What are companion diagnostics?

Companion diagnostics (CDx) are medical devices, specifically an in vitro diagnostic device (IVD), providing important information regarding the safe and effective use of therapeutics. The Food and Drug Administration (FDA) ascribes them three crucial functions: 1) identify patients more likely to benefit from a therapeutic; 2) determine patients at increased risk of serious side effects; and 3) monitor treatment responses for the purpose of adjusting dosage or regimens to improve safety and effectiveness.  In our estimation, CDx act as a compass that directs the healthcare provider to the most appropriate treatment for each patient¹.   

The inception of CDx can be traced back to 1998, when the FDA granted concurrent approval for trastuzumab, a targeted cancer drug, and HercepTest™, a HER2 immunohistochemical assay. This milestone marked the birth of the drug-diagnostic co-development model, a transformative approach that has since witnessed consistent and substantial adoption². 

However, over the next 14 years, CDx advancement was slow, with the majority of new approvals occurring only in the past decade. In fact, from 1998 to 2012, approximately 20 new CDx were approved, whereas from 2013 to 2023, that number rose to 134³. 

Today, approximately 50% of all new molecular entity (NME) approvals in oncology have an associated CDx or biomarker listed in the label required for safe and effective use (based on FDA approvals from 2021 and 2022 of NME in oncology³). Despite the historical tendency toward oncology products, applications in rare diseases and metabolic syndromes are evolving, paving the way for CDx to become an intrinsic part of precision medicine clinical trials across many indications.

Why develop companion diagnostics?

The use of a companion diagnostics strategy in clinical trials, which we define here as using one or more biomarkers to pre-select and enroll patients more likely to respond to the experimental therapy, is commonly employed in oncology. In these trials, identification and pre-selection have significant advantages, allowing smaller patient groups to power the statistical analysis, potentially reducing overall costs, and increasing the likelihood of approval⁴.

But while a CDx strategy makes regulatory approval of a cancer drug more likely, it can simultaneously add complexity to the process:

• After predictive biomarker selection, a prototype assay (often called a clinical trial assay or CTA)  must be developed and extensively validated to demonstrate analytical robustness and performance.
• Regulatory approval of exploratory or experimental diagnostics must be granted on a country-by-country basis.
• Attaining the requisite level of quality and regulatory support, and ensuring turnaround times compatible with the incorporation of testing in clinical trials requires these assays to be set up in one or several reference laboratories.
• Assuming a successful clinical development, both regulatory and marketing applications are required to demonstrate the analytical and clinical performance of the CDx. 
• The CDx must be easy to use and broadly available in the commercial market so that healthcare providers can readily test patients to establish treatment eligibility.
• The CDx strategy must be coordinated with the development and approval of the corresponding therapeutic (Tx).

Despite the evident complexity, the widespread adoption of next-generation sequencing (NGS) has made using companion diagnostics and deploying biomarker-driven strategies in clinical trials easier by permiting screening for multiple biomarkers simultaneously. Rather than rely on a one-biomarker-one-test model, NGS permits patients to be screened for eligibility for multiple therapeutics or clinical trials.. Moreover, targeted gene panels and broader approaches, such as comprehensive genomic profiling (CGP) and whole exome sequencing (WES) have further streamlined the development of multi-biomarker-driven CDx.

Returning to our analogy, while CDx acts as the compass, NGS technologies are the roadmap to determine the most suitable treatment for each patient.

How are companion diagnostics approved?

There are two well-defined pathways to approval for companion diagnostics:

1. Kitted/Distributed Model:  The CDx is developed and validated as an IVD kit that can be run at qualified laboratories worldwide. 
2. Single-Site Model: The CDx is developed at a single laboratory approved by the regulators to provide testing services. The assay cannot be transferred to another laboratory or developed into a kitted solution without further regulatory filings.

HercepTest™ followed the first pathway where the physical kit, produced by an IVD manufacturer, received a Pre-market Approval (PMA). In contrast, the precedent for the single-site model was only established much later with the publication of clinical evidence supporting the hypothesis that BRCA-mutated patients were more likely to benefit from treatment with olaparib—a PARP inhibitor first approved for the treatment of advanced ovarian cancer^5,6.

Requiring a complex workflow and expert oversight, BRCA analysis was more conducive to the simplicity of the single-site model since the very nature of this pathway streamlines validation – validating a workflow within a single lab is less time-consuming than across multiple labs. This new approach played a pivotal role in rapidly advancing the commercial adoption of NGS applications.

Today, most NGS-powered CDx assays follow the single-site pathway³, creating a new set of challenges. Despite the increased simplicity, this model confines assays to single locations, limiting the capacity for sample analysis, significantly increasing turnaround times, and reducing patient access. In the new age of precision medicine, these limitations are being addressed through a decentralized testing and analysis model supported by technology-agnostic and easy-to-implement workflows.

How are companion diagnostics developed?

While direct co-development of a CDx and therapeutic stands as the preferred regulatory model by the FDA, alternative approaches may be utilized due to the inherent challenges of aligning IVD and drug development.

1. Co-developed CDx:
   1. Direct: In the original model, the diagnostic assay and the therapeutic product are developed simultaneously within the same pivotal clinical trial(s). Regulatory and marketing applications are synchronized to ensure approval and timely access to the CDx, supporting the successful launch of the associated therapeutic product.  
   2. Bridging/Concordance Study: Due to the complexity of CDx development described above, diagnostic assay development often lags behind the therapeutic.  This delay is often due to the iterative nature of CDx prototype refinement during the testing period. Given that the market-ready CDx may differ from the assay used in the trials, extensive bridging studies become essential to validate and establish concordance between the two.

2. Follow-on CDx: Follow-on CDx assays have the same therapeutic indication and use as the reference CDx but may employ different technologies or approaches to expand access, reduce turnaround time, or other critical performance metrics.  While a follow-on CDx is not developed through a pivotal clinical trial, these diagnostics require extensive analytical validation to establish concordance with the original reference CDx methodology.  This model helps drug developers account for differences in CDx availability across different markets and potentially enhance access to targeted therapies.

While the development of a CDx and therapeutic are tightly entwined, drug developers and IVD manufacturers remain separate entities with a few exceptions. This requires the carefully selection of partner(s) within the IVD and CDx ecosystem to ensure successful programs. 

Many questions must be addressed early in the process, as even suboptimal approaches can significantly delay and impact commercial uptake:

• Is the selected technology platform broadly available and widely implemented in the healthcare ecosystem?
• Can the test provide results in a timely manner, considering that longer time-to-treatment can significantly increase patient risk? ⁷
• Are results easily interpretable within a treat-or-do-not-treat framework?
• Has reimbursement for the test and technology been established?

Tackling the challenges of CDx co-development and global implementation

The advent of NGS technologies has heralded a healthcare revolution, propelling us toward data-driven precision medicine. Yet, as we push ahead in developing biomarker-driven applications for a plethora of indications, we face the potential for increased implementation challenges, threatening to complicate the patient journey.

The adoption of a decentralized, globally accessible, intuitive, and technology-agnostic SOPHiA DDM™ Platform, leveraging proprietary algorithms and a vast portfolio of robust NGS-based applications, is well positioned to streamline CDx co-development and implementation, enhancing access to analytically robust solutions without overtaxing healthcare resources.

Our holistic approach to co-development is poised to chart a course toward a more integrated future, arming developers with the necessary data and insights to tackle potential hurdles and maximize the time and resources allocated to clinical research programs.

At SOPHiA GENETICS, our unwavering commitment is to collaboratively engineer deployable solutions that elevate implementation and accessibility in precision testing while streamlining the process of analysis and interpretation. Explore the possibilities of SOPHiA DDM™ for BioPharma by visiting our dedicated page.

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