Zara Malik, head of regulatory affairs, LFH discusses companion diagnostics in Europe and the evolving regulatory landscape.
Companion diagnostics (CDx) are becoming a key part of personalised medicine, enabling healthcare providers match patients with the most effective treatments and therapies. As the demand for precision treatments grow, so does the importance of having robust and reliable diagnostics that guide clinical decisions.
In Europe, the regulatory environment for CDx has undergone significant change with the introduction of the In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR). This framework imposes stricter requirements for demonstrating the safety, performance and clinical diagnostic devices.
For CDx manufacturers, understanding and navigating the IVDR is essential. Gaining CE marking, now requires a full conformity assessment by a notified body and ideally, alignment with the drug’s development timeline. Early planning and regulatory engagement are critical to ensuring timely patient access to both the diagnostic and its corresponding therapy.
What exactly is a CDx?
The IVDR now formally defines a companion diagnostic as:
A device that's essential for the safe and effective use of a related medicine specifically to:
(i) identify which patients are most likely to benefit from it, or
(ii) highlight those at higher risk of serious side effects.
This aligns broadly with definitions from other major regulatory agencies, such as Japan’s PMDA, the US FDA, and Canada’s HCSC. However, one key distinction is that under the IVDR, devices used solely to monitor a treatment's ongoing effects are not considered CDx.
Common CDx development scenarios
There are three primary development pathways for CDx’s in Europe:
1. Co-developed CDx
Developed in parallel with a new medicine during clinical trials, these devices are often linked to to a new drug or a new indication.
2. Follow-on CDx
These diagnostics targets the same biomarker as an existing CDx but were not developed in parallel with the drug. They may offer alternative technologies or testing platforms.
3. Transitioning CDx
Devices initially approved under the older IVDD framework now need to be reassessed and updated to meet IVDR requirements, often requiring additional data and documentation.
How are CDx devices classified?
Under the IVDR, In Vitro Dianostic devices are grouped into four risk classes, A through to D based on risk. Most CDx fall under Class C (as per Rule 3(f)), meaning they pose moderate to high risk to individuals and public health.
As Class C devices, CDx must undergo a full conformity assessment by a notified body, which includes;
- Review of technical documentation
- Evaluation of the manufacturer’s quality management system (QMS)
Additionally, the European Medicines Agency (EMA) also plays a role, reviewing whether the CDx is suitable for use alongside the relevant medicine.
Working with notified bodies and regulators
IVDR implementation has introduced a more integrated approach between manufacturers, notified bodies, and regulators. Unlike standard IVDs, the approval process for CDx is multi-layered.
Once technical files are complete, they are submitted to the notified body. However, before final approval, the notified body must consult with the EMA to obtain a scientific opinion on the CDx's suitability for use with the specified drug.
This collaborative review can significantly extend timelines. As such, early engagement with regulators and notified bodies is essential to avoid delays that could impact patient access and market launch.
Risks and challenges in CDx development and approval
Despite their potential, developing and launching a CDx in Europe under IVDR can be complex. Here are some of the main risks and how they can be addressed:
1. Navigating complex regulations
The IVDR has raised the regulatory bar. The conformity assessment process now demands significantly more documentation, clarity on intended use, and involvement from medicines regulators. Lacking this information can lead to serious delays.
Solution: Understand the IVDR in detail, engage with regulatory consultants (where necessary) and involve a Notified Body early.
2. Managing stakeholder coordination
CDx development involves cross-functional teams, from pharmaceutical partners and diagnostic teams, notified bodies and regulatory authorities. Misalignment across these groups can lead to project delays.
Solution: Develop a Regulatory Strategy. Promote open communication and ensure integrated project planning.
3. Meeting evidence requirements
Strong clinical and analytical performance data is essential, often using patient samples or prospective studies which are both time and resource intensive. Small changes in study design can trigger rework later down the line.
Solution: Begin studies and literature searches early. Validate that available evidence is sufficient. Identify gaps that need additional studies.
4. Classification
While most CDx fall under Class C, there may be cases where classification is unclear. If classification is challenged by a notified body, it can impact the entire regulatory pathway and delay approval.
Solution: Conduct a robust classification rationale, engage with regulatory consultants (where necessary)
5. Market access isn’t guaranteed
Even with CE marking, a CDx may face hurdles at the national level. Health technology assessment (HTA) bodies and payers will still scrutinise the device’s clinical and economic value. Without a clear reimbursement pathway, some CDx devices may struggle to reach patients despite regulatory approval.
Suggestion: When conducting strategies, feasibility assessments and business planning, review the devices economic value. Will it be profitable to put on the market?
Final thoughts
Companion diagnostics are essential to the future of personalised medicine, offering better-targeted therapies and improved patient outcomes. In the EU, bringing these devices to market under the IVDR is no small task.
Success hinges on early preparation, strategic planning, and ongoing collaboration with both pharmaceutical partners and regulators.
While the IVDR introduces more rigorous oversight, it also ensures higher-quality diagnostics and ultimately, safer, more effective treatments for patients. For developers willing to navigate this new landscape, the opportunity to lead in personalised medicine has never been greater.