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We are definitely in the era of precision medicine, an innovative approach to tailoring disease prevention and treatment that takes into account individual differences in people’s genes, environments, and lifestyles.

An important requirement for precision medicine is the availability of methods to measure the effect of the drug on the target and the underlying disease process, ultimately allowing to determine whether the selected therapy is likely to be effective. Those objective measures that are indicative that a biological process in the body has happened or is ongoing are known as biomarkers [1], and are actually essential for the diagnosis and treatment of several diseases at present, such as diabetes, osteoporosis and many cancer types.

In this context, companion diagnostics (CDxs) emerge as powerful tools to make precision medicine possible.

What is a companion diagnostic?

According to the Food and Drug Administration (FDA), a CDx is a medical device—an in vitro diagnostic device or an imaging tool— “which provides information that is essential for the safe and effective use of a corresponding drug or biological product” [2]. Thus, these tools help match a patient to a specific drug or treatment, becoming fundamental for the therapeutic decision-making process.

CDxs are therefore medical devices to detect biomarkers, and as such they can [2]:

  • Identify patients who are most likely to benefit from a particular therapeutic product.
  • Identify patients likely to be at increased risk for serious side effects as a result of treatment with a particular therapeutic product.
  • Monitor response to treatment with a particular therapeutic product for the purpose of adjusting treatment to achieve improved safety or effectiveness.

The benefits of developing and implementing CDxs are clear for both patients and pharmaceutical companies and are supported by some interesting data. Thus, in the clinical trial setting, the probability of progression from Phase I to approval is 8.4%, but the addition of a CDx device increases the approval rate to 25.9% [3]. Additionally, the availability of a marketed CDx seems to facilitate the prescription of certain drugs, especially when expensive, as it has been observed that physicians are more likely to prescribe those treatments if they feel confident that they will be effective for their individual patient [4].

Historically, the term “companion diagnostic” appears for the first time in the literature in an article published in Nature Biotechnology in 2006 [5]. However, as early as 1998, this concept was conceived when the FDA, through a new coordinated procedure, simultaneously granted approval for a drug, trastuzumab (Herceptin®), and for an immunohistochemical (IHC) assay, HercepTest (Dako), designed to detect the overexpression of the biomarker HER2, necessary to benefit from trastuzumab treatment. As a result, HercepTest became the first CDx assay linked to the use of a specific drug, paving the way for the strategic co-development of pharmaceutical products and CDxs [6]. Since then, several more have been approved mainly in the field of oncology, with few exceptions approved for other disease types. As of June 2022, a total of 142 CDxs have been cleared by the FDA [7], and this number is expected to grow over the next years as healthcare shifts towards precision medicine. From a methodological point of view, CDxs have also evolved over time, from IHC and in situ hybridization assays, which were the dominating technologies until 2011, to next generating sequencing-based assays, which have burst onto the CDx scene in the last decade [8]. These are all in vitro diagnostic devices but, what about imaging-based CDxs?

The opportunity for imaging-based companion diagnostics

To date, only one imaging-based CDx allowing iron concentration measurement in magnetic resonance imaging (MRI), FerriScan, has been approved by the FDA to be used alongside deferasirox, a non-anti-cancer drug for the treatment of thalassemia [8]. Despite this major imbalance, imaging-based CDxs offer undoubted advantages over in vitro devices and the number of approved imaging tools will for sure increase in the coming years.

Firstly, the screening of a biomarker or a panel of biomarkers can be performed in a non-invasive, quicker, and less costly way than for example, with biopsy-based in vitro assays. The non-invasive nature of imaging, furthermore, facilitates the repeat measurements needed to assess response to treatment, avoiding potential serial biopsy-related issues including sampling error, patient discomfort, and risk of complications. Secondly, and in particular, in the oncology setting, imaging-based CDxs may offer a more comprehensive view of the lesion, as biopsies usually represent a small portion of the region of interest. Additionally, and unlike biopsies, they may leverage the unique ability of imaging to measure the regional heterogeneity of target expression, especially in patients with advanced disease in which target expression may vary from site to site. Finally, imaging-based CDxs are more scalable that in vitro diagnostic devices, since as digital tools, they can be more seamlessly integrated into both development and practice.

In Quibim, we are fully committed to developing imaging solutions to real-world problems with the ambition to turn imaging into a catalyst for precision health, and as such, we believe that imaging-based CDxs are valuable tools worth focusing our efforts on. Going hand in hand with radiomics, a high-throughput quantitative imaging analysis method which extracts a large number of features from medical images [9], Quibim works hard on developing imaging-based CDxs that make personalized medicine, the medicine of the future, possible.

Companion diagnostics: facing challenges

Despite their numerous advantages, there are still several barriers to the development and implementation of CDxs, such as the reliability and consistency of the biomarker test quality, the timely availability of test results or the sufficient reimbursement among others. Importantly, CDxs also need to face important regulatory challenges. Thus, in Europe, the recent implementation of the new In Vitro Diagnostic Medical Devices (IVD) Regulation, has definitely changed the regulatory framework, impacting on all stakeholders involved in the IVD industry. Previously, IVD assessment was usually the manufacturer’s responsibility, with intervention from Notified Bodies for high-risk products. With the new regulation, the European Medicines Agency (EMA) has to interact with national authorities and Notified Bodies in the assessment of drug/CDx products. This interaction may be challenging, so it will for sure take some time to establish know-how and efficient working structures within and between authorities.

In Quibim we are aware of how challenging developing and implementing CDxs may be. However, challenges are our driving force, and we will continue to strive to make “The right medicine at the right dose to the right patient at the right time” a reality.

References

  1. Labmate. What are biomarkers and why are they useful? [Accessed July 2022]. Available from: https://www.labmate-online.com/news/news-and-views/5/breaking-news/what-are-biomarkers-and-why-are-they-useful/31934.
  2. Food & Drug Administration (FDA). Companion Diagnostics. [Accessed July 2022]. Available from: https://www.fda.gov/medical-devices/in-vitro-diagnostics/companion-diagnostics.
  3. Bio. Clinical development success rates 2006-2015. [Accessed July 2022]. Available from: https://www.bio.org/sites/default/files/legacy/bioorg/docs/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf.
  4. Blair, ED et al. Aligning the economic value of companion diagnostics and stratified medicines. J Pers Med, 2012. 2(4): p. 257-66.
  5. Jørgensen, JT et al. Companion diagnostics-a tool to improve pharmacotherapy. Ann Transl Med, 2016. 4(24): p. 482.
  6. Amplity Health. Time to embrace companion diagnostics to accelerate precision medicine. [Accessed July 2022]. Available from: https://www.amplity.com/images/how-we-can-help/Time-to-Embrace-Companion-Diagnostics-to-Accelerate-Precision-Medicine.pdf.
  7. Food & Drug Administration (FDA). List of cleared or approved companion diagnostic devices (in vitro and imaging Tools). [Accessed July 2022]. Available from: https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.
  8. Jørgensen, JT. The current landscape of the FDA approved companion diagnostics. Translational Oncology, 2021. 14(6): p. 101063.
  9. Aerts, HJWL et al. Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nature Communications, 2014. 5(1): p. 4006.

Almudena Fuster

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