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“We focus on early proof-of-concept and biomarker-based studies, encouraging investigator-initiated trials…”
Biomarkers are biological indicators that signal a changed physiological state due to disease or a therapeutic intervention. In inflammatory diseases, typical biomarkers include cytokines (e.g., IL-1, TNF-alpha), metalloproteinases and small molecule mediators (e.g., prostaglandins). We measure biomarkers as either expression at the mRNA and protein level or as functional activity.
Three principal purposes to measure biomarkers
Surrogate markers are special type of biomarker that may be used in place of clinical measurements as a clinical endpoint for drug approval purposes. For example, the measurement of cholesterol levels is now an accepted surrogate marker of atherosclerosis.
Proof-of-concept biomarkers, are used to aid in the development decision process so that “Go/No Go” decisions can be made without requiring clinical efficacy endpoints. In addition, the mechanism of drug action can be explored by determining the biological effect of a treatment on biomarkers.
The initial human trials conducted on a potential therapeutic agent are designed to determine safety and tolerability, not efficacy. Phase I trials are often relatively small, typically 20-90 patients, and of short duration, often lacking the statistical power for conventional signs and symptoms endpoint analysis. In order to make an informed decision about proceeding with development, phase I studies are often divided into to stages. Phase IA trials are performed on healthy subjects to determine a safe and tolerated dose. Phase IB studies focus on patients with disease in order to provide information on disease specific side effects. If a drug passes this phase I, it can then be tested in a larger efficacy trial. Often, clinical investigators measure clinical or laboratory markers during a phase IB trial with the hope of obtaining suggestive (trend) data that can help determine if a phase II trial is warranted.
The use of biomarkers as secondary endpoints formalizes the process of obtaining disease state information for that can support a decision on continued development. For instance, a biomarker may not provide true surrogate endpoint information, but may indicate downstream effects consistent with the therapeutic model. Expression of the cytokine IL-6 in the synoviom is not a surrogate marker of rheumatoid arthritis. However, as a regulator of acute mediators, IL-6 down regulation in the synovium can be an important and time sensitive indicator of drug action. This would not assist directly in the approval process, but it may help justify proceeding to phase II. Equally important, a drug that is safe and well tolerated, but changes no markers may not be ready for phase II commitment.
In hypothesis-driven drug development, targets have been selected based on preclinical models; Biomarker analysis can be used for target validation and mechanism determination. In addition to inflammation markers, markers tightly coupled to the target can be evaluated at the disease site. Demonstrating downstream drug action at the site of disease is a hallmark of the biomarker approach to translational research. Another important advantage of leveraging short and small phase I trials is the ability to have a pre-study washout period. With the ever-increasing standard of care in inflammatory diseases, it is difficult to conduct long-term studies without concomitant administration of approved drugs. In a short study, patients can withdraw from their current therapy before starting the new drug, greatly simplifying trial design without jeopardizing long-term health of the patient. This also enhances the probability of recognizing a novel drug that has a similar therapeutic effect, but improved side effect profile over the current standard.
Historically, it has proven technically difficult to reliably measure markers such as cytokines at the sites of inflammation. New technologies, such as TaqMan quantitative PCR have greatly improved our ability to reproducibly make sensitive measurements on disease related tissues. Measurement of disease site tissues is another hallmark of our approach. Measurement of soluble factors in the blood is important and often valuable, particularly in large studies. Measurement at the site of disease provides obvious advantages for evaluating mechanism-of-action in situ. We have developed extensive biopsy sampling and processing technologies to improve overall reliability.
Study design is also an important factor. The use of paired samples simplifies analysis and reduces the influence of patient variation. Pre-treatment patient samples are obtained after drug washout to establish a baseline. A post-treatment sample can be obtained and compared to the pre-treatment sample. The import observation is a change in state, rather than an absolute value. Demonstrating a multifold reduction in expression of a proinflammatory cytokine due to treatment provides valuable insights.
In summary: The addition of a biomarker component to early clinical trials can provide highly leveraged information for the subsequent development decisions.
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