W Taylor & Francis
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`~
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`Taylor&.Franc1~Group
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`Expert Opinion on Drug Delivery
`
`ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20
`
`Development of the SoloSTAR® insulin pen device:
`design verification and validation
`
`Andreas Bode
`
`To cite this article: Andreas Bode (2009) Development of the SoloST AR® insulin pen device:
`design verification and validation, Expert Opinion on Drug Delivery, 6:1, 103-112, DOI:
`10.1517/17 425240802636187
`
`To link to this article: https://doi.org/10.1517 /17425240802636187
`
`ti Published on line: 10 Dec 2008.
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`ExP.ert
`Opinion
`
`1.
`
`Introduction
`
`2. Case studies
`
`3. Discussion
`
`4. Conclusions
`
`5.
`
`Expert opinion
`
`informa
`
`healthcare
`
`Technology Evaluation
`
`Development of the SoloST AR®
`insulin pen device: design
`verification and validation
`Andreas Bode
`Device Design & Development, sanoji-aventis Deutsch/and GmbH, Frankfort, Germany
`
`Background: SoloSTAR® (SOL; sanofi-aventis, Deutschland, GmbH) is a new,
`disposable insulin injection pen device for use by people with type 1 or
`type 2 diabetes to administer long- or short-acting insulin. Objectives: To
`discuss factors that have underlined the design process of the SOL device. In
`addition, to highlight the studies that shaped the direction of its develop(cid:173)
`ment, such as addressing the unmet needs of people with diabetes, which
`included a need for better differentiation features and a lower injection
`force compared with existing prefilled disposable pen devices. Results: The
`development of the SOL pen device was an iterative process involving both
`patients and the design team, which has lead to a manufacturable, tailor-made
`pen device. Patients' needs have been taken into account in the pen design;
`there are numerous differentiators on the device, which avoids confusion
`between insulin types. Furthermore, the SOL device has a lower injection
`force compared with other marketed pen devices. Finally, studies have
`shown that the SOL device is more accurate, easier to use and is preferred
`by patients over other pens on the market. Conclusions: The SOL device has
`undergone rigorous user and laboratory testing, which has captured evolving
`improvements to better meet the needs of people with diabetes.
`
`Keywords: design, development, device validation, device verification, diabetes mellitus,
`engineering, insulin pen device, long-acting insulin, short-acting insulin
`
`Expert Opin. Drug Deliv. (2009) 6(1):103-112
`
`1. Introduction
`
`SoloSTAR® (SOL; sanofi-aventis, Deutschland, GmbH) was developed for use
`by people with type 1 or type 2 diabetes for the administration of long- or
`short-acting insulin. Both SOL devices were approved in Europe in 2006 and for
`the long-acting insulin pen, approval was given in the United States in 2007.
`SOL is a disposable insulin pen device with a 3 ml capacity (300 units of insulin)
`designed for use once or several times a day (Figure 1). Studies have found that these
`products are easy to use [I-3], easy to teach [41, they dose accurately and have a
`lower injection force than both the FlexPen® (FP; Novo Nordisk, Bagsvaerd,
`Denmark) and the Lilly disposable pen device (LP; Humalog®/Humulin® pen;
`Eli Lilly and Company, Indianapolis, United States) [5,6].
`The SOL pen device was effectively developed from the ground up and the
`development process took into consideration not only laboratory testing (design
`verification) and user testing (design validation), but also extensive human and
`ergonomic factors, which will be discussed here using two case studies to illustrate
`the stages in the process. Design verification and validation were fed into an iterative
`design process at every stage of development from initial concept design through
`proof of principle and proof of concept. As a result, the SOL pen device is an
`intuitive, easy to use device [Il with a similar user interface (i.e., common mode
`of operation) as other pen devices, but also fulfils patients' needs to a degree that
`
`10.1517/17425240802636187 © 2009 lnforma UK Ltd ISSN 1742-5247
`All rights reserved: reproduction in whole or in part not permitted
`
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`Design verification and validation of SoloSTAR (SOL)
`
`Pen cap
`
`Pen needle (not included)
`
`Pen body
`
`(
`
`Outer
`needle
`cap
`
`Inner
`needle
`cap
`
`Needle
`
`Dosage I I Injection
`
`selector
`
`button
`
`Figure 1. Schematic diagram of the Lantus® SOL (insulin glargine) and Apidra® SOL (insulin glulisine) products.
`
`advances SOL close to the ideal mechanical disposable device.
`Indeed, some of the features such as addressing the unmet
`needs of the patient, which included better differentiation
`features and a lower injection force compared with existing
`devices that will be discussed, were identified during the
`development programme in user testing and subsequently
`incorporated into the end product.
`
`1.1 What are design verification and validation?
`The core of design verification and validation
`is best
`described by two simple questions: 'Did I design the product
`right?' must be answered positively to pass design verification;
`'Did I design the right product?' needs to be evaluated in
`design validation. Design verification is a laboratory-based
`exercise and involves the assessment of device function,
`including individual components, from a technical perspective.
`International standards have to be fulfilled and compliance
`proven. In addition to parameters set by the International
`Organization for Standardization (ISO), other parameters
`are defined as part of the design brief and, therefore, are
`implicit in the verification process. One such factor is the
`injection force of the device. Testing operating forces and
`torques has become state of the art and has been included to
`verify the end product against the design brief The aim of
`design verification is to quantitatively ensure the individual
`components and the device fulfils the technical requirements.
`For design validation it has to be demonstrated that the
`user can operate the device and that it answers their needs,
`and that the collection of objectives (i.e., design brief) is
`achieved. There are many ways to understand the degree
`of overlap of user requirements and device functionality.
`Ergonomics and human factors specialists can be consulted,
`as well as medical advisors who oversee large numbers of
`patients. However, to best validate a product, it has to be
`bought to the user. User surveys and studies in clinical
`settings, which were performed continuously during the
`development, are appropriate means to get direct feedback
`and understand the degree of overlap, and demonstrate that
`
`the end product fulfils the needs of the users as reflected in
`the design brief
`
`1.2 Why was a new insulin pen device needed?
`The use of the vial and syringe is still relatively common in
`some regions, particularly in the US. It had been estimated
`that in the US, only 14% of patients using insulin were
`using insulin pen devices (prefilled pens or cartridges) as a
`percentage of total insulin use, whereas in Europe, 92% of
`patients were using insulin pen devices [7]. However, it has
`been demonstrated that switching from the vial and syringe
`to insulin pens results in increased medication adherence
`and reduced treatment costs [SJ. There are several prefilled
`and reusable
`insulin pen devices now on the market,
`although availability may vary in some regions/ countries.
`Each device offers the patient specific advantages compared
`with the other pen devices. However, despite the multitude
`of pens available, there remains scope for further development
`of insulin pen devices in response to unmet patient needs.
`Some of these unmet needs will be discussed here, in relation
`to the development of the SOL pen device.
`
`1.3 Original development requirements/design brief
`The original design specification of the SOL pen device was
`based on the feedback from users with respect to existing
`devices plus research to understand the basic needs of
`customers (2001/2002). Here, users are considered to be
`patients as they inject insulin using the pen, as well as
`doctors, nurses and pharmacists as they prescribe, train and/or
`advise the patients on the pen. In addition, human factors
`analysis by means of a literature search provided basic
`requirements. The intent was to provide a pen device with
`better characteristics than the FP and the LP, as those were
`the most commonly used prefilled pen devices on the market
`at the time. Factors such as maximum length, diameter
`and injection force provided an integral part of the initial
`specification. Refinement of the requirements was done on
`the basis of human factor and ergonomic analyses.
`
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`Sanofi Exhibit 2116.003
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`IPR2018-01675
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`

`Bode
`
`1.4 Guidelines and standards for insulin pen devices
`Insulin pen devices are subject to several regulatory guidelines
`developed by the national/international medical regulatory
`bodies, for example, FDA and the European Agency for the
`Evaluation of Medicinal Products (EMEA). Before approval
`from the FDA and EMEA can be sought, pen devices and
`related materials must also meet several criteria specified by
`ISO, in particular, ISO 11608-1 for insulin pen devices [9].
`The guidelines for insulin pen devices cover not only
`specific aspects of device use, such as dose accuracy or visibility
`of the selected dose, but also that the pen device doses
`correctly afrer storage in a range of environmental conditions
`(e.g., temperature and humidity), functions properly afrer
`being dropped from a height of 1 m at various orientations
`and that labels or other distinguishing marks are durable
`during use. However, factors such as injection force and
`design features such as colour and size are not covered by
`the ISO standards. Thus, for the design verification and
`validation of the SOL pen device, tests were performed to
`ensure it met the ISO guidelines and that it met the more
`stringent targets that were set internally. Furthermore, user
`testing was carried out to ensure that the SOL pen device
`was intuitive to use by the intended population.
`
`1.4.1 Unmet needs
`1.4.1.1 Insulin dose
`Increasing doses of insulin are required over time to overcome
`the insulin resistance and relative insulin deficiency. Indeed,
`many patients need to administer individual doses of insulin
`> 60 units, the maximum dose of many insulin pen devices,
`thus necessitating several injections. As a result, the design
`brief of the SOL pen device included the recommendation
`of a maximum dose of 80 units.
`
`1.4.1.2 Hand function and injection force characteristics
`Limited joint mobility of the hand, commonly referred to as
`cheiroarthropathy, is frequently observed in patients with
`diabetes, particularly elderly patients, which may occur as a
`result of connective tissue disorders or diabetic neuropathy,
`and is characterised by low grip strength and/or limited
`dexterity [10-15]. As a result, the recommendation in the
`design brief was for the SOL pen device to have a lower
`injection force than other prefilled devices available at the
`time, as well as a short dial extension length to reduce the
`mechanical strain on
`the user's
`thumb.
`Indeed, one
`would anticipate that a short dial extension with low force
`requirements would be easier to use for most of the patients.
`
`1.s Overview of the SOL pen design verification and
`validation process
`Numerous concepts were initially investigated; all could fulfil
`the design brief, but used different mechanical principles.
`Complex designs, such as an odometer mechanism for
`displaying the dose, were investigated, as well as toothed rod
`type mechanisms and simple tampo-printed dose scales. Of
`
`the proposals mentioned earlier, very few were selected afrer
`mechanism concept evaluation, which used quality function
`deployment techniques (QFD). These techniques ensured
`end user requirements were the main focus of selection. Extra
`parameters, such as complexity, technical risk or perceived
`patent infringement risk, were taken into consideration.
`The selected concepts were then progressed through the
`design verification and validation processes. As described
`earlier, the verification and validation of the SOL pen device
`followed an iterative process: at each stage of the process,
`studies were done to assess
`technical aspects (i.e.,
`the
`mechanical/physical properties) and user aspects (i.e., feedback
`from the intended user population). Additionally, structured
`risk assessment was done at each stage, with the results used
`for risk management of the device. Failure mode and effects
`analysis (FMEA) and user task analyses served as tools for
`risk assessment and provided an approach from two different
`directions. The FMEA helped us
`to understand which
`component failure or feature malfunction could lead to critical
`loss in performance and the user task analyses highlighted
`potential ambiguity leading to reasonably foreseeable misuse.
`Studies done at each stage of the process assessed not only
`the pen device itself (block models, proof of principle rigs,
`proof of concept prototypes and eventually the industrialised
`pen), but also individual components and features (including
`dial display, pen colours, label size and format, dose knob,
`pen cap and clip, overall dimensions). Results of these studies
`were fed back into the iterative design process, as summarised
`in Figure 2, to ensure the ongoing developments in pen
`device design and function continued to meet not only the
`original design specification, but also subsequent suggestions
`and recommendations leading to an updated design brief to
`further meet the patients' needs.
`As shown in this figure, there are two key areas that govern
`the design and development process. On the one hand, it
`is important to understand the patient's needs through a
`combination of literature research, ergonomics studies and
`user testing. On the other, it is important to respond to
`these needs with rational design and adaptation to ensure a
`solution is found before the next stage of development can be
`entered. User testing and laboratory-based testing performed
`at each stage of the development cycle helps ensure that the
`design is verified and validated.
`
`1.6 Objectives
`The design validation process involved nine user studies,
`which were done with a total of> 2,300 participants, including
`health-care professionals (nurses and physicians) and people
`with diabetes. Moreover, 12 ergonomics analyses were done in
`addition to numerous meetings with health-care professionals
`(nurses and physicians), which are part of an advisory board
`that allows medical experts to provide feedback on most
`aspects of product development. Technical tests of all
`products and components were performed in advance of each
`user/ergonomics study to ensure the product and component
`
`Expert Opin. Drug De/iv. (2009) 6(1)
`
`105
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`IPR2018-01675
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`

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`Design verification and validation of SoloSTAR (SOL)
`
`Initial
`des;go bdef
`
`\
`
`~ Specify
`
`design criteria
`
`Proceed to next step
`in development
`process
`
`patient needs
`
`Realise
`patient needs
`
`\
`0
`
`~
`
`Final product
`for manufacturing
`
`J
`
`Continuous
`improvement
`programme
`
`Figure 2. A simplified diagram illustrating the feedback loops for the input of technical testing and user testing results on
`the design and development of the SOL pen device.
`
`met the design brief and ISO guidelines. It is not the aim of
`this paper to discuss all details of the extensive test programme
`(in excess of several 10,000 pen devices and components were
`tested). Instead, we have focused on two key events that
`helped shape the development of the SOL pen device; these
`two events are exemplary for the development process and systems
`applied for SOL. An overview of the development method
`is shown in Figure 3. In brief, each stage of the development
`process involved an iterative approach, and the process was
`guided by user research as well as laboratory testing.
`First, we wish to discuss the rationale for developing the
`SOL pen devices with distinct body colours specific for the
`delivery of long- or short-acting insulin devices. Second, we
`wish to discuss the impact of mechanics on the function of
`the dose dial extension and injection force. For both charac(cid:173)
`teristics, we will present the results of studies in which these
`characteristics were identified, provide a summary of the impact
`on the verification process and the final validation testing.
`
`2. Case studies
`
`2.1 Colour differentiation
`Problems with visual acuity are relatively common in diabetes,
`and may be either age related, such as macular degeneration
`or cataract formation [16,17], or diabetes related, with onset
`and progression of diabetic retinopathy [18-20]. People with
`
`diabetes, particularly those with type 1 diabetes, but also
`some with type 2, often use more than one type of insulin
`to manage the basal and prandial insulin requirements,
`which can be provided by insulin glargine and insulin
`glulisine, respectively.
`Owing to the differences in typical dose and pharmaco(cid:173)
`dynamic characteristics of basal and prandial insulins, it is
`important that the delivery devices (pen device or vial) are
`sufficiently differentiated to ensure a low risk for confusing
`the two insulin formulations and to minimise the risk of
`hypoglycaemia. Typically,
`this may involve some colour
`applied to the label and dose button of the device along
`with text and potentially tactile features.
`
`2.1.1 Colour deficiencies
`Colour deficiencies in people with diabetes occur primarily
`as a result of retinopathy [21], which is associated with altered
`colour perception owing to a reduction of light falling on
`the retina and the death of cones where the oxygen supply
`is restricted, or maculopathy, such as age-related macular
`degeneration, which is associated with an accumulation of
`fluid in the cone-rich area of the fovea, leading to distorted
`vision along with altered colour perception [16]. People with
`poorly controlled diabetes (type 1 or type 2) are at increased
`risk of developing retinopathy, whereas risk factors for
`maculopathy include aging, smoking and poor glycaemia
`
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`Mylan v. Sanofi
`IPR2018-01675
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`

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`User input
`
`Risk
`management
`
`Bode
`
`SoloStar
`design process
`
`Design
`requirements
`-Intended use
`-TPP
`-PDS
`
`Evaluation/
`verification
`
`Survey
`
`Survey
`
`Survey
`
`Survey
`
`Design
`validation
`study
`
`1st risk
`analysis
`
`Concepts
`
`Proof of principle
`prototype
`
`Proof of concept
`prototype, V1
`
`Proof of concept
`prototype, V2
`
`Design
`evaluation
`
`Design
`evaluation
`
`Design
`verfication
`
`1st FMEA
`
`Revised
`FMEA
`
`Design ready for 00-series
`
`Revised risk
`analysis 1-------
`
`00-series
`prototype
`
`Design
`verfication
`
`Revised risk
`1------..
`an a I y sis
`
`>--------
`
`Design ready for production
`
`Patient
`trial
`(Australia)
`
`Initial post
`market
`surveillance
`
`Design
`verfication
`
`Production
`devices
`
`Launch
`
`Continuous
`improvement
`programme
`
`Figure 3. A summary of the key stages of the SOL pen device development process and tests done at each stage.
`FMEA: Failure mode and effects analysis; PDS: Product design specification; TPP: Target product profile.
`
`Expert Opin. Drug De/iv. (2009) 6(1)
`
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`

`

`Design verification and validation of SoloSTAR (SOL)
`
`control [22]. In addition, colour perception is altered with
`aging; as the lens of the eye ages, it becomes less transparent
`and absorbs more blue light. This results
`in a slight
`blue-weak colour deficiency, particularly in adults aged > 30.
`Inherited colour deficiency, although not related to diabetes,
`is a significant concern; as many as 8% of Caucasians are
`thought to be colour deficient, with deuteranopia (impaired
`middle wave receptor; confusion between red and green)
`being the most common [23].
`
`2.1.2 Colour discrimination
`Discrimination of colour is based on three dimensions:
`
`1. Hue: the perceptual quality of light of different wavelengths.
`2. Saturation: the purity of a hue, which is reduced as more
`black, grey or white, is introduced into the hue.
`3. Brightness: the amount oflight reflected by a surface.
`
`People with normal colour vision are unable to differentiate
`hue in low lighting levels, whereas people with colour vision
`deficiencies are restricted in their perception of hues, even at
`normal lighting levels. As a result, to aid colour discrimination,
`colours should differ sufficiently on all three dimensions.
`
`2.1.3 Implications for the treatment of diabetes
`Traditionally, insulin vials and pen devices have relied on
`text for differentiation of the type of insulin, although colour
`swatches were also used. The International Diabetes Federation
`(IDF) introduced a colour coding scheme to help identify
`certain insulin formulations.
`
`2.1.4 Study: review of colour pairings based on
`human factors for two insulin pen devices
`The development of the SOL pen device was initially planned
`to provide one pen device body colour, with differentiation
`between the long- and short-acting insulins provided by colours
`on the label and the dose button, as well as the text on the label.
`Results of some user and ergonomics/human factors studies
`indicated that the differentiation provided is sufficient and in
`line with common practice, but that further means would be
`beneficial. The results of these earlier studies suggested that there
`was potential to improve the differentiation of the two insulin
`pen devices; two distinct colour schemes should be used for
`pens that deliver the long- or short-acting insulin. A range of body
`colour options were considered to help differentiate between the
`two insulins, as well as differentiate within the sanofi-aventis
`portfolio and relative to pen devices already available on the
`diabetes market. Therefore, a study was designed to determine
`the optimal pairings of colours for the two SOL pens.
`The team investigated potential options for further colour
`differentiation; the largest area of the pen device is the pen body
`itself; hence, it was decided to differentiate the two insulins
`through distinct pen body colours. A variety of colour options
`was developed from a technical perspective (what is technically
`feasible) and analysed as part of the design validation [24],
`and the optimal colour pairing is shown in Figure 4.
`
`2.1.s Discussion
`In terms of insulin pen differentiation, the structured develop(cid:173)
`ment process has proven to be a successful tool to detect user
`needs (i.e., the need for differentiating features), highlight
`room for improvement (i.e., introduce body colour as well
`as labels for differentiation), make the best choices between
`available options (i.e., optimal colour pairs) and confirm that
`the optimal solution has been identified (i.e., user testing).
`As a result of the studies described earlier, the SOL pen
`device is available in two body colours to aid differentiation
`between the long- or short-acting insulins (Figures 1 and 4),
`which have been validated in studies with patients with poor
`visual acuity or colour blindness. Furthermore, the SOL pen
`device contains several extra features that can help the user
`discriminate between a SOL pen device that delivers long- or
`short-acting insulin, including label text and colours, dose
`injection button colour and tactile features. The use of two
`differentiated body colours has also been validated in user
`studies, and the SOL pen device was associated with low
`risk of confusion in terms of insulin type as well as pen
`devices from other manufacturers (unpublished observations).
`
`2.2 Ease of injection
`The design brief for the SOL pen device required a low
`injection force and short dial extension to allow easy injection.
`However, these two factors are inextricably linked in terms
`of mechanics of operation. Reducing the injection force or
`the dial extension is relatively simple; however, development
`of earlier injection devices indicated that reducing the one
`will normally increase the other. Thus, for the SOL pen
`device, the challenge was to inject large doses on short
`strokes at low forces.
`To achieve this, the team developed a totally new concept.
`As the low injection force and short dial extension are
`conflicting criteria, detailed mathematical modelling of the
`mechanism concepts was required, as well as stress and
`material analyses such as Finite Element Analysis or Moldflow.
`Careful selection of materials was needed both for low
`friction and high stress resistance.
`During the continuous user studies, the benefit of low
`and consistent injection force was identified to be a key
`differentiating factor with regard to ease of use. As a result,
`the injection mechanism was exposed to several stages of the
`iterative design verification (from a technical perspective)
`and validation (from a user perspective) process, to ensure
`the injection force characteristics were as good, or better,
`than both the FP and LP.
`
`2.2.1 Study: dose injection force
`The design brief for
`the SOL pen device defined an
`injection force lower than FP and LP. In user studies, a variety
`of injection forces were tested to determine the impact of
`the different forces on the perception of users; the data
`helped the team to have a set goal to design an appropriate
`mechanism to achieve this.
`
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`Mylan v. Sanofi
`IPR2018-01675
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`

`Bode
`
`Lantus®
`
`Figure 4. The Lantus® SOL (insulin glargine) and Apidra® SOL (insulin glulisine) products showing the colour pairing
`(with European labels).
`
`In addition to the earlier-mentioned user studies, the dose
`injection force characteristics of SOL versus FP and LP have
`been assessed in two separate studies, and all force characteristics
`were lower with SOL, particularly peak injection force and
`mean injection force [5,6].
`The mean injection force required to dispense 40 units in
`4 sec for the SOL, FP and the LP in these two studies was
`in the range of 10.7 - 10.8 Newtons [NJ, 15.5 - 17.1 N
`and 23.5 - 24.9 N, respectively [5,6]. Peak dose force for the
`SOL, FP and the LP was in the range of 14.4 - 14.7 N,
`22.9 - 25.0 N and 30.9 - 31.8 N, respectively [5,6]. The mean
`injection force was similar across the two studies; SOL had
`- 40% lower value than LP and - 30% lower than that
`measured for FP [5,6]. These laboratory-based studies are
`consistent with the subjective assessment by people with
`diabetes, as more people rated the effort to dispense a
`40 unit dose with SOL (63% of participants) as best compared
`with either the FP (19%) or LP (16%) [25].
`
`2.3 Patient usability of insulin pens
`Finally, it is important to consider the end result of the
`design process; the impact the pen has on patient usability.
`An open-label study done by Haak et al. across four countries
`(United States, Germany, France and Japan) compared four
`pen devices (SOL, LP, FP and Pen X [a prototype pen]) in
`510 patients with diabetes [25]. A significantly higher proportion
`of patients correctly prepared the pen and performed an
`injection into a receptacle with SOL (94%) compared with
`the FP (90%; p < 0.05), LP (61 %; p < 0.05) and Pen X
`(64%; p < 0.05). Similar results were seen regardless of
`previous pen use, age and manual/visual impairments. In
`addition to usability, a higher proportion of patients had an
`overall preference for SOL (53%) compared with FP (31 %;
`p < 0.05) or LP (15%; p < 0.05) [25].
`
`3. Discussion
`
`Here, we have provided a brief overview of the design and
`developmental process to bring the two SOL insulin pen
`devices that deliver either long- or short-acting insulin from
`a concept on paper to mass-produced insulin pen devices.
`The processes involved in the design and development of
`
`the SOL pen device can be likened to those involved in
`developing pharmaceutical drugs, which requires preclinical
`(i.e., concept design and selection) and Phase I - IV studies
`(i.e., validation and verification). However, there are significant
`differences with respect to the iterative process, in which a
`prototype is tested from both a technical and user perspective,
`and the resulting data are used to change the design as
`needed to then go into testing (user and technical); this
`approach introduces an element of consumer products into
`the development process. Only a lively dialog with several
`iterations between users and the development/device design
`team allowed the SOL pen device to be tailored to suit
`the patient needs and be manufacturable. The primary
`considerations in the design brief were to develop an easy to
`use insulin pen device with an injection force lower than
`that of other pens on the market. Within a laboratory
`setting, the SOL pen device has a lower and smoother injection
`force than both FP and LP [5l.
`The ease of use of the SOL pen device has also been
`demonstrated
`in a single-centre,
`two-group sequential
`study [3]. In that study, after a training session on the day
`before assessment, patients were able to correctly administer
`three doses of insulin.
`As demonstrated in the Haak et al. study, more patients
`correctly used and preferred SOL and FP than the LP and a
`prototype pen [25]. Similar ease of use and patient preference
`for the SOL were seen regardless of age, manual dexterity or
`visual impairments, factors that may have particular importance
`when considering elderly patients with diabetes, or patients
`that have peripheral neuropathy, a common complication
`of diabetes [26,27].
`the dose
`injected
`the users
`In
`these
`three studies,
`into a receptacle or injection pad; in the case of the
`force measurement
`[5l, dose deliveries were performed
`by a force stand. As these studies do not provide evidence
`of the usability of the SOL pen device in a clinical setting
`(i.e., at least once each day for a duration of time),
`an observational survey of everyday clinical practice was
`done in Australia to evaluate the usability and safety
`of SOL, which showed that most of the participants
`(95%) were very satisfied or satisfied with using SOL to
`inject insulin [Il.
`
`Expert Opin. Drug De/iv. (2009) 6(1)
`
`109
`
`Sanofi Exhibit 2116.008
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Design verification and validation of SoloSTAR (SOL)
`
`4. Conclusions
`
`Here, we have presented data from two aspects of the design
`verification and validation of the SOL pen device and have
`shown how these have impacted the final production model,
`which was approved for use in a clinical setting to administer
`either long- or short-acting insulin. We have presented
`selected aspects from a wealth of data that we collected
`through the iterative development process. This comprehensive
`design verification and validation process with rigorous
`testing has resulted in a final product that is easy to use
`with a dose injection force lower than both FP and LP and,
`in a nonclinical environment, is preferred by more people
`than the FP and LP. Finally, within a clinical setting, the
`use of SOL delivering long-acting insulin in 5,983 patients
`with type 1 or type 2 diabetes was associated with a low
`incidence of adverse events (0.3%) and adverse reactions
`(0.15%; such as skin reactions, hypoglycaemia, pruritis),
`in addition to a low rate of reported technical problems
`(0.6%; such as leakage, defective dose knob or incomplete
`dose delivery) [28].
`
`s. Expert opinion
`
`Insulin therapy becomes a necessary part of a patient's disease
`management in order to reach appropriate glycaemic control
`in type 1 diabetes mellitus and following disease progression
`in type 2 diabetes mellitus. Common stressors of injection
`based insulin therapy affecting people with both types of
`diabetes include the psychological aspects of injecting an
`accurate dose and the reproducibility of doing so;
`this
`can lead to a decrease in patient compl