Does the rapid integration of both targeted and immuno-oncology drugs into treatment guidelines across solid tumors and hematologic malignancies herald the beginning of the end of chemotherapy as a foundational element in systemic cancer treatment? We respond to similar assertions posited after the 2018 American Society of Clinical Oncology Annual Meeting with an analysis of past, current, and future treatment of breast cancer—a tumor central to the evolution of modern cancer treatment principles. Our conclusions assert that reports of the demise of chemotherapy are greatly exaggerated and, as chemotherapy is likely to remain foundational for years to come, research is warranted to improve its patient-centricity.

Scientific achievements and regulatory enhancements have resulted in a dramatic increase in targeted and immunologic cancer drug approvals.

The resulting change in clinical guidelines has caused some to posit a chemotherapy-free future for cancer treatment.

The realities of disease natural history, current practice, and ongoing clinical trials suggest that such a future is much further off.

As long as chemotherapy remains critical to cancer treatment, additional research is needed to increase its patient-centricity.

The listserv headlines accompanying the opening of the 2018 American Society of Clinical Oncology Annual Meeting were intended to be provocative. Medscape ran the headline

“&thinsp;‘End of an Era’ for Chemo in Non-Small Cell Lung Cancer” on June 3, 2018.

 The reality was more nuanced, as the research suggested that those patients with advanced non—small cell lung cancer (aNSCLC) whose tumors expressed progressive death ligand-1 might avoid having chemotherapy as a first-line treatment.

 But the point wasn’t to be nuanced; rather, it was intentional—a shot across the bow to herald the beginning of a new era in cancer medicine, one in which chemotherapy was no longer the backbone of systemic treatment. An expanding arsenal of targeted and immunologic therapies was not only resulting in chemotherapy-free treatment guidelines for rarer cancers like renal cell carcinoma and melanoma but was also transforming the treatment of the most common and lethal of cancers. The declaration was met with giddy optimism, teasing the reader with the notion that chemotherapy may soon become a footnote in cancer treatment history alongside Coley’s toxin and cobalt. What did the emergence of targeted therapies, checkpoint inhibitors, chimeric antigen receptor T-cell therapy, vaccines, and novel gene therapies mean for systemic cytotoxic drugs as the backbone of solid tumor, lymphoma, and much of leukemia management? A review of the past, current, and near future of the systemic treatment of breast cancer (BC)&mdash;the archetype of cytotoxic therapy development&mdash;might shed light on the continued role of chemotherapy in the management of advanced cancer in both the near and long term.

The Origins of Systemic Chemotherapy Treatment of BC 

The innovation of targeted and immunologic therapies and the resulting rapidly evolving treatment paradigms we witness today very much mirror the sequential advancement of chemotherapy 60 years ago. Following the introduction of 5-fluorouracil (5-FU) in the late 1950s, considerable advances in the understanding of cancer carcinogenesis, cell cycle kinetics, and mutational targets led to numerous paradigm shifts in the systemic treatment of advanced malignancies.

 After an initial surge of drug approvals with differing mechanisms of action, research shifted to combination chemotherapy in the hopes of increased efficacy with less dose-limiting toxicity.

 At the forefront of this research was investigation into BC treatments, beginning with the combination of cyclophosphamide, methotrexate, and 5-FU in the 1970s, followed by anthracycline-based regimens in the 1980s and taxane-based combinations in the 1990s.

This golden age of chemotherapy discovery appeared to sunset as explorations of dose density and dose intensification, supported by bone marrow (stem cell) transplant, ended the decade with one of the darker chapters in BC research.

Although progress continued in the development of new chemotherapeutic agents for the salvage treatment of metastatic BC (mBC) (capecitabine, 1998; nab-paclitaxel, 2005; ixabepilone, 2007; eribulin, 2010), researchers at the start of the new millennium seemed more focused on limiting chemotherapy toxicity via improved supportive care while reducing chemotherapy exposure via genetic profiling.

 Clinical trials testing hormonal and human epidermal growth factor receptor 2 therapies dominated meeting presentations.

More recently, novel therapeutics including cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, poly (ADP-ribose) polymerase inhibitors, and checkpoint inhibitors have gained FDA approval, thus rapidly altering treatment guidelines and establishing new standards of care for first-line treatment of mBC. The latest additions to this arsenal—likely to continue this trend&mdash;are the phosphoinositide 3-kinase inhibitors. The rapid expansion of the mBC systemic, nonchemotherapy cancer arsenal would appear to support the contention that, like in aNSCLC, the need for conventional chemotherapy in mBC is fading. However, critical differences in the mBC patient journey challenge that prediction.

There are stark differences in the epidemiology of BC versus aNSCLC. First, unlike aNSCLC, in which the majority of patients are initially diagnosed with advanced disease, more than 85% of patients with BC present with lower-stage disease, with many receiving adjuvant chemotherapy.

 Given the longer clinical trial time required for proof of superiority in the adjuvant setting, it is unlikely that chemotherapy will be displaced from adjuvant BC treatment in the foreseeable future. Second, overall median survival from diagnosis of mBC is much longer than that of aNSCLC (approximately 24 months and 10 months, respectively), with patients exposed to many more lines of systemic therapy.

 Real-world studies have shown that an increasing number of patients with mBC receive more than 5 lines of therapy.

 In a retrospective analysis, the proportions of patients with BC receiving fifth, sixth, and seventh or greater lines of therapy in 2007 were 15.8%, 8.2%, and 5.1%, respectively, which increased to 28.2%, 18.7%, and 12.3% in 2010.

 These patients derived a clinical benefit, with each subsequent line extending their overall survival by 8.7, 8.2, and 7.5 months in the fifth, sixth, and seventh lines of therapy, respectively.

 The fact that chemotherapy is foundational to the neoadjuvant, adjuvant, and metastatic treatment of BC, as well as its use in combination with targeted and immuno-oncology approved drugs, would suggest that current and future patients with BC will be receiving multiple lines of systemic chemotherapy for many years to come. However, could the scientific and regulatory processes that have expedited the changes in the guideline treatment of aNSCLC alter the chemotherapy paradigm much sooner than history would predict?

Expedited drug approval processes (eg, Accelerated Approval Program, cohort expansion trial design, tumor-agnostic mutational drug indications), in conjunction with policy initiatives, are revolutionizing drug development. What had been a historical benchmark of 12 years to navigate phase 1 to 3 trial completion and FDA approval has, in recent years, been slashed to half that duration. What does this rapid pace of change herald for traditional cytotoxic chemotherapy? A review of BC trials in progress may shed some light. A ClinicalTrials.gov search of all actively recruiting US clinical trials of pharmacologic interventions in mBC was conducted on September 20, 2018. There were 311 identified trials: 146 included a chemotherapy component, with 91 including chemotherapy in combination with a novel agent. In comparison, 27 studies were of CDK 4/6 inhibitor therapy without chemotherapy. Phase 3 studies consisted of 18 evaluating CDK 4/6 inhibitors, 13 evaluating chemotherapy in combination with a novel agent, and 7 comparing chemotherapy with a novel agent. A similar search of phase 3 trials of actively accruing adjuvant BC trials found 26 studies: 15 involving chemotherapy, with 8 using chemotherapy in the experimental arm, both alone and in combination with targeted and immunologic drugs. The extent to which chemotherapy remains a component of mBC research leaves little doubt as to its critical role for years to come.

The development of precision medicine approaches in the treatment of advanced malignancy has dramatically altered the management and outcomes of patients with cancer. Despite the rapid advances of science and improved regulatory processes that are allowing those advances to move from bench to bedside in as little as 3 to 5 years, chemotherapy remains a critical component of solid tumor and hematologic malignancy treatment today and likely for years to come. We chose to illustrate this with an exploration of the development of systemic therapies for BC, given its history as a field that has heralded many of the hallmarks of modern cancer treatment. A similar case could have been made for researching treatments of many of the most common and lethal cancers: colorectal, ovarian, and even lung. Although effective, the current arsenal of chemotherapeutic interventions presents its own particular set of patient-centric challenges due to the agents’ impact on quality of life, their limited efficacy, and their significant adverse effects. However, despite this and the explosion in targeted and immunologic therapy approvals, as well as the ongoing research that will likely extend their number and indications, research on traditional systemic cytotoxic drugs should not be abandoned. The end of the chemotherapy era is not near; chemotherapy will play a significant role in the treatment of mBC, among a host of other common cancers, in the years if not decades to come. Further research is warranted to understand the comparative effectiveness of the currently approved chemotherapeutic agents and to explore new agents with greater patient-centricity.

This work was funded by Athenex, Inc. Cardinal Health conducted the literature review and drafted the manuscript content. Athenex provided editorial review.

 Cardinal Health Specialty Solutions (BF, JK, KL), Dublin, OH; Athenex, Inc (ID, JW), Buffalo, NY.

 Dr Kish reports employment with and stock ownership in Cardinal Health. Drs Dokubo and Wojtynek report employment with and stock ownership in Athenex, Inc. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (BF, JK, ID, JW, KL); acquisition of data (BF, JK, KL); analysis and interpretation of data (BF, JK, KL); drafting of the manuscript (BF, JK, ID, KL); critical revision of the manuscript for important intellectual content (BF, JK, ID, JW, KL); obtaining funding (ID); administrative, technical, or logistic support (BF, JW); and supervision (JK, JW).

 Kevin Lord, PhD, MHS, Cardinal Health Specialty Solutions, 7000 Cardinal Pl, Dublin, OH 43017. Email: kevin.lord@cardinalhealth.com.

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Articles

COMMENTARY

The expanding arsenal of targeted and immuno-oncology drugs has unalterably changed the landscape of systemic cancer treatment, but chemotherapy will remain critical for years if not decades to come.

Reports of the Demise of Chemotherapy Have Been Greatly Exaggerated

 The causes of oncology drug price growth remain unclear. Analyzing corresponding trends in revenue can help understand these causes. This study seeks to assess changes over time in prices, patient counts, and drug-level revenues in the US market for oncology therapies and to investigate whether price growth is driven by an increased ability by pharmaceutical firms to capture profits.

 Nineteen-year retrospective study (1997-2015).

 We used panel regression to investigate trends in prices, patient counts, and revenues within a US national data set consisting of targeted oncology therapies launched in different eras.

 We find that prices have roughly tripled, whereas average patient counts per therapy have fallen by 85% to 90% over this period. However, the entire distribution of annual revenues has fallen: For instance, median revenues for drugs launched in the early 2010s are about half of what they were for drugs launched in the late 1990s.

 Future research on the causes of quantity decline can help inform pharmaceutical policy.

Comparing targeted oncology therapies launched in the intervals 1997-2002, 2003-2009, and 2010-2015, we investigate trends over time in prices, the number of patients using each drug, and revenues within the US market.

We confirm the previously documented result that prices are rising over time.

However, revenues are not rising concurrently with prices.

This decline is attributable to contemporaneous declines of 85% to 90% in per-drug average patient counts.

Insurers, healthcare providers, and others have noted that prices for novel oncology treatments are rising over time.

 Price per episode of treatment has risen steadily, and prior research suggests that although the efficacy of cancer therapies (as measured by gains in overall survival) is certainly improving over time, prices are rising even faster.

 If improved efficacy or effectiveness does not provide the dominant explanation, then what else might be contributing to the observed increase in prices?

One possibility is that firms today possess greater market power and use it to earn greater rewards for their drugs. If true, higher prices would coincide with higher revenues. At first blush, the magnitude of price growth in the oncology market may make growth in revenues seem self-evident. However, it becomes more difficult to assess when one considers the fact that newer drugs tend to treat fewer patients, as we document later. This decline in patients treated may be due to greater personalization of therapy, slower incremental progress that fails to force older drugs out of the market, or other factors. Regardless, rising prices alongside falling quantities make the trend in revenues an empirical question.

An empirically interesting context for this investigation is the market for targeted oncology therapies, first introduced in the late 1990s. Prior research has documented that targeted therapies have quickly come to dominate the market: For example, targeted therapies accounted for about two-thirds of all chemotherapy expenditures by 2011.

 In this study, we investigate trends in prices, quantities, and revenues for targeted oncology therapies. We aim to determine whether higher prices have coincided with higher revenues and rewards for innovation or whether, instead, price growth has coincided with flat or falling revenues. Analyzing a sample of targeted therapies intended to treat common tumor types, we estimate the growth in price per patient-year, the reduction in the average size of the annual patient base using each drug, and the resulting change in revenue. In auxiliary analysis, we also estimate the implied increase in costs of drug development per patient-year.

We focused on targeted cancer drugs launched since 1997, when the first targeted agent (monoclonal antibody) was approved by the FDA. We considered all drugs primarily aimed at extending survival and/or progression-free survival for patients with cancer and focused on the 6 most common tumor types: breast, colorectal, melanoma, non-Hodgkin lymphoma, non—small cell lung, and prostate.

 As some drugs are indicated for more than 1 tumor type, the unit of analysis for this study was therapy—tumor pair. To account for the fact that many drugs have more than 1 indication, and that approvals for new indications are frequently granted subsequent to the initial approval, we computed estimates for all possible therapy–tumor pairs, including all indications known at the time of this analysis. We estimated relative usage of a single agent for different indications by assuming usage proportional to relative disease incidence. After we dropped data for indications not of interest, our final sample consisted of 29 therapies and 33 therapy–tumor pairs (see 

Using data for each of these therapy—tumor pairs, we defined 3 measures of interest: therapy price, the number of patients using each drug for each indication, and annual revenues. We estimated each of these quantities for each therapy–tumor pair of interest, for each year in our analysis sample (1997-2015), and then used panel regression to investigate how they changed with respect to drug launch year. In supplementary analysis presented in the eAppendix, we also estimate trends in per-patient research and development (R&D) cost.

Therapy Price, Patient Count, and Revenues

We estimated the total number of patients and the estimated price of treatment using the IQVIA National Sales Perspective (NSP) data set.

 The NSP reports nationally representative estimates of the total annual units of individual therapies distributed in the United States and of the total related revenues received by manufacturing firms. We combined these data with monthly dose and average length of treatment values specific to each therapy—tumor pair (obtained from FDA labels and clinical trials) to derive our price and patient count outcomes. Price was calculated as the cost for a full course of treatment (ie, the total revenue estimated to return to the manufacturer as a result of 1 patient being treated). Patient counts were imputed through analysis of the total number of therapy units distributed in combination with label information on dosing for a full course of treatment. Revenues were calculated within-year as the product of price and patient count. Revenues were calculated at the therapy, rather than therapy–tumor, level because this captures the total return on launching a new drug. Complete details on the construction of these measures are provided in the eAppendix.

To validate our findings regarding trends over time in the average number of patients, we separately analyzed patient counts in an independent data set, the Medicare Current Beneficiary Survey (MCBS). The MCBS is a survey of a representative sample of Medicare beneficiaries and contains data on diagnosis and drug utilization.

 For each of the therapy—tumor pairs of interest, we counted the number of individuals in the MCBS sample who (1) had an indication for that tumor type and (2) reported using that therapy. We then used sampling weights to inflate these counts to the population level. We note that the MCBS results are estimates of counts for the Medicare population only and should not be construed as separate estimates for the aggregate US population. We repeated this process for the individual years between 1997 and 2012. (At the time of this analysis, 2012 was the most recent year for which MCBS data were available.) Finally, we compared trends over time in average patient counts as estimated in the IQVIA and MCBS analyses.

We sought to determine whether each of our main outcomes (therapy price, number of patients, and annual revenues) was correlated with therapy launch year. To do this, we fit a series of regression models using the above measures as outcomes and therapy launch period as the key independent variable. We converted therapy launch year into a categorical variable with 3 groups: drugs launched between 1997 and 2002 (reference category), drugs launched between 2003 and 2009, and drugs launched between 2010 and 2015. We present results from 2 sets of regressions. In the first, we regress each of our outcomes of interest on this categorical variable corresponding to launch time period. In the second, we include an additional regressor (years post launch) to control for life cycle trends in the price and quantity of a drug following its market entry. We report trends in average regression-adjusted price and quantity and then report movement over time in the entire distribution of regression-adjusted annual revenues per therapy. We conducted sensitivity analyses involving (1) adding covariates to the base-case model, (2) using alternative values for key parameters related to the cost of R&D, and (3) asserting a linear relationship between launch year and outcomes, rather than the period fixed-effects structure described above. These are discussed in detail in the eAppendix.

We begin with an analysis of the first study outcome, episode treatment price. The fact that newer oncology products are increasingly costly has been extensively documented in the literature.

 This trend is also readily apparent in our data on targeted agents. 

 presents the results of a series of regressions that use therapy price as the dependent variable and launch year as the key independent variable and that follow the specifications defined previously.

We find a statistically significant positive correlation between price and launch year. The episode treatment cost for drugs launched between 2003 and 2009 was, on average, $23,000 greater than that for drugs launched between 1997 and 2002. The difference was even greater for drugs launched between 2010 and 2015—a statistically significant average difference in episode treatment cost of about $43,000.

This study sought to examine whether price growth has coincided with revenue growth. Thus, trends in annual average patient counts play a crucial role.

 presents the results of the regressions for the patient count outcome, first without and then with the control for time since launch. Figure 2 demonstrates a strong negative relationship between launch year and average patient count. Relative to therapies launched in the early period, the dummy models suggest that therapies launched in the middle period were used by, on average, 28,000 to 35,000 fewer patients annually, whereas therapies launched in the late period were used by 33,000 to 44,000 fewer patients. Detailed time-series plots of patient counts for individual therapy—tumor pairs, and for average values within launch period, are presented in 

To confirm these results, we conducted a separate analysis of patient counts by therapy—tumor pair in the independent MCBS data set. Comparative results are presented in 

Note that the IQVIA data set covers the entire US population, whereas MCBS covers Medicare patients only. Each is designed to be nationally representative for its particular sample frame.

There is clear evidence that annual patient populations are smaller for more recently launched drugs: In the main analysis using IQVIA data, the average patient count fell from 48,520 per drug for drugs launched in the early period to 4781 per drug for drugs launched in the late period, a decline of 90%. A decline of similar magnitude (85%) is observed in the Medicare data.

The reduction in quantity seems to have offset growth in price. The entire distribution of annual revenues has fallen over time. We use the regression-adjusted (ie, predicted) revenues from our regression model of revenues as a function of years since launch and time period. We also aggregate this up to the therapy level to eliminate the possibility that newer drugs spawn more indications and thus artificially lower revenues per tumor type. This permits uniform comparisons over time that account for the way in which revenue evolves over the life cycle of a drug. 

 (A and B) presents the distribution of regression-adjusted annual revenues (at the therapy level) for each of the 3 launch periods; the difference between the 2 panels is that Figure 4B removes a single influential outlier—bevacizumab&mdash;from the data set. Both panels show that the distribution of regression-adjusted annual revenue has shifted left over time. In both cases, the most recent distribution ranges from $250 million to $500 million, whereas the earliest period shows a distribution from about $250 million to more than $900 million (all values are reported in 2015 US$). The sole difference between the distributions lies in the middle period. In the full sample, the main mass of the distribution lies between those of the early and late launch periods, but significant right skew is present. This long right tail is caused by the presence of a single drug, the blockbuster bevacizumab. Annual revenues for that drug (limited to the 6 indications of interest to this study) routinely exceeded $1 billion, in part because it was approved for more than 1 of those tumor types.

 presents the shifts in the distributions at key percentile points. Because bevacizumab is such an outlier, the Table accurately describes the distributions in both panels of Figure 4 (ie, the bevacizumab data points lie beyond the 90th percentile).

Annual adjusted revenues for the median drug have fallen from about $580 million to $287 million, a decline of about 50%. There is a decline of roughly 40% at the 25th percentile and nearly 60% at the 75th percentile. The only region of increase occurs at the 10th percentile, where revenues increased from the early to middle period, only to fall back down in the final period.

Results from the sensitivity analyses are presented and explained in the eAppendix.

The rising cost of novel oncology therapies has been a source of great controversy in recent years.

 Our analysis confirms that prices of oncology drugs are indeed rising rapidly. We show that the number of patients taking each drug has dropped substantially over the same period of time. As a result, revenues have fallen at every point in the distribution, after accounting for life cycle growth in revenues over years since launch. This suggests that price growth is unlikely to have resulted from greater pricing power, at least within this market segment. Profit-maximizing firms with more pricing power would never willingly make decisions that lead to lower revenues for each drug launched. One exception to this point might occur if costs of drug discovery or production have fallen significantly. Although the extant academic literature on the costs of drug discovery remains controversial, all of it points to rising costs.

 We know of no academic publications on trends in the costs of oncology drug production; more research is called for in this area.

This study has several important limitations. The IQVIA NSP data set, which provided much of the source data for this study, contained “restrictions” (partially missing values) for some therapies in some years; we recoded these as missing. This step will not affect the results of the study, as long as the circumstance of missing data is not correlated with our outcomes of interest. Also, our measure of the cost of individual therapies contains only the component of total cost that returns to pharmaceutical manufacturers; it does not incorporate markups by wholesalers or hospitals, nor does it include any confidential rebates paid by manufacturers to purchasers. In addition, we focus on only treatments for the 6 most common tumor types; as such, our results have limited generalizability to other forms of cancer. Finally, to estimate therapy prices, we assume that average treatment duration is equal to the duration indicated on the drug label. In practice, individual patients’ duration of therapy may be longer or shorter than is suggested by the label because of factors such as mortality, discontinuation, and extended treatment at the discretion of the physician.

Previous research has suggested that we should be skeptical of the notion that prices are rising solely because effectiveness is rising.

 Our study also casts doubt on an explanation for price growth that relies solely on rising R&D costs: If this were so, firms would necessarily respond by launching drugs capable of earning higher revenues. Our findings suggest instead a relationship between price growth and average patient counts, although the precise nature of this relationship is not fully clear. One possible explanation for declining patient counts is relatively slow growth in effectiveness over time; this would improve the ability of older drugs to remain on the market. The consequences of this longevity would be reduced market share and reduced revenue for newer drugs. A second possible hypothesis for declining patient counts would be increased competition: All else being equal, an increase in the number of drugs approved for a given tumor type would lead to a decline in the average number of patients per drug. This explanation, however, would also suggest an increase in price competition, which is inconsistent with the observed data.

A final possible explanation for the trends we observe is growth in the development of drugs that target patients with specific biomarkers (sometimes referred to as personalized medicine) within the targeted oncology market. By design, these drugs target subsets of the total population of patients with the indicated cancer. Shrinking patient counts might be in part the result of more personalized therapies that treat narrower indications. For example, trastuzumab is indicated for human epidermal growth factor receptor-2—overexpressing breast cancer, which comprises only 15% to 20% of invasive breast cancer cases.

 Mechanically, personalization leads to lower revenue when we hold prices constant. From another perspective, this is a cost to society of personalization: Without significant offsetting price growth, personalized therapies generate lower revenues and returns to innovators; this reduction in returns may reduce the rate of drug discovery in the long run.

 More research is needed on these and other hypotheses for the causes of drug price growth and the observed decline in average patient counts.

Despite acknowledged limitations, this study provides surprising new data on declining patient populations treated by targeted cancer agents. This pattern is likely an important and, to our knowledge, previously undescribed factor that lies behind trends in revenues and rewards from innovation in oncology.

Precision Health Economics (JS, JV-O, DV, DL), Oakland, CA; Genentech (HPG), South San Francisco, CA.

 Dr Vanderpuye-Orgle is an employee of and owns stock in Amgen, Inc, which manufactures oncology therapies. Mr Goertz is employed by Genentech/Roche and owns Roche stock; Genentech manufactures and sells several of the oncology therapies covered in this manuscript. Dr Lakdawalla is a consultant to Precision Health Economics, a healthcare consultancy with clients in the life science and insurance industries, including firms that market oncology treatments; he holds equity in Precision Medicine Group, parent company of Precision Health Economics. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (JS, JV-O, HPG, DL); acquisition of data (JS, DV); analysis and interpretation of data (JS, JV-O, HPG, DL); drafting of the manuscript (JS, DV); critical revision of the manuscript for important intellectual content (JS, JV-O, HPG, DL); statistical analysis (JS); provision of patients or study materials (HPG); obtaining funding (HPG); administrative, technical, or logistic support (JS, DV); and supervision (JS, HPG, DL).

 Jesse Sussell, PhD, Precision Health Economics, 555 12th St, Ste 1725, Oakland, CA 94607. Email: jesse.sussell@pheconomics.com.

1. Chhatwal J, Mathisen M, Kantarjian H. Are high drug prices for hematologic malignancies justified? a critical analysis. 

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2. Lotvin AM, Shrank WH, Singh SC, Falit BP, Brennan TA. Specialty medications: traditional and novel tools can address rising spending on these costly drugs. 

. 2014;33(10):1736-1744. doi: 10.1377/hlthaff.2014.0511.

3. Kantarjian H, Rajkumar SV. Why are cancer drugs so expensive in the United States, and what are the solutions? 

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4. Howard DH, Bach PB, Berndt ER, Conti RM. Pricing in the market for anticancer drugs. 

POLICY

The prices of targeted oncology therapies have grown substantially, but revenues have not. This is due in part to large declines in per-drug patient counts.

Understanding Price Growth in the Market for Targeted Oncology Therapies

 To update an ongoing assessment of care pathway development, implementation, and evaluation, and to evaluate the emerging relationship between care pathways and other components of value-based care.

 Targeted literature review followed by an online survey and in-depth interviews.

 The PubMed/Cochrane databases and gray literature were searched for publications on care pathways (January 1, 2014, to March 3, 2017); a supplemental targeted search was completed in October 2017. Qualitative data were collected via an online survey and semistructured, in-depth interviews with payers, providers, pathway vendors, and opinion leaders.

 A total of 112 articles or posters were identified in recently published research. The survey and interviews included 32 and 19 respondents, respectively. Care pathways are increasingly driven by providers and provider networks. Overall, we found increased awareness of and adherence to codified best practices or standards, and prioritization of high-quality evidence during development. Research findings suggest stronger links between outcomes-based measures and both physician reimbursement and care pathway evaluation. Integration with other value-based care initiatives, including alternative payment models, is also gradually emerging.

 This study identified growing use of high standards of evidence and adoption of other best practices in the development, implementation, and evaluation of care pathways. As the influence of care pathways on patient care continues to expand, additional efforts are needed to increase transparency, disclose conflicts of interest, engage with patients, effectively align care pathways with improvements in patient outcomes, and integrate efficiently with other value-based care initiatives.

As the use of care pathways has expanded in the United States, development, implementation, and evaluation processes have evolved.

Research findings support notable increases in process transparency, codification of standards, and prioritization of high-quality evidence.

Provider groups emerged as the driving force behind development and implementation, although physician resistance and administrative burden remain barriers to adoption.

Despite efforts, patient education and engagement remain inadequate.

There are indications of stronger links between outcomes-based measures, rather than traditional compliance measures, and both physician reimbursement and care pathway evaluation.

The movement toward value-based care may significantly affect the development and expansion of care pathways.

In the last decade, the use of care pathways—designed to provide evidence-based treatment options for disease management, improve quality of care, reduce unnecessary variation, and lower costs&mdash;has expanded rapidly in the United States.

 Although pathway use is increasingly prevalent for chronic diseases,

 use in oncology is well known, with 58% of oncology practices reporting use of pathways in 2016,

 Best practices to guide pathway development, implementation, and evaluation have been established in oncology, and the American Society of Clinical Oncology (ASCO) has issued a policy statement and a set of detailed criteria to ensure the integrity and quality of oncology pathways.

At the same time, other value-based healthcare initiatives and alternative payment models (APMs) are being adopted. In 2016, approximately 31% and 28% of physicians across specialties participated in bundled payment programs and medical homes, respectively.

 Overall, 43% of physicians received some form of value-based reimbursement. With the goals of improving quality of care while reducing cost, care pathways not only have objectives similar to those of other value-based initiatives but also may be critical in the transition to value-based care.

A January 2016 landscape assessment of care pathways revealed a wide range of development, implementation, and evaluation methods but a critical absence of transparency.

 In this follow-up study, we assessed changes in development, implementation, and evaluation of pathways and reviewed the latest evidence on integration of pathways with value-based care initiatives in the United States.

Similar to the 2016 study, a targeted review of published literature was followed by an online survey and in-depth interviews. Results were compared with those of the prior study, providing a perspective on the state of care pathways today and direction for the future.

Our search covered the PubMed and Cochrane Reviews databases and selected conferences’ websites. Publications, posters, and abstracts discussing care pathways in US healthcare settings that were in English and published between January 1, 2014, and March 3, 2017, were reviewed. We further searched trade journals and websites of professional organizations, pathway vendors, payers, and major provider groups. A supplemental search was completed in October 2017.

In screening materials identified in our search, we again required that a care pathway have stated objectives defining goals or key elements of care and was limited to specific disease states in defined patient populations, used evidence-based medicine or clinical guidelines to develop treatment recommendations, included a monitoring and evaluation mechanism, and included criteria for the use of pharmacologic therapies.

 Between June and September 2017, we conducted online surveys (n = 32) followed by in-depth interviews (n = 19). Respondents were selected to represent a mix of payers, providers from a range of specialties and practices, commercial care pathway vendors, and opinion leaders. Although all respondents were screened for involvement in pathway development, implementation, evaluation, or use, questions were administered only to those with experience and knowledge relevant to given sections (rated ≥3 on a 5-point scale). Respondents were offered honoraria for survey and interview participation.

 The survey was structurally similar to the 2016 study, with new sections on value frameworks and APMs. Descriptive analyses were conducted in Microsoft Excel.

 Interviewers administered an hour-long, semistructured discussion guide with open-ended questions. Interviews were designed to supplement information from the survey with additional detail on key areas of interest.

We identified 750 unique citations. Full-text review was conducted for 138 publications; 68 full-length articles and 44 abstracts and posters matched the selection criteria. Key themes and gaps in the literature informed the design of the survey and interviews. We found more transparency and codification of the development process, particularly in oncology, where pathway use has matured and more research has been published.

 More studies documented pathway adherence, resource use, and patient outcomes,

 but implementation and evaluation are still inconsistently documented or communicated. Engagement with stakeholders, particularly patients, remains inadequate.

 Efficacy and toxicity still supersede cost as key considerations during pathway development, yet pathways are viewed as a means to provide downward pressure on rising drug prices.

 Nevertheless, closer linkages with features of value-based care have emerged. As payers experiment with linking pathways and APMs,

 barriers to such integration need to be further understood. Interest is also growing in incorporating value frameworks in pathway development.

Twenty-five providers and 7 payers completed the survey. Eleven providers, 4 opinion leaders, 3 payers, and 1 pathway vendor were interviewed (

 Among all respondents with knowledge of pathway development, cost of care was the most frequently identified consideration for therapeutic area selection when care pathways are developed (77% [20/26]), followed by clinical outcomes, variation in treatment patterns, and prevalence rates (

). In 2016, the internal selection process was most cited, followed by cost of care. Pathways for relatively prevalent cancers, such as breast, colon, and lung, remain common; however, interviewees noted that rare cancers with high treatment costs are being identified for pathway development, citing recent FDA approvals of chimeric antigen receptor T-cell therapies and advances in precision medicine. Over the next 5 years, most survey respondents expect pathway use to expand in both oncology (78% [25/32]) and nononcology (84% [27/32]) areas. Pathways have also broadened to cover the care continuum, including symptom management and palliative care. Further, respondents had experience with pathways for common or high-cost chronic diseases, particularly in the areas of rheumatology, diabetes, asthma, and cardiology.

 Nearly all provider respondents (96% [24/25]) had a role in developing, implementing, evaluating, or using 2 or more pathways. Among respondents who addressed pathway development, 92% (24/26) identified clinicians as stakeholders, with fewer indicating a role for health plans (46% [12/26]) or pathway vendors (12% [3/26]). Most providers with development experience (74% [14/19]) indicated that their practice develops or implements pathways separate from those developed by payers or vendors.

Evidence considerations and transparency in care pathway development.

 Treatment guidelines (88% [23/26]) and published systematic literature reviews (73% [19/26]) were identified as key data sources for pathway development (

). Fewer identified retrospective or observational studies than in 2016. Providers were less likely than payers to identify prospective studies (53% [10/19] vs 100% [7/7]) or randomized controlled trials (58% [11/19] vs 86% [6/7]) as influential.

Interviewees identified experts and published or validated data from existing pathways as data sources for pathway development; survey results also confirmed that data from existing pathways informed development (77% [20/26]). Grading evidence quality appears to be less influential than in 2016 (58% [15/26] vs 81% [17/21]).

Efficacy (96% [25/26]), safety/toxicity (88% [23/26]), pharmaceutical costs (88% [23/26]), and medical resource use and costs (85% [22/26]) were the main factors considered when selecting treatments for the clinical algorithm. All (7/7) payers indicated considering medical resource use and costs versus 79% (15/19) of providers. In 2016, respondents identified safety (95% [20/21]), efficacy (86% [18/21]), and medical costs (81% [17/21]) as main factors. In both studies, efficacy was ranked as the most important. Although all interviewees indicated considering costs, particularly pharmaceutical costs, and clinical outcomes during development, less than half described cost as an initial consideration, and many indicated that clinical benefit precedes cost.

More than half (62% [16/26]) reported that their organizations followed best practices as detailed by ASCO’s policy statement; of these, 81% (13/16) noted that best practices, standards, or methodology were available to key stakeholders, including patients and payers. However, access may be restricted through means such as an intranet, patient portal, or membership. Further, awareness of processes for disclosing and managing potential conflicts of interest varied.

 Most (90% [28/31] with knowledge of pathway implementation) reported that pathways typically provide physicians with multiple treatment options for a given diagnosis, and 94% (29/31) reported that physicians have a choice about placing patients on a pathway. Compared with 68% (13/19) in the 2016 study, only 39% (12/31) reported a relationship between pathway compliance and reimbursement (

]). All of these respondents noted financial penalties or disincentives for noncompliance; 83% (10/12) indicated significant or extremely significant penalties. Interviewees expected incentives for performance, patient satisfaction, and other quality metrics captured in value-based care to receive traction in the near future. Process-oriented indicators, like compliance, were viewed as intermediate, surrogate measures. All payers (7/7) indicated that prior approval is required compared with 58% (14/24) of providers.

 Quality metrics (78% [18/23] with knowledge of pathway evaluation) were most commonly used to evaluate pathway performance, followed closely by readmission rates, compliance, and hospitalization rates (

). Quality metrics, readmission rates, and adverse event rates were each identified by 43% (10/23) as top 3 metrics. In the 2016 study, compliance was top-ranked and identified by most as a top 3 metric.

Interviewees observed that compliance remains an important measure. Target compliance rates of 75% to 80% were reported in 2016; however, only 43% (10/23) of respondents in the current research experienced 70% or greater compliance. Respondents reported challenges collecting or analyzing pathway data, including 75% (9/12) who encountered data collection issues.

 Some respondents (35% [11/31] with knowledge of pathway implementation) recognized changes in patient engagement over the last 3 years, among whom 91% (10/11) indicated that patients increasingly sought information on care pathways and 64% (7/11) observed increasing involvement of patient advocacy groups. Less than half of respondents (42% [13/31]) reported that on-pathway patients are provided disclosure or education about pathways; this included 46% (11/24) of providers, compared with 20% (1/5) of providers in 2016 (

). Interviewees also suggested that treatments may not be described as being part of a pathway. Financial incentives may not be transparent; 38% (5/13) of respondents who reported patient disclosure believed that patients were aware of financial incentives provided to physicians. Moreover, 26% (8/31) indicated that details on financial incentives are publicly available to all stakeholders, including patients.

Patient feedback on pathways is not generally mandated, with 30% (7/23), 43% (10/23), and 26% (6/23) reporting always, sometimes requested, and not formally engaged, respectively, among those with knowledge of pathway evaluation. Increased patient involvement is expected (78% [25/32]) in the next 5 years, particularly in evaluation (50% [16/32]) compared with development and implementation.

 The majority of survey respondents (93% [26/28] with knowledge of APMs [accountable care organizations, medical homes, and bundled payments]) and interviewees noted that care pathways are very or somewhat likely to be used in APMs; in APMs using pathways, 43% (12/28) estimated that greater than 50% of patients are on-pathway. Some interviewees noted that pathways could be key to value-based contracting and outcomes-based payments but also cautioned that costs could drive clinical care as a result. Even so, 57% (16/28) reported barriers to pathway use in APMs, including administrative burden (81% [13/16]) and lack of technological integration (75% [12/16]).

 Most survey respondents (74% [14/19] with knowledge of prominent US value frameworks) reported the use of value assessment frameworks in pathway development. Sixty-four percent (9/14), 57% (8/14), 50% (7/14), and 43% (6/14) noted value frameworks developed by the National Comprehensive Cancer Network (NCCN), American College of Cardiology and American Heart Association, ASCO, and Institute for Clinical and Economic Review (ICER), respectively. Interviewees often mentioned NCCN, ASCO, and ICER and generally advised considering value frameworks during development but not in isolation.

 Increased cost containment efforts (75% [24/32]), use of bundled payments (66% [21/32]), and applicability beyond oncology (47% [15/32]) may advance care pathway expansion and uptake. Other catalysts included the popularity of value frameworks (44% [14/32]), integration of clinical trials (34% [11/32]) and biomarker testing (25% [8/32]), and proliferation of medical homes (25% [8/32]). Interviewees additionally highlighted the value of standardization. In general, more providers reported the use of value frameworks in development; however, more payers felt that the popularity of value frameworks may expand the use of care pathways.

Physician resistance (pushback) remains the largest potential barrier to expansion (84% [27/32]), followed by administrative burden (

). Payers were more likely than providers to believe that administrative burden (71% [5/7] vs 56% [14/25]) and perceived implementation costs (71% [5/7] vs 32% [8/25]) are greater potential barriers, but more providers than payers found that the failure to demonstrate cost savings was a greater potential barrier (40% [10/25] vs 29% [2/7]). Reports of insufficient information technology (IT)/tracking systems and failure to demonstrate patient outcomes and cost savings have declined.

Care pathway development, implementation, and evaluation continue to play a significant role in utilization management in the United States, with cost considerations serving as a core motivation for these activities, collectively. During the development process, however, efficacy and safety continue to be prioritized overall. In large part, this trend continues to reflect efforts to manage care in the treatment of patients with cancer. Although pathways continue to be used in prevalent cancer types, primarily, we found a wider range of therapy areas for which pathways have been implemented, from rare cancers to chronic diseases.

We observed a higher bar for evidence during development, including greater emphasis on prospective studies and clinical guidelines, compared with the lack of codified standards and transparency in development we noted in our 2016 research. Although transparency has improved, access to specific development methodology remains limited to internal stakeholders, and disclosure of potential conflicts of interest is inconsistent. To some extent, challenges with transparency contribute to the difficulty in presenting a more definitive picture of conflicts or tension between pathways that guide medical care versus initiatives motivated by the imperative to manage expenditures, particularly in oncology.

Efforts to improve patient engagement with care pathways were among the most notable recent trends. About one-third of respondents observed changes over the past 3 years, noting increases in patient requests and patient advocacy group involvement, and more providers reported informing patients about pathway use. Most respondents anticipated future increases, with respondents also suggesting that patient engagement is becoming a feature of pathway evaluation, although this was not formally assessed in the prior study. Despite these efforts, a fundamental lack of patient awareness remains regarding the use of, and financial incentives associated with, pathways.

 We observed trends toward provider-driven pathways, the use of value frameworks during pathway development, and the growing relationship between pathways and APMs. Providers are increasingly central to the development and implementation of care pathways.

 In the 2016 study, providers were consistently identified as critical stakeholders, but the role of payers was often dominant. Pathway vendors still play an important role—particularly in serving payers that use pathways to manage plan member benefits&mdash;but providers are becoming the key drivers. Although we observed some trends distinguishing payer and provider behavior (data sources for pathway development, consideration of medical resource use and costs, requirement of prior approval, views on value frameworks, and barriers to expansion), further research in this area must be conducted.

Continued pressure to reduce costs has the potential to further expand the scope and development of care pathways. Value frameworks are often integral in the development process, ranging from being the primary approach for pathway construction to a reference for a component of treatment selection. The influence of value-based care was also noted in pathway implementation, with some respondents pointing to a shift in incentive structures. Now, fewer respondents indicated physician reimbursement being tied to pathway compliance; instead, reimbursement may become more directly linked to patient outcomes. Additionally, respondents believed that patient outcomes and other quality measures may eventually become standard pathway evaluation metrics. Pathways can be an effective tool in the delivery of value-based care, particularly in oncology.

 There is potential for more integration between pathways and APMs, which have similar objectives.

 Moreover, catalysts for pathway uptake include use of bundled payments and medical homes.

However, care pathways continue to face barriers to adoption. Although prior concerns with IT/tracking systems and the demonstration of patient outcomes and cost savings have decreased, concerns with physician pushback and administrative burden persist. Such concerns could be mitigated with provider-driven pathways and availability of evidence on patient outcomes, long-term efficiency, and reduced practice costs.

We utilized a hybrid approach with a targeted literature review followed by qualitative primary research, entailing survey and interview components, similar to the 2016 study. The survey and interview findings aligned with those of the literature review; however, the literature review findings are not exhaustive and are subject to the limitations of keyword-based searches of publication databases and ad hoc searches of the gray literature. Although survey and interview respondents had oncology and nononcology experience, the samples are not necessarily representative, and findings may not be generalizable to the wide diversity of care pathways. Several factors also limited our ability to cross-validate responses between the current and prior studies and perform statistical tests. The samples’ size and composition differed, and both the survey structure and responses to questions were updated to adapt to changes in the pathway landscape.

METHODS

The authors examined the latest trends in development, implementation, and evaluation of care pathways and the impact of the movement toward value-based care.

US Care Pathways: Continued Focus on Oncology and Outstanding Challenges

 To assess the association of a clinical decision support (CDS) algorithm for hospital discharge disposition with spending, readmissions, and postdischarge emergency department (ED) use.

 A retrospective study in a cohort of fee-for-service Medicare patients 65 years or older linked to a database of patients receiving CDS.

We evaluated (1) patients whose discharge disposition was concordant with the CDS recommendation versus those whose disposition was not and (2) patients receiving CDS for discharge disposition versus those not receiving CDS, regardless of concordance. Outcomes were spending over a 90-day episode, 90-day readmissions, and postdischarge ED utilization not associated with a readmission.

 Analysis of concordant versus discordant cases showed decreased spending for concordant cases ($860 savings; 95% CI, $162-$1558; 

 = .016), a decrease in readmissions (adjusted odds ratio [OR], 0.920; 95% CI, 0.850-0.995; 

 = .038), and no change in rate of postdischarge ED use (adjusted OR, 0.990; 95% CI, 0.882-1.110; 

 = .858). Analysis of patients receiving CDS versus not receiving CDS showed no significant difference in spending ($221 savings; 95% CI, —$115 to $557; 

 = .198), ED use (adjusted OR, 0.959; 95% CI, 0.908-1.012; 

 = .128), or readmission rate (adjusted OR, 1.004; 95% CI, 0.966-1.043; 

 Following the recommendation of a CDS algorithm for hospital discharge disposition was associated with lower spending, fewer readmissions, and no change in ED use over a 90-day episode of care.

Following the recommendation of a clinical decision support (CDS) algorithm for hospital discharge disposition was associated with lower spending and reduced readmissions with no change in emergency department (ED) use.

A CDS algorithm incorporating cognition, ambulation, activities of daily living, capable caregiver availability, skilled therapy needs, and skilled nursing needs was evaluated in 15,887 patients participating in Medicare’s bundled payment program.

Following the algorithm’s recommended level of care (home vs home with home health agency vs postacute facility) was associated with an $860 decrease in spending, fewer readmissions, and unchanged postdischarge ED use over a 90-day episode compared with those patients for whom the recommended level of care was not followed.

The judicious use of postacute care resources by the hospital discharge team can be enhanced by using a CDS algorithm.

Spending on postacute care accounts for a substantial portion of overall healthcare costs and is growing faster than other spending categories.

 For conditions like pneumonia, chronic obstructive pulmonary disease, heart failure, and joint replacement, Medicare spends nearly as much in the 30 days after discharge as it does during hospitalization.

 Moreover, postacute costs are associated with large geographic variation across the United States, with three-fourths of all regional variation in Medicare spending attributable to postacute care spending.

Achieving the judicious, appropriate use of resources following hospitalization can be a critical success factor for organizations participating in full risk capitation and in payment models such as accountable care organizations and bundled payments. Additionally, Medicare spending per beneficiary—a measure of spending encompassing the 30 days subsequent to hospitalization&mdash;is publicly reported and tied to financial incentives for all US Inpatient Prospective Payment System hospitals as part of Hospital Value-Based Purchasing and is a component of the physician payment formula under the Merit-based Incentive Payment System.

Despite growing pressure for hospitals to develop a systematic approach to using postacute care for all patients, most published studies examining such approaches address a single diagnosis, such as stroke or joint replacement; describe a method that may be too complex and time-consuming for widespread use; or rely on information that is unavailable early in the hospitalization, when factors influencing discharge destination may be modified.

We sought to build a clinical decision support (CDS) algorithm to assist hospital discharge planning teams in identifying the most appropriate discharge care level while avoiding untoward effects such as increases in readmissions, emergency department (ED) use, and overall spending. To assess the algorithm, as a convener in CMS’ Bundled Payments for Care Improvement initiative (BPCI),

The use of clinical decision support for hospital discharge disposition was associated with a reduction in spending and readmissions without negatively affecting emergency department use.

June 2019

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US Care Pathways: Continued Focus on Oncology and Outstanding Challenges

Association of Decision Support for Hospital Discharge Disposition With Outcomes

Cancer Care Spending and Use by Site of Provider-Administered Chemotherapy in Medicare

Will 2019 Kick Off a New Era in Person-Centered Care?

Enhanced Care Coordination Improves HIV Viral Load Suppression Rates

Impact of Care Coordination Based on Insurance and Zip Code

Changing Electronic Formats Is Associated With Changes in Number of Laboratory Tests Ordered

Health Insurance Design and Conservative Therapy for Low Back Pain

Improving Quality Measure Maintenance: Navigating the Complexities of Evolving Evidence

From the Editorial Board: Patrick H. Conway, MD, MSc