November 1, 2007 (Vol. 27, No. 19)

Translating Validated Information into Evidence-based Outcome Data is Crucial

The Genetic Alliance hosted a meeting in September entitled “Eyes on the Prize: Truth-Telling about Genetic Testing.” The prize in question is better health for everyone through genetic tests. A group of roughly 200 stakeholders in the rapidly advancing field of genetic research and testing weighed in on various aspects of the field.

Sharon F. Terry, president and CEO of the Genetic Alliance, set the tone by emphasizing a small-workshop ethos of collaboration and communication and calling for a removal of barriers to information sharing. She estimated that realization of the final goal will require moving from the “siloed” approach of advocating for single diseases to the definition of a broader paradigm that goes beyond return-on-investment strategies.

Genetic Alliance’s symposium kicked off with a discussion on how the advent of DNA technology has resulted in the construction of large databases. The bottom line is that there needs to be an emphasis on translation of standardized, well-validated genetic information into clinically meaningful outcome data. This in turn will have to go through a well-defined regulatory process that will allow it to enter the market safely.

The consensus seemed to be that a centralized genetic test database should be created. There also appeared to be general support for an as yet undefined integrated regulatory body that included a peer review process coupled with standard proficiency examination of individual laboratories and test offerings.

Validating Genomic Data

At the heart of the genomics revolution is the possibility of this research translating into molecular diagnostics. Howard McLeod, Pharm.D., of the University of North Carolina, identified the problem to this transition as not access but judicious application of data and knowledge. Both clinicians and consumers have access to a bewildering array of genetic information that must be presented in a clear and useful format. Dr. McLeod recommended a flexible approach to dealing with new information, cautioning that “one size does not fit all” when it comes to health policy.

As an example, Deborah Driscoll, M.D., University of Pennsylvania, as well as Kathy Hudson, Ph.D., of John Hopkins, and Jeffrey Kant, M.D., Ph.D., of the University of Pittsburgh, presented a history of arguably the most mature and varied genetic test, screening for cystic fibrosis (CF). They demonstrated how counseling and patient education has changed along with the test panel for CF, as more mutations have been discovered over a number of years.

The CF model has increased in complexity over time and demanded a sophisticated effort in translation of complex concepts as well as bedside-manner sensitivity in communicating the implications of diagnosis. In addition, no fewer than 10 methods are being used to identify CF mutations, a situation that may reflect the current status of gene testing, per se. Despite professional society guidelines, there is a wide variety in application and lag in understanding which test to use amongst labs and providers.

The main issue is coming to agreement on standards for testing across platforms to create valid and useful outcomes for the physician and patient. Linda Bradley, Ph.D., a CDC geneticist, pointed to the center’s initiative to establish a systematic, evidence-based process for assessing genetic tests.

Called Evaluations in Genomic Applications Practice and Prevention (EGAPP), this project is one example of an integrated approach to validation. EGAPP is an independent, non-Federal working group, possessing no regulatory authority. It is assessing a more broad-based view of validation in an effort to shorten review time frames and to maintain the quality and reliability of data.

Ensuring Laboratory Quality

Another aspect of seamlessly translating genomic research into genetic testing is to ensure laboratory quality. Judy Yost, director, Centers for Medicare & Medicaid Services’ (CMS) division of laboratory services, described a plan to educate labs on the importance of both technical quality and the laboratory’s role in educating the public. Gail Vance, M.D., of the College of American Pathologists delineated its already rigorous laboratory accreditation plan, which is integrated with a CLIA checklist.

While Joseph Boone of the CDC concurred with the importance of proficiency testing, he called for more regulatory and perhaps legislative action to make the necessary changes for strengthening laboratory practices.


Even once the wrinkles in validation standards and quality are ironed out, there still remains a natural tension between basic research and marketplace realities. There was a general recognition that IP and licensing practices must be dealt with in a creative manner but no clear answer as to how this may be done. The necessary leap from testing availability to physician adoption must be addressed, perhaps in a variety of ways.

Stephen Ferguson of the NIH encouraged public/private partnerships and nontraditional relationships such as licensing ideas from nongovernmental organizations.

Raju Kucherlapati, Ph.D., of Harvard University outlined the Harvard-Partners Center for Genetics and Genomics effort to identify genes important for clinical care through a prospective clinical trial based on EGFR genetics and subsequently devising clinical decision-making tools for physicians. Their results are expected to reach 500,000 physicians once it is launched this fall as a Continuing Medical Education module.

Timothy Stenzel, M.D., Ph.D., of Abbott Molecular (, detailed the intricacies of the regulatory process and cautioned that the FDA has many reasons to say no, as the agency is under-resourced for legal management of novel nucleic acid tests.

With more complicated testing paradigms on the way, another concern is who will pay for them. A double standard seems to apply to genetics testing and drug testing at the economic level. While genetic testing is held to the same rigor as pharmaceutical trials, they are reimbursed at a significantly lower rate.

Regulatory Oversight

To address current shortcomings of regulatory control, participants debated the question of what needs oversight and who should have this responsibility. There was much agreement on what should be regulated but a fair amount of discord on who.

For direct-to-consumer (DTC) products, David Mongillo, vp of policy for the American Clinical Laboratory Association, advocated stringent administration in this growing sector that occasionally embraces the frivolous. CMS, the Federal Trade Commission, and Congress, through the passage of the Genetics Information Nondiscrimination Act (GINA), were deemed sufficient in this regard.

For the remaining testing modalities, Mongillo asserted that regulation is already robust and that CLIA had the ability to function as an effective oversight body. Janet Woodcock, M.D., CMO at the FDA, maintained that the agency has made appropriate regulatory forays in this area. She added, though, that risks are rising especially related to consumers and to emerging fields like pharmacogenomics.

The primary question is the FDA’s authority in regulating genetic testing. The legal representatives generally viewed FDA as having true legal authority over manufacturer-produced testing kits and analytes but not laboratory-developed tests. Responses varied widely from a legal point of view, but there was general agreement that areas in which the FDA and CLIA overlap must be closely examined to avoid further confusion.

In addition, the panelists agreed that changes should come through a formal Notice and Rule-Making process to allow public input and participation on what should then be a predictable regulatory pathway for all test development.

Dr. Woodcock asserted the FDA’s authority in this area and described the agency’s policy of enforcement discretion as a means of dealing with the current testing situation. Future directions depend on outcomes and continuous improvements in testing, which is the reason FDA issues guidance, especially in controversial areas. Because formal outcome assessment is extremely expensive, Dr. Woodcock echoed earlier suggestions to consider alternative ways to measure results.

Closing the perceived disconnect between regulatory bodies and federal agencies will be a significant challenge. Other obstacles for policy makers are numerous: balancing appropriate oversight to not impede innovation, resolving the division between private and public R&D, funding for validation and outcome studies, and integrating the genomics paradigm into health care economics.

Changing Face of Medicine

Genetic testing is bound to change the way medicine is practiced. The Genetic Alliance meeting also touched upon the impact of genetic testing on clinical practice as well as health care initiatives and policies.

Andy Faucett explained how NIH’s Collaboration Education Test Translation (CETT) recognized that many new genetic tests for rare conditions lack both clinical validity and utility. CETT’s purpose is to build collaborations with researchers, laboratories, and advocacy organizations to obtain the necessary data in order to ensure proper application of these tools in the clinical setting.

W. Gregory Feero, M.D., Ph.D., of the NIH encouraged wide latitude for decision making and choosing the right instrument that will demonstrate how clinicians gauge the clinical impact of genetic testing. Margaret Gulley, M.D., of the University of North Carolina, recommended taking advantage of current CLIA regulations, which require the presence of a medical director in every laboratory.

Another program discussed was the HHS’ Personal Health Care initiative, which is designed to bring tailored medical care to individuals based on their genomic makeup. Gregory Downing, Ph.D., speaking for HHS Secretary Michael Leavitt, delineated the many challenges of a national, integrated plan.

Some of the issues included disseminating genetic knowledge into clinical practice, identifying the value of personalized health care, managing the overflow of clinical data and information deficits, aligning medical product review with quality of care, motivating prevention, and identifying barriers to the practice of healthy behaviors.

The Road Ahead

Strong leadership and clear guidance are critical to moving forward in genomic testing, with its myriad of implications for both personal health and public health policy.

Overall, there was agreement that regulation is indeed necessary, with overwhelming support for strictly vetting DTC products. For medical genetic testing, the consensus was that the existing regulatory toolkit is adequate, but better enforcement is needed. Risk-based regulation, focusing resources on priority areas that need the greatest attention, and the flexibility to deal with different tests and delivery models may help expedite the path to the clinic.

The concept of a centralized test registry governed by clear, evidence-based standards with open access was roundly accepted. There were calls for the NIH to put more strings on funding and to find the resources to increase genetics expertise at the FDA.

Reimbursement codes and updating antiquated categories and processes was also a clear need. All participants recognized the importance of strong, evidence-based outcomes both for quality of patient testing and acceptance at the physician and payer level. Immediate passage of GINA was also a point of consensus.

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