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FDA Guidance Needed for PGx-Based Dosing Dxs Before Medical Community Adopts Them

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Without guidelines supporting the use of pharmacogenomics-based drugs in the clinic, FDA clearance of molecular diagnostics or updates to drug labels with genetic-testing information is not enough to ensure that such technology will be adopted by physicians, a draft HHS report found.
 
Despite clearing Roche’s AmpliChip and including genetic information in the label for Pfizer’s colorectal cancer drug Camptosar, the FDA hasn’t necessarily clarified how physicians should use the tests, the HHS Secretary’s Advisory Committee on Genetics, Health, and Society reported last week in the draft report.
 
“Aside from FDA’s role as market gatekeeper for PGx products, the agency requirements and actions – or the lack thereof – influence the ways in which marketed PGx technologies are used in clinical practice,” according to the draft report, entitled Realizing the Promise of Pharmacogenomics: Opportunities and Challenges. “For example, FDA approval of a PGx test does not necessarily result in dosing guidelines for accompanying therapy.”
 
Pharmacogenomic-based testing can identify patients who are likely to respond differently to particular drugs and indicate the need for customized dosing, “but that testing does not necessarily translate into dosing instructions,” the report added. “As such, patients will have to be monitored and have their dosing adjusted empirically.”
 
Convened five years ago to advise the HHS Secretary regarding policy issues surrounding genetic technologies, the SACGHS ranked PGx “a high-priority issue warranting in-depth deliberation and analysis.”
 
The group began studying the issue in 2005. Before releasing its report, the committee gathered data on issues surrounding the emerging discipline by speaking with industry representatives, health care providers, and government agencies involved in PGx on a policy level.
 
The draft report, developed by SACGHS, its PGx Task Force, and the Lewin Group, is available for public comment until June 1. After considering the public’s input, SACGHS will issue a final version in 2008.
 
Due to industry’s growing interest in exploring PGx tools, the FDA has begun taking a more active role in the discipline by promulgating guidelines for PGx data submissions. The agency is also slated to release a draft guidance from an earlier concept paper on drug-diagnostic co-development.
 
Although a companion diagnostic does not need to be cleared by the FDA to be included in a drug’s label, conventional wisdom has held that FDA clearance raises the status of a test in the eyes of customers. However, SACGHS found that a nod from FDA alone is not enough to fuel adoption of PGx tools.
 
The question of whether gene-based diagnostics cleared by the FDA will influence how the medical community uses them recently came up after the agency cleared Agendia’s MammaPrint breast cancer recurrence test. The test became the first FDA-approved in vitro diagnostic multivariate index assay [see PGx Reporter 02-14-07].
 
While Agendia felt that the agency’s approval would fuel adoption of its product, rival Genomic Health noted that FDA approval of its Oncotype DX test, which is also indicated to predict breast cancer recurrence, will not necessarily translate into greater market adoption [see PGx Reporter 02-07-07].
 
Since PGx is still an emerging field, there is not enough data regarding how PGx tools can inform clinical decisions such as dose adjustments. According to the report, the FDA needs help defining these gaps in knowledge.
 
Ultimately, the report recommends the FDA work with professional medical organizations to develop dosing guidelines, encourage clinical trials exploring the relationships between diagnostics and drug response, and seek input from stakeholders in industry and academia to translate the findings from prospective studies into treatment guidelines.
 
Although Laboratory Corporation of America markets a homebrew UGT1A1 test, the company isn’t in the business of defining dosing guidelines, a spokesperson told Pharmacogenomics Reporter this week. However, LabCorp recently held an information-sharing meeting with stakeholders, including PGx experts, patients, physicians, and industry representatives, to discuss the issues surrounding the adoption of PGx tools. The company rep added that among the things discussed at the meeting was the need for dosing guidelines for PGx drugs.
 
Do Labeling Updates Matter?
 
The FDA changed Camptosar’s label in June 2005 recommending a lower starting dose in patients homozygous for the UGT1A1*28 allele.
 
While the revised label describes the relationship between adverse reactions and genetic testing, it stops short of outright recommending a genetic test. The label “does not include a requirement or recommendation for UGT1A1 testing due to an insufficiency of data to support a recommendation on dose schedules by genotype,” the report states. 
 
Camptosar’s label only notes that “a reduction in the starting dose by at least one level of Camptosar should be considered for patients known to be homozygous for the UGT1A1*28 allele. … However, the precise dose reduction in this population is not known, and subsequent dose modifications should be considered based on individual patient tolerance to treatment.”
 
Felix Frueh, head of the FDA’s Interdisciplinary Pharmacogenomics Research Group, has previously maintained that there is “a very subtle difference” between actually recommending a companion diagnostic in labeling versus just discussing the availability of a genetic test for a drug [see PGx Reporter 11-15-06].
 
“We have labels … that do not ‘recommend’ a test, yet put the reason for testing in fairly plain language,” Frueh at the time said.
 
One such example is the label for Lilly’s attention-deficit/hyperactivity disorder drug Strattera, whose label states:
 
“Routine laboratory tests are not required. CYP2D6 metabolism — Poor metabolizers (PMs) of CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration to a given dose of Strattera compared with extensive metabolizers. Approximately 7% of the Caucasian population are PMs. Laboratory tests are available to identify CYP2D6 PMs. The blood levels in PMs are similar to those attained by taking strong inhibitors of CYP2D6. The higher blood levels in PMs lead to a higher rate of some adverse effects of Strattera.”
 
Need for Studies
 
Despite the FDA’s clearance of Roche’s AmpliChip, there are still unanswered questions regarding the technology’s ability to guide dosing decisions, the report noted.
 
AmpliChip tests for CYP2D6 and CYP2C19 genetic variants, which affect how certain antidepressants, antipsychotics, immunosuppressives, and anticancer drugs are metabolized. However, “as neither Roche nor FDA has provided recommendations for appropriate drug dosing, the clinical utility of the chip is not well defined,” the report said.
 

“In the absence of relevant clinical data, it is not apparent that FDA has the ability or responsibility to insert recommendations concerning PGx test results and drug dosing into product labels.”

“Clinical trials of PGx diagnostics and drug responses across patient subgroups could provide the basis for such recommendations, yet few such trials are underway,” according to the report.

 
“In the absence of relevant clinical data, it is not apparent that FDA has the ability or responsibility to insert recommendations concerning PGx test results and drug dosing into product labels.”
 
Ultimately, the HHS report concludes that dosing recommendations “may need to come from medical professional organizations in the form of practice guidelines, although they too would seek adequate evidence” on which to base their guidelines.
 
“Some have suggested that FDA seek more input from academic experts, practicing physicians, and pharmaceutical companies to translate findings from large prospective studies into dosing guidelines for use in clinical practice,” the report states. 
 
Hoping to fill the gaps in knowledge that appear to be hindering the adoption of PGx technologies, various stakeholders in industry and academia have recently launched high-profile studies for widely used drugs that may pose a high risk for adverse reactions.
 
For instance, the Harvard-Partners Center for Genetics and Genomics is studying the value of PGx-based dosing for the anticoagulant warfarin [see PGx Reporter 11-15-06].
 
Additionally, two pharmacy benefit managers have started exploring whether PGx technologies may ease payor anxiety regarding reimbursement decisions for companion diagnostics [see PGx Reporter 12-06-06 and 09-20-06].
 
Although the FDA has said it is close to updating the drug labeling for warfarin, it is unknown if the agency will outright recommend a genetic test for warfarin or simply describe the relationship of testing to adverse reactions in labeling. The specific language may be influenced by the data available to the agency from PGx dosing studies, like those described above.

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