Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework

  title={Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework},
  author={Arthur J. Jr. Atkinson and Wayne A. Colburn and Victor DeGruttola and David L DeMets and Gregory J. Downing and Daniel Hoth and John Oates and Carl C. Peck and Robert T. Schooley and Bert A. Spilker and Janet Woodcock and Scott L. Zeger},
  journal={Clinical Pharmacology \& Therapeutics},
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… 

Chapter 8 – Biomarkers

Contribution of DNA and tissue microarray technology to the identification and validation of biomarkers and personalised medicine in breast cancer.

The role of DNA microarrays and tissuemicroarrays in the validation of biomarkers in breast cancer is reviewed, with emphasis on their potential application to determine mode of personalised therapy in the future.

Biomarker Analysis as a Decision-Making Tool in Drug Discovery and Development

  • S. StochJ. Wagner
  • Biology, Medicine
    International Journal of Pharmaceutical Medicine
  • 2012
Biomarkers discovered with the aid of molecular profiling may have particular utility in approaching complex diseases with poorly characterised pathophysiology, as in type 2 diabetes mellitus and may have broader utility in both a regulatory context and in clinical practice.

The Biomarkers Consortium: On the Critical Path of Drug Discovery

  • C. Altar
  • Medicine, Biology
    Clinical pharmacology and therapeutics
  • 2008
Using biomarkers to predict whether a drug or other intervention is safe and effective in a shorter time and at lower cost than clinical outcomes studies helps promote regulatory approval of new therapeutic entities by pharmaceutical, biological, and device development teams.

Molecular profiling approaches for identifying novel biomarkers.

This review will summarise experimental and computational efforts in the field of molecular profiling and discuss the significant challenges in interpreting molecular profiling data and qualifying novel transcriptional biomarkers.

Molecular profiling approaches for identifying novel biomarkers

This review will summarise experimental and computational efforts in the field of molecular profiling and discuss the significant challenges in interpreting molecular profiling data and qualifying novel transcriptional biomarkers.

Mass spectrometry-based biomarkers in drug development.

Describing of the different classes of biomarkers that have utility in the drug development process as well as review specific, protein-centric, mass spectrometry-based approaches for the discovery of biomarker and development of targeted assays to measure these markers in a selective and analytically precise manner are provided.

3.04 – Biomarkers

Opportunities and challenges for hybrid immunoaffinity LC–MS approach for quantitative analysis of protein biomarkers

The use of biomarkers represents a competitive advantage in drug discovery and development to improve drug discovery effectiveness, facilitate dose selection, evaluate pharmacodynamic (PD) effect and target engagement, assess safety and select patients for treatment.



The contribution of clinical pharmacology surrogates and models to drug development--a critical appraisal.

  • P. Rolan
  • Medicine
    British journal of clinical pharmacology
  • 1997
The objective of exploratory drug development is to identify drugs which may have selected and studied patient groups, with confirmatory been labelled as having a tolerability problem due to efficacy and ‘safety’ in Phase III, and the following are examples of drugs.

Efficacy Measures: Surrogates or Clinical Outcomes?

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

Meta-analysis for the evaluation of potential surrogate markers.

A meta-analysis approach using Bayesian methods enables one to obtain prediction intervals for the true difference in clinical outcome for a given estimated treatment difference in the effect on the potential marker.

New molecular endpoints and methods for routine toxicity testing.

These new in vivo techniques will greatly enhance the ability to extrapolate laboratory data to human health risk and allow in vitro screening for product development, in vivo hazard identification, and early risk assessments in animal models and direct risk assessment in humans.

Importance of surrogate markers in evaluation of antiviral therapy for HIV infection.

In chronic diseases, like cancer, cardiovascular disease, and human immunodeficiency virus (HIV) infection, standard clinical end points may be either distant in time or rare, and thus require a trial of long duration, large sample size, or both to demonstrate the value of a new treatment.

Surrogate End Points in Clinical Trials: Are We Being Misled?

Surrogate end points are rarely, if ever, adequate substitutes for the definitive clinical outcome in phase 3 trials and proper justification for such replacement requires that the effect of the intervention on the surrogate end point predicts the effect on the clinical outcome.

Surrogate endpoints in clinical trials: definition and operational criteria.

A rather restrictive criterion is proposed for use of the adjective 'surrogate' - it is proposed that a surrogate for a true endpoint yield a valid test of the null hypothesis of no association between treatment and the true response.

DNA Damage as an Intermediate Biomarker in Intervention Studies

  • R. Santella
  • Biology, Chemistry
    Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine
  • 1997
Methods for DNA adduct measurement include immunoassays, [32P] postlabeling, high-performance liquid chromatography with fluorescence or electrochemical detection, and gas chromatography/mass spectroscopy, which suggest they can provide important mechanistic information in support of larger scale studies.

Surrogate end points, health outcomes, and the drug-approval process for the treatment of risk factors for cardiovascular disease.

Surrogate end points sometimes fail to serve as valid predictors of important health outcomes, and one remedy would be to require, prior to approving new drug therapies for cardiovascular risk factors, large, long-term clinical trials to assess the drug’s effects on major disease end points.

Evaluating surrogate markers.

  • M. HughesV. DeGruttolaS. Welles
  • Biology
    Journal of acquired immune deficiency syndromes and human retrovirology : official publication of the International Retrovirology Association
  • 1995
Designs in which marker evaluation is undertaken only for a random sample of subjects within a randomized trial and for all other subjects who develop a major clinical outcome will be useful in clinical trials in which a highly significant treatment difference on clinical outcome has been obtained.