As combination products become more prevalent, they pose a number of regulatory challenges. Essentially, it isn’t always clear whether a product should be regulated as a drug, biologic or medical device. This means pharma companies need to start thinking about these issues from very early on in the process. Steve Dew, associate director of combination products and medical devices at Biogen, speaks with Emily Gibbs about the key issues.
Combination products are becoming more widespread – and more complex. Referring to any medical product with two or more constituent parts – a drug combined with a device, or a device combined with a biologic – these therapies can take many forms. They might include, for example, autoinjectors, pre-filled syringes, transdermal patches and drugeluting stents.
Demand for such products is rising. According to a recent report by Reportlinker, the global drug-device combination products market is expected to reach $177.7 billion by 2024, and is growing at a compound rate of 7.9% a year. Since these products are minimally invasive, they are typically popular with patients and lead to better clinical outcomes than the alternatives.
Over the years to come, we are likely to see ever more examples, including some that seem to defy usual categories. While this is probably good news for the end users, it also means asking some thorny questions.
To quote a research paper written as early as 2005, “Imagine a nanoparticle-monoclonal antibody combination, that, when exposed to light, emits toxic oxygen radicals that kill cancer. Or imagine a photo-activated polymer combined with autologous cartilage to tissue engineer a new knee joint. Are these products drugs or devices? How should they be approved and regulated, and how should we bill and pay for them?”
This is not a simple question. Since medical devices typically have faster approval times than drugs, it isn’t immediately obvious what kind of regulatory pathway these products should follow.
In fact, the FDA’s ‘combination products’ category was born out of precisely such a dilemma. In 2002, The US Congress passed the Medical Device User Fee and Modernization Act, which created the FDA’s Office of Combination Products (OCP). While the OCP does not itself regulate these products, it does assign products to the appropriate agencies, and acts as a bridge between the various parties.
This solved a problem that had been foxing regulators since the 1970s. The first combination products, which included radiobiologics and in-vitro diagnostics, were regulated on an ad hoc basis. And although certain legal provisions were introduced in the 1990s, the need for more clarity was acute.
16 years after the OCP was established, the regulatory questions are as salient as ever. For pharma companies looking to develop a combination product, it is necessary to jump through hoops that would not be there with a simple drug or medical device.
As Steve Dew, associate director of combination products and medical devices at Biogen, explains, these issues need to be considered at a very early stage of development.
“One of the biggest challenges is to acknowledge that the device element of a combination product needs to be addressed early within drug development programmes,” he says. “If a delivery system will be required, development needs to be considered in parallel and not as serial add-on. In order to avoid costly delays, due consideration needs to be given to clinical assessment and any bridging studies that may be required.”
He adds that how a combination product is regulated is highly dependent on its format and its primary mode of action (PMOA). The PMOA is perhaps more complex than it might seem at first. While in principle it simply means what the product is used for, in practice it is subject to interpretation.
According to the FDA’s guidance, it refers to the “single mode of action of a combination product that provides the most important therapeutic action of the product”. This can get confusing when both parts of the product play a role in its therapeutic action, as in the case of a drug-eluting stent where the stent and the drug seem essential. In these cases, the manufacturer will need to undertake a thorough analysis.
“There are also jurisdictional variations depending on whether combination products are defined,” says Dew. “For example, a single integral product comprised of a drug and delivery device is classified as a combination product in the US, yet classified as a medicinal product in Europe.”
The first step for a pharma company is to establish what the PMOA actually is and how the product will be presented. For instance, is it a drug with device (the PMOA being the drug); a device with drug (the PMOA being the device); a drug with drug, or a drug product with a separate device?
In the US, if it’s not possible to determine the PMOA, the pharma company can use a mechanism called ‘request for designation’. This involves submitting a petition to FDA to determine the product’s classification. However, it is essential to provide as many details as possible – nearly half of all requests for designation fail owing to lack of information.
Ultimately, the product will be assigned to the Center for Devices and Radiological Health (CDRH), the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). These are the agencies responsible for medical devices, drugs and biologics respectively.
The next step is to establish what your primary markets are going to be, and understand how your presentation may be classified in those markets or regions.
“Ensure medical device expertise and consult is obtained early, and, if needed, seek Competent Authority input,” says Dew. “This needs to be done from the outset to ensure regulatory strategy is understood and appropriate deliverables can be identified to meet the device design, development and GMP requirements to support drug submissions in the markets you need.”
Risks for ample reward
So how can the relevant parties best work together to merge their technologies, and at what stage of drug development should the device manufacturer typically get involved? Dew says there are no simple formulas for determining this.
“The commercial product form is rarely available for pivotal studies and there may be several drug product changes throughout the development cycle,” he says. “Early engagement with appropriate stakeholders, internally and externally, is critical, to identify when and who to bring into the development team.”
Often, he says, a suitable risk-based clinical bridging study will need to be designed.
“This must be managed early with subject matter experts to ensure an appropriate strategy is developed depending on risk, requirements for pharmacokinetics, pharmacodynamics and human factors as appropriate,” he says. “This requires good teamwork and an understanding that medical device expertise will be critical in bringing a drug product to market in its desired commercial form.”
On the converge: bridging the gap in communication
Convergence of expertise is a well-known challenge in this field. For instance, a biotech company and a medical device manufacturer might have perfectly matched technologies, but may not be especially good at communicating with each other. It might be difficult for them to understand how their strengths might be pooled. In the future, the industry can expect to see a growing demand for experts whocan bridge that gap.
From a purely regulatory standpoint, some of the biggest challenges at the moment pertain to the new Medical Device Regulation in Europe. Published in May 2017, the ruling will come into force in May 2020 and will affect all companies marketing devices in the EU. The Medical Device Regulation is much more prescriptive than the law that preceded it (the Medical Devices Directive) and sets the bar higher for clinical evidence.
One section in particular will affect the drug and device combination product manufacturers. It states even though the device is regulated as a medicinal product, and does not need to be CE-marked, a notified body (NB) will need to get involved. Its job is to provide evidence about the product’s compliance with the regulation.
“It is still not clear on how this requirement will be implemented,” says Dew. “As from the end of the transition period, single integral products will now require an NB opinion for new medicinal product marketing applications, and there are significant concerns that unless the implementing framework for such products is in place there may be delays in patient access to complex technologically advanced drug products.”
With less than two years to go, there are many questions remaining unanswered. Since pharmaceutical regulations are also in a state of transition, it’s crucial that manufacturers understand all applicable areas of regulation, not least the Falsified Medicines Act and the Identification of Medicinal Products (IDMP) standards.
In the US, manufacturers are grappling with new GMP rules for combination products, which came about following the 21st Century Cures Act of 2016. As of June 2018, they have been offered a list of flexible mechanisms that can be used to help them comply.
With so many different aspects to consider, it’s clear that combination products are more challenging to develop than any of their constituent parts. However, there is really no looking back. There are many promising areas of technology, now in their infancy, which could lead to a wave of new opportunities further down the line.
Projection for production: what’s in the pipeline for combination products
For Dew at Biogen, combination products will unquestionably remain a key focus. “Biogen has a number of combination products already on the market, such as Plegridy and Avonex Pre-Filled Pens, and a vibrant development programme for future pipeline drug products,” he says.
“Biogen manages these projects utilising internal design and development, regulatory and quality medical device expertise alongside the drug development teams and also bringing external expertise as appropriate.”
Ultimately, combination products will force the need for collaboration, breaking down the siloes that exist between pharma companies, biotechs and medical devices manufacturers. And as the various branches of life sciences continue to converge, the onus is on the industry to find a way.