By Robert Cote
In 2004, the U.S. FDA recognized that, despite the huge increase in R&D spending and in the number of identified drug targets, submissions for new drugs and biological products had stagnated. Investigating the causes of this stagnation, the agency found a widening gap between scientific discoveries and innovative medical treatments.
Breakthrough technologies used for academic research and target discovery were rarely adopted during drug development or safety/efficacy assessments. To cite one example, the renal protein KIM-1 has been published as a sensitive biomarker for kidney toxicity. However, less-sensitive biomarkers for blood urea nitrogen (BUN) and creatinine remain the most common standards for defining kidney toxicity.
Hoping to improve this situation, the FDA released a landmark report in 2004 entitled, “Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products.” According to the agency, the report was intended to “sound the alarm on the increasing difficulty and unpredictability of medical product development.” Following the report’s release, the FDA launched the Critical Path Initiative (CPI) to “drive innovation in the scientific processes by which medical products are developed, evaluated and manufactured.”
Industry and regulatory agencies quickly recognized that biomarker assays presented an excellent opportunity for improvement along the critical path. Whereas biomarkers had been primarily used as tools for diagnostics and target identification, they also have tremendous potential for use in drug development to assess proximal (target engagement) and distal (disease-related) markers for new therapeutics, as well as for regulatory evaluations of markers for safety and efficacy. Today, the role and perceived value of biomarkers is expanding to include virtually every aspect of disease treatment from diagnosis to drug discovery and development, and from drug safety to guiding therapy at the patient’s bedside.
Recognizing the importance and rapid growth of biomarker applications, leaders in the biomarker field gathered in September, 2010, at the University of Oxford, United Kingdom, for the European Biomarker Symposium. The meeting, which was organized by Dr. Ron Bowsher of EMD Millipore’s BioPharma Services, brought together representatives from pharmaceutical companies, biotechnology companies, life sciences research suppliers, CROs, regulatory agencies, diagnostics companies, academic research, and consultancies to discuss challenges and opportunities for biomarker assay development.
Opportunity 1: Accelerate Breakthrough Biomarker Science
Novel biomarkers and biomarker assays can increase the sensitivity and specificity of preclinical and clinical tests, according to many of the symposium speakers. Dr. Thomas Joos, head of the Biochemistry Department at the University of Tuebingen, believes that high quality immunoassays serve as the foundation for successful application of biomarkers in creating new diagnostics and supporting drug development.
For example, intact cells may increase biomarker assay specificity by providing a more physiologically relevant matrix. Institut National de la Santé et de la Recherche Médicale (INSERM) Research Director Dr. Michael Tovey has developed a whole-cell reporter assay that excited many at the symposium. Combining a reporter-gene assay with engineered, nonreplicating cells, the assay eliminates the variability resulting from cell culture and sample preparation.
Innovative immunoassays have also rapidly increased the understanding of cell signaling pathways. Dr. Joos is optimistic that peptide immunoassays can advance multiplex detection of biomarkers. Such immunoassays quantify phosphorylation changes across signaling pathways and cell phenotypes. Not only can researchers measure changes in the levels of individual proteins, but they can also assess effects of therapy, disease, or toxicity in multiple biological pathways.
Dr. John Bloom, consultant and special employee of the FDA, cited recent assertions by Bert Vogelstein of Johns Hopkins University that the majority of cancers can be linked to 320 genes in only about 12 pathways. However, using this knowledge to fight cancer, as is being done in the BATTLE nonsmall cell lung carcinoma clinical trial, requires prohibitively large resource investments. Each patient enrolled in the BATTLE umbrella trial undergoes a tumor biomarker analysis used to assign them to one of four different phase 2 clinical studies. Such investments are prohibitive for most studies until additional improvements in biomarker applications are made.
Although it is too early to make definite extrapolations, improvements in biomarker science have the potential to get drugs to market faster and, as a result, save millions of dollars.
Opportunity 2: Implementing Fit-For-Purpose Biomarker Assays
In the “fit-for-purpose” approach to method development and validation for biomarker measurement, analytical methods are validated as appropriate for their intended applications and not necessarily validated further. Theoretically, this approach should enable conservation of time, cost and other resources during early biomarker discovery, and application of these savings towards rigorous assay validation for later stage trials and high-stakes clinical uses of biomarkers.
Dr. Bowsher notes the degree of assay quantitation will depend on the stage of drug discovery and development in which biomarker will be used. As a result of users’ diverse requirements, it is acceptable — even desirable — that varying degrees of analytical validation are used at different points along the drug R&D continuum.
Fit-For-Purpose: The Regulatory View
Michelle Beharry of the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) agreed that fit-for-purpose biomarker qualification is being embraced by regulatory agencies as well. She noted the new formal process now available to drug developers for working with both the FDA and European Medicines Agency (EMEA) to obtain approval for biomarker qualification and analytical methods (Figure 1).
For the first time, drug developers can get help from teams of experts jointly representing both the FDA and EMEA (“working party” and “qualification team” in Figure 1). By involving regulatory agencies early in assay development, drug developers can better plan resource allocation and later-stage drug testing strategies, potentially decreasing time to market.
Beharry emphasized the extent of analytical assay validation is deliberately not specified by the committee. Rather, the committee takes into account multiple factors, including risk to patients, differences in the assay from established techniques, and improvements over current methods.
There are several advantages to not specifying the extent of validation required, according to Beharry. First, because patient risk is considered case by case, the risk of undervalidation is decreased. Second, by being open to data from new biomarker assays (still undergoing further validation) with significantly higher potential sensitivity and specificity, regulatory agencies facilitate the introduction of breakthrough technologies into drug development, as recommended by the CPI.
Implementing A Fit-For-Purpose Strategy For Biomarker Assays
Drug developers might ask, “Why not validate every assay with maximum rigor?” Citing the rising costs of drug development, as well as the need to evaluate the utility of the ever-increasing number of research-grade biomarker kits, Dr. Bowsher recommends balancing the “extent of validation you need for your intended purpose with the amount of resources you’re willing to expend. Ask yourself, what is the benefit of increasing the rigor of your validation versus the cost? Are you looking at an exploratory marker or a confirmatory marker? What are you going to do with the data?”
Dr. Bowsher presented a graph at the symposium (Figure 2) to aid in deciding how extensively to validate commercially available assays. The graph, for simplicity, suggests a linear relationship between cost and extent of validation. However, the true relationship is most likely nonlinear.
Opportunity 3: Expanding Multidisciplinary, Cross-Sector Research
Accelerating drug development and getting therapies into the clinic will require collaboration between diverse scientific disciplines. One example of such collaboration is the synthesis of genomics technology with therapeutics. Dr. Bloom notes that “10% of drug labels now require pharmacogenomic data prior to clinical use.” With personalized medicine ultimately culminating in the codevelopment of drugs with companion diagnostics, Dr. Bloom predicts corresponding changes in intellectual property and increased need for strong regulatory strategies to guide the process.
The FDA is expected to issue its guidance on the codevelopment of drugs and diagnostic personalized medicine products in 2011. This issuance will no doubt require an increase in public-private partnerships, enabling sharing of funds, individual patient data, and expertise to expand the scope of projects.
The global nature of multidisciplinary efforts now requires regulatory agencies from disparate geographies to work together. The joint FDA/EMEA biomarker qualification process described by Michelle Beharry is the first of its kind, and the qualification of seven nephrotoxicity biomarkers that emerged from this process in 2009 represented the first joint guidance.
Cross-sector cooperation will mean increased scientific communication with contract research organizations and reagent suppliers to guarantee reagent supply and quality, facilitating rolling qualification of biomarker assays and fit-for-purpose validation. Dr. Bloom predicts increased mergers and acquisitions between pharmaceutical and diagnostics companies to address the current “siloed” status of biomarker development and application, in which there is little continuity of reagents. “Pharma needs providers of broader solutions,” he said, “both upstream and downstream of particular technologies.”
Challenges In Biomarker Assay Development
Several speakers at the EU biomarker symposium, including renowned biomarker statistician Dr. Viswanath Devanarayan, cited factors that may negatively affect the reliability of a fit-for-purpose-validated biomarker assay. Some of the most important factors discussed include:
- Variations in sample collection and processing:l presence of anticoagulants and other common pre-analytical factors
- collection vessel types
- stability in staff and expertise at clinical sites and CROs
- calibration of sampling equipment.
- Reference material used to develop the original assay:
- potential impact of disease-state matrix
- lot-to-lot variability of reference material
- limited availability of reference material for further validation.
- Statistical analysis of data:
- parallelism: standard curve (using reference material) and test sample analyte should have an acceptable agreement in their slope values
- importance of appropriate weighting in nonlinear curve-fitting to maximize the range of reportable concentrations: recognition that the standard deviation is a nonconstant function of the mean response of calibrators
- assays should be optimized with respect to precision profile of each condition.
Symposium organizer Dr. Bowsher suggests that, although processes are still not clear-cut and may be controversial, certain strategies can help biomarker-based treatments consume fewer costs and human resources than they do today, while still minimizing patient risk:
- General adherence to fit-for-purpose strategies: At each stage of drug discovery and development, use a chart such as in figure 2 to balance the cost of validation with the level of acceptable risk, in order to best conserve resources to maximize validation for late-stage trials.
- Increased conversations between assay developers and assay customers: Communicate the level of acceptable risk to the assay developers in detail, and implement detailed records of sample collection, processing, reagents, and reference materials.
- Increased guidance on validation from regulatory agencies
About The Author
Robert Cote, MBA, is the business development manager for EMD Millipore's BioPharma Services group. He has more than 18 years of business development experience in the pharmaceutical, biotech, personal care, academia, and government arenas