The emergence of literally hundreds of oncology therapies and combination therapies in recent years provides hope for patients with cancer, and expanded options for oncologists. Ongoing breakthroughs in both biomarker-indicated therapies and immuno-oncology therapies provide cause for celebration throughout the oncology community. “Only about 10% of malignancies are currently treated using biomarker-directed therapies, but that number is likely to rise exponentially in coming years, and this is adding complexity to patient-selection and decisionmaking for all stakeholders,” says Bruce Feinberg, DO, VP and Chief Medical Director for Cardinal Health Specialty Solutions. In particular, the development of clinical pathways, driven by medical researchers plumbing health outcomes data for best practices, combined with pharmacy benefit managers (PBMs) and insurers evaluating the economics of cancer care, is becoming more fraught.
Clinical pathways in oncology aim to create a useful, evidence-based framework to help oncologists make sense of the complex choices available, and to help enforce, where possible, a certain amount of standardization in cancer care. The goal is to focus prescribing efforts — in terms of optimal sequencing and timing of diagnostic testing and treatments, and optimal medication selection — favoring those choices that present the strongest clinical evidence as it relates to efficacy, safety and cost-saving opportunities. Clinical pathways committees typically review all of the available, up-to-date clinical evidence (such as clinical practice guidelines, peer-reviewed journals, scientific media, Medicare compendia, FDA labeling indications and so on) when devising their pathways protocols.
According to ASCO’s Task Force on Clinical Pathways, the four leading oncology pathways that dominate the scene in the US (in no particular order) are provided by:
* Anthem/AIM Cancer Care Quality Program (AIM)
* New Century Health, a specialty-care advisory firm
* Value Pathways by McKesson, USOncology Network and the National Comprehensive Cancer Network (NCCN)
* Via Oncology (which was acquired by Elsevier in January 2018)
Managing a tsunami of clinical evidence
“Pathways typically incorporate complex, regularly updated information related to disease staging, line of therapy, histology, driver mutations and protein expression and typically present it in a decision-tree logic to support the oncologist at the point of care,” explains Janet Serluco, MS, VP, Payer Access Solutions and Oncology Lead at Precision for Value, specialists in payer marketing.
“Clinical pathways take into consideration all the different treatment options available and narrow them down into a succinct list of choices that drive the most value, which is simply defined as the best possible outcome at the lowest cost,” “Oncology pathways are needed more than ever today with ongoing advances in precision medicine,” says Marcus Neubauer, M.D., Vice President and Medical Director, Payer and Clinical Services, McKesson Specialty Health. “Consider a busy oncologist trying to keep track of new cancer-causing mutations and the rapid entry of new cancer drugs to market. Pathways serve as guides through this much more vast and complex space.”
In recent years, a growing number of oncology practices and insurers have adopted (and even mandated) use of pathways. Oncologist use of clinical pathways (OCP) has reached 58%, according to a recent article in JAMA Oncol.  The American Society of Clinical Oncology (ASCO) reports a 42% increase in the number of oncology practices reporting compliance with a pathways program from 2014 to 2016. 
Meanwhile, an estimated 60 individual health insurance plans in the US have mandate the use of a particular oncology pathway — representing more than 170 million individuals, according to ASCO. To ensure and measure physician compliance, health plans typically use a carrot-and-stick approach, offering a mix of incentives such as increased reimbursement rates for medical procedures and medications, and reduced administrative requirements (such as burdensome prior authorization and step therapy protocols) when treatment is carried out within the proscribed pathways, notes Serluco.
To increase their utility, today’s competing oncology pathways typically offer various types of decision-support tools and software, and some are able to flow directly through the oncology practice’s chosen electronic health records (EHR) system, so the information is readily available within the physician’s workflow at the point of care. When the oncologist enters clinical data into a patient’s medical record, the EHR system flags a clinical pathway that is appropriate for the patient’s set of circumstances and provides relevant prompts for the physician. When a physician goes “off pathway” or chooses not to follow a clinical pathway for legitimate medical reasons, the EHR system will ask the oncologist to select and document the reason for doing so.
Additional benefits of pathways adoption
In addition to improving clinical outcomes and containing costs, adherence to pathways benefits oncology practices in other ways, says Neubauer of McKesson:
Contract leverage with payers. By adhering to the required oncology pathway and aligning incentives with the payer, the oncology practice benefits from lower operating costs and less administration hassle for both the prescriber and office staff.
Reduction in drug-inventory costs and cash flow. Oncology practices typically rely on the buy-and-bill model, whereby they purchase and inventory oncology therapy options and are reimbursed after they administer the drugs to patients. “Rather than ordering and storing the full range of potential medications for patients, practices can order and store only the medications they use most, based on their clinical pathways, and when they do, reimbursement for very expensive drugs is rarely declined,” says Neubauer.
Increasing clinical trial enrollment. The ability of today’s oncology pathways to embed details about available clinical trials directly into the decision-support tools provides an important advantage for both oncologists and patients. “Currently only 3% of adult cancer patients participate in randomized controlled clinical trials and those who do are younger, healthier and less diverse than their real-world counterparts,” notes Cardinal Health’s Feinberg.
While many stakeholders agree that the concept of oncology pathways is sound and has already proven to be effective in recent years, opportunities for ongoing improvement exist. Today’s pathways publishers are all grappling with how to effectively incorporate treatment options that aim to provide increasingly personalized care, based increasingly on the specific genetic nature of each patient’s malignancy and other clinical and socioeconomic factors. Similarly, pathways are being modified with the addition of biomarker-directed therapeutic options.
“Many people still think wrongly that oncology pathways are these broad, simple statements that aim to put all patients into the same lane,” notes Kathy Lokay, General Manager of Via Oncology. “To the contrary, they are actually very precise tools, and are becoming even more so, as more biomarker-approved indications keep coming to market.”
“Today’s pathways are already asking about a number of actionable biomarkers that were not being asked about even just a year ago, so they are evolving rapidly and that’s good news,” adds Robin Zon, MD, FACP, FASCO, Senior Partner, Michiana Hematology Oncology, and Chair of the ASCO Pathways Task Force.
“If we don’t continue to keep up with these discoveries, our pathways will become irrelevant,” adds Neubauer of McKesson.
Too much of a good thing?
While oncology pathways aim to streamline and focus the clinical information for oncologists, they also provide added administrative burden and workflow interruption — especially because most oncologists must adhere to multiple, parallel pathways programs, because different insurers mandate the use of different progams, and the oncology practice may have adopted or developed its own oncology pathway as well. The oncologist needs to move seamlessly among several competing pathways programs from during the course of every day is antithetical to the idea of streamlined efficiency, and this begs the question: How many is too many and is consolidation among today’s oncology pathways inevitable?
“Many prescribers report feeling overwhelmed by the intellectual, ethical and administrative burden they face, as they are forced to embrace numerous similar-yet-different pathways programs— and move seamlessly among them at the point of care — depending on which private or government insurance plan is held by every single patient who walks through the door, hour by hour,” says oncologist Zon.
While all of the competing pathways are developed from the same general body of clinical evidence, they do not necessarily offer identical treatment protocols or cookie-cutter recommendations. “Each of today’s competing oncology pathways varies in how comprehensive and restrictive the options are, what compliance thresholds are used, what level of evidence that will be accepted, the role of real-world data, and more,” says Feinberg of Cardinal Health.
“Without head-to-head comparison trials for most drugs, it’s like comparing apples to oranges. It requires a lot of nuanced involvement from the experts on the pathways committees and this leads to inevitable differentiation among today’s competing oncology pathways,” adds Lokay of Via Oncology.
“Today’s oncology practices must routinely support multiple pathways depending on their practice choices, institutional protocols, and payer preferences related to their patient coverage mix in terms of working within the patient’s insurer-preferred pathway,” explains Serluco of Precision for Value.
In general, oncologists tend to favor those those pathways that preserve more latitude in prescribing. With more latitude, the oncologist is then able to factor in other considerations, such as the cost burden for the patient (based on available coverage or copay burdens), co-morbidities, or socio-economic factors (such as access to transportation) that may or may not enable them to show up for weekly chemotherapy treatments. The level of reimbursement from payers for drugs that an oncology practice has purchased can also be a factor.
“Some practices report that they must be able to abide by four or five different pathways, and for any given patient, they must use the pathway that is promoted by that patient’s insurance plan,” says oncologist Zon. “As a community, we must find ways to reduce this burden for oncologists.”
“Given this added complexity, there is likely to be consolidation over time because it is a lot of work to develop and maintain them and markets tend to become more efficient when there is less duplication of effort in both the development and the use of oncology pathways,” adds Lokay.
“It is possible that NCCN, ASCO and others may eventually align with a consensus universal pathway, in which case vendors will be differentiated by their technology solution rather than their content,” adds Feinberg of Cardinal Health.
How drug developers can stay in the game
While the rise in oncology pathways use is providing demonstrable benefit to both payors and patients, it can also create barriers for pharmaceutical manufacturers, by limiting patient and provider access to therapies don’t make the cut. If an existing or newly approved oncology therapy option is not incorporated into one or more of the published pathways, the drug’s ability to gain traction in the market will be hampered, and may also engender less-than-favorable reimbursement terms from private and government insurers.
Today’s pathways-development committees all strive to maintain independence and autonomy, so the extent to which pharma manufacturers can influence the pathways-development process is limited and the pathway committees are very strict about the type of information drug companies can submit for consideration. For these committees, there is very little room for drug developers to plead their case, outside of the strict confines of evidence published in peer-reviewed journals and presented at peer-reviewed meetings, says Lokay of Via Oncology, adding: “To let anything else in opens the floodgates and it could be problematic.”
“We strive to keep free from bias and make our pathways decisions based on efficacy, toxicity and cost differences (the clinical facts). In order for our pathways to be respected by providers and payers we can’t show favoritism to one pharmaceutical company. If one company’s drug is in the same class as another’s, it usually comes down to price differences. However, most companies price their drug similarly to their competitors’ products, so we don’t even have much wiggle room there,” adds Neubauer of McKesson.
Nonetheless, industry observers agree there are still some strategies pharma companies can adopt to increase the likelihood that their drugs will be recognized within the leading clinical pathways. For instance, Lokay notes that in the absence of head-to-head clinical trials for most oncology medications, pathways committees are often left to “compare apples to oranges” when trying to interpret the findings and identify which treatment protocols will make the cut,” and this leaves room for improvement.
To further illuminate some perhaps-less-obvious benefits or distinguishing characteristics of their therapeutic options, drug manufacturers should strive to develop ongoing real-world evidence, and present or publish it in peer-reviewed journals and meetings. The ability to demonstrate, for instance, safety, tolerability or ease-of-administration advantages over competitor products in the same therapeutic space using real-world evidence may provide added insight for the pathways committees.
“The onus is really on pharma companies today to demonstrate that their product is not only safe and effective in the real world, but has favorable or justifiable cost implications in the populations payers are covering,” says John J. Doyle, SVP & General Manager, Real-World & Analytic Services, IQVIA, and faculty member, Department of Epidemiology, Mailman School of Public Health, Columbia University. “Without that, they are unlikely to be placed favorable in competing clinical pathways.”
Similarly, when drug makers are able to devise innovative contracting strategies that can bring down the cost of the care—for instance, data that confirm reduced hospital admissions related to the use of the therapy—such insight can also help to position the drug more favorably in the eyes of the pathways committees.
Going forward, Lokay also suggests that drug developers should also strive for improved clinical trial design — with closer collaboration with pathways developers. “This can help drug makers to develop the most appropriate evidence right from the outset — clinical evidence that showcases some specific competitive advantage for the investigational therapy against the therapies and treatment protocols that represent the existing standard of care.”
“Drug makers working to launch new therapies must be cognizant of the current state of the existing oncology pathways,” adds Doyle of IQVIA. “If you’re aiming to be incorporated into an existing pathway, you should be modeling what the implications would be of including your product in terms of overall costs and outcomes.”
“Sometimes even the ‘best therapy’ doesn’t work for all patients, so if your drug can meet the needs of a specific subset of patients and show improvement over the competitor’s drug (in terms of the route of administration, tolerability, side effects) then you’ll have a better chance of making it into the oncology pathways,” says Lokay.
Traditionally, tumor location has been the primary driver of treatment choice in oncology, and all of the current oncology pathways are organized according to the affected organ system, such as lung cancer, breast cancer, colorectal cancer and so on.
However, the May 2017 FDA approval of Merck’s Keytruda (pembrolizumab) as the first so-called “tissue-agnostic” oncology agent was a watershed event, demonstrating an important proof-of-concept and ushering in a new era in cancer care. Keytruda was granted accelerated approval as a tissue-agnostic oncology agent for the second-line treatment of adult and pediatric patients who had “microsatellite so-called instability-high” (MSI-H) or mismatch repair deficiency (dMMR) solid tumors — irrespective of tumor histology. “Keytruda’s MSI-H and dMMR approval blew open the doors, proving you could get a drug approved across multiple tumor types by using the ‘basket’ clinical trial approach, and that has now become a viable registrational strategy to pursue a tissue-agnostic drug approval,” says Jillian Godfrey Scaife of Trinity Partners, who co-authored a 2018 study and paper that surveyed the landscape in oncology basket trials currently under way. 
Trinity Partners’ study evaluated 37 ongoing basket trials in oncology involving 31 unique oncology therapies and 16 different biomarkers or genetic mutations. Two therapies are far enough along to be considered registrational (meaning they are clearly pursuing a tissue-agnostic regulatory filing): arotrectinib (LOXO-101, co-developed by Loxo Oncology and Bayer) and entrectinib (co-developed by Ingyta, Inc. and Roche). Nine others are potentially registrational, and the remaining 26 are exploratory, according to the study. “The process by which Keytruda gained approval provides a template for how these more exploratory trials could lead to tissue-agnostic approvals in the future,” says Scaife of Trinity Partners, and one of the report’s co-authors. “We expect the results of these trials, could lead to further registrational trials the years to come
Widespread genomic testing — the great enabler
There is no little irony in the fact that, as pathways become more personalized, the healthcare system is dealing with resistance to the genetic and biomarker testing that makes this personalization possible. Many physicians note that payer failure to cover the costs of comprehensive genomic testing, and the need for greater education to understand and interpret the output of such testing, stand out as a major barrier to broader adoption. Ongoing efforts to commercialize newer, less costly molecular diagnostic testing methodologies are also expected to help oncologists be able to more effectively match biomarker-directed and tissue-agnostic therapies to the right patient sub-populations over time.
“Integration of regular, comprehensive genomic testing will be essential to allow oncologists to quickly identify patients who may benefit from newer tissue-agnostic oncology agents and thus enable this new paradigm shift to take hold meaningfully,” says John Doyle, IQVIA. “Once next-gen tumor sequencing reaching the tipping point where a comprehensive panel is routinely run for most patients (and not just in an academic oncology setting to support clinical trials), then the full promise of this new approach will be realized in cancer care, in terms of being able to enroll more patients in tissue-agnostic clinical trials, and helping oncologists to quickly identify patients with actionable biomarkers once more tissue-agnostic therapy options are approved.”
“Maybe at the end of the day we have to rethink the way we describe oncology pathways. Perhaps ‘standardization’ is not the best word. It is more accurate to describe it as a precision medicine-management tool — delivering the right drug to the right patient at the right time,” says Zon.
1 JAMA Oncol. 2018;4(2):255-257. doi:10.1001/jamaoncol.2017.4473; https://jamanetwork.com/journals/jamaoncology/article-abstract/2666756?redirect=true).
2 ASCO’s State of Cancer Care in America 2017 report (LINK)
3 Trinity Partners, Oncology Basket Trials: An Emerging Paradigm Shift in Trial Design & Treatment Approach? http://www.trinitypartners.com/index.php/case-studies-examples/oncology-basket-trials-whitepaper