IOM: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease

In 2008, the Food and Drug Administration (FDA) asked the Institute of Medicine (IOM) to conduct a study on the evaluation process for biomark­ers, focusing on biomarkers and surrogate endpoints in chronic disease.

Biomarkers are characteristics that indicate biological processes, and are essential for monitoring the health of both individuals and communities.

According to IOM’s report released this month entitled Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease, “doctors, scientists, and other health professionals use biomarkers as tools to obtain information about a person’s health status or response to interventions.”

The study, which was initiated by FDA’s Center for Food Safety and Applied Nutrition, noted how “some biomarkers, called surrogate endpoints, are used as sub­stitutes for actual clinical endpoints such as incidence of disease or death.” These surrogate endpoints are “intended to predict benefit or harm based on scien­tific evidence, and they are used in practice when it is difficult to collect data based on clinical endpoints.”

The committee used examples of case studies using biomarkers and surrogate endpoints in various diseases, such as low-density lipoprotein (LDL) and high-density lipoprotein choles­terol levels in cardiovascular disease.  In evaluating these case studies, the report’s authoring committee recommended that the “FDA adopt a consistent scientific process and framework for biomarker evaluation in order to achieve a rigorous and transparent process for all stakeholders.”

IOM believes it is important to create such a framework because although “LDL cholesterol level is an excellent biomarker in many situations, it does not always fully predict cardiovascular disease outcomes; in other words, it cannot be assumed to be a surrogate endpoint.”  This led them to assert that “no surrogate endpoint is a perfect substitute for a clinical endpoint.”

FDA and Surrogate Endpoints

FDA has the responsibility of examining data and making deci­sions about whether biomarkers or surrogate endpoints can be used for regulatory reviews. The FDA sometimes uses surrogate endpoints such as LDL to make decisions about health claims and drugs. When manufacturers present evidence to the FDA that a product reduces LDL levels, the FDA considers the evidence in relation to the sur­rogate endpoint and makes decisions about car­diovascular health claims or drugs based on that evidence.

As a result of this process, the committee recommended that the “FDA use the same degree of scientific rigor for evaluating biomarker use across regulatory areas, includ­ing drugs, medical devices, biologics, foods, and dietary supplements.” In carrying out this proposal, IOM noted that Congress may need to strengthen FDA authority to accomplish these goals.  While legislative action has not been taken yet, IOM noted that the biomarker evaluation process should consist of the following three steps:

–   Analytical validation – Biomarker tests need to be reliable, reproducible across multiple laboratories and clinical settings, and main­tain adequate sensitivity and specificity before data based on them can be used in subsequent evaluation steps;

–   Qualification – Qualification requires: (1) eval­uation of the nature and strength of evidence regarding whether a biomarker is associated with the disease, and (2) assembly of available evidence demonstrating that interventions targeting the biomarker impact the clinical endpoints of interest; and

–   Utilization – Decisions to use biomarkers depend on the specific use proposed in addi­tion to the strength of the available evidence. Strong evidence and a compelling context are needed for the use of a biomarker as a surro­gate endpoint.

In addition to this process, IOM recommends that for biomarkers with regulatory impact, the FDA convene expert panels to evaluate biomarkers and bio­marker tests. The committee noted that the initial evaluation of analytical vali­dation and qualification should be conducted separately from a particular context of use, and then expert panels should reevaluate ana­lytical validation, qualification, and utilization on a continual and a case-by-case basis. Other recommendations included the need for:

–   Congress to strengthen the FDA’s authority to request and enforce post-market surveillance across drugs, devices, and biologics when approvals are initially based on putative sur­rogate endpoint data;

–   Congress to grant the FDA authority to request studies and suffi­cient authority to act on the results of studies on consumer understanding of claims on foods and supplements.

–   HHS to facilitate a coordinated, department-wide effort to encour­age the collection and sharing of data about bio­markers for all uses, including drugs, biologics, devices, and foods; and

–   FDA, in coordination with other federal agencies, to build data infrastructure and surveillance systems to handle the information necessary to gain sufficient under­standing of the effects of biomarker utilization.

Conclusion

IOM’s recommendations underscore their own acknowledgement that “biomarkers are important in that they can enable faster clinical trials for interventions, improve understanding of healthy dietary choices, assist public health professionals in identifying and tracking health concerns, and help health care practitioners and patients make decisions.”  These obvious benefits from allowing a smooth and simple process for biomarkers overwhelmingly outweighs any risks.

While IOM seems to downplay the critical role biomarkers play, they do recognize that scientific information is always evolving and “allows for the introduction of new, life-saving health interventions.”  As a result, they correctly assert that “modern medicine depends on biomarkers.” Yet by suggesting a seemingly burdensome process to evaluate bio­markers in general, and surrogate endpoints spe­cifically, IOM has essentially proposed to limit innovation. Moreover, IOM’s report did not address the feasibility or cost of these recommendations, which will likely divert important resources and staff away from helping patients.

With thousands of drugs in the pipeline being developed, hundreds more waiting approval at FDA, and a severe shortage of staff and resources at numerous health agencies, does IOM really want to make it harder for drugs to get approved? Patients are presently waiting for treatments for severe and chronic illnesses, such as cancer and heart disease. Does making those individuals wait longer, so that FDA can increase its “degree of scientific rigor” actually protect patients or harm them?