Both large and small pharmaceutical companies have learned that the value of their development candidates increases once clinical
research has demonstrated their proof of concept. Sponsor companies face the challenge of moving new blockbuster drugs to
market as rapidly as possible. During development, they try to recognize, and minimize their spending on, products that can
never make it through the registration process because of toxicity or lack of efficacy. Focused drug development using the
best scientific approach accepted by regulatory authorities has become (or at least should become) a major objective for clinical
research departments. That approach can include the use of appropriate biomarkers during preclinical and clinical drug development.
As a general principle, a suitable clinical biomarker must be selected for which a reasonable relationship has been demonstrated
to the clinically relevant endpoint. A few biomarkers are so closely linked to the clinical outcome that regulatory authorities
have considered them valid primary variables in pivotal clinical trials and a substitute for a hard clinical endpoint during
the marketing authorization process. It generally takes considerably less time and fewer subjects-and therefore less money-to
demonstrate a significant effect of a drug on such a surrogate than on a "hard" endpoint. Based on these clinical biomarkers,
preclinical models should be chosen that have some relevance to the effect of the drug in patients with the target disease.
Biomarker defined In April 1999, the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) cosponsored a conference
on "Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications."1 The concepts of biomarkers and surrogates
have been summarized by the NIH Definitions Working Group as follows:
- A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes,
pathogenic processes, or pharmacologic responses to a therapeutic intervention.
- A clinical endpoint is a characteristic or variable that reflects how a patient feels, functions, or survives.
- A surrogate endpoint is a biomarker that is intended to substitute for a clinical endpoint. 2
Figure 1-3.
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Although more complex definitions have been suggested since then, the NIH definitions present a concise summary of the basic
concepts. Preclinical project team members should choose appropriate (and, if possible, "humanized") biomarkers that are relevant
to normal and/or pathological biology or physiologically associated with the target disease and the action of the new drug
in humans.
In early clinical studies, suitable biomarkers should be applied to help to demonstrate proof of concept and identify appropriate
dose regimens for efficacy studies. Doing so-and learning, for example, which subpopulations are most likely to benefit from
the new treatment-can help in planning later efficacy studies. Although the approach may seem straightforward, the use of
biomarkers and surrogates carries with it a number of practical problems and pitfalls. Cardiovascular research will be used
as an example here, because the concepts have often been applied in this clinical field.
It should be noted that any clinical observation in a given subject might serve different purposes, and each purpose can have
implications for the way these characteristics are used, documented, validated, and interpreted. In clinical practice, for
example, blood pressure (BP) is measured to assess the individual risk for a given patient and to decide upon that patient's
further diagnostic and therapeutic management. The same characteristic may be determined in epidemiological research, for
example. Finally, blood pressure may be used as an outcome measure for a company's decision making in a research project.
It may help to answer such questions as "Does the antihypertensive drug work?" or "Does the new drug create any side effects
related to blood pressure?" The same measure may become a valid surrogate and an essential element in the regulatory review
process to be used for the decision about marketing approval for the new drug. Researchers in cardiovascular drug development
have access to clearly defined and rigorously validated biomarkers, surrogate endpoints, and clinical endpoints.
Biomarkers include biochemical and functional characteristics or signals; ideally they should be noninvasive. Examples for
biochemical biomarkers for cardiovascular conditions are high-density lipoprotein (HDL) cholesterol, lipoproteins, creatine
kinase MB band (CK-MB), troponins (markers for myocardial cellular damage), high-sensitivity C-reactive protein (hs-CRP, a
marker for inflammatory processes), fibrinogen, or plasminogen activator inhibitor-1 (PAI-1, an indicator of the activity
of the blood coagulation system-and thus a risk for intravascular thrombus formation).3, 4 Functional or physiological characteristics
include endothelial function, arterial or venous blood flow, arterial stiffness, and left ventricular systolic or diastolic
volume or function. Finally, examples for signaling characteristics are ST depression recorded in the ECG (exercise or pharmacological
stress testing, for example), and findings obtained by an imaging method such as quantitative coronary perfusion, coronary
calcification (electron beam tomography), intravascular ultrasound, magnetic resonance imaging (MRI), or nuclear imaging (99mTc-SPECT)
that include exercise or pharmacological stress testing.
The most important criteria for valid biomarkers to be used in drug development are their clinical relevance; their sensitivity,
specificity, and reliability (do they measure what they are supposed to); and their practicality and simplicity.5
The list of cardiovascular biomarkers that have been accepted as surrogate endpoints is much shorter, of course, and includes
such characteristics as blood pressure, cholesterol, and low-density lipoprotein (LDL).
