Working Group Meeting April 30 – May 1, 2007

Hilton Garden Inn Atlanta Airport / Millenium Center – Atlanta, GA

MEETING SUMMARY

View Meeting Agenda

Sub-Committee Meetings

The Topics, Methods and Products Subcommittees (SC) met from 8:30 – 9:30 AM to finalize deliberations and presentations for the full Working Group (WG).

Conflicts of Interest

Dr. Berg and Dr. Bradley reviewed the Conflict of Interest (COI) forms submitted by all the WG members in April 2006.  No conflicts of interest were identified for this meeting.

Welcome and Opening Remarks

The EGAPP WG meeting was convened by Dr. Al Berg, Chair.  Dr. Berg welcomed the EGAPP WG and provided a brief review of the overall status of EGAPP project.

Dr. Khoury, Director of the Office of Public Health Genomics, thanked the EGAPP WG for their work and introduced Dr. Kathleen Toomey, the new director of the CDC’s Coordinating Center for Health Promotion (CoCHP).  Dr. Toomey praised the dedication of the EGAPP WG and emphasized the importance of the project to OPHG and CDC.  Dr. Khoury highlighted the increasing interest in genetic testing for common complex disorders, the Personalized Health Care Initiative of the Secretary of Health and Human Services, and the recent passage of the Genetic Information Nondiscrimination Act (GINA) by the US Senate.  He also mentioned a recent editorial in the British Medical Journal written in response to the EGAPP sponsored evidence report on CYP450 testing in individuals with depression treated with a class of antidepressants (selective serotonin uptake inhibitors) that was recently released by the Agency for Healthcare Research and Quality (AHRQ).

It was noted that additional discussion is needed to put EGAPP’s work into context with other processes, such as the American Health Information Community (an advisory body to the Secretary of Health and Human Services on accelerating the development and adoption of health information technology) and the Personalized Medicine Coalition (PMC).

In response to questions about funding, Dr. Khoury reiterated the importance this initiative, the intent of OPHG to support the extended EGAPP pilot study, and the need to consider CDC’s potential future role and other innovative ways to maintain an EGAPP-like program (e.g., collaborations, public-private partnerships).

Review Planning: Cardiogenomic Profiling

Glenn Palomaki gave a description of the ”virtual evidence center” approach proposed for this review.  Briefly, a small group of consulting scientists from different centers will collaborate on planning the review, defining the disorders of interest, the specific variants to be tested, the clinical scenarios for testing; planning, and developing an analytic framework and key questions.  One center will conduct the review, with guidance from a Technical Expert Panel that includes the consulting scientists and Working Group members.  Since the approach for conducting this review will be different from that of the Agency for Healthcare Research and Quality Evidence-based Practice Centers, the methods and process will need to be well-documented and subject to careful peer review.  There was discussion on a proposed timeline; however this evidence review may be deferred to allow prior finalization of other topics.

Options and plans: Hereditary Nonpolyposis Colon Cancer (HNPCC)

Glenn Palomaki presented recent findings on HNPCC testing strategies that were provided by investigators for the WG to review.   Dr. Bradley proposed options for the supplementary review requested by the WG; this review will be completed on a short timeline to inform the development of the Recommendation Statement.  The WG discussed and finalized plans for the supplementary review, and agreed that the status of the WG review should be posted on the egappreviews.org web site.

AHRQ EPC Topic Selection

Dr. Kolor presented a brief history of the past topic selection that occurred at the January 2007 meeting.  Concerns surrounding the scope of the ethical, legal and social implications (ELSI) topic and other potential options for the next AHRQ review were discussed.

Update: FDA Review of Genetic Tests

Dr. Becker presented some history and current status of the FDA regulation of genetic tests. There is a small but growing list of genetic/genomic tests that have been brought to FDA for review. Tests concerned with heritable markers have centered on thrombophilia, drug metabolism, and cystic fibrosis. Tests for a variety of somatic and cancer-related markers have been submitted over the years, especially for ploidy/aneusomy markers, FISH for gene amplification, and immunohistochemistry for protein expression. Growing interest focuses on tests associated with cancer prognosis and on characterizing patients in the context of some chemotherapeutic agents (i.e. as a predictor of adverse events or beneficial effect).

The regulatory route to market for any new in vitro diagnostic test is determined largely by the risk associated with use of the device and by precedent (if any) from review of similar devices. In the cancer arena, in many cases, a prognostic test will be a Class II (moderate risk) device, suitable for pre-market clearance via 510(k) provisions in which the sponsor demonstrates substantial equivalence (i.e., for intended use and performance) between the new device and a previously cleared device. If there is no previously cleared device for comparison, and if risk for use of the new device is sufficiently low, Class II clearance might be achieved through de novo classification. Otherwise, the new device will be Class III and subject to pre-market approval (PMA) as safe and effective. The latter circumstance can be expected often when the device is intended to drive patient management (e.g., as with a predictive test) with more significant upside and downside impact.

In pre-market review of any device, FDA determines whether there is a reasonable assurance of safety and effectiveness for the device under its conditions of use (see 21CFR860.7(c)(2)). Considerations of safety and effectiveness are informed by reviewing the analytical validity, clinical validity, and clinical utility of the test. Benefits of FDA oversight, with cleared or approved devices, include clear definition of claims for the device (as stated in labeling), requirement for manufacturer’s adherence to a Quality System for the device, and reporting of problems with the device for appropriate action.

Recommendation Statement – CYP450 and Depression

The Recommendation Statement has gone out for initial peer-review and most comments have been received; the comments, without attribution to the reviewers, were provided to the WG in a spreadsheet.  After revision, the draft Recommendation Statement will be distributed for review by additional stakeholder groups.

Recommendation Statement – Genetic Testing for Ovarian Cancer

Drs. Dolan and Armstrong presented two format options for the current draft Recommendation Statement on proteomic testing.  The WG agreed on the need for consistency in format for all Recommendation Statements.  Suggested changes in format and content will be integrated and the Recommendation Statement will be redistributed for WG comment.

Evidence Report/Recommendation Statement – UGT1A1 Testing for Treatment of Colorectal Cancer with Irinotecan

Dr. Bradley presented the status of the Evidence Report, which is currently undergoing external review; most reviewers have responded and the comments, without attribution to the reviewers, were provided to the WG in a spreadsheet.  The Evidence Report will be revised and provided to the WG with responses to all comments and a summary of substantive changes made. The writing team has been selected and a draft Recommendation Statement is in development.

Report on Changes for the Stakeholders Advisory Group

Dr. Toby Citrin reviewed the development and history of the informal Stakeholders Advisory Group on EGAPP (SAGE) that was organized by the University of Michigan Center for Genomics and Community Health.  As recommended by the EGAPP Steering Committee, the newly named EGAPP Stakeholders Group (ESG) will become a formal component of the  EGAPP project, with support from CDC.  At a planning meeting held on April 23, 2007 in Washington, DC, the mission of ESG was proposed to be facilitating the incorporation of EGAPP recommendations into practice.  It was proposed that the composition of the ESG would eventually be 25-45 members representing identified categories of stakeholders (e.g., healthcare providers and payers, policy makers, consumer groups).  The ESG planners also proposed including categories that were not originally designated as key EGAPP stakeholders to be included in evaluation activities (e.g., educators, industry, media and science writers, information technology vendors).

Types of membership on the ESG would probably be core representatives and ad hoc representatives (groups likely to be impacted by a particular review).  The objectives of the ESG were proposed to include:

• Identifying specific stakeholders for each review
• Engaging stakeholders in the EGAPP process
• Assisting in identifying and framing messages
• Assisting in identifying and facilitating dissemination strategies
• Assisting in EGAPP stakeholder evaluation activities

Dr. Citrin presented for discussion possible ways that the ESG might interact with the WG.  The planning group will continue working on the development of the ESG and report to the WG at the next meeting.

Key discussion points:

• Clarification that individuals would be representing their category of stakeholder and/or the organization they belong to, but not their own opinions.
• The Products SC offered to be the first to explore collaborative work with the ESG.

EGAPP Staff Updates

Dr. Bradley presented objectives for the meeting:

• Select a topic for the pending AHRQ Request for Task Order (RFTO)
• Develop a plan and timeline for moving forward with the Cardiogenomic Profiling review
• Consider options and develop a plan and timeline for the HNPCC report and recommendation
• Deliberate on the Depression/CYP450/SSRI Recommendation Statement, consider peer review comments, plan the second round of peer review, and agree on a timeline for finalization
• Deliberate on the proteomics recommendation statement from the Ovarian Cancer review and develop a plan and timeline for finalization and peer review
• Consider expert reviewer comments on the CRC/UGT1A1 report and manuscript and develop a plan and timeline for finalization of this report
• Discuss the plan for 2007 reviews
• Consider revisiting the voting process on recommendations
• Receive reports from subcommittees and consider documents proposed for vote

Dr. Bradley also updated the WG on the breast cancer expression profiling review and the Office of Management and Budget (OMB) review of the proposal for stakeholder surveys.

New CDC staff and EGAPP project staff and consultants were introduced and the expected roles of each were outlined.

Dr. Bradley informed the WG that, per the budgetary discussions,, additional funds will not be put into the AHRQ Interagency Agreement this year, so there is one EPC review in progress and one to follow this year.  However, consultants were added and more hours budgeted for existing consultants in some cases.  The budget for experts for general consultation, technical expert panels (TEPs), and reviews has been increased, and there is funding for writing team working meetings.

Web site Preview

Mr. Douglas gave an overview of the www.EGAPPreviews web site that was recently made available online.  The WG was asked for feedback on the next items for the web site.  The CDC staff plan to post the Topics Narrative, Topics List and Topics Summaries following approval from the WG and CDC clearance.  Additional items of interest include:  a topics solicitation page, a description of EGAPP methods; a preface to go along with the recommendations; a description and list of objectives for the Stakeholders group; a description of the project evaluation; and links to other sites.

UGT1A1 Recommendation

Dr. Botkin presented a draft Recommendation Statement to the WG for consideration.

The Next Topic for an AHRQ EPC Review

The WG decided the ELSI topic is probably not a good candidate for an EPC review.  This could be done internally and/or with other academic centers.  Other options for the review were discussed, and the WG elected to investigate Factor V Leiden/Factor II as a first choice topic.

Products SC Report

Dr. Kaye presented the report of the Products SC breakout session.  The presentation included the current process and a request for approval on the peer review processes for non-EPC reports and summary articles, Recommendation Statements, and web approval.

The written protocol for the peer review process for non-EPC reports and summary manuscripts was reviewed.  The WG decided that sequential internal and external review was preferable, and that expertise in modeling and biostatistics should also be included among reviewers.  The WG discussed and elected to, in future, attribute comments to reviewers of non-EPC reports (those in progress will remain unattributed).  The WG and staff will recognize peer reviewers by sending a general thank you statement that acknowledges receipt and explains that comments may or may not be incorporated.  Responses to all comments and a summary and rationale for all substantive changes will be provided to the WG by the report writers.

The written protocol for the peer review process for Recommendation Statements was reviewed.  The WG discussed and elected not to attribute comments directly to reviewers for the writing teams.  NOTE: Subsequent discussions resulted in the decision to attribute comments directly to reviewers in the future.  The WG and staff will recognize the peer reviewers by sending a general thank you statement that acknowledges receipt and explains that comments may or may not be incorporated.  Responses to all comments and a summary and rationale for all substantive changes will be provided to the WG by the Recommendation writing team and the staff.

The written protocol for the EGAPP web approval process and the CDC web clearance process was reviewed.  Topics summaries to be posted on the web site would go through the Topics SC review and then the full WG is given one week to comment.  Links to other web sites must be cleared, including links to Evidence Reports and informational web sites.

Topics SC Report

Ms. Scott presented the report of the Topics SC breakout session.  The presentation included a request for approval on the web site materials, including the topics narrative (a brief description of the topic selection process), the current list of topics under review and topics under consideration, and the brief summary paragraphs describing the topics under review and consideration.  The SC also presented a high priority plan for further development of a topics horizon scanning process.  CDC staff will develop and test methods and search criteria, evaluate each for staff time and yield, and report to the Topics SC.  The Topics SC felt most topic suggestions would come through the clinical community, but the stakeholder group could also be helpful.

Action Items:

• Investigate options for a web-based solicitation form for topic suggestions.
• Staff will develop short summaries on cardiovascular disease and bucindolol use, TCF7L2 for Type 2 diabetes risk, and the use of CGH arrays to test for developmental disabilities.

Methods SC Report

Dr. Teutsch presented the report of the Methods SC breakout session.  The presentation included the updated draft of the methods document and a future work plan.

New sections to be developed for the methods document include development of analytic frameworks and key questions, determination of inclusion and exclusion criteria, and review and approval of key questions prior to beginning a review.  The WG would like to publish the document, possibly as a companion piece to a report or recommendation.

Closing Remarks

Dr. Berg thanked everyone for their participation and the meeting was adjourned.