`mobility of the hand, commonly referred to as cheiroarthropathy,
`is frequently observed in patients with diabetes, particularly elderly
`patients, and is characterized by low grip strength and/or limited
`dexterity [31,32], which can impede the efficient administration of
`insulin, in such patients, using pen devices.
`Problems with visual acuity are common in patients with dia(cid:173)
`betes and occur primarily as a result of diabetic retinopathy [33,34].
`People with diabetes, particularly those with Type 1 diabetes,
`often use more than one type of insulin to manage basal and
`
`prandial insulin requirements, which can be provided by insulin
`glargine and insulin glulisine, respectively. The doses and
`pharmacodynamics of prandial and basal insulins differ; accord(cid:173)
`ingly, it is important that the delivery devices are sufficiently dif(cid:173)
`ferentiated to ensure low risk of users confusing the two insulin
`formulations. Patients with visual problems also place a greater
`reliance on non-visual modes when selecting dose. Dose setting
`and injections can be aided by audible recognition (the click
`sound), which occurs when a dose is dialed [35].
`
`The SoloSTAR pen
`An overview of the SoloSTAR pen & how it works
`The continual evolution of insulin devices has led to the Solo(cid:173)
`STAR pen, which is a prefilled, disposable insulin pen device
`designed for use once or several times daily. It is available for
`the administration of basal insulin glargine and prandial insulin
`glulisine for patients with either Type 1 or Type 2 diabetes,
`with two colors to differentiate the two pen devices. The insu(cid:173)
`lin glargine SoloSTAR pen is approved for use in both the EU
`and the USA, whilst the insulin glulisine pen is approved for
`use in the EU.
`The SoloSTAR pen is very easy to use. The user checks that they
`have the correct insulin pen. The user then attaches a new pen
`needle and performs a safety shot of 2 units to verify that the nee(cid:173)
`dle is working. The user then dials their dose and delivers the dose
`subcutaneously by pressing down on the injection button. The
`user will then remove the pen afrer counting to ten at the end of
`the injection to ensure the full dose is delivered. The needle is then
`taken off the pen and discarded safely. The pen cap is replaced
`and the pen can be stored until the next use. New, unopened
`
`www.future-drugs.com
`
`115
`
`Sanofi Exhibit 2128.003
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Garg, Kelly & Garg
`
`® -
`
`200
`
`150
`
`Modal day by baseline HbA10 DISPLAY (periods 2 and 3)
`
`®
`
`350
`
`300
`
`250
`
`200
`
`150
`
`Modal day by baseline HbA10 BLINDED (period 1)
`32 35 0 - t - - - - - - - - - - - - - - - - - - - - - - -=
`Cl
`,§,
`g> 300
`'6
`m 250
`0 rn
`C:
`GJ rn
`GJ rn
`0
`tJ
`::::J c,
`C: ca
`~ 100 +--------------------_____,, 100 + -~~~ -~ -~~ -~ -~~~~ -~ -~___ __ , ,
`
`12 am
`
`6 am
`
`Noon
`TI~~~
`
`6 pm
`
`12 pm
`
`12 am
`
`6 am
`
`Noon
`TI~~~
`
`6 pm
`
`12 pm
`
`Baseline HbA10
`.$ 6.0% (n = 5)
`-
`8.1-9.0% (n = 1) -
`-
`6.1-7.0% (n = 1) -
`-
`
`9.1-10.0% (n = 7)
`7.1-8.0% ( = 33)
`>10.0% (n = 5)
`
`Figure 2. Modal day by baseline HbA1c while subjects were blinded (A) to continuous glucose data or while subjects were
`given real-time access to continuous glucose values (B), trend graphs and high/low alerts.
`Significant postpradial elevations in blood glucose levels were observed across all HbA1c levels in both periods.
`Copyright© 2006 American Diabetes Association. Reproduced from [Ill with permission from The American Diabetes Association.
`
`SoloSTAR pens should be kept in the refrigerator (2-8°C). Once
`opened, the SoloSTAR pen should be kept at room temperature
`for up to 28 days in accordance with storage condition recom(cid:173)
`mendations, which differ in the EU (recommendations being
`below 25°C) and US (being below 30°C).
`
`Evaluation of the SoloSTAR pen & responding to
`unmet needs
`The SoloSTAR pen builds upon the strengths of current
`devices while including additional features, which have been
`ergonomically tested in order to establish their usability and
`effectiveness. Testing included collection of anthropometric
`data in intended user populations in order to recommend
`the most suitable user dimensions of the pen and develop
`the strength and robustness of the SoloSTAR pen, which
`compliments its user population.
`
`Sensitivity & specificity
`During development of the SoloSTAR pen, human factors
`were also considered, which led to a short-dial extension
`design facilitating easier grip during injection and enabling
`the user to administer even the maximum insulin dose with
`ease. This is an essential feature of the SoloSTAR pen when
`taking into account cheiroarthropathy, which is a significant
`problem in some patients with diabetes [31 ,32], with estimates
`that up to 58% of patients with diabetes have limited joint
`mobility of the hand [36] and significantly lower-grip strength
`compared with healthy controls [37]. The Solo STAR pen has
`
`a maximum dose administration of 80 units, which exceeds
`the maximum dose of other available pens, except OptiClik
`(also 80 units), but including FlexPen and Lilly pen, which
`both administer a maximum of 60 units (TABLE I). With higher
`doses of insulin required in obese patients especially with
`Type 2 diabetes, this is an important feature of the SoloSTAR
`pen, as it enables higher dose users to minimize the number
`of injections required.
`Also, under varying temperature conditions, the SoloSTAR pen
`successfully passed dose accuracy testing, ensuring consistent and
`reliable insulin dose accuracy in a laboratory setting (TABLE 2) [38].
`Moreover, the measured dose accuracy of SoloSTAR, when
`used by patients in a clinical setting, was within the limits of
`the International Organisation for Standardisation dose accu(cid:173)
`racy standard [39]. This reassures patients that, when used cor(cid:173)
`rectly, the SoloSTAR pen will deliver the dialed dose, which
`facilitates the titration of insulin dose without an increased risk
`of hypoglycemia or hyperglycemia. Injection force testing was
`performed to measure the force and force characteristics
`required to dispense a known volume of insulin (40 units)
`within a 4-s time period (TABLE 3) [38]. Findings from these tests
`showed that the SoloSTAR pen's highly efficient drive mecha(cid:173)
`nism translates into a lower injection force than that of the
`Flexpen and Lilly pen [38].
`To facilitate the differentiation of the insulin glargine pen
`from the insulin glulisine pen and to avoid the mistaken
`administration of basal instead of prandial insulin, or vice
`versa, the SoloSTAR pen is manufactured in two different
`
`116
`
`Expert Rev. Med Devices 5(2), (2008)
`
`Sanofi Exhibit 2128.004
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Table 1. Features of the SoloSTAR®, FlexPen® and Lilly pen.
`
`SoloSTAR® pen
`
`SoloSTAR®
`(Sanofi-Aventis)
`
`FlexPen®
`(Novo Nordisk)
`
`80
`
`60
`
`Lilly pen
`(Eli Lilly and Company)
`
`60
`
`* Availability may vary.
`NPH: Neutral protamine Hagedorn.
`
`- Insulin glargine (LANTUS®)
`- Insulin glulisine (Apidra®)
`
`- Insulin detemir (Levemir®)
`- Insulin aspart (NovoLoi®)
`- NPH insulin (lnsulatard )
`- NovoMix® 30 (30% insulin aspart and 70% protaminated insulin aspart)
`
`- Insulin lispro (Humalo~®)
`- NPH insulin (Humulin )
`- Humalog Mix75/25™ (75% insulin lispro) protamine suspension,
`25% insulin lispro)
`- Humalog MixS0/50™ (50% insulin lispro protamine suspension,
`50% insulin lispro)
`
`colors: grey for insulin glargine and blue for insulin glulisine.
`This makes the SoloSTAR pen the first disposable insulin pen
`device to differentiate in pen body color.
`This feature was included after consultations and assistance
`from healthcare providers, who suggested it to further minimize
`any confusion between the two insulins, especially in patients
`with visual impairments (FIGURE 4). In addition, another difference
`between insulin glulisine and glargine SoloSTAR pens includes a
`tactile differentiation of a raised ring on the dose button of the
`insulin glulisine pen, and other differentiation features include
`different colors in the labels and packaging.
`
`Cost-effectiveness
`Results from a recent study demonstrated that, in patients with
`Type 2 diabetes treated in a managed care setting, conversion
`from insulin injection with a syringe and vial to administration
`with an insulin analog pen device was associated with significantly
`lower annual treatment costs (US$16,359 vs 14,769, respectively;
`p < 0.01) as a result of improved medication adherence, fewer
`hypoglycemic events and reduced emergency department and
`physician visits [40]. These reductions could be as a result of the
`increased accuracy in dosing and timing of injection when using
`the insulin pen, which leads to a lower risk of hypoglycemia.
`Medication adherence was significantly improved after conversion
`to the insulin pen device (from 62-69%; p < 0.01).
`A further potential cost saving for direct treatment could be
`made using pens when considering that insulin in vials is dis(cid:173)
`carded by physicians after 28 days as per US FDA guidelines.
`Accordingly, insulin pens could be more cost effective for chil(cid:173)
`dren and those taking small amounts of insulin. Since each insu(cid:173)
`lin pen only contains 300 units, there will be less wastage, main(cid:173)
`tainance of biological activity of insulin and greater likelihood
`to follow the FDA label in clinical practice.
`Recent results on the usability of the SoloSTAR pen reported
`by 65 healthcare professionals in clinical practice consider the
`SoloSTAR pen to be both easy to teach and easy to use for people
`
`with diabetes [41]. Of 65 healthcare professionals interviewed,
`most (n = 52; 80%) were able to spend less than 10 min train(cid:173)
`ing their patients to use SoloSTAR. This ease of use for both
`patients and healthcare professionals can translate into signifi(cid:173)
`cant cost savings in relation to the time and resources spent
`training users of the SoloSTAR pen.
`
`Use of the SoloSTAR pen in in-patient/hospital settings
`In an in-hospital setting, the accuracy of the dose delivered is a
`key factor when selecting an insulin delivery system. This is
`because lack of accuracy may increase the risk of hypo- or
`hyperglycemia, jeopardizing patient welfare and in turn increas(cid:173)
`ing diabetes-related treatment costs [38]. Used correctly, Solo(cid:173)
`STAR pens will accurately administer the dialed dose of insu(cid:173)
`lin, allowing reliable dose adjustment and minimizing the risk
`of resulting hypo- or hyperglycemia. In addition, color differ(cid:173)
`entiation of the insulin glargine and glulisine SoloSTAR pens
`reduces the potential for hospital staff to confuse the two
`devices [38]. Furthermore, due to the ease of use, the introduc(cid:173)
`tion of insulin therapy in the hospital setting is easier with
`SoloSTAR pens than with traditional syringes and vials and this
`may result in patients being more likely to continue insulin
`therapy when discharged from hospital [38].
`
`Clinical profile & post-marketing findings
`Haak et al. recently conducted a preference study across four
`countries
`(US, Germany, France and Japan)
`involving
`510 patients with Type 1 and Type 2 diabetes investigating the
`usability of the SoloSTAR pen, FlexPen and Lilly pen [42].
`Patients were assessed on their ability to correctly perform a
`number of tasks involved in using each pen (including getting
`started and removing the cap, attaching a needle, setting and
`delivering a safety dose and dialing and delivering a 40-unit
`dose) and their preference of pens. The assessed steps for the
`SoloSTAR pen and FlexPen devices were correctly completed
`by a similar proportion of patients: 94% for the SoloSTAR pen
`
`www.future-drugs.com
`
`117
`
`Sanofi Exhibit 2128.005
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Garg, Kelly & Garg
`
`Table 2. Dose accuracy of the SoloSTAR® pen
`device (insulin glargine) at dialed doses of 1, 40
`and 80 units at temperatures of 5°C, ambient
`temperature (18-28°() and at 40°C.
`
`Recommended
`range according to
`ISO standards
`
`Cool temperature
`(5°C)
`
`Ambient
`temperature
`(18-28°C)
`
`Hot temperature
`(40°C)
`
`0-2
`
`38-42
`
`76-84
`
`1.22 ± 0.18
`
`39.85 ± 0.28 79.75 ± 0.29
`
`1.09 ± 0.15
`
`39.92 ± 0.34 79.82 ± 0.28
`
`1.15 ± 0.11
`
`39.87 ± 0.11 79.73±0.14
`
`Results are means± standard deviation; 30 pens were used for each dose, with
`two replicates per pen.
`ISO: International Organisation for Standardization.
`
`and 90% for FlexPen; however, fewer patients correctly com(cid:173)
`pleted the same steps with the Lilly pen (61 %), When patients
`were asked to rate their preference for each pen based on vari(cid:173)
`ous usability features, the feature 'easy/intuitive to figure out'
`was rated as 'best' most frequently for the SoloSTAR pen (55%
`of the time) followed by FlexPen (32% of the time) and least
`frequently for the Lilly pen (13% of the time),
`Similar findings were also observed in the usability subgroup
`analyses based on age, previous pen experience and visual/dex(cid:173)
`terity disabilities, A high proportion of patients aged 60 years or
`over correctly completed the assessed steps with the SoloSTAR
`pen (90%) and FlexPen (83%) compared with the Lilly pen
`(47%), A high proportion of patients with dexterity (91%) and
`visual (94%) impairments correctly completed all steps analyzed
`with the SoloSTAR pen, which was similar to that observed with
`FlexPen (84% of patients with dexterity and 89% of patients with
`manual impairment), Only half of all patients with either dexter(cid:173)
`ity (52%) or visual (52%) impairments correctly completed all
`analyzed steps with the Lilly pen,
`The ease of use of SoloSTAR has also been demonstrated in
`a single-center, open-label, single-arm sequential study, which
`investigated the usability of the SoloSTAR pen by patients
`with Type 1 or Type 2 diabetes, aged 21-78 years [39], After
`either face-to-face training (Part 1) or self-training (Part 2),
`subjects performed three dose-delivery repetitions into an
`injection pad using separate pens; pens were weighed before
`and after each dose delivery, The primary end point was the
`proportion of subjects delivering successful doses with all
`three repetitions, In Part 1, all 50 subjects delivered successful
`doses (100% success rate; 95% lower confidence bound
`[LCB]: 94,2%) and was within the limits of the ISO dose
`accuracy standard, In Part 2, 53 out of 54 validation subjects
`delivered successful doses (98%; 95% LCB: 91.5%), This
`study validates the SoloSTAR pen device for use by people
`
`with diabetes, with or without face-to-face trammg and
`showed that the SoloSTAR pen accurately delivered the dose
`that was dialed,
`In order to determine the usability and safety of the Solo(cid:173)
`STAR pen in clinical use, a 3-month observational study of
`2029 participants (1067 with Type 1 diabetes and 926 with
`Type 2 diabetes) was undertaken, with the primary end point
`defined as absence of serious adverse events directly related to a
`validated technical failure of the pen, Eight product technical
`complaints (PTC) were investigated and most were due to han(cid:173)
`dling errors, In total, 62 participants reported 77 adverse
`events, none of which were related to a PTC Overall, most
`(95.4%) patients reported that they were either 'very satisfied'
`or 'satisfied' with the SoloSTAR pen, and 96,8% of patients
`continued to use SoloSTAR at the end of the study [43],
`
`How does the SoloSTAR pen fit in the current treatment
`of diabetes?
`With evidence from the DCCT [7] and UKPDS [8] studies indi(cid:173)
`cating that improving glycemic control in patients with either
`Type 1 or Type 2 diabetes delays the onset of microvascular and
`macrovascular complications, intensive insulin treatment as a
`means of achieving and maintaining glycemic control has
`increased, The availability of the SoloSTAR pen for basal (insu(cid:173)
`lin glargine) and bolus (insulin glulisine) insulin provides both
`clinicians and patients alike with a simple approach for manag(cid:173)
`ing diabetes, With the gradual progression of Type 2 diabetes,
`the ADA recommend lifestyle approaches, including nutrition
`and exercise, as important components of diabetes manage(cid:173)
`ment followed by the introduction of one or more OADs, par(cid:173)
`ticularly metformin or sulfonylurea [44], In addition to the
`aggressive approach for achieving target HbA1c levels of less
`than 7,0%, step two of the ADA recommended treatment
`pathway (Box 1) now includes basal insulin, such as insulin
`glargine, as an option, Also, if HbA1c levels are above 8,5%
`with a first-line approach, it is wise to move to insulin therapy
`as additional oral medications are not likely to achieve target
`HbA1c values,
`This concept is supported by a wealth of clinical data,
`including trials such as the 36-week Lantus and Metformin
`(LANMET) study, comparing with NPH and metformin in
`Type 2 diabetes, conducted by Yki-Jarvinen et al, [45], which
`demonstrated that the early introduction of insulin glargine
`(with adequate titration of dose) to one OAD improved glyc(cid:173)
`emic control with a low risk of hypoglycemia (during the last
`12 weeks of this study, fasting plasma glucose [FPG] averaged
`5,75 ± 0,02 mmol/1 and mean HbA1c was 7,14 ± 0,12%),
`The next step in the treatment pathway should be the intro(cid:173)
`duction of one prandial dose of insulin, such as insulin gluli(cid:173)
`sine, A recent study on the basal plus approach demonstrated
`that the addition of insulin glulisine at breakfast or the main
`meal, for patients with Type 2 diabetes allows more patients to
`reach target HbA1c, while offering patients a flexible injection
`time (insulin glargine can be administered immediately after a
`
`118
`
`Expert Rev. Med Devices 5(2), (2008)
`
`Sanofi Exhibit 2128.006
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`SoloSTAR® pen
`
`Device Profile
`
`Fasting (nocturnal period)
`
`Post pradial (daytime period)
`
`11.5
`
`10.0
`
`8.4
`4.4
`
`0.7
`
`15
`
`14
`
`13
`
`12
`
`11
`
`10
`
`9
`
`8
`
`7
`
`6
`
`5
`
`-s
`
`0
`E
`.§.
`C:
`0
`
`~
`"E
`Q) u
`C:
`0 u
`Q)
`UI
`0 u
`:::J
`a
`
`0
`
`2
`
`4
`
`6
`
`8
`
`14
`12
`10
`Time of the day (h)
`
`16
`
`18
`
`20
`
`22
`
`24
`
`Figure 3. The 24-h recordings from continuous glucose monitoring in people with Type 1 diabetes.
`Curve 1 (blue): HbA1c < 6.5%; curve 2 (red): 6.5 to <7%; curve 3 (green): 7 to <8%; curve 4 (orange) 8 to <9%; curve 5 (purple):~ 9%.
`With increasing duration of Type 2 diabetes, post-prandial glucose elevations precede rise in fasting blood glucose levels.
`Copyright© 2006 American Diabetes Association. Reproduced from [13] with permission from The American Diabetes Association.
`
`meal, if necessary) [46]. This then offers a platform on which
`further prandial doses can be added, if patients are not reach(cid:173)
`ing target [47]. Patients using the SoloSTAR pen would benefit
`from not having to undertake additional learning to use a dif(cid:173)
`ferent type of pen when adding prandial insulin to their exist(cid:173)
`ing basal insulin regimen, and the different colors and tactile
`features mean that patients are at a low risk of confusing their
`insulin pens.
`The low injection force with SoloSTAR compared with Flex(cid:173)
`Pen and the Lilly pen [38] may offer advantages, particularly for
`people with limited manual dexterity, which may be age-related
`or as a result of other complications [31,32]. In the study by Haak
`et al. [42], 81 participants had dexterity impairments; of these
`91 % of participants completed a dose delivery with SoloSTAR
`versus 84% with FlexPen and 52% with the Lilly pen.
`Two devices, the Autopen® (Owen Mumford, Ltd, Oxford,
`UK) and lnnolet® (Novo Nordisk), both have low injection
`forces, thus making them potentially suitable for people with
`limited dexterity. Autopen is differentiated by body color and
`is a reusable cartridge-based pen, while the lnnolet has a large
`dose dial, with color differentiation on the injection button.
`However, t