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PMC Urges Stakeholders to Provide Feedback as PCORI Opens Comment Period for Methodology Report

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The Personalized Medicine Coalition is urging its members to comment on how a draft methodology report from the Patient-Centered Outcomes Research Institute can better address comparative-effectiveness research involving molecularly targeted personalized treatments.

Earlier this week, PCORI began accepting feedback on the draft report, which lays out strategies for improving study designs for comparing the impact of different medical interventions on health outcomes.

As PCORI has outlined its research priorities and its study methods, personalized medicine supporters have questioned the degree to which patient-centered outcomes research will involve comparisons of standard, one-size-fits-all treatments against molecularly targeted personalized interventions.

"Right now I am not convinced that the report adequately addresses personalized medicine as an important factor in improving health outcomes through patient-centered outcomes research methodology," Amy Miller, VP of public policy at the Personalized Medicine Coalition, told PGx Reporter this week.

The PMC is a non-profit organization that educates healthcare stakeholders about the regulatory and financial changes that will advance personalized medicine products and strategies. The coalition, which draws members from the drug and diagnostics industries, academia, and government, has strongly advocated conducting comparative effectiveness research that will help define the value of targeted treatments in molecularly defined subpopulations of patients compared to one-size-fits-all therapies.

"PMC will comment on the methodology report and we urge our member organizations to do the same," Miller said. "Active input from the community is required so that the research will live up to the high expectations that we have for it."

The first draft of the methodology report doesn't specifically address how comparative effectiveness research studies should be designed to address differential treatment responses in molecularly defined patient populations. However, PCORI does outline in the report standards for studying the heterogeneity of treatment effects in various patient subgroups and acknowledges that "subgroups" can be defined by a variety of patient characteristics, including genetic differences (PGx Reporter 6/20/2012).

Another aspect of the report that could be important for the personalized medicine community is PCORI's recommendations for conducting comparative-effectiveness research for diagnostics. According to PCORI, although clinical trials readily establish the accuracy of diagnostic tests, studies to capture whether testing improves patient outcomes are rarely conducted because such investigations are time consuming and require large patient cohorts. The report advises researchers to "adapt the principles of randomized trial design" to capture the impact of diagnostics on patient outcomes.

"Studies of clinical outcomes after diagnostic testing should use a prospective randomized study design when possible," PCORI states in the draft methodology report. "If a non-randomized design is proposed, the reason for using an observational study (or modeling and simulation) should be addressed and efforts to minimize confounding documented."

However, prospective randomized-controlled trials for diagnostics, particularly when being used to determine which patients should receive a molecularly targeted personalized treatment, aren't always possible or ethical once the impact of a molecular marker on drug response has been well established in the literature. Regulatory agencies have shown a willingness to accept data from retrospective studies instead. For example, the US Food and Drug Administration asked the sponsors of the colorectal cancer treatments Vectibix and Erbitux • Amgen and Bristol-Myers Squibb/Merck/Lilly, respectively • to submit data from retrospective analysis to establish whether patients with KRAS mutations lack response to the treatments.

Furthermore, Qiagen, the developer of the companion test that helps doctors discern which patients are likely to respond to Erbitux, recently received approval from the FDA for the diagnostic based on retrospective analysis of patients' tumor samples enrolled in the clinical trial to support Erbitux's initial approval in 2004 (PGx Reporter 7/11/2012).

Finally, although PCORI has stated that patient choice and input will be a big focus of the comparative effectiveness research that it will advance, the draft methodology report notes that additional research is required to figure out how patients will be involved in the decision-making process for which studies are funded. Although PCORI believes that peer review of research proposals is "indispensible" to the work of the institute, it expressed concerns in the draft report about whether involving "patients and their representatives" will introduce conflicts into its research and funding priorities.

"Including patients or their representatives in the peer review process will introduce new conflicts of interest due to potential links of these stakeholders to particular investigators, advocacy groups, and other patients with the condition," PCORI states in the draft report. "Methodological research is needed to understand the potential threats to independence that could arise from conflicts of interest when patients and related stakeholders are involved in the peer review process."

The 60 research standards currently included in the draft report were drafted by PCORI's 17-member methodology committee. Experts in the committee were appointed by the US Government Accountability Office. According to the group, the methodology report is a "critical step in guiding health care stakeholders towards the best and most appropriate methods for conducting" patient-centered outcomes research. "The committee will review the comments received and revise the draft so that it reflects the perspectives of the full health care community."

Stakeholders in the life sciences community have until Sept. 14 to comment on the draft report via an online survey. PCORI will analyze the comments and consider which feedback to incorporate into a revised version of the report at its board of governors meeting in November. The revised report will be submitted to PCORI's board of governors for approval.

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