Administration of Biosimilar Insulin Analogs: Role of Devices

Abstract

With the expiration of patent protection for several originator insulin analog molecules, the availability of insulin analog copies is set to increase. Many regulatory authorities have developed, and continue to refine, guidelines for the approval of biosimilar insulin analogs. Aspects such as the structure, pharmacokinetics and pharmacodynamics, efficacy, safety, and immunogenicity of biosimilar insulin analogs are extensively addressed in these guidelines, but how the biosimilar insulin analog is administered to people with diabetes is not usually a topic. The aim of this article is to highlight that the delivery device–drug combination is of particular importance. Regulatory, legal, and practical aspects of the delivery device, be it a syringe, pen, or pump, have to be considered in the context of biosimilar insulin analogs. Although the safety and efficacy of biosimilar insulin analogs per se are of primary importance for physicians and people with diabetes, functions and features of the devices used for administration also require attention from a practical point of view. Unfortunately, although there are several clinical studies investigating the technical aspects of and patient preference for the originator insulin analog pens, there are currently very little published data for nonoriginator or biosimilar insulin analog pens. In addition, it is not known if it is safe to assume that a biosimilar insulin analog cartridge is compatible with an existing originator insulin analog pen. We believe that there is a need for more discussion on the role of devices for administration of biosimilar insulin analogs.

Introduction

The patent protection for several insulin analog molecules has expired or is about to expire in the near future. Currently, insulin glargine is the primary target for companies trying to develop an insulin analog copy. To date, only one biosimilar insulin analog (Abasaglar^®; insulin glargine; Eli Lilly and Boehringer Ingelheim) has been approved in the European Union (EU), becoming the first insulin analog approved through the biosimilar pathway of the European Medicines Agency (EMA)¹; the Eli Lilly and Boehringer Ingelheim insulin glargine has also been approved in the United States under the trade name Basaglar™.² The Basaglar new drug application was filed through the US Food and Drug Administration's 505(b)(2) regulatory pathway (and is thus considered a follow-on biologic). It is clear, however, more biosimilar insulin analogs will come to market in the coming years as several companies have insulin glargine biosimilars undergoing clinical trials, including Merck/Samsung Bioepis and Mylan.³ Copies of insulin glargine (and human insulin formulations) are already on market in some countries where there were less stringent regulatory procedures in place at the time of authorization, for example, Glaritus^® in India, Basalin^® in China, and Bonglixan^® in Mexico.³ Both insulin lispro and insulin aspart biosimilars are being developed by Mylan in partnership with the Indian biotechnology company, Biocon, and it is likely that other companies, including the manufacturers of originator insulin analogs, are also developing biosimilar insulin analogs.

Although many regulatory guidelines (and publications) cover aspects such as the structure, pharmacokinetics and pharmacodynamics, efficacy, safety, and immunogenicity of the biosimilar itself,^4
–6 an important aspect for the practical usage of biosimilar insulin analogs is somewhat ignored—the device used for administration. Some biosimilar insulin analogs will be marketed with pharmaceutical company-specific administration devices, and switching a person with diabetes from an originator insulin analog to a biosimilar insulin analog will therefore include a change in administration devices.

The devices most often used nowadays are pens and syringes (for subcutaneous injection of rapid-acting and long-acting insulin analogs) or pumps (for infusion of rapid-acting insulin analogs with different rates to cover prandial and basal requirements). As people with diabetes become familiar with a particular pen device, changing the pen might be more of a concern for them than the change in the insulin analog product. Being confident with a given pen may align with preferences for certain pens and a switch to a different insulin analog pen may be associated with requirements for additional training in pen usage. For the treating physician, this might increase the organizational efforts associated with such a switch. If funding to cover the costs for additional training is not provided, such organizational efforts may affect the potential cost savings associated with use of biosimilar insulin analogs.

The aim of this article is to discuss several aspects that in our opinion are relevant when it comes to the safe and efficient administration of biosimilar insulin analogs.

Regulatory and Legal Aspects

In recent years, many countries have developed, or are in the process of developing, regulatory guidelines for biosimilars (including insulin analogs) led by the EU, which issued its first guidelines in 2005, although it continues to develop and update them.^6,7 The regulations for market approval of biosimilar insulin analogs differ markedly across geographical regions. Whereas some regions have strict well-defined guidelines, others have regulations, but with key elements less well-defined, and some regions have little to no specific regulations.⁸ In addition, not all regulations address the specific issues around biosimilar insulin analogs. For example, although the EMA has provided product-specific guidance within their guidelines for developing biosimilar insulin analogs, in the United States, insulin analogs are not currently regulated as biosimilars.⁸

Specifications or recommendations with regard to insulin analog delivery devices are currently covered under different regulatory pathways and several relevant aspects require attention. Insulin analog delivery devices have stringent regulatory requirements in some countries, which address a variety of functional and packaging aspects (e.g., product labeling, dose graduation and visibility, dosing accuracy, storage, handling).⁴

In the EU, directives concerning the regulation of medical devices (currently under revision) are implemented by national legislation and may vary.⁹ In some EU countries, regulation of insulin analog delivery devices may depend on their properties. For example, in the United Kingdom, although reusable insulin analog pens and single-use syringes are covered by medical device regulation, disposable pens with integral cartridges are regulated under medicine legislation, although relevant requirements from the Medical Devices Directive concerning safety and performance also apply.¹⁰

There has been a call from several bodies, including the European Association for the Study of Diabetes, for the development of a single, coordinated European system to oversee the evaluation, approval, and postmarketing surveillance of medical devices.¹¹ Whether such coordination of regulations might impact the approval requirements for delivery device–biosimilar combination remains to be seen.

In the United States, the FDA has produced guidelines describing the technical and scientific data it expects in a marketing application for a pen, jet, and related injectors for use with biological products to have, which cover aspects such as design features, performance testing, and labeling.¹²

In the case of biosimilars, in their draft guidance, Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009: Guidance for Industry,⁵ the FDA has stated that a biosimilar product may have some design differences in the delivery device compared with the reference product. For example, the biosimilar may be licensed in a prefilled syringe or an autoinjector despite the reference product being administered using a vial and syringe, contingent upon adequate performance data being obtained—a definition of adequate is not provided.⁵ The FDA also states that a proposed biosimilar product in a delivery device will be considered a combination product and may, in some instances, require a separate application for the device.⁵ In the United States, however, insulin analogs are not currently regulated as biosimilars.

To our knowledge, from a legal point of view, the manufacturer of the device is responsible for its safety and is obliged to track, document, and investigate all complaints or adverse events considered to be device related, even if a different insulin analog (a biosimilar insulin analog) is used.

Devices

Devices used for insulin analog administration are of paramount importance for people with diabetes and their physicians and nurses. For example, precision of insulin analog dosing is a key concern, but the ease of use, comfort, and convenience of using the device are also important and can influence patient adherence and therefore potentially impact efficacy.

We will focus on pens and syringes because currently no biosimilar rapid-acting insulin analogs are approved that can be used in pumps; however, such insulin analogs are in clinical development and may come to market in the coming years. In addition, a majority of insulin analog users worldwide use a pen, although this does vary geographically, with the vial and syringe method remaining a popular choice in some countries. Insulin analog pen use is not as extensive in the United States as it is in Europe, likely due to limited funding approval by medical insurance providers^13,14; however, this rate has been increasing over the past few years. In addition, many people with diabetes in the United States have larger than normal insulin analog dose requirements (i.e., >50 to 60 units), which may explain why administration using a pen may sometimes be impractical given that only four to five doses per pen can be provided.

Both reusable and disposable pen devices are available, which have different implications in terms of patient preference and costs. Pharmaceutical companies have invested greatly into the development of pens over the past 30 years. Table 1 outlines several features of pens that are important to ensure safe, efficient, and convenient insulin analog administration. Although most pens share characteristics such as push-button delivery, dialed dosing, and dose confirmation at end of dose, they can vary by the number of these characteristics provided per pen. For example, the vast majority of currently available originator insulin analog pens have an end-of-content feature, which means they do not allow the user to dial a dose higher than the volume left in the cartridge. For some pens, the remaining dose still required is displayed should the pen deliver a dose lower than that which has been set. However, with some pens, doses can be set that exceed the amount of remaining insulin, with no indication of a compromised dose being given (Table 2). Pens without an end-of-content feature may pose a potential safety issue because people with diabetes will be unaware of the actual dose delivered. This scenario might lead to unexpected hyperglycemia where the person with diabetes may have to give himself/herself a correction dose and mistakenly increase the basal dose for the next day. This feature is lacking from some insulin analog copy delivery devices (Table 2).

Table 1.

Insulin Device Features for Safety, Ease of Use, and Patient Comfort

Feature	Explanation
Reusable or disposable	Possible implications in terms of patient preference and, potentially, costs
Unique color coding and tactile identifiers	Important for ease of identification to prevent confusion between different devices/insulin
Dose range and deliverable dose	Larger maximum doses may be preferable in patients who take large insulin doses, whereas children may benefit from the ability to select half-unit increments
Dose capacity/volume (i.e., number of units available per device)	Most currently available models are either prefilled with 3 mL (300 U) of insulin or are designed for use with 3-mL cartridges, which may be less convenient for patients requiring higher doses
Dose accuracy	Required accuracy of delivering the dose that is set to be administered
Dial back	Allows readjustment if dose is dialed incorrectly
End-of-content feature	Prevents dosing errors by not allowing a dose to be dialed which is greater than the remaining insulin in the device
Low injection force; reduced button extension; autoinjection (spring assisted) delivery	Impact on comfort and ease of use, and may be of particular importance to patients with impaired hand function
Auditory/tactile feedback (e.g., confirmatory click on full delivery)	May be of particular importance for patients with visual impairment
Robustness against environmental impact	The device should meet requirements during or after different use scenarios (e.g., temperature, humidity, after free fall)
Electronic memory function	May be particularly useful for patients prone to omitting or forgetting their insulin injections

Table 2.

Characteristics of Currently Available Disposable and Reusable Insulin Pen Devices (Biosimilar Insulin Marked in Gray)

			Dialing features
Pen device	Insulin/manufacturer	Dose range (U)	Dial back	End-of-content feature ^a	Additional features
Disposable pens
Humalog^® U100 KwikPen^®	Insulin lispro	1–60	Yes	Yes
Humalog^® U200 KwikPen^®	Insulin lispro
Basaglar™ Kwikpen^®	Biosimilar insulin glargine
Lantus^® SoloStar^®	Insulin glargine	1–80	Yes	Yes	Raised tactile dot on push button of Apidra^®SoloStar^®
Toujeo^®SoloStar^®	Insulin glargine
Apidra^® SoloStar^®	Insulin glulisine
Insuman^®SoloStar^®	Human insulin
NovoLog^® FlexPen^®	Insulin aspart	1–60	Yes	Yes
Levemir^®FlexTouch^®	Insulin detemir	1–80	Yes	Yes	No dose button extension; spring-assisted injection
Tresiba^® U-100 FlexTouch^®	Insulin degludec	1–80			No dose button extension; spring-assisted injection
Tresiba^® U-200 FlexTouch^®	Insulin degludec	2–160
Glaritus^® DispoPen	Insulin glargine	1–60	Yes	No
Reusable pens
NovoPen Echo^®	Novo Nordisk	0.5–30	Yes	Yes	Half-unit incremental dosing
					Memory function records dose and time since last injection
NovoPen^® 5		1–60	Yes	Yes	Memory function records dose and time since last injection
NovoPen^® 4		1–60	Yes	Yes
ClikSTAR^®	Sanofi	1–80	Yes	Yes
JuniorSTAR^®		0.5–30	Yes	Yes	Half-unit incremental dosing
AllStar^®		1–80	Yes	Yes
TactiPen^®		1–60	Yes	Yes
HumaPen^®Luxura™ HD	Eli Lilly	0.5–30	Yes	No^b	Half-unit incremental dosing
HumaPen^®Savvio™		1–60	Yes	Yes
HumaPen^®Memoir™		1–60	Yes	No^b	Memory function records time, date, and amount of the last 16 doses
ServoPen	Dongbao	1–60	Yes	Yes	Short stroke distance; spring-assisted injection
SulinPen		1–60	Yes	Yes
AutoPen24		1–21 or 2–42	No	No^b	Spring-assisted injection
Wosulin Pen Royale	Wockhardt	1–60	Yes	No
Xiulin Pen	Gan Li	1–60	Yes	No
INSUPen^®	Biocon	1–60	Yes	Yes
INSUPen^{® EZ}
GensuPen^® 2	Copernicus/Bioton	2–40	Yes	No^b	Spring-assisted delivery system and a lateral trigger device

Pens do not allow the user to dial a dose higher than the volume left in the syringe.

Pens allow the user to dial a dose higher than the volume left in the cartridge, but the amount of insulin not received is shown postadministration if insufficient insulin in the pen for the dose set was received.

In principle, a biosimilar insulin analog delivery device is expected to be as safe, efficient, and convenient to use as the originator insulin analog pen and to not impose additional burdens on people with diabetes.¹⁵ As far as perceptions of biosimilar insulin analogs are concerned, a majority of people with diabetes in a recent survey expressed willingness to use biosimilar insulin analogs.¹⁶ However, although efficacy and safety were their primary considerations, the design of the delivery device was also of importance for many¹⁶ and one can speculate that reliability, functionality, ease of use, and comfort of the delivery device are likely to have an influence on their willingness to use biosimilar insulin analogs. The delivery device, pen, or syringe for a biosimilar insulin analog would ideally have comparable features with the originator insulin analog device.

For insulin pumps, data on insulin stability in-use will need to be provided to regulators as well as reassurance that infusion set occlusion will not be any more of a problem with a given biosimilar insulin analog than it currently is with the originator insulin analog. The excipients used in biosimilar insulin analog formulations may also affect issues such as this.¹⁷ Normally, these types of issues are covered by a comment in the label/summary of product characteristics; without such a comment, physicians would need to use their own clinical judgment.

Current Evidence on Device Differences Among Biosimilar Insulin Analogs or Copies

To date, there are no clinical or patient-level trials comparing originator insulin analog pens or syringes with biosimilar insulin analogs or copies and very few published technical or patient preference data. Given the narrow therapeutic window of insulin, if biosimilar insulin analogs are marketed with their own delivery device, adequate quality control of delivery devices and demonstration of equivalence with the originator device (with regard to key function features and precision, e.g., dose accuracy) would be important to be confirmed.

Several studies have shown that dosing accuracy of originator reusable insulin analog pens (ClikSTAR^®, NovoPen^® 4, and HumaPen^® Luxura™)¹⁸ and of disposable originator insulin analog pens (SoloStar^®, FlexPen^®, Next Generation FlexTouch^®, and Humulin^® N KwikPen^®) is within the International Organization for Standardization (ISO) limits across the dosing range and by multiple dosing.^19,20

However, data for pens of insulin analog copies are less consistent. A recent study compared the technical performance of three pen devices used to deliver insulin glargine-based copies—the reusable Wosulin Pen Royale and the disposable Wosulin DispoPen (Wockhardt) used for Glaritus and the reusable GanLee Pen (Gan and Lee) used to deliver Basalin—with the originator insulin analog pen devices (ClikSTAR and SoloStar for Lantus^®).²¹ Although all tested pen devices were found to deliver comparable average doses within technical performance standards (ISO 11608-1 requirements), dose variability was higher with the three pen devices used to deliver insulin glargine-based copies compared with the originator insulin analog pen devices.²¹ The study also found that the injection force required to administer the insulin was higher for the pen devices used to deliver insulin glargine-based copies²¹ compared with the originator insulin analog pen devices. In addition, unlike the originator insulin analog pen devices, there was no end-of-content feature in the pen devices used to deliver insulin glargine-based copies, which meant that doses exceeding the remaining insulin could be dialed and, in one case, apparently dispensed. A study of patient preference for different insulin analog pens in Brazil, China, Egypt, India, and Malaysia found that locally made pen devices used to deliver insulin analog copies tended to perform less well than the originator insulin analog pen devices across a range of parameters related to ease of use and dose setting, which were considered important from a patient preference perspective.²² However, one has to keep in mind that studies of this type are often initiated and supported by the manufacturer of the originator insulin analog pen devices.

Biosimilar insulin analogs will soon become available for previously approved delivery devices. For example, Basaglar has been tentatively approved by the US FDA for use with Eli Lilly's prefilled KwikPen (currently used with insulin lispro).² However, this approval followed filing of Basaglar as a new drug, in contrast to in Europe, because it is not considered a biosimilar in the United States.

To date, there are no data on the effects of differences in pen devices used for biosimilar insulin analogs on adherence to therapy or clinical outcomes relative to originator insulin analogs or indeed for any other biosimilar. From a clinical point of view, it would be great if randomized studies with different devices would be performed, with a focus on patient-reported outcomes.

Experience with Devices Used for Administration of Other Biosimilar Products

There is some evidence of increased adverse events associated with the delivery device following switching from an originator biologic to a biosimilar.

In a study sponsored by the manufacturer of a biosimilar recombinant human growth hormone (rhGH), 98 children who switched to a biosimilar rhGH delivered by a new injection device were compared with the originator rhGH.²³ It was found that there was no apparent negative impact on growth in patients who persisted with the biosimilar.²³ However, 18 patients experienced injection site pain and 1 patient had pitting edema; of these patients, 6 switched back to the originator product. The authors concluded that the high rate of adverse events may be partly explained by the need for patients to learn how to use, and to get accustomed to, a different injection technique. The authors also stated that most patients who reported injection site pain initially continued with the biosimilar product following advice on injection technique by a specialized endocrinology nurse.

However, the suitability of the particular model used in this study has been questioned by the manufacturer of the originator product given the heterogeneity and young age of the patient population and short study duration.²⁴ The study had a relatively high rate of adverse events associated with the new injection device (18.4%) compared with that seen with another different injection device for rhGH, which reported 8 device-related AEs (injection site hematoma, n = 3; and injection site pain, n = 5) in 7 of 136 patients (5.1%).^24,25

Switching

Currently, switching is only discussed in the context of switching from an originator insulin analog to a biosimilar insulin analog, with respect to the insulin itself. It must be remembered that such a switch will most often involve a switch in the administration device also. Given previous patient experience in switching between rhGH administration devices, a switch in the device might introduce potential dosing errors and occasional treatment lapses associated with having to learn how to use a new administration device. The impaired adherence related to patient frustration and anxiety is a relevant potential concern; therefore, any impact of switching between administration devices on patient adherence and, potentially, on efficacy in patients with diabetes should be considered.²⁶

Discussion

Although several studies have shown that functional requirements (e.g., dosing accuracy) of reusable or disposable pens for originator or biosimilar insulin analog products are within the ISO limits,^19,20,27 devices for insulin analog copies have been found to be less consistent compared with the pen devices of originator products in terms of higher dose variability and injection force required.²¹ Moreover, important features such as the end-of-content feature may be missing, which may lead to safety implications. In addition, locally made pens (manufactured in India, China, or Brazil in the referenced study) have been shown to not perform as well as originator devices in terms of ease of use and dose setting.²² However, data regarding adherence to therapy or comparisons of clinical outcomes between originator or biosimilar insulin analog devices are currently unavailable. Nevertheless, it might be that manufacturer of biosimilar insulin analogs come up with delivery devices, that may be superior to the devices used with the original insulins.

The availability of biosimilar insulin analogs is undoubtedly going to increase over the coming years, and it is important that physicians are aware of the possible challenges they present. Perhaps more so than any other long-term treatment, insulin therapy for diabetes relies not only on the insulin itself but also on the administration device to achieve optimal efficacy and safety. However, this is a topic that is under-recognized and which warrants more attention and discussion. Some additional potential questions that may arise as a result of differences among devices include whether a biosimilar insulin analog is fully compatible or will perform similarly if it were made available with a different reusable administration device because dosing and injection parameters may differ by devices; and if there are any legal or regulatory ramifications should any disparities in performance arise from such a device–drug combination.

Although the product information for some insulin analog products does include a precaution on device use, from our point of view, there is perhaps a need for product-specific guidelines for insulin analog administration devices. It is to be hoped that there will be harmonization of regulatory approaches to ensure globally comparable safety profiles of biosimilar insulin analogs and the devices used to administer these. In view of their clinical relevance, delivery devices may very well be used as discriminatory advantages for biosimilar insulin analogs in the future. It will be of interest to see how much effort the manufacturer of biosimilar insulin analogs put behind the development of devices and if they will come along with pen devices that transfer dose information automatically into the Cloud. Information about the dose applied and when the doses are applied is important information that is missing currently when it comes to data analysis. The data from blood glucose meters are available for automated data analysis but not the insulin dosing information.

In summary, various aspects of the device–drug combination of biosimilar insulin analogs and pen devices are of importance. The patient preference for delivery methods may have an association with adherence and with clinical outcomes. However, this aspect of biosimilar insulin analogs is currently under-recognized. Physicians and prescribers should be aware of potential issues when it comes to the devices used for administration of biosimilar insulin analogs to ensure they have the best options for the management of people with diabetes. Regulatory agencies should provide more guidance for approval of devices used for the administration of biosimilar insulin analogs.

Footnotes

Acknowledgments

The contents of the article and the opinions expressed within are those of the authors, and it was the decision of the authors to submit the manuscript for publication. The authors took responsibility for writing of the manuscript, including critical review and editing of each draft, and approval of the submitted version. The authors received writing/editorial support in the preparation of the manuscript provided by Katherine Roberts, PhD, of Excerpta Medica, funded by Sanofi.

Author Disclosure Statement

L.H. is an employee of Science & Co.; advisor for Biodel, Eli Lilly, Halozyme, Novo Nordisk, and Sanofi; and partner of Profil Institut für Stoffwechselforschung, Neuss, Germany, and Profil Institut for Clinical Research, San Diego, CA, United States. I.F. is an employee of Sanofi and stockholder of Sanofi. H.K. is a former employee of Sanofi. S.V.E. is a consultant for Sanofi, Lilly, and Novo Nordisk.

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