Early Clinical Drug Development

A key objective in early clinical drug development is to establish the relationship between dose and the PD effects. The use of PD biomarkers can accelerate early clinical drug development by providing valuable information verifying the mechanism of action and demonstrating dose- and time-dependent PD effects. This information will support dose selection for phase II. If there is no effect on the PD biomarkers at any of the doses tested in phase I, the biomarker results can support a no-go decision to end clinical development.

Biomarkers can objectively be measured to study the PD effects of drugs; for example, the enzymatic activity of angiotensin-converting enzyme (ACE) and the concentration of angiotensin I and II can be measured in plasma to study PD effects of ACE inhibitors.30 The PD biomarkers play an important role in the first clinical studies of a new drug. In these studies, under controlled conditions, the PD bio-markers allow us to study the dynamic effects of a drug. In most first-in-human studies, healthy subjects are used to evaluate drug safety. In these studies, the PD

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Omapatrilat (mg)

FIGURE 3.2 Effects of ascending single doses of omapatrilat on the urinary excretion of atrial natriuretic peptide (ANP) in healthy subjects. (From Vesterqvist, O., and Reeves, R.A. Curr. Hypertens. Rep. 2001; 3[Suppl. 2]: 22-27. With permission.)

biomarker results provide valuable information about the duration and magnitude of the PD effects (Figure 3.2),31 especially as the clinical end points may not be meaningful to study in a healthy population. Together with the PK data, the PD biomarker results will be important in establishing the dose and dose regimen for further clinical studies in a patient population.

Transitioning of Pharmacodynamic Biomarkers from Discovery to Development

Most potential PD biomarkers are identified in the discovery phase of drug development. One of the biggest challenges in choosing the right PD biomarkers is the successful translation of these biomarkers from preclinical to clinical development. The initial validation of the value of a PD biomarker will therefore come from preclinical studies using in vivo animal models or from ex vivo studies using either animal or human samples. However, animal models often do not predict human biology, and many of the PD biomarker methods that are used in preclinical laboratories have gone through only limited analytical validation and characterization. It is, therefore, important that potential PD biomarkers be identified early in the research and development process to allow adequate time to validate the biomarker methods and also to define the intended use of the biomarkers prior to the start of

Early Discovery

Early Discovery

Biomarker

- identified

Validation

-limited

Validation

-extensive

Evidence

-prospective studies

Method

-developed

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Level 1

FIGURE 3.3 Staged approach to biomarker validation in drug discovery and development.

the phase I clinical studies. PD biomarker results from preclinical in vivo drug studies can be used to predict the PD effects of the drug on the biomarkers in the early clinical studies.

As a biomarker is used in early and full (late) drug discovery and eventually in clinical drug development, the level of biomarker validation can be addressed with a staged approach (Figure 3.3). For each level, the extent of validation and the confidence level in the PD biomarker are concomitantly increased. The intended use of a PD biomarker or a set of PD biomarkers in early clinical drug development will, to a great extent, dictate the evaluation of the biomarkers and the validation of the associated methods. However, there is limited time to develop and validate clinical biomarker methods and to evaluate the potential PD biomarkers prior to the initiation of phase I studies. The time available for method validation will limit the extent of the validation/evaluation, and this limitation has to be acknowledged by the clinical drug development teams.

Using Pharmacodynamic Biomarkers in Early Clinical Drug Development

The analytical validation of biomarker methods is often performed in an environment that differs from the one in which the methods will be performed during the clinical studies. In addition, analysts other than those who performed the method validation may perform the analysis of specimens from the clinical studies. Therefore, method performance during the actual analysis of clinical specimens may differ from that observed during assay validation.

Many of the preanalytical variables that challenge data interpretation can be addressed in the study design. Clinical studies can be designed to minimize the effects of preanalytical sources of variability, such as effects of posture, exercise, diurnal ip c

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Urine Collection Interval

FIGURE 3.4 Urinary excretion of atrial natriuretic peptide (ANP) in placebo-treated healthy subjects in a phase I study. At a mean individual urinary excretion of ANP ranging from 3.1 to 13.8 pg/mg creatinine, the overall intrasubject variability in the urinary excretion was 22% ± 9% CV (mean ± SD, N = 18) and a range from 10% to 45% CV. Arrows indicate placebo administration time. (From unpublished data provided by Bristol-Myers Squibb Company. With permission.)

biorhythms, and food intake. The use of a placebo group will give valuable information on the total variability in the PD biomarker results: the sum of the biological and analytical errors (Figure 3.4).

To support decision making in early clinical drug development, it is absolutely necessary that the PD biomarker results be delivered in a timely fashion. New multiplexing technologies and improved automation have enabled laboratories to quickly provide measurements of many PD biomarkers in a single study. The management of the enormous quantities of data alone can become a rate-limiting factor, and there is a need for efficient bioinformatics solutions. These solutions must include data storage, management, and analysis as well as a predefined process for providing the PD biomarker results to the clinical team. This is especially important in the single and multiple ascending dose studies, where timely information about the PD biomarker results following each dose group can give the clinical team additional and valuable time to prepare and plan for upcoming phase II and III clinical studies.

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