Characteristics of Cost-effectiveness Studies for Oncology Drugs Approved in the United States From 2015-2020.

Importance: Increasingly, cost-effectiveness analyses are being done to determine the value of rapidly increasing oncology drugs; however, this assumes that these analyses are unbiased. Objective: To analyze the characteristics of cost-effectiveness studies and to determine characteristics associated with whether an oncology drug is found to be cost-effective. Design, Setting, and Participants: This retrospective cross-sectional study included 254 cost-effectiveness analyses for 116 oncology drugs that were approved by the US Food and Drug Administration from 2015 to 2020. Exposures: Each drug was analyzed for the incremental cost-effectiveness ratio per quality-adjusted life year, the funding of the study, the authors' conflict of interest, the threshold of willingness-to-pay, from what country's perspective the analysis was done, and whether a National Institute for Health and Care Excellence cost-effectiveness analysis had been done. Main Outcomes and Measures: The main outcome was the odds of a study concluding that a drug was cost-effective. Results: There were 116 drug approvals with 254 studies and country perspectives. Of the country perspectives, 132 (52%) were from the US. Forty-seven of 78 drugs with cost-effective studies had been shown to improve overall survival, whereas 15 of 38 of drugs without a cost-effectiveness study had been shown to improve overall survival. Having a study funded by a pharmaceutical company was associated with higher odds of a study concluding that a drug was cost-effective than studies without funding (odds ratio, 41.36; 95% CI, 11.86-262.23). Conclusions and Relevance: In this cross-sectional study, pharmaceutical funding was associated with greater odds that an oncology drug would be found to be cost-effective. These findings suggest that simply disclosing potential conflict of interest is inadequate. We encourage cost-effectiveness analyses by independent groups.

An urgent call to raise the bar in oncology.

Important breakthroughs in medical treatments have improved outcomes for patients suffering from several types of cancer. However, many oncological treatments approved by regulatory agencies are of low value and do not contribute significantly to cancer mortality reduction, but lead to unrealistic patient expectations and push even affluent societies to unsustainable health care costs. Several factors that contribute to approvals of low-value oncology treatments are addressed, including issues with clinical trials, bias in reporting, regulatory agency shortcomings and drug pricing. With the COVID-19 pandemic enforcing the elimination of low-value interventions in all fields of medicine, efforts should urgently be made by all involved in cancer care to select only high-value and sustainable interventions. Transformation of medical education, improvement in clinical trial design, quality, conduct and reporting, strict adherence to scientific norms by regulatory agencies and use of value-based scales can all contribute to raising the bar for oncology drug approvals and influence drug pricing and availability.

CFTR modulators: transformative therapies for cystic fibrosis.

DISCLOSURES: No funding contributed to the writing of this commentary. Both authors are employed by the Cystic Fibrosis Foundation. The Cystic Fibrosis Foundation has entered into therapeutic development award agreements and licensing agreements to assist with the development of CFTR modulators that may result in intellectual property rights, royalties, and other forms of consideration provided to CFF. Some of these agreements are subject to confidentiality restrictions and, thus, CFF cannot comment on them.

The effectiveness and value of novel treatments for cystic fibrosis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Seidner, Rind, and Pearson are employed by ICER. Tice reports contracts to his institution, University of California, San Francisco, from ICER during the conduct of this study. Wherry has nothing to disclose.

Potential Cost Implications for All US Food and Drug Administration Oncology Drug Approvals in 2018.

Importance: The growth of cancer drug spending in the US has outpaced spending in nearly all other sectors, and an increasing proportion of the drug development pipeline is devoted to oncology. In 2018, there was a record number of drugs entering the US market. Objective: To estimate the number of patients with cancer who are eligible for the newly approved drug-indication pairs, and project potential spending and use of the approvals in the US. Design, Setting, Participants: This is a retrospective review of 2018 US Food and Drug Administration (FDA) oncology drug approvals with estimation of the eligible population. The cost of new therapy was estimated, and savings from displaced therapies were subtracted. Two-way sensitivity analysis explored uncertainty in pricing and market diffusion. Data were collected between March 1, 2019, and September 30, 2019. Exposures: Data related to the cancer drug approval (ie, indications, approval pathway, basis for approval), cancer incidence, and drug price were extracted from publicly available sources, including the FDA, National Cancer Institute, and American Cancer Society websites, as well as the RED BOOK database. Main Outcomes and Measures: The primary outcome was the projected net expenditure in the US associated with the new therapies. The secondary outcome described how variable market diffusion and pricing permit expected levels of spending. Results: A total of 46 oncology approvals were included in the analysis, with 17 novel drugs and 29 new indications. The average price per patient per treatment course was $150 384. From a national perspective and with 100% market diffusion, the projected net expenditure for newly approved drugs was $39.5 billion per year. To maintain the recent trend of cancer drug spending, the 2018 cancer drug approvals need to be used in fewer than 20% of eligible patients. Conclusions and Relevance: New cancer drugs approved by the FDA in 2018 would drastically increase cancer drug spending in the US if used widely. Alternatively, only low-level use of the new drugs is consistent with market forecasting.

A novel method for predicting the budget impact of innovative medicines: validation study for oncolytics.

BACKGROUND: High budget impact (BI) estimates of new drugs have led to decision-making challenges potentially resulting in restrictions in patient access. However, current BI predictions are rather inaccurate and short term. We therefore developed a new approach for BI prediction. Here, we describe the validation of our BI prediction approach using oncology drugs as a case study. METHODS: We used Dutch population-level data to estimate BI where BI is defined as list price multiplied by volume. We included drugs in the antineoplastic agents ATC category which the European Medicines Agency (EMA) considered a New Active Substance and received EMA marketing authorization (MA) between 2000 and 2017. A mixed-effects model was used for prediction and included tumor site, orphan, first in class or conditional approval designation as covariates. Data from 2000 to 2012 were the training set. BI was predicted monthly from 0 to 45 months after MA. Cross-validation was performed using a rolling forecasting origin with e^|Ln(observed BI/predicted BI)| as outcome. RESULTS: The training set and validation set included 25 and 44 products, respectively. Mean error, composed of all validation outcomes, was 2.94 (median 1.57). Errors are higher with less available data and at more future predictions. Highest errors occur without any prior data. From 10 months onward, error remains constant. CONCLUSIONS: The validation shows that the method can relatively accurately predict BI. For payers or policymakers, this approach can yield a valuable addition to current BI predictions due to its ease of use, independence of indications and ability to update predictions to the most recent data.

Association Between the Use of Surrogate Measures in Pivotal Trials and Health Technology Assessment Decisions: A Retrospective Analysis of NICE and CADTH Reviews of Cancer Drugs.

OBJECTIVE: To assess whether using surrogate versus patient-relevant endpoints in pivotal trials of cancer drugs was associated with health technology assessment recommendations in England (National Institute for Health and Care Excellence [NICE]) and Canada (Canadian Agency for Drugs and Technologies in Health [CADTH]). METHODS: Cancer drug approvals from 2012 to 2016 were categorized by demonstrating benefit on overall survival (OS), progression-free survival, disease response, or having no comparator. Approvals were analyzed by benefit category and health technology assessment recommendation. The association between benefit (surrogate vs OS) and recommending a drug was examined using descriptive statistics and linear probability models controlling for unmet need, orphan designation, and cost-effectiveness. RESULTS: Of 42 cancer indications that NICE recommended, 15 (36%) demonstrated OS benefit. Cancer indications with OS benefit were less likely to receive a recommendation from NICE than those without (P = .04). In linear probability models, availability of OS benefit was no longer associated with a recommendation from NICE (P = .32). Cost-effective cancer drugs had a 55.6% (95% CI: 38.9%-72.3%) higher probability of receiving a recommendation from NICE than those that were not. In Canada, 15 of 37 (41%) cancer indications that were recommended showed OS benefit. There was no detectable association between surrogate measures and CADTH recommendations based on descriptive statistics (P = .62) or in linear probability models (P = .73). CONCLUSION: When cost-effectiveness was considered, pivotal trial endpoints were not associated with NICE recommendations. Pivotal trial endpoints, unmet need, orphan status, and cost-effectiveness did not explain CADTH recommendations.

Estimated costs of pivotal trials for U.S. Food and Drug Administration-approved cancer drugs, 2015-2017.

BACKGROUND: Pivotal clinical trials provide critical evidence to regulators regarding a product's suitability for marketing approval. The objectives of this study are (1) to characterize select features of trials for oncology products approved by the U.S. Food and Drug Administration between 2015 and 2017; and (2) to quantify the costs of these trials and how such costs varied based on trial characteristics. METHODS: We identified novel oncology therapeutic drugs, and their respective pivotal trials, approved between 2015 and 2017 using annual summary reports from the Food and Drug Administration. Cost estimates for each pivotal trial were calculated using IQVIA's CostPro, a clinical trial cost estimating tool based on executed contracts between pharmaceutical manufacturers and contract research organizations. Measures of drug and trial characteristics included trial design, end point, patient enrollment, and regulatory pathway. We also performed sensitivity analyses that varied assumptions regarding how efficiently each trial was conducted. RESULTS: A total of 39 pivotal clinical trials provided the basis for Food and Drug Administration approval of 30 new oncology drugs from 2015 to 2017. Among these trials, primary end points were objective response rate in 20 (51.3%), progression-free survival in 13 (33.3%), and overall survival in 6 (15.4%). Twenty trials (51.3%) were single-arm studies. The median estimated cost of oncology pivotal trials was $31.7 million (interquartile range = $17.0-$60.4 million). Trials with objective response rate as primary end point had a median estimate of $17.7 million (interquartile range = $11.9-$27.1 million), compared with trials examining progression-free survival ($42.3 million, interquartile range = $34.6-$101.2 million) or overall survival ($79.4 million, interquartile range = $56.9-$97.7 million) (p < 0.001). Estimated costs for single-arm trials ($17.7 million, interquartile range = $11.9-$23.7 million) were less than for trials with a placebo-controlled ($56.7 million, interquartile range = $40.9-$103.9 million) or active control arm ($67.6 million, IQR = $35.5-$93.5 million) (p < 0.001). CONCLUSIONS: Relative to the estimated costs of drug development, the costs of these oncology pivotal trials were modest, with trials that produced more valuable scientific information costing more than their counterparts.

"Stick or Twist?" Negotiating Price and Data in an Era of Conditional Approval.

BACKGROUND: Changes in the regulatory context enable faster approval of transformative medicines. They also lead to health technology assessment (HTA) agencies having to make decisions with less evidence. In response, HTA agencies have also initiated forms of conditional approval. When the evidence base for a new oncology treatment leaves substantial uncertainty, the new Cancer Drugs Fund allows the National Institute for Heath and Care Excellence to give the manufacturer two options: (1) offer a low price based on conservative assumptions and obtain immediate approval ("stick") or (2) wait until the evidence base has further matured before finalizing a potentially higher agreed price ("twist"). OBJECTIVES: The purpose of this article is to explain how, using the theoretical framework of the expected value of sample information, simulation methods can help inform a manufacturer's decisions when faced with the option to stick or twist. METHODS: We first summarize a general model to help frame the manufacturer's negotiating strategy. We then use a motivating case study, based on a hypothetical immunotherapy, to illustrate how manufacturers can use simulation methods to robustly characterize the uncertainty inherent to further data collection and incorporate this uncertainty within their decision making. RESULTS: Our approach allows us to estimate the commercial value of generating additional data (the difference between the estimated net present value of stick and twist). We test the sensitivity of the results to different assumptions via scenario analyses. CONCLUSIONS: This article shows that simulation methods can be used to help pharmaceutical managers make informed strategic decisions in contexts of uncertainty.

Potential Life-Years Lost: The Impact of the Cancer Drug Regulatory and Funding Process in Canada.

BACKGROUND: Canada has an established publicly funded health care system with a complex drug approval and funding process. After proof of efficacy (POE; key publication/presentation) and before becoming publicly accessible, each drug undergoes a Health Canada approval process, a health technology assessment (HTA), a pricing negotiation, and finally individual provincial funding agreements. We quantified potential life-years lost during this process. METHODS: We analyzed drugs for advanced lung, breast, and colorectal cancer that underwent the HTA process between 2011 and 2016. Life-years lost were calculated by multiplying documented improvement in progression-free and overall survival, number of eligible patients, and time from POE to first public funding. For conservative calculation, we assumed all eligible patients in Canada had access at the time of first public funding, whereas in reality provinces fund at different time points. RESULTS: We analyzed 21 drugs. Of these, 15 have been funded publicly. The time from POE to first public funding ranged from 14.0 to 99.2 months (median 26.6 months). Total overall life-years lost from POE to first public funding were 39,067 (lung 32,367; breast 6,691). Progression-free life-years lost from POE to first public funding were 48,037 (lung 9,139, breast 15,827, colorectal 23,071). CONCLUSION: The number of potential life-years lost during the drug regulatory and funding process in Canada is substantial, largely driven by delays to funding of colorectal cancer drugs. Recognizing that interprovincial differences exist and that eligible patients may not all receive a given drug, if even a fraction does so, the impact of delays remains substantive. Collaborative national initiatives are required to address this major barrier to treatment access. IMPLICATIONS FOR PRACTICE: Patients may spend lengthy periods of time awaiting access to new and effective cancer drugs. Patients with private drug insurance or personal funds or who reside in certain Canadian provinces may obtain some drugs sooner than others, potentially creating a two-tiered access system. The cancer drug access and public funding system must be expedited to improve equity.

Achieving equal and timely access to innovative anticancer drugs in the European Union (EU): summary of a multidisciplinary CECOG-driven roundtable discussion with a focus on Eastern and South-Eastern EU countries.

The Central European Cooperative Oncology Group (CECOG) and 'ESMO Open-Cancer Horizons' roundtable discussion brought together stakeholders from several European Union (EU) countries involved in drug development, drug authorisation and reimbursement or otherwise affected by delayed and unequal access to innovative anticancer drugs. The approval process of drugs is well established and access delays can be caused directly or indirectly by national or regional decision-making processes on reimbursement. The two key aspects for those involved in reimbursement decisions are first the level of evidence required to decide and second pricing, which can be challenging for some innovative oncology compounds, especially in Eastern and South-Eastern European countries. Other important factors include: available healthcare budget; the structure and sophistication of healthcare authorities and health technology assessment processes; societal context and political will. From the point of view of the pharmaceutical industry, better alignment between stakeholders in the process and adaptive pathway initiatives is desirable. Key aspects for patients are improved access to clinical trials, preapproval availability and reports on real-world evidence. Restricted access limits oncologists' daily work in Eastern and South-Eastern EU countries. The roundtable discussion suggested considering the sequencing of regulatory approval and reimbursement decisions together with more flexible contracting as a possible way forward. The panel concluded that early and regular dialogue between all stakeholders including regulators, payers, patient stakeholders and industry is required to improve the situation.

Application of pharmacoeconomics to formulary management in a health system setting.

PURPOSE: A novel value-based approach to evaluate costly specialty drugs for formulary addition was developed. SUMMARY: In February 2016, Stanford Health Care launched the specialty drug subcommittee (SDSC), a subcommittee of the pharmacy and therapeutics committee, responsible for the formulary review of specialty pharmaceuticals. A process was developed for value-based review that includes not only consideration of clinical trial data and institutional acquisition costs but also internal patient outcomes and a cost-effectiveness model using internal financial data. A Markov model was developed to assess the value of trabectedin, which was approved for formulary addition in April 2016, relative to the addition of dacarbazine. The economic model and internal patient outcome analysis were presented to the prescribing oncologist and the SDSC for review. Internal data revealed that fewer patients than had been estimated received trabectedin, with outcomes significantly worse than those observed in the clinical trial leading to Food and Drug Administration approval. In the cost-effectiveness model, trabectedin had higher costs and poorer outcomes compared with dacarbazine. Based on the economic model, low utilization, and real-world outcomes, trabectedin was removed from formulary and a restrictive treatment pathway for nonformulary use, developed by the primary prescriber, was implemented. This process has since been applied to 11 more specialty drugs. CONCLUSION: Internal cost-effectiveness models in combination with real-world patient outcomes data can be effective formulary management tools. Engagement and collaboration with the requesting provider are key to developing thoughtful treatment pathways.

Financial conflicts of interest of clinicians making submissions to the pan-Canadian Oncology Drug Review: a descriptive study.

OBJECTIVES: This study examines financial conflict of interest (FCOI) of clinicians who made submissions to the pan-Canadian Oncology Drug Review (pCODR), the arm of the Canadian Agency for Drugs and Technology in Health that recommends whether oncology drug indications should be publicly funded. Final reports from pCODR published between October 2016 and February 2019 were examined. DESIGN: Descriptive study. DATA SOURCES: Website of pCODR. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOMES: The primary outcome is the number of submissions declaring FCOI. Secondary outcomes are the number of times where clinicians agreed and disagreed with preliminary recommendation from pCODR and the association between the distribution of individual clinicians' FCOI and pCODR's funding recommendations. RESULTS: There were 46 drug indication reports from pCODR. Clinicians made 261 submissions. Clinicians declared they received payments from companies 323 times and named 38 different companies making those payments a total of 500 times. Financial conflicts with drug companies were declared in 176 (66.3%) of all submissions. In 21 (45.7%) of the 46 drug indications, 50% or more of the clinicians had a conflict with the company making the drug. Clinicians commented on 37 preliminary recommendations. In all 25 where pCODR recommended funding or conditional funding, the clinicians either agreed or agreed in part. pCODR recommended that the drug indication not be funded 12 times and 9 times clinicians disagreed with that recommendation. The distribution of clinician responses was statistically significantly different depending on whether pCODR recommended funding/conditional funding or do not fund p<0.0001 (Fisher exact test). The distribution of clinicians' FCOI differed depending on whether the recommendation was fund/conditional fund or do not fund p=0.027 (Fisher exact test). CONCLUSION: Financial conflicts with pharmaceutical companies are widespread among experts making submissions to the pCODR.

To HTA or Not to HTA: Identifying the Factors Influencing the Rapid Review Outcome in Ireland.

OBJECTIVES: Reimbursement systems are evolving and endeavor to balance access and affordability. One such evolution in Ireland is the compulsory rapid review (RR) process, the outcome from which is a recommendation for a health technology assessment (HTA) or no HTA. For drugs that avoid an HTA, evaluation times are shorter, lengthy price negotiations are avoided, and access is faster. In the absence of formal decision-making criteria around the requirement of an HTA, this study examines the factors influencing the outcome of the RR process in Ireland. METHODS: A database was developed combining data from publicly available sources for drug evaluations conducted by the National Centre for PharmacoEconomics (NCPE) (January 2010-June 2017, n = 296). Because Irish cost data were not publicly available for all drugs, cost data from the Scottish Medicines Consortium were employed as a proxy. Employing logistic regressions, the factors influencing the RR outcome are revealed. RESULTS: After an RR, an HTA was recommended for 55% of drugs. The regression results revealed therapeutic area (endocrine, musculoskeletal, and neoplasm), first-in-class and orphan disease increased the probability of an HTA. Furthermore, when proxy costs were included, results revealed that every €1000 increase in annual drug costs per patient increased the probability of an HTA being required by 1% and that an HTA was more likely than no HTA when annual drug costs exceeded €15 000. CONCLUSION: Given the current focus on access and affordability, this study identifies the factors influencing the requirement of an HTA in Ireland.