Contributed Commentary by Angela Brown and Nicole Cowan
February 11, 2021 | The rise of personalized medicines has led to an increased demand for companion diagnostics (CDx). These in vitro diagnostics (IVDs) increase the probability of clinical success by identifying patients with the presence of biomarkers or disease-specific therapeutic targets that can dramatically improve outcomes and decrease costs by ruling out therapies that are less likely to be effective. As personalized medicines become more innovative and complex, so will CDx.
In addition, with growing trends toward stricter regulatory enforcement for IVD testing and quality, manufacturers face great pressure to bring products to market quickly, while balancing the regulatory environment. One of these regulations, the European Union’s In Vitro Diagnostic Regulation (IVDR), introduced a new risk-based classification system, significantly impacting complementary and companion diagnostics. The IVDR also defines a CDx, for the first time in Europe, creating new challenges for device manufacturers and pharmaceutical companies producing CDx. Under the previous directives, CDx could be self-certified. Now, considered a high-risk class C device, CDx requires conformity assessments by a notified body (NB), including increased clinical evidence.
Despite these new obstacles, many CDx devices with regulatory approval in other countries, such as the US or Japan, already have much of the clinical evidence existing from studies conducted for these submissions. Further, developers can leverage real-life clinical evidence and outcomes data for CE marking for CDx devices currently on the market to the IVDR to meet the May 2022 deadline.
Understanding Companion Diagnostics Definition and Classification
Under the IVDR, CDx is defined as a device that is essential for the safe and effective use of a corresponding medicinal product to:
- Identify, before and/or during treatment, patients who are most likely to benefit from the corresponding medicinal product;
- Or identify, before and/or during treatment, patients likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product.
Note that devices used to monitor treatment with a medicinal product to ensure that the concentration of relevant substances in the human body are not considered to be companion diagnostics under this regulation.
This new definition—combined with the introduction of a risk-based classification system based on the IMDRF system of device classification—has resulted in a shift from CDx devices being self-certified general IVD devices to high-risk class C devices, requiring the submission of clinical evidence and a greater scrutiny of data.
Now, under the IVDR, it is mandatory for CDx devices to require conformity assessment by an NB in consultation with the European Medicines Agency or the Member State Competent Authority for Medicines. This represents an additional layer of inspection, as well as an added challenge to the sponsors of the new drug and CDx.
Without a clear understanding of how the various stakeholders will work together, many concerns remain as to the capacity and technical capability of the agencies to adequately review the information provided.
Obtaining Performance and Clinical Evidence Requirements
While the IVDR uses the same basic regulatory processes as the current In Vitro Diagnostic Directive (IVDD), including the continued need for technical documentation to demonstrate device performance, now manufacturers are required to obtain considerably more detail. For example, there are additional activities to be executed under the IVDR in planning and conducting a performance evaluation, which will be continuous throughout the lifecycle of the IVD. In addition, the performance evaluation must be developed and planned to provide adequate evidence that demonstrates scientific validity, analytical performance and clinical performance, and should be transparent, free of bias, and clinically relevant.
Further, CDx requires a performance study to be conducted, which includes analytical and clinical studies. Requirements for planning, executing, and reporting on the studies is dependent on the type of study design, such as observational or interventional, and whether surgically invasive sample taking is needed. These studies are subject to authorization by the member state competent authority and approval by an ethical committee in accordance with national law.
Meeting the Approaching Deadlines
The broadening scope of the rules means that approximately 90% of IVDs will now be required to be reviewed by an NB, further adding burdens on and creating a bottleneck for NBs. With less than two years to the date of application, only five IVDR NBs—compared to 21 under the IVDD—are operating. Further, the number of NBs will decrease by one, as BSI UK will lose its EU designation at the end of this year.
With TÜV SÜD Product Service being the first, and only (as of Dec 15), EU NB to issue an IVDR certificate, the IVD industry as a whole is lagging behind to meet quickly approaching deadlines. Other ongoing disruptions continue to affect the medical device industry regarding device design timelines, manufacturing capabilities and distribution logistics.
While many areas remain unclear, there are activities that CDx manufacturers and sponsors should already have started throughout the transition period. By the time a drug is being submitted, all of the data requirements for the CDx should have been completed and in place under the IVDR for review and approval.
Achieving medical device compliance starts with an understanding of the latest guidelines, in addition to creating a strategy to obtain proper clinical evidence and documentation throughout a product lifecycle. Implementing a strategic framework can save precious time and ensure operational efficiency during product development.
Angela Brown, B.S., Global Head and Senior Director, Regulatory Affairs, has over 20 years of global regulatory affairs experience interacting with regulatory health authorities for various products in the medical device industry specializing in international regulatory affairs working with universities, start-ups and blue chip companies. Her expertise spans the globe with experience to successfully navigate country specific requirements by providing strategic global regulatory routes to market, submissions and navigating changing regulatory environments to bring products to the marketplace. She can be reached at Angela.Brown@iconplc.com.
Nicole A. Cowan, Director, Project Management, IVD Operations & Strategy, has over 15 years’ experience in clinic, academia, CRO, and central laboratory services landscapes. She leads strategy for In Vitro Diagnostics (IVD) research and development, bringing applied aptitude directing highly cross-functional global teams with proven excellence in successful program management, particularly for global, Class III Medical Devices and logistically complex IVD studies. She can be reached at Nicole.Cowan@iconplc.com.