Cancer remains the second leading cause of death in the United States.

 As 2018 comes to a close, an estimated 1,735,350 new cancer cases will have been diagnosed and 609,640 individuals will have died from the disease.

 Although cancer therapies continue to improve outcomes, more effective screening technolgies— enabling more people to get screened and more cancers detected at an earlier, more curable stage– are needed. Better and more convenient screening tools for a variety of cancer types will help us achieve the targets set forth by leading healthcare organizations. Screening for common cancers is generally cost effective,

and an increase in screening rates accompanied by earlier detection of cancer and improved treatment regimens offer the potential to reduce the cancer-related healthcare cost burden through improving outcomes and survival.

As we look optimistically to a future state with more than 80% of the population screened for colorectal cancer (CRC),

 we are also faced with 2 primary challenges. First, although CRC screening rates are modestly improving,

 they have not yet reached stated goals, despite national campaigns led by influential organizations including the American Cancer Society (ACS), National Colorectal Cancer Roundtable (NCCRT), and large integrated delivery systems and advocacy groups. The barriers to screening include factors related to patients, healthcare providers, health systems, and communities. These barriers are difficult to overcome even though CRC screening reduces the incidence of CRC by one-half and mortality by one-third.

 Second, evolving epidemiologic evidence demonstrates that there is a disturbing “birth cohort” effect that highlights a 51% increase in the incidence of CRC from 1994 to 2014 and an 11% increase in mortality from 2005 to 2015 among individuals 55 years and younger.

 Based on these incidence and mortality data, the ACS has recommended that screening begin earlier, at age 45, for average-risk individuals.

With a goal of 80% of the average-risk population screened according to guidelines, clinicians, population health specialists, payers, employers, and large integrated health networks must fundamentally change and improve CRC screening programs. Improvements in CRC and other cancer screening programs aligns with the Triple Aim of healthcare: (1) better, higher quality of care; (2) healthier populations and communities; and (3) more affordable care.

 One positive pivotal change that occurred in health policy was for the US Preventive Services Task Force (USPSTF) to provide an “A” rating for CRC screening for individuals aged 50 to 75 at average risk for CRC.

 With their recommendation for any 1 of 7 screening strategies in the 2016 USPSTF update, patients and providers are encouraged to “choose the best test that gets [it] done.” The NCCRT, established in 1997 by the Centers for Disease Control and Prevention and ACS, developed webinars, handbooks, and other resources for hospitals and health systems to support implementation of best practices in CRC.

A high-quality screening test must have 3 characteristics: (1) high sensitivity, (2) compliance and adherence, and (3) access via insurance and shared decision making. Patient values and preferences play a significant role in compliance and adherence.

 The majority of patients in the United States continue to be screened with colonoscopy,

 which requires bowel preparation, time away from work, sedation/anesthesia, and risk of complications from preparation, sedation, or the procedure.

 Many patients are apprehensive, if not fearful, about screening

 and may prefer a noninvasive stool-based screening test.

According to the 2018 ACS guideline update, “Although prevention is highly valued by patients, test preparation, invasiveness, potential costs, and other considerations will lead some patients to prefer a noncolonoscopy test for screening.”

Currently there are several noninvasive tests, including the fecal immunochemical test (FIT), the guaiac fecal occult blood test, and the multitarget stool DNA, which are all included in the USPSTF recommendations.

 Stool-based tests vary in sensitivity, with the multitarget stool DNA having the highest sensitivity for CRC (92% vs the FIT test’s 74% sensitivity in a head-to-head trial),

 and the highest sensitivity for adenomatous and sessile serrated precursors.

 In addition to test performance and considerations of patient preference, another evidence-based component of successful screening programs is patient navigation.

 Patient navigation programs vary in scope and effectiveness by hospital and health systems; however, 1 screening strategy, the multitarget stool DNA test, includes an embedded nationwide patient navigation program.

There is also now 1 blood-based screening test for CRC that is available by FDA label to patients who are unwilling or unable to screen with other recommended CRC screening choices in the 2016 USPSTF guidelines. The Epi proColon test detects methylated Septin-9 and has a sensitivity of 68% and specificity of 80%.

 Although liquid biopsy for CRC screening is desired, current scientific and engineering limitations delay the availability of a blood-based screening test for precancer and cancer with sensitivity and specificity as high as stool-based testing. There are numerous research and development efforts underway to improve the molecular technology necessary to commercialize an effective blood-based screening test for CRC. The future of CRC is one where patients and providers make choices based on patient values and preferences, clinical performance, and awareness of risks, benefits, and alternatives, with the inclusion of patient navigation systems to optimize compliance and adherence.

Because molecular testing for early detection of CRC has made such inroads into the clinical space, we and others anticipate that similar chemistry could be applied to screening for the leading cancer killers. Of these, lung cancer alone accounts for 25% of all cancer deaths, with a loss of 154,000 lives annually.

 To date, the only effective screening option for lung cancer is a low-dose computed tomography (LDCT) scan. The National Lung Screening Trial (NLST) involved over 53,000 current or former smokers, who were randomized between screening with LDCT versus chest x-ray. After 3 screens, there was a 20.0% reduction in lung cancer deaths.

 Based on these results, the USPSTF recommends LDCT screening for those aged 55 to 80 with a 30 pack-year history of smoking and who either still smoke or have quit within 15 years.

 Endorsement of a screening strategy represents a major leap forward; however, this approach is currently applied to too few at risk. A study based on the findings of the NLST found that if computed tomography (CT) screening was implemented among screening-eligible US populations, only 12,250 deaths, fewer than 10% of the current annual lung cancer mortality, would be averted each year.

 Too few of those who are at high risk for lung cancer do not fit the recommended criteria; especially those who quit smoking more than 15 years ago. Additionally, lung cancer screening by CT may result in unnecessary intervention due to a false-positive rate that exceeds 96%.

A blood-based screening test may offer superior clinical performance and improve access for patients. One promising approach entailed examining DNA methylation patterns using next-generation DNA sequencing in primary lung tumors and high-risk control tissues to identify highly sensitive and specific methylated DNA markers (MDMs) of lung cancer. These MDMs were validated in DNA extracted from independent tissue samples and clinically validated in archival (EDTA)-buffered plasma specimens from 23 cases and 80 controls. Early results showed that a 4-MDM panel achieved an overall sensitivity of 96% and specificity of 94%.

 The MDM panel is currently being optimized for improved sensitivity of early stage lung cancers, and prospective enrollment of a phase 2 validation study is currently in progress. The future of lung cancer screening is promising as molecular techniques pave the way for a more accurate and convenient blood-based test.

Lung cancer screening by blood-based assays is biologically rational due to circulatory anatomy that gives tumor-specific DNA access to the plasma compartment; 100% of cardiac blood output passes through the lung. Another organ that receives high cardiac output is the liver, which outflows directly into systemic venous circulation. Although substantially less common than lung cancer in the general US population, primary cancers of the liver (hepatocellular carcinomas [HCCs]) are the second leading cause of cancer deaths worldwide and are projected to be the fourth leading cause of cancer death in the United States by 2030.

 HCC primarily arises in patients with chronic liver disease. The most common of these are hepatitis B and C infections, alcoholic hepatitis, and non-alcoholic fatty liver disease (NAFLD). Because of the obesity epidemic, NAFLD is the most rapidly increasing risk factor for HCC.

Surveillance for HCC is supported by the results of a randomized controlled trial in patients with hepatitis B in China, which demonstrated a near 40% reduction in mortality among those surveilled by ultrasound and serum assay of alpha-fetoprotein (AFP).

 While this trial has not been replicated in the West or by using patients with other liver diseases, there is ample observational data that patients under surveillance are more likely to be diagnosed with HCC at earlier stages, which may improve survival. The main drawback to this approach is low sensitivity for curable-stage disease. A recent meta-analysis estimates that ultrasound and AFP in combination are only 63% sensitive for early-stage HCC.

 Moreover, adherence to surveillance testing is quite poor.

In a similar approach to the discovery of lung cancer markers described earlier, DNA from primary HCC tumors and control liver tissues was sequenced to identify MDMs associated with HCC. The candidate MDMs were validated in independent samples before pilot testing in archival plasmas of 21 patients with HCC and 30 patients in the cirrhosis control group. A 2-marker MDM panel was found to be 89% sensitive and 87% specific in the pilot phase of clinical testing.

 A larger phase 2 study assayed MDMs from archival plasma samples of 95 HCC cases, 51 cirrhotic controls, and 98 healthy controls, and a 6-marker MDM panel was found to be 95% sensitive for HCC at 92% specificity.

 Most importantly, 93% of HCC tumors that were of curable stage were detected at the same specificity threshold. Larger phase 2 and phase 3 studies are in progress to set strict cut-offs for MDM markers in a clinical assay and determine if MDMs can detect HCC prior to other surveillance modalities. As with lung cancer screening test development, advances in liver cancer screening using a blood-based test show promise.

For lung and liver cancer, surveillance is targeted to high-risk patient subsets where the prevalence of cancers is enriched by a predisposing chronic illness. Yet most cancer deaths occur in persons without a known predisposition. Unfortunately, population screening has not been justified for most other cancers due primarily to individual prevalence rates that are insufficient to allow cost-effective interventions. At a population-wide level, benefits of single-organ screening have been demonstrated most robustly for breast, cervix, colorectum, and, to some extent, prostate cancer. The relatively high prevalence of these cancers directly affects the positive predictive value of screen testing and the number of patients needed to screen to identify a specific cancer. For instance, roughly 1 CRC will be found among 170 persons screened. However, 500 to 1000 persons would need to be screened to identify pancreatic or esophageal adenocarcinomas, respectively, due to lower prevalence of these very fatal diseases. As a result of screening so many persons, even a very specific test is anticipated to generate an unacceptable number of false-positive results, resulting in expensive downstream testing and unnecessary patient anxiety.

A screening test capable of detecting multiple cancer types is an attractive option to fill this gap. If lower and higher prevalence cancers could be screened simultaneously, the combined prevalence in the screened population would dramatically lower the number needed to screen.

Next-generation DNA sequencing and other emerging technology platforms are being leveraged to identify markers that appear to have high sensitivity and specificity for cancers and appear to identify patterns predictive of the anatomic origin of the primary tumor. Our group has demonstrated proof-of-concept data that multiple cancer types can be detected from the same biological media, including blood and stool, using MDM assays directed towards markers of both pancreatic cancer and CRC.

 Other investigative teams have combined DNA mutation and protein markers to detect multiple cancer types and have developed data models that associate biomarker patterns with each primary cancer type.

 These observations herald an exciting and potentially transformative new direction in the fundamental approach to cancer screening. Noninvasive multicancer screening is expected to be a near-term reality and will fuel rapidly increasing competition in research and commercialization efforts to bring this concept to clinical practice.AUTHOR INFORMATION

John B. Kisiel, MD, is a consultant in the Division of Gastroenterology and Hepatology, Department of Internal Medicine, and an associate professor of medicine at the Mayo Clinic. His research focus is the prevention and early diagnosis of cancers and precancers in high-risk patients, including those with inflammatory bowel disease.

Philip Parks, MD, MPH, is the senior director of medical affairs, Exact Sciences. He is a board-certified practicing physician with more than 16 years of clinical, corporate medicine, and managed care experience. Dr Parks served in the US Navy as a diving and undersea medical officer and held technology assessment leadership roles.

 Mayo Clinic and Exact Sciences jointly own intellectual property on which Dr Kisiel is listed as an inventor and may receive royalties.References:

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Articles

Evidence-Based Oncology

John B. Kisiel, MD, and Philip Parks, MD, MPH, provide an update on the future of cancer screenings and explain how improved treatment regimens offer the potential to reduce the cancer-related healthcare cost burden.

Increasing Rates of Cancer Screening

Andrew W. Lo, PhD, the Charles E. and Susan T. Harris Professor at the MIT Sloan School of Management, has a wide variety of research interests. He's best known in the healthcare world for ideas that could greatly increase the development of new drugs and access to expensive cures. The director of the MIT Laboratory for Financial Engineering, Lo is a principal investigator at the MIT Computer Science and Artificial Intelligence Laboratory and an affiliated faculty member of the MIT Department of Electrical Engineering and Computer Science. He is a past winner of the Battermarch, Guggenheim, and Sloan fellowships and has been named one of the 100 most influential people in the world by 

His proposals seek to increase investment in medical innovation and utilization by giving investors many more ways to support both research organizations and individual patients. For example, Lo sees opportunities for attracting new investment via securitization, the practice of combining individually risky assets into large pools that provide more predictable returns. The resulting cash flows are then divided into tiers based on levels of risk and reward favored by different investors.

Lo’s proposals typically rely solely on investors, drug developers, and patients acting in their own self-interest to produce the desired outcomes. However, he does see some opportunities for relatively small investments by philanthropies or the public sector to produce outsized returns in areas like pediatric cancer, where traditional finance tools would not be enough to attract socially optimal levels of investment. Indeed, by simply protecting private investors against loss during the riskiest phases of pediatric drug development, charities or governments may secure far more investment than they could fund on their own.

 This concept was presented in June at the American Society of Clinical Oncology annual meeting,

with full results published in September in 

) spoke with Lo about his ideas, including those in his recent paper.

: How did you get interested in how we finance drug development and usage?

It was really for personal reasons. A few years ago, a number of friends and a family member were dealing with different types of cancer, and it was through the process of trying to understand what they were dealing with that I realized that finance actually plays a pretty significant role in drug development.

For example, even though we seem to be on the verge of a number of breakthroughs in how we deal with these diseases, funding for early-stage drug discovery is actually getting scarcer. Why do we see this so-called “Valley of Death” for preclinical [research and development] and phase 1 clinical trials? In trying to make sense of this conundrum, I began doing research on the economics of the biopharma industry and realized that we could actually make a difference for patients if we used better methods for financing drug development.

My conjecture, which now has substantial supporting evidence, is risk. Drug development is really at its riskiest between the preclinical stage and phase 2 clinical trials. As financial pressures have increased on drug companies and venture capitalists [VCs] to improve performance, the response has been to focus on better bets, bets that are more of a sure thing. This means waiting until drug development projects reach certain milestones before investing.

Another risk that drug companies face is the risk that—thanks to all the recent biomedical innovation that’s been going on&mdash;a better drug gets developed, destroying the valuable franchise that these companies have invested billions in. We see this happening now with gene therapies that are on the verge of curing certain diseases that used to be chronic manageable conditions. It’s going to be a very interesting market dynamic as we see patients choosing between one kind of therapy and another and what kinds of pricing policies will emerge.

Despite those risks, overall returns on drug development are high enough to suggest we’re not investing nearly enough in it.

Drug development has 3 unique characteristics that, taken together, make it very challenging for investors. First, it takes a long time: typically 3 to 5 years before you hit the first major milestone and 10 to 15 years until you get an approved therapy. Second, it takes a large amount of capital to bring a single product to market, typically 1 or 2 orders of magnitude more than you need for start-ups in other industries. Third, the success rate is very low, about 5% in oncology for example, based on historical data.

There’s a small group of traditional biotech investors that are very sophisticated and understand how to manage these risks, but the larger pools of capital from ordinary investors that have been rushing into other areas like technology, social media, or cryptocurrencies simply aren’t there for this market. This is where the opportunity lies for better financing. If you structure the investments differently, you can make biotech attractive to more people and draw more money into drug development.

There are actually 2 ideas that have been used for decades in other industries and demonstrated the ability to reduce risk and improve average returns for investors. The first idea is “multiple shots on goal,” to use a hockey or soccer analogy. If you put together series of investments into a single financial vehicle, you are, in most cases, going to be able to reduce the risk and increase the likelihood that you have at least 1 or 2 successes. And in biomedicine, you only need 1 or 2 approved drugs to pay for all the other tries and still earn significant profits for investors.

But to create a large enough portfolio of multiple shots on goal, you need [a] much larger scale than the typical VC would have— on the order of billions of dollars in the case of cancer therapeutics, rather than a few hundred million dollars. This is counter to the traditional VC view that “small is beautiful.”

Which brings us to the second idea: using different kinds of financial instruments to fund these multiple shots on goal. Traditionally, biotech VCs use convertible preferred debt and then eventually equity to finance these start-ups. That’s certainly the tried-and-true approach. But to create a large enough portfolio of multiple shots on goal for drug development, you need to attract more capital, and the way to do that is to offer different kinds of securities. You can divide the underlying portfolio of assets—claims on future drug sales of multiple drug targets&mdash;in ways that let you sell low-risk, low-return bonds to investors who want safety, higher-risk equity to investors who want to gamble for big returns and every other type of security for investors who fall somewhere in between.

: You also believe that finance can increase utilization of expensive short-term treatments that either cure diseases or provide lifelong benefits. The idea is to find pools of capital that would be used to lend patients money that could be paid back over time.

Yes, but that’s not the new idea. It’s being done right now for all sorts of elective surgeries. Dental reconstruction is a good example. The typical cost of full-mouth reconstruction can range from $20,000 to $50,000, and candidates for these kinds of procedures can get consumer loans to pay for them right now.

What’s new in our proposal is to do this on a much larger scale, greatly increasing patient access to costly therapies, and to be able to securitize and package these “healthcare loans” and sell them to investors who are perfectly happy to take on large pools of diversified kinds of risks. Again, the investors get multiple shots on goal, but in this case, you’re talking about multiple consumer loans or loans to health insurers.

The idea really came about because of the possibility of curative gene therapies as well as other shorter-duration treatments like Sovaldi and Harvoni, 12 weeks of pills that can cure hepatitis C. Taking traditional medications is like renting an apartment: You pay for your benefit a month at a time and keep on paying as long as you want to live in that apartment. New medications like gene therapies are more akin to buying a house. You pay the whole cost up front and the benefit lasts for many years. But most people can’t afford to pay for the entire house in cash, so they get a mortgage, and that’s what we’re talking about here: drug mortgages. It’s the difference between “renting health,” one pill at a time, versus “buying a cure” and paying for it in installments.

The reason that this is an interesting approach is not just because it makes expensive one-time therapies more affordable for patients and payers. It can also serve as a way of dealing with cures that don’t really cure. We don’t yet know how permanent the effects of gene therapies really are; they’re supposed to be permanent, but we don’t have any real experience to rely on. What if it turns out that, after 2 or 3 years, the “cure” stops working and the patient relapses? Well, if you’ve paid for the therapy through a drug mortgage, you can simply stop making payments. That aligns the interest of the drug companies with the patients and the payers.

Based upon some very simple simulations that we’ve run by paralleling this submarket with the student loan market, we think there are tremendous amounts of resources that could be devoted to increasing patient access to these kinds of therapies. And with the 300-plus gene therapies currently in clinical trials, this is only the beginning of a huge wave of cures coming to patients over the next few years.

: You have also explored the idea that insurance companies, rather than patients, would take out these loans.

Yes, the idea of stretching out payments over a period of time is pretty straightforward, but the big question is who’s going to be paying that mortgage, and the natural response is insurers. That’s why we have health insurance.

The problem is that insurers expose themselves to potentially huge losses when they make large up-front payments for treatments that provide their policyholders with decades of benefits. This wouldn’t be true if policyholders always stayed with the same company. If you pay for a cure for one of your policyholders and that policyholder now lives for the next 30 years instead of dying in 1 or 2 years, you’ve got 28 more years of premiums that you can use to offset the cost of this cure.

But in practice, that policyholder can leave her health plan at any time. Suppose she moves to another state after only 5 years. So now, instead of having 28 years of premiums, you’ve only collected 5 years’ worth; the remaining 23 years of premiums go to an insurer in another state. That insurer will benefit from a healthy policyholder who’s now cured of this disease, thanks to the previous insurer. She may have other problems, but that’s one really serious disease that the new insurer doesn’t have to pay for.

There are a number of ideas for solving this patient-migration problem through regulation or legislation to protect insurers. This is critical because insurers are going to be very reluctant to finance expensive cures until they’re protected against this scenario. And currently, they’re the only ones who have the resources to finance the most expensive cures.

: Because the idea of lending money directly to patients doesn’t work when the loans get much bigger than $40,000?

Exactly. There are very few patients that can afford million-dollar therapies. And we’re now on the verge of developing a gene therapy for hemophilia. The best guess today for that price tag is about $1.5 million. There are few enough people who can afford $1.5-million homes, never mind $1.5-million drugs. And in the case of a home, at least there’s some pretty substantial collateral. In the case of your health, it’s very difficult to repossess a lung, so that’s why we used student loans as a model for this market: You purchased a college education, but they can’t really repossess your math courses. That’s why, ultimately, insurance companies are the ones that will be taking out these loans, and we need to deal with the patient-migration issue that they face.

: Talk about the research on how you could use these financial tools on pediatric disease, particularly cancer. Why doesn’t the market work now, and how can finance improve it?

Ironically, I think part of it is because we care so much about our children. Traditionally, pharma companies have not developed drugs for children exclusively. They start with adults for the simple reason that drug testing is a very dangerous business that often involves toxic side effects. Patients do die in clinical trials, so it’s a matter of ethical consideration to have adults take on these risks first before we expose children to them. But the consequence of that kind of ethical perspective is that pediatric oncology drugs are harder to come by. Drug developers will focus first on adults and unless, and until, they develop a successful therapy, they won’t try it on children. Now that’s changing, particularly with recent legislation requiring drug companies to develop therapies for adults and children simultaneously. But historically it’s been a challenge.

It’s also harder to develop pediatric oncology drugs because children have far fewer mutations than adults, implying fewer genetic biomarkers and druggable targets. Also, the biology of a 5-year-old can be quite different from that of a 12-year-old, and both are different from the biology of an adult, so it can be more complex to develop therapies for pediatric indications. Finally, the smaller patient populations make the economics of pediatric cancer drugs less attractive than those of adult counterparts, even with incentives like priority review vouchers and orphan drug designation. We ran the numbers and were shocked to discover that the simulated rates of return for pediatric oncology drug-development programs typically yielded double-digit negative returns on capital. Companies still do develop pediatric cancer drugs, but it’s probably more for ethical than financial reasons. And while it’s laudable that companies and investors still do invest in pediatric cancer drug development, they don’t invest nearly enough because the financial risk/reward profile isn’t very compelling.

Our proposal to get more investment into this field is a public—private partnership where the government and/or philanthropic organizations get involved in funding some of the riskiest parts of the development chain, preclinical R&D and phase 1 trials, and then hand it off to the private sector for completion after phase 1. We found that relatively reasonable amounts of public-sector funding, certainly much less than what goes into other areas of the drug development, could actually go a long way toward making the private sector interested in these kinds of health issues. Now that our paper is published (including our simulation software), our hope is that it’ll attract the attention of industry participants as well as philanthropic organizations and government agencies and that might spur them to collaborate with private-sector investors and biopharma companies.

: If you were the Trump administration’s health policy czar, what’s the first thing you would do?

The first thing that I would do is to use the convening power of the White House to bring together various stakeholders to work together collaboratively to develop solutions to some of the biggest medical challenges facing our country. The 3 areas I would prioritize are Alzheimer’s, infectious diseases, and antibiotics. These 3 areas present huge challenges, both current and pending, not only for our country but for the world, and they’ve gotten far too little resources and attention to date. As we saw with the Biden Cancer Moonshot, the White House can be extremely effective in coordinating the efforts of various groups to deal with the biggest issues facing humankind.

 How could things improve on the regulatory side?

Having now spent some time interacting with the FDA, I have to say that I’m incredibly impressed by the quality of their staff, their dedication, and how effective they’ve been. One of the most surprising things about them is their openness to new ideas and constant focus on improving “regulatory science.” To that end, I’ve been collaborating with several of their researchers to incorporate patient preferences into drug approval decisions. The standard approach for weighing the evidence from a clinical trial is to use a fixed statistical threshold of significance, also known as a 

 value or false positive rate, of 5% to determine whether a treatment is meaningful. Clinical trials with treatment effects that have a 

 value lower than 5% have traditionally been interpreted as statistically significant and those with higher 

 values are interpreted as insignificant. This 5% threshold is almost always applied across all diseases, but there’s reason to think that patients would be better served if the threshold were disease-specific.

For example, if we’re dealing with a disease that’s not particularly life-threatening, say acne medication, using a threshold of 5% for screening out false positives may be perfectly reasonable. But if we’re dealing with a potential therapy for a deadly disease like glioblastoma or pancreatic cancer where there’s currently no existing effective therapy and patients are likely to die anyway, patients might prefer to take more of a risk of a false positive so as not to miss a potentially effective therapy. We’ve developed a method for calculating the optimal threshold of false positives, given the severity of a disease and patient preferences regarding the costs and benefits of false positives versus false negatives. The FDA has been collaborating with us to construct a practical version of this framework.

: What are you doing to get your ideas for financing healthcare put into practice?

I’ve advised a number of companies pro bono on how to apply these ideas and have been more directly involved in 2 start-ups, BridgeBio and Roivant, as a seed investor and a director. I’m now in the process of talking with a number of stakeholders about possible financing structures that can make gene therapies more widely accessible. The hope is that we can get something in place in time to be used as a template for the many other gene therapies that are coming online.

: How enthusiastic are people about working with you and putting these ideas into practice?

I’m seeing tremendous enthusiasm from investors, drug manufacturers, and patients. There’s definitely money out there, waiting to be deployed and clearly a need for these new financing structures. Where we’re getting some hesitation—not so much pushback, but cautiousness&mdash;is among payers. State Medicaid plans don’t have an ability to amortize expenses; their budgets are set year to year and it’s not trivial for them to borrow funds or move expenses across budget years. As a result, they’re interested but more hesitant because they don’t really know what’s involved and they’ve got enough challenges to deal with currently. But given how many gene therapies are likely to be approved over the next few years, I suspect they’ll figure out a way to use these creative financing methods when the time comes.

Andrew W. Lo biography. MIT website. alo.mit.edu/biography/. Accessed October 19, 2018.

Das S, Rousseau R, Adamson PC, Lo AW. New business models to accelerate innovation in pediatric oncology therapeutics: a review. 

. 2018;4(9):1274-1280. doi: 10.1001/jamaoncol.2018.1739.

Das S. Rousseau R, Adamson PC, Lo AW. The challenge of pediatric oncology: new business models to accelerate innovation. 

. 2018;36(suppl 15). ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.10528.

Evidence-Based OncologyTM sat down with Andrew W. Lo, PhD, to discuss his proposals to increase investment in medical innovation and utilization by giving investors more ways to support both research organizations and individual patients.

Renting Health vs Buying Cures: How New Financing Tools Can Boost Cancer Therapy Development

One can get an excellent sense of the pace of cancer care innovation and the controversies and failures that are part of this grand narrative by tracking cancer-related cover stories in 

Dating back 70 years, these cover stories have told the dynamic story of the failed promises, bold advances, and unintended consequences of advances in cancer treatment and their impact upon patients affected by this diverse set of disorders. In ready this series of stories, it is difficult not to wonder how this narrative will continue to evolve over the next 10 to 20 years. 

In the early 1970s and 1980s, stories in the popular media embraced the idea of anticancer “magic bullets” that would prove the key to providing cures for all types of cancer. In the end, there was no magic, just a growing appreciation for the fact that curing cancer is not based upon some underlying simplicity in cancer biology or fortune in identifying a universal cure. Instead, there was a growing realization that conquering cancer would require a deep level of scientific inquiry into the genetic and molecular underpinnings of each type of cancer, so that individual cures could potentially be crafted to manipulate the underlying biology of the disease. The requisite quantum intellectual leap from a belief in magic bullets toward a mindset that embraced the inherent complexity of cancer biology led to the “precision medicine” mindset. The future of cancer care lies in this continuing, dynamic journey of discovery while ensuring that our systems of delivering care can match this clinical promise, so that patients can benefit equitably from these advances in care. 

The promise of targeted anticancer therapeutics was first demonstrated through the extraordinary success of imatinib (Gleevec) and the tyrosine kinase inhibitors (TKIs) in the treat- ment of patients with chronic myelogenous leukemia (CML). By exploiting the mechanism of action of the unique fusion protein created by gene fusion specific to CML, daily dosing of the TKIs could produce a significant percentage of molecular complete remissions for a population of patients whose prognosis prior to the advent of these innovative therapeutics was poor, with a median survival of less than 3 years.

Although the information derived from convention cytogenetic studies on cancer have had some impact upon the development of targeted anticancer therapeutics, the Human Genome Project has produced a veritable Rosetta Stone for identifying unique tumor-related mutations in the cancer cell genome and leveraging this information in the pursuit of innovative targeted therapeutics.

 This process has been accelerated by increasing numbers of patients with cancer whose tumors have undergone genomic testing, including whole exome sequencing, as well as the availability of supercomputer analysis of these data. The availability of supercomputer-based analytics allows for very high throughput of immense amounts of unstructured genomic data that can help identify potentially relevant cancer-related mutations.

 These advances in our understanding of tumor genomics and the identification of new tumor neo-antigens as marks for targeted therapeutics and immune-oncologic therapeutics have accelerated the pace of development for these therapeutics. 

In a relatively short period of time, these data and other data obtained from basic science research directed at identifying tumor genomics and potential targets for innovative immuno-onco- logical treatments have produced significant, tangible results for patients with previously unmet cancer care needs. Earlier this year, in a randomized phase III trials of checkpoint inhibitors added to the standard treatment of non—small cell lung cancer (NSCLC) for patients without mutations of 

produced a significant prolongation of survival and improvements in progression-free survival.

 The standard of care for patients with NSCLC has evolved dramatically during this period, with inclusion of genomic testing as part of the assessment of patients with advanced disease prior to treatment. Moreover, these treatment guidelines also reflect increasing therapeutic options, including targeted therapeutics for patients with selected mutations of 

Many types of cancer that have proven historically refractory to standard chemotherapeutic approaches may respond dramatically to targeted immune-oncological agents, often producing an excellent quality of life for patients affected by these diseases.

 This pace of innovation continues to increase at a previously unprecedented pace. Between 2014 and 2017, there were more than 50 FDA approvals for targeted anticancer therapeutics.

 Although some of these reflect approval of a single agent for multiple indications, most reflect a breadth of therapeutics that include bispecific molecules, checkpoint inhibitors, small molecules, and monoclonal antibodies that demonstrated effectiveness in a broad array of tumors, including many cancers that have been refractory to standard chemotherapeutic approaches. Moreover, the future pipeline for new, targeted anticancer therapeutics looks robust.

 As more potential therapeutic targets are identified through genomic, molecular, proteomic, and metabolomic investigation and data analysis, there is enormous hope that the promise of precision medicine will translate into greater opportunities for patients with historically refractory and poor-prognosis cancers.

 These advances portend a future in which cancer survival rates will continue to rise and the number of cancer survivors in the United States will continue to grow.

Yet, inasmuch as the future is likely to bring enormous progress and innovative treatments for patients with unmet care needs, it is also likely to bring a series of increasingly complex challenges to our healthcare system. The first of these relates to concerns about the financial sustainability of delivering these innovations, given their rapidly escalating price tags. In a recent study, the average cost of an anticancer drug approved between 2006 and 2015 rose more that 5-fold to an average of $13,176 per month.

 Although the challenge of paying for new therapeutics with an average annual cost of $160,000 sounds daunting, the example of chimeric antigen receptor (CAR) T-cell therapeutics stands as a bellwether for some of the expected cost challenges to come. Thus far, 2 CAR T-cell products have been approved, with the possibility of a third in the near term. These genetically modified agents are manufactured on a per-patient basis for the treatment of young patients with relapsed, refractory B-cell acute lymphoblastic leukemia (ALL) and patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), respectively. Both products have demonstrated clinical activity that is superior to historical approaches, and the Institute for Clinical and Economic Review report on

CAR T-cell therapies found that these products met the threshold for cost-effectiveness for both treatment indications.

Yet the line-item procurement costs of the 2 commercially available therapeutics ($373,000 for DLBCL and $475,000 for B-cell ALL) has been met with significant concern.

 These represent some of the most expensive therapeutics released to date in the United States. This has led policymakers to wrestle publically with the question of how to deal with therapeutics whose cost is seen as a challenge to the sustainability of our government-based payment systems. In the 2019 Inpatient Prospective Payment System (IPPS) rule, a large part of the cost of delivering these treatments was left unreimbursed, thus leaving the hospitals and healthcare systems that offered these therapeutics to cover half or more of the cost of product procurement alone.

 This issue seems to have had a chilling effect upon the availability of these therapeutics to patients who may need them. Recently, FDA Commissioner Scott Gottlieb, MD, said the failure to resolve the issue of CAR T-cell reimbursement could stifle future therapeutic innovations for patients with cancer.

Although the rising costs of pharmaceuticals and engineered therapeutics pose a challenge, it is inappropriate to consider the issue of therapeutic cost in isolation. In one study, a review of the cost of care for third- and fourth-line treatments for patients with relapsed or refractory DLBCL ranged from $600,000 to $750,000.

 This is a sum that may actually exceed the cost of much more effective care for this population of patients. The difference is that the transactions costs associated with CAR T-cell procurement have created a perception of greater overall costs where that may not, in fact, be true.

The idea of shifting toward payment for value, rather than volume, is a concept that is routinely cited as an essential principle in gaining control over care-related costs. Experts and national leaders— from Michael E. Porter, PhD, MBA, and Thomas H. Lee, MD, both of Harvard, to former HHS Secretary Sylvia Mathews Burwell&mdash;have all embraced this as an essential principle of creating a high-quality, financially sustainable system of care delivery.

 Yet we have made amazingly little global progress in this regard in creating a national value-based care model in the oncology domain. There are some important pilot projects, including the Oncology Care Model (OCM) from the Center for Medicare and Medicaid Innovation, but we have yet to see the creation of a national ecosystem that consistently fosters and rewards high-value oncology care, especially a system that can support and reward the appropriate and effective use of high-cost therapeutics.

Joseph Alvarnas, MD, discusses the history of cancer care and what the future might look like in the space.

December 2018

Increasing Rates of Cancer Screening

Renting Health vs Buying Cures: How New Financing Tools Can Boost Cancer Therapy Development

The Future of Cancer Care

Cancer Today and Cancer Tomorrow: Analysis of US Cancer Claims, 2007-2017

McAneny Discusses OCM, Community Practices, and Building the Right Rewards

Data and Collaboration Are Key for Value-Based Care Success

Getting the Patient's Viewpoint in the Oncology Quality Equation

Our Contributors/Value-Based Care

Medical World News: Managed Care Updates

Medical World News: Clinical Updates

Medical World News: Regulatory Updates

Biosimilars Updates

From the Editor-in-Chief: Why the Future Never Arrives