Companion diagnostics (CDx) are an essential part of the personalized medicine landscape, playing a pivotal role in delivering the most effective therapies tailored to a patient’s specific biological makeup. As the medical field moves toward individualized treatment plans and personalized medicine, CDx assays have emerged as indispensable tools that facilitate the safe and effective use of targeted therapies[1]. This blog provides an overview of what CDx are, how they differ from complementary diagnostics, their role in personalized medicine, and the common pathways for their development.
What is a companion diagnostic?
According to the US Food and Drug Administration (FDA), a CDx is an in vitro diagnostic (IVD) device that provides information that is essential for the safe and effective use of a corresponding therapeutic product[2]. The use of a device as a CDx should be stipulated in the instructions for use and in the labeling for both the diagnostic device and the corresponding therapeutic product. FDA has defined what a CDx must include for safety and effectiveness:
- Identifying patients who are more likely to benefit from the use of the therapeutic product
- Identifying patients likely to be at increased risk for serious adverse reactions as a result of treatment with the therapeutic product
- Monitoring response to treatment with the therapeutic product for the purpose of adjusting treatment
- Identifying patients for whom the product is known to be safe and effective
A CDx helps to identify patients who are more likely to benefit from a particular treatment or those who may be at risk of adverse reactions. CDx assays are often developed alongside their corresponding therapeutic products to ensure that both are ready for market at the same time, but there are exceptions where development occurs later, or an existing diagnostic is repurposed for use with a therapeutic. FDA maintains a list of currently cleared or approved CDx and their therapeutics[3].
The key is that the diagnostic is essential for the proper administration of the therapeutic product.
CDx vs. complementary diagnostics
It is important to distinguish between CDx and a complementary diagnostic (CompDx). While a CDx is necessary for the therapeutic product’s safe and effective use, a CompDx provides additional information about whether a treatment might be beneficial but is not required for the therapy to be administered[4].
For instance, a CDx might identify patients who are likely to respond to a specific cancer therapy, while a CompDx offers insights into a treatment’s general benefits across a broader patient population[5]. The FDA is still in the process of developing guidance on CompDx assays, highlighting the evolving nature of diagnostic tools in medicine.
The benefits of CDx in personalized medicine
Companion diagnostics are not just technical tools but crucial components of the personalized medicine paradigm1. In our experience, their benefits extend beyond just matching a patient to a treatment, offering multiple advantages that reshape the patient care landscape.
- Tailored treatment plans: One of the core benefits of CDx is the ability to create treatment plans specific to a patient’s genetic profile. This improves the likelihood of therapies being effective, reducing the guesswork in prescribing treatments.
- Enhanced treatment efficacy: A CDx can guide healthcare providers in selecting the right patients for a particular drug, increasing the likelihood of success. The result is a higher response rate and improved clinical outcomes compared to a one-size-fits-all approach.
- Minimized Adverse Effects: By identifying patients who may be at higher risk of side effects, CDx helps healthcare providers avoid treatments that could cause harm. This leads to a safer patient experience and fewer complications during treatment.
- Optimized resource allocation: CDx focuses resources, especially costly therapies, on patients who are more likely to benefit. This reduces unnecessary healthcare costs and prevents the overuse of ineffective treatments.
- Improved drug development: Pharmaceutical companies benefit from CDx by focusing on developing therapies targeted at specific biomarkers. This accelerates drug development and results in more effective and efficient treatments reaching the market.
- Long-term monitoring and disease management: In some cases, CDx can be used for ongoing monitoring, allowing for adjustments to treatment plans as a disease progresses. This is especially useful in chronic conditions or cancers where continuous management is crucial.
- Reduced trial and error: Traditional treatment approaches often rely on trial and error, but a CDx can reduce this uncertainty. By providing precise insights from the start, the CDx can help guide clinicians toward the right therapy, reducing unnecessary steps and treatments.
- Increased Patient Engagement: A CDx often involves patients more directly in their care as patients gain a better understanding of why certain treatments are recommended. This leads to better compliance, improved satisfaction, and a more personalized care experience.
Pathways for CDx Development
There are several pathways through which companion diagnostics are developed. Understanding these can help stakeholders in the healthcare sector grasp the nuances involved in bringing a CDx to market.
- Parallel (Co-development) Pathway: In this approach, the CDx and the therapeutic product are developed simultaneously. Clinical trials are designed to gather data for both the diagnostic and the therapeutic, ensuring that both products are ready for market at the same time. A bridging study might also be necessary to assess the concordance between the initial clinical trial assay and the final CDx intended for use in the broader market[6].
- Sequential Development Pathway: Sometimes, the therapeutic product is developed first, and only once it demonstrates efficacy and safety do efforts begin to create a corresponding CDx. This pathway is useful when the need for a CDx becomes clear only after the therapeutic product shows potential[7].
- Retrospective Development Pathway: In this scenario, an existing diagnostic test may be repurposed as a CDx after its potential is discovered. Retrospective studies are conducted to validate the diagnostic’s use, and, if successful, it is adopted for that purpose.[8]
- Follow-On Development: A follow-on CDx is created based on an already established CDx but may target the same biomarker or have the same intended use as the original. This pathway is used when expanding the availability of a CDx for broader applications or for related therapeutics[9].
CDx Development Models
Drug developers are increasingly incorporating a companion diagnostic (CDx) strategy into their programs to deliver safer, more effective, and appropriate therapies to the right patients. Choosing the right development model would also have a significant impact on time to market and development cost.
Two primary development models dominate the industry:
- IVD Partnering Model: This traditional model involves a collaboration between an in vitro diagnostic (IVD) manufacturer and a drug developer. The IVD manufacturer seeks regulatory approval for the assay, which results in a diagnostic kit that can be deployed globally in a decentralized manner[10].
- LDT Partnering Model: This model involves a reference or clinical laboratory developing a laboratory-developed test (LDT) to support specific clinical trials. It is typically carried out under CAP/CLIA[11] requirements and may lead to a single-site premarket approval (PMA). However, we believe there are opportunities to bridge the single-laboratory PMA to a globally deployable IVD assay, and the two models are not mutually exclusive.
Conclusion
The evolution of Companion Diagnostics is shaping the future of personalized medicine, allowing for treatments that are more precise, effective, and safe. As CDx assays continue to develop alongside therapeutic products, they are expected to play an increasingly critical role in healthcare by facilitating the right treatment at the right time for the right patient. The combination of improved drug development, optimized resource allocation, and enhanced patient outcomes makes CDx a cornerstone of modern medicine, leading to a future where healthcare is truly personalized.
For those involved in the development, regulation, and use of CDx, understanding these pathways and models is critical for maximizing the potential of this innovative technology in improving patient care.
[1] Companion diagnostics: the key to personalized medicine, Expert Review of Molecular Diagnostics, 2015. https://www.tandfonline.com/doi/full/10.1586/14737159.2015.1002470
[2] Companion Diagnostics, FDA. https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics
[3] List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools), FDA. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools
[4] IVD companion diagnostics Guidance on regulatory requirements, TGA, Oct 2022. https://www.tga.gov.au/sites/default/files/ivd-companion-diagnostics.pdf
[5] Current Status of Companion and Complementary Diagnostics: Strategic Considerations for Development and Launch, Clin Transl Sci., March 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5355969/
[6] Guidance Document – Principles for Codevelopment of an In Vitro Companion Diagnostic Device with a Therapeutic Product – Draft Guidance for Industry and Food and Drug Administration Staff (July 2016) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/principles-codevelopment-in-vitro-companion-diagnostic-device-therapeutic-product
[7] Guidance Document – In Vitro Companion Diagnostic Devices, Guidance for Industry and Food and Drug Administration Staff (August 2014) https://www.fda.gov/regulatory-information/search-fda-guidance-documents/in-vitro-companion-diagnostic-devices
[8] The Retrospective Approach To Companion Diagnostics https://www.wsgr.com/a/web/65/law360-1015.pdf
[9] Changes in Companion Diagnostic Labelling: Implementation of FDA’s April 2020 Guidance for Industry for In Vitro CDx Labeling for Specific Oncology Therapeutic Groups https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356945/
[10] The Regulatory Constraints in Making Your LDT/CDx Partnership Choices in China
[11] 42 CFR Part 493—Laboratory Requirements, Code of Federal Regulations. eCFR :: 42 CFR Part 493 — Laboratory Requirements
