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Issuing RFI, NIGMS Hopes to Identify Most Pressing Needs in PGx Research

In an effort to develop a more robust pharmacogenomic research agenda, the National Institutes of Health's Institute of General Medical Sciences last week issued a request for information about what the most pressing needs are for the field to move forward. 
“The RFI was issued so that NIH as a whole, all institutes working together, could learn from the scientific community what researchers view as the most pressing needs for pharmacogenomics,” Rochelle Long, chief of the Pharmacological & Physiological Sciences Branch at NIGMS, told Pharmacogenomics Reporter last week. “This is a comprehensive request, and it spans the field from basic research [and] discovery to implementation.”
NIGMS is reaching out to all stakeholders for information in this regard, including scientific organizations, pharmaceutical companies, federal agencies, and other research organizations interested in the discipline. In the RFI, respondents are asked to describe “crucial needs, gaps, and roadblocks to pharmacogenomics esearch,” and to specify whether their suggestions are intended to “enable research efforts” or “translate discoveries into clinical practice.” 
The deadline for comment is April 30.
Within the request, NIGMS explains that an RFI is “for planning purposes only, and should not be construed as a solicitation for applications or proposals and/or as an obligation in any way on the part of the United States Federal Government.”
However, Long noted that RFIs are conducted as “a needs assessment by NIH, and typically such an activity precedes discussions about whether research programs should be developed that can transform or catalyze the field.” 
Before completing a formal survey of the field, Long would not comment on what the NIH currently feels are the most pressing areas for pharmacogenomics research. She explained that the Trans-NIH Pharmacogenomics Working Group plans to review all responses regarding the gaps and roadblocks to PGx research and then make an assessment of the most salient needs of the field.
“The working group recognizes that there are many steps along the way from discovery to implementation, including development of the appropriate platforms for tests and clear interpretation of results, to very practical matters related to point-of-care testing, including accuracy and speed of delivery of test results and reimbursement for the cost of testing,” Long said.
According to Long, pharmacogenomics strategies offer several “promising opportunities for breakthroughs.” She ranked cancer and cardiovascular disease as the areas in which pharmacogenomics research currently show the most promise, followed by neuropsychiatric disorders and diabetes. 
“Some of the initial applications [of pharmacogenomics] will be for drugs that have a narrow therapeutic index, comparison of toxic dose to the therapeutic dose, because it may be easy and realistic to adjust the dosage of a drug to fall within the 'safe and effective' range,” she added. “This is already being done in an empirical fashion by physicians, and it will become more practical to use tests that are predictive.”
While in recent years companies have introduced numerous tests that claim to guide drug dosing for various indications, many industry observers believe that the adoption of these tests are being severely hampered by the lack of prospective, randomized clinical trials confirming the clinical validity of these tests.

“I have heard the phrase that 'everything takes longer in the short run than expected, and in the long run, progress occurs more rapidly than would have been guessed.' That is true for the implementation of pharmacogenomics.”

The anticoagulant warfarin, with its very narrow therapeutic window and wide inter-individual variability, is one drug that, according to the US Food and Drug Administration, can benefit from pharmacogenomic-guided dosing. Although in August, the FDA requested pharmas update warfarin’s label to reflect the fact that people with variations in the CYP2C9 and VKORC1 genes may respond differently to the drug, the agency stopped short of including stronger language in the label that would require physicians to genetically test patients, noting the need for additional outcomes studies [see PGx Reporter 9-5-2007]. 
Certainly, the lack of randomized clinical studies confirming that CYP450 testing is helpful in dosing a class of antidepressants, called selective serotonin reuptake inhibitors, led the CDC's Evaluation of Genomic Applications in Practice and Prevention Working Group to discourage the use of such tests [see PGx Reporter 01-09-2008]. Roche, which markets the CYP450 test AmpliChip, has sponsored a study evaluating CYP2D6 testing in patients being treated for serious psychiatric disorders, such as schizophrenia or bipolar disorder in an in-patient setting.
According to Long, within the next decade, the public is more likely to see pharmacogenomics more readily applied to make choices between multiple drugs to treat a particular disease.
Although the RFI is an attempt to refine its research agenda, NIH is already focused on pharmacogenomics through its flagship program, the Pharmacogenetics Research Network and Knowledge Base, and through various PGx-related studies. The PGx Research Network is a trans-NIH-funded effort to advance pharmacogenomics in basic, clinical discovery and mechanistic studies. According to Long, the Pharmacogenetics Research Network has received approximately $30 million in annual funding in FY '08. 
NIH is coordinating its PGx research efforts with other US federal agencies, including the Agency for Healthcare Research and Quality, the Centers for Disease Control, FDA, as well as the HHS Secretary's Advisory Committee on Genetics, Health, and Society. Long also highlighted PharmGKB, an NIH-funded effort focused on developing international data-sharing consortia, notably the International Warfarin Pharmacogenetics Consortium and International Tamoxifen Pharmacogenetics Consortium.
Outside the US, the NIH Pharmacogenetics Research Network is developing alliances with scientists in the UK, Germany, Sweden, Canada, Japan, Taiwan, Korea, and Israel. This week, the NIH and the Center for Genomic Medicine in Japan announced plans to create a Global Alliance for Pharmacogenomics (see related story, in this issue).
NIH is also becoming increasingly focused on conducting and funding PGx studies.
In the October issue of the American Journal of Psychiatry, researchers from the National Institute of Mental Health published data showing a strong association between markers within the GRIK2 and GRIA3 genes and treatment-emergent suicidal ideation during therapy with citalopram, marketed as Celexa by Forest Laboratories. The genetic associations were made in a substudy of the four-year, 4,000-patient Sequenced Treatment Alternatives to Relieve Depression Study (STAR*D), sponsored by NIMH, the National Institute for Alcohol Abuse and Alcoholism, the National Human Genome Research Institute, the NIH, and the Swedish Research Council [see PGx Reporter 10-31-2007]. 
Also, in March, NIMH announced plans to grant around $2 million to seven investigators studying ways to apply pharmacogenomic strategies to the treatment of depression. Applications are due by June 20.
“There are other related initiatives that are ongoing at NIH ... including ancillary studies to ... develop statistical tools for genome-wide studies, best practices for electronic medical records and biobanks, and to standardize phenotype definitions,” Long said. These efforts “should [also] be recognized as valuable accomplishments that demonstrate concepts that can be applied to PGx.” 
Long noted that “PGx studies are funded through other mechanisms at NIH,” but did not offer an estimate for how much total funding the NIH has allocated specifically for clinical trials in this area.
The working group has not yet decided whether a report of the feedback from the RFI will be provided to the scientific community. “While that is possible ... the primary purpose was to inform NIH,” Long said.

“I have heard the phrase that 'everything takes longer in the short run than expected, and in the long run, progress occurs more rapidly than would have been guessed,'” she added. “That is true for the implementation of pharmacogenomics.”

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