WASHINGTON - Two years after launching its voluntary genomic data submissions initiative, the US Food and Drug Administration is planning on using knowledge gained from around 30 VGDS submissions to help update the pharmacogenomics guidance document it released last year.
At a workshop held here this week, FDA officials said they plan to update the guidance with an “attachment” to address a number of technical questions that the original document left unanswered. The proposed attachment, which will likely be available in about a year, will provide recommendations on a number of issues, such as sample preparation, labeling systems, hybridization protocols, and reporting formats.
Federico Goodsaid, senior staff scientist in the genomics group of FDA’s Office of Clinical Pharmacology, said that the agency’s experience with VGDS submissions has underscored the need for more clarity on what drugmakers should submit and how.
In addition, some sponsors have already begun to submit genomic data as part of investigational new drugs and new drug applications that the FDA reviews under so-called “consults,” and the agency expects these submissions to continue to increase in number and complexity.
VGDS has been “helpful” for the FDA’s understanding of genomics data, Goodsaid said, but it has also highlighted “the need for consensus in a field that is constantly changing.”
The two-day workshop, “Best Practices and Development of Standards for the Submission of Genomic Data to the FDA,” was co-sponsored by the FDA, the Drug Information Association, the Pharmaceutical Research and Manufacturers of America, and the Biotechnology Industry Organization in order to identify key issues that the upcoming guidance attachment should address.
The workshop also served as an informal post-mortem for a handful of VGDS submissions. In two panel discussions during the meeting, representatives from Abbott Laboratories, Bristol-Myers Squibb, GlaxoSmithKline, Millennium Pharmaceuticals, and Pfizer provided candid accounts of their VGDS experiences. While the panelists highlighted a number of limitations in the process, they all characterized the experience as a positive one, and described their interactions with FDA scientists as productive.
The panelists also agreed that the FDA needs to clarify its recommendations for genomics data submitted outside the scope of VGDS as part of the standard review process. For example, several said they were still not sure how much underlying data the FDA would require to support the selection of genomic markers used in a clinical trial.
FDA has already taken steps to flesh out its initial pharmacogenomics guidance, which the agency made intentionally light on details in order to encourage industry involvement in VGDS. The agency recently released a draft “concept paper” that outlines a number of recommendations in areas where there is some consensus in the field. The concept paper, “Recommendations for the Submission and Review of Genomic Data,” addresses four main topics: gene expression microarray data, genotyping, genomic data in clinical study reports, and genomic data from nonclinical toxicology studies.
Goodsaid told Pharmacogenomics Reporter that the agency plans to gather feedback on the draft concept paper from workshop attendees and the broader community over the next year and that it will take that input into consideration for the final attachment to the pharmacogenomics guidance.
During the workshop, Goodsaid and other FDA officials got plenty of feedback from drugmakers regarding their experiences with VGDS.
Several panelists expressed concern that FDA researchers reanalyzed their genomic data using different methods and reference databases than they did, which led to different results. In most cases, FDA and sponsors ultimately reached the same biological interpretations of the data, but it did raise a few red flags for some pharma representatives.
Brian Spear, director of pharmacogenetics at Abbott, noted that FDA researchers reanalyzed Abbott’s data — gene expression microarray files related to a preclinical toxicogenomics study — “independent of the study design,” which led them to “draw conclusions beyond our questions.” He also said that the FDA reviewers exhibited an “unavoidable desire to look at individual genes,” which was beyond the scope of Abbott’s submission.
Spear said that while the FDA researchers and Abbott did not identify the same gene sets, they did reach “identical conclusions with regard to the biological interpretation” of the data. He added that he was impressed with FDA team’s analytical capabilities. Its assessment of the data set was “brilliant,” he said, “and not just because they agreed with us.”
Spear characterized Abbott’s decision to submit data through VGDS as an opportunity to learn about the process, but other pharmaceutical companies approached the program with different goals. BMS, for example, decided to “test” the FDA’s ability to analyze complex transcriptome datasets for three different studies. Bruce Car, executive director of discovery toxicology for BMS, said the company submitted the data sets with the goal of seeing how the agency handled tricky problems like off-target effects, dose-response effects, and degraded RNA samples.
Car said that the experience was “generally very positive,” but noted that the results indicated it might have been more effective to use smaller datasets rather than whole-genome data.
Michael Lawton, director of drug safety R&D at Pfizer, described another effort to push the VGDS envelope, in this case toward what the agency calls VXDS, in which the X stands for proteomics, metabolomics, or other -omics data types [see 11/1/2006 PGx Reporter].
Pfizer submitted genomic, proteomic, and metabolomic data related to a study on vascular injury biomarkers that it is working on with Genstruct, which has developed a pathway-based “knowledge model” based on the study data.
Lawton said that the submission highlighted the FDA’s relative inexperience with multiple -omics data types, and the challenges of comparing results from “novel” data analysis to “traditional methods.” Nevertheless, he said, he was “impressed” with the agency’s turnaround time of six weeks.
Millennium’s VGDS submission was a “test case for prospective pharmacogenomics in the course of drug development.”
In addition, he noted that even though the FDA did not have access to the Genstruct model, its own pathway analysis was in “concordance” with Pfizer’s conclusions.
Other companies viewed VGDS as more of a dress rehearsal for genomics-based regulatory submissions. Millennium, for example, submitted gene-expression profiles of multiple myeloma biopsies related to its development of Velcade. George Mulligan, senior scientist at Millennium, said that the VGDS submission was a “test case for prospective pharmacogenomics in the course of drug development.”
The goal, he said, was to help better define mechanisms for developing multi-gene classifiers for subsequent testing.
Despite the “lack of a prior prospective study as a benchmark,” which required the Millennium team to spend more time than it would have liked “trying to come to an agreement of what ought to be reported,” Mulligan said that the experience was ultimately deemed a success, and that the results were used in the company’s submission for accelerated approval of Velcade.
Mulligan noted, however, that Millennium struggled internally with the decision to submit genomic data supporting what one attendee described as a “live bullet in the chamber.” He said that the VGDS process was under a “high degree of scrutiny” within Millennium. There was a “difference of opinion as to whether the VGDS submission would distract the [FDA] review division,” he said.
Patrick Wier, vice president of safety assessment at GSK, described another VGDS example in which there was a bit more at stake than curiosity. GSK’s submission “was more than a VGDS to us,” Wier said. “It was foreshadowing what we’re doing continuously” as part of the drug-development process.
GSK submitted a 137-gene TaqMan panel called HepatoTaq that it has developed for drug safety profiling. GSK performs between 70 and 100 studies with the panel each year, Wier said.
Wier said that even though the FDA treated the data “as if it were a 137-gene mini-array” rather than a TaqMan panel, its analysis still agreed with GSK’s predictions.
The experience raised the “key question” of how sponsors can prove that their gene associations are valid when they are based primarily on internal databases, Wier said.
FDA’s Goodsaid noted that the FDA will likely not require sponsors to submit underlying data for how they derived particular biomarkers or gene panels, but it does expect drugmakers to provide ample evidence that their final gene lists actually perform as promised if they are to be used in clinical trials.
“Say you’ve got 20 genes that are to be used in a clinical trial,” he said. “You’ve only got one chance. If that has to be repeated, people will start not liking genomics.”
Goodsaid added, “That’s not a regulatory worry. That’s a worry about the field of genomics.”
Felix Freuh, associate director of genomics at the FDA, reinforced Goodsaid’s comment. “You can pick a gene list based on astrology and get lucky,” he said. “What counts from a regulatory perspective is that it performs consistently in a prospective study.”