In the fdas recent guidance document, two tumor assessment endpoints emerge as clear favorites. Food and drug administration fda has considered large durable treatment effects on tumor burden and large effects on progressionfree survival pfs in randomized controlled trials rcts to predict effects on overall survival os, a direct measure of clinical benefit. While endpoints such as overall survival or progression free survival are often used in a superiority study as the primary endpoint to demonstrate efficacy, in a biosimilar study, a primary endpoint such as overall response rate, which measures the activity of the product, may be adequate to demonstrate that the experimental product and the. Medical device manufacturers are regulated in two different but related ways by the fda. Missing data and measurement variability in assessing progression free survival endpoint in randomized clinical trials. Clinical trial endpoints for approval of cancer drugs and. The term overall survival can be easily confused with the survival rate or can be easily thought as the survival rate. Relationship between eventfree survival and overall survival. Study 024 is a randomized, blinded registrational phase 3 study designed to evaluate the effect of dacarbazine in combination with 10mgkg ipilimumab or placebo on progression free survival and overall survival in 500 patients with previously untreated metastatic melanoma frontline. Additionally, they suggest that total pathological complete response could be an early indicator. Fda approves abemaciclib for hrpositive, her2negative. Thirteen cases who met the following two criteria1 may 15, 20 progression free survival pfs is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors, because of both practical and clinical considerations. Fda issues draft guidance for software updates in medical. Clinical trial endpoints for the approval of cancer drugs.
Although in its simplest form pfs is the time from. Lanreotide in metastatic enteropancreatic neuroendocrine tumors. Pazdur has distinguished himself in clinical and academic oncology. Aug 17, 2017 however, the value of incorporating pro into cancer research is fully endorsed not only by several funding agencies and research organizations but also by regulatory agencies such as the fda, 1 in the united states, or the european medicines agency ema, in europe. Results from the urovysion kit are intended for use as a noninvasive method for monitoring for tumor recurrence in conjunction with. The results of this work, which after evaluation by the recist working group led to most of the changes in this revised guideline, are reported in detail in a separate paper in this special issue. For survival and progression free survival analyses, use kaplanmeier plots. Fda did not agree with the proposed coprimary endpoints of progressionfree survival pfs and overall survival os and recommended that gsk evaluate os as the sole primary endpoint. When a trial is performed in an unblinded manner, however, there is the potential for bias between the treatment arms because of the subjective aspects of the progression end point. Replacing a guidance from 2007, this latest guidance from the us food and drug administration fda clarifies how certain oncology endpoints can serve different purposes based on the context of use, and it provides the agencys current thinking on factors considered in making these determinations on which endpoints are used in what context. Sep 21, 2016 progression free survival is an attractive end point for clinical trials when an overall survival end point may be confounded by additional treatments administered after progression.
Fda noted that there was insufficient information to determine if an effect on pfs would predict and effect on survival and stated pfs should not be a. Progressionfree survival pfs is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors, because of both practical and clinical considerations. Quantification of pfs effect for accelerated approval of. Overall survival is a measure of time to event and survival rate measures the percentage of subjects who survived at the end of the study, after 3 years, 5.
Fda guidance document focuses on cancer trial endpoints. Verastem announces regulatory strategy for duvelisib new drug. Statistical considerations in evaluating a biosimilar product. Fda filing will include survival data from this randomized phase. Progression free survival was significantly prolonged with lanreotide as compared with placebo in the primary analysis median progression free survival, not reached vs.
While these two terms are related, they measure different things. Median progression free survival for patients taking abemaciclib with fulvestrant was 16. A new method to model and predict progression free survival. Progressionfree survival as a clinical trial endpoint in. Progression free survival triples in select metastatic lung cancer patients with surgery or radiation after standard chemotherapy aggressive shift in clinical care may improve outcome, study finds. Guidance for industry food and drug administration. In oncology, these surrogate markers might include endpoints like pathological complete response, objective response rate, event free survival, disease free survival, or progression free survival.
Results of phase iii pix306 trial evaluating progression. The us food and drug administration fda has approved new drugs in several cancers using progression free survival pfs rather than os as the criterion for approval. Nonetheless, the principal criterion used by the fda for approval of new drugs in acute myeloid leukemia aml remains an improvement in os. Everolimus proves effective in trial march 4, 2008 an independent data monitoring committee has halted a phase iii trial of novartis everolimus in kidney cancer after interim results showed subjects taking the drug experienced significantly better progressionfree survival than those taking placebo. Although in its simplest form, pfs is the time from randomization to a predefined endpoint, there are many factors that can influence. The study has already met its primary endpoint of prolongation of progressionfree survival, the results of which were announced last year.
Pfizer stops ibrance trial early due to efficacy 20150421. Time from randomization to disease progression, death, or discontinuation of treatment for any reason eg, toxicity, patient preference, or initiation, of a new treatment without documented progression. Lanreotide in metastatic enteropancreatic neuroendocrine. There has been interest in using progressionfree survival as a surrogate endpoint for overall survival in oncology clinical trials. Progressionfree survival pfs denotes the chances of staying free of disease progression for a group of individuals suffering from a cancer after a particular treatment. Analysis of the primary end point showed that patients who received pertuzumab, trastuzumab, and docetaxel pertuzumab group had a significantly longer median progression free survival, as. Unveiled this week, the draft applies to medical devices, like mri machines, that were put through fdas 510k submission process a pathway, meant for products that pose a mediumtolow risk to patients, that. The fda has compassionate use policy for providing excess to promising experimental drugs. Fda approves the novottf100a system for the treatment of patients with recurrent glioblastoma multiforme gbm brain tumors first ever medical device therapy indicated as an alternative to. Assuming positive results demonstrating an improvement in radiographic progressionfree survival rpfs as our primary endpoint, fda indicated that the general design and planned analysis of our. In the fda s recent guidance document, two tumor assessment endpoints emerge as clear favorites. Progressionfree survival as a clinical trial endpoint in advanced renal cell carcinoma article pdf available in current oncology 18 suppl 2suppl 2. The fda granted ibrance accelerated approval in february as a firstline treatment for women with metastatic estrogen receptor positive, her2 breast cancer, based on results of a phase ii trial that showed patients gaining approximately 10 months of progressionfree survival.
Should aveo run second study of kidney cancer drug, fda asks. Endpoints based on tumor assessment include diseasefree survival, objective response rate, time to progression, and progressionfree survival. Publications from office of biostatistics staff fda. Progressionfree survival pfs is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. A description of fda expedited programs is in the guidance for. Ahead of thursdays fda panel, the agency asks if aveo should conduct a second clinical trial. Aug 10, 2016 the food and drug administration released new draft guidance to help clarify when makers of certain types of medical devices may need additional clearance for a software update. Progression free survival pfs, which is the time from the start of treatment until disease recurrence or progression, ranges from 22. Progression free survival progression free survival is defined as the time when a patient is treated to the first documentation of objective disease of death of the patient by any cause.
The primary endpoint was progressionfree survival pfs while overall survival os, complete response rate cr, overall response rate orr and safety were secondary endpoints. Serial test results obtained with the vitros ca 153 assay, in patients who are clinically free of disease, should be used in conjunction with all relevant information derived from diagnostic test, physical examination and full medical history in accordance. Fda regulation of software for medical device manufacturers. Improved understanding on how to deal with the pfs endpoint in trial conduct and data analysis has mitigated some regulatory concerns about this endpoint.
Fda decision on bmys drug postponed, entas pbc study. A new method to model and predict progression free. In order to objectively define this endpoint, clear understanding of what progression means, how it is measured and what its. Oct 25, 2017 a handful of new guidance documents released by the fda on tuesday aim to pave the way for medical device innovation by allowing developers to make iterative changes to the device and software. Department of health and human services food and drug administration. Inhibitor therapeutics submits investigational new drug. Endpoints based on tumor assessment include disease free survival, objective response rate, time to progression, and progression free survival. Followup studies have determined that none of the five responders in the phase 2 component of the trial have had disease progression to date. Censoring of data for progressionfree survival and response duration was based on fda censoring rules. Apr 21, 2015 the fda granted ibrance accelerated approval in february as a firstline treatment for women with metastatic estrogen receptor positive, her2 breast cancer, based on results of a phase ii trial that showed patients gaining approximately 10 months of progression free survival. Nevertheless, more patients in the chlorambucil plus ofatumumab group had. Fda finalizes new guidance to support medical device. Fda guidance on surrogate endpoints lacks specificity.
There has been interest in using progression free survival as a surrogate endpoint for overall survival in oncology clinical trials. Missing data and censoring in the analysis of progression free survival in oncology. Fda approves the novottf100a system for the treatment of. Although in its simplest form, pfs is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease. Progression free survival pfs is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Food and drug administration fda regarding the regulatory path for duvelisib, the companys firstinclass, oral, monotherapy, dual inhibitor of phosphoinositide 3. Additionally, they suggest that total pathological complete response could be an early indicator of longterm outcome in early. European statistical meeting on survival analysis and its. Interim durability analysis of ptx200 in breast cancer. Pertuzumab, trastuzumab, and docetaxel in her2positive. Progression free survival and disease free survival at 5year followup show large and overlapping cis, but support the primary endpoint pathological complete response and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel.
Progression free survival triples in select metastatic. However, as the available options for continuing therapy increase, the use of os as a clinical trial endpoint has become problematic because of. Proposal for the use of progressionfree survival in. Women need to be able to make health care decisions based upon the highest possible quality of evidence.
Use of progressionfree survival as a surrogate marker in. Traditionally, overall survival os has been considered the gold standard for evaluating new systemic oncologic therapies, because death is easy to define, is easily compared across disease sites, and is not subject to investigator bias. Progressionfree survival pfs progressionfree survival is the time from the beginning of an intervention until a patient shows sign of disease progression. Dia in cooperation with fda and ph progressionfree survival.
Pdf progressionfree survival as a clinical trial endpoint. Aug 15, 20 in oncology, progression free survival pfs is increasingly used as such a surrogate of overall survival os in phase iii confirmatory trials. Clinical trial endpoints for oncology studies applied. From the end of treatment to 3 years after 1, 2, and 3 years of followup, the percentage of the alive subjects with no signs of tumor progression. Pfizer stops ibrance trial early due to efficacy 201504. The evaluation of efficacy in oncology studies, in particular for solid tumors, is pretty standard and well defined by several regulatory guidance e. Clinical trial endpoints for the approval of cancer drugs and biologics. Progressionfree survival was significantly prolonged with lanreotide as compared with placebo in the primary analysis median progressionfree survival. Progression free survival oncology workshop conference october 89, 2009 dia in cooperation with fda and phrma richard pazdur, md, director, office of oncology drug products, cder, fda in addition to his experience as a regulatory expert at fda, dr. Vstm, focused on discovering and developing drugs to improve the survival and quality of life of patients with cancer, today announced that a meeting was held with the u. Progressionfree survival and diseasefree survival at 5year followup show large and overlapping cis, but support the primary endpoint pathological complete response and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. For monitoring claims, use 2x2 tables showing agreement between the new assay versus the reference method or clinical. Clinical trial endpoints for the approval of cancer drugs and biologics guidance for industry december 2018. The aim of the present work was to develop a model where target lesion dynamics and risk for nontarget progression are jointly modeled for predicting pfs.
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