Over the last decade or so, the trend toward self-administration of injectable drug therapies has grown in an increasing number of disease states — including auto-immune diseases (such as rheumatoid arthritis, lupus and psoriasis), diabetes, multiple sclerosis, and chronic pain management, and is emerging in others, such as the long-term management of asthma and chronic obstructive pulmonary disease (COPD), high cholesterol, hemophilia disorders, mental health and certain cancers. Increasingly, patients with one or more chronic diseases face greater responsibility to manage their treatment regimens, typically by self-administered subcutaneous injection at home. This creates a great burden — and in many cases, increased anxiety — for many patients. If emotional and logistical obstacles are not effectively overcome, adherence to therapy will suffer, leading to less-than-optimal clinical outcomes.
Today’s advanced drug-administration devices must overcome a variety of hurdles related to factors such as pain, mechanical complexity, physical dexterity or cognitive challenges, and needle phobia, all of which can undermine the success of any at-home drug-administration device and can help patients to justify skipping their medication — often without the physician’s knowledge. The stakes are high and this has upped the ante for both developers of subcutaneous drug formulations and the makers of the advanced devices used to administer them at home, as these parties often collaborate closely to develop and commercialize specific drug-device combination products.
“These pressures have led to an ongoing evolution in self-injection devices and delivery technologies that are aimed at making it easier and more reliable for the patient,” says Graham Reynolds, VP and GM, Biologics, for West Pharmaceutical Services (Exton, PA). “The drug-delivery challenge is compounded by the fact that today’s high-cost biologic therapies (such as monoclonal antibodies and therapeutic proteins) tend to be very complicated molecules that often come in high-viscosity formulations and must be dosed at higher concentrations — inherent factors that often make them incompatible with traditional syringe or auto-injection devices that use very slender needles and typically have an upper dosing limit of 1 mL or so.” By contrast, many of today’s advanced wearable and handheld drug-administration devices rely on prefilled cartridges, and are able to administer 2, 3 or even 10 mL of the medication in a single dosing episode.
A wearable drug-administration device is loosely defined as a hands-free device that adheres to the body and administers the medication over some extended period of time (typically minutes or hours). Such advanced devices are often able to ease administration, reduce pain, and minimize overall hassle factor compared to traditional syringes and legacy auto-injection devices. This can help patients to adhere more faithfully to therapy and not skip doses.
“Through extensive patient interactions and user studies, we continue to make ongoing design improvement, with the goal of making the device as easy as possible to use, with minimal steps and minimal discomfort, and we continue to innovate on how to administer even-larger-dose volumes, because we believe ultimately all of these improvements will continue to have a direct impact on adherence,” says Reynolds of West. “You have to design a device that patients really want to use — not just something they have to use.”
As noted, such advanced devices are proving to be particularly valuable for the delivery of biologic therapies, which typically require subcutaneous administration in doses that can be two to ten times as high as the doses required for traditional small-molecule drugs. “Because today’s auto-injector devices are typically limited to delivering a drug payload of up to 1.2 mL, this limitation has created a sweet spot for today’s newer devices to enable subcutaneous drug delivery,” says Wendy Dwyer, Chief Business Officer for Portal Instruments (Cambridge, MA).
The ability of these devices to administer larger doses in a single sitting has also opened the door for drug manufacturers to expand existing drug franchises, for instance, by pursuing a new version that enjoys less-frequent dosing protocols — going from, say, daily or weekly dosing to monthly dosing. The ability to offer a monthly dosing option not only reduces the burden for patients (and thus can help to improve adherence to therapy), but can also be an important market differentiator for a drug that is competing in a crowded therapeutic space. “This trend toward less-frequent dosing options demands a different administration option, and has been a big driving force for ongoing advances with these types of wearable device technology platforms in recent years,” notes Reynolds of West.
When Amgen (Thousand Oaks, CA) received FDA approval in July 2016 for the its new monthly, single-dose monthly injection option for Repatha (evolocumab; a PCSK9 inhibitor for the treatment of high cholesterol), the drug-device combination was predicated on the use of a wearable on-body infuser with prefilled cartridge, dubbed Pushtronex, from West Pharma, and is based on West’s SmartDose technology platform. In February 2017, this monthly form of Repatha received EU approval. The wearable Pushtronex device allows the single 420-mg dose of Repatha (in a 3.5-mL solution) to be administered subcutaneously, in just nine minutes, says Reynolds. Once the patient puts the pre-filled drug cartridge into the Pushtronex device, peels off the adhesive packing and sticks the device to the skin, a push of a button forces a small needle to deliver the drug subcutaneously in a matter of minutes. Onboard electronics show when the drug administration is done and it’s okay to remove and dispose of the device.
“Today’s high-cost biologics aren’t going to work if the patient isn’t going to take them as prescribed,” says Reynolds of West. Toward that end, West developed the SmartDose technology platform with extensive human factors testing and analysis to understand the interaction between the patient and the delivery system, he says. Today, the SmartDose platform devices can deliver 3.5-mL and 10-mL doses of relatively high-viscosity drug formulations subcutaneously, helping to ease and shorten injection times and reduce patient discomfort.
“Early prototypes of wearable devices have been sometimes cumbersome, so human factors testing, will be important, and should be confirmed in longer-term studies of such advanced drug-delivery systems,” says Viveca Livezey, MD, medical director for Parexel. “Additionally, if these devices store patient information, concerns with maintaining patient privacy, wireless connectivity and cloud systems must be addressed by device manufacturers and their biopharma partners.” Finally, she notes that these wearables typically require recharging and have battery lives, which may limit their use in certain disease states.
Removing barriers, adding incentives
In addition to making drug administration as hassle- and pain-free as possible, West’s SmartDose drug-administration devices offer patients further motivation by allowing them to download an optional app and link adherence to therapy with a reward or gamification program offered by HealthPrize Technologies (Norwalk, CT). For example, every time the patient completes a dose of the medication, he or she enters the information into the app, which is linked with rewards and gamification options. “For some patients, this interactive rewards-based approach is more effective than just receiving reminder alerts to take or refill their medication,” says Reynolds. Patients who have access to the HealthPrize platform accumulate points for engaging in healthy behaviors, such as refilling prescriptions, administering their medications at home, taking educational quizzes and more, and can then redeem those points for real-world prizes, such as gift cards or charity donations, giving patients one more reason to engage.
Form and function
Device makers are striving to develop products that combine ergonomic design with advanced technological capabilities, data capture and data analytics, in order to encourage consistent use of the device. Ease-of-use features — such as the need to simply push a button rather than depress a syringe plunger to initiate drug administration, and the use of visual and audible indications once dose administration is complete — can be particularly important for patients with cognitive or dexterity challenges.
Improved adherence to therapy has the potential to improve health outcomes, potentially reducing long-terms costs for payers by avoiding additional hospitalization, emergency room visits and medication use to help patients deal with uncontrolled symptoms of their chronic conditions. And for drug makers, it can help to driving sales and protect market share.
Meanwhile, advanced data-collection and data-analytics capabilities can help these wearable and handheld drug-administration devices to a more seamless bridge to both physicians and caregivers, to support the patient and bring fresh insight to physicians treating patients with chronic conditions. “Up to now, physicians have traditionally been relying on patient-reported outcomes to help guide ongoing care, but such devices open the door for greater availability of empirical data that shows what the results really are, and can even be compared with additional patient-reported details,” says John J. Doyle, SVP & GM, real-world & analytic services, IQVIA, and faculty member, Department of Epidemiology, Mailman School of Public Health, Columbia University.
For instance, too often, physicians are dependent on patient-reported changes in their symptoms or vital signs (such as glucose levels or blood pressure), and often lose track of the patient’s ongoing experience between office visits.
By contrast, when a digitally enabled wearable and handheld drug-dispensing devices is able to collect, communicate and analyze such data in a timely, reliable fashion — that information can be stored in the cloud (to be accessed later, when needed), or integrated into an EHR system. Such a rich data stream has the potential to further improve the quality of care and increases the opportunity for more-timely interventions.
“Adding further value, some wearable devices are also equipped with added capabilities, enabling them to monitor signs and symptoms of the underlying disease,” says Livezey. For instance, she notes that in neurological disease, wearable devices embedded accelerometers are being used to monitor and track movements in diseases such as Parkinson’s disease, multiple sclerosis and stroke. “We have conducted studies and partnered with companies aiming to investigate how data derived from these wearables can help improve diagnosis, aid in recognition of symptoms on a continuous basis, and improve quality of care, including titration of medications,” says Lizezey.
Any disorder that relies on self-administration of medication would benefit from the ability to obtain more data on safety and effectiveness during drug dispensing outside of the clinical setting has the potential to benefit from the use of today’s advanced wearable and handheld devices, notes Michelle Hoiseth VP, real-world data services for Parexel.
“Beyond the clinical advantages of capturing a richer data stream, regulators are also increasingly receptive to the use of real-world data (RWD) that can be collected from such drug-administration devices and translated into real-world evidence (RWE) to prove the drug therapy is safe, effective and economical,” says Doyle of IQVIA. “In recent years, we’ve seen both FDA and EMA really warming to the use of RWE during the regulatory-approval process.”
For instance, in August 2017, FDA issued non-binding recommendations, entitled The Use of Real-World Evidence to Support Regulatory Decision-Making for Medical Devices.” : “FDA recognizes that a wealth of RWD covering medical device experience exists and is routinely collected in the course of treatment and management of patients. Data collected during clinical care or in the home setting may not have the same quality controls as data collected within a clinical trial setting. Even so, under certain circumstances RWD may be of sufficient quality to help inform or augment FDA’s understanding of the benefit-risk profile of devices at various points in their life cycle. RWD…may provide new insights into the performance and clinical outcomes associated with medical device use. This information can potentially be used by sponsors to demonstrate compliance with regulatory requirements and to aid FDA in our regulatory decision-making.”
When it comes to using wearable diagnostic and drug-delivery devices in applied research settings and clinical trials, in order to demonstrate the value that they bring and support regulatory approval, Parexel works closely with both device maker and pharmaceutical company to design the studies, analyze the resulting data, advise on market-access issues, write the clinical study report, and support submissions for regulatory approval and reimbursement, says Hoiseth. “The effective use of wearable health devices is crucial to our ability to deliver patient-centric solutions in research, respond to the requirements of regulators to consider real-world data, and to provide the evidence required to define the value of therapy,” she adds.
The Agency also recognizes the value of post-marketing data collected during use once the product is on the market already, writing: “Aggregation of RWD (e.g., in medical device registries) may prove useful as a postmarket control suitable for providing ongoing device safety surveillance and additional evidence for effectiveness… FDA believes that applying postmarket controls to reduce premarket data collection, when appropriate, can help improve patient access to safe and effective medical devices. “
Making the data relevant
As this nascent field of data-enabled wearable and handheld devices to ease drug administration continues to mature, Doyle of IQVIA cautions against the tendency of some wearable devices to “add digital capabilities just for the sake of being digital.” Instead, he says, the types of digital data that is to be collected and communicated “must be able to be translated to proof points that make a compelling case for regulators and payers — data that can demonstrate that the therapy or device is working better, and is resulting in improved patient adherence and better health outcomes that ultimately translate into better economic value for all stakeholders.”
To be truly useful, the data generated by these advanced devices should have the following hallmarks says Doyle:
- Validity — actually reflecting some relevant parameter
- Reliability — in terms of ensuring consistency of the data collected both for individual patients, and for different patient cohorts using the device
- Utility — in terms of whether the data collected can really make a difference in overcoming obstacles and supporting adherence objectives, and demonstrating the ultimate impact of using the device on health outcomes.
“Regardless of the indication for the wearable device, using a structured assessment of measurement sensitivity and reliability, intuitive ease of use, minimal intrusiveness, data-transmission and device performance and monitoring functions, and ability to meet the data analytics requirements are the key considerations to ensure an optimal design that will be widely used,” adds Hoiseth of Parexel.
Taking the story to payers
“The challenge for companies marketing today’s biologic therapies is to demonstrate the clinical value of these high-cost products — and to provide information that demonstrates the impact on adherence to therapy and ultimately, the improvement on the overall health outcomes for patients and for society as a whole,” says Reynolds of West. “The ability to maintain and demonstrate desired clinical outcomes for patients depends heavily on being able to confirm appropriate medication use and being able to detect clinical deterioration as soon as possible.”
“Many payers are skeptical of adherence programs offered by drug manufacturers, viewing them as thinly veiled marketing programs to sell more drugs,” Doyle continues. “But when drug makers can put a solid, data-rich story behind it, payers are more likely to be receptive because they know that adherent patients are cost-effective patients. Thus, the onus is on the pharma company and the makers of the wearable devices to incorporate the most robust data-analytics offerings possible into these advanced devices.”
Ultimately, such RWD and RWE — if robust enough — may be able to be used to support so-called outcomes-based agreements (OBA) for results-based pricing and reimbursement. These types of contracts aim to pin the drug’s price point, reimbursement rate or applicable rebates to actual performance in the marketplace. “We’ve seen a steady drumbeat of these kinds of contracts in recent years, especially with high-cost specialty medications, and in disease states (such as diabetes and mental health) where reliable use of the drug therapy is so closely linked with outcomes and the ability to reduce further hospitalization and other costly interventions,” says Doyle. “As such, you can imaging a growing number of OBA arrangements that are rooted in the data coming directly from these advanced wearable and handheld drug-administration devices,” he adds.
In marketing its Neulasta Opro Kit, Amgen emphasizes its patient-centric appeal, uses the advertising tag line “Enjoy the comforts of home.” This drug-device combination allows patients undergoing chemotherapy treatment to receive a needed dose of Amgen’s Neulasta (pegfilgrastim), an adjunct therapy that is widely used to boost white blood cell counts and help reduce the risk of infection following chemotherapy — the day after receiving treatment, thus helping them to avoid another trip back to the physician’s office or clinic. Once the healthcare provider applies the small, lightweight, pre-loaded On-body Injector device to the patient’s skin, it automatically delivers the Neulasta dose over 45 minutes, approximately 27 hours after chemo. The patient then removes and discards the device. “This improved administration option not only provides patients with the freedom and independence they seek, but the optimally timed delivery gives peace of mind to physicians and caregivers knowing it helps fight the risk of infection,” says the company.
Rethinking the traditional syringe and legacy auto-injector
To overcome the traditional limitations of legacy auto-injection devices and improve the self-administration of high-volume, high-viscosity biologic therapies, Portal Instruments has commercialized a needle-free, digitally controlled jet-injection device, called Prime. While not a wearable device, this easy-to-use, handheld drug-administration device is designed to enable the subcutaneous injection of high-viscosity biologic drugs with less pain for the patient and without the anxiety of handling and disposing needles.
The Portal Prime device uses sophisticated electronics to generate a thin jet of liquid medication. This allows it to pierce the skin to reach the desired subcutaneous, intradermal, or intramuscular space in a relatively pain-free manner. Overcoming one of the key limitations of legacy auto-injector devices, Portal’s Prime device is “agnostic to viscosity,” says Dwyer, relying instead on a finely tunable actuator mechanism that generates the high forces needed. “This unique capability enables the device to reliably deliver monoclonal antibodies and other large therapeutic proteins,” she says.
Suitable therapies are in rheumatology, gastroenterology, dermatology, diabetes, gastro-intestinal and opthamology indications, among others — essentially any medication that now relies on traditional auto-injectors, says Dwyer. Similarly, she notes that biologics aimed at pediatric indications are good candidates for the needle-free Prime device “because no mother likes to give her child an injection with a needle on a regular basis.”
The device can be Bluetooth-enabled for data collection and reporting. “This data-capture process is guided by disease-specific questions and prompts developed with the help of KOLs in each disease state,” says Dwyer. Last October, Portal entered its first pivotal commercial agreement with Takeda Pharmaceutical — valued at $100 million — to combine Portal’s needle-free drug-delivery device with the pharmaceutical company’s biologic medicines aimed at inflammatory bowel diseases. Takeda is currently carrying out Phase III clinical trials to investigate the efficacy and safety of the device with a subcutaneous form of Entyvio (vedolizumab) — a monoclonal antibody for the treatment of ulcerative colitis (UC) or Crohn’s disease (CD), which is currently administered through intravenous infusion — for adults with moderate to severely active UC or CD.
“Takeda gets a period of limited exclusivity to use the device within its competitive space, and Portal received an upfront payment, success-based milestone payments and ongoing royalties,” explains Dwyer. “Such an arrangement brings value to the drug manufacturer, allowing market differentiation against any competitors in the same therapeutic space.” She notes that the company is working to finalize additional partnerships with a variety of drug manufacturers across many different disease states, adding: “On a cost basis, we’re comparable to auto-injectors on a cost-per-injection basis, so that won’t be a major hurdle for us, and the economies of scale will continue to drive our cost down as more of these pharma partnerships are finalized.” Sanofi is an early investor in Portal Instruments, and has a seat on the company’s Board of Directors.
Outsmarting blood-glucose highs and lows
Regular glucose monitoring is a way of life for patients with diabetes, and is typically carried out with patients pricking their fingers and placing a drop of blood on a test strip. While this approach provides accurate results, each test strip only verifies the patient’s glucose level at one point in time.
By contrast, continuous glucose monitors (CGM) provide real-time, continuous monitoring, allowing patients to gain greater insight into blood-glucose patterns over time, and to identify blood-glucose excursions much sooner — even in advance of the event.
In March, Medtronic plc received FDA approval for its Guardian Connect Continuous Glucose (CGM) system for people with diabetes who inject insulin. It combines continuous blood-glucose monitoring with predictive alerts to help patients identify and manage high and low glucose excursions more proactively.
At the heart of the system is the wearable Guardian Sensor 3, which collects realtime glucose levels, a slim sensor that can be worn up to seven days on the abdomen or upper arm. It measures glucose levels from the interstitial fluid under the skin.
A discreet Bluetooth transmitter (that can be worn almost anywhere on the body) sends glucose readings every five minutes to the Guardian Connect app (which displays sensor glucose data, trends and alerts in a straightforward format that can be easily accessed via smart phone), a wearable monitor, or an insulin pump every five minutes, helping the patient to control blood glucose levels and ultimately maintain AIC levels in the desired range.
Using proprietary, predictive diabetes-related algorithms from Medtronic and artificial intelligence technology from IBM Watson Health, the data are continually analyzed and the system alerts patients (and their caregivers) to potential high-glucose (hyperglycemia) and low-glucose (hypoglycemia) events up to 10 to 60 minutes in advance of the event, says Todd Robin, VP of Connected Care, Medtronic Diabetes Group (Northridge, CA). “According to one study, we know that three out of five people with diabetes are very worried about the risk of hypoglycemia, and another study confirms that ‘fingersticks’ alone (to draw blood manually and test it using a blood-sugar test strip) can miss up to 78% of high and low blood sugar episodes,” he says. [2, 3]
Medtronic layers other digital services on the Guardian Connect app, including CareLink diabetes-management software and Sugar.IQ, which analyzes how an individual’s glucose levels responds to their food intake, insulin dosages, daily routines and other factors.
West Pharmaceutical Services also offers a comprehensive CGM technology platform that is available for drug manufacturers in the diabetes market.
“These types of smart, wearable drug-delivery devices hold the potential to change the way that healthcare decisions are made — by creating greater insight throughout the patient’s healthcare journey, and an opportunity to either alert patients to risks they face, or enable rapid determination of needed treatment changes earlier, based on the availability of realtime data that is generated outside the clinical setting,” says Hoiseth of Parexel. “In this way, wearables have the potential to reduce the total cost of healthcare for a patient, doing much more to deliver affordable care than just the controlling the cost of pharmaceuticals can alone. As such, we expect to see increases in the number of studies that evaluate these device-related interventions in concert with the biopharmaceutical product under study.”
2 Kaufman FR, Gibson LC, Halvorson M, et al. A pilot study of the continuous glucose monitoring system. Diabetes Care. 2001;24(12):2030-2034.
3 Nicolucci, A, Kovacs Burns, K. et al. Diabetic Medicine. 30, 767–777 (2013). Research: Educational and Psychological Issues Diabetes Attitudes, Wishes and Needs second study.