Figure 1: Overview of Precision Medicine

“Companion Diagnostic” is an aptronym for the class of devices it describes -- Companion, in that it is often developed alongside a specific therapeutic drug; Diagnostic, in that it is a biochemical assay that determines if the patient is likely to benefit from treatment.

CDxs can serve 3 main purposes³, to identify any of the following: Genetic subgroups that have a higher likelihood of benefitting from a specific therapeutic; patients at a higher risk of serious side effects from treatment with a specific therapeutic; and any adverse responses to modify treatment to increase its suitability and safety.

Figure 2: Overview of Medical Devices, IVDs and CDxs, adapted from US FDA

CDxs accompany and expedite the process of showcasing its corresponding drug’s effectiveness in the specific population most likely to benefit from it, in order to highlight the drug’s efficacy. Predictive biomarkers are key in the successful implementation of precision medicine⁴, and the number of US FDA approved CDx has steadily increased ever since the introduction of the drug-companion diagnostic co-development model in the late 1990s.

A brief history of CDx: Case study of Herceptin

The term “companion diagnostic” was first introduced in the late 1990s – with the pivotal point being the simultaneous approval⁵ of Herceptin (trastuzumab) and its corresponding CDx, HercepTest™. The parallel development of this monoclonal antibody targeting HER2 overexpression, along with its corresponding immunohistochemical assay (IHC) identifying its target as a biomarker⁶ has since welcomed a new era for cancer drug development. Due to the targeted mechanism of action of Herceptin by binding to the HER2 protein (whose expression levels vary across individuals), it was a critical challenge to identify the patient subpopulation who was most likely to benefit from its treatment.

Genentech (Herceptin’s developer) used a clinical trial assay (CTA) to select for HER2 positive patients during its clinical development, and HercepTest™ was an optimised IHC assay that was developed by Dako during Herceptin’s phase III trials. Since HercepTest™ showed concordance with this CTA, Herceptin and HercepTest™ were simultaneously approved by the FDA in September 1998.

HercepTest™ was vital to the market authorisation of Herceptin. Alternative sample size calculations published in Clinical Cancer Research based on the data from the phase III trials of Herceptin in metastatic breast cancer showed that had the 469 patients not been pre-screened for HER2 overexpression, the number of patients that would have been required to demonstrate the same statistical difference between treatment arms would have been over 8000⁵.

Former ASCO president Gabriel Hortobagyi echoed the importance that CDxs played in the success of Herceptin by stating in Seminars in Oncology: “If an assay did not exist to identify the patient population likely to respond to therapy, trastuzumab might have been discarded during development because of insufficient activity in an unselected patient population.”⁵

Furthermore, the benefit that CDxs bring to the therapeutics they accompany even reaches beyond their main purpose of spearheading regulatory approval as CDxs contribute further to the actual uptake of the therapeutic they accompany. Herceptin was initially not recommended for general gastric cancer treatment² in the UK, and only received a favourable recommendation when HercepTest was able to identify the subgroup of cancer patients that overexpressed the HER2 protein target of Herceptin.

CDx trends in oncology

Precision oncology has been a burgeoning field as scientists seek to better understand the specific pathophysiology of different types of cancer to reduce off-target side effects⁷. As such, it is important to identify the unique biomarkers of cancer patients that may predict their response to treatment. It is therefore of no surprise that almost all approved CDxs are indicated for use with cancer therapeutics, as opposed to other fields.

Traditionally, therapeutic products that accompany CDxs in oncology involve a single drug, although the US FDA has encouraged the use of CDx with a specific group of related drugs targeting the same mutations, to maximise the benefit that CDxs bring to patient treatment. The labelling of US FDA-approved CDx for a group of related drugs (i.e., for patients with the same mutation(s) instead of individual drugs) reduces the need for clinicians to order separate CDx that identify the same mutation (e.g., EGFR mutations of NSCLC). This minimises the turnover time for the patient to receive appropriate treatment. Although, the US FDA has established this guidance with the caveat that clinical evidence must be developed for at least one device, for the same specimen type, for each drug.

In fact, as much as customising treatments to patients has increased success in oncology treatments for drugs with a CDx, the pace at which such drugs develop at can also paradoxically present as a challenge, as corresponding CDxs may not be implemented fast enough⁸ to match the speed at which new therapeutics enter the market.

In 2020, a large-scale study of newly diagnosed advanced NSCLC patients in the US found that ~23% of patients did not receive genomic testing for any of four guideline-recommended therapeutic targets (ALK, BRAF, EGFR, and ROS1 alterations) before first line treatment⁸. This is problematic as NSCLC mutations are not homogenous across all patients, and most advanced NSCLC patients (~65%)⁹ have the potential to receive treatment that targets their specific genomic alterations. First-line treatment for patients with the mutations in the aforementioned targets should have been customised to their unique mutations.

Recent trends in CDx

As CDxs have gained traction, their regulations have also evolved over the years. For an overview of how this evolution has materialized, one can look to the evolution of regulations for CDxs in the U.S., where the first final guidance was issued in 2014. Even now, regulations are still evolving in the U.S. such as obtaining broader labelling. Additionally, the U.S. FDA is also piloting a program for oncology-specific IVDs.

Figure 4: Adapted from US FDA CDx submission process¹¹

Figure 5: Adapted from EU EMA CDx submission process¹²

CDx landscape in APAC today

While the discussion so far has been about the progress of CDx regulations in the US and EU, Asia Pacific (APAC) is a market that has been expanding alongside these bigger markets. In fact, the CDx market in APAC is projected to have a CAGR of 13.55% during 2022-2030, with the region having the highest growth rate in the world¹³, although North America still dominates in terms of market share¹⁴.

Figure 6: CDxs market growth rate around the world, adapted from Mordor Intelligence¹⁴

Despite the general market trend in APAC, countries in the region differ in the extent of regulations in place for CDx, with only South Korea¹⁵, Japan¹⁶, Australia¹⁷ and Taiwan¹⁸ publishing established guidelines for CDxs so far.

Although the definition of CDx align with reference agencies in most countries, there are notable differences in availability of CDx-specific guidelines and requirement of concurrent submission of drug and CDx. For a quick cross-country overview, see the table below.