Pointed Debate

Increasing numbers of biological drugs are being developed, driving a strong demand for innovative injection technologies. This need extends far beyond the traditional syringe, and companies are now packaging their biological products into more advanced products, such as autoinjectors. Although these devices may be more expensive than basic syringes, they offer the potential for patients to self-administer a therapy outside of healthcare settings.

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The biopharmaceutical industry is under increasing pressure to justify the cost of therapies, particularly if they want them to be included in national healthcare programs. Self-administration is one way of significantly reducing costs and offers further benefits, such as being more convenient for the patient. Here, industry experts discuss the importance of self-administration and what technologies are best suited to this cause.

BioPharm: Why has patient self-administration of therapies become such an important driver in the healthcare and biopharmaceutical sectors?

Kaufman (SHL Group): Self-administra-tion therapies have become an important driver in the healthcare and pharma sectors for a number of reasons. Empowering patients and giving them the freedom to take medications at home or while on the road is more than just a trend; it is vital to the economic viability of healthcare systems worldwide. Enabling patients to self-administer their medication means that healthcare practitioners can use their time more effectively. Most importantly, it has the potential to save money as fewer trips to the hospital can amount to millions in healthcare cost savings.

This trend has had a significant impact on the evolution of injectable drug delivery technologies. Many people are familiar with self-administered medications, such as inhalers for treating asthma, but few individuals, other than diabetics, have experience of injecting themselves using a syringe. As a result, drug delivery companies have had to develop devices that are both intuitive and safe. With the increasing number of approvals for new biologics in recent years, demand will also be quite strong for autoinjectors and pen injectors. However, developing and producing an injection device that is safe, ergonomic, easy to use, and accurate enough for a patient to self-administer involves meticulous designs, innovative technologies and consistent manufacturing. For example, the spring mechanism inside an autoinjector controls the force and timing of the injection and is designed to accommodate the desired injection specifications, while the outer shell of the device may be affected in size and design by the primary container inside and human factor constraints. Once a proven mechanism is designed, ensuring consistent manufacturing then becomes vital because quality needs to be built into every device produced. At this time, there are only a few companies in the world that can design, develop, manufacture, and assemble these pen-like devices, and these companies will need to work closely with biopharmaceutical partners to ensure that patients get the best drug-delivery devices possible.

Novara (BD): There is a growing prevalence of individuals living with chronic disease in the world. However, the good news is that pharmaceutical medicine is working in order to keep pace with this increase. Advancements in therapeutic agents and medicine have resulted in the availability of more sophisticated biologics for the treatment of many chronic diseases. In addition, there is a growing trend in self-administration medicines where patients can self-medicate. This trend has supported the need for further advancement in self-injection technology.

These biologics often have complex technical requirements for injection. For example, they have higher volume or are more viscous, so the technical specifications of these biologics are more challenging and require complex delivery technology. This trend explains why self-administration has become so important. In this respective, device manufacturers must be proficient in patient-centric design and should consider the ergonomic and human factors.

Integrating those biologics with the right delivery system has become critical, not only from a technical specification standpoint, but also from a competitive perspective. The competitive dynamics for new drugs in different fields will require different considerations in the selection of an injection device. Patient consideration is also a factor; for example, a patient with rheumatoid arthritis may have dexterity issues, requiring certain design specifications to make the device easy-to-use. In this respective, it's important for device manufacturers to be proficient in patient-centric design and to consider the ergonomic and human factors.

Integrating the primary container with the secondary device successfully is also critical. Companies offering self-administration technology need to have that expertise in order to improve performance of a drug-device solution, reduce risk of failure, and accelerate speed to market.

Potter (Glide): Rising healthcare costs mean that treating patients is becoming more and more expensive. If a patient can self-administer their medication then this reduces the time they need to spend with a healthcare professional and, thus, reduces cost. Most medications can be taken orally, but many peptides and proteins have to be injected to ensure they are not damaged by the acidic environment in the gastrointestinal tract. If a patient is to be trained to self-inject, however, then the technology needs to be simple to ensure that it is operated correctly. In addition, medication compliance is a serious issue with many patients; the easier and more convenient the product is to use, then the more likely the patient is to take their medication. These needs for lower cost of goods, ease of use, and convenience are also shaping the evolution in drug delivery technologies suitable for self-injection.

Sadowski (Antares): Self-administered products currently account for about half of the of therapeutic biologics market. The simple reason for this is that more biological agents requiring injection are being used in chronic conditions, such as rheumatoid arthritis, psoriasis, and multiple sclerosis. Since it is both costly and inconvenient for patients to go to their healthcare provider to administer these biologics daily or weekly on a chronic basis, the burden falls upon the patient. Fortunately, technologies exist that make the self-medication process as comfortable and easy as taking a pill.

BioPharm: Which technologies are most suited for self-administration and why?

Kaufman (SHL Group): As patients are not medically trained, empowering them to feel comfortable enough to properly inject themselves requires a device that can make them feel safe both mentally and physically. To address this, devices with special features and technologies, such as the autoinjector, are often designed so the patient never sees the needle and may finish administering the drug within a relatively short period of time. While reactions to physical pain may vary for each patient, the mental pain connected to visually seeing a needle inject can be reduced, especially when the patient also has control over when to initiate the injection. As a result, autoinjectors are becoming a commonly accepted drug-delivery technology for self-administrated injectable therapies.

Which injection technology is gaining the most ground in the market? ( POLL, BIOPHARM INTERNATIONAL ONLINE, 2012)

However, it is important to note that each patient needs to be properly trained on how to use such devices and they must be provided with very clear instructions for use. The use of picture-oriented instructions and video has been a good step towards addressing this issue. Another potential drawback related to self-administration technology is the cost associated with developing a drug delivery device and the actual cost of each device. At this time, it is much easier for larger biopharmaceutical companies, which have the necessary financial resources, to initiate these programmes. Additionally, the market value of the drug must be able to justify the cost of the device.

Novara (BD): The most suitable technology depends on many factors:

• Technical specifications: A high volume or highly viscous biologic, which may be infused in a hospital setting, may require a patch injector/patch pump to deliver the medicine in the home setting. It is also important that careful consideration is given to the delivery of drugs that have a unique viscosity or volume that needs to be delivered.

• Competitive dynamics: Pharma and biotech companies are increasingly looking to their device as a source of differentiation.

• Patient factors: Certain patients will have certain needs and preferences given their condition and how mature that market is with devices.

• Frequency of administration: Whether a drug is injected on a daily basis, versus a weekly or monthly basis, is also an important factor (along with the cost factor).

All these considerations are crucial factors in selecting the right technology. For device manufacturers, it's important to have expertise across a range of delivery platforms and technologies in order to meet the above needs for customers.

Potter (Glide): Autoinjectors and pen-injectors have been designed for self-administration. These technologies are widely used, work very well, and are far easier to use and more convenient for patients than a standard needle and syringe. However, they still use a needle, which brings about issues related to needle reuse, needle disposal and needle phobia. In addition, many drugs that have to be injected are not very stable in a liquid formulation. Some biologics are stored in a powdered form to provide better stability, but they need reconstituted prior to injection, which adds to costs and treatment complexity. Liquid jet injectors avoid the issues with needles, but still incorporate a liquid formulation. They are also very expensive and have not achieved significant market traction.

None of the technologies mentioned really provide a simple way to inject a controlledrelease formulation. Typically, a controlledrelease formulation comprises polymer microspheres in a solution, but because of the issues of needle clogging these expensive products are normally injected by specially trained healthcare professionals. Other injection technologies, such as solid dose injectors and microneedle patches, are in development, but they are not yet ready for routine patient use.

Sadowski (Antares): The key to considering self-administration technologies is to focus on the patient. Our company, for example, is not committed to any particular injection technology type. Companies should design the technical solution that best fits the circumstances in a given therapeutic application. In particular, it's important to consider the patient's needs and limitations in the target disease condition, and then to look at how best to apply technology to make the patients' self-injection experience most acceptable and successful.

BioPharm: What extra steps do companies need to take to have a drug approved for use in a self-administrative form?

Kaufman (SHL Group): Generally, a biological drug will need to be first approved as an independent drug, regardless of whether or not it is to be used in a self-administrative form. For the device constituent of a combination product, the medical device manufacturer will generally support biopharmaceutical companies by filing a master access file and/or 510K to help with the customer's submission process.

Self-administered biological drugs can generally be placed inside a primary container such as a prefilled syringe or cartridge, which will then reside in a device that possesses the mechanical system to perform the injection. The two together are a drug/device combination product that, although not yet official, has been identified by FDA as an area that requires regulatory guidance. Companies that wish to introduce a drug in a self-administrative form will need to start regulatory planning at a very early stage to ensure that approval times do not become a potential bottleneck to a successful global launch.

Novara (BD): The complexity of clinical development and the regulatory process is increasing, and companies must take every appropriate step to ensure that their products are in full compliance. In addition, companies have to bear in mind the lead times for regulatory processes.

Potter (Glide): Any pharmaceutical product in development must undergo clinical trials. In addition, a product that is to be self-administered needs to undergo trials with volunteers and patients to ensure that the delivery system can be safely used by different patient groups in a non-clinical setting. Some of these trials may be userhandling trials, with no drug involved, just to demonstrate that the volunteer can safely use the delivery system. These trials are far simpler and cheaper to conduct than active drug trials. Once trials have been carried out for a first product, then further trials to investigate the handling and use of the delivery technology may only be required if the product is for a different patient group (e.g., elderly patients or patients with rheumatoid arthritis who may struggle to handle a delivery device).

BioPharm: How are designers and manufacturers of selfadministration devices approaching the challenges of ensuring sterility and accurate dosing outside of healthcare settings?

Kaufman (SHL Group): Accurate dosing is achieved through specially designed delivery mechanisms, rigorous testing, and precise manufacturing. For example, in a mechanical device, highly accurate dosing can be achieved using the appropriate spring technologies. Sterility is ensured again by designing a suitable device for the primary container selected by the biopharmaceutical partner; for example, a prefilled syringe that is assembled into an autoinjector under controlled procedures in line with related regulations and standards.

Sadowski (Antares): First, it is important to consider the fact that the product will be used without the direct supervision of healthcare professionals. Companies should conduct extensive background research and ethnographic studies to fully understand the patient and the likely environment of use. The design can be established based on the findings of the investigations and the pilot device can be tested with the patient in a variety of expected actual-use settings to confirm that the product will perform as intended.

BioPharm: The ability to offer adjustable doses, for example in diabetes, has great potential. What progress is being made in this area?

Kaufman (SHL Group): We see progress in the development of unique and robust mechanical designs that can accommodate the need to offer adjustable doses. This allows for the device to remain cost effective, as some drugs do not have a market price that justifies complex drug delivery technology. However, we do see a renewed drive to incorporate electronics into some of the more expensive devices, which is perhaps inspired by the trend of cutting-edge designs related to smart phone and tablet innnovations.

Sadowski (Antares): Technologies that provide dose adjustability have already been developed and commercialized. Cartridge-based, multidose pens, for example, have achieved excellent acceptance in the administration of insulin. Companies are now working on improving dose adjustability and confirmation of correct dose by applying advanced electronics that aid ease of use and add intelligent features.

BioPharm: What are the challenges of manufacturing devices suitable for self-administration?

Kaufman (SHL Group): Main challenges include anticipating numerous device usage scenarios against which to test the device, ensuring quality consistency, and providing robust production lines to respond to mass production needs. To address these challenges, device manufacturers should work closely with biopharmaceutical companies to better understand end-user feedback and use it to more accurately reflect and construct usage scenarios for device testing. In addition, device manufacturers need to continually invest in the latest in-house capabilities and processes.

Novara (BD): In most cases, customers will want some level of customization; they rarely want off-the-shelf devices. The challenge for manufacturers is delivering these differentiated customized devices at an affordable cost—for both the customer and the manufacturer. Companies are utilizing modular platform technology to develop and customize devices.

The market place is also uncertain and highly dynamic. Manufacturers are business-to-business organizations selling devices to pharma and biotech companies. If their business changes, suffers, or is impacted, so is that of the device manufacturer. This requires methodical portfolio management and operational planning to optimize the business.

When customers choose a device partner, they make device-based decisions, but also company-based decisions. They will be looking for factors such as a global reach and full service support, including support with global registration, and the ability to offer a differentiated benefit.

Sadowski (Antares): The most important aspect of making devices for self-administration is ensuring that they perform as intended in the hands of the patient. That means we need to first understand the patient. There are well-established ethnographic research methodologies that can be used to learn about patients and the environment in which they will use medicine. However, even today, many companies delay addressing this aspect in clinical programs. As a consequence, products have been launched in a configuration that is clearly not well suited for self-administration. Only later, after the product fails to meet market expectations, does the company initiate programs to address the needs of self-administration. It can be argued that keeping the configuration as simple as possible (e.g., in a vial) reduces development risk and cost,but this must be balanced against the resulting market risk, particularly when competitors introduce a product that better addresses self-administration challenges.

BioPharm: Needle-free devices seem to have lost some traction in the market, why might this be the case?

Kaufman (SHL Group): At this time, innovations in drug delivery devices with needles continue to move forward in addressing the growing need to administer biologics. Autoinjectors and pen injectors have been proven to be effective, safe and reliable devices. With this established track record, needle-based devices will continue to strengthen their position in the self-administration market.

Novara (BD): There are two factors that may have contributed to this. First, needle-free technology can be more complex, and there are various safety and operational challenges. Secondly, needles are now available that are very fine, as well as being shorter and less painful than previous generations of needles. Self-injection devices also continue to become more advanced.

Potter (Glide): The needle-free devices that have been commercialized are all liquid jet injectors. These devices work by firing a tiny jet of liquid through the skin. The concept was first patented many decades ago and niche products have been on the market for years. The products are either disposable devices or reusable actuators with a singleuse drug component.

The reusable devices have been used in the past in the developing world and in the military for vaccine studies, but lost favour when the potential for cross-contamination between patients was identified. Single–use jet injectors are expensive and have never been widely used. I believe this is because the benefit of needle-free technology does not outweigh the increase in costs over alternative technologies. Liquid jet injectors will continue to be used for a number of niche products, but they will struggle to increase their market share. However, other technologies in development, some of which are needle-free, are likely to get good market traction as they are commercialized.

Sadowski (Antares): It's not a matter of needle-free having lost traction; it's a matter of the matching the technology to the needs of the patient population. I have no doubt that we will see greater applications of needle-free technology as additional biologic drugs are developed for populations best served by that approach, such as pediatric patients.

BioPharm: What recent groundbreaking innovations have you seen in the area of selfadministration devices?

Kaufman (SHL Group): Ground-breaking is a powerful statement. I have seen a number of significant innovations in the area of autoinjectors over the past seven years, particularly when it comes to the look and the size of devices. Autoinjectors are more discreet and are now available in sizes that are not much bigger than a marker pen, which allows patients to travel and use the devices whenever and wherever they wish without feeling embarrassed. Industrial designers have also worked closely with human factors engineering groups to make several devices (launching soon) that are completely customized to suit the needs of a specific patient group. For example, if rheumatoid arthritis patients have difficulty removing a cap, industrial designers can overcome this by engineering a new solution for cap removal. These may not be groundbreaking, but to me they represent a significant shift in the way devices are being made—working more with patients at the earliest stages and making drug delivery devices that are simple and intuitive.

Novara (BD): The innovations I am very impressed with are the patch injectors/patch pumps. This new technology is allowing companies to deliver therapies, which historically have been infused in a hospital setting, in the privacy and convenience of the patient's home. For example, technology is in development that can allow patients to have continuous infusion at home with a ready-to-use hands-free, device.

Potter (Glide): I believe that the two biggest innovations in the area of self-injection devices are microneedle patches and solid dose injectors.

Patches are being commercialized that incorporate tiny needles to aid the delivery of drugs and vaccines across the skin. The microneedles are either solid and coated in a film of drug; hollow to allow liquid formulations to be pushed through them and into the skin; or solid and made from the drug. The key is to ensure that the microneedles penetrate the skin so that the drug or antigen can be accurately delivered. Several companies are commercializing microneedle patch technologies and these will be suitable for the delivery of a range of peptides, proteins and vaccines.

Solid dosages are currently injected using a needle and trocar. This is a painful procedure and is not suitable for self-injection. Our solid dose injector technology differs in that a tiny rod of drug is produced with a point on one end so that it can be pushed into the skin without the need for a needle. When placed in the skin, the rod dissolves and releases the drug or vaccine into the tissue. Storing the drug in a solid dosage form offers stability benefits and may avoid the need for refrigeration. Solid dosages have been shown to dissolve quickly in clinical trials, providing bioequivalence compared with a subcutaneous needle and syringe injection. However, the formulations can also be designed to provide controlled release, if desired, by incorporating polymers in the formulation. The device is simple to use and could be used for self-injection. Most applications will comprise a small, lowcost, disposable cassette that will be prefilled with the drug or vaccine dosage, and a handheld, springpowered, reusable actuator. The cost per injection will be low and the technology will be suitable for a wide range of peptides, proteins and vaccines.

BioPharm: What is your overall assessment of the future of injectable drug delivery?

Kaufman (SHL Group): With the wave of biologics coming to market, several new devices, such as autoinjectors, will see increased competition. One clear way that companies will differentiate themselves will be in the choice of drug delivery device. Designing, developing, producing and launching a biologic in an innovative device will not only enhance patient compliance, but could result in more revenue. For biopharmaceutical companies, the trend is clear: find the right partner, and develop devices for your biologics and future biologics now. It takes time and money, but it will be well worth it.

Novara (BD): The future is very bright. There is a steady increase in chronic diseases, but therapeutic developments are keeping pace by offering very sophisticated treatments that can be used with self-administration and injectable systems. However, there is an increasing need for differentiation and customisation of self-injection delivery solutions to help customers strengthen brand loyalty and to increase patient adherence and compliance with therapy. Device manufacturers with a broad portfolio of differentiating devices, full-service expertise, a commitment to quality-by-design, and global scale are uniquely positioned to meet the needs of pharma and biotech customers, payers, and healthcare professionals. Most importantly, injectable drug delivery systems afford a unique opportunity to patients with chronic disease to optimally treat their condition with minimal disruption to quality of life.

Potter (Glide): Biologics is one of the key growth areas in the pharmaceutical industry. Biologic products typically need to be injected and injection technologies will be required for these products, whether they are new products or lifecycle management strategies of existing products. I believe that there is a fantastic future for injectable drug delivery technologies. In particular, those technologies that can deliver a range of drug and vaccines, and that are suitable for self-injection and have a low cost of goods, will be used to develop products for both existing drugs and new drugs in development.

Sadowski (Antares): Pharmaceutical pipelines are increasingly reliant upon biological products and the range of therapeutic applications for biologics is expanding to chronic conditions. We are also seeing improved cancer survival rates, in part due to improved, targeted biologic therapies, which mean that cancer will be treated more often as a chronic condition using self-injected biologic therapies. Cost pressures and patient preferences will drive pharmaceutical firms to shift the administration approach from higher cost settings, such as infusion centers, to self-administration. All of this will expand the range of therapeutic applications for self-injected products, leading to greater reliance upon and advances in technologies suited to meet the needs of increasingly diverse patient circumstances.

Roundtabe particpants include: Steven Kaufman, marketing director, SHL Group (Scandinavian Health Group); Mark Novara, worldwide director, Strategic Marketing, Self Administration and Injectable Systems, at BD; Charles Potter, chief technical officer at Glide Pharma; and Peter Sadowski, chief technology officer at Antares Pharma.