Drug development, particularly clinical programmes, tend to focus on adult patients – and it’s easy to see why. The challenges and potential risks associated with evaluating new drugs in paediatric patients are numerous.
The result is that many drugs prescribed to children have only been tested in adults. The FDA estimates that before it introduced a dedicated paediatric programme, only about 20% of approved drugs were labelled for paediatric use.
To address the situation, both the FDA and EMA have encouraged research and development through incentives and legislation. The Pediatric Research Equity Act enables the FDA to require paediatric studies. Whereas the Best Pharmaceuticals for Children Act includes a paediatric exclusivity provision which provides companies with an additional six months of marketing exclusivity if they conduct studies in children. This has proven an effective financial incentive, with increasing numbers of pharmaceutical companies agreeing to test their drugs in paediatric patients.
Delivering medicine to a child is tricky enough, but the additional challenge of accurate metering and delivery at small volumes should not be underestimated. This is something we have faced on a number of projects at Team. A typical anti-TNF therapy (such as etanercept, used to treat a range of chronic conditions in adults) requires a 1mL dose, and is a relatively easy starting point; whereas a more specialist application like an intravitreal injection (such as Eylea or Lucentis), might require an adult dose in the region of 50μL – a more challenging proposition. It’s perfectly feasible that without a change to the formulation, this could translate into a paediatric dose of 10μL or less. From a device perspective and usability, this poses significant challenges:
• the relative size and position of the air bubble in relation to the delivered dose can lead to inconsistent dosing or, in extreme cases, no dose being delivered at all;
• the residual volume contained within the hub or needle can exceed that of the delivered dose;
• even experienced HCPs can struggle to set such a small dose accurately and exhibit unexpected behaviour and use errors.
While it’s great to see pharma clients undertaking clinical studies to establish the safety and efficacy of their drugs for all age ranges, available devices may not adequately address the technical and use-related risks involved. The challenge of accurately metering and delivering these small doses is something often underestimated.
LARGE IS GETTING LARGER
The first generation of wearable injectors could deliver up to 3mL. With new therapies on offer, it’s now common to see enquiries for doses of 10, 20, or 30mL. As with auto-injectors, a host of new delivery devices and technologies are appearing in response to these demands. Larger doses require different methods of injection.
The alternatives to pushing the drug out with a spring or motor drive include drawing out and delivering drugs with a pump, or squeezing it out by compressing a flexible primary pack.
Several companies are developing innovative products in this area, notably Sensile Medical with its range of pump-based devices. Another is Enable Injections and its development of compact on-body devices ranging between 5 to 50mL. In parallel, Quantex Arc has focused on developing a range of cost-effective, single-use pumps that can form the foundation of a custom device development rather than an off-the-shelf device. The potential improvement in user experience enabled by these new delivery technologies is significant, but careful due diligence and technical evaluation is essential to determine their suitability for a given application.
We have seen instances with certain devices where large protein molecules have been adversely impacted, resulting in reduced efficacy by the shear stress applied during the pumping process; but the same molecules have been unaffected in other technologies.
THE INCREASING RANGE AND CAPABILITY OF AUTO-INJECTORS
Gone are the days when auto-injectors were limited to a 1mL BD Hypak syringe. Over the past decade there has been a marked shift in what is perceived to be acceptable for the user. We are seeing an increasing number of programmes focused on 2mL or more of drug delivered into subcutaneous tissue.
There have been pulls from pharmacos with formulations that were not stable within a 1mL limit, or increased efficacy enabled through the delivery of a larger overall volume. Similarly, this has been enabled by larger volume, handheld auto-injectors and safety syringe products from SHL Group, Ypsomed, Bespak, Nemera and BD; coupled with the supply of ready-to-fill 2.25mL syringes. It appears that there may be room to expand further, as SHL Group have just introduced a 3mL cartridge-based auto-injector, ‘Maggie’ onto the market.
How much is too much?
At the moment there are very few auto-injectors over 1mL that have made it to market. Concerns remain over the impact of injecting larger volumes into sensitive subcutaneous tissue. Is the increased discomfort and pain experienced by users acceptable?
FILL AT POINT-OF-CARE
Some of the technologies available have the ability to automate filling at the point-of-care, traditionally seen as a negative from a user perspective. This presents some interesting benefits and opportunities:
What’s in it for the pharmacos?
• biologics and other sensitive drugs can be stored in standard glass primary containers (vials, cartridges and syringes) with established stability data. Pharmacos may be able to leverage existing stability data to further reduce development risk and time to market;
• a wider range of materials could now be used to hold the drug within the device for the relatively short injection time. This provides designers and engineers with greater flexibility over the design and layout of the components. This could then lead to compact, space-efficient devices that are better suited to being worn on the body;
• packaging the drug and device separately mitigates some of the risks associated with recall, as the two can be treated separately. If a component within the device falls out of specification then this can potentially be recalled independently of the drug.
What’s in it for the end user?
The challenge is in making a fill at point-of-care system as simple and easy to use as a pre-filled device. The benefits need to outweigh the additional steps required from the end user and the potential for error. Progress has been made and some of the latest devices have sought to simplify and automate the filling process, which goes a long way to addressing these issues. Enable Injections has designed a user-filled syringe system for “optimum patient ease of use”, and we may see more of these systems in future.
PLATFORM PRODUCTS ARE WELL ESTABLISHED BUT HAVE DRAWBACKS…
The availability and quality of platform auto-injectors has increased dramatically over the last five years. A wide range of products is available from established suppliers such as SHL and Ypsomed, with newer offerings designed around novel technologies from the likes of Bespak and Oval. It’s easy to see why these devices are so popular with pharma clients; putting your drug into a proven device goes a long way towards mitigating development risk, and can significantly reduce time to clinic and eventual commercial launch.
These companies have benefitted from knowledge and insights from existing marketed products, and have made efforts to continually improve their products and address known use issues. In addition, the technical capability of the devices available has broadened, with products now available that allow for in-device reconstitution and variable dosing.
First across the line
While there is a lot to be said for licencing a platform device for a new blockbuster drug or biosimilar, there are some potential downsides. Device suppliers are keen to licence their device to as many potential partners as possible. Exclusivity deals are sometimes possible around a specific disease or therapeutic area, but can be prohibitively expensive.
The year 2015 saw the race to see which PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) would be first to market – Amgen or Sanofi-Regeneron. Amgen won out with Repatha, and Sanofi-Regeneron’s Praluent followed a few months later. Surprisingly, these competing drugs were initially launched in the same device: SHL Group’s DAI auto-injector. The opportunity to differentiate these competing therapies through device design or user experience improvements wasn’t possible in the race to launch.
Running the race again
The above situation is likely to be repeated with several blockbuster drugs reaching the end of their patent life and numerous biosimilars preparing to enter the market, often in unmodified platform devices. There is reason to be positive though, as most of the devices offer scope to customise or tailor the design to the specific needs of end users, either with changes to the design of external casework or through the addition of clip-on shells.
Differentiation doesn’t have to be limited to incremental improvements to the design or usability of a device. As part of their life cycle management, Amgen launched their market-leading white cell boosting Neulasta in a custom version of the OmniPod device, ‘OnPro’. In doing so, they not only raised the bar for biosimilars in development, but offered clear benefits to users: following a strong dose of chemotherapy, users are able stay home, where previously they would visit their doctor the following day to receive the injection.
TREND TOWARDS A SINGLE UNIFIED SEQUENCE OF USE…
Over the last few years there has been a clear convergence towards a single, simple sequence of use. Most devices we see in development have a two-step sequence of use: the user removes a cap, and pushes the front end against the injection site to actuate.
There are several variations on the theme. Caps can twist off or pull off, the needle is either pushed in manually by the user or automatically as the device is actuated. This trend towards a common interface is equivalent to the evolution of ‘dial-a-dose’ insulin pens. The diabetes market is filled with devices from multiple vendors, all with the same core ‘dial-up, dial-down’ interface. Rather than challenging the fundamental interaction, technical effort is focused on refining and improving the end user experience. Sometimes these may be almost imperceptible, such as tuning the sound and feel of the dose-increment clicks. They may be more obvious improvements like integrating a spring mechanism to automatically deliver the drug by pressing a button (as found in Novo Nordisk’s FlexTouch), that maintains the same ‘dial-up, dial-down, push to deliver’ interaction, while automatically delivering the drug with the simple press of a button.
Giving the right feedback despite the convergence on a common interface, and the learnings from previous generation products, opportunities still exist to improve both the usability and user experience of these devices. Accurate and helpful feedback both during and at the end of injection is a known issue, and unfortunately many devices provide the user with potentially misleading feedback; clicks or haptic feedback prior to the end of delivery could easily confuse the user.
THE ELEPHANT IN THE ROOM
Any article looking at trends in drug delivery would be remiss not to acknowledge the potential impact connected devices may have. The topic warrants an entire article of its own, but it’s worth considering a few initial thoughts here.
It’s likely that the high cost of drugs and patient non-compliance, coupled with the increase in payment by results deals between healthcare providers and pharma companies, will accelerate the drive towards the monitoring of both patient compliance and clinical outcomes.
For us as device developers the key challenge lies in delivering a tangible benefit to the end user. Navigating the evolving regulatory landscape and implementing appropriate sensing and data security measures is essential but secondary if the product or service isn’t accepted by end users.
There are good examples of companies getting this balance right in the respiratory and diabetes space; One Drop and Propeller Health are enabling healthcare providers to monitor progress and adherence and gain a greater insight into the condition and effectiveness of the therapy while offering the end user a simpler, better experience. It will be interesting to see how this sort of approach could be applied to single-use disposable devices such as those typically used for self-injection in a manner that enhances the user experience.
There are exciting and interesting trends emerging. Therapies once only feasible within a clinical setting are now being self-administered at home, enabled by innovations in delivery technologies. Established platforms are being refined and continually improved. Patient preferences for devices can now be a market reality while remaining commercially viable. Careful consideration of the device in conjunction with the therapy is essential to ensure potential pitfalls are avoided and the device is an enabler rather than a barrier to market success.