This Statement has been prepared in accordance with paragraph 22(2) of Schedule 19 of the UK Finance Act 2016 for the financial year ending December 31, 2024.

How GRAIL manages UK tax risk

GRAIL seeks to be as compliant as possible with local tax legislation, worldwide tax regulations, and corporate social responsibility.  We seek to report and pay the fair amount of tax due, in the appropriate jurisdiction, at the correct time. This is part of GRAIL’s desire to build trust in the tax system amid a period of large-scale international tax reform. GRAIL will not engage in artificial activity purely for tax purposes.  

GRAIL’s attitude towards tax planning

GRAIL’s goal is to fully and accurately comply with our tax obligations with the highest integrity.

Where material uncertainty exists in any area of its business, GRAIL seeks advice to ensure that it is fully compliant with applicable laws.

GRAIL will uphold the applicable tax laws in each country of operation through non-abusive methods of practice and therefore aim to be compliant both with the law as written and the law’s intended effects, where known.

The level of risk that GRAIL is prepared to accept for UK taxation

Rather than fixing set thresholds for acceptable UK tax risk, GRAIL assesses risk on a case-by-case basis based on the relevant facts and circumstances, within the context of the business activities and with the assistance of external advisers where appropriate.

GRAIL’s approach towards its dealings with HMRC

GRAIL seeks to remain transparent and to establish a constructive relationship with HM Revenue & Customs (“HMRC”).  Additionally, we will proactively engage with HMRC, in order to build trust and to reduce uncertainty and risk. GRAIL is cooperative and is committed to working collaboratively with all taxing authorities.

We believe screening individuals for many types of cancer with a multi-cancer early detection (MCED) test represents a significant opportunity to reduce the burden of cancer. Today, with a unanimous vote to advance the “Nancy Gardner Sewell Medicare Multi-Detection Early Detection Screening Coverage Act,” the House Committee on Ways and Means took an important step on the path to ensuring Medicare beneficiaries and their doctors can access these innovative screening tests once they are FDA-approved. While this is a necessary legislative step, in order to become law the bill would have to be passed by the House and the Senate, and then signed into law by the President.

GRAIL stands with the policymakers and cancer community leaders who are working to ensure, through legislation, that Medicare beneficiaries — who have the highest risk for cancer due to age — do not face unnecessary barriers to access.

We believe screening individuals for many types of cancer with a multi-cancer early detection (MCED) test represents a significant opportunity to reduce the burden of cancer.  However, without Congressional action, Medicare beneficiaries and their doctors may face significant delays in accessing these innovative screening tests once they are FDA-approved.  Led by the American Cancer Society’s Cancer Action Network and the Prevent Cancer Foundation, a group of 52 national advocacy organizations today shared their enthusiastic support for meaningful, timely access to MCED technologies and their endorsement of advancing this legislation with its associated policy updates.  GRAIL stands with the policymakers and cancer community leaders who are working to ensure, through legislation, that Medicare beneficiaries — who have the highest risk for cancer due to age — do not face unnecessary barriers to access. 

View the presentation deck here.

To read the blog post from NHS England, click here.

The NHS-Galleri trial, which started enrolling participants in 2021, was designed to inform implementation of the Galleri test as a national screening programme if recommended by the UK National Screening Committee on the basis of the final study results, which are expected in 2026. The trial was designed with three consecutive years of screening in order to achieve the primary endpoint, which is the absolute reduction in the number of late stage (Stage III and IV) cancer diagnoses. 

As described in March, NHS England planned to look at a snapshot of selected first year results (the prevalent screening round with one year of follow-up) from the NHS-Galleri trial to assess whether there is enough compelling early evidence to initiate a pilot of Galleri within the NHS setting. This first year analysis was conducted solely to determine whether there was an early sign of compelling patient benefit, sufficient for the NHS to accelerate an implementation before the final study readout. Three robust, ambitious and pre-specified criteria were assessed: the positive predictive value (PPV) of the Galleri test, the number of late-stage cancers detected and the total number of cancers detected in the intervention arm compared with the control arm. Notably, this was not an interim analysis of the trial primary endpoint, as that analysis requires data from all three rounds of screening.

Based on a snapshot of first-year results from the ongoing NHS-Galleri trial, NHS England has decided to await final results from the three-year trial before determining whether to initiate a pilot of the Galleri test in the NHS.

Advised by a multidisciplinary expert panel, NHS England determined that, while the early analysis showed that the assessed clinical performance of Galleri was very promising — consistent with or better than Galleri’s clinical performance observed in previous published studies — there is not yet enough early compelling evidence to accelerate implementation through a pilot programme at this stage.

As described by the NHS, “Committing to accelerate implementation of the test in the NHS at scale would have been an exceptional step, requiring exceptional data after just one year, and while what we have seen is very promising, the data so far do not support moving at such a fast pace.” Instead, NHS England will make a decision on the basis of the final trial results, expected in 2026. 

This early look at certain selected metrics provides only a limited view. As demonstrated in previous cancer screening trials, results from the first screening round do not always reflect the final results, especially for reduction in late stage diagnosis. In the US National Lung Screening Trial (NLST) for example, participants underwent three annual screenings. Ultimately, the trial demonstrated a significant relative reduction in mortality for those who received low-dose CT screening. However, no reduction in stage IV cancers was observed after the first year of screening. This is because a prevalent screening round often includes many asymptomatic cancers in later stages that have not been ‘swept out’ by that first year of screening. In NLST, the stage IV incidence was reduced after that first year of screening – and was maintained throughout the follow-up period. 

The NHS-Galleri trial – like numerous other cancer screening trials – was designed with multiple years of screening, and thus it remains important to complete the trial and evaluate the primary objective and endpoints at the end of the study. 

Diagnosing more cancers before they present symptomatically is central to GRAIL’s mission and is also a core part of NHS England’s Long Term Plan to transform cancer outcomes. NHS England has reiterated its belief that multi-cancer early detection is an important innovation that could become a core component of its ambition to reduce late-stage cancer diagnosis in the future.

The NHS-Galleri trial completes appointments with the final blood samples being taken in July 2024 and the ongoing involvement of participants (and any subsequent diagnostic follow up in the NHS) remains critical to fully understanding the test’s potential benefit at population scale. We await the final results and I would like to reiterate my sincere appreciation to the more than 140,000 participants who generously volunteered to take part in the trial to contribute to, and advance, this valuable field of science and medicine. 

GRAIL remains focused on our mission to detect cancer early, when it can be cured.

Revenue for the first quarter of 2023, comprised of Galleri test sales and biopharmaceutical partnerships revenue, was $26.7 million. 

We continue to see uptake for Galleri in health systems, clinics and the employer and life insurance channels across the U.S. We surpassed 10,000 Galleri prescribers in early 2024, and we have completed more than 180,000 commercial Galleri tests cumulatively as of the end of March. With forward leaning payors and employers across a multitude of sectors, commercial engagements remains strong. 

Our registrational clinical studies are progressing. The NHS-Galleri study is anticipated to complete its third and final round of planned blood draws in July, and we have enrolled more than 30,000 participants in our PATHFINDER 2 study. Study results for NHS-Galleri are anticipated in 2026. Interim results from PATHFINDER 2 are expected in 2025 when we have a full year follow-up on the first 25,000 patients. Together, these studies are anticipated to include approximately 175,000 participants and support our PMA submission to the FDA. 

Additionally, the Galleri-Medicare study (REACH) will enroll 50,000 Medicare beneficiaries for three annual tests, evaluating the performance and clinical impact of Galleri compared to a matched synthetic control. This study is an important addition to our body of clinical and real-world evidence for multi-cancer early detection.

We continue to pursue potential applications for our technology in precision oncology settings and recently announced a novel risk-classification assay to be included in a lung cancer study in collaboration with AstraZeneca. Data evaluating our methylation technology’s capability in molecular subtyping were recently presented at the American Association for Cancer Research (AACR) Annual Meeting 2024. 

Recent Business Highlights

In the precision oncology setting, we shared data illustrating the potential adaptability of our methylation platform in identifying cancer histological and molecular subtypes through blood samples. 

Cancer accounts for just over a quarter of all deaths in England in a typical year. The NHS Long Term Plan (LTP) was published in January 2019 and set out stretching ambitions and commitments to improve cancer outcomes and services in England in the following ten years. Earlier and faster cancer diagnosis are among its central ambitions.

It is with considerable humility, but also great pride, that I have the honour of working for a company, GRAIL, which has embarked on an extraordinarily challenging mission to find many types of cancer earlier, before symptoms appear, when there are more treatment options, and a greater potential for cure. 

Galleri® , GRAIL’s multi-cancer early detection (MCED) test, has been assessed in published case-control and interventional studies in the intended use population. The results demonstrate consistent findings throughout, and Galleri is now the subject of real world evidence generation and the largest prospective randomised controlled trial of an MCED test ⎯ the NHS-Galleri trial conducted in England. 

Traditionally, cancer screening programmes have taken a decade or more from publication of effectiveness to be implemented on a population-scale. This means that, including the duration of clinical trials, it has historically taken some 20-30 years from having a validated technology  to achieving broad benefits for patients and society. With the rapidly growing burden of cancer ⎯ it is soon to become the world’s biggest killer ⎯ and the pace of technology change, many experts believe this paradigm must change.

As set out in a recent letter from NHS England to the Lancet, the NHS is keen for its patient population to benefit as quickly as possible from new, safe and effective technologies where there is an urgent unmet need, such as with late cancer diagnosis. Therefore, in addition to the long-term aim, NHS England plans to look at a snapshot of selected first year results (the prevalent screening round with one year of follow-up) from the NHS-Galleri trial to assess whether there is enough compelling early evidence to initiate a ‘pilot’ of up to one million tests within the NHS setting. This type of ‘in-service evaluation’ would offer a Galleri test to a similar ‘asymptomatic’ population as the trial. As well as generating real-world data to supplement the trial evidence, this pilot opportunity would allow the NHS to learn about how best to implement a multi-cancer screening programme rapidly. 

NHS England will base its decision on robust, demanding, pre-specified criteria, including the positive predictive value (PPV) of the Galleri test, the number of late stage cancers detected, and the total number of cancers detected in the intervention arm compared with the control arm. Notably, this is not an interim analysis of the trial primary endpoints, as any such analysis requires data from all three rounds of screening. The pilot will only proceed if the early results are exceptionally compelling enough to begin implementing a pilot program before the trial completes and the final results are known. Similarly, these results will only be made public should the pilot proceed, in order to place necessary focus on the integrity of the ongoing trial. 

Importantly, the early look at certain selected metrics will provide only a limited view, which may or may not be seen in the final results in 2026. Early results from cancer screening trials do not always reflect the final results, and often do not tell the whole story. The National Lung Screening Trial, for example, provides a salutary example: participants similarly underwent three annual screenings. Ultimately, the trial demonstrated a significant relative reduction in mortality for those with low-dose CT screening. However, no reduction in stage IV cancers was observed after the first year of screening because it was a prevalent screening round. This is because a prevalent screening round includes many asymptomatic cancers in later stages that have not been ‘swept out’ by that first year of screening. As expected, in NLST the stage IV incidence reduced after that first year of screening – and was maintained throughout the follow-up period. Crucially, the trial also demonstrated a 20% relative reduction in mortality that was maintained throughout the longer-term follow-up period. The NHS-Galleri study design and primary endpoints accept this ‘prevalent screening round effect’ and acknowledge that assessing a lasting reduction in late-stage disease requires multiple years of screening to ‘sweep out’ those later stage cancers.

Working in partnership with NHS England, world-class statisticians, epidemiologists and clinicians, we designed the 140,000 person NHS-Galleri trial to include three successive rounds of Galleri screening in addition to standard screening for those in the intervention arm, compared to a control group only receiving standard screens. This trial was conducted with a view to informing eventual implementation of Galleri within a national screening programme if recommended by the UK National Screening Committee.To ensure a representative, diverse population was recruited, we employed a fleet of mobile clinics staffed with phlebotomists, to enable access for participants in places with access challenges to health clinics ⎯ from ethnically and socioeconomically diverse cities to remote rural outposts. This approach had the additional benefit of not burdening overstretched GP surgeries, not least as the bulk of the recruitment took place during the COVID-19 pandemic in 2021. 

The active period of the NHS-Galleri trial comes to an end with the final blood draw anticipated to take place in July 2024. The primary objective of the trial is to demonstrate that the use of Galleri, alongside standard of care, can lead to a significant reduction in the incidence of late stage cancers ⎯ in-line with the UK’s overall goal of increasing the proportion of early-stage cancers detected. This will require an assessment of the data accumulated following all three annual rounds of screening, and it is expected that this analysis will be completed in 2026. Exploratory mortality analyses and modeled mortality based on observed stage-shift will also be undertaken, as well as longer term follow-up via national centralised data collection.  Planned, comprehensive health economic evaluation and analysis will provide necessary cost-effectiveness data.

We hope that NHS-Galleri will demonstrate highly compelling early evidence from which the NHS is able to make a decision to move forward with the proposed Multi-Cancer Blood Test Programme so that more patients can benefit more quickly. Such a pilot, if so agreed, would provide a suitable balance between being able to learn valuable implementation lessons to fulfill an unmet need rapidly, with the subsequent further decision dependent on longer-term measures of effectiveness. Whether or not a pilot is undertaken, for any number of reasons, GRAIL would continue to request that the UK National Screening Committee makes a decision about a population screening programme in due course, based on the final study results and full economic evaluation. We look forward to the NHS’s assessment of the early results in the coming months.

GRAIL continues to execute on our strategy towards population scale early cancer detection, and we are pleased with our progress in building the market for Galleri, driving our robust evidence generation programs and advancing future product development.

Revenue for the fourth quarter of 2023 was $30 million and for the full year 2023 was $93 million, comprising Galleri test sales and biopharmaceutical partnerships revenue. Full year revenue increased 68% in 2023 as compared to 2022. 

Galleri adoption continues to grow, with more than 9,000 ordering providers and more than 150,000 commercial tests completed as of year end 2023. We have established early commercial leadership in multi-cancer early detection (MCED) and secured coverage of Galleri with several forward-leaning payers and self-insured employers in various sectors, such as technology, healthcare, life insurance, and financial industries. 

We were pleased to announce the groundbreaking Galleri-Medicare study (REACH), which will enroll 50,000 Medicare beneficiaries and evaluate the clinical impact of Galleri compared to a matched synthetic control. Findings will add to our robust body of evidence evaluating the potential for MCEDs to change the future of cancer detection, particularly in diverse populations. Medicare will cover the costs of Galleri and related and routine items and services for study participants. The Galleri-Medicare study will further enhance our expansive clinical evidence program, which includes our pivotal NHS-Galleri randomized clinical trial, bringing planned enrollment to more than 385,000 participants. We are in the final round of blood draws for the NHS-Galleri trial and expect to complete final study visits in the third quarter of this year. 

GRAIL’s proprietary targeted methylation platform combined with our growing body of clinical and real-world data provide us with unique insights into cancer biology that enable product improvements and new product introductions over time. Potential applications for our technology in a precision oncology setting include pre-treatment prognosis, post-treatment prognosis or minimal residual disease (MRD), recurrence and clinical monitoring, and novel biomarker discovery.

Recent Business Highlights

2023 was an exciting year for GRAIL. We are seeing continued strong early adoption of GalleriⓇ, our multi-cancer early detection (MCED) blood test, surpassing 150,000 commercial tests completed. Real-world use of Galleri has detected some of the most aggressive cancers in early stages, including endometrial, esophageal, gastrointestinal stromal, head & neck, liver, pancreatic and rectal cancers. For the majority of these cancer types, there are no alternative screening options available. We are passionate about our mission to detect cancer early, when it can be cured, and energized by the powerful stories we have heard from patients who have benefited from Galleri and from physicians and health systems who are successfully implementing Galleri into their practice. 

As an early leader in the field, we continue to establish strong relationships within the cancer and primary care communities, including collaborations with academic and community medical centers, opinion leaders, policy and advocacy groups. We are building on our clinical evidence program, and announced in December the Galleri-Medicare study (REACH), bringing planned enrollment for our clinical research programs to more than 385,000 participants. We were also pleased to publish results from our seminal PATHFINDER and SYMPLIFY studies in 2023 in The Lancet and The Lancet Oncology, respectively—two premier medical journals.

Cancer is a major public health crisis, and we are looking to a future where we can detect more cancers through screening, before symptoms arise, which we believe will ultimately save lives and reduce costs of care. Galleri works by detecting DNA fragments shed into the bloodstream by tumor cells. Cancer DNA has specific methylation patterns that can be used to both identify a shared cancer signal and localize that signal to a specific organ or tissue type. Galleri remains the only validated MCED test available for detection of a shared cancer signal across more than 50 cancer types. 

GRAIL’s proprietary targeted methylation platform, which underlies Galleri, and our growing body of clinical and real-world data, provide us with unique insights into cancer biology that enable product improvements over time, and the development of other products beyond asymptomatic cancer screening. Potential applications for our technology in a precision oncology setting include pre-treatment prognosis, post-treatment prognosis or minimal residual disease (MRD), recurrence and clinical monitoring, and novel biomarker discovery. We are leveraging a range of ongoing collaborations with leading academic oncologists and pharmaceutical companies to further develop these product opportunities.

In 2023, GRAIL continued to build on our key strengths:

Galleri has established early commercial leadership in MCED 
We are pleased to report that, to date, we have established over 100 commercial partnerships, including leading employers, payors, life insurance providers and health systems, such as HCA Healthcare—the largest health system in the U.S. Through these partnerships, we have also secured coverage of Galleri with several forward-thinking self-insurers in various sectors such as technology, healthcare, entertainment, life insurance, and financial industries.  

We have established a network of more than 9,000 ordering healthcare providers in the pre-reimbursement setting, with prescribers in private practices across the United States. We are encouraged by the consistency of the cancer signal detection rate we are seeing in commercial implementation with what we have observed in our clinical studies. We continue to build the key components of our commercial and laboratory infrastructure and capabilities that are required to support rapid, population-scale testing in a reimbursed environment.

We have worked closely with providers to develop and roll-out a suite of services to ensure that patients with a Galleri positive cancer signal, and their health care providers, are supported through the confirmatory diagnostic process.

Healthcare providers are offered direct support from our medical science liaisons and access to a specialized Galleri experience council—a cohort of physicians with Galleri experience (including experts from National Cancer Institute-Designated Cancer Centers) who can provide peer-to-peer consultations. We also operate an early cancer detection board that includes third-party experts across specialties to provide consultative advice for any challenging cases. 

For patients with a Galleri positive test result, we offer a support center that provides materials explaining the cancer signal detected result that can be shared with health care providers managing follow-up diagnostic evaluation. 

We are driving critical scientific and clinical research in the field
We have undertaken a rigorous approach to identify the informative cfDNA-based markers of cancer through what we believe is the largest clinical program in genomic medicine. Our robust clinical development program consists of studies that are planned to collectively include more than 385,000 participants, of which more than 300,000 have already been enrolled, and includes case-controlled, observational, interventional and real-world studies. 

In 2023, we reported final data from two key studies. Together with leading experts in the field, we published seminal results from the interventional PATHFINDER study in asymptomatic patients in The Lancet and from the SYMPLIFY study – the first prospective study of an MCED test in a symptomatic patient population – in The Lancet Oncology. Overall throughout the year, we published more than 20 manuscripts in clinical and scientific journals and more than 50 abstracts at renowned global congresses, including the American Association of Cancer Research (AACR), American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO).

We also completed second year study visits for the NHS-Galleri trial with a high retention rate of 91.3%. We have entered the third year of the trial and expect to complete participant visits this coming summer. The NHS will review early metrics from the first screening round of the study in 2024, and based on those results may commence the commercial implementation of the Galleri test in up to one million patients in England over two years.

In addition, we announced plans to initiate the Galleri-Medicare (REACH) study. This study is a first of its kind real-world study designed to evaluate the clinical impact of Galleri among 50,000 Medicare beneficiaries. The findings will add to our robust body of evidence evaluating the potential for MCEDs to change the future of cancer detection, particularly in diverse populations. Medicare will cover the costs of Galleri and related and routine items and services for study participants.  

Our clinical trial recruitment strategies are specifically designed to reach diverse and underrepresented populations. For example, we are partnering with medical centers and clinics in both rural and urban settings to recruit individuals with a representation consistent with the latest US census data in the PATHFINDER 2 study; the NHS-Galleri study includes enrollment centers in areas of high deprivation index and ethnicity mix in England; and the Galleri-Medicare real-world study is designed to include Medicare participants from underrepresented populations across race, ethnicity, socioeconomic status and underserved communities. 

We are building our pipeline 
Our proprietary targeted methylation platform, as well as our growing body of clinical and real-world data, provide us with unique insights into cancer biology that enable development of products beyond asymptomatic screening. We are developing our precision oncology portfolio and launched our research use only (RUO) technology solution, which couples our proprietary targeted methylation platform with customizable machine learning classifiers. We have partnered with a number of leading oncology therapeutics companies, and we shared our first lung adenocarcinoma data in collaboration with our partner AstraZeneca in December at the IASLC North America Conference On Lung Cancer. Some of our partnerships also include development of customized applications to support clinical studies and companion diagnostic development and commercialization.

In 2023, we published data from the SYMPLIFY study, demonstrating that our methylation platform was able to detect many cancer types and identify where the cancer signal origin was located in the body with high accuracy in a symptomatic patient population. Based on these findings, we are developing our diagnostic aid for cancer (DAC) test to accelerate diagnostic resolution for patients with non-specific signs and symptoms, but with a clinical suspicion of cancer. Through a blood test, DAC is designed to provide physicians with a powerful decision-making tool to aid diagnosis, achieve resolution more quickly, and avoid unnecessary workups. 

We are focused on MCED access
GRAIL is committed to broad and equitable access to our technology to help address healthcare disparities and improve clinical outcomes. By partnering with the healthcare community and its stakeholders, we are advancing the education of diverse and medically underserved communities about the importance of early cancer detection and supporting equitable access to our technology.

In addition to our clinical development program, GRAIL is pursuing innovative partnerships to improve cancer early detection rates for underserved populations, such as our partnerships with Ochsner Health, Whitman-Walker Institute and Cancer Support Community, and the U.S. Department of Veterans Affairs (VA) Veterans Health Administration and the Veterans Health Foundation. 

We are building a strong culture and team 
We have built a multi-disciplinary organization of leading scientists, engineers, clinicians and other talented professionals driven to improve outcomes for patients with cancer. We believe our mission, values, and leadership attributes all contribute to this vibrant and inclusive culture and serve as a powerful magnet for talent.

GRAIL was named on Fortune’s 2023 Change the World List, which recognizes companies addressing society’s biggest challenges and having a positive social impact, and Galleri was recognized with a 2023 Edison Award, one of the highest accolades a company can receive in the name of innovation. GRAIL was also voted a Best Place to Work by several organizations, including BuiltIn and Comparably.  

These achievements and accolades are only possible through the passion and commitment of our team. Pursuing scientific breakthroughs, scaling for growth and driving change across a dynamic environment requires that our team think big, bring an open mind, be courageous, solve problems together, and embrace change. Coupled with our mission, these core values provide the framework for how we work with each other, our commercial and research partners, healthcare providers, governments and others to drive the field forward and ultimately improve public health. I am grateful to our employees for their commitment to GRAIL and our mission every day.

Looking ahead
We anticipate that 2024 will be another transformative year as we expect to complete participant visits for the NHS-Galleri study, initiate the Galleri-Medicare study, further our innovative research, and continue to drive access to Galleri and advance our commercial and research partnerships. Looking beyond, we are focused on clear strategic goals including seeking Galleri FDA approval, pursuing CMS coverage and broad commercial reimbursement for Galleri, and launching additional products. 

On behalf of GRAIL’s leadership team and employees, we thank you for your continued support of our efforts to advance our mission to detect cancer early, when it can be cured. 

ELECTRONIC SUBMISSION AT www.regulations.gov

Attn: Jarrod Collier, M.S.
Designated Federal Officer
FDA Advisory Committee
Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee
Docket FDA–2023–N–4720
US Food and Drug Administration
Silver Spring, MD 20993

Dear Mr. Collier:

GRAIL, LLC (“GRAIL” or “we”) appreciates the opportunity to submit a public comment to docket FDA–2023–N–4720 on the Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee on the topic of Multi-Cancer Detection (“MCD”) Devices.  We have focused our comments on the design of MCD in vitro diagnostic devices (tests) and methodological considerations for evaluation of benefits and risks of MCD tests, together with recommendations for study design and study outcomes of interest. We commend the FDA’s commitment to engage with stakeholders, including test developers, providers, and most importantly patients, to inform the Agency’s regulatory decision-making regarding these important and novel tests.

Background

GRAIL is a healthcare company whose mission is to detect cancer early, when it can be cured.  Through our population-scale clinical studies and machine learning and data science, we have developed the Galleri(R) multi-cancer early detection blood test. 

The Galleri test is an analytically- and clinically-validated test for early detection of multiple types of cancer. In clinical studies, Galleri has shown the ability to identify a shared cancer signal across more than 50 types of cancer, often at an early stage, demonstrating a high positive predictive value (“PPV”) and low false positive rate.[1], [2] If a cancer signal is detected, Galleri also predicts the tissue type or organ associated with the cancer signal (the cancer signal origin) with high accuracy.[3] Galleri works by detecting DNA fragments shed into the bloodstream by tumor cells, referred to as cell-free DNA (“cfDNA”).[4] DNA has specific methylation patterns that can be used to both identify a general cancer signal and to localize that signal to a specific organ or tissue type. Importantly, Galleri is intended as a complement to recommended standard of care single cancer detection tests, not as a replacement.

As part of the FDA breakthrough designation and PMA submission process, GRAIL has consulted numerous experts, and diligently assessed the complex and challenging issues involved in developing novel MCD technology and designing first-of-its-kind study and outcome measures.  Our learnings in key areas of discussion identified for consideration by the FDA Advisory Committee are shared below.

Design of Multi-Cancer Detection Tests

Based on discussions and consultations with key opinion leaders, medical practitioners, patient advocates and clinical experts, GRAIL believes the following are essential features for any MCD test to be implemented as a screening test in an average risk, asymptomatic population (e.g., >50 years of age) in addition to currently recommended single cancer screenings, optimizing the benefits of screening overall while mitigating potential risks:[5]  

The Galleri test detects a cancer signal shared by a broad spectrum of cancers, including the most deadly types of cancers that are not covered by cancer screening guidelines, enabling detection of a broad range of cancer types.[7]Currently, cancer screening guidelines cover only five cancer types (breast, cervical, colorectal, lung, and prostate). These single-cancer detection (“SCD”) approaches are estimated to cover only 15% of cancer diagnoses and 30% of cancer deaths in the United States, meaning that 70% of cancer deaths are due to cancers without a current screening paradigm.[8] Of these deaths, many are attributable to rare cancer types. By leveraging the biology of the “shared cancer signal,” Galleri enables the detection of a broad spectrum of cancers, including less common cancer types. We believe that the only way to conduct general population screening for multiple types of cancers, including rare cancers and those that predominantly affect racial/ethnic minority groups, is to aggregate them for screening.  By targeting this aggregate incidence, Galleri has the potential to increase the yield of cancers diagnosed through screening from 15% to 49%.[9]  

Additionally, a “shared cancer signal” approach to MCD, which Galleri uses, allows for a single low false positive rate (FPR), which we believe contributes to optimizing PPV.[10] This shared cancer signal is rarely observed in individuals known not to have cancer. For a condition like cancer that has a low prevalence in the population, PPV is significantly impacted by prevalence and specificity, such that PPV increases with the prevalence of cancer in the population and with the specificity. Asymptomatic screening tests designed to optimize PPV (and likelihood of benefit) appropriately balance the potential risks involved in confirmatory diagnostic workups. We believe that the Galleri test’s “shared cancer signal” approach is clinically preferable to multiple SCD tests intended for multi-cancer screening, whether independently administered or designed by stacking a set of individual screens combined into a single test.  SCD tests generally are designed to optimize sensitivity, and thus tolerate a higher FPR.  Screening individuals with multiple SCD tests adds to the cumulative FPR. Ten SCD tests, each optimized for one deadly cancer type, used in annual screening of 100,000 persons aged 50-79 in addition to USPSTF-recommended screening, would result in a cumulative FPR of 12%, while the Galleri test FPR remains at 0.4%. A single, low FPR with an MCD test limits unnecessary workups in patients who do not have cancer, and associated harms, which is important in evaluating the overall risks of the test.

The Galleri test has been shown to preferentially detect more aggressive cancer types, potentially limiting overdiagnosis of indolent cancers.[11], [12] Data across our clinical studies suggests that although Galleri detects cancer signals for some of the most aggressive cancers, detection of cancer signals for indolent cancer types, which people are less likely to die from, is low. This is because more aggressive cancers shed more DNA into circulation, making them more detectable; conversely, less aggressive, more indolent cancers, like early-stage prostate cancer, shed less, and are less detectable through cfDNA tests. As a result, the design of the Galleri test helps limit potential risks from overdiagnosis and the harms potentially caused by unnecessary procedures and workups.

In addition to a low FPR and limited detection of indolent cancer types, the ability to predict with high accuracy the cancer signal origin and direct diagnostic workup further reduces MCD screening risks.[13] Accurate cancer signal origin helps limit unnecessary diagnostic tests and procedures. Galleri has a 88% cancer signal origin prediction accuracy for identifying the location of cancer, which supports targeted and more efficient diagnostic resolution through established workup pathways. Our PATHFINDER study showed that 80% of screened subjects achieved diagnostic resolution by cancer signal origin-directed initial evaluation and generally facilitated diagnosis in less than 3 months (median of 79 days) among participants who had a cancer signal detected.[14]

Further, Galleri has been validated in large clinical studies across diverse populations in behaviors (such as smoking), non-cancer diseases, environmental exposures, age, gender, race, ethnicity, socio-economic status, and other confounding indications and differences.[15] For example, in published data from our CCGA study, we found no meaningful differences in performance across racial subgroups.[16] Understanding cancer signals associated with demographic diversity is pivotal to our ability to account for biological noise and underpin the high-specificity of our test while allowing for use in a broad and diverse screening population.

GRAIL has studied and evaluated the most clinically appropriate MCD design features, and believes that any MCD test should optimize early cancer detection, particularly of aggressive cancers, limit risks of unnecessary diagnostic tests and procedures, and have the potential to achieve reduced overall cancer mortality and morbidity, when added to existing guideline-based screening paradigm.

Methodological Considerations for Evaluation of Benefits and Risks of MCD Tests and MCD Study Designs and Study Outcomes of Interest

As part of developing our large clinical evidence program for MCD over the past seven years, GRAIL has diligently assessed and implemented key study designs, methodologies, and outcomes appropriately suited to evaluate the probable benefits and risks of MCD screening tests. This experience, and ongoing consultation with leading experts in the field, has informed our thinking. In this comment, we focus on two methodologic considerations for evaluating the benefits and risks of MCD tests.  We believe that (1) the primary study endpoint of absolute incidence of late stage cancer represents the most promising strategy for robust yet accelerated evidence regarding the clinical utility of MCD tests and (2) the performance or clinical utility of MCD should be evaluated by the the aggregate measure of detecting cancer in the intended use population, rather than by individual cancer type, as discussed below.

There have been debates on what constitutes appropriate endpoints for the study of cancer screening trials. Towards that, some have cited the applicability of mortality including all-cause mortality. A primary endpoint of mortality may not capture in a timely manner the substantial morbidity reduction and patient-reported benefits of earlier cancer detection.[17] Given the high and growing number of cancer deaths still occurring under current screening recommendations, there is substantial opportunity cost in deferring adoption of screening tests with the potential to reduce cancer morbidity and mortality.  As such, more rapid and more patient-centric yet rigorous evaluation of their clinical utility is needed. The relevance of trial results reported after a decade or more will be diminished by the rapid evolution of MCD technologies and cancer treatments during that time.  In the same way that modern drug trials are being redesigned to fit with modern therapies (e.g. basket and umbrella trials),[18] cancer screening trials also need a major reconsideration with regards to endpoints, design, and analytical methods to keep up with rapidly advancing technology.

Groups such as the MCED Consortium are working to rethink traditional strategies for clinical utility evidence generation involving trials with nearer-term and more patient-centric endpoints, real-world data collection, and more sophisticated modeling of longer-term endpoints.  A range of alternative trial endpoints have been suggested, including reduction in late-stage cancer incidence, candidacy for curative interventions at diagnosis, overall cancer detection rate, reduced treatment morbidity for early-stage cancers, increased treatment response rates, improved quality of life during and after treatment, and rates of metastatic recurrence.

Observations from screening trials for breast, colorectal, and lung cancer provide evidence supporting the demonstration of a reduction in the incidence of late-stage cancer as a relevant surrogate for cancer-specific mortality. For example, while a meta-analysis of nine randomized controlled trials of mammography reported an overall mortality benefit of 22%, the trials that reduced advanced stage disease by >20% showed an even greater (28%) reduction in mortality, corresponding to a 40% reduction in those who actually participated in screening.[19] Furthermore, reductions in advanced stage disease in these trials accounted for two-thirds of the benefit from screening. As such, at least two ongoing breast and colorectal cancer screening trials have chosen incidence of late stage disease as their measured endpoint and used the mortality reduction modeled from that measure to make decisions that are both timely and less burdensome with respect to sample size/statistical power.

Therefore, we believe that absolute incidence of late stage cancer as a directly measured primary endpoint in clinical studies, followed by sophisticated computational disease modeling to understand potential impacts on cancer-specific mortality, represents the most promising strategy for robust yet accelerated evidence regarding the clinical utility of MCD and other technologies that detect cancer in average-risk populations. Designing and powering clinical utility studies to directly measure cancer-specific or all-cause mortality invoke intractable challenges related to efficiency and complexity under rapid evolution of cancer screening and treatment technologies. While some researchers express interest in the relationship between cancer screening and directly measured all-cause mortality,[20] we consider that endpoint insensitive for understanding the impact of the cancer-directed intervention,[21], [22] and will be difficult to interpret due to competing deaths from non-cancer over long time periods, but point out that it can certainly be modeled and evaluated from studies followed to an endpoint of cancer stage at diagnosis. A recent commentary led by Dr. Ruth Etzioni and National Cancer Institute researchers agree that building a rigorous program of objective analytical and modeling studies is our best bet for accelerating evaluation of novel screening tests in a way that balances scientific rigor with timely answers.[23]

Another important consideration for the evaluation of MCD tests involves the appropriate endpoint across all cancer types that can be detected by the test under investigation. Studies should primarily aim to determine the aggregate performance or clinical utility of a test in the intended use population, not stratified or powered to subtypes of targeted cancers. It is not possible to know in advance the cancer type to be detected at the time when an MCD test is administered – just as individuals are not able to choose which type of cancer they develop. Although the benefits, risks, and performance characteristics of any MCD test will ultimately vary by cancer type detected, these considerations are secondary to the primary public health goal of increasing the total number of cancers diagnosed in a population at measurable risk of any and all cancer types. Thus, we believe that the appropriate evaluation endpoint for an MCD test is the performance across all cancer types that can be detected by the test.

GRAIL has leveraged these methodological underpinnings in assembling what we believe is the largest clinical development program in genomic medicine, aimed at robustly validating our breakthrough device technology responsibly and expeditiously, to allow for its deployment in improving public health.  GRAIL has enrolled over 300,000 subjects in over 8 different studies to develop and demonstrate the clinical validity, utility and value of methylation-based MCD testing that has a shared cancer signal and highly accurate CSO prediction. 

These studies include our foundational case-control Circulating Cell-free Genome Atlas (CCGA) and PATHFINDER studies, which included more than 21,000 participants to develop, validate, and launch our Galleri technology, and additional ongoing multiple large-scale observational and interventional studies.[24], [25]

The CCGA study is a large multicenter case-control study that enrolled approximately 10,000 participants with newly diagnosed cancer and 5,000 participants without a diagnosis of cancer from medical institutions and health systems and followed them for outcome information.[26] The CCGA study was divided into three sub-studies to develop, train, and validate classifiers for cancer and non-cancer signal detection, as well as CSO prediction. The CCGA-3 sub-study demonstrated detection of a shared cancer signal across more than 50 cancer types and accurate CSO prediction, with a false positive rate of 0.5%.[27]

The PATHFINDER study was an interventional multi-center study of 6,662 participants representing the first pilot implementation of the Galleri test into clinical practice.[28], [29] The study was conducted under an FDA-approved investigational device exemption (“IDE”) application. Test results, including CSO, were returned to study investigators who determined the appropriate diagnostic evaluation. The study objectives were (a) to assess the extent of cancer diagnostic testing required to achieve diagnostic resolution following a cancer signal detected test result, (b) evaluate clinical performance of the Galleri test, and (c) assess participant-reported outcomes. Critically, performance was consistent with our case-control CCGA study: a pre-specified retrospective re-analysis of samples with the Galleri version of the test showed a PPV of approximately 43%, cancer signal origin prediction accuracy of approximately 88%, and specificity of 99.5%.[30]

GRAIL is currently conducting two additional population-scale interventional studies, both of which are conducted under FDA-approved IDEs: the PATHFINDER 2 study and the National Health Service (“NHS”)-Galleri trial. These studies have been designed to evaluate the safety and performance of Galleri, including, among other endpoints, a measurable outcome of whether an MCD test program can reduce the proportion of late-stage cancers detected.[31]

The PATHFINDER 2 Study is an interventional, multi-center study of participants receiving the Galleri test.[32] The study is enrolling approximately 35,000 participants aged 50 years or older from clinical study sites in North America over an anticipated enrollment period of approximately 36 months. 22% of the enrolled subjects are intended to be from minority and under-served populations.The primary objectives of this study are to evaluate the safety of the Galleri test in terms of cancer diagnostic workup triggered by a test result and performance of the test in individuals eligible for cancer screening, with a three year follow-up period.  Test results are being returned to the healthcare providers and information on the ensuing cancer diagnostic workup is recorded.

The NHS-Galleri trial is a blinded, randomized, controlled study of the clinical utility of the Galleri test that is being run through a public-private partnership with The Cancer Research UK and King’s College London Cancer Prevention Trials Unit, in partnership with the NHS and GRAIL.[33] The NHS-Galleri trial has enrolled 142,966 asymptomatic participants by inviting an estimated 1.5 million people from the general population aged 50-77 years who reside in England. Blood samples will be collected at three annual study visits. Following the baseline visit, participants were randomized 1:1 to either the intervention arm (blood samples tested) or control arm (blood samples not tested but stored for potential future use). Only participants in the intervention arm with a cancer signal detected are receiving the test result and referral for diagnostic investigations by the NHS. The primary objective of the trial is to evaluate whether there is a statistically significant reduction in the absolute numbers of stage III and IV cancers diagnosed in the intervention arm compared with the control arm.  This endpoint is expected 3.5 years after randomization. Additional near-term endpoints of interest include cancer-specific mortality modeled from the stage distribution, receipt of curative cancer surgery and treatment, and patient-reported outcomes.  Longer-term endpoints of interest include cancer-specific and all-cause mortality. However, serious methodologic challenges with these longer-term endpoints in the context of MCD and/or genomic technologies for early cancer detection are outlined above and provide justification for utilization of nearer-term outcomes to understand the range of benefits and harms potentially associated with MCD and to accelerate adoption.

Conclusion

Despite 50 years of the “war on cancer,” most cancers in the United States still are detected too late, after a person develops symptoms and once the cancer already has spread. This is because the currently recommended cancer screening programs only find at most 15% of the total cancer burden among those eligible for screening.

Recommended screening tests can find cancer early and improve outcomes, but are only available for five types of cancer. We know that cancer found in an early stage is associated with improved survival versus cancer found in later stages, which can be more difficult and costly to treat and may have fewer therapeutic options. In fact, the 5-year survival rate across all cancers is 89% when cancer is found while it still is localized, but drops to 21% once it has spread. Screening for one cancer at a time—and for so few cancers—is simply not going to materially reduce deaths from cancer, as most cancers are not covered by the current screening paradigm.

We believe making validated MCD tests, with features described herein, available as a complement to recommended screening programs will dramatically increase cancer detection from screening in the population, and improve public health. GRAIL feels great urgency to address the burden of cancer and to work in collaboration with the FDA and other key stakeholders to achieve our shared mission to end late-stage cancer as we know it. We greatly appreciate the opportunity to comment and for the FDA’s ongoing work to accelerate the regulatory evaluation of MCD tests.

Respectfully submitted,

Lakshman Ramamurthy
On behalf of GRAIL, LLC
Lakshman Ramamurthy, Ph.D
Vice President, Regulatory Affairs
GRAIL, LLC

[1]Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. 2021;32(9):1167-1177.
[2]Hubbell E, Venn O, Shanmugam A. Shared cancer signal: evidence from cross-training. USC Computational Biology Symposium; May 19–21, 2022, Los Angeles, CA
[3] Klein (n 1).
[4]Jamshidi A, Liu MC, Klein EA, et al. Evaluation of cell-free DNA approaches for multi-cancer early detection. Cancer Cell. 2022;40(12):1537-1549.e12.
[5]Hackshaw A, Clarke CA, Hartman AR. New genomic technologies for multi-cancer early detection: Rethinking the scope of cancer screening. Cancer Cell. 2022;40(2):109-113.
[6]Ahlquist DA. Universal cancer screening: revolutionary, rational, and realizable. NPJ Precis Oncol. 2018;2(1):23.
[7]Klein (n 1).
[8]Hackshaw A, Cohen SS, Reichert H, et al. Estimating the population health impact of a multi-cancer early detection genomic blood test to complement existing screening in the US and UK. Br J Cancer. 2021;125(10):1432-1442.
[9]Ibid.
[10]Hubbell (n 2).
[11]Chen X, Dong Z, Hubbell E, et al. Prognostic Significance of Blood-Based Multi-cancer Detection in Plasma Cell-Free DNA. Clin Cancer Res. 2021;27(15):4221-4229.
[12]Bredno J, Lipson J, Venn O, at al. Clinical correlates of circulating cell-free DNA tumor fraction. PLoS One. 2021;16(8):e0256436.
[13]Klein (n 1).
[14]Schrag D, Beer TM, McDonnell CH 3rd, et al. Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study. Lancet. 2023;402(10409):1251-1260.
[15]Klein (n 1).
[16]Tang WHW, Yimer H, Tummala M, et al. Performance of a targeted methylation-based multi-cancer early detection test by race and ethnicity. Prev Med. 2023;167:107384.
[17]https://www.fda.gov/about-fda/cdrh-patient-science-and-engagement-program/patient-preference-information-ppi-medical-device-decision-making.
[18]Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics Guidance for Industry. Published March 2022. Accessed November 15, 2023. [PDF Link]
[19]Tabár L, Yen AM, Wu WY, et al. Insights from the breast cancer screening trials: how screening affects the natural history of breast cancer and implications for evaluating service screening programs. Breast J. 2015;21(1):13-20.
[20]Carr D, Kent DM, Welch HG. All-cause mortality as the primary endpoint for the GRAIL/National Health Service England multi-cancer screening trial. J Med Screen. 2022;29(1):3-6.
[21]Duffy SW. All-cause mortality in multi-cancer screening trials. J Med Screen. 2022;29(1):1-2.
[22]Prasad V, Lenzer J, Newman DH. Why cancer screening has never been shown to “save lives”–and what we can do about it. BMJ. 2016;352:h6080.
[23]Etzioni R, Gulati R, Patriotis C, et al. Revisiting the Standard Blueprint for Biomarker Development to Address Emerging Cancer Early Detection Technologies [published online ahead of print, 2023 Nov 6]. J Natl Cancer Inst. 2023;djad227.
[24]Liu MC, Oxnard GR, Klein EA, et al. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745-759.
[25]Klein (n 1).
[26]Ibid.
[27]Ibid.
[28]Nadauld LD, McDonnell CH 3rd, Beer TM, et al. The PATHFINDER Study: Assessment of the Implementation of an Investigational Multi-Cancer Early Detection Test into Clinical Practice. Cancers (Basel). 2021;13(14):3501.
[29]Schrag (n 14).
[30]Ibid.
[31]Neal RD, Johnson P, Clarke CA, et al. Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial. Cancers (Basel). 2022;14(19):4818.
[32]https://classic.clinicaltrials.gov/ct2/show/NCT05155605
[33]Neal (n 31).