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Selecting and validating biologic markers for drug development

W A Colburn1

  • 1Harris Laboratories, Phoenix, Arizona 85040, USA.

Journal of Clinical Pharmacology
|May 1, 1997
PubMed
Summary
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Biologic markers accelerate drug development but require different validation for decision-making versus regulatory approval. A rational basis, preclinical/clinical proof, and validated methods are essential for reliable surrogate markers.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Clinical Trials

Background:

  • Biologic markers, or surrogate markers, are crucial for drug development, especially when clinical outcomes are delayed.
  • They are used in early-phase decision-making and for accelerated regulatory approvals of drugs for critical conditions like cancer and AIDS.
  • The validation requirements for markers differ based on their intended use, such as guiding early decisions or supporting regulatory approval for life-threatening diseases.

Purpose of the Study:

  • To differentiate the validation requirements for biologic markers used in early decision-making versus those used for regulatory approval.
  • To emphasize the need for a strong theoretical basis, empirical evidence, and validated methods for all surrogate markers.
  • To highlight the potential pitfalls of inappropriate marker use, citing CD4 counts as an example.

Related Experiment Videos

Main Methods:

  • Review and analysis of the rationale and validation standards for biologic markers in drug development.
  • Comparison of marker utility in early-phase studies versus pivotal trials for regulatory submission.
  • Case examples illustrating appropriate and inappropriate use of surrogate markers (e.g., renin-angiotensin system markers vs. CD4 counts).

Main Results:

  • The validation foundation for markers used in regulatory approval must be more rigorous than for those used in early decision-making studies.
  • CD4 counts were deemed an inappropriate surrogate marker for prolonged survival in certain contexts.
  • Changes in renin-angiotensin system markers demonstrated a drug's intended effect and served as a valid decision-making tool, predicting reduced blood pressure and cardiovascular events.

Conclusions:

  • Biologic markers should only be employed if they possess a rational theoretical basis, are supported by preclinical or clinical data, and are measured using validated methodologies.
  • Distinct validation and acceptance criteria for decision-making markers versus regulatory approval markers must be prospectively defined and acknowledged.
  • Appropriate use of validated surrogate markers can significantly enhance the efficiency of new molecular entity development and regulatory pathways.