The Adherence and Outcomes Benefits of Using a Connected, Reusable Auto-Injector for Self-Injecting Biologics: A Narrative Review

Abstract

Many biologics are now self-administered by patients at home. A variety of self-injection devices are available, including vials and syringes, prefilled syringes, and spring-driven prefilled pens or auto-injectors. Each has advantages and drawbacks, and different devices suit different patients. For example, some patients have difficulty achieving consistent and successful self-injection due to poor manual dexterity, or experience anxiety at the prospect of self-injection or injection-site pain. These factors can reduce patients’ medication adherence and overall experience. Furthermore, while self-injection brings patients many benefits, the proliferation of single-use injection devices has implications for environmental sustainability, including the reliance on single-use plastics, repeated freighting requirements, and need for incineration as hazardous waste. Recently developed, innovative electromechanical auto-injector devices offer technological enhancements over existing devices to overcome some of these issues. Features include customisable injection speeds or durations, consistent rate of injection, electronic injection logs and reminders, and step-by-step, real-time instructions. Indeed, a growing body of evidence points to higher adherence rates among patients using electromechanical devices compared with other devices. Further, with time, the reusability of electromechanical devices may prove to lighten the environmental impact compared with disposable devices, especially as research continues to optimise their sustainability, driven by increased consumer demands for environmental responsibility. This narrative review discusses the differences between prefilled syringes, spring-driven prefilled pens, and electromechanical devices. It also explores how these features may help reduce injection-associated pain and anxiety, improve patient experience, connectivity and adherence, and drive sustainability of biologic drugs in future.

Plain Language Summary

Biologics are a type of medicine becoming widespread in the treatment of many diverse diseases. Biologics are injected under the skin and can sometimes be injected by patients themselves at home. Many injection devices are available to help patients with this self-injection, and fall into three broad categories: prefilled syringes, prefilled pens, and electromechanical devices. Each has its own advantages and disadvantages, and different devices suit different patients. For example, some patients have difficulty achieving consistent and successful self-injection because of limited hand movement or become anxious at the prospect of self-injection or injection-site pain. These factors can reduce patients’ ability and willingness to take medication as prescribed and may worsen their overall experience. Further, many disposable devices involve single-use plastics and may pose an environmental toll. Reusable electromechanical devices are the newest of the available devices and offer enhanced features over some earlier devices. These include customisable injection speeds or durations, consistent rates of injection, electronic injection logs, reminders, and real-time instructions. Evidence suggests that patients using electromechanical devices may have higher rates of adherence (i.e. more patients take their medication as prescribed) than those using other devices. Additionally, with time and further research, the reusability of electromechanical devices may prove to lighten the environmental impact compared with disposable devices. Here we discuss the differences between prefilled pens, prefilled syringes, and electromechanical devices, and explore the features that may help reduce injection-associated pain and anxiety, improve patient experience, connectivity, and adherence, and drive greater sustainability.

Key Summary Points

Various injection devices are available to help patients self-inject biologic medications, including vials and syringes, prefilled syringes, and spring-driven prefilled pens or auto-injectors.

Prefilled pens offer a range of benefits over prefilled syringes and are preferred by patients, although newer electromechanical devices may offer further enhancements to support disease management, including customisable injection speeds or durations, consistent rate of injection, electronic injection logs and reminders, and real-time instructions.

Together these features aim to improve patients’ experience of injection: reducing their anxiety, minimising injection-site pain, as well as offering them greater comfort and control over their injections and increased connectivity with their healthcare professionals and other devices.

A growing body of evidence points to higher adherence rates among patients using electromechanical devices compared with other devices, with adherence rates in the region of 90%.

The proliferation of single-use injection devices has implications for environmental sustainability but, with time, the reusability of electromechanical devices may deliver a lighter environmental impact than disposable devices, especially as research continues to optimise their sustainability.

Introduction

Over the last few decades, the advent of biologic medicines has caused a paradigm shift in the management of various chronic and acute medical conditions, and improved outcomes for countless patients. To name but a few, the treatment of chronic immune-mediated conditions such as rheumatoid arthritis [1], multiple sclerosis [2], chronic inflammatory bowel diseases [3], and some dermatological conditions [4] has been transformed by the availability of biologic drugs, as have other diverse fields such as oncology [5], fertility [6], and paediatric endocrinology [7, 8]. In many cases they have substantially improved disease outcomes and quality of life for patients with these conditions [9–12].

Many biologics are administered as subcutaneous injections, often by patients at home [13], and this has various benefits. Self-injection gives patients a sense of autonomy, allowing them to rely less on caregivers and healthcare providers, with reduced attendant healthcare costs [14, 15]. The ability to confidently self-inject may also reduce the psychological impact of living with a chronic condition and improve health-related quality of life [16–18].

A variety of devices for self-injection are available for biologics, including vials of powder and solvent solution for injection provided with syringes (‘vial and syringe’), prefilled syringes, and spring-driven prefilled pens or auto-injectors. Each has advantages and drawbacks, and different devices are suited to different patients [15]. For example, some patients may have difficulty achieving consistent and successful self-injection. Pain in the hands or impaired hand function can increase the difficulty of using a self-injection device and may increase the risk of drug administration errors and injection-site reactions, thereby impacting adherence [18]. Additionally, patients or their carers (or parents) may be anxious or fearful at the prospect of self-injection [15, 18–20]. Indeed, these concerns have been reported as reasons for treatment discontinuation among patients with rheumatoid arthritis [21]. Such anxieties may be most acute in those who are new to self-injecting. Some may need additional support at first; others may feel pressure to inject correctly because of the costs of some biologics and a consequent desire not to waste any product. Concerns over injection-site pain are commonly reported with subcutaneous biological agents, with the degree of pain largely dependent on formulation and device stability, and the perception or reality of pain reduces their medication adherence and overall experience [22, 23]. Reducing the physical burden of injection and providing more control and feedback to the user are desirable attributes for injection devices of any type. Indeed, well-designed injectors may help improve patients’ self-injection confidence and medication adherence.

While self-injection brings many benefits to patients, the proliferation of single-use injection devices has implications for sustainability and poses questions on reducing single-use plastics and shipping needs. Indeed, over 7.5 billion needles and syringes are used annually by people who self-inject medication, and all of these become hazardous waste after use, requiring sharps bin disposal and incineration [24].

To overcome some shortcomings with existing devices, electromechanical auto-injector devices have been recently developed to address the needs of certain patients [15]. These innovative devices have various features that aim to overcome injection hesitancy, and difficulty, and to help improve patients’ experience of self-injection. They may also help reduce plastic waste and improve sustainability. Medical devices of all kinds are now being developed that aim to reduce the resource loss and environmental damage resulting from manufacture and disposal of extracted materials in a single cycle, and indeed some auto-injectors are being developed with reusability and refurbishment in mind [25, 26].

This review will discuss the differences between prefilled syringes, traditional spring-driven prefilled pens, and newer electromechanical devices. It will also discuss how these features may help reduce injection-associated pain and anxiety, and how this may improve adherence, experience, connectivity, and sustainability of biologic drugs. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Adherence: A Big Challenge when Treating Chronic Diseases

Medication adherence—the extent to which the biologics delivered correspond to the treatment regimen prescribed by their healthcare provider [27]—is a large determinant of a medication’s overall effectiveness [28]. Ensuring adequate medication adherence is a huge challenge in many areas of medicine: estimates suggest that over a third of therapies are not taken as recommended, regardless of the seriousness of disease or condition [29]. Even for symptomatic conditions such as rheumatic diseases, reported medication adherence rates typically range from 55% to 96% [30–32], although they can be much lower. For example, a US study assessed adherence rates to various biologics for psoriatic arthritis, and found these to be poor: even the medication with the highest adherence was only 46% [33]. Similarly low rates have been reported for patients with rheumatoid arthritis and psoriasis (16–81%) [34, 35].

Poor medication adherence has been systematically shown to worsen outcomes and reduce medication effectiveness. A 2002 meta-analysis assessing the association between patient adherence and the outcomes of medical treatment found the outcome difference between patients with high and low adherence to be 26%, with the association particularly strong in patients with chronic conditions [28]. Another study showed that poor adherence among patients with insulin-dependent diabetes was associated with poor glycaemic control, as well as an increased risk of hospital admission for diabetic ketoacidosis and acute diabetes complications [36]. Further, a study of children taking growth hormone reported that after 2 years’ follow-up, children who missed more than half of their monthly doses had lower annual growth than those who missed fewer than half of their doses [37].

The Causes of Poor Adherence are Complex, Involving Patient, Psychological, and Disease Factors

Research into biologic therapies for rheumatoid arthritis suggests that adherence is influenced by various patient factors including age and socioeconomic factors [15]. For example, older patients seem more likely than younger patients to have high adherence [38–40], and more ownership of self-managing medications may also improve adherence [41]. Adverse factors contributing to non-adherence include stress at home, and unemployment [40].

Patients’ perceptions of their illness and treatment play a large role in their adherence to medications. Negative illness perception among patients with rheumatoid arthritis is significantly associated with low treatment adherence, as well as with poor disease control and comorbidity [40]. Increased treatment awareness and understanding, professional or family support, perception of medication necessity, and being in control of treatment were all associated with higher adherence [38].

Patients with chronic conditions often need to take lifelong therapies, and treatment fatigue can erode a patient’s motivation and vigilance in taking regular therapies. For example, ‘pill fatigue’ is a well-recognised problem in HIV medicine: adherence to daily oral antiretroviral therapies can sometimes wane, and this is the largest factor interfering with the success of these oral treatments [42, 43]. Indeed, similar trends are seen elsewhere: longer disease duration was associated with lower adherence in a study of patients receiving adalimumab for rheumatoid arthritis [38].

For some conditions, the symptoms of the condition itself can make adherence challenging. For example, multiple sclerosis can cause forgetfulness, depression, fatigue, and poor motor skills, which may further reduce adherence [44]. Similarly, rheumatoid arthritis impairs manual dexterity and can make treatment self-administration challenging [18, 45]. Other conditions, such as growth hormone deficiency and haemophilia, are usually diagnosed in childhood and this can carry its own adherence challenges such as adolescent lifestyles, heightened discomfort with injections, and low levels of understanding why treatments are needed [46].

Injectable Therapies have Unique Adherence Challenges

In addition to these adherence-influencing factors common to long-term therapy of any kind, some factors affecting medication adherence are unique to injectable therapies. Injection-site pain is a subjective side effect that is commonly reported with subcutaneous biological agents, including those used for rheumatoid arthritis [47]. Subcutaneous administration effectively delivers medications slowly and at a sustained rate, because fatty tissues allow the uptake of large proteins via the lymphatic system [48, 49]. However, injections into the subcutaneous space can cause local pain, either actual or perceived. This pain has many causes, resulting from a combination of irritation from the needle puncture and its location, as well as the composition of the medication, its formulation, speed of injection and location [49, 50], as well as device stability and injection technique. The pain may also be exaggerated by a patient’s feelings of anxiety and expectation.

Factors contributing to subcutaneous injection-site pain have been comprehensively reviewed by St Clair-Jones et al. [50], and fall into three categories: (1) product-related factors, including the formulation itself, mode of delivery, needle gauge size, and device type; (2) injection-related factors, including injection speed, location, technique, and frequency, as well as fluid viscosity and temperature; and (3) patient-related factors, including low body weight, injection anxiety, expectations and catastrophising, as well as some comorbidities and susceptibility to a nocebo effect.

Regardless of their cause, a patient’s perception or reality of pain associated with injections reduces their medication adherence and overall experience [22, 23]. Up to a fifth of patients can feel anxiety around the need to receive an injection [51], and for some this can reduce their confidence in being able to inject correctly [18]. In a study of adherence to anti-tumour necrosis factor alpha (anti-TNFα) therapy in patients with rheumatoid arthritis, having lower injection-site pain and skin sensations at baseline was significantly associated with an increased likelihood of medication adherence [22]. In some, catastrophising about injection pain can reduce subjective outcome achievements and the likelihood of achieving remission [23].

Data from the administration of adalimumab in patients with rheumatoid arthritis suggest that reducing injection-site pain may increase injection adherence. Over 3000 patients receiving one of two formulations of adalimumab were retrospectively studied: either the original citrate-containing formulation, or a new citrate-free formulation. Previous studies had shown the presence of citrate as an excipient to be associated with injection-site pain, so the researchers questioned whether eliminating citrate would affect medication adherence. Patients who received the citrate-free formulation were shown to have significantly greater adherence (p < 0.0001) during the 12-month follow-up period than those who received the citrate-containing formulation, and the percentage of patients with over 80% of days covered was almost 20% higher (p < 0.0001) [52]. Similar results regarding pain were seen in a phase 3 randomised trial of etanercept for rheumatoid or psoriatic arthritis. Patients who received a subcutaneous phosphate-free formulation reported significantly lower mean pain scores (p = 0.048) than patients who received the original phosphate-containing formulation, and the authors suggest that this may improve the patient experience and inform patient–physician discussions [53].

As we have seen, patient adherence is critical to access the treatment benefits that subcutaneous biologic treatments can offer, so removing obstacles to adherence is vital [54]. Since injection-site pain—both the fear and reality of it—is a significant barrier to adherence and acceptability of subcutaneous biologic formulations, efforts are being made to mitigate these effects and many approaches have been investigated [54]. One such approach is the development of drug–device combination products to aid delivery, including prefilled spring-driven devices, and electromechanical devices. The next section of this review will discuss the features of these devices and present the evidence to show how electromechanical devices may help improve adherence and offer further benefits over existing delivery approaches.

A Range of Drug Delivery Devices Provide Options for Patients who Self-Inject Biologics

Three main types of drug delivery device are available to assist patients with the self-injection of subcutaneous biologics for chronic inflammatory diseases: prefilled syringes and cartridges, prefilled pens, and (electro) mechanical auto-injector devices [15]. Prefilled syringes consist of a needle and a syringe filled with the appropriate drug, and various ergonomic variants are available to suit different patients [45]. Patients manually operate the syringe by pressing its flanges against the plunger rod to inject the drug under the skin [15]. For home use, these have the disadvantage that the patient must have the necessary force and dexterity to deliver the product, which becomes more difficult with increasing viscosity. The patient can also see the needle entering the skin, which may increase the anticipation of pain and consequently the experience of pain. Prefilled pens and auto-injector devices are designed to automate the injection process and reduce patients’ physical effort, and some available devices incorporate digital features. Prefilled pens contain a prefilled syringe or cartridge to minimise dosing errors, and instead of a manually operated plunger, injections are activated by depressing a button or the needle shield, which activates the spring-driven delivery mechanism [15]. Therefore, the delivery speed from a prefilled pen starts high when the spring is most compressed and reduces over the course of the injection (Fig. 1). The force at the end must still be high enough to overcome the plunger friction and any variation in siliconization of the container. The needle shield hides the needle from the patient and prevents access to contaminated needles after use. More advanced features include individual QR codes or a near field communication tag that can be scanned/detected using a mobile phone. Representative images of various prefilled pens are shown in Fig. 2.

Fig. 1.

Theoretical depiction of force over time: Electromechanical auto-injector devices deliver a constant force of injection across the entire stroke volume, unlike spring-driven devices that are subject to spring-force decay. Electromechanical devices can be set to inject at different speeds depending on user preference. Different approaches can be taken. The fastest injection speed of an electromechanical device may be set to replicate the injection speed of an already established prefilled pen device. Patients may select slower injection speeds to experience lower forces

Fig. 2.

Representative images left to right of prefilled pens (first 4 images) and electromechanical devices (last 5 images). Prefilled pens shown range in size up to 160 mm in height. Electromechanical devices shown range in size up to 228 mm height

Various studies have shown how prefilled pens offer a range of benefits over prefilled syringes and are preferred by patients. For example, in a phase 2 crossover study involving patients with rheumatoid arthritis, patients reported their experiences using a prefilled syringe versus a prefilled pen for self-injection of adalimumab. Patients reported experiencing less pain and higher preference for the prefilled pen and found it to be easier to use and more convenient [55]. Similar results have been reported for etanercept syringes/pens [56], adalimumab biosimilar prefilled pens [57], as well as for indications outside of rheumatology [58–60]. If well designed, prefilled pens can be discreet and not much larger than a pre-filled syringe. One disadvantage of their size is that the contact area with the skin is small, resulting in higher pressure to operate compared with larger devices.

Most recently, electromechanical auto-injector devices have been developed on the basis of earlier prefilled pen designs, but which offer more advanced technical features to support disease management, including on-screen instructions, injection logs, skin sensors, and injection speed control [15]. Electromechanical devices consist of a reusable electronic delivery device that must be loaded with a prefilled cartridge or syringe. The cartridge or syringe can be inserted into a door in the device which opens with a mechanical or electronic switch. The addition of a motor and software enables increased functionality to the user such as the control of injection speed (Fig. 1), animated on-screen instructions, clear timed feedback, and records of dosing history. Additional control of stopper travel and position may also be possible, and assistance with calculations of partial or split doses. Although electromechanical devices are generally larger than mechanical options, they can be ergonomically designed, and users may gain familiarity with just one injector for a range of prescribed medicines. Electromechanical devices with dose-dispenser cartridges are now approved for the delivery of anti-TNFα treatments for example [61–63], with the merits of several individual electromechanical devices reviewed by van den Bemt et al. [15]. See Fig. 2 for representative images of various electromechanical devices.

Electromechanical devices provide another drug delivery option that may better meet the needs of patients for whom existing options are less than optimal. Indeed, evidence suggests that having a choice of self-injection devices and using a preferred device may increase patients’ confidence and tolerance of self-injection and improve adherence [64]. In patients with multiple sclerosis, electromechanical devices are reported to be highly rated by patients, improving injection tolerability and patient satisfaction compared with manual injection and helping to increase adherence [65, 66].

As we have seen, injection-site pain—both actual and anticipated—is a key barrier to adherence and the acceptability of subcutaneous medications [22, 23]. Electromechanical devices have been developed in concert with patient groups to overcome some of the key causes of pain and hesitation, and now have several technical features that may improve the patients’ experience [15]. The next section of this review will discuss some of these technical features in detail and define how these features may help to overcome some of the limitations of prefilled syringes and pens, and possibly improve treatment compliance. A comparison of these features is shown in Table 1.

Table 1.

Comparison of the technological features of electromechanical auto-injector devices and prefilled pens

Function	Mechanical injection device	Electromechanical injection device
Instructional material	Mechanical devices rely on providing mechanical cues to the user (such as audible sounds, tactile and visual feedback); however, they rely on a user following appropriate instructional material alongside	Electronic devices can more easily cater the feedback to the user on the basis of the need. A screen can show images of how a user should interact with a device, lights can glow different colours depending on the process, and sounds can change throughout to provide positive reinforcement to the user
Error handling	When mechanical devices fail there is no indication to the user of why they have failed. Additionally, when a use error is performed it may not be clear what the user is doing incorrectly	Electronic devices contain sensors to monitor both the device functionality and the user input. If the device is not behaving as expected an error message could be provided to the user on a screen. If the user behaves incorrectly the device could tell them why what they have done is incorrect or, if required, prevent them from performing an injection until remedy actions have occurred
Needle insertion	Before injection either a user must manually insert the needle or a spring fires the needle into the skin. Both options may cause fear-induced hesitation in the user The spring-driven needle insertion requires a high force to jolt the syringe forward and insert the needle. This often comes as a sudden impulse and could make an unpleasant sound	A separate motor could provide a constant force to insert the needle into the subcutaneous layer of skin. This force only needs to be high enough to insert the needle
First contact with the stopper	When the plunger is released, the spring, at its maximum compressed force, accelerates the plunger towards the stopper with enough energy to carry the stopper movement to the end of the syringe. When the plunger hits the stopper, energy is transferred to the stopper, causing potential for high stresses through the whole syringe	The plunger moves either at a constant force or injection speed. There is no requirement to have all energy for the full injection at the start of movement so a lower force can be used
Variations in friction throughout injection	A spring-driven device relies on the spring having enough force at the start of injection to overcome any opposing forces until the end of stopper movement. This includes (but is not limited to) break-loose force, silicone variations on the glassware, stopper and glassware diameter tolerances, drug product viscosity tolerance, and needle diameter tolerance	An electronic device maintains injection speed or force by applying a voltage or current and monitoring with a feedback system. This means the system does not require large forces at the start and can rather maintain a constant, measured force or adjust the force to maintain an injection time as required
End of injection	Generally spring-driven systems create a displacement-initiated sound to inform the user when the injection is complete. As a result of tolerance requirements, the sound generally occurs slightly ahead of the plunger being in its final position, so a user is required to add a hold-time to ensure the injection is complete and minimise likelihood of a wet injection	Electronic devices can monitor plunger movement and force, knowing when the end of travel is reached. Additionally, an end of injection sound can be programmed with a hold-time built in, removing the responsibility from the user and ensuring consistency between patients
Injection history	A user is expected to track, manually, all injections performed which would have to be done separately from the device. This manual log has the possibility of being updated incorrectly if dates/times/symptoms are misremembered	An electronic device with memory would retain the entire injection history. Additionally, there is a potential for linking a phone application to automatically update with injection information from the device
Injection speed	Mechanically driven devices generally have one injection speed based on the spring stiffness and the mechanical tolerances of all the parts	Electronically driven injectors have the possibility of driving the motor with different speeds or forces. This would allow the user the option of altering the injection time on the basis of preference
Cost	Both device types have their merit from a cost perspective. Drug product volume and injection frequency both weigh into which device is preferable from a cost perspective. Generally, in lower frequencies a mechanical injection device may be the most cost-effective solution; however, additional factors such as adherence should be considered. Although electromechanical devices have a higher initial unit cost (per device), over their full lifetime they can prove to be cost neutral or even more cost-effective to the drug manufacturer compared to single-use disposable pens From a global perspective in general electromechanical devices and cartridges are often provided as an additional option to prefilled syringes, prefilled pens or syringe and vial presentations. The devices are not sold standalone, and the initial unit cost is generally absorbed by the company and provided to the health system and/or patients at no extra cost. Usually, pharmaceutical companies charge similar prices for different presentations (i.e. prefilled pen vs cartridges for electromechanical devices) In Japan, virtually all prescription drugs are reimbursed by the publicly funded National Health Insurance system with 30% or lower co-payment. Patients are required to pay an extra one-time co-payment for the electronic device at the time the reusable device is prescribed
Size	Generally, mechanical devices can be smaller as the drive system is primarily a spring held in a tube with the remaining mechanism radially contained around the drug product primary packaging	Electromechanical devices generally comprise many electronic components. Although functionality may be increased compared with a mechanical device, this comes with a size compromise and the overall package for the user is generally larger. However, cartridges are smaller than those for prefilled pens, and so take up less room in the fridge when stored; this is appreciated by patients, families, and pharmacists
Sustainability	Mechanical devices generally comprise multiple plastic components, springs, and a drug product primary container. Once used, the entire device is put into a sharps bin and incinerated. Although some energy can be reclaimed from incineration this still results in the entire device, including the spring-driven mechanism, being disposed of after each use. The footprint of the devices has implications for shipping and storage	Electronic devices are reusable so just the primary container and surrounding cartridge housing are put into the sharps bin and the rest of the device is used multiple times. There are implications from an electronic waste perspective as well as for any accessories included with the devices (cases/chargers etc.). In general, only one device needs to be shipped to a patient and then multiple cartridges of drug product (including packaging), which should overall constitute a reduction of volume/weight shipped
User experience	Instructional material used alongside the device No feedback if injection error occurs Force of injection and injection speed are not constant (manual or spring driven) User is responsible for the duration of the hold-time in order to prevent a wet injection Manual tracking of injection history Smaller than electromechanical devices but with multiple plastic components that need incineration	Interactive feedback and instruction Injection error feedback with preventative measures Motor provides constant force and injection speed (adjustable slow to fast) Hold-time is built in, ensuring consistency, and removing the responsibility from the user Device and phone app (if available) may record injection history Larger than mechanical device but ergonomically designed. Small cartridges use less fridge space and the device is reusable

Electromechanical Devices have Various Features that Distinguish them from Pens and Syringes, Improving Patient Comfort and Possibly Improving Adherence

Electromechanical Devices May Reduce Injection-Related Anxiety

Anticipation of the pain of injection can cause patients to hesitate and may impact their overall treatment experience [23, 50]. When using a prefilled syringe or pen, a patient must either manually insert the needle into their skin or press a button that deploys a spring-driven needle. With some prefilled pens, the spring-driven mechanism uses significant force to jolt the syringe forwards, and for some devices this causes an impulse and sound, which can be surprising and disturbing for the patient. The spring force reduces as the spring extends and is therefore at its maximum at the start of the injection when inserting the needle. Therefore, unfortunately, the jolt cannot be reduced because the force must still be high enough to deliver the drug product even at the end of the injection stroke.

As with some prefilled pens, electromechanical devices have hidden needles to reduce associated anxiety [61, 67]. They can also have a separate motor that provides a constant force while deploying the needle, to prevent any sudden jolts. This force only needs to be high enough to insert the needle; there is no requirement to release all the energy for the full injection at the start of movement. Further, the electronic drive system has a large and well-controlled power reserve, meaning it can overcome the break-loose force to start the stopper moving while still controlling the rate of injection.

Since some patients feel concern and anxiety about being able to carry out self-injection procedures correctly [18], a device that is easier to use and less prone to user error may be valuable, especially for elderly patients [15, 68]. Some electromechanical devices give step-by-step instructions or have compatible training cartridges to help those who are new to self-injection achieve the correct technique and build their confidence, reducing anxieties and concerns over drug wastage.

Electromechanical Devices Allow the User a Greater Degree of Control over Their Injections

Speed of injection may also be a key mediator of injection-site pain, as well as patient acceptability and treatment adherence [22, 50]. Spring-driven systems are generally sized to ensure delivery of the full dose, but afterwards have no mechanisms to control the rate of injection. At this point, injection rate is driven by the physics of spring-force decay versus the resistive force of the syringe barrel and liquid flow through the needle.

By contrast, many electromechanical devices allow the user to select their preferred speed or duration of injection from typically three or four options, giving them greater control over their injections [61, 67, 69, 70]. Since evidence suggests that patients are more likely to feel satisfied with self-injecting biologics if they feel in control of the administration process, the ability to alter the speed or duration of injection may improve satisfaction and adherence [70].

Electromechanical Devices Deliver the Injection at a Constant Rate

Injection rate and the force required to inject are important parameters for self-injectable formulations, and this is impacted by formulation, needle size, container shape, and grip ergonomics. Higher injection forces reduce the user’s control of the device stability during injection, and this affects the pain associated with injections [71]. Evidence from patients with diabetes who self-inject insulin suggests that needle size and length also play a role in device acceptability [72]. By allowing adjustment of injection speed or duration, and concealment of the needle during injection, electromechanical devices may assist patients to overcome the psychological barriers to self-injection and improve comfort [73].

When using mechanical devices, the force required at the end of delivery varies depending on the break-loose force, silicone variations on the glassware, stopper, and glassware diameter tolerances, drug product viscosity tolerance, and needle diameter tolerance. For a spring-driven device, variations in these resistive forces can lead to variation in injection times. Electronic devices maintain a more consistent injection speed by applying a voltage or current, and monitoring with a feedback system (Fig. 1). Because the full force is available throughout the entire injection stroke, the electromechanical system can accommodate variations in resistive forces.

Electromechanical Devices May Improve Patient Experience, Ease of Injection, and Connectivity

Typically, spring-driven systems create a displacement-initiated sound to inform the user when the injection is complete. As a result of tolerance requirements, this typically happens slightly before the plunger is in its final position, meaning that users must be instructed to hold the injector in place for a while after hearing the sound before removing. Removing the pen from the skin prematurely may result in a ‘wet’ injection, with drug discharged onto the skin or clothing. Contrastingly, electromechanical devices can monitor plunger movement and force, and sense when the end of travel is reached. An end-of-dose sound is software-controlled and programmable, reducing the training needed to understand when the injection is complete and the device can be removed [61, 67, 69, 70], and making injection technique consistent and easier to explain to new users. The audio-visual end-of-dose indication sounds only after the end of the full stroke time and hold-time, meaning the user can be confident exactly when it is safe to remove the device. Furthermore, the hold-time (the time between the plunger having been completely depressed and being at its final position until the needle is withdrawn from the skin) is programmable to further minimise the chances of uncomfortable wet injections or drug wastage.

Electromechanical devices may enable easier self-administration for patients with impaired manual dexterity or inflamed joints. While typically larger than mechanical devices, owing to the need to accommodate reusable electronic components, electronic devices are designed to be ergonomic, with buttons positioned to allow easy pressing, allowing easy use with just the thumb, rather than requiring complex dexterity involving the whole hand. Indeed, users of abatacept or certolizumab pegol for rheumatoid arthritis rated such ergonomic factors highly in their assessment of overall device acceptability [69, 74]. Furthermore, in a study evaluating an electromechanical device for injection of certolizumab pegol, subgroup analysis revealed that those with hand impairment were more likely to prefer the electromechanical devices (over prefilled syringes) than patients without hand impairment [70]. Electromechanical devices can also more easily cater their feedback to a user, based on their need. A screen can show images of how a user should interact with a device; lights can glow different colours depending on the process; and sounds can change throughout to provide positive reinforcement, and confidence, to the user.

Some electromechanical devices incorporate a skin sensor that ensures the device is correctly positioned on a patient’s skin before beginning the injection [69]. Such devices will not activate in air, helping to reduce misfire and thus drug wastage [17]. Electromechanical devices are programmable in advance with dosing strengths and schedules and can give reminders when injections are due, or when the last dose was given [69, 75]. They also offer injection logs to capture usage information, and this can sometimes be downloaded to mobile phone apps, helping patients to be more active in managing their care in partnership with their physicians. As an additional safety feature, some devices can warn a patient should they not complete a prepared injection, or they are about to administer another one too soon after the last. These features may prevent accidental overdoses and increase the likelihood of adherence.

Electromechanical devices may improve pharmacovigilance and medical device reporting data. Some also record injection history, which supports better communication between patients and healthcare professionals (HCPs) about self-injection patterns [15]. This information can then be downloaded onto an app to help patients understand their usage patterns and discuss this with their HCPs. Others record product identification, lot number and expiry information, incorporate anti-counterfeiting precautions, and sense device malfunction and provide error messages.

The value of many of these features was recently shown by Boeri et al. [17]. When, as part of a discrete-choice experiment, they investigated rheumatology patients’ willingness to pay for various features of a next-generation self-injection device, they found a skin sensor to be the most preferred feature, followed by injection speed control, injection reminders, and an electronic log.

Electromechanical Devices May Increase Adherence

A growing body of evidence is showing that patients can benefit from electromechanical devices when compared with prefilled pens or syringes [69, 70, 74], and that they may improve patients’ adherence. Moccia et al. did a retrospective study of an electromechanical device for injecting interferon β-1a for 114 patients with relapsing–remitting multiple sclerosis. They found that with around 1.5 years’ follow-up, 95% of patients adhered to therapy, of whom over a third (37.7%) were fully adherent, having missed no doses over the study period (follow-up 1.5 ± 1.0 years) [76]. This study utilised the inbuilt injection log feature of the electromechanical devices, permitting an objective measurement of adherence that was independent of patients’ recall, and a reliable record of administered or missed doses that could facilitate patient–physician conversations. Together, these results suggest that the injection logging features may improve patients’ adherence to their prescribed dosing schedule.

A similar study with the same electromechanical devices showed comparable results in the longer term: median adherence was 96.5% over the entire 5-year study period, with a median treatment duration of 979 days [77]. Other studies—including one with over 50,000 patients [78]—have found adherence rates to be as low as 39% with conventional, manually injected presentations [79, 80]. Edo Solsona et al. also reported that in patients with relapsing–remitting multiple sclerosis who were self-injecting interferon β-1a, increased adherence correlated with better clinical outcomes, including relapse risk (odds ratio 0.953; 95% confidence interval 0.912–0.995). Indeed, every percentage unit increase in adherence resulted in a 4.7% decrease in relapse incidence [77]. Over the study period, 77.3% of patients were relapse-free.

These studies, and others with similar findings [81, 82], provide powerful evidence showing how electromechanical devices may go some way to improving self-injection adherence in some patients with chronic diseases.

Considerations for the Sustainability of Auto-Injectors

Mechanical devices generally comprise multiple plastic components, springs, and a drug product cartridge. Once used, the entire device must be disposed of in a sharps bin and either incinerated or landfilled [24]. This wastes resources, and the single-use plastic burden is substantial, and this is an increasing concern to those who use these products. Furthermore, their single-use nature means these devices need to be shipped repeatedly to users, producing considerable CO₂ emissions. Contrastingly, electromechanical devices are reusable, so after each use only the drug container and its surrounding housing needs sharps bin and incineration disposal. Since sharps bins themselves are unrecyclable, single-use plastics, it is desirable to use as few as possible. The disposable components of electromechanical devices are smaller than prefilled pens and so take up less space in bins (and in patients’ fridges; an attribute appreciated by both patients and their families); this may help further reduce the single-use plastics burden by reducing the frequency of bin replacement. Only the drug cartridges need repeated shipping, reducing packaging and freighting needs. However, end-of-life disposal needs for electronic components may offset some of these gains, and differences in manufacturing, supply chain, cold storage, international freight, and distribution mean that the environmental impacts of reusable devices are difficult to quantify and need further study.

Given the scale of single-use plastics use associated with self-injection [24], the feasibility of used-device refurbishment—i.e. their disassembly, repair, testing, and repackaging, and redelivery to customers [25]—as well as built-in sustainability, may become key topics of research as companies seek to reduce the environmental impact of self-injection devices. Refurbishment is already well established for high-value consumer electronics such as phones and tablets, as is sustainable design. An example of a sustainable design concept for medical devices is facilitate disassembly—a principle ensuring that ease of separating the devices’ parts is built into a device’s design, to facilitate materials recovery and resynthesis at the end of its life [25].

Some injection devices in development, such as the Phillips–Medisize Aria^® auto-injector, are being developed with sustainability, reusability, and refurbishment specifically in mind [25]. The SmartClic^® made by PHC Corporation may reduce single-use plastic by around 40% over its lifetime compared with prefilled pens [83].

Other innovations, such as the use of bioplastics, improvements in outer packaging, and recycling schemes for drug delivery cassettes and electronic components, may further reduce the environmental impact of electromechanical devices in future [25].

Conclusions

Self-injectable biologics have various benefits to patients, caregivers, and health systems, and their use is becoming more widespread as these benefits are being realised. Prefilled syringes and pens have been available for some years to assist patients with self-injection, and both are extremely useful and valued options for patients who self-inject and offer various advantages over vials and syringes. However, prefilled pens and syringes are not suitable for everyone, and some patient needs remain unmet, meaning there is room for further improvement: notably in reducing injection-site pain, suboptimal adherence, and the large single-use plastics burden associated with prefilled pens.

Electromechanical devices are new innovations that offer technological enhancements over some prefilled syringes and pens. These include customisable injection speeds or durations, consistent rate of injection, electronic injection logs and reminders, and step-by-step, real-time instructions. Together these aim to improve patients’ experience of injection: reducing their anxiety, minimising injection-site pain, as well as offering them greater comfort and control over their injections. Indeed, a growing body of evidence points to higher adherence rates among patients using electromechanical devices compared with other devices, with adherence rates in the region of 90%.

With time, the reusability of electromechanical devices may prove to have a lighter environmental impact compared with disposable devices, especially as research continues to optimise their sustainability, driven by increased consumer demands for environmental responsibility.

These innovative devices provide a welcome addition to the landscape of self-injection devices, which we hope will make accessible the benefits of self-injection to a wider group of people who need them.

Author Contributions

A Antalfy, K Berman, C Everitt, R Alten, M Latymer and CM Godfrey contributed to content, commented on, and revised the manuscript at every stage, and read and approved the final manuscript for submission.

Funding

This review was funded by Pfizer. The Rapid service fee for publication was funded by Pfizer.

Declarations

Conflict of Interest

Claire Everitt, Kyle Berman, Charles M Godfrey, and Mark Latymer are employees of Pfizer and hold stock and/or stock options with Pfizer. Attila Antalfy is a former employee of Pfizer and holds stock and/or stock options with Pfizer. Rieke Alten discloses interests with AbbVie, BMS, Celltrion, Galapagos, Lilly, Janssen, Novartis, and Pfizer.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.