Evaluation and Qualification of Biomarkers

Many disease biomarkers are well characterized and are used extensively in drug development. However, there is the frequently need to develop new biomarkers, especially in new therapeutic areas and/or when dealing with innovative therapeutic approaches. Development of new biomarkers should start at the preclinical stage with the intent to have a new biomarker when the lead candidate enters the human development stage. The objective of bio-marker development should be clearly defined, such as the need for markers related to disease progression or the pharmacological effect of the drug or for markers indicating therapeutic activity.

In the evaluation phase, the candidate biomarker should be measured against the following attributes that define a biomarker (Lesko and Atkinson, 2001):

• Clinical relevance, which may theoretically reflect a physiologic or pathologic process or activity over a relatively short period of time. Ideally, this effect should be related to the MoA of the drug and to the clinical endpoint. This obviously requires an understanding of the pathophysiology of a disease and of a drug 's mechanism of action, taking into consideration the fact that diseases frequently have multiple causal pathways.

• Sensitivity and specificity to treatment effects, defined as the ability to detect the intended measurement or change in the target patient population.

• Reliability, defined as the ability to measure the biomarker analytically with accuracy, precision, robustness, and reproducibility.

• Practicality, defined as noninvasiveness or only modest invasiveness.

• Simplicity, for routine utilization without the need for sophisticated equipment or operator skill, extensive time commitment, or high measurement cost.

Validation of Biomarkers

The validation of a biomarker is a work in progress that ends when the bio-marker is validated as a surrogate endpoint. During the development of a biomarker, aside from the characteristics mentioned above, the investigator should take into account the risk of a false positive or false negative result [which occurs when the value(s) of specific biomarker(s) does not reflect a positive change in the clinical endpoint(s)]. During the validation process, the assay that is used must be highly reliable and reproducible. As far as the demonstration of the predictive value of the candidate as a surrogate endpoint for the clinical outcome is concerned, regulatory guidance does not specify which methodology should be used in validating biomarkers as surrogate endpoints. It is well recognized that developing a single biomarker as a surrogate endpoint can become rather cumbersome for a pharmaceutical sponsor (Lesko, 2007). To complicate matters further, a biomarker may become a surrogate endpoint for efficacy but not for toxicity. Indeed, there are few biomarkers of toxic effects (such as the QTc prolongation) that predict torsade de pointe, or the increase in aminotranspherases predicting liver failure.

Biomarkers may also be misleading in areas where they may result in a short - term beneficial effect but a long- t erm deleterious effect. As a consequence, the benefit/risk ratio can rarely be evaluated based on a surrogate marker, hence the use of biomarkers as surrogate endpoints only in those areas with critical unmet medical needs.

In the process for biomarker validation, the following properties should be evaluated: (1) feasibility of a surrogate marker in predicting the clinical outcome, and (2) statistical relationship between a biomarker and the clinical outcome. This should first be demonstrated by the natural history of the disease, then by adequate and well-controlled clinical trials that estimate the clinical benefit by changing the specific surrogate endpoint. It should be noted that during the biomarker validation process, it is insufficient to show only that the biomarker correlates with the clinical endpoint; it is also necessary to demonstrate that the effect on the surrogate endpoint interferes with the treatment effect on the clinical endpoint. In rare cases, a biomarker is elevated to the status of surrogate endpoint based solely on the results obtained from one drug. A metaanalysis of multiple clinical trials with different drugs and different stages of disease may be required to determine the consistency of effects and strengthen the evidence that a change in the biomarker level resulted in an effect on the clinical outcome.

With the FDA Modernization Act of 1997, the U.S. Food and Drug Administration (FDA) has gained a legal basis for using surrogate endpoints in ordinary and accelerated drug approvals. Indeed, the FDA was given explicit authority to approve drugs for the "treatment of a serious or life -threatening condition ... upon a determination that a product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit," leading to market access of new drugs and drug products. The standards for linking a biomarker to a clinical outcome are higher for ordinary approvals than for accelerated approvals. This difference is based on consideration of many factors, including the degree of scientific evidence needed to support biomarker surrogacy, public health needs, relative risk/benefit ratio, and the availability of alternative treatments. For ordinary approvals there are relatively few approved surrogate endpoints, such as "lower cholesterol and triglycerides" for coronary artery disease, "lower arterial blood pressure" for stroke, heart attacks and heart failure, "increase cardiac output for acute heart failure," "reduce HIV-RNA load and enhance CD4+ cells" for AIDS, "lower glycosilated hemoglobin" for diabetes, and "reduced tumor size" in solid tumors.

Oncology is an interesting example of this practice. In oncology, survival is the ultimate clinical outcome. However, approvals in the United States in the field of oncology from 1990 to 2002 highlight that tumor response was the approval basis in 26 of 57 regular approvals, supported by relief of tumor-specific symptoms in 9 of these 26 regular approvals (Table 1). Relief of tumor- specific symptoms provided critical support for approval in 13 of 57 regular approvals; approvals were based on tumor response in 12 of 14 accelerated approvals.

In Europe, regulatory awareness is increasing and some initiatives are ongoing, such as the EMEA/CHMP Biomarkers Workshop, which was held in 2006. However, while biomarker development is encouraged during early-stage development, there is significant hesitancy in accepting biomarkers as surrogate endpoints for drug approval. As an example, a review of the

TABLE 1 Summary of Endpoints for Regular Approval of Oncology Drug Marketing Applications, January 1, 1990 to November 1, 2002

Parametera

Endpoint

Total

S?

Survival

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