By Matthew Pillar, Editor, BioProcess Online
Doug Mead has been building his body of medical device knowledge since 1978, when he graduated from Drexel university with an MS, BME in Biomedical Engineering and went to work as associate director at ECRI Institute. He spent 12 years there advancing the non-profit’s mission protecting patients from unsafe and ineffective medical technologies. For the past 20 years, that expertise has focused more exclusively on drug delivery. He’s held senior leadership roles with companies like Elan Pharmaceuticals (now Perrigo) and Janssen Pharmaceuticals, where, for the last 13 years, he was responsible for the overall direction of CMC/Device regulatory activities for Janssen’s portfolio of combination products and drug delivery devices.
Last month, Mead struck out on his own to found CP Pathways, LLC, a consulting firm focused on startup biotech companies developing combination products. In these early days of his practice, he’s getting a lot of interest—and encountering a lot of confusion—from clients and prospects concerned about EU MDR (European Union Medical Devices Regulation) Article 117. We caught up with Mead to get his take on Article 117 of the MDR and its implications on manufacturers of drug-device combination pharmaceutical products.
PILLAR: What does Article 117 state, and what new regulations and expectations does it introduce?
MEAD: Historically, we've been demonstrating conformity to the Medical Device Directive, the predecessor to the MDR, for our combination products. In preparing our drug dossiers, we've had to show conformance to what's called the Essential Requirements, a long list of expectations outlined in the Directive. The intent of the regulations was for individual country drug regulators to assess this information in the Marketing Authorization Application (MAAs) that they review. What’s different here is that the MDR is actually a specific regulation that all countries in the European community must directly comply with, so it has more teeth, so to speak.
The new base requirement for biopharma companies comes out of Article 117, a very short article within the MDR, which addresses drug delivery devices and amends the Medicinal Product Directive (Directive 2001/83/EC). It says that, for integral drug-device combination products (e.g., a pre-filled pen), you must show conformity to the general safety and performance requirements, or Annex I of the MDR, and you must find a Notified Body to review that information and issue an opinion that you're in conformance with it. This requirement goes into effect for MAAs submitted on and after May 26, 2020. In addition, if you kit a device with your drug, the device must conform to the new MDRs by that date based on current interpretations. [Editor’s Note: For more history and insight into Pharma’s new role on the medical device regulation landscape, see the sidebar A Brief History Of The EU MDR below]. We in the biopharma industry that just developed drugs have never before had to work with Notified Bodies, the designated regulators for medical devices in Europe.
PILLAR: To whom does the regulation apply?
MEAD: Any company that requires getting an MAA for a combination product would be subject to this rule for submissions made as of May 26th of next year. It's pretty cut and dry and it’s coming up fast. If you submit an original MAA application to market a drug in Europe and it has the delivery device integral to the drug, then you're going to need this Notified Body opinion.
"Any company that requires getting an MAA for a combination product would be subject to this rule for submissions made as of May 26th of next year. It's pretty cut and dry and it’s coming up fast.”
Doug Mead, Founder, CP Pathways
As it relates specifically to biologics, CAR-T products and other cell therapies are designated as Advanced Therapy Medicinal Products (ATMP). The regulations guiding ATMP designations already indicate that a Notified Body is likely to be involved in terms of reviewing the delivery device aspect. Also, for many years, medical devices with an ancillary drug component, like a drug-eluting stent, would be reviewed by a Notified Body with consultation review performed by a drug competent authority.
What's not been in the regulations, for drugs and biologics like monoclonal antibodies, has been this interaction with another competent authority—or Notified Body—to get the device part of the product reviewed for the drug reviewers.
That's been a gap in European regulations for many years and we've found a way to deal with that by providing, essentially, a technical file in our marketing application that addresses the Essential Requirements conformance. We've already had that content in our MAAs. What's different now is that we need to pull that technical information out and send it to a notified body to get their opinion before we submit the MAA. But that “file” must now address the Annex I general performance and safety requirements list, an even longer and more specific list than the MDD’s Essential Requirements.
It was not unexpected that, as delivery devices became much more sophisticated, drug regulators would need the help of a Notified Body to ensure the safety and effectiveness of the overall combination product.
Historically, when pharma companies went to their representative drug regulators and explained that they had a delivery device and would be doing sophisticated tests on them for the application, they regulators said that's not a problem. Some had that expertise or could walk down the hall and have an informal review by the device competent authority and, to whatever degree that happened, it has been a workable system. Now, they want to formalize that in a much more regulated way.
PILLAR: Does the requirement apply to any new therapy or molecule, even if it uses an existing delivery technology, or is the requirement relaxed for those that use a proven delivery vehicle?
MEAD: Exactly which devices are involved is one big question that arises around the scope of Article 117. The EMA (European Medicines Agency) produced a Q&A document in February 2019 and a guidance document in June, 2019 outlining the plans for an MAA application in the context of Article 117. The regulations and guidelines apply to auto injectors, they apply to metered dose inhalers, and they apply to prefilled syringes, which impacts biopharmaceutical manufacturers in particular because so many biologics are prepared in prefilled syringes.
The industry’s standard syringes are manufactured by just a few suppliers, but even if a biopharma has historically been using a particular syringe for any (or multiple) of its prefilled biologics, they now have to demonstrate the compatibility and performance of that syringe for any new prefilled drug compound – and get a unique Notified Body opinion.
This creates a lot of redundancy. Obviously, if you're doing three or four new drugs with the same model of syringe, you would be obligated to show its performance with that new drug. And of course, all the companies that are using that same syringe would be submitting similar information.
PILLAR: Will pharma companies and their combination product suppliers have to collaborate on the attainment of Notified Body approval?
MEAD: I think we're still assessing the impact on that front. Pharma companies are not that expert in prefilled syringe technology. They certainly know it as a primary container for their drug(s), but the technical information on needle characteristics, their syringe’s design and materials, and manufacturing processes are really determined by the suppliers. So yes, to some extent, we would likely have to then work with them more closely to develop a sufficient technical dossier to satisfy a Notified Body. We would also have to work with the suppliers of sophisticated auto injectors that are more or less “off the shelf” to get the information necessary to satisfy general safety and performance requirements.
PILLAR: Does the regulation apply to combination products that were on the market pre-MDR?
MEAD: There is no new expectation that products already on the market have to undergo this review, with the exception of significant device design changes. But again, there isn’t absolute clarity on what constitutes a “significant” change.
Normally, when a manufacturer submits a change to a medical device, it’s done as a variation to the MAA and reviewed by EMA for general safety and effectiveness. Now, it seems that for significant changes to a medical delivery device, it would have to go back to the Notified Body to get a new opinion on the change made in the device. The Notified Bodies are trying to determine how that process would actually work.
PILLAR: What challenges does Article 117 create as it relates to the development of delivery devices and dossiers?
MEAD: It’s certainly having a significant impact on how and when we develop our delivery devices. What is specific to Article 117 are those medicinal products that are integral with an auto injector or a meter dose inhaler or any delivery device that is prefilled with a medicine. Normally, we would submit an MAA with evidence that we conform to the Essential Requirements. Now, we have the additional challenge of first submitting a technical file to a Notified Body and getting an MDR opinion from them, and only then submitting that opinion with our MAA in sufficient time for the opinion to be part of the MAA review.
PILLAR: Walk us through a few of the material impacts combination product manufacturers can expect to contend with as a result.
MEAD: Even under normal circumstances, an MAA would take upwards of a year to produce internally. Now, we have to figure out how to schedule the delivery device development, final design reviews, and all of the information that we'd normally submit in the MAA, but we need to do it six to eight months earlier. That's quite a big impact on device development schedules, and it adds significantly to what we've traditionally done to prepare applications, whether for the FDA or the MAA.
So, assuming a pharma company has a product target of May 2020, they would probably need to have already submitted their MAA, despite the fact that Notified Bodies aren't yet even issuing quotes for the required product reviews. The Notified Body’s cost and scope of work are also unanswered questions. They’re largely independent of one another, so there’s industry-wide concern that their recommendations or expectations may not be consistent.
In terms of resources, it's also hard to imagine not needing an employee devoted solely to preparing for Notified Body reviews, adjusting dossiers and preparing, in a templatized format, their best attempt at a submission. All this uncertainty is a major element of the impact on pharma, and the pharma industry doesn't like regulatory uncertainty.
PILLAR: It sounds like a risky endeavor to march forward without much direction, knowing full well that you may need to take two steps back to retool or reconfigure when more direction is provided. Is there an upside?
MEAD: I think the best thing to do with the scenario we’re presented is to prepare for what we think is really needed based on the best information we have at the time, and then adjust based on feedback from the Notified Bodies.
This European regulatory framework is effectively in its infancy, like CDRH was when it started doing consulting reviews of combination products for the FDA drug center, CDER. As the agency evolved, it became more specific about what it was looking for. If you look at the FDA on the whole, it developed multiple guidance documents for combination products over many years that clarify its expectations, and it’s done that through experience gained reviewing dossiers and evolving the regulations and guidance. Today, the pharma industry is pretty much aware of FDA expectations. I would expect the EMA and Notified Bodies to develop expertise after reviewing multiple submissions, which will refine their expectations and provide additional and better guidance.
In terms of how we adjust our marketing applications, there's quite a bit of overlap in the content that goes into different modules of our application that involve the device. For example, the device functional stability section is part of the drug section. It would also be part of a Notified Body submission or technical file. One of the questions that industry has been asking is, who's the authority here if there's a difference in opinion between the Notified Body and EMA? We are in our infancy and some of those things will have to be worked out. The key issue right now for the biopharma industry is awareness, by the broader CMC Regulatory Affairs staff, R&D leadership, and manufacturing, quality and compliance functions, that this new requirement is real and becomes effective next May - and brings with it many new challenges and much regulatory uncertainty.
A Brief History of The EU MDR
While medical device manufacturers will bear the brunt of still-unfolding EU MDR compliance requirements, the Regulation bears significantly on pharma companies that manufacture combination products, too. Article 117 of the EU MDR will have measurable impacts on the design, development, and commercialization timelines of combination products. The implications of the regulation will require pharma and medical device manufacturers to work more closely together than they have in the past to ensure the viability of their collaborative products. Here’s the backstory on the regulation and how it fits into the regulatory environment in the U.S., courtesy of Doug Mead, Principal Consultant and President at CP Pathways LLC.
In 2012, the European Commission (EC) proposed a major revision to the Medical Device Directive that included a change to the Medicinal Product Directive - which was not broadly appreciated then. The impetus was the European Medicines Agency’s recognition that delivery devices were becoming more sophisticated and should therefore be subject to third-party expertise in their regulation. Included in EC’s proposal then was Article 91, which generally outlined the Commission’s expectations that pharmaceutical manufacturers must get a Notified Body review of the delivery device components of their combination products. This later was refined to Article 117 in the final MDR in 2017.
Just a few statements in the MDR, however, did not provide enough guidance in terms of the specific requirements or what was really expected. As a result, trade groups (e.g., EFPIA and EBE) and industry have been asking a lot of questions about what the words in the regulation mean, how it will happen, and what Notified Bodies are doing in preparation.
Meanwhile, the Notified Bodies were somewhat in the dark, as was the EMA itself. The Agency had asked for device experts to facilitate the new MDR Article 117 requirements, but being a drug authority it wasn’t necessarily expert on all the regulations that would actually apply to the medical device component of a combination product. It seems to have taken the agency a while to come to grips with that, but through consultation with device experts, they did—to a degree – start preparing some guidance documents that explained their expectations and addressed some of industry’s outstanding questions. These officials have also participated in many recent public conferences and meetings to outline expectations and address industry’s more specific questions. Still, the Agency’s written guidance to date doesn’t really consider the perspective of Notified Bodies and what exactly the EMA’s and Notified Bodies’ roles should be in these reviews, as device functionality and drug properties often go hand-in-hand. A key question is what happens if the drug and device reviewers disagree on one or more of the overlapping combination product attributes or risks.
In contrast, the FDA, with the CDER (Center for Drug Evaluation and Research) and the CDRH (Center for Devices and Radiological Health) have effectively recognized their joint role in regulating combination products, handling jurisdiction issues, and addressing design controls and human factors, for example. This collaboration started as far back as with the Safe Medical Devices Act of 1990. The agency now has many guidance documents and regulations on combination product requirements in general, and also guidance documents prepared for specific types of combination products.
In most cases, because the FDA has been the major regulator of combination products for years, if you met the FDA's expectations, you were pretty much ready for any of the regulators around the world. That may not be the case anymore. Europe has added a new twist to what we need to focus on in the planning and preparation of our future drug submissions.