A grey zone in regulation

It’s the end of the pen and paper era in diabetes management, according to Søren Smed Østergaard. “People will no longer need to manually write down how much insulin they take,“ predicted the VP of Digital Health at Danish diabetes specialist Novo Nordisk at the beginning of this year. It’s planning to begin the global launch in April of its first connected insulin pens, the NovoPen 6 and NovoPen Echo Plus. On a rolling basis, the devices will be able to communicate with continuous glucose monitoring (CGM) systems and blood glucose meters (BGM) to record how much insulin has been injected automatically. For patients and doctors that means goodbye to logs, as well as no more forgotten doses or accidental insulin stacking. The smart pens will start providing people with access to the same types of reports that pump users have been using for years to recognise patterns and subsequently adjust their insulin intake. “The key element for us is to ensure data is collected passively without requiring extra effort from users,” Østergaard explains. “We believe this will help people spend less time managing their diabetes, and more time living their lives.” The durable pens work with all Novo Nordisk medicines that come in 3ml Penfill cartridges. Each pen stores information on the last 800 insulin doses taken, including the time of injection and how much a patient injected – typically at least three months’ worth of data.

In early 2017, the pharma firm teamed up with universal diabetes data management specialist Glooko/Diasend for an initial pilot study of the next-gen insulin pens. It included 12 of the biggest hospitals in Sweden, and data about time­stamp, insulin dose, type and brand were uploaded from more than 300 connected pens to Glooko’s diasend® solution. “This is a big step in using data to improve diabetes management. Until now, data from insulin pens was self­-reported and subject to error, or often simply not captured,” says Glooko CEO Russ Johannesson. The collaboration enables patients and providers to seamlessly sync data to the software, which provides a simple but comprehensive overview of parameters like glucose levels or activity information. The system should allow more informed conversations and decisions about the insulin regimen and other aspects of a treatment plan.
At the Advanced Technologies & Treatment for Diabetes (ATTD) trade show in Berlin earlier this year, Glooko shared real­-world examples of how the insights it provides can improve outcomes for dia­betes populations. On average, populations using the Glooko product experience a 12% improvement in blood glucose within three months.
In a move to visualise and integrate insulin injection data coming from the new smart pens into apps, Novo Nordisk recently announced more partnerships with Abbott, Roche (MySugar) and DexCom.  
Beyond reusable pens, which are more popular outside the US, Novo Nordisk also announced that connectivity for select medicines sold in disposable prefilled pens is coming later in 2019.

Digital medicines on the way

Digital treatment approaches that combine connected devices with data science, patient experiences and services to help deliver better outcomes can now be found for nearly any indication. In February, Finnish drugmaker Orion signed a partnership with US-based Propeller Health to connect its Easyhaler line of inhalers for asthma and COPD to Propeller’s digital medicine platform. The project includes the development of a sensor attached to the inhalers that pairs with a mobile app. The platform kicks off this year, and the firms have plans for subsequent clinical trials and potential real-world evidence projects.
It’s aimed at addressing a fundamental problem. Many asthma medicines require patients to take two slow, deep hits from the inhaler over a period of 30 to 60 seconds to deliver the correct dose. But an estimated four out of five patients may be using their inhalers incorrectly, potentially making medications less effective and increasing their risk. Doctors have known for years that many patients don’t follow the recommended instructions. According to Propeller’s Senior Vice President of Medical and Clinical Affairs, David Stempel, this is the first time objective data from digital medicines has been generated for observation outside the clinic. Together with the University of Colorado School of Medicine and Children’s Hospital Colorado, Stempel analysed data from over 7,500 patients, and discovered that two-thirds of asthma sufferers waited less than 15 seconds between inhalations, and only 16% performed the steps correctly over the correct period of time (Journal of Allergy and Clinical Immunology, doi: 10.1016/j.jaip.2019.02.006). “We hope that with this data from digital medicines, patients and doctors will stimulate a renewed push to address known issues in inadequate inhaler technique, which we know can have a significant impact on how patients experience their disease. We are entering an era where medicines can not only treat your disease, but where new technology can help you optimise that treatment,” says Stanley Szefler, director of pediatric asthma research at the Children’s Hospital Colorado.

Where medtech meets pharma

A diabetic uses a human GLP-1 receptor antagonist in a pen injector system to give themselves a subcutaneous injection. An asthma patient uses a breath-activated powder inhaler to deliver the bronchodilator albuterol sulfate to prevent wheezing and shortness of breath. What the two patients have in common is that both are employing a classical drug-device combination product made up of a medical device (MD) and an active pharmaceutical ingredient that are combined to more effectively deliver a treatment. Other examples of such combination products include drug-eluting stents or balloons, infusion pumps, anti­microbial wound dressings, prefilled syringes or transdermal delivery systems.
According to a report from Allied Market Research, the global drug-device combination products market was valued at around US$81.4m in 2017 and is projected to reach US$139.2m by 2025, as demand is growing for more patient-centric drug delivery, and improved healthcare cost management via self-administration. The situation is compounded by a rise in the incidence of chronic diseases such as diabetes, cancer and respiratory problems, more casualties due to accidents and trauma, ageing populations, growth in the home-based healthcare market, and technological advances like the development of subcutaneous formulations of established intravenous treatments.

Fuel the dialogue

Combination products can lead to safer, more effective disease management and treatment, because they offer precise drug delivery, local administration, and individualised therapy. “Almost all big pharma companies have combined or combination products in their portfolios,” according to Shayesteh Fürst-Ladani, President of the Medtech & Pharma Platform (MPP) and founder of the consultancy company SFL. Starting with an annual international conference in 2014 that brought together pharmaceutical and medtech companies, SFL and Swiss Medtech officially founded the industry association in 2017. “With all the scientific and technological development, the boundaries between pharma and medical device products are overlapping more and more,” she says. “And you can no longer see straight off whether the combination product is to be classified as a drug or a device.” That’s a crucial question for manufacturers and developers, as it can dramatically speed up or slow down market access. Deciding whether a product falls under Directive 2001/83/EC for medical products or MDR 2017/45 for medicinal devices depends on the primary mode of action of the product. The Medtech & Pharma platform is currently working with its members to fuel dialogue with authorities at the European Commission and others like the European Medicines Agency (EMA). It wants to help set up appropriate and necessary guidelines and legislation that will provide a regulatory framework for combined products.

EU: Too much uncertainty about regulatory pathways

To illustrate the issue, let’s look at a common example. When a plaque blocks a blood vessel, a stent is generally used to reopen it. The device can also be coated with a drug that helps in this task, so it has a drug component, but the primary mode of action still lies in the physical action of the stent. The coating only provides an additional benefit. Therefore it is a combination product classified as a medical device under the medical device directives (MDD) and future medical device regulation (MDR). “If the product is regulated as a medical device, approval will be a less complex and faster process than for a medicinal product,“ explains Bassil Akra, Vice President of the Global Focus Teams Active Implantable, Cardiovascular, Orthopedic, Aesthetic Devices and Clinical from TÜV SÜD Product Service GmbH, the largest Notified Body (NB) in Europe. An NB is an organisation designated by an EU member state to assess the conformity of certain medical devices before they are released on the market.

New regs are a source of problems

One date in particular is hanging like the sword of Damocles over many medtech companies. May 25th of 2020 marks the end of a transitional period for the new EU Medical Device Regulation (MDR). More than half of the three-year transitional period has now passed, and there are still a lot of open questions. The MDR sets higher requirements, not only for combination products, but for all medical devices. “This means that manufacturers must decide which products can be put on the market in a meaningful way, and rethink the profitability of their portfolio,” says Akra. “I’ve already seen many manufacturers reduce portfolios by 30%.”
Additionally, NBs are growing more scarce. To date, there is just one Notified Body which was notified by the EU Commission after the new Regulation, and it’s located in the UK. In the event of a hard Brexit, it won’t be able to take work either. “We know that to date, there are 33 applications for designation under the new regulations of a NB that have been submitted under the MDR in the EU,“ states Akra. TÜV Süd expect their decision by the end of this quarter. “However, this doesn’t mean we are some kind of salvation for the system. We are indeed the largest European Notified Body, but then there would be 2 out of a total of 59 NBs working in the transition period able to approve combination products and medical devices.”

Take a page out of the FDA book

Both Shayesteh Fürst-Ladani from the Medtech & Pharma Platform industry association and Bassil Akra from TÜV Süd praise the regulatory requirements for combination products in the US. “I would say the US regulatory framework for combination products is more advanced. On the one hand, they have a clear definition for combination products, which still doesn’t really exist in European law. And the Food and Drug Administration (FDA) oversees the regulation both of drugs and devices, so there is only one office that deals with approval of combination products,” says Fürst-Ladani.
When it comes to smart devices like Novo Nordisk’s injection pens for example, regulatory frameworks have to mature with regard to questions related to software as a medical device (SaMD). Companies are entering areas where the end-to-end product is expanding. What used to be a drug-device has evolved into a drug-device-app. “Every­one has to work in new ways if we want to bring these smart technologies to people – and that is the most important thing in the entire process,” says Novo Nordisk VP of Digital Health Søren Smed Østergaard. “We’ve seen that authorities are very willing to collaborate in helping to find solutions and a path forward.”