Insights | Outlook · Zachary Zimmerman with Sue Flood and Edward D. Helton March 17, 2004 | Genomic data — specifically, microarray analysis — will be a keystone in establishing drug safety and delivering personalized medicine. The FDA's recent "Guidance for Industry — Pharmacogenomic Data Submissions" indicates that pharmacogenomics is here to stay. The pharmaceutical focus has switched to small molecules with an understanding of biological impact gathered from phenotypic results. But serious drug withdrawals due to adverse events, such as fen-phen-induced cardiac valvulopathy, teach that chemical attributes do not always reveal biological impact.
|The pharmaceutical industry and the FDA hope pharmacogenomics will resolve unexpected safety issues.
To date, our ability to perform predictive modeling on drug safety incorporates the mechanism of action and/or reaction kinetics and structure-activity relationships. But extrapolation using these paradigms is only moderately predictable regarding idiosyncratic, iatrogenic, and idiopathic adverse drug events. The pharmaceutical industry and the FDA hope pharmacogenomics will resolve unexpected safety or efficacy issues. Pharmacogenomics should lead the way in the utilization of surrogate markers for a greater understanding of both drug safety and efficacy. But to be successful, the challenge of assembling sufficient data on adverse events to accurately assess safety risks without crossing ethics boundaries must be resolved.
An estimated 85 percent of biopharma companies are utilizing array technology in drug research, in areas including target identification and validation, lead optimization, toxicological profiling, and in clinical trials to characterize patients most at risk for adverse events or, conversely, to identify those who respond well to lower doses.
However, many hurdles remain: The novelty of these technologies, plus the lack of standards, suggests an incomplete understanding of cause and effect. There is a strong need for more controlled experimental design and testing standards — concepts that are already well utilized within clinical environments.
Growing utilization of genomic technologies in the clinical process has pushed the FDA to drive change. Recognition of the widespread usage and the need to champion the standardization of pharmacogenomic data in clinical stages for a better understanding of safety and efficacy has driven the agency to release its pharmacogenomics guidelines. The guidelines seek to foster a relationship with the industry and craft mutually agreeable rules about utilization of microarray and genomic data in the drug approval process.
The FDA's guidelines are the beginning of a long, arduous process of standardizing tests that will offer real value in public health. The preclinical safety process has been refined and internationalized under Good Laboratory Practice regulations over several decades. Learning how to curate and annotate new endpoints with standard ranges for clinical significance will take time and effort.
Concurrent with these guidelines are the activities Roche has spearheaded to obtain regulatory approval of microarray-based diagnostic tests for its AmpliChip P450. Information gathered during the device approval process, such as analysis of reliability and reproducibility, will influence the progress of the array test as diagnostic tool. Using genomics-based diagnostics for patient treatment monitoring is also of great interest to hospitals and insurance providers. Many groups are investigating the use of genetic and genomic information for improving treatment protocols and proactively identifying safety issues.
Despite great expectations when genomics was first utilized, the novelty of the information has prevented pharmaceutical companies from incorporating genomic results into their submission data, even though they were collecting them during the clinical process. The FDA's pharmacogenomics guidelines will push life science companies into seriously reviewing genomic data as they prepare for submissions. With the pharmacogenomic guidelines listed as a top priority for 2004, the FDA clearly recognizes their completion as an essential milestone on the path to personalized genomics.
Sue Flood is lead strategist for discovery and scientific research at SAS. E-mail: firstname.lastname@example.org. Edward D. Helton is chief strategist for regulatory and biomedical affairs at SAS. E-mail: email@example.com. Zachary Zimmerman is senior research analyst for Life Science Insights at IDC. E-mail: firstname.lastname@example.org.