genome are dramatically reshaping the research and development pathways for drugs, vaccines, and diagnostics. The growth in the number of molecular entities entering the drug development pipeline has accelerated as a consequence of powerful discovery and screening technologies such as combinatorial chemistry, mass spectrometry, high throughput screening, celland tissue-based DNA microarrays, and proteomic approaches.1 As a consequence, there is an escalating number of therapeutic candidates, which has caused the need for new technologies and strategies to streamline the process to make safe and effective therapies available to patients. One approach to the achievement of more expeditious and informative therapeutic research is the use of precise clinical measurement tools to determine disease progression and the effects of interventions (drugs, surgery, and vaccines). For example, gene-based approaches such as single nucleotide polymorphism maps are now being developed to distinguish the molecular and cellular basis for variations in clinical response to therapy.2 Another approach is the use of a wide array of analytical tools to assess biological parameters, which are referred to as biomarkers. Biomarker measurements can help explain empirical results of clinical trials by relating the effects of interventions on molecular and cellular pathways to clinical responses. In doing so, biomarkers provide an avenue for researchers to gain a mechanistic understanding of the differences in clinical response that may be influenced by uncontrolled variables (for example, drug metabolism). There are a variety of ways that biomarker measurements can aid in the development and evaluation of COMMENTARY

Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework*

Context Hemoglobin-based blood substitutes (HBBSs) are infusible oxygen-carrying liquids that have long shelf lives, have no need for refrigeration or cross-matching, and are ideal for treating hemorrhagic shock in remote settings. Some trials of HBBSs during the last decade have reported increased risks without clinical benefit. Objective To assess the safety of HBBSs in surgical, stroke, and trauma patients. Data Sources PubMed, EMBASE, and Cochrane Library searches for articles using hemoglobin and blood substitutes from 1980 through March 25, 2008; reviews of Food and Drug Administration (FDA) advisory committee meeting materials; and Internet searches for company press releases. Study Selection Randomized controlled trials including patients aged 19 years and older receiving HBBSs therapeutically. The database searches yielded 70 trials of which 13 met these criteria; in addition, data from 2 other trials were reported in 2 press releases, and additional data were included in 1 relevant FDA review. Data Extraction Data on death and myocardial infarction (MI) as outcome variables. Results Sixteen trials involving 5 different products and 3711 patients in varied patient populations were identified. A test for heterogeneity of the results of these trials was not significant for either mortality or MI (for both, I2 = 0%, P ≥ .60), and data were combined using a fixed-effects model. Overall, there was a statistically significant increase in the risk of death (164 deaths in the HBBS-treated groups and 123 deaths in the control groups; relative risk [RR], 1.30; 95% confidence interval [CI], 1.05-1.61) and risk of MI (59 MIs in the HBBS-treated groups and 16 MIs in the control groups; RR, 2.71; 95% CI, 1.67-4.40) with these HBBSs. Subgroup analysis of these trials indicated the increased risk was not restricted to a particular HBBS or clinical indication. Conclusion Based on the available data, use of HBBSs is associated with a significantly increased risk of death and MI.Published online April 28, 2008 (doi:10.1001/jama.299.19.jrv80007).

Cell-Free Hemoglobin-Based Blood Substitutes and Risk of Myocardial Infarction and Death: A Meta-analysis

Pharmacokinetic/pharmacodynamic (PK/PD)-modeling links dose-concentration relationships (PK) and concentration-effect relationships (PD), thereby facilitating the description and prediction of the time course of drug effects resulting from a certain dosing regimen. PK/PD-modeling approaches can basically be distinguished by four major attributes. The first characterizes the link between measured drug concentration and the response system, direct link versus indirect link. The second considers how the response system relates effect site concentration to the observed outcome, direct versus indirect response. The third regards what clinically or experimentally assessed information is used to establish the link between concentration and effect, hard link versus soft link. And the fourth considers the time dependency of pharmacodynamic model parameters, distinguishing between time-variant versus time-invariant. Application of PK/PD-modeling concepts has been identified as potentially beneficial in all phases of preclinical and clinical drug development. Although today predominantly limited to research, broader application of PK/PD-concepts in clinical therapy will provide a more rational basis for patient-specific dosage individualization and may thus guide applied pharmacotherapy to a higher level of performance.

Modeling of pharmacokinetic/pharmacodynamic (PK/PD) relationships: concepts and perspectives.

Chemically modified or genetically engineered haemoglobins (Hbs) developed as oxygen therapeutics (often termed 'blood substitutes') are designed to correct oxygen deficit due to ischaemia in a variety of clinical settings. These modifications are intended to stabilize Hb outside its natural environment--red blood cells--in a functional tetrameric and/or polymeric form. Uncontrolled haem-mediated oxidative reactions of cell-free Hb and its reactions with various oxidant/antioxidant and cell signalling systems have emerged as an important pathway of toxicity. Current protective strategies designed to produce safe Hb-based products are focused on controlling or suppressing the 'radical' nature of Hb while retaining its oxygen-carrying function.

Oxygen therapeutics: can we tame haemoglobin?

Introduction Responsibilities of the Data Monitoring Committee and Motivating Illustrations Composition of a Data Monitoring Committee Independence of the Data Monitoring Committee: Avoiding Conflicts of Interest Confidentiality Issues Relating to the Data Monitoring Committee Data Monitoring Committee Meetings Data Monitoring Committee Interactions with Other Trial Components or Related Groups Statistical, Philosophical and Ethical Issues in Data Monitoring Determining When a Data Monitoring Committee Is Needed Regulatory Considerations for the Operation of Data Monitoring Committees Index

Data Monitoring Committees in Clinical Trials: A Practical Perspective

Diaspirin-crosslinked hemoglobin reduces blood transfusion in noncardiac surgery

Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: The diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial

T he use of surrogate endpoints in drug and biologic development has received a great deal of attention since it was determined in the mid-1980s that new therapies for acquired immune deficiency syndrome (AIDS) and cancer were desperately needed.1 Although pure surrogate markers, such as improved lipid profiles for the prophylaxis of coronary heart disease, decreases in blood pressure for coronary and cerebrovascular disease, and decreases in serum glucose concentrations for diabetes, have been successfully used in efficacy studies for decades, the use of surrogate markers in accelerated approval programs resulted in heightened awareness and scrutiny of surrogate efficacy endpoints. The term “surrogate” is used too liberally today when clinical and regulatory scientists seek to develop accelerated approval programs and other efficacy programs.2 In the context of a clinical trial, surrogates are selected because they are more readily observed, are less invasive, and/or are apparent sooner or more frequently than the ultimate outcome measure.3 For ethical and practical reasons, it is neither possible nor desirable in most cases to select mortality as the primary endpoint in efficacy trials. Prolonging the life of an individual for a few days should not be acceptable when the ultimate outcome, death, has not been extended, but prolonging the life of a patient for several months or years may be acceptable even when the ultimate outcome is not altered. The term “surrogate” has been misused or poorly defined in many situations, resulting in inaccurate classifications of trial endpoints. Improvised terms such as “pseudo-endpoints” and “quasi-endpoint” have been coined and are often derisively applied to surrogate measures. A view often taken is that an endpoint is either a surrogate, and therefore suspect, or it is a direct measure and is not suspect. The situation is not that simple. A more clinically rational

Efficacy Measures: Surrogates or Clinical Outcomes?

Low doses of stroma-free diaspirin cross-linked hemoglobin are administered to patients undergoing hemodialysis, to achieve hemostabilization and avoid hypotensive episodes in susceptible patients Hemoglobin therapy when implemented prophylactically in hemodialysis also partially obviates the need for further interventions to control circulatory system instability

Hemoglobin therapy in hemodialysis

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

John W. Blue

Author Tools

Chat about Author

Papers

Diaspirin-crosslinked hemoglobin reduces blood transfusion in noncardiac surgery

Monitoring a clinical trial conducted under the Food and Drug Administration regulations allowing a waiver of prospective informed consent: The diaspirin cross-linked hemoglobin traumatic hemorrhagic shock efficacy trial

Efficacy Measures: Surrogates or Clinical Outcomes?

Hemoglobin therapy in hemodialysis