The potential relevance of uniform pricing is that the non-small-cell lung cancer molecular targeted therapies are characterised by a lower number of NICErecommended indications (usually one or two, occasionally three) as compared to checkpoint inhibitors. NICE has issued guidance, for example, on sixteen occasions in the case of pembrolizumab and ffteen times for nivolumab, and many further appraisals are in development. Moreover, pembrolizumab has been appraised in seven clinical areas: colorectal cancer, head and neck cancer, Hodgkin lymphoma, melanoma, non-small-cell lung cancer, renal cell carcinoma and urothelial carcinoma, and nivolumab has been appraised in these seven clinical areas plus oesophageal cancer. This is in marked contrast to the twelve targeted therapies which, with a single exception, only have non-small-cell lung cancer indications. The sole exception, entrectinib, also has an indication for NTRK fusion-positive solid tumours. The potential foregone revenue to the manufacturer from setting a single uniform price would thus be expected to be less in the case of the targeted therapies. While a drug included in the Cancer Drugs Fund will need to be offered at a potentially cost-effective price, since it is not part of routine commissioning the scope for price to vary across indications is much greater. Consequently, manufacturers might have a stronger incentive to seek inclusion of their checkpoint inhibitors in the 2016 Cancer Drugs Fund.

The multiple therapeutic indications for some new drugs were noted in NICE's 2021 consultation on changes to its appraisal processes, in which they specifcally highlighted pembrolizumab, nivolumab, and atezolizumab. They posed the question whether "the current approach to conduct a full technology appraisal for every new indication is proportionate or if an alternative simpler approach to evaluation … may be more appropriate for technologies that are evaluated multiple times" and sought views concerning different approaches (NICE 2021). Thus, NICE's interest in considering alternative approaches stems primarily from constraints on the organisation's evaluative capacity, however, as we have seen, multiple indications also raise at least as important issues with respect to the pricing of these therapies.

#### **Conclusions**

While this review is based on experience in non-small-cell lung cancer it offers insights regarding the evaluation of targeted therapies and checkpoint inhibitors across oncology. The differences with respect to economic evaluation, such as, in terms of the clinical evidence underlying the modelling of cost-effectiveness, and the differences observed with respect to life-extending end-of-life status and with respect to inclusion in the Cancer Drugs Fund, are not anticipated to be specifc to non-small-cell lung cancer but arise from differences between immune checkpoint inhibitors and molecular targeted therapies.

Although it appears that some of the differences between oncology treatments and non-oncology treatments are beginning to reduce, this looks like being achieved by moving appraisal and decision-making with respect to non-oncology drugs closer to that of oncology drugs. An increasing proportion of non-oncology treatments will be subject to appraisal by NICE. Also, the general election at the end of 2019 brought forward a proposal to extend the Cancer Drugs Fund to create a new Innovative Medicines Fund. Additionally, NICE have recently consulted on changes to their methods of appraisal, expressing a clear desire to replace the life-extending end-of-life criteria with a severity criterion (NICE 2020c). While many oncology medicines are still likely to qualify for a more favourable treatment of their health benefts, it is anticipated that they will be joined by a number of non-oncology medicines. Just how many non-oncology medicines and the new severity criteria are yet to be revealed. Thus, the study of the recent past of decision making with respect to oncology drugs is likely to be increasingly relevant to a much wider range of medicines, as differential weighting of QALYs and the use of managed access schemes are extended beyond oncology drugs.

This chapter describes where we are rather than how we got here. There is clearly a suggestion that the differences observed between the appraisal of molecular targeted therapies and that of immune checkpoint inhibitors derives from the more limited clinical data and the more restricted application of the targeted medicines. However, clinical studies are not designed, and indications are neither sought nor granted without human agency.

#### **References**

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## **Real-World Data in Health Technology Assessment: Do We Know It Well Enough?**

**Jiyeon Kang**

#### **Introduction: The Growing Importance of Data in Health Care**

Oncology research has been accompanied by important health care innovations in cutting-edge technology over the last decades. In the era of information technology, a remarkable amount of biological clinical data has been generated. As the data accumulated, the demand for bioinformatics fared up. Advanced data science has rapidly emerged in oncology research, where it is used for the analysis and interpretation of biological data for cancer diagnosis and clinical treatment planning (Bayat 2002). The paradigm of cancer treatment has shifted from chemotherapy to immunotherapy, evolving into 'precision oncology' guided by highly sophisticated biomarkers. The growing precision medicine market is predicted to exceed USD 119 billion by 2026 (Ugalmugle and Swain 2020). Advances in technologies such as data science are leading the fourth industrial revolution. Data are not only pushing the technology forward but are also seen as a key factor to achieve success in the fourth industrial revolution. Data are expected to advance the development of new technology and industry like artifcial intelligence (AI). Health care is one of the most commonly addressed applications of the technological data revolution. Not only contributing to developing new technologies, but data such as big data or realworld data (RWD) are also expected to help provide scientifc and systematic evidence to policymakers by combining all available evidence.

As a way of example, in the United States, the 21st Century Cures Act enacted in 2016 was designed to help accelerate medical product development, bringing new innovations and advances into patients who need them faster and more effciently (FDA 2020a). This Act also placed additional focus on the use of RWD to support the regulatory decision making, including approval of new indications for approved

J. Kang (\*)

London School of Hygiene and Tropical Medicine, London, UK e-mail<EMAIL_ADDRESS>
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A. Bremer, R. Strand (eds.), *Precision Oncology and Cancer Biomarkers*, Human Perspectives in Health Sciences and Technology 5, https://doi.org/10.1007/978-3-030-92612-0\_12

drugs (FDA 2020b). Three years after, the US Food & Drug Administration (FDA) approved the palboclib for treating male breast cancer based on RWD from electronic health records (Wedam et al. 2020). Rare diseases such as male breast cancer have the challenge of obtaining evidence from RCT, which is a big hindrance to developing drugs. However, in this case, RWD played an important role as primary evidence instead of RCTs in getting the FDA's approval. Using RWD, FDA enabled the early approval of new health technology, which fulfls the unmet medical needs. This example shows that the data utilisation impacts early stages of drug development and the whole process of development, such as drug approval and reimbursement decision making.

Data have therefore become a central topic in health care. The objective of this chapter is to look at the opportunities and challenges of using RWD in health technology assessments, in particular by using examples of the NICE technology appraisals. In order to do so, we will frst look at the defnition of RWD and big data in section "Real-world data and big data: some defnitions". The following each sections "Health Technology Assessment in the era of information technology" and "Opportunities related to using RWD in HTA" will describe the opportunities and challenges of using RWD in health technology assessment (HTA) with detailed example, how manufacturers, evidence review groups (ERGs) and committee have used RWD in appraisals. In the last section, it will briefy emphasise the deliberation of using RWD based on understanding of its potentialities and limitations.

#### **Real-World Data and Big Data: Some Defnitions**

When looking at the current trends in terms of data in health care, there are two key concepts – big data and RWD. Commonly, the terms RWD and big data are used interchangeably. However, the relationship between RWD and big data is not as straightforward. Although there is no consensus on their defnitions and the boundary between big data and RWD, the two terms are not identical. The Head of Medicines Agencies and European Medicines Agency set up a joint task force for the best use of big data, including RWD such as electronic health records and data from patient registries in 2019 (HMA, EMA 2019). Broadly speaking, big data usually refers to "the explosion in quantity (and sometimes, quality) of available and potentially relevant data, largely the result of recent and unprecedented advancements in data recording and storage technology"(Gibbs and McKendrick 2015, 235). Characteristics of big data are summarised into volume (massive amounts), velocity (high-speed processing) and variety (heterogeneous data), the so-called 3Vs of big data (2020). On the other hand, RWD is data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources, including electronic health records, medical claims and billing, product and disease registries, as well as health-related data from mobile devices (FDA 2018). Data such as NHS electronic hospital data, cancer registry data, claims data, and even patientreported information collected from wearable devices are all RWD.

Big data and RWD are inherently complex, encompassing a wide range of information specifc to the health and everyday life of individuals. This is an extensive defnition that leaves room for interpretation. For example, NHS electronic hospital data and cancer registry data are routinely collected, large and unprocessed data can be used in potentially different ways. Therefore, they can be RWD as well as big data. Nonetheless, it is incorrect to say that all RWD is big data, even if the attributes of big data seem substantially transferable to RWD. Since big data collectively indicate all data, it is not necessarily RWD. For example, the Big Data Institute at the University of Oxford is working on clinical AI for the patient-centred management and treatment of chronic disease (Oxford Big Data Institute 2019). In order to understand the complexity of the disease, it includes clinical trials, NHS hospital data and all available forms of data from all over the world. Whereas these collective data are considered big data, it is wrong to classify these data as RWD. Similarly, RWD is not always big data. Data from Compassionate Use Programme (CUP) are an example. The CUP is the scheme, which allows the patient who cannot enter a clinical trial to use unauthorised medicine under strict conditions (EMA n.d.-a). The drug in development can be available to patients who are not eligible for clinical trials or use unapproved therapies (EMA n.d.-b). According to the defnition, it is RWD, a retrospective observational cohort study routinely collected from the realworld. The CUP was used in appraising the clinical effectiveness and costeffectiveness of idelalisib for treating refractory follicular lymphoma by the National Institute for Health and Care Excellence (NICE) in the UK. In the NICE appraisal of idelalisib (TA604), CUP data collected in the UK and Ireland (n = 65) was submitted in order to complement the evidence. It generates valuable information which belongs to a category of RWD in patient populations with unmet needs, and it informs future RWD use (Balasubramanian et al. 2016, 251). While the study furnished the information on the real-world evidence, the study's characteristics deviated from the attributes of big data in terms of volume, velocity, and veracity. In this chapter, the scope of data only focuses on RWD in order to understand the issues around RWD more comprehensively.

#### **Health Technology Assessment in the Era of Information Technology**

In this era of information technology, "evidence-based practice" has been a keyword. Evidence-based practice is the "integration of best research evidence with clinical expertise and patient values (De Brún 2013, 3)." When integrating the evidence, it is necessary to consider all available data in an unbiased, transparent and scientifc manner. HTA is an example of evidence-based practice aiming to provide the best evidence to health care decision-makers. As briefy mentioned above, HTA is a systematic evaluation of short- and long term safety, clinical effects, and costeffectiveness of health technology and technology-related social, economic, and ethical issue in terms of health care resource use (Henshall et al. 1997; Potter et al. 2008; WHO 2015). Over the last decades, HTA has become more critical as evidence-based decision making has become more prominent in the health system. Specialised HTA bodies such as NICE have worked hard to enhance the methods of synthesising the evidence. Based on the evidence, the NICE produces guidance, including technology appraisal guidance (TA guidance) and advice for health, public health and social care practitioners (National Institute for Health and Care Excellence (NICE) n.d.). In evidence-based medicine, randomised controlled trials (RCTs) are regarded as the highest level of evidence because they are designed to be unbiased and have less risk of systematic bias (Burns et al. 2011). In the drug approval process, RCTs have been mainly required to show effcacy and safety compared to a control group. Whilst RCTs are the gold standard of evidence for establishing effcacy, it is sometimes diffcult to conduct RCTs. For example, the medicine treating rare disease has diffculty in conducting RCTs due to lack of appropriate trial design, proper measurements to complement the trial design, selection of the correct sample and ethical recruitment to participation (Augustine et al. 2013). Moreover, trial-based economic evaluation raises questions regarding generalisation, how representative is the trial of the patient population (Sculpher et al. 2004, 2). Health economic models require a range of data, not all of which are available from RCTs. It is being explored how RWD are able to supplement and enrich the evidence in the arena of HTA (Makady et al. 2017a). Consequently, HTA is reshaping to now be incorporating RWD as evidence, and critical questions are posed regarding the most appropriate ways to incorporate RWD as evidence in HTA. While the NICE has been already committed to embracing all available evidence to appraise innovative health technologies, they set out their ambitions to increase and extend the use of data, including RWD in the development and evaluation of NICE guidance. In February 2020, the NICE announced a statement of intent that a broader range of data will be utilised to address evidence gaps, including electronic health record data and RWD "looking at health and social care practice outside of trials, such as registries and clinical audits" (NICE 2020a, b). In November 2020, the NICE launched the consultation on reviewing their methods for health technology evaluation (NICE 2020b). In their proposal, the NICE explicitly addressed their preference for RCTs but also emphasised the role of the comprehensive evidence base, including non-RCTs and real-world evidence. NICE mentioned that "This type of evidence (real-world evidence) is an important topic, and NICE health technology evaluations are ambitious in ensuring that we make the most of this valuable resource" (Aggarwal et al. 2017; NICE 2020a).

#### **Opportunities Related to Using RWD in HTA**

RWD can be used in HTA in several ways. First, RWD can help to extrapolate the long-term survival curve after the trial period for economic evaluation. The NICE makes appraisal recommendations based on the cost-effectiveness or the estimated

costs of interventions in relation to expected health benefts over the lifetime of patients (NICE n.d.). The health beneft, usually survival rate in oncology, is then extrapolated from clinical trials, as they only show the health outcome over a limited time period. As the clinical evidence from trials is often limited, the extrapolation is likely to be biased. In that case, RWD can positively supplement the extrapolation of the survival rate by documenting some patients' characteristics and clinical practice over a longer observation period. For example, in the NICE technology appraisal of pembrolizumab with carboplatin and paclitaxel or nab-paclitaxel for untreated metastatic squamous non-small-cell lung cancer (NSCLC) (NICE TA600 iussed in 2019c), the manufacturer used RWD to extrapolate overall survival (OS) in its submission. In the appraisal, the OS at cancer stage 4 was not available due to the small number of surviving patients. Therefore, the company mentioned that:

It was considered necessary to assess longer-term OS for the trial chemotherapy arm using available population data for squamous NSCLC patients and compare to results from parametric ftting. (p: 141, company submission)

In order to assess the survival, the company analysed the real-world registry data, the US Surveillance, Epidemiology and End Results (SEER) database. The SEER database is an authoritative source for cancer statistics in the United States. It is considered to be the gold standard for data quality amongst cancer registries in the US and globally (Duggan et al. 2016, 4). As real-world and big registry data, the SEER registry is a large, population-based sample, which represents over onequarter of the US population as well as has long follow-up periods. The company compared OS beyond 12 months, from the projection by the parametric ftting approach of trial data and the SEER population data in order to examine the potential bias of using the SEER registry. As SEER data provided long-term data, it was able to observe that mortality risks within SEER gradually declined until around year 10 and then appeared to stabilise in the range of roughly a 10% risk per year. The company addressed the potential over-estimation of long-term mortality when using available clinical trial data for the best ftting parametric extrapolation model. Therefore, the company's model used SEER data in both intervention and comparator arms. Although the committee preferred the model, which did not use the SEER database in NICE TA600, because of the absence of second-line treatment in the database, and too optimistic assumptions in the model, it shows how registry data can be used to estimate the long-term survival in HTA.

The second way RWD is used in HTA is when it provides information regarding the comparators such as choice of relevant comparators and treatment effects. As new health technologies become more sophisticated, they can have several comparators, and as the number of potential comparators increases, it becomes less likely that there are head-to-head RCTs comparing their clinical effectiveness. It is unavoidable to synthesise the evidence using other RCTs or other types of research for data for the comparators. In the technology appraisal of cabozatinib for treating previously treated advanced renal cell carcinoma (NICE TA463 issued in 2017b), four comparators, namely axitinib, everolimus, nivolumab and best supportive care,

**Fig. 1** The evidence network for clinical outcome of TA463

were selected. However, the METEOR phase 3 trial of cabozatinib only included everolimus in the comparator arm since nivolumab was approved during its trial. Due to the lack of comparator data, an indirect comparison was conducted based on available RCTs (Fig. 1). Combining RWD and RCTs in evidence synthesis has the potential to support the fndings from RCTs, increase precision and enhance the decision-making process (Efthimiou et al. 2017).

Furthermore, in order to provide fast access to novel treatments, drug regulatory agencies like FDA and EMA accelerate approval based on the results of single-arm trials (Miller and Joffe 2011). The single-arm trial is the simplest trial design to obtain evidence of the effcacy of treatment among individuals with the targeted medical condition without randomisation and a control arm (Evans 2010, 1). Singlearm trials provide the outcome based on the hypothesis that they are also clinical trials designed to test the effcacy or safety of the intervention when there is no comparator. When the information of the comparator is not available in the same trial, the effcacy of comparators mostly comes from other data sources such as RWD or historical RCTs, which exploit the data of previously conducted RCTs (Zhang et al. 2010). NICE published an appraisal of axicabtagene ciloleucel (NICE TA559 issued in 2019a), in which an observational cohort study was used to provide data for the comparators. Axicabtagene ciloleucel is recommended for use within the Cancer Drugs Fund as an option for treating diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma after two or more systemic therapies. It is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, which is an innovative technology that modifed genetics. As this technology has been approved based on ZUMA-1, a single-arm study, comparator data needed to be taken from an alternative source, SCHOLAR-1. This database is a retrospective patient-level study with pooled data from two observational cohorts and follow-up of two large phase 3 RCTs. As the different patient characteristics in two data were likely to impact the clinical outcome, the company adjusted for patient performance status in order to exclude patient in SCHOLAR-1 who would not have been eligible for ZUMA-1. Even though it was noted that comparative-effectiveness results from single-arm studies were prone to bias, the committee concluded that using two single-arm studies was suitable and that it would consider the results of these studies in its decision making given the population characteristics (poor prognosis and vulnerability) and potential diffculties with randomisation. Another example is the guidance for venetoclax for treating chronic lymphocytic leukaemia (NICE TA487 issued in 2017d). The company set two comparators, including best supportive care and palliative care. Since, the clinical evidence for venetoclax came from one phase I (M12-175 trial) and two phase II (M13-982, M14-032) single-arm trials, the data for the comparator came from a different source. The company chose the UK CLL (chronic lymphocytic leukaemia) Forum registry data for survival outcome of palliative care in its submission. In the appraisal, the ERG comments that palliative care was not valid comparator as patients suitable for palliative care have the more advanced disease than those for whom ventoclax is an option. The committee concluded that best supportive care was a more appropriate comparator, and the evidence of palliative care was excluded in fnal decision-making. These examples show that RWD can help to fll the evidence gaps in some instances.

The third way RWD is used in HTA is when RWD supplements the information on a generalisation of evidence. Eichler et al. (2011) pointed out the limitation of RCTs with respect to the effcacy-effectiveness gap of results on the therapeutic effcacy of medicines from tightly controlled RCT settings and the effectiveness of medicine in the real-world. In the appraisal of afatinib for treating epidermal growth factor receptor mutation-positive locally advanced or metastatic non-small-cell lung cancer (NICE TA310 issued in 2014), the ERG highlighted that:

in view of the important uncertainties around the roles played by specifc mutations (singly or in combination) in determining clinical beneft from TKIs (tyrosine kinase inhibitors), it would be most valuable to have data from a long-term clinical registry of all UK patients treated with TKIs. Such a data source could provide a basis for research and audit to inform future assessments of TKIs in a UK specifc population.

This implies that RWD such as clinical registry can help generalise the result of RCTs, by including some of the uncertainties, complexity and non-linearity that characterise the effcacy of a treatment in a real-world setting. Also, RWD could give additional information, which is able to refect the current clinical practice. In appraisal of oncology medicine, the choice of comparators and subsequent treatments is important to populate the cost-effectiveness model as it impacts not only survival outcome but also the cost. Usually, the clinical guideline indicates the treatment line, which clearly informs which drugs are available in each treatment line. However, the treatments are not equally used in clinical practice. Some treatments can be more frequently used than others due to better compliance or clinical prognosis. Also, there is a lack of an established standard of care in the latter line of treatment. In these cases, RWD can provide a snapshot of drug usage. In the technology guidance for Ibrutinib for treating Waldenstrom's macroglobulinaemia (NICE TA491 issued in 2017e), the company demonstrated that the physician's choice is the most relevant comparator due to the lack of a standard of care in the clinical guideline. In order to try to delineate the composition of a physician's choice, a pan-European chart review was used. A medical chart review of Waldenstrom's macroglobulinaemia (WM) patients was used to generate data on epidemiologic/treatment patterns and effcacy outcomes for WM over a prolonged period of time, specifcally on subsequent lines of treatment (i.e. 3L and 4L) because WM patients tend to receive multiple lines of treatment during their lifetimes. RWD would help to maintain the validity and generalisability of the evidence by capturing the current clinical practice.

Lastly RWD is used in HTA to appraise the treatments for rare diseases or conditions, the so-called orphan medicines (EMA n.d.-c). Orphan medicines have diffculties gathering the information to populate the economic evaluation model due to the small patient population. It is challenging to conduct good quality of RCTs. In most cases, the assumption of the model is based on the clinical experts' opinions. RWD can give a wide range of information required in the cost-effectiveness analysis. It could be a treatment effect of the comparator or the resource use data such as the frequency of hospitalisation. For example, among 1930 people diagnosed with follicular lymphoma annually in the UK, only 52 double refractory patients are eligible for the idelalisib (NICE TA604 issued in 2019d). The manufacturer of idelalisib submitted DELTA, a single-arm trial, as primary clinical evidence along with a comparator cohort created from the registry data (HMRN; haematological malignancy research network). The committee acknowledged that it was likely that the HMRN was the only source of comparative data available for the UK population, and agreed to accept the estimate of progression-free survival from HMRN even though HMRN data had limitations. RWD also can supplement the information on choosing a survival model of rare cancer. The choice of survival distribution model has a huge impact on the estimate of survival. It is critical to know how hazard is changed over time. However, clinical trials of treatment for a rare cancer are less likely to provide the full picture of changing hazard due to the small size of the trial population. RWD such as registry which the long-term observed outcome is available, can help validate the model assumptions, including the choice of survival model. Likewise, in the appraisal of precision medicines, RWD might be able to fll the evidence gap created by diffculties in showing the statistical signifcance due to small populations.

To summarise, RWD is used in HTA for four main reasons:

#### **Challenges of Using RWD in HTA**

Despite the opportunities of using RWD in HTA mentioned in the previous sections, and the growing hype regarding big data, RWD is not a panacea for the evidence paucity in HTA. Indeed, we lack an understanding of the potential benefts, risks and limitations of using RWD. The frst important challenge to the use of RWD in HTA, and despite an increasing interest in RWD worldwide, is that there is no consensus on the precise contours of what constitutes RWD, and many different defnitions can be found (Makady et al. 2017b). This is one of the signifcant obstacles to using RWD in HTA. Indeed, while the fexible defnition of RWD allows representing different concepts or types of information, it also limits the potential role of RWD in HTA (Berger et al. 2017, 3). With the objective of strengthening the use of RWD in HTA, Makady and colleagues (2017a, b) proposed four broad categories to defne RWD: (1) data collected in a non-RCT setting, (2) data collected in a noninterventional/non-controlled setting, (3) data collected in a non-experimental setting, and/or (4) remainders. Among these four categories, 'data collected in a non-RCT setting' was the most commonly used defnition of RWD. These defnitions focus on the setting of collecting data. However, defnition of RWD by FDA highlights the way to collect the data. As an umbrella term, FDA defnes that RWD is the data relating to patient health status and/or the delivery of health care, which is routinely collected from a variety of sources (FDA 2018). In most cases, two defnitions get along well; however, some studies can be interpretated in different way by the choice of defnition. For example, A. Lloyd and colleagues on health state utility value is frequently used in the NICE appraisals. In this study, they interviewed the general public to get access to some of the societal preferences about treatment of metastatic breast cancer. The study was designed to include 100 people in order to try and represent the preference of the general public once in the study period (Lloyd et al. 2006). Whilst the health utility values were collected outside clinical data, data about health status was not routinely collected. Depending on which defnition is chosen, this study can be defned as either RWD or not. According to the defnition of FDA, the data from this study is not RWD as the data is collected once outside clinical trial. On the other hand, it can be RWD as the study is non-RCTs. Without any consistency in the defnition of RWD, the potential benefts of using RWD in HTA are weakened.

One of the main concerns of using RWD in the appraisal is the issue of confounding. In statistics, a confounding variable is a variable, other than the independent variables of interested that may affect the dependent variable. It can lead to erroneous conclusions about the relationship between the independent and dependent variables (McDonald 2009). RWD is prone to be manipulated and biased by residual confounding since it is hard to control all the confounding factors, including explicit factors as well as underlying factors, without randomisation (Grieve et al. 2016). It is inadequate to distinguish between the effect of the treatment, a placebo effect, and the effect of natural history (Evans 2010, 2). For example, patient's health status such as cancer stage and underlying health condition are highly likely to infuence clinical outcomes. As the response rate to second-line treatment differs from frst-line treatment, it is critical to understand the patient characteristics for precise assessment. The appraisal of Ibrutinib for treating relapsed or refractory mantle cell lymphoma (NICE TA502 issued in 2018) included the HMRN audit data for comparator data since the main clinical evidence was a single-arm trial. The HMRN data consisted of evidence from a unifed clinical network operating across 14 hospitals in Northern England (Yorkshire). The company used data on the beneft of the comparator (R-chemo; rituximab + chemotherapy) from the HMRN audit of 118 patients with mantle cell lymphoma that had been treated with frst-line treatment. However, the ERG had a concern about the evidence that the HMRN audit did not specifcally relate to patients with relapsed or refractory mantle cell lymphoma. The ERG also highlighted that:

It is also noteworthy that since this is not a trial, differences in outcomes between patients receiving R-chemo and those receiving chemotherapy alone may be subject to confounding. The HR (hazard ratio) reported in the audit includes adjustments only for age and sex. (ERG document, 67)

Another set of challenges to the use of RWD in HTA are the unanchored comparisons. Unanchored treatment comparison result from the network of studies being disconnected or single-arm studies (Phillippo et al. 2016). When treatment outcomes come from single-arm studies such as phase 1/2 clinical studies or observational studies, the comparison is unanchored. Unanchored comparison is highly likely to misguide the result as it is confounded by the differences between the two populations. Since the number of technologies in which single-arm trials are the primary clinical evidence has increased for drug approval and reimbursement assessment, the population adjustment methods such as matching adjusted indirect comparison (MAIC) and simulated treatment comparison (STC) were highlighted (Phillippo et al. 2016). The methods assume to take account of all effect modifers and prognostic factors and control them. If the assumption fails, it will lead to a biased conclusion. In the appraisal of cemiplimab for treating metastatic or locally advanced cutaneous squamous cell carcinoma (NICE TA592 issued in 2019b), only two single-arm trials of cemiplimab were available. The comparator data were very limited. Therefore, a non-UK retrospective chart review study was included in company's base case. The study evaluated the outcome of patient who took systemic therapy reviewing patient hospital records (Jarkowski et al. 2016). The company tried to use STC and MAIC for indirect treatment comparison. However, it concluded to choose the naïve comparison due to the uncertainty around missing unmeasured prognostic factors and the validity issue of survival curve, which comes from signifcantly reduced effective sample size (65% of the original sample size). The committee noted that it was not methodologically recommended because outcomes were likely to be confounded by differences between the populations of the studies (Fig. 2).

Besides, when incorporating RWD into HTA, different approaches should be applied due to the variation of the contents in RWD. As RWD include the diverse type of data, each dataset has different attributes. It means that all RWD does not

**Fig. 2** Indirect treatment comparison of TA592

necessarily provide the same information. For example, Korean healthcare claims data collected by Health Insurance Review and Assessment Service (HIRA) are national-wide data of over 50 million people (Kim et al. 2020). The database includes the information of age, gender, diagnosis, and utility volume of medical intervention (diKhi n.d.). Although the data have useful information in terms of resource use, the clinical data of patients is not available. Inevitably, clinical research such as survival analysis using the claims data sets the operational defnition by an individual researcher. It is a strong assumption that the effect modifers are adjusted by variables defned operationally. Eventually, it could bring uncertainty into the appraisal. Therefore, several approaches of incorporating RWD by characteristics should be discussed in order to use RWD in the appraisals without distortion.

Moreover, the quality of RWD questions the reliability of the outcome as evidence. To evaluate the quality of RWD, we need to know precisely how the data has been collected and how it has been used in HTA. Due to the characteristics of observational studies, RWD has limitations in the quantity and quality of information. In the aforementioned venetoclax technology appraisal guidance (NICE TA487), the quality of data is the issue to include as the key evidence for decision making. The target population for the decision problem was stratifed by 17p deletion/TP53 mutation group and failure of B-cell receptor pathway inhibitor (BCRi). Therefore, information on chromosomal abnormality and disease staging is essential. While the registry data have information on time from BCRi treatment failure to death, staging information is not complete. The lack of staging information introduced the signifcant mismatch between comparators group and intervention group. In company submission, it reported that:

As patients without the deletion have a better prognosis than patients with the deletion, and given the fact that UK CLL forum data were not stratifed by del(17p)/TP53 mutation, this may contribute to overestimating the survival of palliative care which appears better than BSC on the long term. (CS, 145)

Another challenge is that of generalisation. RCTs provide effcacy and safety data with relatively high internal validity, but their results may not be readily generalisable to a broader, more heterogeneous population (Makady et al. 2017b). RWD is expected to provide more information to refect the clinical practice. Notwithstanding the expectation for improving the external validity of RCTs, RWD has limitations in terms of representativeness of the population. It is highly questionable whether all RWD fully capture a holistic picture of reality. For example, the GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib) study predominantly includes the Asian population to represent the general UK population in the evaluation of sorafenib for treating advanced hepatocellular carcinoma (NICE TA474 issued in 2017c). Since the treatment effect of sorafenib differed by global regions, it is questionable to use GIDEON data to predict the treatment effect in the UK population. Another example is ceritinib for previously treated anaplastic lymphoma kinase positive nonsmall-cell lung cancer (NICE TA395 issued in 2016). The manufacturer of certinib submitted additional real-world evidence (Gainor et al. 2015), which were medical records reviewed to determine OS and PFS (progression free survival) in patients who were treated with sequential crizotinib and ceritinib between 2008 and 2014. The ERG criticised that this retrospective non-randomised study did not clearly show how similar these participants are to those in the ceritinib studies. In the appraisal of nivolumab for treating relapsed or refractory classical Hodgkin lymphoma (NICE TA462 issued in 2017a), the generalisability of RWD into UK practice was questioned. The company used the Cheah et al. study for evidence on the clinical outcome estimates of comparator, OS and PFS. The data used in the study came from the American hospital database (Cheah et al. 2016). The committee considered whether the population and composition of treatments in the Cheah et al. study refected clinical practice in the UK. It considered that the study population partially matched the population of interest. Furthermore, it deemed that the study may not refect UK practice, notably regarding subsequent treatment rates of allogeneic stem cell transplant. Even if RWD is collected from routine practice, the context of collecting data could be different by country or region. The difference is likely to introduce a bias in representativeness. As the study type such as observational study does not guarantee the generalisability of the evidence, the clinical and social context should be carefully considered when using RWD.

To summarise, these are some of the key challenges related to the use of RWD in HTA:

• RWD is not necessarily generalisable as it does not always refect whole patients or up-to-date practices.

#### **What Is Next: Do We Want RDW in HTA Be the Cynosure of All Eyes?**

The hope for advances in health care through the use of big data, and more specifcally RWD, is getting stronger. The pharmaceutical industry has been using RWD for decades to conduct post-market research, inform its decision-making, respond to requests from external stakeholders, and improve market positioning (Mckinsey&Company 2020). The advances in digital and advanced analytics allow RWD to be more employed in the health care ecosystems. The quality of RWD itself is also steadily enhanced as the research using RWD has increased drastically in the last decade (Booth et al. 2019; Evans et al. 2021). Growing interests in RWD clearly create more and more opportunities to generate new evidence from drug development to post-approval studies (Rudrapatna and Butte 2020). In the era of digitalised RWD, the progression in the use of RWD makes the public hold great promise in the ability of it to transform the entire health care system (Berger et al. 2015). The FDA approval of palbociclib shows that RWD can take a central role in the regulatory process. While the FDA accepted RWD in limited use, such as informing the prognosis or natural history of the disease, it was the frst approval based on RWD in oncology. The FDA shows confdence that leveraging data such as RWD using modern techniques will unlock new insight and provide state-of-the-art tools to enhance public health. Such potentialities have inundated public discourses with optimistic narratives of cutting-edge scientifc innovation and hopes for a complete cure for devastated cancer patients, praising modern science progress and putting forward opportunities for accessing innovative technology at the earliest possible time. However, it is still questioned that RWD can replace the state of RCTs (Ramagopalan et al. 2020). Without appropriate consideration of using RWD, the regulatory body has to take much greater level of uncertainty than the beneft of accelerating patient access to treatment.

In HTA process, diverse types of data such as RWD are already incorporated into evidence. As the interest in RWD is growing, the use of RWD in treatment effects receive more attention. But as discussed above, using RWD in HTA is intricate. Indeed, we have seen that there are many uncertainties related to what RWD can actually bring to HTA in particular, and health care systems in general. RWD are complex, diffcult to grasp and to defne, and it is also diffcult to evaluate their quality. In addition, RWD has limitations to assess the relative treatment effects due to confounders and dysconnectivity. Therefore, it is crucial to think to what extent RWD can be incorporated in HTA, in which part of evidence synthesis it can actually contribute, and what are its limitations. Diverse defnitions and data formations allow RWD to be used widely, but also present challenges of consistency, quality, generalisation, and purpose. It is important to critically scrutinise RWD and the hope it might convey, and carefully examine the quality of RWD as a source of evidence. RWD is not, and should not be considered as, an easy fx to the complex question of how to assess health technologies. Arguably, a more systematic approach to RWD could help enhance its robustness when used in HTA. In this chapter, I questioned the idea of RWD as a corrective measure, by critiquing the effectiveness of RWD utilisation in HTA. By critically questioning the drawbacks, limitations and challenges of using RWD in HTA, we can expect to have a more balanced and responsible use of RWD in the future, that does not overpromise results that are unachievable in a context of high uncertainties and complexity. It would also help form more realistic expectations of what RWD can and cannot bring to HTA and health care in general. And fundamentally, before expanding the use of RWD in technology assessment, we should think about exactly what are RWD, to what purpose we want to use them, and how we can meaningfully evaluate their quality. From that line of critical questions, we would be able to think more realistically about the practical benefts and challenges to incorporate these data into evidence synthesis, and to what extent RWD actually contributes to the evaluation of new technology.

#### **References**

tuximab vedotin have poor outcomes. *Annals of Oncology* 27 (7): 1317–1323. https://doi. org/10.1093/annonc/mdw169.

———. 2020a. *21st Century Cures Act*. https://www.fda.gov/regulatory-information/selectedamendments-fdc-act/21st-century-cures-act. Accessed 14 Mar 2021.

experience and a review of the literature. *American Journal of Clinical Oncology: Cancer Clinical Trials* 39 (6): 545–548. https://doi.org/10.1097/COC.0000000000000088.

**Open Access** This chapter is licensed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

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## **Just Caring: Precision Health vs. Ethical Ambiguity: Can we Afford the Ethical and Economic Costs?**

**Leonard M. Fleck**

It is easy to see "precision medicine" and "precision health" complementing one another.  At the same time, we would rationally prefer to take advantage of whatever medicine might offer us that would prevent the emergence of that cancer in the frst place or treat it in its earliest stages, which is the goal of precision health. However, precision medicine and precision health can just as easily and realistically be seen as competing for resources with one another, as we will explain below.

#### **Just Caring: Cancer, Targeted Therapies, and Cost Control**

The fundamental ethical and economic problem with health care today is that we have limited resources (money) to meet virtually unlimited health care needs. From an ethical perspective, this is what I refer to as the "Just Caring" problem (Fleck 2009). What we would identify as health care needs have multiplied exponentially as a result of very costly, life-prolonging medical technologies that have been developed over the past ffty years, targeted cancer therapies being one pre-eminent example.1 This has strained social budgets in both the United States and the

L. M. Fleck (\*)

<sup>1</sup>More than 90 targeted cancer therapies or immunotherapies have received approval from the Food and Drug Administration (FDA). The median list price for a course of treatment or a year of treat-

Center for Ethics, College of Human Medicine, Michigan State University, East Lansing, MI, USA e-mail<EMAIL_ADDRESS>
European Union, as much recent research has demonstrated (Vokinger et al. 2020; Wilking et al. 2017; Hofmarcher et al. 2020; Peppercorn 2017; Yabroff et al. 2019; Bender 2018; Leopold et al. 2018).2 Relieving that strain means controlling health care costs by controlling access to these very expensive life-prolonging technologies, especially in clinical circumstances where the clinical beneft is very marginal relative to costs. This is health care rationing that has ethically substantial consequences. Hence, the ethical challenge is to determine how such limitations can be justly decided. Having said that, we might not see very easily how this challenge has anything to do with pursuing precision health at the expense of precision medicine and unlimited access to these targeted cancer therapies.

Prevention is supposed to be quite inexpensive: do not smoke, consume alcohol in moderation, use sunscreen, get a reasonable amount of exercise, eat a healthy diet. However, in spite of adhering with saintly devotion to these health directives, some individuals will still fnd themselves faced with a cancer diagnosis. This could be for genetic reasons, or environmental reasons, or just the random breakdown of cellular machinery.  The projections in the United States for 2020 are that 1.8 million individuals will be diagnosed with cancer; cancer deaths will be a little over 600,000 (National Cancer Institute 2020). Comparable fgures for Europe are 3.9 million cancer diagnoses in 2018 and 1.9 million deaths (Ferlay et al. 2018). These cancer deaths are the product of metastatic disease. Metastatic cancer is a terminal condition. The targeted cancer therapies and immunotherapies that are at the leading edge of cancer research are all used to treat metastatic disease. However, none of them can justifably claim to yield a cure. In the vast majority of circumstances these interventions yield marginal gains in life expectancy measurable in months, though for a small fraction of patients there will be extra years of life. From a social point of view, it is unclear that this represents either a wise or just use of social resources.

ment is now \$150,000 (Manz et al. 2019). At the upper end of these therapies is CAR T-cell therapy, a form of immunotherapy that has a front-end cost of \$475,000 with \$200,000 in addition (or more) to manage the predictable complex side effects of this therapy (cytokine release syndrome or various neurotoxicities).

<sup>2</sup>The primary messages from these articles would be the following: (1) The very high prices of these drugs do not refect the very marginal clinical value produced in most cases; (2) The projected aggregated social costs of these targeted therapies is not sustainable; (3) If nothing is done to control these escalating prices and costs, both social equity and solidarity will be unjustly compromised. The following passage (Bach 2019) summarizes nicely the problem: "Introductory prices of cancer drugs have risen more than 100-fold since 1965. The trend is unabating. Prices were up last year and again this year. Prices are increasing not only for new drugs as they frst enter the market, but also for drugs already in use, often in cases where there is no suggestion that the treatment is any better than originally thought." To illustrate this last point, imatinib [Gleevec®] was introduced in 2002 at a price of \$36,000 per year. In 2017 the price had risen to \$146,000. To be sure, unlike the vast majority of targeted cancer therapies, imatinib has been very benefcial for the vast majority of patients needing this drug. Still, that does not justify that price increase over the years.

#### **Cancer: Finding the First Cell/Preventing Future Cells**

If cancer cannot be completely prevented by good health behavior, and if metastatic disease is essentially incurable, then the next best preventive strategy would be to identify and attack cancer at its earliest possible stages. This is the perspective embraced by Dr. Azra Raza in her recent book, *The First Cell* (Raza 2019). Dr. Raza is an oncologist who has been in practice for more than thirty years. Her cancer research has been focused on myelodysplastic syndromes [MDS], a pre-leukemic condition. Her husband's research was in the same area, though, ironically, he died of acute myelogenous leukemia [AML], which happens in about 33% of patients with MDS. The basic thesis of her book is that we are wasting tens of billions of dollars every year on cancer therapies that are extraordinarily costly and that yield only marginal gains in life expectancy and maximal increases in suffering (physiological, psychological, fnancial and social). She believes that these same resources should be redirected to destroying cancer in its earliest stages, those "frst cells," through multiple preventive strategies. On one level, this is an eminently reasonable position for which she advocates. On another level, this is an ethically radical proposal, given that she wishes to redirect tens of billions of dollars from aggressive life-prolonging care to a preventive strategy that would reduce the need for such aggressive life-prolonging care. This generates the key questions we will address in this chapter: Is this strategy ultimately ethically defensible? Is this a strategy that ought to be embraced by a "just" and "caring" society, given that the consequence of embracing such a strategy would be the "premature" death of hundreds of thousands of metastatic cancer patients each year, most of whom would be denied extra months of life?3

A frst response to this ethics problem might be that it represents a false choice. We should be doing whatever is possible to prevent cancer, or to attack it in its earliest stages, but if those efforts fail, then we certainly ought to pursue therapeutic life-prolonging options for those unfortunate patients who are faced with metastatic disease, even if those efforts might never be curative. Why would Raza not endorse that view? Here is one scenario Raza has in mind that would suggest a response to this question. She suggests that "everyone from birth to death is regularly screened for the frst appearance of cancer cells in the body." Once those cancer cells had been identifed "protein markers would be identifed, providing a zip code for the cancer cells. A tube of blood from the individuals would be obtained, and T cells would be isolated, activated, and armed with the address for the cancer based upon the unique protein bar code and the RNA signature it expressed" (Raza 2019, 238).

<sup>3</sup>To be clear, I am using the term "premature" to characterize a death when we have the medical technology that would provide additional length of life for a patient facing an imminent death but that technology is denied to the patient for whatever reason. Relative to that future point in time when a patient's death would occur as a result of the life-prolonging technology, their death now would be "premature."  That is, I am not saying in any specifc circumstances whether that "premature" death is right or wrong.

This scenario has something of a futuristic quality to it.4 However, what we do have in reality is a new "liquid biopsy" test introduced by a company named GRAIL (Oxnard 2019). This test can detect twenty different cancers in their earliest stages by examining cell-free DNA in the blood. More recent news reports suggest that the test might be capable of detecting ffty different cancers as well as the source of that cancer in 89% of cases. To be clear, this is not a perfect test. Dana-Farber reports that the test has a sensitivity of 32% for a Stage I cancer, 76% for Stage II, 85% for Stage III, and 93% for Stage IV (Oxnard 2019). The test is far from ready for clinical deployment. Consequently, no price has been announced for the test. However, another company offers a liquid biopsy test for eight cancers, which is priced at \$500. This fgure is likely too low for the GRAIL test. Recall in the quotation above Dr. Raza imagining that individuals would be "regularly screened" with such a test. What might that mean?

 Given that everyone has a 40% lifetime risk of a cancer diagnosis, it would not be unreasonable to have this screening test on an annual basis. If the test is only offered to adults over twenty-one, that would be 198 million individuals in the United States. At a cost of \$500 per test, the potential cost to "society" would be \$99 billion per year.5 That fgure brings into sharp focus Dr. Raza's imperative that funding this preventive effort ought to come from what she regards as wasteful and marginally effective spending on these targeted cancer therapies for metastatic disease. This, in turn, raises a number of ethics issues which must be addressed.6

We may start by noting that Dr. Raza deserves to be ethically commended for requiring for this preventive effort come from *within* current cancer spending, as

<sup>4</sup>The idea of "screening from birth to death" has a very therapeutic aura around it, but there are some ethical dark spots in that aura. Most cancers arise spontaneously as a result of environmental factors, such as melanoma. Some cancers are hereditary. If we did Whole Genome Sequencing [WGS] of infants at birth, we would identify cancers to which individuals were genetically susceptible (likely later in life). These hereditary cancers would have some probability factor attached to them. If someone has the BRCA1 gene associated with breast cancer, their lifetime risk could be anywhere from 40% to 85%. Children would not be told that as children. However, they would be told that as young adults, though that overrides their putative right "not to know." However, once they know, if they have a certain psychological disposition, they will want frequent testing for any sign of that early cancer. That has societal cost consequences as well as harmful psychological consequences for these patients. In addition, identifying a hereditary cancer through WGS has implications for the vulnerability of relatives, who or may not want that information and related anxieties.

<sup>5</sup>The population of the European Union (still counting the UK) is about 520 million, of which 334 million would be adults over age 21. For that population the hypothetical cost of annual testing with the Grail liquid biopsy would be \$167 billion per year.

<sup>6</sup>To avoid confusion, Dr. Raza herself says nothing about the Grail test. She is, however, an advocate for a radical re-distribution of cancer treatment resources toward prevention. It is only for the sake of discussion and analysis in this chapter that I am attributing to her an endorsement of what I will call the Grail testing protocol as one possible incarnation of that for which she is a clear advocate.

opposed to taking that money from heart disease, or resources dedicated to treating addictions or mental illness, or some other disease category.  We can readily imagine a reasonable argument for saying that it would be unjust to take resources from some other area of health care need where the care provided there was of high-value in order to purchase in its place low-value cancer care. For now, we will simply pass over this issue and focus on ethics issues that arise within the context established by Dr. Raza's proposal.

#### **Trading off Identifed Lives and Statistical Lives: Ethical Issues**

Perhaps the most salient ethical concern would pertain to the implied tradeoff between the *identifed* lives of patients with metastatic cancer and the *statistical* lives that we would hope to save through annual preventive liquid biopsies (Daniels, 2012). The defning feature of statistical lives is that they are nameless and faceless. This is typically true both before the fact and after the fact when considering preventive measures. If we install guardrails at dangerous curves on state highways, we might save ffty lives per year. One year later we might see a decline in fatal slides off the highway of forty-fve lives. We would have no idea who those forty-fve individuals might have been whose lives were saved, or if the guardrails were necessarily what made that difference. By way of contrast, we know with perfect clarity the identities of individuals with metastatic cancer whose lives were extended (if only for months) as a consequence of their having received one of these targeted cancer therapies. Grail's liquid biopsy may correctly identify individuals with a very early stage cancer (no clinically evident symptoms). That cancer may eventually manifest itself symptomatically, at which point it will most likely be effectively treated (minimal likelihood of recurrence). This is why we currently have 17 million cancer survivors in the United States today (Simon 2019). Projections put that survival fgure at 21.7 million by 2029. This projection would not include any assumption about the successful clinical deployment of Grail's liquid biopsy.

 Why does this matter? It matters because Grail cannot claim that its liquid biopsy would have saved all these lives. Most of these lives would have been saved by current cancer therapies provided at the appearance of clinical symptoms. This point is important for judging whether Grail's liquid biopsy represents high-value care. If Grail's liquid biopsy reduced the number of metastatic cancer deaths by 70%, that would constitute signifcant evidence for thinking of the test as representing high-value care. However, that will still leave us with both ethical and economic concerns.

Keep in mind that we are assessing Dr. Raza's proposal (as I have constructed it). The hypothetical under discussion says that we would reduce the number of metastatic cancer deaths in the United States by 400,000 annually. That would still leave 200,000 individuals with a terminal metastatic condition. Dr. Raza would provide those individuals with comfort care, but they would be denied these extraordinarily expensive targeted cancer therapies that for most of them would only yield extra months of life. These are clearly *identifed* individuals, most of whom might desperately wish to gain whatever additional life might be possible with access to these targeted therapies.  From a purely rational, utilitarian maximization perspective, this looks like an eminently reasonable tradeoff. However, those 400,000 individuals are *statistical* lives.

It may sound odd to say that these are statistical lives, but the fact is that we have no ability to identify who those 400,000 individuals might be. Consequently, they have something of an abstract, ghostly status. This is certainly true from a psychological perspective, compared to those patients with metastatic cancer who want to live longer. To clarify, 1.8 million individuals in the United States are diagnosed with cancer each year. Some of them are diagnosed with metastatic disease. However, the vast majority of those cancer diagnoses will be treated with current therapies. Some portion of those individuals, despite treatment with curative intent, will go on to have metastatic disease. Most of those metastatic cases will not be predictable at the time of initial treatment, even though that treatment might have been early in the disease process. Others might have gone on to have metastatic disease, except that they were treated early and effectively. At this point in time these are all statistical lives.

Eventually, however, in this hypothetical example we end up with 200,000 identifable individuals with metastatic disease. Is it just and justifed that we would deny these individuals our very expensive targeted therapies, as proposed by Dr. Raza, because that \$99 billion was allocated to the preventive effort which (by hypothesis) saved 400,000 lives that otherwise would have died prematurely? That brings us back to the question regarding the ethical weight that ought to be attached to statistical lives versus identifable lives when we are allocating resources for purposes of saving/prolonging lives.

Should identifable lives (patients with metastatic cancer) have more moral weight (greater just claims to health care resources) than statistical lives (patients at risk of a premature death from cancer)? Brock (2015) would answer this question negatively.7 He considers and rejects a number of arguments in support of the

<sup>7</sup>See also Paul Menzel (2012). He will defend a position similar to Brock's view. Menzel writes, "If any of us loses our life from lack of adequate prevention, surely, it seems, we lose something *just as valuable* as we do if we lose our life from lack of effective treatment" (2012, 194). This too seems to support Dr. Raza's view. More broadly, these same issues will arise in the context of environmental debates. How much ethical weight should be given to the rights and interests of future generations when we (in the present) need to assess a range of more or less costly options for addressing any number of environmental challenges?

opposite conclusion. I will consider his arguments in the specifc context of this chapter. He frst calls attention to the Rule of Rescue. The Rule of Rescue might seem to require prolonging the lives of the identifable metastatic cancer patients, in part because we have at hand the capacity to do so readily with these targeted cancer therapies. By way of contrast, 99% of the liquid biopsies performed annually would have saved no one since the results would be negative for any cancer cells. However, the typical application of the Rule of Rescue involves huge societal expense to rescue trapped miners deep underground (or others in various dire circumstances, such as the cave rescue in Thailand).8 It would be tragic if we (society) were aware of these situations but had no ability at all to prevent that loss of life. However, it would be unconscionable if we had the ability to intervene but simply ignored the plight of those desperate individuals and allowed them to die. This is the moral logic that says we must do what we can to prolong the lives of those metastatic cancer patients.

Notice that I did correctly describe this latter situation by saying that our goal would be to *prolong, not save,* the lives of these patients. In the typical successful rescue situation individuals have their lives saved; they have an indefnite life expectancy, as in the Thai cave rescue story. That is precisely what is not true with regard to our metastatic cancer patients. Consequently, the moral logic embedded in the Rule of Rescue does not apply in this situation. Perhaps a minor correction is in order when I assert that it is "not true" that these metastatic cancer patients can be saved. In fact, a very small percentage of these patients, sometimes referred to as "super responders", will gain extra years of life from one of these targeted cancer therapies. They may well die of something other than their cancer ten or more years from now.9 What should we conclude from this? Does this mean that the Rule of Rescue does apply, even though the rescue effort in the vast majority of cases will be unsuccessful? Does this mean that these rescued identifable lives outweigh the *merely* statistical lives we would hope to save with our liquid biopsy intervention?

This last question brings us to a second consideration by Brock that would favor allocating life-prolonging resources toward identifed lives over statistical lives, namely, the uncertainty associated with preventive efforts.10 We might invest \$100 million in an anti-smoking campaign, hoping to save 100,000 lives from lung cancer. The campaign might fail abysmally because smoking is addictive and woven in complex ways into the lives of individuals. Lots of uncertainty seems integral to many preventive efforts. By way of contrast, we are certain to get some beneft in

<sup>8</sup>See Cheung and Wong (2018), The full story of Thailand's extraordinary cave rescue. BBC News. 9There is ongoing research aimed at determining why these individuals are so fortunate (Cavallo 2018). One possible explanation is that the evolution of their cancer is genetically stable. In other words, as the cancer proliferates, and millions of daughter cells are generated, the genetic driver of that cancer remains the same in all those daughter cells.  This is an unusual circumstance. The enormously more common scenario involves genetic heterogeneity among the metastatic cancer cells, which is the primary reason why no single targeted cancer therapy can defeat metastasized cancer (Turajlic et al. 2019).

<sup>10</sup>To be clear, Brock's ultimate conclusion is that identifed lives are not intrinsically more ethically valuable (and worthy of costly life-prolonging resources) than statistical lives.

the form of additional life when we provide various targeted therapies to individuals with metastatic lung cancer.11 However, making an analogy with an anti-smoking campaign would be misleading in this case.  We are uncertain which particular lives will have been saved, but those statistical lives are not *merely* statistical lives. Those are real lives (Menzel 2012) that should have substantial moral weight in allocating life-saving resources, as Dr. Raza would insist. In addition, I must emphasize again that in almost all cases no lives are *saved* among the metastatic cancer patients. Only a marginal gain in life expectancy is achieved compared to the 400,000 lives correctly described as being saved.

A third ethically relevant consideration that comes into play is *urgency of need*. Metastatic cancer patients who have failed several therapeutic regimens surely have an urgent need for one of these targeted cancer therapies since they have exhausted all other therapeutic possibilities. In contrast, those individuals who would be discovered to have a relatively early stage cancer through the liquid biopsy would have a substantially less urgent need because they would have many other options for treating their cancer. The conclusion we are supposed to accept, contrary to Dr. Raza, is that these metastatic cancer patients have a stronger just claim to costly targeted therapies than the statistically possible cancer patients have a claim to an annual liquid biopsy.

Daniels (2015) offers a supporting argument to this last conclusion. He refers to this as the "concentration of risk" argument. He asks us to imagine Alice, who has a life-threatening infectious disease certain to kill her unless she receives fve lifesaving tablets of some drug. Five other women have been exposed to Alice. There are only these fve tablets. If each of these women receive one preventive tablet, their lives are certain to be saved. If all the tablets are given to Alice, then one of these fve women will end up dying as a result of the exposure. It appears we have one death either way. Should we just fip a coin? Daniels opposes that idea and asserts that 100% of the risk of death is concentrated in Alice, whereas only a 20% risk of death is associated with each of the fve women. Therefore, Alice has the strongest just claim to the fve tablets. Again, there is a dis-analogy between the Alice example and our 200,000 metastatic cancer patients.

<sup>11</sup>A critical assumption in this sentence is that the targeted therapy provided to these lung cancer patients is correctly matched to the mutation that is the driver of that cancer. However, that requires reliance upon an appropriate biomarker test to make that connection. However, as Seo (2017) has pointed out the validity of most biomarkers test is very uncertain. She writes, "The lack of evidentiary standards is evaluating the clinical effectiveness of a biomarker test is one of the main limiting factors in relation to the integration of a biomarker test into clinical use. Clear evidence requirements should be formulated. No consensus currently exists on methodological approaches in measuring the clinical effectiveness of cancer biomarkers for targeted therapies" (32). We need to add that, as things are now, a valid biomarker may still result in the use of a targeted therapy with uncertain effectiveness at the level of the individual patient. This uncertainty complicates both ethical and economic judgment.

 We might be tempted to call attention to that small cadre of super-responders among those 200,000 metastatic patients. Those individuals can be correctly regarded as being Alice-like; their lives will be saved. However, returning to Dr. Raza's main point, if saving the Alice-like super responders required re-allocating that \$99 billion to these targeted cancer therapies for metastatic cancer patients, then we would be sacrifcing the 400,000 Alice-like lives that (by hypothesis) would be saved by investing in population-wide screening with our liquid biopsy for the sake of that small cadre of super responders. Those may well be statistical lives, but they are not *merely* statistical lives. They have as much moral worth as the lives of any of those metastatic cancer patients.

Brock next calls our attention to the "aggregation" problem as the basis for (in our case) preferring to allocate resources to the metastatic cancer patients as opposed to screening with the liquid biopsy for preventive purposes. In brief, the aggregation problem involves giving very high priority to a small number of patients who will derive very substantial benefts over a very large number of other patients who will only receive a small beneft with some limited budget. For example, we can spend \$5 million to save ten patients by implanting in each of them an artifcial heart (without which they would all have died in six months), or we can use that same money to stabilize 10,000 sprained ankles. We will stipulate that treating the sprained ankles will yield many times the health benefts (by whatever measure) than saving the lives of those ten patients needing the artifcial heart. Still, our fundamental moral intuition would be that such a trade-off would be unconscionable. Once again, however, it can be argued that there is a dis-analogy here. It is a relatively small beneft that accrues to our metastatic cancer patients and an enormously greater beneft that would be denied to those 400,000 individuals whose cancer will go undetected without the liquid biopsy and result in their premature deaths. We may not know the identity of those individuals, either before the fact or after the fact. Nevertheless, that fact does not alter the moral equation.

Finally, there is the argument that the "medically least well off" ought to have priority for limited life-prolonging resources over those who are relatively healthy but at risk for serious illness. When stated in this very abstract form, this argument would strike many as being eminently reasonable. However, specifcation regarding patients who are among the medically least well off will yield results that are far from being either fair or reasonable. The assumption has to be that the medically least well off have some capacity for signifcant beneft if society makes available the necessary resources. Patients in a persistent vegetative state or in the late stages of dementias are clearly among the medically least well off. Just as clearly, they are incapable of signifcant beneft beyond bare life maintenance at costs in excess of \$100,000 per year. Daniels (1985) has argued that what health care justice requires is protecting fair access for all to the normal opportunity range of a society. These are patients who are entirely outside that opportunity range. They have no capacity to participate in life.

Our metastatic cancer patients are also rightly thought to be among the medically least well off. Most of them would still have some access to the opportunity range of a society, though that access will be limited. They are not like patients with very advanced dementia. In most cases they will have had access to multiple cancer therapies that had already provided them with extra years of life that otherwise would have been denied them. In that respect they have not been unjustly ignored. Their just claims to needed health care have been met. If these targeted cancer therapies yielded, say, fve extra years of life on average at a cost of \$150,000 per life-year gained, we would have a much more diffcult problem in determining whether that \$99 billion should not be spent on them or should be spent instead on cancer screening with the liquid biopsy. However, given the factual scenario that is current cancer care, as Dr. Raza would attest, the benefts for the vast majority of these patients are marginal. If we were to forbid allocating that \$99 billion to liquid biopsy screening, we would be sustaining an annual population of 600,000 or more individuals with metastatic cancer who would be for that last year of life among the medically least well off, instead of reducing that population to 200,000 per year by using the liquid biopsy screening technology. On the face of it, that outcome would not seem to be either reasonable or just, whether we were egalitarians or utilitarians or prioritarians in our understanding of health care justice.

#### **Can We Just Abandon Metastatic Cancer Patients to Save Money?**

Up to this point I have presented what I would regard as the most compelling arguments in support of Dr. Raza's position. However, there are ethically problematic features of her position that we now need to consider. In spite of all the arguments above, it will still feel ethically awkward to deny social funding for targeted cancer therapies or immunotherapies for those 200,000 (hypothetical) metastatic cancer patients who would not have beneftted from having annual access to our liquid biopsy screening protocol (Verweij 2015).12 Though I have emphasized marginal gains in life expectancy along with a small cadre of super responders who would gain multiple extra years of life, that is ultimately an inaccurate characterization. There will be a continuum of gains in life expectancy. The most unfortunate patients

<sup>12</sup>Verweij appeals to the value of solidarity as the legitimate ethical basis for supporting the rule of rescue: "Diverting resources from rescue to prevention might be rational if the sole aim is to save as many lives as possible, but it would in fact negate the importance of the fact that people are standing together, sharing hope and fear, and supporting each other in the face of – and the fght against – disaster" (2015, 145). Having said this, Verweij emphasizes that this comment applies to our mining rescue and cave rescue cases. In health care, when we must live with limited budgets, Verweij emphasizes considerations of fairness and justice must dictate the allocation of resources between treatment and prevention.

may suffer harm; others will gain nothing; others will gain a few months; still others will almost gain a year; and more fortunate patients will gain an extra year or two. This makes it a lot harder to endorse with ethical equanimity redistributing all our life-prolonging cancer resources to the preventive liquid biopsy strategy. A simple solution would be to just pour more money into cancer treatment. However, that means we would fail to take seriously the "Just Caring" problem. There are limits to what any society can afford to spend on meeting health care needs, given multiple other legitimate and compelling non-health care social needs. In addition, I am unaware of any arguments that would justify spending unlimited sums of money to meet the needs of cancer patients, as opposed to patients with any of a number of other life-threatening medical conditions.

Cancer is not ethically special. Dr. Raza is clearly correct in calling attention to the vast sums of money we currently spend on low-value care for metastatic cancer patients. The problem, of course, as things are now, is that we only know after the fact that what we provided was low-value care because we spent \$50,000 for a patient who gained only three extra months of life. I will put aside for the moment issues related to efforts at identifying who such patients might be before the fact through the use of predictive biomarkers. Instead, I want to consider the challenge that the liquid biopsy strategy I have described also represents low-value care. This might sound odd since the scenario I sketched suggested that 400,000 lives annually would be spared by such a strategy from progressing to a terminal metastatic disease state. I will remind the reader that this was an arbitrary number, not based upon any empirical evidence at all. The objective was simply to establish an initial framework for ethical analysis.

My critic will point out that if we are doing 198 million liquid biopsies each year, more than 99% of them will be negative at a cost of \$99 billion. That will strike many as an obvious instance of low-value care. In addition, it is far from clear that simply calling attention to the 400,000 lives annually spared from a premature cancer death because of this preventive effort would suffciently justify this massive expenditure of resources.13 The obvious solution would be to be far more selective in the population screened with our liquid biopsy strategy. Here are some possible options: (1) Screen only those individuals and frst-degree family members where there has been a family history of cancer. (2) Add to (1) individuals with established behaviors likely to result in increased risk for various cancers, such as smokers or individuals with signifcant sun exposure. Roughly 40% of all cancers are attributed to behavioral choices by individuals. (3) Add to (1) and (2) individuals who have been diagnosed with a cancer and successfully treated (the assumption being that they are likely at increased risk of cancer recurrence). (4) Add to (1), (2), and (3) individuals who have compromised immune systems that might increase their risk of cancer. (5) Add to all the previous categories

<sup>13</sup>Louise Russell is one researcher who has critically assessed the widespread belief that preventive care saves money. She has argued that, in many circumstances, prevention is just not cost-effective. She would likely conclude that with regard to our annual liquid biopsy screening proposal. See her book *Is Prevention Better Than Cure?* (2010).

individuals above the age of 50, the assumption being that cancer is most often a disease for which older individuals are at risk. Note: In all these cases we are assuming that the cost of this testing would be a social expense. Individuals outside these categories would be free to obtain this testing at their own personal expense.

Trying to identify categories of individuals who would have the most reasonable and strongest just claims to this annual liquid biopsy screening would likely have a strong arbitrary component, as we discuss below. We might imagine avoiding the need to draw these lines if we could show that our initial proposal made economic sense when viewed in total. If we are saving 400,000 lives from a premature death from metastatic cancer each year, then we are also saving the cost of treating those metastatic cancers. We can assume that cost might be \$100,000 per metastatic cancer patient saved. If so, that savings would amount to \$40 billion. That would still leave \$60 billion in screening costs each year for which there were no offsetting economic gains.

Though ethicists would likely not endorse this next point, economists would note that those 400,000 individuals are still going to die, and it would be extremely unlikely that they would die cheaply. Those deaths would most likely be of other chronic degenerative conditions with multiple years of high health costs. A substantial number will develop dementia and require at least a couple years of long-term care at \$100,000 per year. Consequently, if our concern with controlling health care costs is about *all* health care costs, then the bottom-line savings would be substantially less than \$40 billion. For the sake of argument, let us say that the net savings would be \$20 billion.

Someone might then argue that \$20 billion in savings ought to be used to provide \$100,000 worth of targeted cancer treatments for each of the 200,000 individuals each year who would still end up with metastatic cancer in spite of the screening program. However, our erstwhile economist will again call our attention to an awkward economic fact, namely, that the savings we would expect to achieve by not having to pay for targeted cancer therapy for 400,000 individuals will only be realized more than two decades into the future. The costs of doing the screening will all be incurred in the present and represent additions to current health care costs. The assumption behind this conclusion is that it would be unethical for reasons of both justice and compassion to deny the current 600,000 patients who will die this year from their metastatic cancer the targeted cancer therapies and immunotherapies that can give them additional months (sometimes years) of life in order to offset the current costs of the proposed liquid biopsy screening program. In other words, transitioning from our current metastatic cancer therapeutic protocols to the biopsy screening protocol proposed by Dr. Raza would be ethically, economically, and politically problematic. Is there a just and reasonable way of addressing the "transition" challenge?

#### **The Transition Challenge: Effciency versus Compassion**

Menzel (2012) has addressed the transition challenge. He addressed it very broadly, maybe too broadly. This is the question that Menzel started with: "*Should we provide relatively ineffcient treatment to identifable individuals at relatively high risk for relatively immediate harms rather than more effcient preventive care to equally identifable individuals at lower risk for more distant harms"* (214; his italics). He defends what he calls the equivalence thesis, namely, that the lives on either side of the equation are equally worthy of being saved through the allocation of social resources. However, the identifable individuals at high risk can only have their needs met *ineffciently.* In other words, this is an unwise use of social resources, which is what Dr. Raza would argue. Society, he contends, in the form of future generations, would be much better off if the resources now being used ineffciently to purchase marginal gains in life expectancy were to be used instead in the preventive mode to prevent the need for the future ineffcient uses of those resources. However, he argues, we cannot afford to do both things during some sort of transition period. This has the ethically problematic consequence of sacrifcing the lives of a whole generation (in our case) of metastatic cancer patients who would all be denied access to these expensive targeted therapies in order to eliminate the need for such therapies for future generations. This does not appear to be either fair or compassionate.

Menzel asks us to consider the alternative. If we agree that it would be wrong to sacrifce this generation for the sake of future generations, then how would we ever make the transition that he would argue is rationally, ethically, and economically required? We would be stuck in the present circumstances. We would be compassionate to the current generation of metastatic cancer patients but we would be sustaining the pain and suffering and costs associated with metastatic cancer for numerous future generations who would not otherwise need that compassion because they would not have to endure this suffering if we now made a different decision aimed at preventing the need for such care in the future. Menzel writes: "By spending at a lower health productivity rate for that prevention than we do for treatment, we would fail to decrease the incidence of these very diseases for future generations, condemning more people than necessary to never being situated where they can fnd in their rational self-interest to vote for a more limited priority for treatment, with all the benefts of such a policy" (2012, 214). Menzel sees the "long run" perspective associated with prevention as justifying the "unfairness" objection raised in connection with denying life-prolonging care to a current generation of seriously ill patients. This is essentially a utilitarian perspective.14

<sup>14</sup>An alternative response to the unfairness objection has been offered by Callahan (1990). This is the "ragged edge" problem, which very often occurs when we must make a rationing or allocation decision fairly. "We can accept the ragged edge, not because we lack sympathy for those on it, but because we know that, once a ragged edge is defeated, we will then simply move on to still another ragged edge, with new victims---and there will always be new victims. It is a struggle we cannot win….We can ask [instead], not how to continually push back all frontiers, smooth out all ragged

One way of reading Menzel is to imagine a very costly preventive intervention that is completely successful in eliminating that disease from future generations. This reading makes sense since Menzel thinks of this situation as requiring tragic sacrifce from just one generation of patients. However, that is not the scenario that we have sketched with regard to our annual liquid biopsy protocol. In our scenario we do save 400,00 individuals every year from dying as a result of metastatic cancer.  Consequently, what we would have to be willing to sacrifce are those 200,000 individuals every year far into the indefnite future, as opposed to "just" one generation of metastatic cancer patients. That seems to require much more in the way of ethical justifcation than the scenario Menzel has in mind. We can readily imagine the situation Menzel envisions as being tragic, ethically necessary to effect a greater life-saving result, but still regrettable. It is much more diffcult to justify as a "regrettable tragedy" a situation that occurs repeatedly and persists far into the indefnite future without any obvious effort to end it.

If we consider the situation from a very "raw" utilitarian perspective, then the argument can be made that we *save* 400,000 lives with our liquid biopsy protocol while "only" giving up 200,000. In addition, the 400,000 lives are restored to having an indefnite life expectancy while the vast majority of the 200,000 will have lost less than a year of potential life if provided with some targeted cancer therapy. Still, perhaps 20% of those 200,000 individuals, would end up losing prematurely anywhere from one to ten extra years of life (the higher numbers pertaining to the super responders). Of course, as things are now, we would not know who those individuals were who had so much more to lose without treatment. However, to tolerate this outcome as a society, we would have to harden our hearts, close our eyes, and numb the compassion-generating portion of our brains. That, by itself, suggests the need for more critical and creative thinking. How, then, can we effect the transition Dr. Raza recommends in a way that is congruent with what a just and caring society ought to be?

#### **Whole Genome Sequencing: Another Precision Health Ethical Challenge**

That brings us back to the need to slim down dramatically the liquid biopsy screening protocol. Can that be done in a way that is at least "roughly just"? We noted above that one group of patients who would seem to have top priority for access to these liquid biopsies would be those identifed as being at risk for hereditary cancers. That represents only about 10% of all cancers (National Cancer Institute 2017). How would we imagine identifying them? The short answer would be that we do

edges, but how to make life tolerable on the ragged edges" (1990, 65). That is where the importance of palliative care comes in for a just and caring society.

Whole Genome Sequencing [WGS] of almost all Americans alive today and every child born each year. Such sequencing with professional analysis and interpretation and counseling would cost about \$5000 per person, or \$1.5 trillion for 300 million Americans today. In addition, it would cost \$20 billion per year to do WGS of each birth cohort. In the real world we do not have the technological capacity or personnel that would be needed to accomplish this task, never mind managing such huge economic costs. As with our liquid biopsy screening protocol, we would have to slim down and prioritize who would have access to such WGS at social expense. How can that be done fairly?15

I would certainly not endorse as "just enough" the libertarian view that it should be up to individuals with their own resources to determine whether such WGS was "worth it" to them. This would clearly disadvantage the fnancially less well off who would be at risk of a premature death from metastatic cancer that could have been avoided with access to WGS and/or our proposed liquid biopsy. What about an egalitarian perspective? There are several varieties of egalitarianism. Broadly speaking, egalitarians are committed to equal concern and respect for all. Would that mean everyone has an equal claim to WGS to establish their vulnerability to cancer? That would be a practical impossibility and ethically indefensible, given limited resources for meeting unlimited health care needs, not just cancer-related needs. Egalitarians will generally accept the view that greater health needs justly command more social resources (appendicitis commands more resources than a sprained ankle). How serious or urgent is the need for WGS to establish lifetime cancer risk relative to managing heart disease or Parkinson's or multiple sclerosis or dozens of other chronic degenerative conditions? This would not be an easy or obvious answer for an egalitarian.

Keep in mind that if the whole US population underwent WGS, 60% of those individuals would never develop cancer over their entire lifetime.16 Given that statistic, utilitarians would not endorse WGS for the population as a matter of social justice. Prioritarians want to ensure that a society meets the just claims for needed health care for those who are "medically least well off." We might imagine that the 10% of the population at risk for some hereditary cancer would ft that criterion. That would certainly be true if we restrict ourselves to considering only patients at risk for cancer. However, this is where prioritarians might fnd themselves internally conficted. There are the metastatic cancer patients who desperately need the targeted cancer therapies for some additional gain in life expectancy (sometimes a

<sup>15</sup>As I suggested in footnote #4, we should not assume that WGS is an ethically unalloyed good. There are numerous ethical pitfalls associated with its use for various purposes, whether preventive, predictive, therapeutic, or reproductive. An excellent summary of those issues is provided by Dondorp and deWert (2013).

<sup>16</sup>That 60% fgure might be misleading. That is roughly the number of individuals who will develop cancer sometime during their life. However, the large majority of those cancers will be the result of environmental exposure, i.e., choosing to smoke, or lots of sun exposure without protection. None of these cancers would be identifed through WGS. A roughly correct fgure would be 5% to 10% of cancers would be hereditary and identifable through WGS.

signifcant gain in life expectancy, as discussed above), not to mention all the other patients at substantial risk for premature death because they are in the advanced stages of some chronic degenerative condition. These are all patients with *urgent, imminent, actual* health care needs, as opposed to the *potential* health care needs of individuals with a hereditary risk of cancer. In the debate over the moral weight that should be attached to identifed lives as opposed to statistical lives for purposes of allocating life-prolonging resources, prioritarians would generally strongly endorse giving more weight to those identifed lives. What we need to keep in mind is that having a hereditary risk for cancer does not necessarily mean that one will actually have cancer during one's lifetime. Women with a BRCA1 mutation will have a lifetime risk of breast cancer in the 40% to 85% range, depending upon which of several hundred mutations in the gene they might have.

For the moment, let us put aside the practical and ethical challenges of determining who would have a just claim to WGS at social expense. We would (presumably) want to identify the 10% of the population at risk for a hereditary cancer, even though it is a high lifetime risk, but not a certainty. However, we would also have the capacity to determine a polygenic cancer risk score for virtually everyone. Such a score would be the product of literally hundreds of genetic variants in an individual each of which might increase very slightly their lifetime risk of cancer. Their lifetime risk would likely not be as great as someone at risk for a hereditary cancer. They might be told that their lifetime risk was "just average," that is, at 40%. Would they feel that they had a just claim with regard to our annual liquid biopsy? An enormous number of people would get a result like that, which would defeat the need to reduce the use of annual liquid biopsies at social expense. A signifcant number of individuals would also be told that their lifetime risk of cancer was below average, say at 20% or 30%. That is not zero. Some of these individuals will develop a cancer. Most of them will have that cancer caught at an early and treatable stage. Others will be less fortunate. They will progress to metastatic cancer and a premature death. So, one of the things we need to keep in mind, whether for the average or below average cancer risk patients, is that the fewer annual liquid biopsies we do, the greater (statistically) will be the increase in patients with metastatic disease. Should we see this as being unjust, ethically problematic? This is what is referred to in the literature as the "ragged edge" problem (Callahan 1990, chap. 2) or the "cutoff" problem (Rosoff 2017). No perfectly rational or perfectly just rationale can be offered for drawing a line at one point rather than another point. A line has to be drawn (as we have argued above) because we have only limited resources for meeting unlimited health care needs. There will always be patients with health needs or health risks just below that line who could make a reasonable just claim for the resources being provided to those above the line. The most we can reasonably hope for in this regard is rough justice.17

<sup>17</sup>Space does not permit any lengthy discussion regarding acceptable forms of rough justice. However, a quick illustrative example would be helpful. If a line were drawn that systematically resulted in individuals who were already among society's least well off (health-wise and economically) being further discriminated against, then that would be an unacceptable form of rough jus-

Lots of things muck up our intuitions regarding what is ethically required of a just and caring society for purposes of allocating resources toward precision health. We noted earlier that roughly 40% of cancers are linked to individual behavioral decisions (Mendes, 2017). This is something that would get the attention of luck egalitarians, who are committed to a responsibility-sensitive conception of justice. We might imagine luck egalitarians would endorse WGS that provided a polygenic cancer risk score, primarily as a way of educating everyone regarding their cancer risk. Unfortunately, most humans do not seem to be open to educational efforts to alter pleasurable behavior that represents a threat to health. What we might imagine instead as being more likely is that individuals with average or above average or somewhat below average cancer risk scores would be the frst to demand annual liquid biopsy screening with the hope that this would catch an early treatable cancer without having to change the behavior that might have generated that cancer. Given this scenario, luck egalitarians would likely oppose WGS for a population at social expense as both wasteful (unjust) and irresponsible.

Economists again contribute to mucking up our intuitions regarding preventive efforts to reduce the incidence of fatal cancers in our society. We want effciency, justice and compassion refected in our efforts to prevent (reduce) the incidence of fatal cancers. We noted above that the total annual cost of providing access to a liquid biopsy as a screening tool in the US would be \$99 billion.  That yields a cost-per-life-saved of about \$250,000. This is not an unreasonable fgure.18 What makes that even more reasonable is if the average gain in life expectancy for those 400,000 individuals is twenty years. That means the cost-per-life-year-saved is \$12,500. Compare that to the 200,000 individuals per year who would die from metastatic disease but whose lives could be extended (mostly briefy) if they were provided with some of these targeted cancer therapies. If each of those individuals were given a \$100,000 targeted cancer therapy, then for those individuals who gained only three extra months of life, the cost-per-life-year-saved would be \$400,000. This is the sort of number that would support Dr. Raza's proposal for shifting resources away from treating these patients toward the preventive efforts represented by the liquid biopsy screening protocol. However, a signifcant number (at least 20%) of those 200,000 metastatic cancer patients would gain at least an extra year of life for that \$100,000. This is very close to what we spend per year for end-stage renal patients needing dialysis. From the

tice. An acceptable form of rough justice would put all identifable social groups at roughly equal risk of being on the "wrong side" of that resource allocation line. In other words, the result should approximate the result of a pure lottery.

<sup>18</sup> Individuals with end-stage renal failure requiring dialysis will cost the federal government today \$90,000 per year with an average survival of seven years. That represents a cost-per-life-saved of about \$630,000. Individuals with HIV requiring a four-drug combination will have annual drug costs of about \$35,000 per year and can gain thirty extra years of life. Stribild® is a four-drug combination in a single pill with a cost of \$3550 per month, or \$42,600 per year. That would yield a cost-per-life-saved of over \$1 million. (Silverman 2016).

perspective of health care justice and compassion, that makes it much more diffcult to justify sacrifcing these lives for the sake of putting in place the proposed preventive effort. What makes it even more diffcult to justify such sacrifce would be the 5% to 10% of patients in this category who would gain multiple extra years of life from access to one or more targeted therapies (albeit at a cost of at least \$100,000 for each of those extra life-years gained). What is the right thing to do, all things considered?

Answering this question is made more diffcult because, for the most part, we do not know before the fact which individuals with metastatic cancer are likely to live an extra year or more with the help of a targeted therapy. This is mostly a true statement. However, much research regarding cancer biomarkers is resulting in our identifying before the fact patients who are more likely to beneft substantially from access to a targeted cancer therapy. One type of targeted cancer therapy are the drugs known as checkpoint inhibitors, such as nivolumab and pembrolizumab. These drugs target PD-1 and PD L-1 (programmed cell death protein 1), whose job it is to regulate the immune system from over-reacting and generating one of a number of immune disorders. However, cancer cells can use these proteins to hide themselves from the immune system. The checkpoint inhibitors are intended to suppress PD-1 and make the cancer cells more visible to the immune system. For some types of cancer, higher levels of PD-1 expression are a good biomarker of a more effective response to these checkpoint inhibitors. The actual literature in this regard is mixed (Dudley et al. 2016; Ugurel et al. 2020; Yi et al. 2018). What if, however, a slight majority of cancer patients with these higher levels of expression gain one or two extra years of life, not just seven months? Do all these patients then have a just claim to have access to these checkpoint inhibitors at social expense? High levels of tumor mutational burden are also a good (not perfect) biomarker for a more effective response to these drugs (Chan et al. 2018).

These are just illustrative examples I have offered. I could have picked a dozen others. The core ethics question is this: If we develop the capacity to identify with a high degree of likelihood, using various biomarkers, patients who are most likely to gain an additional year of life from access to various targeted cancer therapies or immunotherapies, should we use that capacity to separate moderate and strong responders from marginal responders for purposes of allocating these therapies at social expense? In other words, would considerations of justice and compassion justify this rationing practice as part of an effort to balance providing limited resources to both prevention (our liquid biopsy protocol) and treatment?

We need to consider one more possible scenario. The basic premise behind Dr. Raza's proposal is that the vast majority of metastatic cancer patients today achieve only marginal gains in life expectancy with access to these targeted cancer therapies, which is why she believes we ought to pursue aggressive cancer prevention rather than aggressive treatment. However, that might be changing, perhaps signifcantly. Many researchers (Cajal et al. 2020; Prasetyanti and Medema 2017; Dagogo-Jack and Shaw 2018) now believe that because of the genetic heterogeneity of cancer, and its evolving nature within an individual, multiple targeted therapies need to be used, either in combination with one another or sequentially, a strategy which has yielded considerable success in the treatment of HIV. This can increase substantially the cost per patient per year to achieve several extra years of life with "managed" metastatic disease (nothing curative). For example, Workman et al. (2017) note that the cost of combining nivolumab and ipilimumab would be priced at about \$252, 000 per year for the treatment of advanced melanoma. More recently, Larkin et al. (2019) show a fve-year overall survival rate of 52% for these same patients with this same combination of targeted therapies. Again, these examples are only intended to be illustrative of the direction of advances in cancer care at present.

What I ask you to imagine is that future research is successful in fnding combinations of these targeted therapies that yield three to fve additional years of life for 75% of that batch of 200,000 metastatic cancer patients. How should that alter the balance in the distribution of social resources between our liquid biopsy prevention strategy and the effective treatment needs of these 150,000 metastatic cancer patients? My hypothetical scenario is that we are using combination cancer therapy to achieve this result at a cost of \$200,000 per patient per year for an average of a three-year gain. That would amount to \$30 billion for that frst cohort of patients, \$60 billion for that second cohort, and \$90 billion for that third cohort and every year thereafter. To be clear, that \$90 billion is *only* for the care of these metastatic cancer patients, not any other cancer patients who are treated and cured in any given year. This is roughly the amount we would have to pay every year for our annual liquid biopsy screening proposal of every adult American. This also assumes that we would provide comfort care only for that other 50,000 metastatic cancer patients each year who were not candidates for any of these more successful therapies. That is, we would not provide them with low-value targeted cancer therapies (which would raise the same ethics issues as earlier discussed, albeit on a smaller scale).

As a matter of health care justice, would we be ethically obligated to increase by \$90 billion per year what we spend on cancer, keeping in mind that whatever the moral logic was that justifed an affrmative answer to this question would have to provide a similar answer in every other area of medicine where lives could be prolonged at a similarly high cost? That would represent a rejection of the basic premise behind the "Just Caring" problem. We have only limited resources to meet virtually unlimited health care needs. Alternatively, we could trim the costs of our liquid biopsy protocol. Let us say that we would screen annually only half the American population, thereby saving \$50 billion per year.19 Unless we somehow managed to choose the exactly correct 50% who were at the highest risk for cancer that became metastatic, we would in fact increase the number of patients who would eventually be faced with metastatic disease.

Simple math (under this scenario) would suggest that we would increase the number of annual metastatic cancer cases by 200,000. We will assume instead that

<sup>19</sup>Alternatively, we could screen everyone every two years. That would save the same amount of money. However, that would be neither just nor rational, given that we would know in many cases before the fact that certain identifable population groups were at greater risk for cancer in the future.

we are cleverer than that, and consequently, the increase would be 125,000 (for the sake of argument). 25,000 of that annual cohort would be added to the 50,000 who would receive comfort care only; no targeted therapies or immunotherapies at social expense. The other 100,000 would receive the advanced targeted therapies described above at an annual cost of \$20 billion for the frst cohort, \$40 billion for the second cohort and \$60 billion for the third cohort and every year beyond that, which would really amount to \$150 billion for each of the out years under this scenario for treatment and \$50 billion for the ongoing preventive screening effort. Again, this would be in addition to whatever the current annual costs for cancer treatment are. What choices should a "just" and "caring" society make that has only limited resources for meeting virtually unlimited health care needs? This question is asked with regard to the use of social resources, not private resources. A companion question might be: What choices with regard to all of our scenarios above may a "just" and "caring" society make that would relegate the cost of those choices to individual willingness and ability to pay? I take it that a society that left access to treatment for a heart attack or appendicitis to individual ability to pay would be correctly judged to be both unjust and uncaring. Likewise, a society that refused to pay for purely cosmetic procedures (not needed as a result of disease or accident) would not be open to justifed moral criticism. Where do our questions ft between these two poles?

#### **Rational Democratic Deliberation: Not Precision Ethics But "Roughly Just"**

We have raised a large number of ethically challenging questions above; we have not offered to defend any particular response to those questions. This is because, as I have suggested, there is no "most just" or "most reasonable" response to most of these questions. Many trade-offs are possible that would be "just enough" and "reasonable enough." To be clear, unjust and unreasonable trade-offs are possible as well. The trade-offs are among the core values that defne competing conceptions of distributive justice, as well as with other fundamental social values. The trade-offs we have in mind pertain to policy choices, not choices made by individuals. Consequently, a suffcient level of social agreement is necessary for these policies to be both fair and legitimate. I have argued elsewhere (Fleck 2009, chap. 5) that this agreement should be achieved through fair and inclusive processes of rational democratic deliberation governed by what I refer to as "constitutional principles of health care justice." Before elaborating a bit on that, let us review our key questions for democratic deliberation.

(future possible patients) whose early cancer can be prevented from progressing to metastatic disease?

Why do we need rational democratic deliberation to address these issues? The short answer is that all these questions are about public goods whose fair distribution or resolution cannot be fairly or adequately addressed through any private decisional mechanism. Does the Grail protocol that I described represent high-value care that would justify a very high level of social investment? This is not a question that can be answered fully by asking the relevant experts to work out the costeffectiveness equations. Multiple other social values would need to be considered and trade-offs assessed that are not in the realm of any particular area of expertise. To be sure, lots of relevant expertise needs to be introduced into the social conversation, but the conversation itself should be a matter of inclusive rational democratic deliberation.

In the European context we would be asking the question whether a commitment to solidarity required public funding for the Grail protocol *and permitted reducing or eliminating funding for targeted cancer therapies for patients with metastatic cancer*. In the American context we would be asking whether a commitment to individual liberty meant that individuals should make the decisions for themselves whether it was worth it to them to pay for annual cancer screening with Grail's liquid biopsy. Alternatively, should annual liquid biopsy screening be seen as a public health measure, a dramatic measure to reduce premature deaths from cancer, for much the same reasons that we carefully assess the processing of our food supply or the introduction of pharmaceuticals to protect the health of all. This is a matter of equal concern and respect for all. However, this would be an additional \$99 billiondollar cost in the United States.

Where should that money come from? Should that money come from additional taxes or increased insurance costs? This is one option. However, it would raise the political and ethical question of whether giving cancer this "special" or "supreme" health status would be justifed relative to many other possible health investments in other disease areas where we might be able to save more lives at a lower cost. The alternative proposed by Dr. Raza would have us simply take those funds from what we now spend to provide these targeted cancer therapies and immunotherapies to metastatic cancer patients. It is easy to imagine the reluctance (maybe horror) many would experience in contemplating that option. Of course, nothing requires us to do annual screening with our liquid biopsy for everyone. We could limit that screening to some range of high-risk cancer groups in order to protect funds for treating metastatic cancer patients. However, we could then imagine the anxiety that would provoke in many Americans, knowing that their lifetime risk of cancer was 40% (maybe higher) and that the cancer that might affict them did not present symptoms until a very advanced stage, such as pancreatic cancer. Finally, we might ask, given the emotional overtones expressed in these last few sentences, how we could possibly have a *rational, civil, mutually respectful* conversation about such controversial and emotionally charged issues. How could self-interest not corrupt and disrupt the possibility of such a conversation?

John Rawls (1971) introduced into discussions of political philosophy the notion of a "veil of ignorance." Individuals behind the veil of ignorance would know nothing about their own social or economic or health status. We could imagine this as 330 million life slots in America today. Individuals would, however, know all the possible political, economic, and social structures and policy options that could constitute the basic structure of their society as well as the life prospects for various individuals living within that basic structure. Individuals behind the veil of ignorance would be charged with determining what the principles of justice should be that would determine the basic structure of society. They would know that, after they had achieved agreement, they would be randomly assigned to one or another personal identity in that society. Their life prospects in that identity might be reasonably good or somewhat less good. Their motivation behind the veil of ignorance would be to choose principles of justice that would maximize as much as possible in that framework life prospects for those who were socially and economically among the least well off.

Rawls has been criticized on the grounds that the veil of ignorance thought experiment is totally unrealistic because everyone knows what their interests are. Consequently, no such social conversation regarding justice is possible under that scenario since most people would argue for policies that would protect their personal interests. However, without going into any defense of Rawls' overall views, it is factually true that the vast majority of us at any point in our life are largely behind a health status veil of ignorance. Even at my advanced age, I have no idea what my most likely health risks are or the most likely cause of my future death. Alternatively, we can pretend that in my early twenties I underwent a genetic test that indicated I had a 70% chance that I would die of some specifc cancer before age 60. Would I then want all sorts of social resources allocated for research and treatment of my specifc cancer?

In purely private moments I might answer that last question affrmatively. But if I am part of a social policy conversation regarding the allocation of health dollars for social health insurance, as well as prevention and research, I would be reminded by my fellow citizens that, if I seemed too single-minded an advocate for my cancer, many members of my family, as well as friends and co-workers, were vulnerable to many other health problems that could result in their succumbing to a premature death. I would also be reminded that I likely had forty years ahead of me and that I was vulnerable to lots of other diseases or serious injury related to accidents for which social resources would need to be allocated. It would be irrational for me to focus exclusively on my risk of that cancer. In addition, it would be unkind for me to ignore the health risks to which all whom I cared about were vulnerable.

I would also be reminded that I was engaged in this very broad social conversation regarding the allocation of health care resources. We could allocate as much money as we wished to meeting health care needs, not just my health care needs, but everyone else's health care needs as well. However, if we wanted to increase the size of the health care budget to cover anything and everything in the way of treatment that might be offered by contemporary medicine, then I would have to be willing to pay unlimited sums as taxes or insurance premiums to make that possible. On the other hand, if I want limits on that budget and my wallet, then I would have to work with everyone else who is part of this social conversation to establish what sort of health needs will justify accessing that social budget to meet those needs.

I do understand what health needs are, and how unmet health needs can greatly disrupt or shorten a life. Consequently, I want allocation policies that are fair, compassionate, and that represent a wise use of limited resources. I want those policies to refect the best medical and scientifc knowledge that is available so that we are funding therapies that are most likely to be effective. I am certainly inclined to be mindful of the health care needs of my friends and family and acquaintances. It is more diffcult to be very mindful of the health needs of the numerous faceless strangers who make up our society. However, I will be reminded that I am a complete stranger to all of them as well. I do endorse the view that every member of our society is entitled to equal concern and respect. I can imagine a situation in which at age sixty I am afficted with the cancer that I have feared.  I can imagine a targeted cancer therapy that would cost \$200,000 and offer me only a 25% chance of six extra months of life. I would want to have that paid for from this insurance pool. Given a commitment to equal concern and respect, that would mean that I would have to be willing to absorb those same costs for all the other metastatic cancer patients who would want that costly treatment for a very uncertain marginal gain in life expectancy. If I thought that was a poor expenditure of my money for those others who are strangers to me, then they would have the right to make the same judgment regarding the cancer treatment I want for myself since I am just as much a stranger to them.

What this last paragraph illustrates is how, in reality, we can begin to achieve social agreement regarding health care priorities and corresponding limits.

Individuals must be willing to be reasonable. If I want to be treated justly, then I must be willing to treat others justly as well. What counts as being "just enough" will have to be articulated through this process of rational democratic deliberation.

What keeps this deliberative process from becoming biased, dominated by special interests that skew the results unfairly? First, the relevant medical and scientifc facts (such as they are at a point in time) must be rationally respected. Some facts are mushy, such as survival curves with most of these targeted cancer therapies, which adds to the complexity of social decision making through democratic deliberation. Second, there are what I (Fleck 2009, chap. 5) refer to metaphorically as "constitutional principles of health care justice." These principles are intended to prevent majoritarian abuse and tyranny of those who are not capable of defending their basic interests. For example, in the United States today with employer-based insurance, many of these policies include very high deductibles and co-pays, especially with regard to these targeted cancer therapies. What that means in practice is that well-paid managers and executives can afford those co-pays and deductibles. Hence, they have effective access to these therapies. Ordinary workers would fnd it impossible to meet those requirements. Hence, they have no practical access to these therapies, though a portion of the cost of that insurance will be paid by them. In other words, they will be subsidizing access for the very well off. That would violate "equal concern and respect" as a constitutional principle of health care justice, which is to say that such a policy would not be an option for democratic deliberation, much less legitimation. It represents a form of exploitation.

Third, Rawls' notion of "wide refective equilibrium" constrains democratic deliberation as well (1971, 1996).20 Complex policy choices typically have wideranging dispersed consequences. What needs to be avoided are policy choices that generate a more unjust situation than the situation a policy change was intended to correct. If enormous social resources fow into cancer treatment, research, and prevention and yield mostly marginally benefcial results, other areas of medicine can justly inquire why comparable resources are not available for treatment, research, and prevention where there is a greater likelihood of more substantial health outcomes. This is the sort of "imbalance" that needs to be avoided or corrected in order to maintain overall a wide refective equilibrium with respect to the just allocation of health care resources. In the earlier portions of this chapter I have tried to illustrate the sort of imbalances between our liquid biopsy protocol (precision prevention) and targeted cancer therapies (precision medicine) that must be addressed.

Let me conclude with an illustration of how a deliberative question might be talked through. I assume we cannot afford to do that annual liquid biopsy for all adult Americans at social expense. I also assume we would not endorse providing only comfort care for metastatic cancer patients in order to afford the liquid biopsy protocol (given that some patients might gain several extra years of life from one or

<sup>20</sup>Rawls himself offers only a very sketchy description of wide refective equilibrium here and there in his writings. One of his students was Norman Daniels (1996) who has elaborated considerably on that notion and its application. It has been a focal point for philosophic discussion for the past thirty years.

another targeted therapy). I also assume we would not endorse providing unlimited access to all cancer therapies, no matter how high the cost, no matter how marginal the beneft. All these assumptions are ethical and economic; all (I believe) are reasonable (even if not self-evident). That means we need limits and compromise in all three regards.

Can we come to agreement regarding when it is ethically permissible to allow access to either advanced cancer therapies or our preventive liquid biopsy on the basis of an individual's willingness and ability to pay from their own resources? I think we could agree that if we can identify individuals at reasonable cost who are at signifcantly elevated risk for cancer, then those individuals ought to have access at social expense to our liquid biopsy annually. We will recall that any random American has a 40% lifetime risk of cancer. That is a signifcant number. However, if that is a number that triggers anxiety in a large portion of the population who demand annual liquid biopsy testing for a potential cancer at social expense, then we would be compelled to spend (wastefully) that \$99 billion per year. What can be pointed out in the deliberative process is that 70% of individuals diagnosed with cancer will have it treated successfully and will not die of their cancer. We noted earlier that 40% of cancers are linked to behavioral choices by individuals. Increased efforts at public health education in this regard would be much less expensive than funding annual liquid biopsies.