Companion Diagnostics Key to Individualized Healthcare

Advanced in vitro diagnostics (IVDs) are accelerating our understanding of disease. In lockstep with the dramatic capabilities arising from the genomics field and modern molecular technologies, diagnostics procedures are transforming the practice of healthcare, providing faster and more accurate results and helping to usher in the promise of precision and personalized medicine. Companion diagnostics (CDx) play a vital role in this evolution.

At its most basic premise, precision medicine leverages genetic and genomic data to improve health outcomes with specific, personally tailored treatment plans and therapies. A companion diagnostic is essentially a test that helps unlock insights for better understanding of the specific genes, biomarkers and other biomedical factors impacting an individual's potential to acquire disease or be effectively treated for it.

The ability to determine whether a patient may or may not respond to a given treatment helps to better ensure the safety and effectiveness of targeted therapies while also enabling the selection of the best treatment and medicine for that patient without wasting precious time with trial and error. In this way, CDx are invaluable for aligning healthcare more effectively with value-based care (VBC) efficacy models.

To the extent that diagnostics provide a lens into not just what's wrong, but also what's working, they provide a trifecta of benefits throughout the system — medical, social and economic. It's been estimated that in vitro diagnostic tests influence potentially 70% of all medical decisions, so given this assumption, the more information and insight providers are given, the better chance they have for fulfilling improved patient outcomes.

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Right Patient, Right Treatment, Right Time... and for Less Cost

Companion diagnostics answer a simple question: Is a specific treatment definitely for you? Framed differently, from the perspective of pharma development: Which patients are most likely to benefit from a medicinal product or be at increased risk of serious adverse reactions as a result of treatment with this medicinal product? The CDx answers the why and how of these questions.

Leveraging CDx for better alignment of drug development efforts with specific patient subgroups based on their genetic makeup helps pharma steer clear of long costly pursuits of ineffective treatments. Early identification of appropriate patients for a clinical trial based on biomarker data means that a study will likely be able to demonstrate efficacy and achieve primary trial endpoints within smaller populations. This in turn saves significant time and financial cost bringing the therapy to market.

The most commonly accepted cost estimates for developing a new drug comes from the Tufts Center for the Study of Drug Development (DiMasi, et al) which determined that, between 1995 and 2007, the average cost of developing and bringing a new compound to market was $2.6 billion, while the success rates of these new medicines in clinical development averaged approximately 12%.

Pharma and Diagnostics: Better Together

Traditionally, to capture the greatest market-share possible and recoup such hefty R&D investments, pharmaceutical firms have pursued drug development strategies aligned towards the promise of uncovering a potential blockbuster drug. This practice — as borne out by the numbers above — is costly and time-consuming. However, working together, pharma and diagnostics can smooth these cost curves and transform the drug development landscape.

In fact, according to some studies, CDx-guided drug development can reduce clinical trial costs by as much as 60%. By helping to identify a patient population with the greatest likelihood of responding to therapy before the trial is conducted, companion diagnostics not only narrow the trial size (saving time and administration costs) but also help to better ensure a more comprehensive testing of a drug study's hypothesis.

Companion diagnostics provide the industry a very compelling economic incentive with advantages distributed across the ecosystem of stakeholders. Pharmaceutical firms can get to market faster with proven drugs, validated at less cost through clinical trials. Payers benefit from a dramatic reduction in cost toward unnecessary or ineffective treatments, while targeted therapies with fewer adverse events face a less fraught path towards regulatory submissions.

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CDx Market Players and Milestones

The first treatment on the market in combination with a companion diagnostic was the breast cancer drug trastuzumab (Herceptin®, Roche/Genentech). Trastuzumab's mechanism of action targets the HER2 oncogene. During the drug's development, it was recognized that only women whose tumors overexpressed the HER2 oncogene were benefitting from trastuzumab. Determining whether a given patient would respond to treatment with trastuzumab required the development of a novel in vitro diagnostic test that could accurately and reproducibly detect and quantify HER2 in a specific patient. In 1998, this immunohistochemical assay for HER2 (HercepTest®, Dako) was approved together with trastuzumab.

For several years, immunohistochemical and in situ hybridization has been the technology of choice for CDx. In 2011, Roche introduced its cobas® 4800 BRAF V600 Mutation Test to market, an in vitro diagnostic device intended as an aid for selecting melanoma patients whose tumors carry the BRAF V600E mutation. BRAF is a serine/threonine protein kinase whose mutations lead to unregulated cell growth and cause different types of cancers. Accurate detection of this mutation ensures the appropriate assignment of vemurafenib (a targeted therapy to slow the growth and spread of cancer cells) to patients with unresectable or metastatic melanoma.

Roche's cobas® 4800 BRAF V600 Mutation Test is the earliest CDx test approved by the FDA for BRAF V600 mutation in melanoma using a real-time polymerase chain reaction- (PCR) based CDx assay. Today, PCR is the most often used technology for CDx. Close to 36% of all FDA-approved CDx assay are based on PCR.

Next-Generation Sequencing: Companion Diagnostics' Technology of the Future

In recent years, however, due to advantages in terms of low cost per sequenced base and high throughput, next-generation sequencing has taken on more of a starring role in diagnostics. NGS-based companion diagnostics are increasingly used to match patients with new therapies for cancer and other diseases. While a PCR test can only detect a few markers per test, NGS delivers more than 3 billion bases in the human genome and may identify millions of genetic variants in a single test. Also, NGS-based tests can be applied to as little as 10 nanograms of nucleic acid. In CDx, where an ever-increasing number of mutations must be assessed, this can save significant time when selecting and initiating the proper cancer treatment procedure.

In 2017, the FDA granted marketing approval to the FoundationOne CDx, a CDx assay for the detection of alterations in tumor tissue from patients with ovarian cancer. Brought to market by Foundation Medicine, Inc. this was the first next generation sequencing-based in vitro diagnostic. It was also the first device with the FDA's Breakthrough Device designation to complete the pre-market approval process and the second IVD authorized under the FDA and Centers for Medicare & Medicaid Services' (CMS) Parallel Review program.

Earlier this year Thermo Fisher Scientific announced FDA pre-market approval for its Oncomine Dx Target Test as a companion diagnostic for Takeda's drug for non-small cell lung cancer (NSCLC) patients. The test can assess 23 genes linked to NSCLC at once and help identify patients that are epidermal growth factor receptor (EGFR) Exon20 insertion positive.

Next-generation sequencing technology — particularly its capability to identify rare variants — is critical to the continued success and wider distribution of companion diagnostics solutions. In their press announcement, Thermo Fisher Scientific specifically cited NGS superiority for early detection and suitable characterization of tested patients, noting that standard PCR methods can miss half or more of EGFR Exon20 insertion mutations.

In September 2021, Thermo Fisher Scientific's clinical sequencing business and AstraZeneca announced they are working together with NGS-based companion diagnostics to support the latter's expanding portfolio of targeted therapies. It's worth noting that more than 90% of AstraZeneca's clinical pipeline — across all main areas, from oncology, cardiovascular and renal to metabolic and respiratory disease — are targeted precision medicine therapies.

A Robust Companion Diagnostics Market — But the Best Is Still to Come

Considering the technology's momentum, as well as the proven advantages and benefits companion diagnostics provide to different stakeholders across the healthcare ecosystem, the number of FDA-approved companion diagnostic tests remains modest. The total number of approvals from 1998 to the end of 2020 is just 44 tests.

Yet, according to competitive market analysis, growth in the CDx market is robust, driven by NGS innovations — like the ones just discussed — as well as increasing application in drug development and within clinical trials. Major Tier 1 and 2 companies, like Roche Diagnostics, Agilent Technologies, Qiagen, Thermo Fisher and Abbott Laboratories, are all vying for position to capitalize on the exciting opportunities in a sector projected to reach valuations of USD $6.8 billion by 2025 (up from USD $3.7 billion in 2020), at a CAGR of 12.9% during the forecast period of 2020 to 2025.

Peter Keeling is a pharmaceutical industry veteran, leading proponent of precision medicine and the founder/CEO of Diaceutics, an early mover in pairing Big Data with diagnostics in pharma development. Central to fulfilling the promise of precision medicine, in Keeling's view, is the importance of companion diagnostics stakeholders working together. As a case in point, multiple pharma competitors each promoted PD-L1 testing in recent years. By doing so, they reduced the time required to reach the optimal testing rate (80% of patients tested) from seven years to three years. Programmed death-ligand 1 (PD-L1) is an immune-related biomarker; testing for PD-L1 expression helps to identify patients most likely to benefit from treatment with PD-L1 inhibitors.

Keeling is also a believer that the industry is only just scratching the surface in terms of optimizing the potential offered by CDx. He suggests that there are four primary objectives that need to be reached in order to boost CDx growth and better serve patients, providers and pharma development efforts.

1. Lab Decentralization Will Help Speed Awareness/Acceptance

While, traditionally, in vitro tests are sited within a central lab, the industry’s overall shift toward tests that are closer to the patient will lead to a more diverse, functional structure of people involved in testing and include various distribution channels. Decentralization — into the hospital owned lab, the drug store or even toward tests ordered online for home use — will bring greater awareness of available tests and testing options. 

2. A More Robust Value Case Will Support Economic and Regulatory Acceptance

How much value does the upfront testing bring? Or, asked differently: How does the test help to save costs, and how much? CDx's value proposition to pharma companies needs to be integrated into the mindset earlier with these questions front and center. Clinical trial phase III should run in parallel with the clinical validation and utility of the diagnostic test.

3. Develop a Commercialization Strategy Supported by Both Partners — Pharma and Dx

Both sides, pharma partner and diagnostic partner, need to commit to the synergistic benefits of a coordinated commercialization strategy, and one that begins early on. Educating clinicians on the availability of both the treatment and the biomarker tests available should be viewed as a shared benefit. Said another way, both pharma and diagnostics should ensure that each side has a basic understanding of the other's requirements.

4. Work Together with Key Opinion Leaders to Broaden Inclusion in Guidelines and Clinical Testing

Key opinion leaders (KOLs) should be engaged early in the development phase, again as part of a close partnership between the pharmaceutical and diagnostic company. Due to their in-depth knowledge of the application and market needs, KOLs can guide the development and support clinical testing, and once the treatment or test is launched, they can advocate for the CDx solution and support in redefining clinical guidelines once the clinical data is available.

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How Can Jabil Healthcare Help?

Successful CDx product commercialization relies on the close partnership between pharma and diagnostics and the recognition that a co-development model will provide their solutions the most momentum in the market. Jabil Healthcare is in an ideal position to deliver even more value within this arrangement.

We understand the needs and requirements of the pharma partner as well as the diagnostic partner. Our strong regulatory backbone provides essential experience for guiding customers from development through market approval and assisting in their alignment of treatment and test development. Our digital health expertise facilitates data integration challenges during clinical trial and market surveillance after launch. Additionally, Jabil Healthcare's vast operational footprint supports customer execution of their global and regional commercialization and market penetration plans.

Patients facing the uncertainty inherent in disease and illness want clarity; they want answers. They want to know the treatment course they're embarking on has been correlated with success — not just broadly across the wider patient population, but for them personally. Companion diagnostics help deliver precise and personal insights that are quantifiable and actionable, enabling doctors to create effective treatment plans that allow patients to recover as quickly as possible with the least incidence of complications and the greatest chance for success.

As the number of companion diagnostics in development continues to grow, their role within healthcare is expanding. Regulatory agencies across the world are embracing the efficacy and safety benefits at the heart of CDx and in this way are providing incentive for drug developers to pursue this path for the treatment of all types of diseases. With the embrace of companion diagnostics, we are moving closer each day to truly fulfilling the promise of personalized medicine.

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