Companion Diagnostics (CDx) – Strictly Monitored In Vitro Diagnostic Devices

Companion diagnostics (also known as CDx) are used together with a medicinal product. Physicians use them, for example, to make sure that a particular medicinal product is actually suitable for a patient. This means that CDx play a particularly big role in personalized medicine.

As the companion diagnostic and the medicinal product are inseparably linked to one another, there are some specific features in their development and authorization.

In this article you will learn:

• How companion diagnostics are defined
• What the development and approval of CDx looks like in practice
• What regulatory hurdles have to be overcome in Europe and the USA
• What tips we have for you so you can make a success of CDx development and authorization

1. What are companion diagnostics (CDx)?

The success of some drug therapies requires the use of an in vitro diagnostic device (IVD). Laboratories use this IVD to determine whether a biomarker that the drug targets is present in the patient. Physicians can use the analysis from the IVD to make sure that a particular therapy is actually suitable for their patient.

Usually, the CDx detects gene sequence changes or the presence of certain proteins in the analyte.

Typical platforms are:

• Immunohistochemistry
• Quantitative PCR
• Next-generation sequencing
•  In-situ hybridization (FISH, CISH)

If a particular result from the IVD is a prerequisite for a safe drug therapy, then this IVD is called a companion diagnostic (CDx). Ideally, CDx are developed in close collaboration with medicinal product manufacturers.

Based on Recital (11) of the IVDR, the main intended uses of CDx are as follows:

• Defining patients' eligibility for specific treatment with a medicinal product through the quantitative or qualitative determination of specific markers
• Identifying subjects at a higher risk of developing an adverse reaction to the medicinal product in question
• identifying patients in the population for whom the therapeutic product has been adequately studied and found safe and effective. Such biomarker or biomarkers can be present in healthy subjects and/or in patients.

However, the definitions of CDx in Europe and the USA are different.

a) Different definitions of CDx

Europe

In Europe, the term “companion diagnostic” is defined by Regulation 2017/746 on In Vitro Diagnostic Medical Devices (IVDR):

Explicitly not CDx

This exception is particularly important because it does not exist in the USA. The FDA's definition of companion diagnostic is different to the European definition:

USA

The FDA defines “IVD companion diagnostic devices” as follows:

Manufacturers who want to place their in vitro diagnostic medical device for monitoring a treatment with a medicinal product on the market in Europe and the USA should make sure they are aware of these different definitions.

b) Difference from complementary diagnostics

There is another group of IVDs that are not companion diagnostics but that could be confused with them: “complementary diagnostics.”

Complementary diagnostics are neither defined nor described in the IVDR. Their use is recommended in combination with a specific medicinal product, rather than being mandatory before the medicinal product can be used. Therefore, they are used only to help decision-making, not as a required part of the therapy.

This means complementary diagnostics do not have a close link with a drug in the way that companion diagnostics (CDx) do. As a result, from a regulatory perspective, complementary diagnostics are treated in the same way as “traditional IVDs,” i.e., the specific features that apply to CDx do not apply.

Example:

One FDA-approved complementary diagnostic is an immunohistochemical assay for the detection of PD-L1 proteins in patients with non-small cell lung cancer who are candidates for cancer immunotherapy (nivolumab).

This is a complementary diagnostic and not a CDx because a therapeutic benefit has been demonstrated for ALL patients who receive the medicinal product irrespective of their biomarker status. Nevertheless, there are some patients who respond better to the medicinal product than others: patients who express particularly high levels of the protein PD-L1.

Therefore, the use of the IVD is not mandatory, but does provide a prognosis for how effective the drug treatment might be.

CDx based on genetic testing: No patient counseling

If a CDx is based on genetic testing, patient counseling, which is required for other genetic tests, is not required (Art. 4(3) IVDR).

Performance evaluation

Generally speaking: CDx always require clinical data and fall under the scope of the “certain performance studies” referred to Art. 58(2) IVDR.

The three pillars of clinical evidence – scientific validity, analytical performance and clinical performance – naturally also apply to CDx.

• The scientific validity should also clarify the clinical performance of the associated medicinal product in the patient population stratified/selected by the CDx.
• The analytical performance evaluation should be completed before the clinical trial of the medicinal product is started (see also section 2c  “Co-development process”).
• Clinical performance studies are required to demonstrate clinical performance.

MedTech Europe has summarized further information on this topic.

Otherwise, there are no special requirements for CDx performance evaluations.

Labeling

The CDx's instructions for use must include the international non-proprietary name (INN) of the associated medicinal product that it is a companion test for.

Under German legislation, the CDx is not mentioned in the medicinal product's patient information leaflet (AMG Section 11).

b) Specific features in the USA

The US authorities have more experience with CDx than the European authorities and notified bodies. The following specific regulatory features apply in the USA:

• The complete process is handled by the FDA and not by two authorities (notified body and EMA) as in Europe.
• Most CDx are “high-risk devices” and are classified as class III, which entails a requirement to submit a premarket application (PMA).
  Only a few CDx can be authorized through a 510(k) application.
• In an oncology context, the FDA also allows CDx to be intended for a specific group of medicinal products and not just for individual medicinal products. The requirement is that there is sufficient evidence that the IVD is suitable for this group of medicinal products.

There is an FDA guidance document available on this topic: Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products.

• There is a List of Cleared and Approved Companion Diagnostics in the USA.
• Labeling: In the USA, the use of CDx together with a therapeutic product must be mentioned in the instructions for use and on the labeling of both the diagnostic device AND the corresponding therapeutic product (see the FDA's comments on this).

c) Guidance (or lack thereof)

There is still a lack of guidance on CDx. However, we recommend reading the following documents that are available already:

• Clinical Evidence Requirements for CE certification under the In-Vitro Diagnostic Regulation in the European Union from MedTech Europe
•  EMA concept paper
• The EMA's website also provides information on implementation. However, it hasn’t been updated since February 2019.
• The pending sixth revision of the EMA's Guideline on the clinical evaluation of anticancer medicinal products aims to provide better guidance on regulatory expectations for biomarker-driven development.
• FDA guidance on oncological research and CDx
• FDA recommendation on co-development: The development of biomarker-based diagnostic methods should be considered at an early stage of the clinical development of the medicinal product. The aim is to maximize the clinical applicability of the technology.
• MedTech Europe and the European Federation of Pharmaceutical Industries and Associations (EFPIA) have produced a document that lists the areas where the regulations for CDx are unclear and suggests solutions.

4. Bringing CDx to the European market

You can use the standard steps for authorization as a guide to safely launch a companion diagnostic on the market. However, note the specific requirements for CDx in each step.

a) Step 1: define intended purpose as CDx

Use the intended purpose of your in vitro diagnostic device to check whether it is actually a CDx. This is only the case if there is an actual dependence on the therapeutic agent (see section 1 “Definition”).

b) Step 2: quality management system

The next step is to set up your quality management system according to ISO 13485 and the IVDR. In this regard, there are NO differences from other types of IVD.

c) Step 3: compile the technical documentation

There are also no specific requirements compared to other IVDs with regard to the technical documentation according to Annexes II and III of the IVDR. The requirements of Annexes II and III of the IVDR must be met. See our comments on the performance evaluation (see the “Specific regulatory features” section).
IVD manufacturers should be in contact with their pharmaceutical partners during device development.

d) Step 4: conformity assessment

The conformity assessment procedure is more complex than with other IVDs (see the “Consultation with medicinal products authorities” section). It starts with the formal application to the notified body. In addition to the name and classification of the CDx, the specific intended purpose including the reference to the specific medicinal product, among other things, has to be specified.

The medicinal products authority, generally the EMA, is involved through the notified body. The EMA, notified body, IVD manufacturer and, if necessary, the pharmaceutical company as well should attend a pre-submission meeting intended to support the preparation of the application.

The consultation process follows the procedure described above (section 3 a).

5. Tips for CDx development and authorization

To ensure that everything runs smoothly during the development and authorization of your companion diagnostic, we recommend the following:

a) Choose your partner well

Be discerning when choosing your partner from the IVD or pharmaceutical sector. Developing a CDx requires a huge amount of coordination and cooperation. For it to go smoothly, the framework conditions must be right. The CDx project will be easier if your partner has prior experience with companion diagnostics.

b) Reach clear agreements

Functioning agreements and a high level of communication are important for guaranteeing the compatibility of the IVD and therapeutic agent.

The planning should be coordinated to ensure that IVD development is consistent with the requirements concerning the medicinal product.

Prototype development, including the analytical performance evaluation, should be coordinated to ensure that the clinical trial can be started on time and as planned.

The FDA recommends that:

c) Involve the CDx in medicinal product development from an early stage

The alignment of the therapeutic agent and CDx should be started as early as possible. It is therefore important for the medicinal product manufacturer to involve the IVD manufacturer as early as possible.

d) Plan more time than usual

If a companion diagnostic accompanies a medicinal product, both development and authorization are more costly and complex than for a medicinal product or IVD on their own. The involvement of the medicinal products authority also adds time to the procedure. These factors should definitely be taken into account in your planning.

6. Conclusion

Companion diagnostics (CDx) are becoming increasingly important in modern medicine. They play a big role in personalized medicine in particular.

However, for manufacturers of IVDs or medicinal products, this means more work as CDx come with additional regulatory requirements. Good planning and effective coordination between all parties involved is therefore crucial. But if their development is successful, CDx can bring huge benefits and take therapy to a new level for patients.

The Johner Institute’s experts will be happy to help you with any questions you may have on IVD authorization strategies or on the issue of companion diagnostics (CDx) specifically. Simply contact us via our contact form or email us.