The Impasse on Overall Survival in Oncology Reimbursement Decision-Making: How Can We Resolve This?

Figures & data

Box 1 Definitions

Regulator: here, refers to medicines licensing agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Payer: here, refers to post-regulatory agencies involved in the funding and reimbursement of healthcare services or drugs, such as national health technology assessment (HTA) agencies and local funding/access decision-makers. Endpoints: used in a clinical trial setting to evaluate whether a drug provides a clinical benefit.13 See the CBER/CDER guidelines for an overview for cancer drugs and biologics.14 Intermediate or biomarker endpoints can be endpoints in their own right or can be considered as surrogates when used to substitute for OS or other endpoints in clinical trials. Overall survival (OS): the time from randomization until death from any cause. Maturity in OS is often defined by median OS, the time at which the Kaplan–Meier survival curve crosses the 50% cumulative survival probability.15 Note that median OS does not always fully assess the OS benefit, for example when a proportion of patients has a long survival time (‘tail of the curve’ phenomenon; eg, in immuno-oncology trials).16 In these cases, landmark analysis can be used.17 Surrogacy: endpoints can substitute for OS or other final endpoints if they are validated, ie they have shown statistical correlation with treatment effect for the specific setting and patient population.18 This means that an endpoint may be a surrogate in one disease setting but not another. Managed entry schemes: financial agreements between manufacturers and payers to allow introduction of innovative medicines while managing uncertainty around the treatment’s financial impact or clinical evidence. Managed entry schemes may encompass patient access schemes, risk-sharing agreements, payment by results and performance-based risk-sharing agreements.

Abbreviations: CBER, Center for Biologics Evaluation and Research; CDER, Center for Drug Evaluation and Research.

Table 1 Sample of Regulators’, Payers’ and Clinical Societies’ Positions on Types of Endpoints

Agency Region/Country	Stated Position
Regulators
EMA, 201719 Europe	● OS is the most persuasive endpoint ● Prolonged PFS or DFS are in most cases considered relevant measures of patient benefit, but the magnitude of the treatment effect should be sufficiently large to outbalance toxicity and tolerability problems
FDA, 201814 USA	● OS is the most reliable and preferred cancer endpoint ● Endpoints based on tumor assessments (DFS/EFS, ORR, CR, TTP and PFS) can be important
Payers and HTA agencies
EUnetHTA, 201529 Europe	● OS is the preferred clinical endpoint ● PFS is an acceptable endpoint   – for cancer trials in the adjuvant, but not the metastatic, setting – if there is a strong association between the effect of the surrogate and the effect on the final endpoint of interest
ICER, 202030 USA	● Direct OS measurement preferred ● If surrogate outcomes are used, they need to be validated
IQWiG, 201731 Germany	● Most endpoints are not good surrogates for OS and may be unreliable and misleading ● Surrogates are only considered if they have been validated by appropriate statistical methods within a sufficiently restricted patient population and within comparable approved interventions
NICE, 2012,32 201933,a England	● Surrogates may be used to infer the effect of treatment on mortality and HRQoL, if evidence in support of surrogacy is provided ● A modeling framework is required to establish the strength of the surrogate relationship between the treatment effects on the surrogate and the final outcome, and to explore the uncertainty related to it
PBAC, 201634 Australia	● Submissions should not rely on surrogacy for effectiveness
Clinical societies
ASCO Value Framework Net Health Benefit (ASCO-NHB)35 USA	Assesses the relative value of cancer therapies by assigning a net health benefit score, depending on the treatment’s clinical benefit, toxicity and symptom palliation ● The framework puts weight on OS and toxicity; therapies without significant OS or DFS/EFS benefit (improved median values or hazard ratios) are marked down ● Bonus points are awarded for tail of the OS curve
ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS)36,37 Europe	Ranks cancer treatments by benefit, ie whether patients lived longer (improvement in OS or surrogate for OS) or better (improvement of QoL or surrogate for QoL, or reduced toxicity) ● Treatments without mature OS data or those without OS as an endpoint are scored lower

Notes: ^aNew guidance is being developed and is, at the time of writing, in the consultation phase.38.

Abbreviations: ASCO, American Society of Clinical Oncology; CR, complete response; DFS, disease-free survival; EFS, event-free survival; EMA, European Medicines Agency; ESMO, European Society for Medical Oncology; EUnetHTA, European Network for Health Technology Assessment; FDA, Food and Drug Administration (USA); HRQoL, health-related quality of life; HTA, health technology assessment; ICER, Institute for Clinical and Economic Review (USA); IQWiG, Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (Germany); NICE, National Institute for Health and Care Excellence (England); ORR, overall/objective response rate; OS, overall survival; PBAC, Pharmaceutical Benefits Advisory Committee (Australia); PFS, progression-free survival; QoL, quality of life; TTP, time to progression.

Box 2 Example for Impact of Earlier Time to Reimbursement for Patients

An analysis published by the European Federation of Pharmaceutical Industries and Associations (EFPIA) in 2020 estimated the impact on patients of time to reimbursement in six European countries.9 Compared with the actual situation, it was estimated that very early reimbursement (at the time of European marketing authorization) of midostaurin for acute myeloid leukemia (AML) would have led to 1689 additional patients receiving treatment, living for an additional 6910 years; less rapid access (180 days after marketing authorization) was estimated to lead to 369 more patients receiving treatment, living for an additional 1509 years. Note that an EU Transparency Directive stipulates that decisions on joint pricing and reimbursement of medicines should be made within 180 days of dossier submission.46

Table 2 Considerations When Proving an OS Benefit is Difficult to Achieve or is Not of Primary Relevance to Patients

Consideration	Factors and Examples
Indolent disease therapies	Patients will have long life expectancy, with OS highly relevant to patients but requiring a long duration of follow-up to assess For example, in chronic lymphocytic leukemia, life expectancy often reaches 10 years or more; here, PFS and minimal residual disease are relevant endpoints^Citation51,Citation52 accepted by regulators
Early-line therapies	Patients have long life expectancy requiring a long wait to assess OS data, which may be confounded by treatment with other therapies Patients may value highly time before progression, for example, if they experience more symptoms or receive more intensive therapies post-progression (eg, chemotherapy after endocrine-based therapy in HR+ metastatic breast cancer), making endpoints such as PFS/DFS highly relevant
Palliative therapies or when OS is not the goal	Patients may prioritize experiencing fewer side effects or a better QoL and symptom improvement over OS gain. So, although OS gain may be shown, it is important that trials evaluate endpoints relevant for the specific setting and therapy For example, in pancreatic cancer, relief of disease-related symptoms was measured using clinical benefit response, in which gemcitabine achieved 24% compared with 5% for 5-FU (p = 0.0022). The median survival was 5.65 months for gemcitabine compared with 4.41 months for 5-FU (p = 0.0025)^Citation53
Early unblinding	Trials that show an early signal of strong benefit may be stopped early and automatically unblinded,^Citation54 limiting the ability to show OS gain, because the control group will be treated differently after unblinding (eg, crossover will be allowed) For example, in the Phase 3 trial of osimertinib, unblinding was recommended by an Independent Data Monitoring Committee after the drug showed “overwhelming efficacy” in patients with Stage IB, II and IIIA epidermal growth factor receptor-mutated NSCLC with complete tumor resection^Citation55
Confounded treatment effect	Trials with crossover, or in which the study treatment is followed by several lines of different therapies, can have a confounding treatment effect on OS, making it difficult to identify how much OS gain can be attributed to the treatment of interest; although statistical methods have been developed^Citation56,Citation57 For example, in a phase 3 trial with the PARP inhibitor olaparib in patients with ovarian cancer with a BRCA1 or BRCA2 mutation, median OS did not reach significance vs placebo (HR for death, 0.74; 95% CI: 0.54–1.00; p = 0.054); after adjusting for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy, the HR was 0.56 (95% CI: 0.35–0.97)^Citation58
Rare cancers (single-arm trials or trials with low power)	Difficulty in recruiting patients to trials can lead to single-arm trials or trials with low power that are unlikely to show statistical differences in OS between treatments As well as rare cancers, use of very detailed inclusion and exclusion criteria (eg, requirements for the presence of baseline predictive factors or previous therapies) or selection for rare mutations can lead to small population sizes and low power For example, the FDA granted accelerated approval for brentuximab vedotin in anaplastic large cell lymphoma based on a single-arm multicenter clinical trial of 58 patients after failure of at least one prior chemotherapy regimen. The primary endpoint, objective response rate by independent review, was 86% (95% CI: 77–95%) with a median duration of 12.6 months^Citation59
Curative or approaching cure	For curative therapies, the active treatment arm of the clinical study would reflect the normal life expectancy of the population For example, the life expectancy of men with a diagnosis of testicular cancer at 30 years of age is 2 years less than cancer-free men of the same age, and the difference approaches zero with increasing survival time^Citation60 As the science of oncology advances, we would expect to see more therapies and disease areas fall into this scenario

Abbreviations: 5-FU, 5-fluorouracil; CI, confidence interval; DFS, disease-free survival; FDA, Food and Drug Administration (USA); HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HR+, hormone receptor-positive; NSCLC, non-small-cell lung cancer; OS, overall survival; PARP, poly (ADP-ribose) polymerase; PFS, progression-free survival; QoL, quality of life.

Box 3 Example of a Progressive Shift Away from OS

When AIDS was a life-threatening diagnosis with extremely poor survival, survival was the most relevant endpoint.^Citation61 Through advances in antiretroviral therapy, HIV infection is now a chronic, manageable condition, and life expectancy is similar to the general population.^Citation62 Today, CD4 cell count and viral load are considered clinically relevant endpoints, and QoL outcomes are prioritized.^Citation63,Citation64 It is likely that many cancers will also become chronic diseases with long survival with novel therapies.

Abbreviations: AIDS, acquired immune deficiency syndrome; HIV, human immunodeficiency virus; OS, overall survival; QoL, quality of life.

Table 3 List of Endpoints to Consider as Potential Valid Measures of Efficacy

Endpoint	Definition
(p)CR	(Pathologic) complete response: defined as the disappearance of all signs of cancer in response to treatment
EFS/DFS/RFS	Event-free survival/disease-free survival/relapse-free survival: defined as the time from cancer treatment end to the appearance of first signs or symptoms of that cancer, or the appearance of first complications that the treatment was intended to prevent/delay, or death from any cause EFS is normally used in the neoadjuvant setting and DFS is used in the adjuvant setting
iDFS/MFS	Invasive disease-free survival: defined as the time between randomization and first invasive disease recurrence; primarily used in studies of patients with breast cancer Metastasis-free survival: defined as the time from start of treatment for cancer that a patient is still alive and the cancer has not spread to other parts of the body; primarily for patients with prostate cancer
MRD	Minimal residual disease: defined as the small proportion of cancerous cells that may remain after treatment when the patient shows no signs or symptoms of the disease; primarily used in trials with patients with hematologic malignancies
ORR	Overall/objective response rate: defined as the proportion of patients with a confirmed response of complete or partial response (usually tumor size reduction)
PRO	Patient-reported outcome: can directly measure clinical benefit (severity of cancer symptoms) Evaluated using validated measures that are routinely incorporated into clinical trial design, such as EQ-5D or SF-36 Some endpoints include a QoL component, such as TWiST (time without symptoms of disease and toxicity of treatment) or QAPFS (quality-adjusted PFS) NB: capturing QoL endpoints and powering for them may not always be feasible in RCTs; a high follow-up rate is needed for questionnaires
PFS	Progression-free survival: defined as the time from randomization to the date of first disease progression or death Related measures include PFS2 (time from randomization to tumor progression on next-line treatment or death from any cause), TTD (time to treatment discontinuation) and TTNT (time to next treatment)

Notes: Based on the FDA’s table of important cancer approval endpoints⁷⁹ and the National Cancer Institute dictionary of cancer terms.⁸⁰.

Abbreviations: EQ-5D, 5-dimension EuroQol questionnaire; FDA, Food and Drug Administration (USA); PRO, patient-reported outcome; QoL, quality of life; RCT; randomized controlled trial; SF-36, 36-item short-form health survey.

Box 4 Example of Clinical Benefit Shown with RWE

While the PALOMA-2 study of first-line palbociclib plus letrozole in patients with HR+/HER2– metastatic breast cancer is ongoing and yet to report mature OS data, a significant OS benefit was shown from an analysis of electronic health records from a heterogeneous, real-world population (HR vs letrozole, 0.58 [95% CI: 0.46–0.73]) and among subgroups.97

Abbreviations: CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; HR+, hormone receptor-positive; OS, overall survival; RWE, real-world evidence.

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