Endpoints In Clinical Research Research Articles

(Re-) Defining "Successful Aging" as the Endpoint in Clinical Trials? Current Methods, Challenges, and Emerging Solutions.

"Successful aging" as defined in Rowe & Kahn's model aims to include the major domains of aging under a single overarching concept. From here the question arises how "successful aging" itself can be implemented as an endpoint in clinical research in a way that it is compliant to methodological regulatory framework and recommendations as formulated, for example, by the FDA. This article discusses from an applied perspective approaches and examples of how "successful aging" as a multi domain concept can be put into measurement practice. Narrative literature review. Existing methods of merging insights from, e.g., functional, social, and cognitive outcomes, can fail to perform under conditions of extreme heterogeneity, as often present in samples of older adults. In research on rare diseases, the methodological approach of a Multi Domain Responder Index (MDRI) has been proposed to handle heterogeneity. MDRIs may also provide a solution to combine aging outcomes from different domains into a single "successful aging" endpoint. However, strict measurement criteria will need to be fulfilled to find acceptance in decision making and validated meaningful change thresholds are a critical prerequisite. Gerontology can spearhead methodological approaches of handling multidimensional measurement under heterogeneity by validating a "successful aging" MDRI suitable for use as an endpoint in clinical research.

Trajectories of quality of life in people with diabetes mellitus: results from the survey of health, ageing and retirement in Europe.

Previous longitudinal studies identified various factors predicting changes in Quality of Life (QoL) in people with diabetes mellitus (PwDM). However, in these studies, the stability of QoL has not been assessed with respect to individual differences. We studied the predictive influence of variables on the development of QoL in PwDM across three waves (2013-2017) from the cross-national panel dataset Survey of Health, Ageing, and Retirement in Europe (SHARE). To determine clinically meaningful changes in QoL, we identified minimal clinically important difference (MCID). Linear regressions and Linear Mixed Models (LMM) were conducted to determine factors associated with changes in QoL. On average, QoL remained stable across three waves in 2989 PwDM, with a marginal difference only present between the first and last wave. However, when looking at individual trajectories, 19 different longitudinal patterns of QoL were identified across the three time-points, with 38.8% of participants showing stable QoL. Linear regression linked lower QoL to female gender, less education, loneliness, reduced memory function, physical inactivity, reduced health, depression, and mobility limitations. LMM showed that the random effect of ID had the strongest impact on QoL across the three waves, suggesting highly individual QoL patterns. This study enhances the understanding of the stability of QoL measures, which are often used as primary endpoints in clinical research. We demonstrated that using traditional averaging methods, QoL appears stable on group level. However, our analysis indicated that QoL should be measured on an individual level.

Marginal versus conditional rate estimation for count and recurrent event data with an estimand framework

Count and recurrent event endpoints are common key efficacy endpoints in clinical research. For example, in clinical research of pulmonary diseases such as chronic obstructive pulmonary disease (COPD) or asthma, the reduction of the occurrence of a recurrent event, pulmonary exacerbation (PEx) caused by acute respiratory symptoms, is often used to measure the treatment effect. The occurrence of PEx is often analyzed with nonlinear models, such as Poisson regression or Negative Binomial regression. It is observed that model-estimated within-group PEx rates are often lower than the descriptive statistics of within-group PEx rates. Motivated by this observation, we explore their relationship mathematically and demonstrate that it is due to the difference between conditional PEx rates and population-level PEx rates (marginal rates). Our findings corroborate the recent FDA guidance (2023) [1], which discusses considerations for covariate adjustment in nonlinear models, and that conditional or subgroup treatment effects with covariate adjustment may differ from marginal treatment effects. In this article, we demonstrate how covariate adjustment impacts the estimation of event rates and rate ratios with both closed form and simulation studies. Additionally, following the ICH E9 addendum on the estimand framework [2], we discuss the estimand framework for count and recurrent event data.

Making Sense of Composite Endpoints in Clinical Research

Multiple drugs currently used in clinical practice have been approved by regulatory agencies based on studies that utilize composite endpoints. Composite endpoints are appealing because they reduce sample size requirements, follow-up periods, and costs. However, interpreting composite endpoints can be challenging, and their misuse is not uncommon. Incorrect interpretation of composite outcomes can lead to misleading conclusions that impact patient care. To correctly interpret composite outcomes, several important questions should be considered. Are the individual components of the composite outcome equally important to patients? Did the more and less important endpoints occur with similar frequency? Do the component endpoints exhibit similar relative risk reductions? If these questions receive affirmative answers, the use and interpretation of the composite endpoint would be appropriate. However, if any component of the composite endpoint fails to satisfy the aforementioned criteria, interpretation can become difficult, necessitating additional steps. Regulatory agencies acknowledge these challenges and have specific considerations when approving drugs based on studies employing composite endpoints. In conclusion, composite endpoints are valuable tools for evaluating the efficacy and net clinical benefit of interventions; however, cautious interpretation is advised.

Abstract LB119: Recurrence score for recurrence over survival outcome in the landmark TAILORx trial

Abstract Overall survival is the most relevant endpoint in clinical research and patient care. Nonetheless, cancer recurrence has been frequently utilized as a surrogate endpoint, particularly in the context of multi-gene assays and molecular signatures. The 21-gene recurrence score (RS) was originally established against distant recurrence for prognosis in breast cancer. However, it is unclear whether RS has a weight for the recurrence over survival prognosis. We investigated RS on the choice of clinical endpoints in the Trial Assigning Individualized Options for Treatment (TAILORx), which had OS, invasive disease-free survival (DFS), and recurrence-free interval (RFI) in addition to distant recurrence-free interval as the clinical endpoints. Both midrange (11-25) and high-range (26-100) scores were associated with RFI, high-range only with DFS, but not significantly associated with OS in the multivariable Cox proportional-hazards regression models. Of 462 death events, 33.1% (153 events) were ascribed to breast cancer and 91.8% (424) were due to DFS-related events that included 24.5% other cancers, 34.2% unknown and 33.1% breast cancer. It is DFS that was wound up as the most representative surrogate endpoint for survival. The lack of survival significance was probably due to the nature of 21-gene assay weighted for recurrence rather than not having enough event numbers in the TAILORx clinical trial. The data call for establishing biomarkers directly towards OS or DFS to increase survival with more precision. Citation Format: Sherry X. Yang, John Yu, Molin Wang. Recurrence score for recurrence over survival outcome in the landmark TAILORx trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB119.

Prospect of Direct Benefit in Pediatric Trials: Practical Challenges and Potential Solutions.

Clinical research in pediatric patients is necessary to develop safe and effective medicines for children. US Food and Drug Administration (FDA) human subject protection regulations (21 Code of Federal Regulations 50, subpart D) require that, with limited exceptions, research in children that exceeds a defined level of risk must offer a prospect of direct benefit to the individual child that is sufficient to justify those risks. Growing attention to the merits of initiating pediatric clinical trials earlier in the drug and biological product development process has led the FDA to look more closely at the meaning of the regulatory term prospect of direct benefit. In collaboration with the FDA, the Duke-Margolis Center for Health Policy convened a workshop with leading experts in the fields of biomedical ethics, pediatric clinical research, and pediatric product development, as well as patient representatives, to discuss the FDA's approach to characterizing prospect of direct benefit in the context of scientific advances in product development. Workshop topics included the extrapolation of adult efficacy data to children, use of nonclinical models of disease, use of modeling and simulation to support pediatric dosing, and reliance on biomarkers and surrogate end points in clinical research. Discussion from the workshop is provided herein to communicate the challenges that investigators, industry sponsors, regulators, and institutional review boards face when evaluating pediatric research and to outline several approaches to maximize prospect of direct benefit, minimize unnecessary risks and burden, and facilitate timely access to safe and effective medicines for children.

Bipolar affective disorder

Abstract BodyAbstract: Biomarkers for diagnosis and treatment of Bipolar Disorder: hope or hype? Professor Allan Young, Centre for Affective Disorders, IoPPN, KCL London, SE5 8AF. allan.young@kcl.ac.uk The use of “biomarkers” (biological markers) in basic and clinical research as well as in clinical practice has become so commonplace in many areas of medicine that their presence as primary endpoints in clinical trials is now widely accepted. In clinical disciplines where specific biomarkers have been well characterized and repeatedly shown to correctly predict relevant clinical outcomes across a variety of treatments and populations, this use is entirely justified and appropriate. However, the validity of biomarkers in most psychiatric disorders continues to be evaluated. This lecture will review the current conceptual status of biomarkers as clinical and diagnostic tools for bipolar disorder and as surrogate endpoints in clinical research in bipolar disorder. The conceptual background in terms of current diagnostic categories and research domain criteria will be discussed and the various approaches with putative value (e.g., brain imaging, genetics, and neuroendocrinology) reviewed (1, 2). The lecture will end with a discussion of approaches to evaluating biomarkers of lithium response (3).ReferencesWise et al, Mol Psychiatry. 2016 May 24. doi: 10.1038/mp.2016.72. [Epub ahead of print]; Young AH. Harv Rev Psychiatry. 2014 Nov-Dec;22(6):331–3 Bellivier F, Young AH, et al, Bipolar Disord. 2020 Oct 23. doi: 10.1111/bdi.13023. Online ahead of print.DisclosurePaid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, COMPASS Principal Inve

Risk factors for hospital readmission in adult patients with heart failure with reduced ejection fraction: a systematic review.

The objective of this review was to identify and synthesize evidence on risk factors associated with hospital readmission within the first year after heart failure hospitalization among patients with heart failure with reduced left ventricular ejection fraction. Heart failure is associated with a high risk of hospital readmission. Readmissions are associated with higher mortality and health care costs. It is a high health care priority to identify vulnerable patients with heart failure who may potentially benefit from targeted personalized care interventions aiming to reduce readmissions. This review considered studies including adult patients who had heart failure with a reduced left ventricular ejection fraction ≤ 40% who were discharged after a heart failure hospitalization. The authors included studies with experimental and observational designs evaluating risk factors for i) all-cause hospital readmission, ii) heart failure hospital readmission, and iii) composite outcomes within seven, 15, 30, 60, 90, 180, and 365 days after hospital discharge. Composite outcomes included end points where all-cause readmission and/or heart failure readmission were part of a defined end point (i.e. all-cause readmission or mortality; heart failure readmission or mortality; cardiovascular readmission; cardiovascular readmission or mortality; and readmission, mortality, or cardiac transplant). Studies reporting all-cause readmission and/or heart failure readmission as a primary outcome, secondary outcome, or part of a composite outcome were included. PubMed, Embase, CINAHL, Cochrane CENTRAL, PsycINFO, OpenGrey, MedNar, DART-Europe, ProQuest Dissertations and Theses, and the Grey Literature Report in Public Health were searched to find both published and unpublished studies in English, Swedish, Norwegian, or Danish from 2000 to June 2018. Study selection, critical appraisal, data extraction, and data synthesis followed the JBI approach for systematic reviews. Statistical pooling was not possible due to clinical and methodological heterogeneity of the studies included and the lack of risk factors reported more than once. A narrative summary of the findings was performed. Fifty-two studies, including one randomized controlled trial and 51 cohort studies with a total of 128,186 participants, were included. Risk factors for readmission were reported for 30-day outcome in 16 studies, 60-day in three studies, 90-day in 15 studies, 180-day in 12 studies, and 365-day outcome in 15 studies. Based on multivariable analyses from 43 cohort studies and results from one randomized controlled trial, the authors identified several factors associated with higher risk of all-cause readmission, heart failure readmission, and composite outcomes (e.g. readmission or death) within 30, 60, 90, 180, and 365 days after discharge for a heart failure hospitalization. This review provides a comprehensive overview of factors associated with a clinical outcome after a heart failure hospitalization in patients with heart failure with left ventricular ejection fraction ≤ 40%. Owing to the heterogeneity of variables investigated and the lack of comparability of findings, the clinical impact of the identified risk factors remains uncertain. This review highlights research gaps and the need for a standardized way to define and measure all-cause readmission, heart failure readmission, and composite end points in clinical research to improve study quality and enable comparison of findings between studies.

Revisiting endpoints in clinical research: Quality of cure above simply cure

Revisiting endpoints in clinical research: Quality of cure above simply cure

Composite End Points in Clinical Research: A Time for Reappraisal.

Advances in cardiovascular medicine fueled by innovative clinical trials have dramatically improved the lives of patients worldwide. Commensurate with this progress has been a decline in morbid and mortal events. Accordingly, an increased propensity to collate patient outcomes in clinical trials has emerged that combines death and nonfatal complications into a single composite event. Despite the acknowledged benefits in trial efficiency from such an approach, this method assumes uniform directionality of each component, does not distinguish the relative clinical significance of each, and counts only the first occurrence of any event in the final tally within a conventional time to first event analysis. In this article, we evaluate the criticisms that have been leveled at this approach and provide an overview of recently published phase III cardiovascular trials using primary composite end points. We then explore what to anticipate from the large cohort of as-yet unpublished clinical trials in this arena. Last, we propose a variety of novel approaches that use composite end points and suggest a path forward to enhancing their use in future clinical trials.

Identification and content validation of wound therapy clinical endpoints relevant to clinical practice and patient values for FDA approval. Part 1. Survey of the wound care community.

Wounds that exhibit delayed healing add extraordinary clinical, economic, and personal burdens to patients, as well as to increasing financial costs to health systems. New interventions designed to ease such burdens for patients with cancer, renal, or ophthalmologic conditions are often cleared for approval by the U.S. Food and Drug Administration (FDA) using multiple endpoints but the requirement of complete healing as a primary endpoint for wound products impedes FDA clearance of interventions that can provide other clinical or patient-centered benefits for persons with wounds. A multidisciplinary group of wound experts undertook an initiative, in collaboration with the FDA, to identify and content validate supporting FDA criteria for qualifying wound endpoints relevant to clinical practice (CP) and patient-centered outcomes (PCO) as primary outcomes in clinical trials. As part of the initiative, a research study was conducted involving 628 multidisciplinary expert wound clinicians and researchers from 4 different groups: the interdisciplinary core advisory team; attendees of the Spring 2015 Symposium on Advanced Wound Care (SAWC); clinicians employed by a national network of specialty clinics focused on comprehensive wound care; and Association for the Advancement of Wound Care (AAWC) and Wound Healing Society (WHS) members who had not previously completed the survey. The online survey assessed 28 literature-based wound care endpoints for their relevance and importance to clinical practice and clinical research. Fifteen of the endpoints were evaluated for their relevance to improving quality of life. Twenty-two endpoints had content validity indexes (CVI) ≥ 0.75, and 15 were selected as meriting potential inclusion as additional endpoints for FDA approval of future wound care interventions. This study represents an important first step in identifying and validating new measurable wound care endpoints for clinical research and practice and for regulatory evaluation.

Expert meeting obstructive airway disease measuring and evaluating in COPD

This report gives an overview on the contributions presented in an expert meeting in February, 2015. They deal with the analysis and evaluation of the multiple dimensions of COPD. This complex disease not only interferes with pulmonary mechanics and gas exchange, but also with cardiopulmonary crosstalk and the ventilator pump. A bulk of inflammatory and microbial activity develops during the progression of disease. As a consequence, systemic effects on muscles, metabolism and psyche develop.The sections consider the value of multiple endpoints in clinical research. Quantifiable parameters of lung mechanics and gas exchange, of exercise tolerance and biomarkers improve the measurability of effects in interventions. However, do we really know in a biological sense what we are measuring? What conclusions can we draw in terms of prognosis?Vice versa, we have to look into the origin and meaning of integrative endpoints e.g. quality or life, dyspnoea and spontaneous physical activity. As a new dimension, the clinical significance of morphological findings in HRCT and MRT is analyzed.

Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms capable of producing hormones. The development of new treatments has improved progression-free survival, albeit with increased toxicity. Health-related quality of life (HRQoL) has become an important endpoint in clinical research to evaluate patients' well-being in such a contradictory scenario. In this review, we examine key reported outcomes across clinical studies exploring HRQoL in patients with GEP-NETs. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Selection criteria for articles were (1) publication in English between 1995 and 2014, (2) patients with GEP-NET, and (3) analysis of HRQoL, including mental health and psychological symptoms. Forty-nine studies met the inclusion criteria (31 clinical trials, 14 observational studies, and 4 developments of NET-specific HRQoL instruments). The scope and nature of the literature was diverse with 27 instruments used to measure aspects of HRQoL. EORTC QLQ-C30 was the most frequently used, in 38 of the 49 studies. Standardized measures revealed that in spite of generally good HRQoL, GEP-NET patients have specific psychological and physical complaints. The clinical benefit of somatostatin analogs and sunitinib has been clearly supported by HRQoL assessment. Improvement in HRQoL scores or symptom relief over time was also reported in 14 trials of peptide receptor radionuclide therapy, however the absence of randomized studies obviate definitive conclusions. We have also identified several unanswered questions that should be addressed in further research concerning chemotherapy, everolimus, surgery, local ablative therapies, and chemoembolization. Future research should incorporate GEP-NET-specific HRQoL instruments into phase III trials. This review may help both clinicians and researchers to select the most appropriate tools to assess changes in HRQoL in this population.

Validity of Vascular Calcification as a Screening Tool and as a Surrogate End Point in Clinical Research.

On a world scale, in 2013, there have been >17 million cardiovascular deaths, one half of which attributable to ischemic heart disease.1 More than 50% of cases of ischemic heart disease deaths presenting as sudden cardiac death have no history of symptoms heralding the critical event,2 and most myocardial infarctions occur in low or moderate risk subjects (ie, in the largest segment of the general population). On a life-time scale, the risk of myocardial infarction at the age of 40 years is 1 in 2 men and 1 in 3 in women.3 These figures underline the potential relevance of timely screening and treatment of individuals at risk of cardiovascular disease. The Framingham Risk Score or the recently developed risk calculator, which informs the American College of Cardiology/American Heart Association cholesterol guideline,4 the HeartScore,5 or the QRISK calculator,6 are center pieces of current policies for cardiovascular risk assessment and for lipid-lowering treatment. Because in these calculators age is the most informative risk factor for the prediction of cardiovascular events,7 these instruments have limited precision for the prediction of coronary atherosclerosis at individual level particularly in young subjects who have a low absolute risk for cardiovascular disease events.8 Novel biomarkers measurable in plasma or serum have been intensively investigated to refine risk prediction in individuals at low or moderate risk, but the gain in prediction power by these biomarkers is just of modest degree.9 Imaging biomarkers provide an estimate of the atherosclerotic burden in critical areas of the arterial system like the coronary circulation and may provide an integrated measure of life time exposure to risk factors. Among imaging markers of atherosclerosis assessment of vascular calcification, in particular of coronary calcification, is considered as the most valuable one because it outperforms other imaging …

End Points and Trial Design in Geriatric Oncology Research: A Joint European Organisation for Research and Treatment of Cancer–Alliance for Clinical Trials in Oncology–International Society of Geriatric Oncology Position Article

Selecting the most appropriate end points for clinical trials is important to assess the value of new treatment strategies. Well-established end points for clinical research exist in oncology but may not be as relevant to the older cancer population because of competing risks of death and potentially increased impact of therapy on global functioning and quality of life. This article discusses specific clinical end points and their advantages and disadvantages for older individuals. Randomized or single-arm phase II trials can provide insight into the range of efficacy and toxicity in older populations but ideally need to be confirmed in phase III trials, which are unfortunately often hindered by the severe heterogeneity of the older cancer population, difficulties with selection bias depending on inclusion criteria, physician perception, and barriers in willingness to participate. All clinical trials in oncology should be without an upper age limit to allow entry of eligible older adults. In settings where so-called standard therapy is not feasible, specific trials for older patients with cancer might be required, integrating meaningful measures of outcome. Not all questions can be answered in randomized clinical trials, and large observational cohort studies or registries within the community setting should be established (preferably in parallel to randomized trials) so that treatment patterns across different settings can be compared with impact on outcome. Obligatory integration of a comparable form of geriatric assessment is recommended in future studies, and regulatory organizations such as the European Medicines Agency and US Food and Drug Administration should require adequate collection of data on efficacy and toxicity of new drugs in fit and frail elderly subpopulations.

The use of echocardiography in observational clinical trials: the EURECA-m registry

Echocardiography is the most widely used non-invasive imaging technique due to its availability, low cost, transportability and lack of ionizing radiations. However, it suffers from the main limitation of being highly subjective and operator-dependent. Furthermore, specifically, population or disease-dependent issues exist which should be addressed when this technique is applied in multicenter studies. As to the population of patients with end-stage renal disease (ESRD) maintained on chronic dialysis, indexation of echocardiographic parameters and timing of echocardiography in relationship to dialysis represent a specific, main issue that needs to be carefully considered and standardized. Scientific societies recommend the set-up of core laboratories in order to reduce inter- and intra-observer variability when an echocardiographic parameter is considered as an end-point in clinical research. Several studies have shown the superiority of interpretation given by echocardiography core-lab reading. These advantages are counterbalanced by higher costs and complexity. The EURECA-m registry by the EURECA-m working group, an ERA-EDTA initiative, aimed at promoting the scientific collaboration among professionals in the field of cardiovascular and renal medicine. The registry involves several centers in Europe and one of its aims is to measure conventional echocardiographic parameters in ESRD patients on chronic dialysis. A central reading protocol has been set up for the registry in order to give robustness to the echo studies.

Study Designs and Statistical Analyses for Biomarker Research

Biomarkers are becoming increasingly important for streamlining drug discovery and development. In addition, biomarkers are widely expected to be used as a tool for disease diagnosis, personalized medication, and surrogate endpoints in clinical research. In this paper, we highlight several important aspects related to study design and statistical analysis for clinical research incorporating biomarkers. We describe the typical and current study designs for exploring, detecting, and utilizing biomarkers. Furthermore, we introduce statistical issues such as confounding and multiplicity for statistical tests in biomarker research.

Does primary lesion have to be regarded as a target lesion when evaluating response in metastatic renal cell carcinoma (mRCC) treated with sunitinib?

425 Background: Primary lesion in mRCC often shows necrotic change or only density changes to targeted therapy. As most clinical trials for mRCC have enrolled nephrectomized patients (pts), there is no consensus on including primary lesion in target lesion when evaluating response. We investigated whether best overall response (OR) changes when designate target lesions with or without primary lesion, and such discordance lead to difference in predictive value in terms of time to progression (TTP) and overall survival (OS). Methods: We enrolled mRCC pts with intact primary lesion, at least one measurable metastatic lesion, and proper image data who had received sunitinib in our institution between 2003 and 2011. We documented the variation of the sum of the largest diameters (ΔSLD) with all target lesions and with metastasis-only target lesions separately. Response evaluation was calculated with RECIST v1.1. Results: Of 41 pts, 38 received sunitinib as 1st line treatment and 3 did as 2nd line. The most frequent metastatic site was lung (63.4%) followed by lymph node (46.3%) and bone (42.5%). Median ΔSLD of primary lesion and metastatic target lesion were -6.02% (range: -34.00 to 17.60%), and -18.03% (-100.00 to 120.00%). On response evaluation with metastasis-only target lesions, best OR of 2 pts (4.87%) changed from stable disease to partial response. When categorize pts into responders and non-responders, metastasis-only target lesions resulted in significantly better discrimination of TTP (14.949 vs 4.271 mo, p=0.01) and OS (18.497 vs 9.561 mo, p=0.036) between two groups. Using all target lesions, both TTP (14.949 vs 5.355 mo, p=0.056) and OS (17.971 vs 10.579 mo, p=0.155) were statistically insignificant. Conclusions: Our study showed discordance in OR between using all target lesions and using metastasis-only target lesions, and metastasis-only target lesion could have more accurate predictive value. As response rate is often used as an end point in clinical research of mRCC, further discussion is needed whether primary lesion should be included or not in target lesion. [Table: see text]

The use and abuse of surrogate endpoints in clinical research in transfusion medicine

The use and abuse of surrogate endpoints in clinical research in transfusion medicine

Biomarkers and surrogate endpoints in clinical research – some statistical challenges

The mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase and the founding member of a signaling pathway that regulates many fundamental features of cell growth and division. In cells, mTOR acts as the catalytic subunit of two functionally distinct complexes, called mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2). Together, these complexes coordinate a variety of processes that include protein translation, autophagy, proliferation, survival and metabolism in response to nutrient, energy and growth factor signals. Consistent with its role as a growth-promoting pathway, numerous studies have found that mTOR signaling is hyper-activated in a broad spectrum of human cancers. In particular, mTORC2 is considered a primary effector of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, which is mutated in a majority of human cancers, in part through its ability to phosphorylate and regulate the proto-oncogene Akt/PKB. Many biological functions of mTOR have been pharmacologically explored using the natural product rapamycin, an allosteric inhibitor that has been reviewed extensively elsewhere. This review will focus specifically on the development of small molecule ATP-competitive inhibitors of mTOR and their prospects as a targeted therapy.