A Confluence of Forces Is Now Spurring Combination Product Regulatory Reform in Europe

A confluence of forces is intensifying the pressure on and opening pathways to the reform of drug/device combination products regulation in Europe, with legislative changes and strategic priority needs at issue.

An underlying driver, impacting all regulators around the world, is the need to evolve regulatory processes to better accommodate the convergence of medicines, medical devices, and software and the sharing of expertise among stakeholders.

Having an immediate impact in the EU is its medical device regulation (MDR), which entered into full “application” on May 26, 2021.

The MDR introduces new responsibilities and procedures regarding drug/device combination products for the EMA and national medicines agencies as well as for manufacturers and notified bodies.

The proposed revision to the medical device legislation, initially published in September 2012, was finalized in May 2017 and scheduled to come into full force in May 2020. Due to the impact of COVID-19, the transition period was extended by one year. [See IPQ December 30, 2016, November 26, 2017, and July 26, 2019 for more on the MDR. A full, chronological listing of IPQ stories since 2010 that have focused on the dialogue and developments around the regulation of drug/biologic/device combination products, including those addressing the MDR, is provided below.]

The related in vitro diagnostic regulation (IVDR), also published in 2017, brings in even greater changes and more extensive requirements for diagnostic tests – including companion diagnostics – and is due to take full effect in May 2022.

The implications of the MDR and IVDR for the pharmaceutical industry are explained in a “medical devices” section of the EMA website (link provided below).

EMA references have included a Q&A that addresses procedural aspects of the MDR to combination product applications and a draft guidance on quality requirements, which were published in 2019 and discussed at an EMA multi-stakeholder webinar in late November 2020. At the meeting, it was explained that a task force had been convened, involving representatives from the device and drug units of the European Commission, EMA, and national regulatory agencies, to focus on finalizing the guidance.

On June 29, EMA published a revised and updated version of the 2019 Q&A on MDR/IVDR implementation, with extensive changes reflecting the input of the new task force. [Editor’s Note: The revised Q&A will be reviewed in a follow up IPQ story focused on MDR implementation and the implications of its Article 117, which addresses the notified body review of device constituent parts of “single integral products.”]

The EU “pharmaceutical strategy,” released by the European Commission (EC) in late 2020, calls for another round of legislative changes. A “roadmap” for the proposed revisions was open for comment through April 2021.

The roadmap notes that the current legislation “may not be fully equipped to respond quickly to innovation,” as it was developed at a time when certain technologies, such as genomic sequencing, genome editing and artificial intelligence (AI), did not exist or were in their infancy. It points out that “technological progress is leading to the development of complex combination products,” and that the current legislation should be adapted to cover “new scientific and technological developments and models.”

Meanwhile, the strategic priorities of the EMA, European Medicines Regulatory Network (EMRN) and individual member state agencies have been defined, which call for developing more flexible and adaptive approaches to support innovation.

At various venues over the past year, leading experts have been sharing their insights on the related strategies in development and on the cultural, structural and process changes required for the successful regulation of the medicines, medical devices and combination products of the future in Europe and globally.

The four-part story below explores the current dialogue on the drivers and pathways for a more collaborative, streamlined and globally-minded regulatory approach to combination products in Europe.


Part I: EU Pharma Strategy Roadmap, Comments from Industry, and Related Agency Strategies

The first part of the story focuses on the EU pharma strategy and its discussion of the “interplay” of medicines and medical devices. Reviewed are stakeholder comments on the proposals for handling combination products included in the initiatives for innovation and regulatory efficiency. Also reviewed are: ● combination product-related aspects of the EMA Regulatory Science Strategy and European Medicines Regulatory Network Strategy published in March 2020 and December 2020 respectively ● insights from Belgium FAMHP Christophe Lahorte on the evolving mandate of the EU Innovation Office Network, and ● a joint medicines and medical devices agencies initiative outlined in the June 2021 HMA procedures and governance update.

Part II:  Culture/Structure/Process Change and Global Alignment

The second part further explores the increasing convergence between the worlds of medicines and medical devices and the importance of communication and collaboration – issues central to the discussions at a RAPS/TOPRA workshop on the global alignment of combination product regulation in June 2020. In focus is the discussion by former MHRA Devices head John Wilkinson of the changes needed, based on his experience in working with European and international regulators, policy makers, and industry leaders.

Part III: HPRA CEO Lorraine Nolan on HPRA and EMA Strategy

Part three offers insights from Ireland HPRA CEO and Vice-Chair of the EMA Management Board Lorraine Nolan on developing strategic plans for the agencies and dealing with the impact of Brexit and the COVID pandemic. Addressing a mid-2020 PDA Europe conference, Nolan discussed: ● the evolving regulatory role in enabling product access ● globalization, and ● the impact of the medtech sector.

Part IV: EMA’s Zaïde Frias and NB/Industry Perspectives on EU Regulatory Transformation

Continuing the discussion on regulatory transformation and European agency strategy developments, part four focuses on the keynote presentation by EMA’s Zaide Frias and the Q&A that followed at the October 2020 Medtech and Pharma Platform annual conference. Frias described the EMA regulatory science strategy and shared a vision of collaborative regulation for the complex, converging technologies and medicines that Europe’s regulatory system is facing. An integrated approach to combination product review was also espoused at a DIA Europe conference a few months earlier by notified body (NB) expert Bassil Akra and Zealand Pharma’s Lars Hyveled-Nielsen, who provided the small and medium-sized enterprise (SME) perspective.

[Editor’s Note: A companion story will follow providing an update on how FDA, with the help of its Office of Combination Products (OCP) and industry, is evolving its process for handling the combination product regulatory challenges.]   

LINKEMA Medical Devices


The following is a chronological listing of IPQ stories since 2010 that have focused on the dialogue and developments around the regulation of drug/biologic/device combination products. The headline, first paragraph, and a summary of issues covered are provided. The IPQ coverage reveals the focus over the past decade on the need for communication, collaboration and guidance to enable risk-based, proportionate, and efficient review of the increasing number and complexity of combination products in development globally. Many of the key thought leaders cited in the stories below are still active in the current dialogue. Click the headline for access to the story.


FDA-Wide Effort Underway to Clarify and Harmonize CAPA Definitions in Line with New GHTF Guide

FDA Center for Devices and Radiological Health (CDRH) GMP expert Kimberly Trautman is spearheading an effort to clean up and harmonize the definitions around corrective and preventive action (CAPA) across the agency in line with a Global Harmonization Task Force (GHTF) guideline on CAPA that is nearing release.

● importance of standards for drugs, devices and combination products
● evolution of quality system concepts for pharmaceutical and combination products
● systemic corrective actions
● preventive action and continual improvement
● risk management
● FDA CBER, CDER and industry comments


Risk-based Approach to Combination Products Advocated to Improve Communications with Regulators and Streamline Filing

A risk-based approach could clarify and simplify the regulatory pathway for combination products, Lilly CMC Regulatory Affairs Principle Consultant LeAnn Chambers maintained at a DIA CMC Workshop in February.

● using ISO 14971 medical device risk management principles to support functionality and performance of a pen injector system
● ISO 11608 updates
● control strategies for device changes
● data to include in a dossier

Communication with Reviewing Authorities Key to Combination Product Success in Europe and Japan

Communication with reviewing authorities is critical in navigating the combination product regulatory shoals in Europe and Japan as it is in the US. However, the communication channels are not always well-marked, and they differ in each of the three ICH regions.

● industry perspectives on the similarities and differences in the registration processes for combination products in Europe and Japan, including experience with notified body reports

More Guidance Forthcoming from FDA’s Office of Combination Products on CMC & GMP Expectations

FDA’s Office of Combination Products (OCP) will be sharing its growing knowledge base through new guidances and updates to its existing library that will help CP manufacturers better understand the regulatory expectations and navigate the shoals of marketing clearance.

● OCP on eight years of experience in coordinating combination product applications and addressing the questions and unique challenges presented by them

Human Factors/Usability Gaining Prominence in Combination Product Review

Human factors/usability analysis is gaining prominence in the dialogue between combination product manufacturers and regulators. At issue is an effective pathway for companies to follow in conducting and submitting the analysis and for regulators to follow in reviewing it.

● includes insights from FDA’s CDRH and industry’s IPAC-RS Device Working Group


FDA Expectations for Studying Human Factors in Pre-filled Syringes are Taking Shape

FDA is increasing its pressure on sponsors to conduct pre-market human factors (HF) studies for combination products, including pre-filled syringes, and industry is getting clearer on the agency’s expectations as more experience is gained.

● Janssen sharing industry experience, including study requirements, expectations for phase III clinical trials and challenges with biologics


FDA Draft Guidance on Syringe Connection Problems Reemphasizes Need for Early Agency/Sponsor Dialogue on Combo Products; Postapproval Change Guide Issued

A new draft guidance from FDA on glass syringe connection problems, which have been associated with serious adverse events and quality issues over the past few years, reemphasizes the need for early dialogue between combination product sponsors and the agency to avoid potential design and development pitfalls.

● FDA’s CDRH on adverse events that called connection problems to agency attention
● need for pre-filled syringes to be tested with the final drug formulation
● issue of using labeling to address design shortages
● early meetings with reviewers to help get products to market

Better Human Factors Analysis is Driving New Combination Product Technologies Designed to Reduce User Errors

Multi-sensory training tools and design features for auto-injectors, including audio instructions, are among the error-reduction technologies being driven by better human factors (HF) analysis in the drug/device combination product arena.

● industry perspectives on innovations in patient information and training
● benefits of communicating early with FDA and management support to focus on device usability earlier in product development


Focus Intensifying in Europe on Improving Drug/Device Combination Product Regulatory Communication

The challenges of the CMC regulatory process for drug/device combination products are getting increasing attention in Europe as industry and regulators join in the search for clearer and more efficient communication channels and regulatory procedures.

● MHRA on implications of the MDR for the pharma industry and the communication and collaboration needed towards proportionate, appropriate, and risk-based regulation [Editor’s Note: The story focuses on a presentation given by then MHRA reviewer Janine Jamieson, who joined the IPQ staff shortly afterwards.]


Combination Product Regulatory Improvements Remain High on Pharma’s 2017 Wish List

Clearer, more review/inspection coherent, more risk-based, and more harmonized regulatory expectations across the expanding universe of drug/device combination products will continue to be a high-priority focus for the pharmaceutical industry during 2017.

● industry’s collaborative efforts to define the challenges faced in CP development and registration
● terminology and framework differences between US and EU
● leveraging from pre-filled syringes to pens
● how much information to provide
● proposals for harmonization

FDA’s Broad-Based Effort to “Modernize” Combination Product Regulatory Process in Full Swing

FDA’s broad-based effort to “modernize” its regulatory process for products that contain some combination of drugs, biologics and devices gained significant momentum during 2016, and the impact of the effort will continue to increase as 2017 progresses.

● FDA officials on outreach activities, the new Combination Products Policy Council, inter-center consult and pre-request for designation processes, and agency leadership support for OCP

New and Generic Drug User Fees, 21st Century Cures Act, Fuel FDA Regulatory Process and Culture Changes for Combination Products

The process of reauthorizing user fees for new and generic drug products has afforded the Center for Drug Evaluation and Research (CDER) the opportunity to work cooperatively with industry to drive significant cultural and process enhancements in its regulation of drug/biologic/device combination products.

● negotiations between FDA and industry groups on improving combination product review transparency and coordination among centers, with more dedicated funding streams
● FDA on combination products as “transformative” aspect of healthcare, deserving of similar regulatory support to breakthrough therapies
● CP commitments in user fee acts for prescription and generic drugs, biosimilars and medical devices

Europe is Assessing Challenges of Implementing Combination Product Regulatory Changes; Attention on CPs Increasing Globally

The stress on the resources and expertise of the European notified bodies in taking on the assessment of the device component of higher-risk drug/device combination products is among the significant challenges the EU faces as it enters the implementation phase of its new medical device and in vitro diagnostic regulations (MDR/IVDR).

● MHRA on the background to the MDR, limited number of notified bodies, and joint efforts by EU heads of medicine and medical device agencies to solve combination product challenges
● MHRA/FDA/industry discussions on global “harmonization” based on shared principles


Improving Communications on Drug/Device Combination Product Quality and Performance is an Increasing Priority in the US and Europe

Industry and regulators in the US and Europe are wrestling with how best to interpret and communicate drug quality-by-design (QbD) concepts, device design controls (DC) and overall final product risk management in the drug/biologic/device combination product context.

● EMA’s concept paper on developing guidance on quality of combination products and clarification of “single integral product”
● MHRA report on adrenaline auto-injectors
● FDA CP guidance expanding
● EFPIA/EBE CP reflection paper

FDA Inspection Findings Provide Additional Insight on CGMP Expectations for Combination Product Manufacturers

The light being shed on the current GMP regulatory expectations for risk management and manufacturing control of combination products by FDA’s inspection engagement with pharma sponsors and their device partners has been a focal point at recent conferences in the US and Europe.

● FDA warning letters to CP manufacturers
● MHRA on critical thinking for quality risk management of combination products
● FDA CP inspection case studies

Understanding Drug/Device Terminology Differences is Critical to Combination Product Control and Regulatory Communications, Industry Experts are Stressing

Industry experts are stressing that the payoff for combination products in understanding and bridging the drug/biologic/device terminology differences is a smoother development process, a simpler, more effective control system, and better communications with CMC reviewers and GMP inspectors.

● industry leaders on the need to become “bilingual”
● drug “quality by design” and device “design controls”
● “criticality,” “functionality,” “specifications,” “validation,” and “risk” in the combination products context
● emergence of a new term “essential performance” in FDA communications

CMC Priorities of EFPIA’s European Biopharmaceutical Enterprises Include ADCs, Drug/Device Combos and Statistics

Drug device combinations (DDCs), antibody drug conjugates (ADCs), and the use of statistics in comparability assessments are among the current focal points of the European Biopharmaceutical Enterprises (EBE) in its efforts to identify and build consensus around the most pressing issues on the global regulatory agenda for biotech manufacturing and control.

● EFPIA/EBE on MDR Article 117, lifecycle control strategy for CPs, and meshing of review and inspection functions
● UK MHRA and Austria AGES on considering de-centralized in addition to centralized EMA applications and understanding the issues across all stakeholder groups


CDER’s Office of Pharmaceutical Quality is Opening New Regulatory Pathways to Span Its Broad Responsibilities and Global Reach

The “strategic priorities” of the Office of Pharmaceutical Quality (OPQ) for the next few years speak to the wide breadth and global reach of its regulatory responsibilities, and to OPQ’s willingness to open new pathways to fulfill them.

● FDA OPQ’s Ashley Boam (ICH Q12 rapporteur) on science- and risk-based quality, policy and standards related to review and inspections for drugs and combination products, and on coordination with international regulatory authorities, pharmacopoeias and standard setting organizations

EMA’s Draft Guideline on Drug-Device Combinations Sheds Needed Light on Expectations for Device Assessment

EMA’s draft guideline on quality requirements for drug-device combination (DDC) products provides a template for the new concept of the notified body opinion (NBOp), intended to help ensure a consistent interpretation by individual assessors, notified bodies, and industry.

● background and outline by guideline co-rapporteur from HPRA
● key points including platform technologies, quality aspects of bridging to pivotal clinical trials, lifecycle management, and emerging technologies
● working group interactions with notified bodies


Attention Heightens on Creating an Independent Regulatory Pathway for Introducing Novel Excipients

Drawing increasing attention in the global industry/regulator dialogue is the need for excipients that are fit-for- purpose in meeting the complex challenges of formulating, manufacturing, and delivering the new generation of medicines and making them as safe, efficacious, and patient- and distribution-friendly as possible.

● FDA’s novel excipient program proposal and stakeholder comments on critical issues for pharmaceutical, biological and combination products and need for an excipient review pathway to spur innovation
● IPEC-Americas stresses criticality of novel excipients for combination products


Academia/Industry Collaboration Intensifies on Addressing the Pressing Needs in Biopharma Workforce Development

Academia and industry are collaborating more intensely on addressing the pressing needs in biopharma workforce development, in recognition of the challenges of keeping pace with the rapidly evolving process and product technologies and the cross-functional understanding and skills needed to support them.

● ISPE Workforce of the Future session includes outline of UMBC academic course on combination products
● noted are high percentage of drug products in development that are combination products, need for specialized training, and current skills gap

Regulators Are Exploring with Industry How to Strengthen Quality Risk Management Practices, with Revision of ICH Q9 a Key Focal Point

Regulators and industry are sitting down together to mine their experience and map out some clearer directions and expectations about what is needed to empower quality risk management (QRM) in improving the pharmaceutical quality system (PQS) and the industry/regulator communication process at the review and inspection levels.

● shifting QRM focus from “reactive” to “proactive” to address the growing complexity of products and processes
● ICH Q9 revision lead refers to utilising other risk management standards such as ISO 14971 on devices
● industry on aligning Q9 with ISO 14971 revision and adding guidance on combination products

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