Biomarkers: Safety, Speed by Design

Learn to select markers — and providers — appropriately

by Gordon Kapke, Ph.D.

According to the FDA’s Critical Path initiative, biomarkers offer a key opportunity to improve the development process by increasing safety and establishing efficacy. The Critical Path Initiative is the FDA’s effort to stimulate and facilitate a national effort to modernize the scientific process through which a potential human drug, biological product, or medical device is transformed from a discovery, or “proof of concept,” into a medical process. Some predict that within the next 10 years, biomarkers will be a standard aspect of drug development for any new candidate.

Photo courtesy of Covance, Inc.

As biomarkers have gained considerable attention as a way to enhance drug targeting, effectiveness, and safety in clinical trials, some full-service outsourcing providers have enhanced their offerings to accommodate the needs of this growing market. Many critical decisions must be made before a biomarker project can begin, and the selection of an outsourcing partner who can provide the scientific expertise, high-throughput capacity, and technological resources to design a biomarker strategy that will ultimately lead to quicker decisions to continue or suspend a drug’s development is a key consideration.

The critical step in determining any biomarker strategy is having an understanding of biology and the drug’s specific actions. Clinical laboratories may act as consultants in biomarker development; however, drug developers are key players in defining the biomarker strategy, biology, and the drug’s actions.

With such a significant benefit when properly designed, it is important to select the appropriate partner and biomarker, but even more importantly, to design an effective biomarker strategy from the outset. Outsourcing biomarker testing, development, and validation work to a central laboratory is a good way to gain access to technology, equipment and scientific expertise to conduct high-throughput biomarker tests, as well as customized or novel biomarker assays. Outsourcing providers can also play a key role in overcoming some of the challenges in biomarker development, including biomarker selection and establishing time milestones.

The appropriate selection of biomarkers for drug development is very important if they are to serve as an aid to better recognize safety or efficacy concerns. There is also the time constraint — if the data supporting a particular biomarker are going to be beneficial, they must be generated in an agreed upon timeframe, which begins as early as biomarker selection.

Biomarker Development Basics

Because biomarkers play a strategic role in drug development, the key step of biomarker selection based on drug pharmacology and biology will improve the probability that the observed biomarker signals are real and significant and directly related to the studied drug. Sometimes, the correct scientific choice for a biomarker may not be a feasible biomarker choice for many reasons.

After a biomarker has been selected, one of the most common challenges that could hinder development is the lack of a commercially available published assay. On the other hand, a published assay may not be adequately described in the literature to support rapid implementation of the assay, or the stability of the biomarker may not permit the transport of the specimen to a laboratory that can perform the assay.

Once the biomarkers have been identified, the testing service must be defined. An immediate question is whether the testing should be completed within the biopharmaceutical company or outsourced. Selection of the proper testing location can be a challenging process, but this usually becomes clear when the objectives of the data generation and collection process are clearly defined. These objectives, in addition to resource and system constraints, often drive the testing to an outsourcing provider.

When the biomarkers have been selected for a particular development project, the next decision pertains to how the testing will be performed. The service provider will have many questions concerning the biomarker testing, so the more information that can be provided with the testing request, the greater the availability of the testing laboratory to appropriately evaluate the feasibility of delivering the requested services and data.

When a biomarker request is received at a service provider, the two key elements that facilitate a fast response are the number of samples to be tested and the timeframe for data generation. Many of the requested biomarkers will require validation effort, and the anticipated work is critical in determining the feasibility in bidding for the work. One solution for handling the validation cost issue is to commit to the cost as a separate billed item; this allows validation to begin while the wider issues of how the program will be implemented and billed are defined.

Time to biomarker data generation is a critical milestone for all parties. A variety of obstacles can come between the timely generation of biomarker data, including

• obtaining IRB approval;
• patient acceptance of requested testing; sample stability;
• available regulatory compliant assay;
• reliable reagent supply;
• investigatory support of specimen collection, storage, transport; budget constraints.

The Novel Approach

An alternative to the traditional biomarker development process is the novel biomarker approach. A sponsor may want to develop an assay for a biomarker when no commercial assay is available. If the assay is on a common platform, the laboratory should be capable of performing the analytical validation in a four- to eight-week timeframe, contingent on analyst and instrument availability.

When a sponsor identifies a new biomarker and requires an immunoassay to test the expected volume of clinical samples, the timeframe-to-assay creation is typically greater than one year. It must be understood that building an acceptable immunoassay may not be attainable for multiple reasons, including inappropriate sensitivity or lack of antibody specificity.

When moving into a new biomarker assay development, there may be intellectual property issues to consider and define before the validation proceeds. If the biomarker assay is going to be a technology transfer from the sponsor or another laboratory, the timeline is dependent on setting up the workstation and the availability of sponsor and lab personnel to meet for training of the assay. With good coordination and availability of personnel, a technology transfer should be accomplished as quickly as six weeks.

Safety, Speed by Design

Biomarkers offer the opportunity to improve and enhance the drug development process. Careful selection of biomarkers and a comprehensive planning process are essential for successful implementation of a biomarker strategy. Outsourcing providers, especially central laboratories, can be critical enablers for a biomarker strategy; however, substantial information must be shared early in the protocol development to ensure that the specimen collection and storage conditions are appropriately defined, and that the laboratory can validate the biomarker assay and test the samples in a timely fashion.

For a biomarker strategy to be successful, it must deliver economic benefit. A good strategy will produce economic benefit, and there are clear examples of such benefits. The challenge is to find the ideal biomarker strategy.

Gordon Kapke, Ph.D. is senior director, Biomarker Services at Covance, Inc. He can be reached at info@covance.com.