In addition, Dr Oriana Ciani, Postdoctoral Research Fellow in the University of Exeter Medical School and Research Fellow of the Università Commerciale L. Bocconi in Milan, discussed the implications and challenges for regulators, payers and triallists of the issues surrounding the validation of surrogates. 16, 17 Similar conclusions have been reached about PFS as a surrogate for OS in first-line therapy for ovarian cancer. effect. Nevertheless, the majority of approvals rely on OS. 14 OS data may take years to mature, … OHE’s Dr Alastair Fischer presented an outline of modelling work conducted by Prof Marc Buyse which attempts to determine which surrogate endpoints can be validated and which of several surrogates is estimated to be the best. Surrogates have the advantage that they can be assessed earlier than OS and require smaller patient populations. They can also look at overall survival (OS), or how long someone lives after starting on a treatment. However, there are concerns in the scientific community regarding the validity of PFS as a surrogate for OS. Economic analysis could also place surrogate endpoints into a value-of-information framework. This may involve considerable cost and perhaps more importantly, delay patients’ access to new cancer drugs. Absolute ratios between delta PFS and delta OS were explored as the primary outcome of this study but not pursued as an endpoint, as large ratios may result from small numerical differences (e.g. It is not sufficient that PFS be correlated with OS. The most common surrogate used in oncology is progression-free survival (PFS), which for some cancer types and especially for later-line therapies, has a high correlation with OS. Background: Whether progression-free survival (PFS) or overall survival (OS) is the more appropriate endpoint in clinical trials of metastatic cancer is controversial. The second section of the report reflects the experience and opinions of relevant experts (policy makers, academics, and industry representatives) collected, Finally, the authors review methodological advances in the, Policy, Organisation and Incentives in Health Systems, Value, Affordability, and Decision Making, New OHE Research Paper: Extrapolation from Progression Free Survival to Overall Survival in Oncology. validated. The second section of the report reflects the experience and opinions of relevant experts (policy makers, academics, and industry representatives) collected during a workshop and a series of interviews. During the workshop, Professor Rod Taylor, from the University of Exeter Medical School, described the trade-off between getting much faster results and at lower cost using a surrogate endpoint, but at the expense of a less certain eventual outcome. The discussion is currently being followed up with an internet survey. Purpose: Earlier studies suggest progression-free survival (PFS) may be used as a surrogate endpoint for overall survival (OS) in metastatic breast cancer, which could shorten follow-up duration and speed up assessment of treatment effects. endpoint that if . The co-primary end points of the trial were PFS and OS in the ITT and PD-L1–positive populations; key secondary end points included overall response rate, duration of response, and safety. allows inference on the . Traditionally, acceptable primary endpoints in oncology clinical trials include cure rate, OS, and progression- or disease-free survival (PFS/DFS). Would Waiving COVID-19 Vaccines Patents Save Lives? OS is not a primary endpoint in any trial that lists PFS2, but is a secondary endpoint in 13 of the 14 trials. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics . If an endpoint that is highly correlated with OS can be measured much earlier, it can be used as a surrogate for OS. According to the researchers, “the surrogate threshold effect had an overall response (OR) of 1.51, which indicated that an observed OR ≥ 1.51 for PFS24 would predict a significant treatment effect on OS … It aims to measure the impact on how a patient feels, functions and survives. U.S. Department of Health and Human Services Food and Drug Administration We believe that the improvement in survival over time has in part occurred via the cobbling of PFS improvements from multiple lines of treatment to improve OS despite the fact there are no clinical trials in the initial treatment of ovarian cancer that have successfully demonstrated an improvement in OS as the primary endpoint. Secondary endpoints included ORR, OS, and safety and tolerability. PFS is the primary endpoint in 13/14, with time to failure as the primary endpoint in 1 trial. OS is not yet mature. In some disease and treatment settings, an improvement in PFS does not result in an improved OS. the validity of surrogates is affected by multiple factors such as cancer type, drug mechanism of action, phase of development, year of the trial, subsequent treatments and stage of the disease. Another important endpoint for measuring the effectiveness of cancer drugs is progression-free survival, or PFS – how long a person lives without the disease worsening. It was recently stated that Co-primary endpoints were TTUP/PFS, and OS. In some trials, researchers set out to look at progression-free survival (PFS), a measure of how long someone is on a treatment before their cancer starts to grow. In the exploratory analysis, when assessed separately, associations between PFS and OS in patients with melanoma were weaker than associations in patients with NSCLC (at PFS_45 R 2 = 0.08 in melanoma studies vs. R 2 = 0.59 in NSCLC studies), although sample sizes among specific disease types are small … … In oncology, PFS usually refers to situations in which a tumor is present, as demonstrated by laboratory testing, radiologic testing, or clinically.Similarly, … PFS results are typically available earlier in a trial than OS data. Xavier Paoletti, PhD, GINECO (Paris, France), and colleagues conducted a systematic review and meta-analysis of 17 unique trials to evaluate whether PFS is a surrogate endpoint for OS in patients … Overall Response Rate (ORR) There is increasing concern in the scientific community regarding the validity of PFS as a surrogate of OS. shorten. NSCLC treatment: OS, PFS, and ORR (19). Several methods have been proposed in the literature by Prentice(6)andBuyseandcolleagues(7–9)tovalidatesurrogate ... OS, PFS as defined by RECIST criteria v1.1, unstratified OR for ORR, and response rates in the … A clinical endpoint is an aspect of a patient’s clinical or health status that is measured to assess the benefit or harm of a treatment. The most common surrogate used in oncology is progression-free survival (PFS), which for some cancer types and especially for later-line therapies, has a high correlation with OS. Patients were randomized 1:1 to either INLYTA 5 mg twice daily (n=361) or sorafenib 400 mg twice daily (n=362), with dose adjustments allowed in both groups. The PFS24 endpoint was not as robust for OS as PFS was, and it failed to meet the predefined criteria for surrogacy. PFS is considered an indication of disease control and stabilization. Would Waiving COVID-19 Vaccines Patents Save Lives? Usually the sample size guarantees that from a statistical point of view, a positive result is obtained when the absolute improvement value of PFS is not so high, so we still look forward to the research data 2. On Tuesday 28th of June 2016, the OHE organised a workshop aimed at discussing the statistical and health economics issues around the current approaches to extrapolating from PFS to OS. In this survey, workshop participants are asked to summarise their conclusions from the workshop and describe future challenges in the validation of surrogates that should be considered. The workshop was attended by a range of participants including academics, representatives of the pharmaceutical industry and NICE. Additionally, there was a consensus on the fact that the validity of the surrogates is affected by multiple factors such as cancer type, drug mechanism of action, phase of development, year of the trial, state of the disease. OHE’s Dr Karla Hernandez-Villafuerte presented the preliminary results of a systematic review that she is undertaking to identify the principal weaknesses and gaps in current methods and approaches for validating PFS as a surrogate of OS. The review shows that the validity of surrogates is affected by multiple factors such as cancer type, drug mechanism of action, phase of development, year of the trial, subsequent treatments and stage of the disease. Copyright © 2014 OHE - Office of Health Economics. Guidance for Industry . the OS endpoint, 5 and could impede the develop-ment of new potentially active therapies. For example, several studies have shown that PFS is a valid surrogate for OS in colorectal cancer, 12 – 15 and it has been argued that PFS is a reasonable primary endpoint for the disease on its own merit. A clinical endpoint is an aspect of a patient’s clinical or health status that is measured to assess the benefit or harm of a treatment. However, the correlation between TTP/PFS … 3 days of PFS benefit and 1 months of OS benefit result in a 30:1 ratio, whereas a 2 month PFS and a 10 month OS benefit is only a 5:1 ratio). Methods: We partitioned OS into two parts and expressed it as … Median OS at this final analysis was 36.2 months in the TACE plus sorafenib arm, compared with 30.8 months in the TACE-alone arm (HR 0.86; 95% CI 0.61-1.22; P=0.40), representing a numerical benefit of 5.4 months. Primary or secondary endpoints in oncologic clinical trials can be classified into two main categories: “patient-centered clinical endpoints” including overall survival (OS) and health-related quality of life (QoL), and “tumor-centered clinical endpoints” such as progression-free survival , , .The use of OS as a primary endpoint … Posted in Drug Development/R&D, Health Statistics, Health Technology Assessment | Tagged Events. level plot of treatment effect on PFS (a surrogate endpoint) versus treatment effect on OS (a clinical benefit endpoint) in stage 3 colorectal cancer was considered useful in evaluating whether the surrogate endpoint meets the second condition reasonably well when the strict evaluation of the second condi- The Office of Health Economics (OHE) is a company limited by guarantee registered in England and Wales (registered number 09848965) and its registered office is at 7th Floor Southside, 105 Victoria Street, London, SW1E 6QT. This considerably increases the cost of development and delays patients’ access to new cancer drugs. However, measuring OS requires a large number of patients and long follow-up periods. 1,2 1. The Office of Health Economics, in a research project funded by the Pharmaceutical Oncology Initiative (POI), has published a new report entitled: Extrapolation from Progression Free Survival to Overall Survival in Oncology. alternative. In addition, some new therapies may slow tumour growth considerably, but with little or no initial tumour shrinkage. Introduction. A clinical endpoint is an aspect of a patient’s clinical or health status that is measured to assess the benefit or harm of a treatment.Overall survival (OS) is the gold standard endpoint for clinical trials assessing the efficacy of cancer treatments in terms of their effects in improving length of life.However, measuring OS … PFS, and a modified RECIST criteria–defined PFS endpoint as potential surrogate endpoints for OS. Progression free survival (PFS) is the most commonly used surrogate in cancer. true endpoint. On the other hand, if PFS and OS are not strongly correlated, the use of PFS as a surrogate for OS may lead to treatments with … The surrogate is associated with survival time. However, the combination extended median OS (6.24 months vs. 5.91 months) and PFS (3.75 months vs. 3.55 months) by less than 1 month each. Cost-Effectiveness Thresholds and Expert Elicitation: a Bridge Too Far? The FDA approved erlotinib on the basis of this trial. The report contains a literature review analysing the use of extrapolating PFS to OS in oncology as well as determining key limitations, weaknesses and gaps in the current literature and methods used to test PFS surrogacy. However, evidence to support the validity of PFS as a surrogate marker of OS is lacking in this setting. Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". Regulatory decision-makers, such as the EMA and FDA, have used PFS as the basis for marketing approval of some new therapies. A surrogate endpoint is an . Overall survival (OS) is the gold standard endpoint for clinical trials assessing the efficacy of cancer treatments in terms of their effects in improving length of life. Although OS is considered to be the most clinically relevant endpoint in ovarian cancer trials, it is affected by the use of multiple postprogression therapies, and the time required to evaluate OS is often considerable. The increase in the length of overall survival (OS) is the ‘gold standard’ endpoint for clinical trials assessing the efficacy of cancer treatments. For more information contact Karla Hernandez-Villafuerte at OHE. 12 PFS, which measures the time to disease progression or death after treatment with the trial drug, is a useful endpoint because it can demonstrate a clinical benefit and is more rapidly assessable than … In general, presentations, discussions and the preliminary results of the OHE investigation suggest the need for standards for validating PFS as a surrogate of OS, as well as the need for clinical trial protocols that facilitate the use of PFS as a surrogate. over use of PFS or ORR as a primary outcome measure. The trial met its primary endpoint because OS was superior with nivolumab compared with SOC, with an HR of 0.70 (P =.01) and a 1‐year survival rate of 36.0% versus 16.6%, respectively. Factors such as crossover from control to experimental arms in clinical trials as well as the effect of subsequent therapies may distort the relationship between PFS and OS. Additionally, OS is an optimal endpoint because the measurement is accurate, is observed on a daily basis, and provides direct evidence Unfortunately, the OS endpoint was not met. In response to this problem, various surrogate endpoints have been used in place of OS. There was no difference in PFS, and the ORR was 13.3% versus 5.8%, respectively. From the viewpoint of increasing statistical power, no PFS method was a good surrogate endpoint for OS under the alternative … observaion period Surrogate ‘efficacy’ endpoints in oncology aim to replace OS, the endpoint to ‘predict’ Primary endpoints in randomized controlled It is rare that endpoints such as DFS or PFS have been shown to be true surrogates for OS Pren… Bodies such as NICE, that advise on which aspects of healthcare may be covered by national health insurance, are concerned with both the effectiveness and cost-effectiveness implications of the use of surrogate endpoints. Policy, Organisation and Incentives in Health Systems, Value, Affordability, and Decision Making, OHE Workshop: Surrogate Endpoints as Predictors of Overall Survival in Oncology. For more information contact Karla Hernandez-Villafuerte at OHE. often requiring a . The treatment has an effect on the surrogate. The treatment effect on survival is captured by the surrogate. On the other hand, if PFS and OS are not strongly correlated, the use of PFS as a surrogate for OS may lead to treatments with large survival gains being rejected or treatments with small or even negative survival gains being accepted. The Office of Health Economics (OHE) is a company limited by guarantee registered in England and Wales (registered number 09848965) and its registered office is at 7th Floor Southside, 105 Victoria Street, London, SW1E 6QT. There was a suggestion that NICE does not always use a surrogate outcome in its analysis if it believes that direct extrapolation of OS gives sufficient accuracy to allow for good adoption decisions to be made. of an intervention on a . Whether the statements proposed in the present review are confirmed in trials designed with composite primary endpoints, such as OS-PFS for lenvatinib + pembrolizumab vs. lenvatinib (NCT03713593) or OS-ORR for atezolizumab + bevacizumab vs. sorafenib (NCT03434379) is of particular … Overall Survival (OS) is the duration of time from the date of diagnosis or commencement of treatment of a particular disease that a patient is still alive. Because death resulting from liver cirrhosis might confound the treatment outcome, time to progression (TTP) is suggested as a reliable surrogate endpoint compared to progression free survival (PFS) in the clinical trials of hepatocellular carcinoma (HCC). Progression-free survival (PFS) can be deter-mined earlier than OS and has potential both as an independent, valid endpoint and a potential surrogate for OS in certain circumstances. However, measuring OS often requires a large number of patients and long follow-ups. Cost-Effectiveness Thresholds and Expert Elicitation: a Bridge Too Far? The results from the literature review, the workshop discussion as well as the posterior survey will be published by the OHE in the coming months. 13 Measuring OS may be difficult due to trial design, multiple lines of treatment, long survival times, and other factors. The key question is: how much information should be collected before a decision is made on the adoption (or otherwise) of a treatment? If the sample size is greater than 700, PFS wins. Of 16 trials which have been conducted for drug approval, 11 were based on OS as leading endpoint, 2 on PFS, 2 on durable ORR, and 1 on improvement in disease related symptoms, respectively. A valid surrogate for OS should satisfy the Prentice criteria: The treatment has an effect on survival time. In JCOG0102, OS was worse in the preoperative arm with a hazard ratio of 1.33, but the hazard ratios for all of the PFS methods were also attenuated toward null (0.88, 1.03 and 0.90). Copyright © 2014 OHE - Office of Health Economics. Regulatory decision-makers, such as EMA and FDA, have used PFS as the basis for marketing approval of some new therapies. PFS is unaffected by postprogression therapies … Finally, the authors review methodological advances in the statistical theory of surrogacy, and current thinking of surrogacy as an economic question rather than a clinical effectiveness question. Primary endpoint was PFS. OS … Even though PFS and OS may not be highly correlated in such circumstances, such a therapy may be many patients’ best option.