Use Of Intermediate Endpoints Research Articles

Progression-free survival at 3 years is a reliable surrogate for 5-year overall survival for patients suffering from locally advanced esophageal squamous cell carcinoma.

BackgroundDespite 3‐year survival being used as a primary endpoint in some randomized controlled trials (RCTs), limited evidence supports the use of intermediate endpoints to evaluate the effect of new therapies in esophageal squamous cell cancer (ESCC). This study aimed to systematically evaluate progression‐free survival at 3 years (3‐year PFS) and overall survival (OS) among patients with ESCC.MethodsWe identified 528 patients newly diagnosed with locally advanced ESCC who received definitive radiotherapy. OS was compared with an age‐ and sex‐matched general Chinese population using the standardized mortality ratio (SMR). Regression analysis was used to validate the correlation between PFS and OS using published data.ResultsThe annual risk of progression decreased to 11.5% after 3 years. Patients who did not achieve 3‐year PFS had a median postprogression survival (PPS) of 7.3 months, with a 5‐year OS rate of 9.6% and a SMR of 15.0 (95% confidence interval [CI], 12.9–17.5). Conversely, the SMR for patients who achieved 3‐year PFS was 0.9 (95% CI, 0.6–1.3). We observed a significant correlation between log hazard ratio (HR) (PFS) and log HR (OS) at the trial level (r = 0.89; 95% CI, 0.88–0.90). The strongest correlation was observed between 3‐year PFS and 5‐year OS in RCTs and retrospective studies.ConclusionsPatients exhibiting progression within 3 years experienced poor survival, whereas patients achieving 3‐year PFS had excellent outcomes. Our study supports 3‐year PFS as a reliable primary endpoint for study design and risk stratification in locally advanced ESCC.

Use of Intermediate Endpoints in the Economic Evaluation of New Treatments for Advanced Cancer and Methods Adopted When Suitable Overall Survival Data are Not Available.

This study assessed the use of intermediate endpoints in the economic evaluation of new treatments for advanced cancer and the methodological approaches adopted when overall survival (OS) data are unavailable or of limited use. A systematic literature review was conducted to identify economic evaluations of treatments for advanced cancer published between 2003 and 2013. Cost-effectiveness and cost-utility analyses expressed in cost per life-year gained and cost per quality-adjusted life-year using an intermediate endpoint as an outcome measure were eligible. Characteristics of selected studies were extracted and comprised population, treatment of interest, comparator, line of treatment, study perspective, and time horizon. Use of intermediate endpoints and methods adopted when OS data were lacking were analyzed. In total, 7219 studies were identified and 100 fulfilled the eligibility criteria. Intermediate endpoints mostly used were progression-free survival and time to progression, accounting for 92% of included studies. OS data were unavailable for analysis in nearly 25% of economic evaluations. In the absence of OS data, studies most commonly assumed an equal risk of death for all treatment groups. Other methods included use of indirect comparison based on numerous assumptions, use of a proxy for OS, consultation with clinical experts, and use of published external information from different treatment settings. Intermediate endpoints are widely used in the economic evaluation of new treatments for advanced cancer in order to estimate OS. Currently, different methods are used in the absence of suitable OS data and the choice of an appropriate method depends on many factors including the data availability.

The use of intermediate endpoints in the design of type 1 diabetes prevention trials.

This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.

Hypertension and Diabetes: Should We Treat Early Surrogates?

Type 2 diabetes, a major public health problem of great concern, affects millions of patients in both developed and developing countries. These patients run a well-documented increased risk of cardiovascular disease (CVD), the risk of which is two- to threefold greater than that seen in nondiabetic subjects (1). Despite modern methods for treatment of diabetes and its risk factors and complications, the increased risk is still substantial. This is so even if data on risk factor control in national surveys, repeated on an annual basis, have shown improving trends for blood pressure and lipid control, e.g., in the National Diabetes Register in Sweden (2). Because hypertension and lipid disturbances are currently relatively easy to treat pharmacologically, this denotes that the majority of patients with diabetes are also to some extent receiving treatment for their CVD risk factors. Ideally, only studies that could prove the effect on clinical end points should be accepted as fundamental for evidence-based medicine in national or international guidelines. However, in addition, intermediate end points have been advocated for evaluation of intervention effects, as recently shown in studies evaluating drug effects on carotid or coronary atherosclerosis. This has provoked a clinical debate as that related in the following two sets of arguments, i.e., pro or con regarding the use of intermediate end points when hypertension in diabetes is treated. On the pro side, arguments are concentrated in defense of using left ventricular hypertrophy, albuminuria, or arterial stiffness as useful surrogate markers, or intermediary end points, to guide the intensity and mode of treatment. However, on the con side, other more critical arguments are given to state that only drugs that are also able to decrease the rate of clinical events should be used, e.g., those shown to reduce CVD, including myocardial infarction and stroke, and in addition …

Air travel and venous thromboembolism.

There has recently been increased publicity on the risk of venous thrombosis after long-haul flights. This paper reviews the evidence base related to the association between air travel and venous thromboembolism. The evidence consists only of case reports, clinical case-control studies and observational studies involving the use of intermediate end-points, or expert opinion. Some studies have suggested that there is no clear association, whereas others have indicated a strong relationship. On the whole it appears that there is probably a link between air travel and venous thrombosis. However, the link is likely to be weak, mainly affecting passengers with additional risk factors for venous thromboembolism. The available evidence is not adequate to allow quantification of the risk. There are insufficient scientific data on which to base specific recommendations for prevention, other than that leg exercise should be taken during travel. Further studies are urgently needed in order to identify prospectively the incidence of the condition and those at risk.

The future of clinical trials in chronic renal disease: outcome of an NIH/FDA/Physician Specialist Conference. Evaluation of Clinical Trial Endpoints in Chronic Renal Disease Study Group.

For people with chronic renal insufficiency, the therapeutic goal is to prevent progression to end-stage renal disease, a serious condition that can only be treated with dialysis and kidney transplantation. Although restriction of dietary protein slows the progression of renal disease somewhat, the principal treatment to slow chronic renal disease is appropriate reduction of blood pressure. Antihypertensive agents, particularly those that produce sustained, long-term reductions in proteinuria, such as angiotensin-converting enzyme inhibitors, not only decrease blood pressure but also preserve renal function. Clinical trials to evaluate these and other drug therapies in renal disease progression have used both "hard end points" (e.g., dialysis, transplantation, death) and intermediate end points of renal disease progression (e.g., doubling of serum creatinine concentration, reductions in proteinuria). Trials that have used hard end points typically recruited patients with advanced renal disease to demonstrate a difference in therapies within a period of 2 to 5 years. However, proteinuria reduction, along with a decrease in the time to doubling of serum creatinine in very early diabetic renal disease, could demonstrate an altered natural history of renal disease. Although hard end points are indicators of a drug's efficacy in reducing cardiovascular events or preserving renal function, they do not assess the impact of a treatment on altering the natural history of early renal disease. For clinical trials of people with all but the most advanced renal disease, use of intermediate end points of renal disease progression is the only practical option for assessment of treatment efficacy and effectiveness. Given the available data on proteinuria reduction and doubling of serum creatinine from clinical trials, these end points, taken together, appear to provide an acceptable means of assessing a treatment's impact on slowing renal disease progression.

Discovery of cancer susceptibility genes: study designs, analytic approaches, and trends in technology.

Determining the genetic causes of cancers has immense public health benefits, ranging from prevention to earlier detection and treatment of disease. Although a number of cancer susceptibility genes have been successfully identified, design and analytic issues remain that challenge the current paradigm of gene discovery. Some examples are the definition and measurement of cancer phenotype, the use of intermediate end points, the choice of sample (e.g., affected relative pairs versus large extended pedigrees), the choice of analytic method [e.g., parametric logarithm of the odds (LOD) score method versus model-free methods], and the influence of gene-environment interaction on linkage analysis. Furthermore, association methods, based on either the traditional case-control study design or family-based controls, are popular choices to evaluate candidate genes or screen for linkage disequilibrium. Finally, the study design and analytic methods for gene discovery are determined to some extent by what genomic technology is feasible within the laboratory. Many of the main issues related to gene discovery, as well as trends in genomic technology that will impact on gene discovery, are discussed from the perspective of their strengths and weaknesses, pointing to areas in need of further work.

Challenges for research and prevention in relation to work and cardiovascular diseases.

The purpose of this paper is to discuss future challenges for research and prevention in the field of work environment and cardiovascular diseases (CVD). First, research on CVD and work during the last half of the 20th century is discussed. Second, the theories dominating the last 20 years are presented. Third, cardiovascular and occupational epidemiology are compared, and it is stressed that occupational epidemiology should avoid the individualistic bias of mainstream cardiovascular epidemiology. Finally, future challenges are discussed, and improvements are recommended concerning the use of intermediate end points, intervention research, theories about chemical and physical risk factors, the use of a unifying model for society, stress, and health, and the application of integrated prevention. It is concluded that research on CVD and work can play an important part in the development of integrated prevention strategies for the next century.

Epidemiologic issues related to the association between physical activity and breast cancer.

A workshop on physical activity and breast cancer was held in November 1997 to review previous epidemiologic research on this topic and to identify new areas for research. This article is the first of three summaries of the workshop's activities. The material reviewed included 21 studies that reported a measure of physical activity in relation to breast cancer outcomes and were published by December 1997. They were identified in a computerized literature search and a "by-hand" review of journals. The study designs, populations, data collection methods, and results were examined and the strengths and limitations of the studies identified. The strengths and limitations are discussed herein, as are recommendations for future research. Fifteen of the 21 studies suggested that physical activity reduces the risk of breast cancer, whereas four studies found no association and two studies found an increased risk of breast cancer associated with physical activity. Specific subgroups of the population may experience a greater decrease in breast cancer with increased levels of physical activity. These include women who are lean, parous, and premenopausal. Some examination of confounding and effect modification was undertaken. Hypothesized biologic mechanisms for this putative association include an effect of physical activity on endogenous hormones, energy balance, and the immune system. The overall evidence supports a reduction in breast cancer risk with increased physical activity. However, numerous questions remain regarding this putative association. These include the underlying biologic model and the parameters of physical activity that are associated with risk, such as the types of activity (occupational, recreational, and household), the components of activity (frequency, intensity, and duration), the time periods in life that are associated with risk reduction, and the important confounders and effect modifiers of this association. Use of intermediate endpoints for breast cancer may be useful in such investigations.

Use of intermediate end-points to prevent long-term outcomes

Biomarkers may be very useful to assess and control the risk of long-term outcomes associated with exposure to industrial chemicals. Even when dose-effect and dose-response relationships have been demonstrated, the process of standard setting and the definition of ‘safe’ exposure levels is hampered by: (i) the arbitrary nature of attempts to distinguish acceptable from unacceptable effects; (ii) the difficulties in assessing the prognostic value of observed changes; (iii) the influence of the study power on statistically defined thresholds. Integration of epidemiological findings with mechanistic studies is necessary to assure confidence in risk assessment and to undertake sound risk management.

Use of intermediate endpoints in quantitating the response of precancerous lesions to chemopreventive agents.

A current area of emphasis in cancer research is the determination of whether cancer can be prevented through the use of naturally occurring chemopreventive agents such as beta-carotene. A major area of concern in the design of long-term, large-scale population studies to ascertain the efficacy of such chemopreventive agents lies in the paucity of biological data on the activity of these agents in man. The studies described in this paper were performed to determine whether a series of short-term markers could be used in chemopreventive trials as indicators of the possible success of a chemopreventive regime. Three such markers are described. The first involves the measurement of genotoxic damage in the target tissues of carcinogen-exposed individuals by using the micronucleus test on exfoliated cells. This end point has been successfully used to demonstrate a reduction in carcinogen damage (micronuclei production) in the oral cavity of individuals in population groups at elevated risk for oral cancer (tobacco and betel quid users in the Philippines, snuff users in the Northwest Territories). The second marker involves the determination of DNA adducts in exfoliated cells of carcinogen-exposed individuals by the use of DNA postlabelling procedure. The final marker discussed involves a chemical determination of the levels of a chemopreventive agent in target tissues of individuals receiving a supplement in the diet. In this case, the example described is beta-carotene in exfoliated cells of carcinogen-exposed individuals. These three markers may be combined to determine whether a chemopreventive agent reaches a target tissue, affects DNA adduct formation, and prevents genotoxic damage.(ABSTRACT TRUNCATED AT 250 WORDS)