TOPRA/RAPS workshop on alignment of global combination products

Published on: Nov 10th, 2020

The TOPRA/RAPS inter-regulatory and stakeholder two-day workshop held in June 2020 focused on global combination product regulations. The diverse panel of speakers included representatives from the European Medicines Agency (EMA), EU notified bodies, US FDA officials, regulators from Health Canada, the Malaysia Medical Devices Agency, Anvisa, the UK’s Medicines and Healthcare products Regulatory Agency and industry experts, all exploring the challenges and looking for commonalities in the regulation of medical products with both drug and device components.

Brian Savoie, VP of Educational and Professional Development at RAPS and Samantha Cooper, Director of Professional Development at TOPRA, welcomed the attendees and presenters and opened the workshop with an innovative poll about priorities. The focus of the workshop was to discuss different perspectives, share best practices, quality management and solutions for challenges for combination products.

Introduction

The TOPRA/RAPS inter-regulatory and stakeholder two-day workshop held in June 2020 focused on global combination product regulations. The diverse panel of speakers included representatives from the European Medicines Agency (EMA), EU notified bodies, US FDA officials, regulators from Health Canada,
the Malaysia Medical Devices Agency, Anvisa, the UK’s Medicines and Healthcare products Regulatory Agency and industry experts, all exploring the challenges and looking for commonalities in the regulation of medical products with both drug and device components.

Brian Savoie, VP of Educational and Professional Development at RAPS and Samantha Cooper, Director of Professional Development at TOPRA, welcomed the attendees and presenters and opened the workshop with an innovative poll about priorities. The focus of the workshop was to discuss different perspectives, share best practices, quality management and solutions for challenges for combination products.

Combination products, current approaches, challenges, insight & trends: The view from the US

Speaker: John Barlow Weiner, Associate Director for Policy Office of Combination Products, FDA

Combination products are common in everyday medical use, from a simple pre-filled syringe to a complex drug-eluting stent. From a regulatory perspective, however, they fall outside the traditional therapeutic and device pathways and provide unique challenges to both industry and regulatory authorities in ensuring their safety and effectiveness.

Clinical aspects, such as bridging studies and post-marketing requirements, combined with harmonisation are some of the highest pain points industry would like to see addressed.

Most regulatory authorities have formal definitions in regulation, as well as a formal regulatory determination mechanism. However, no specific regulatory submission format exists for combination products. They must use existing drug, device, or biologic application/submission procedures, and, in some instances, multiple applications may be needed. The determination as to which regulations, submission procedure, and pathway to market is to be followed is based on the primary mode of action (PMOA), a risk-based approach that is defined by the FDA as “the single mode of action of a combination product that provides the most important therapeutic action of the combination product”.

The FDA, which recognises combination products as a legally distinct entity, has very few regulations to guide an approval process. However, the FDA has an office dedicated to helping industry known as the Office of Combination Products. The review teams of the three FDA Centres (Center for Drug Evaluation and Research [CDER], Center for Biologics Evaluation and Research [CBER], and Center for Devices and Radiological Health [CDRH]), decide the appropriate pathway for a particular combination product through a determination mechanism called a Request for Designation (RFD) process. This process is designed to give manufacturers the opportunity to present their combination product, describe what they feel is the PMOA with evidence compiled to date, and receive a binding (or non-binding, in the case of a more informal pre-RFD) designation of lead FDA Center and regulatory pathway. The FDA is quick to point out that a combination product is distinct from a device, drug, or biologic. However, the RFD is where the uniqueness of being a combination product, in terms of regulation, stops as the submission format will follow that of the PMOA. If the PMOA cannot be determined or is equal among the components of the combination product, then the submission format of the FDA Center with the most relevant experience in similar combination products or closely matching safety and effectiveness questions is chosen. Unfortunately, unlike the Q-submission programme which enables submitters to have early collaboration and discussions about medical device submissions, there is little opportunity for manufacturers to discuss their combination product during the RFD process except on very rare occasions. This, coupled with the difficulty for device companies to discuss drug delivery devices with the FDA without a therapeutic identified for use with the device beforehand, has severely limited innovation. It has led to development delays, as the need for a large pharma partner tends to be a significant hurdle for the smaller device companies.

EU Medical Device Regulation and In Vitro Diagnostics Regulation – Impact on the EMA

Speaker: Armin Ritzhaupt, European Medicines Agency

The EU does not specify a distinct term by regulation for combination products. The Medical Device Regulation (MDR) that supersedes the previous Medical Devices Directive (MDD) includes articles addressing devices designed and sold with a medicinal product as an integral part. These drug-device
combinations are separated into the following categories: devices integrating a medicinal product, medicinal product integrating a device, and devices intended to administer a medicinal product when presented as a single, integrated unit, not reusable. In addition to defining the categories, Article 117 went on to modify Directive 2001/83/EC3 governing medicinal products for human use. The amendment essentially states that when the manufacturer of a drug-device combination product submits a marketing authorisation application (MAA) to the EMA, it must include an official certificate of conformity that shows that the device portion complies with the MDR. The literal reading of the EU regulation implies that approval is needed for each component of a combination product.

The EMA has attempted to clarify its position by publishing a guideline on quality requirements of medicinal products that have a device component for delivery for use with the medicinal product. The clarification states that the notified body assessment and marketing authorisation review would not result in duplicate assessments. The notified body reviews the device alone, and the marketing authorisation review assesses the implications of drug-device product on the safety and efficacy of the drug product.

The FDA attempts to limit a combination product to a single marketing application to prevent duplication of work by a manufacturer, unlike what the EMA process requires in the case of companion diagnostics (CDx). The FDA is less rigid than the EU process, which requires both a device and drug or biologic submission for approval. Both submissions are approved at the same time resulting in one submission,
usually the device, being held until the other is complete. In addition, although the guidance allows for all device submission types – 510(k), de novo, premarket approval (PMA) – to date, all but one CDx has required a PMA, suggesting that although two separate submissions are required, the risk level of both submissions is determined by the higher risk therapeutic.

As we observe an increased number of innovative combination products in the areas of drug delivery, artificial intelligence, and CDx, the limitations of the current regulatory pathways become more apparent. Regulatory authorities realise the need to be agile and creative in their thinking, but consensus on how to look at combination products differs dramatically based on whether it is viewed from a device or therapeutic perspective. Although PMOA determination is a common way to identify the appropriate regulatory pathway, it is limited and may contribute to “pigeonholing” combination products in one pathway or another. This works in most cases as the presence of a therapeutic usually is enough to guide the pathway. However, it quickly breaks down as device aspects become more complicated and play a larger role in the combination product. The risks associated with artificial intelligence systems and companion diagnostics becomes as much as, or more than, a therapeutic component. Coupled with the fact that industry is the technical expert for its own technology, and not the regulatory authorities, the result is complicated.

PMS/PMCF under the EU MDR for device-drug combination products

Speaker: Sophie Tabutin, WL Gore & Associates, France

From an industry perspective, there is justifiable frustration, but what about for patients?

Although long, and likely requiring some duplication of effort, the review process for combination products that make it to the market is thorough, in terms of safety and effectiveness. Treatment outcomes, in theory, are better for patients, with fewer adverse effects and increased efficacy. However, these new combination products will be much slower to arrive on the market. This greatly delays patient access to technologies with such benefits as decreasing the burden of taking medicines, releasing therapeutics at a regulated rate to increase efficacy, reducing the chance of overdosing or underdosing, and increasing compliance with drug regimens by making them simpler. This further illustrates that regulatory authorities need to take a closer look at how combination products are reviewed and ultimately reach the market. Improved outcomes and fewer adverse events are a distinct primary driver, but caution and careful thought must be considered to continue to ensure combination products are reviewed and determined to be safe and effective.

Challenges for global development and registration of novel and innovative combination products at a time of rapidly evolving regulations

Speaker: Daniela Drago, RAC Senior Director Regulatory Sciences, Biogen

How do regulatory authorities go about achieving effective regulation of combination products?

Fortunately, industry and regulatory authorities can agree on the basis to reach this goal. Clinical aspects, such as bridging studies and post-marketing requirements, combined with harmonisation are some of the highest pain points industry would like to see addressed. Frequent and early communication increases harmonisation and avoids diverging opinions. Clinical studies designed for the combination product and not its constituent parts help prevent overly large studies. Post-marketing requirements specifically designed for combination products allow manufacturers to adequately plan. These examples demonstrate that combination products should be independent of their constituent parts, not only in definition, but also in submission type and regulatory pathway.

QMS as a common global requirement: FDA guidance

Speaker: Kim Trautman, Executive Vice President, Medical Device International Services, National Science Foundation (NSF) International

Consensus standards offer an opportunity to come together and solve the problem. However, caution must be taken to avoid a dominant therapeutic or device viewpoint. A cross-cutting approach must be taken to bring the groups together, something which is difficult, as both the drug and device industry and drug and device regulatory pathways are radically different. A neutral party is sorely needed to step in and bring these thought processes together, but it is still unclear if the various standards organizations can do so. In addition, any standardized effort needs to reach all stakeholders. Current standardization efforts tend to be exclusive to those that have the time and resources to participate in them. Although welcome to all, smaller device companies typically cannot afford to make their voices heard, despite being the very place where most innovation happens. Still, consensus standards do provide the framework where industry and regulatory authorities can come together and solve complex problems, as this process has been proven several times over.

Consistency and transparency with current processes is also key. Sharing of lessons learned can prevent the same hurdles from being resolved each time they arise. Unfortunately, issuance of formal guidance is slow. New recommendations have shown up in FDA submission reviews first, instead of in the draft guidance. This creates difficulties for manufacturers as it implies the landscape of the regulatory process may change part way through, something that can be costly and, ultimately, detrimental. It also shows that conflict and differences of opinion exist within regulatory authorities. This, first and foremost, needs to be resolved. Using FDA as an example, the three Centres must be on the same page with combination products before progress can be made on harmonising the review process. The Office of Combination Products has made great strides in determining the designation of combination products, as well as helping industry identify a regulatory submission type, but perhaps it should have more internal authority to increase consistency and harmonisation of the three Centres.

Regulation of drug-device combination products in Canada

Speaker: Douglas Watson, Senior Policy Analyst, Health Canada 

Pilot programmes and “sandbox” efforts may offer an opportunity for regulatory authorities and industry to collaborate on a review pathway unique to combination products. The Canadian combination product sandbox effort is an excellent example of this and shows promise in coming to a solution on combination product regulation. Pilot programmes in the areas of modelling, simulation, and software applications have been successful in the past with the FDA. Inviting industry to participate in parallel review programmes gives regulatory authorities the ability to test ideas without affecting existing processes. They provide direct application for review teams and allow the participation of both small and large industry to participate. This approach can be coupled with consensus standards efforts to offer insights across geographical regions.

Just like the very definition of the problem to be solved, a combination of the above methods, as well as industry and regulatory authority collaboration, provides a pathway to handle the uniqueness of combination products. The first step must be open communication. As demonstrated by the enthusiasm shown in recent years by regulators and the increase of combination product submissions by industry, it seems all stakeholders are fortunately willing to come together with this goal in sight.

Additional effort will be required to equal the rapid innovations in combination product technologies being developed today. Regulatory authorities and industry must come together to develop solutions through continued open dialogue, standards efforts, and innovative regulatory pathways.