At Enable Injections, we have developed a novel wearable, large volume subcutaneous infusor called the enFuse™. The enFuse is a fascinating design, elegant in its simplicity. As an engineer myself, I marvel at the creativity and skill that has gone into designing and building this innovative delivery device. Enable employees have spent thousands of hours optimizing our technology with the patient in mind. We are all passionate about delivering a superior technology that changes patient lives. The FDA classifies the enFuse as the device constituent of a combination product, which means that in order for the enFuse to deliver on that promise, it must be combined with a drug therapy. Since Enable is a device company, not a drug company, this means that partnerships are critical to our mission.
The Importance of Partnerships
Alliances and partnerships have become pervasive in global industries in the past 20 years. In the biopharmaceutical industry, innovation-based partnerships are a key means of growth. In Q1 of 2019 alone, PricewaterhouseCoopers measured 52 Pharma and Life Science deals worth a staggering $147.3 Billion! Most, if not all, of the top 20 pharmaceutical companies have created internal Alliance Management organizations solely structured to help ensure that these alliances deliver the value intended. I was fortunate enough to be a part of one of the first, the Office of Alliance Management at Eli Lilly and Company in 2000.
Why have so many companies invested so much into the competency of Alliance Management? It is because strategic alliances are difficult and often fail. Based on a 2015 Vantage Partners survey, only 41% of strategic alliances fully achieve their stated objectives. When two organizations combine with different cultures, capabilities, incentives, working styles, operating practices, and risk profiles, the collaboration is bound to have challenges. Without the right expertise and support, the alliance relies on luck to achieve its goals.
While all alliances are challenging, additional challenges emerge when companies in different industries partner. For example, much has been made of the tech titans entering the healthcare space. Pharma and other healthcare companies are now partnering with companies like Google, Amazon, IBM and others that grew up in the world of technology. Putting these companies together is like mixing oil and water. On one hand, the risk averse, highly-regulated companies have rigid processes to manage quality and patient safety and have lengthy product development life cycles of 10 years. On the other, companies that are bred and trained to take risks operate by moving quickly to stave off extinction. These two different types of companies speak different languages with different acronyms that could fill volumes. These types of counter-cultural partnerships require real work to ensure the relationship works well and achieves its goals.
Partnerships with Combination Products
We face similar challenges in the combination product realm. Device companies are staffed with engineers and human factors experts, among others. Pharma companies are life science-based, with chemists, biologists, clinicians, toxicologists and the like. Product design and development processes and development cycles are vastly different. We, too, use different language and acronyms and typically work at a different pace. But at the core, we find commonality in our focus on patients. That is where the magic happens. Whatever differences and challenges we have can be simplified by being reminded of our common bond and the impact we can only have by working together.
We have done a couple of things at Enable to try to maximize our partnership success. First, we have augmented our device expertise by bringing in staff with pharmaceutical backgrounds. Having the combined expertise in-house allows us to more easily consider multiple perspectives, translate terminology, and predict intentions and incentives. We spend a lot of time educating each other, which helps us immensely as we work with our pharma partners. Second, we have invested in establishing an alliance management competency. Many of our partners, unfortunately, don’t allocate their alliance management resources to device partnerships, so we believe by assuring we are implementing best practices in support of the relationship, we can maximize success and ensure that our joint innovation reaches its intended target – the patient. We are still growing and evolving but have established a solid foundation.
One last thought on the topic of partnerships. We tend to think broadly about the partnerships that will be necessary to deliver our disruptive technology: the four P’s – Pharma, Patients, Physicians and Payers. We will have to work effectively with all four if we are to be successful.
We are working to ensure we have active and continuous dialog with each of them. We don’t have all the answers yet and only by working together will those answers be developed. However, patients must remain at the center. While not a “consumer-facing” company, our enFuse device will soon be used daily by millions of patients around the globe. We have conducted many, many, studies to ensure we really understand them – what is important to them, what they worry about, what they like and don’t like about their current treatment options, and how they would use our device. We have made many adjustments and improvements over the years to ensure that our device is designed to be intuitive and convenient with the ultimate goal of making patients’ lives easier.
It is a journey that won’t end for us. Engineers are always seeking to improve upon designs and patients will continue to challenge us to find new ways to make treatment easier. Personally, I can’t wait to see what’s in store and I am looking forward to having millions of patients benefit from what our team has developed. And it will all happen through the partnerships we develop and nurture.
Author: Andy Eibling, CSAP, VP, Business Development and Alliance Management, Enable Injections
The need for something different
Traditional methods of subcutaneous drug delivery include autoinjectors and infusion pumps. These delivery regimens allow for small-volume delivery of low-viscosity drugs, with a high value placed upon minimizing delivery time – getting the drug into the injection site as quickly as possible. Patient experience is becoming more important, as it relates to overall drug efficacy and safety.
The introduction of biotherapeutics, which require higher concentrations of active pharmaceutical ingredient to meet efficacy requirements, has not only challenged the previously established limits of volume, viscosity, and flowrate, but the devices used to deliver them. The trend for subcutaneous administration is moving to large-volume injections of high-viscosity drugs. But there are many questions that are not well understood. What is it like to inject 5, 10, 15 milliliters (mL) and greater volumes of a high-viscosity biotherapeutic into subcutaneous tissue at high flowrates? More importantly, can the patient continue to tolerate this approach?
Many peer-reviewed studies1, 2, 3, 9 have focused on administration volumes of up to 3 mL, flowrates of up to 10 mL per minute, and viscosities of up to 50 centipoise. These studies have been singularly focused on one or two of the abovementioned performance attributes due to limitations with the devices used for delivery. Data is needed on patient tolerability with the combination of large volumes, various flow rates, and higher viscosities associated with subcutaneous infusion.
Devices need to adapt to this new class of drugs. The best design will incorporate a unique set of device attributes and requirements, as well as anticipate key drug and patient variables to produce a safe and efficacious delivery, while maximizing a positive patient experience.
Device Variables and Considerations
Key device design characteristics that may influence patient experience and tolerability during subcutaneous infusion of high-viscosity, large-volume therapeutics include flow rate, skin/needle interface, and needle size. These attributes are discussed further below with respect to patient impact. It is also likely that these variables are interdependent.
Previous studies3 have focused on high speed injection (autoinjectors) or constant flowrate delivery (infusion pumps) of drugs. The value proposition has been to minimize injection time or allow for a fixed injection time, both of which are preferred. This may be true if the user needs to hold an injection device against their skin or be tethered to an infusion pump. However, infusion time may become less relevant if the user is uninhibited during daily activities while receiving therapy, such as using an on-body delivery device.
At Enable, we believe a slower flowrate (and the associated longer injection time) will be preferred by the patient and improve tolerability of large volumes. It is hypothesized that slower flowrates could lead to a lower incidence of site reactions and injection pain.
Skin / Needle Interface (Tissue Tent)
In general, previous studies6, 7, 9 have investigated subcutaneous injections with the use of syringe and needles or infusion sets utilizing butterfly needles. In either case, the user or provider has the ability to control the depth of the needle by either pinching or stretching the tissue at the injection site prior to needle insertion.
The Enable enFuseTM wearable technology includes a tissue tent feature on the bottom of the device to automatically stretch the tissue at the injection site. The tissue tent feature is designed to ensure the needle inserts to the correct depth and that drug is delivered into the appropriate anatomical space.
The tissue tent may also provide a secondary benefit by applying a small amount of pressure at the injection site, which may have several advantages. Injection site pressure could reduce the needle insertion pain by disrupting the tissue at the injection site, similar to a nurse pressing on the injection site prior to needle insertion. It is hypothesized that pressure at the injection site could encourage a deeper deposit of drug into the subcutaneous space, especially in cases of larger volume delivery. It could also potentially prevent leakage and backflow, similar to a nurse applying pressure to the injection site at the completion of delivery.
Previous studies have generally investigated subcutaneous injections/infusions with the use of syringe and needles or infusion sets utilizing butterfly needles. These needles4 range from 31 to 26 gauge, with the majority being larger needle size. Other publications have theorized that smaller gauge needles introduce greater discomfort due to increased fluid velocity at a constant flowrate10, 11. Flowrate in conjunction with needle size could be important.
At Enable, we believe a smaller needle size is preferred based on our experience that smaller needle sizes produce less injection site pain6, 7 and less leakage and backflow.
Drug Variables and Considerations
Drug-contributing characteristics that impact patient tolerability of high-viscosity, large-volume subcutaneous infusion must be considered, which includes delivery volume and viscosity.
Volume and Viscosity
The Enable technology is designed to deliver up to 50 mL of drug product independent of viscosity at a specified subcutaneous site. Studies suggest that injection site pressure is less affected by volume and more dependent on viscosity7, 9. Typically, pharmaceutical companies have had the mindset to pursue high-concentration (high-viscosity) and low-volume formulations based on limitations with previously available delivery systems.
Enable is encouraging pharma and biopharmaceutical companies to take advantage of the high-volume enFuse platform to facilitate drug product formulation development for subcutaneous administration by allowing flexibility in the drug concentration and delivery volume.
Other Drug-Specific Attributes
Other drug-specific variables which affect patient tolerability may include pH, osmolality, excipients, and temperature. Much is known5 about patient tolerability with low-volume subcutaneous injections, but what is the pain tolerance and how is it affected by these drug-specific attributes of the therapeutic?
Patient Variables and Considerations
Injection Pressure and Backpressure
The Enable enFuseTM utilizes a constant, relatively low pressure mechanism to deliver the drug to the subcutaneous space. Unlike constant flowrate infusion pumps, the enFuse platform automatically adjusts the flowrate of the drug based on the backpressure being created within the injection site. This is fundamentally different and potentially advantageous to patient preference and tolerability compared to constant flowrate pumps.
Previous studies2, 8 have investigated tissue backpressure as a function of flowrate, viscosity, and delivered volume. However, all of these studies were executed with constant flowrate pumps.
The abdomen is a popular location for subcutaneous injections, due to its easy access and amount of available space. Additional sites, including the inner thigh and back of the arm, could also be considered for subcutaneous injection, although the suitability of these sites for larger infusion volumes is not established. The impact of other patient demographics, such as Body Mass Index (BMI) and skin integrity/type, on infusion and patient tolerability should also be evaluated.
The Enable enFuseTM
The patient experience must be an integral part of the device design process to ensure overall safety and efficacy of a drug-device or biologic-device combination product. The Enable enFuse is intuitively designed to incorporate these device and patient-centric features to ensure dose accuracy and reliability while maximizing a positive patient experience.
Enable Injections is invested to improve the patient experience for large-volume subcutaneous administration of high-viscosity therapeutics with the enFuse platform. To learn more, visit our Technology page or contact us.
Matt Huddleston, EVP and Chief Technology Officer, Enable Injections
- Berteau, C, et al. “Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance.” Med Devices, 2015 Nov 11;8:473-84. doi: 10.2147/MDER.S91019. eCollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4646585/. Accessed 18FEB2019.
- Zijlstra, E, et al. “Impact of Injection Speed, Volume, and Site on Pain Sensation.” Journal of Diabetes Science and Technology, 2018 Jan; 12(1): 163-168. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761988/ Accessed 18FEB2019.
- Praestmark, K, et al. “Injection Technique and Pen Needle Design Affect Leakage from Skin After Subcutaneous Injections.” Journal of Diabetes Science and Technology, 2016 Jun 28; 10(4): 914-22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928216/ Accessed 18FEB2019.
- Juul, K, et al. “Influence of hypodermic needle dimensions on subcutaneous injection delivery–a pig study of injection deposition evaluated by CT scanning, histology, and backflow.” Skin Research and Technology, 2012 NOV; 18(4): 447-55. https://www.ncbi.nlm.nih.gov/pubmed/22233448
- Dias, C, et al. “Tolerability of High-Volume Subcutaneous Injections of a Viscous Placebo Buffer: A Randomized, Crossover Study in Healthy Subjects.” AAPS PharmSciTech, 2015 OCT; 16(5). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674646/ Accessed 18FEB2019.
- Doughty, D, et al. “Understanding Subcutaneous Tissue Pressure for Engineering Injection Devices for Large-Volume Protein Delivery.” Journal of Pharmaceutical Science, 2016 JUL; 105(7); https://www.ncbi.nlm.nih.gov/pubmed/27287520 Accessed 18FEB2019.
- Allmendinger, A, et al. “Measuring tissue back-pressure–in vivo injection forces during subcutaneous injection.” Pharmaceutical Research, 2015 JUL; 32(7). https://www.ncbi.nlm.nih.gov/pubmed/25537343. Accessed 18FEB2019.
- Torjman, M, et al. “Evaluation of an investigational wearable injector in healthy human volunteers.” Expert Opinion Drug Delivery, 2017 JAN; 14(1): 7-13. https://www.ncbi.nlm.nih.gov/pubmed/27809609 Accessed 18FEB2019.
- Patte, C, et al. “Effect of infusion rate and indwelling time on tissue resistance pressure in small-volume subcutaneous infusion like in continuous subcutaneous insulin infusion.” Diabetes Technology & Therapeutics, 2013 April; 15(4). https://www.ncbi.nlm.nih.gov/pubmed/23427865 Accessed 18FEB 2019.
- Alam, M, et al. “Effect of Needle Size on Pain Perception in Patients Treated with Botulinum Toxin Type A Injections: A Randomized Clinical Trial.” JAMA Dermatol. 2015 NOV. https://jamanetwork.com/journals/jamadermatology/fullarticle/2436035. Accessed 18FEB2019.
- Pathak, P, et al. “Effect of Needle Gauge on Perception of Pain Intensity among Infants Receiving D.P.T. Vaccination.” Nursing and Midwifery Research Journal, Vol-3, No.4, Oct 2007. http://medind.nic.in/nad/t07/i4/nadt07i4p172.pdf Accessed 18FEB2019.