…promote high standards and consistency in the provision of direct-to-consumer genetic tests among commercial providers at an international level in order to protect the interests of people seeking genetic tests and their families.

The Principles, which are ambitious in scope and detailed in their recommendations, represent an important next step in the ongoing debate over the appropriate level of oversight for the emerging DTC genetic testing industry.

Published in draft form, the Principles provide ample room for analysis, and companies and consumers are invited to provide responses and comments until December 6th, 2009.

In this post we take a close look at the draft Principles and summarize the core values and goals that appear to underlie these recommendations.

Part I: The Big Picture

The desire to bring higher standards and greater consistency to the genetic testing industry is far from new. In the United States, the Secretary’s Advisory Committee on Genetics, Health, and Society (SACGHS) published a comprehensive report on genetic testing (pdf), including recommendations for oversight, in 2008. A consortium of DTC companies organized by the Personalized Medicine Coalition continues its work on a long-awaited set of voluntary industry guidelines (pdf). Policy and professional groups such as Genetic Alliance and the American College of Clinical Pharmacology have also sought greater oversight of DTC genetic testing. In the United Kingdom, the Human Genetics Commission’s recommendations come in the wake of, among other guidance, the report on genomic medicine issued in July by the House of Lords which recommended that DTC genetic tests be reclassified as “medium risk” – a classification that would subject the tests to pre-market review before use by consumers.

In the Commission’s recommendations, the recurring theme is a concern for the well-being of the individual consumer:

Genetic tests have the ability to give rise to a broad spectrum of responses . . . When a genetic test is provided outside a framework of healthcare, special attention must be given as to how that individual may respond to the results . . . and the subsequent impact the test results may have on that individual and their family. With this in mind, these Principles have been developed with the best interests of consumers at the forefront.

This is a familiar theme, and the Principles reflect a tension that has already received considerable attention: on the one hand we have concern about the potential harms that can arise from DTC genetic testing in certain circumstances, particularly where information may be inaccurate or may be presented without necessary counseling or other professional services; on the other hand is the reality that DTC genetic testing companies are frequently not intending to provide, nor capable of providing, a clinical service.

The Principles do not address traditional forms of clinical genetic testing. They are, however, intended to cover:

…all aspects of direct-to-consumer genetic testing services, including the marketing and advertising of tests, the collection, analysis and storage of biological samples, the interpretation of results and the provision of results to the consumer.

Significantly, the Principles apply to all DTC genetic tests, except for those specifically excluded. (Exemptions are provided for genetic tests mediated by medical professionals, forensic or court-order testing and testing for “purely medical research…where the results are not disclosed to the consumer,” an exemption which, incidentally, would not cover several emerging genomics research projects including the Personal Genome Project and the Coriell Personalized Medicine Collaborative, both of which return research results to their participants.)

The decision to lump all DTC genetic testing into a single category for purposes of the Principles, including tests with attenuated clinical value (for example, ancestry testing), demonstrates the Commission’s apparent suspicion and discomfort with the entire DTC industry and produces a set of broad-spectrum rather than narrowly-tailored recommendations.

Part II: The Substantive Provisions

Although the Principles themselves will have no legal force, even once finalized, the Commission hopes that they will guide self regulation by commercial testing services and action by “regulatory bodies and/or national jurisdictions [that] should have defined measures in place.”

Definitions. The Principles define “genetic test” to mean “a test to detect the presence or absence of, or a change in, a particular gene or chromosome or a gene product or other specific metabolite that is primarily indicative of a specific genetic change.” Eleven categories of genetic tests are defined, of which three are considered a “genetic test in the context of inherited or heritable disorders” which “may have important implications for the health of the person concerned or members of their family, or have important implications concerning reproductive choices.”

The Principles contain additional definitions for “condition,” “trait,” “test provider,” and “genetics health professional,” the last being a “health professional who has undergone appropriate training in the interpretation of genetic information and has achieved the required competencies.” Not specified is whether a general practitioner would qualify as a “genetics health professional” or whether additional training or certification related to genetic testing would be required.

Information Supplied by DTC Genetic Service Providers. The Principles would impose upon DTC genetic service providers the obligation to educate consumers about genetic testing and the implications of test results so that consumers can make informed decisions. To a large degree the Principles simply articulate customary rules of fair advertising and disclosure that could apply to a variety of consumer services. For example, the test providers should provide information that is specific, easy to understand and does not overstate the utility of a test.

The desire to provide consumers with “easily understood, accurate, appropriate and adequate information” prior to testing is entirely appropriate. It is also hugely ambitious. Respected commentators have noted, generally, the need to “revolutionize our communication of science to non-scientists” in order to improve understanding. Specific Commission recommendations, such as the requirement that providers supply “information about the presentation of results . . . such as relative and absolute risk assessments so that an individual can understand test results” run into identified gaps in scientific understanding and education at the individual level, such as the well-documented difficulty in communicating statistical concepts such as relative risk.

The requirement in Section 10.6 that providers “have in place a process to evaluate how well consumers are able to understand the background information and test results they have received” appears to ask nothing less of these companies than to serve as educators (and educational reformers) in additional to their role as genetic testing providers.

And, in many cases, the very education and analysis that the Commission demands is of exactly the type that requires the participation of medical professionals to develop. Other potentially problematic informational requirements set forth in the Principles include the following:

• A genetic test in the context of inherited or heritable disorders “should only be provided to consumers with individualized pre- and post-test counseling.”
• A provider that intends to recommend a therapeutic product “should also provide information about other lifestyle choices and behavioral modifications that are known to have a preventative or therapeutic value in relation to the trait linked to the genetic markers tested.”
• “Where appropriate, the test provider should inform consumers about . . . actions that may help the consumer to take informed decisions about their health or welfare in light of the test results . . .”

As discussed further below, these proposals suggest that DTC testing services should possess a significant amount of personal information about their customers (quite possibly more than the average customer would want to disclose to a service provider, although information that would be routinely disclosed to a medical professional) and contemplate participation by DTC testing services in the personal and medical decision-making of individuals.

These and the many other informational and educational requirements set forth in the Principles would appear to require DTC genetic service providers to assume many of the responsibilities traditionally carried out by medical professionals and educators. Furthermore, attempts to impose such requirements on DTC providers would almost certainly hinder ongoing volunatry and regulatory attempts to demarcate clinical and non-clinical services.

Informed Consent. The Principles stress that DTC service providers should enable consumers to provide an informed consent that is truly informed. In most respects, the consent recommendations, when combined with the disclosure requirements described above, outline a desirable industry standard. The Principles require that test providers obtain and retain written confirmation of consent, that a separate consent be obtained before biological samples are used for any secondary purposes (such as research), and that consent be obtained before a third person is given access to biological samples or personal or genetic data.

In other respects, however, the informed consent requirements contemplate a significant intrusion by the test provider into the personal lives of consumers. For instance:

• “The test provider should give consideration . . . to the personal and familial circumstances of the consumer.”
• The test provider must “consider the impact of the test results for the consumer” and in doing so should take into account “the potential of the test to have a significant impact on personal relationships and the stability of families.”
• Genetic testing of persons incapable of consent should only “be carried out if testing is in his or her best interest,” which appears to require the test provider to involve itself in, and possibly to second-guess, the decisions of legal guardians.
• With the exception of paternity tests, “genetic tests in respect of children [not having legal capacity to consent] should normally be deferred until the attainment of such capacity unless other factors indicate that testing during childhood is clinically indicated,” a requirement which appears to intrude into the domains of both parents and physicians and runs counter to the policy of 23andMe, one of the leading DTC service providers.

The need for truly informed consent is as important in the DTC context as it is in the clinic or in a genomics research study. However, given the considerable debate that continues to swirl around issues such as pediatric consent and genomic data privacy, the Principles should do more to encourage DTC service providers to develop appropriate informed consent protocols in cooperation with consumers, clinicians, researchers and other relevant stakeholders.

Blurring the Clinical/Non-Clinical Divide. The Principles are suffused with worry that consumers will use DTC genetic testing as a substitute for professional medical advice. This is a concern commonly voiced by critics of the DTC industry. Unfortunately, compliance with the Principles would increase that very risk, because their likely result, if implemented, would be to further blur the line between DTC and clinical testing and services.

Examples of Principles that demonstrate this blurring include the following:

• Genetic tests “in the context of inherited or heritable disorders . . . should only be provided to consumers with individualized pre- and post-testing counseling.”
• “The test provider should provide information about . . . the decisions that a consumer may face after taking the test . . . and identify prospectively any likely further investigations that a consumer or member of their family may wish to pursue after receiving the test results.”
• If the test provider intends to use the test result to promote a therapeutic product, the test provider “should also provide information about other lifestyle choices and behavioural modifications that are known to have a preventative or therapeutic value in relation to the trait linked to the genetic markers tested.”
• “If a test provider intends to use the results of genetic test to make a recommendation to a consumer to alter the dosage of a medicine or to recommend alternative medicines, the test provider should make available information about the link between the genetic test result and the metabolism of the indicated medicines.”
• “Where appropriate, the test provider should inform consumers about recommendations or known actions that may help the consumer to take informed decisions about their health or welfare in light of the test results.”
• “Interpretation of genetic test results should be carried out under the responsibility of an appropriately qualified professional, with recognized training and qualifications, working within the standards determined by an appropriate professional body and regulated by this professional body, employed by or working on behalf of the test provider.

Finally, in determining whether or not the results of a genetic test may be returned directly to the consumer who ordered the test, the Principles set forth a host of factors for DTC service providers to consider in determining “whether the test results should be provided only in the context of a consultation with a suitably qualified genetics health professional…”

These factors include everything from the severity of the condition to be diagnosed to the reliability of the diagnosis to the “likely speed of degeneration,” along with particularly personal criteria such as the likelihood that the results will “have a significant or life-altering impact on the behavior of the individual” or on the personal and family relationships of the individual.

It is almost impossible to conceive of a system in which DTC service providers could evaluate these and the other factors set forth in Section 10.1 of the Principles without engaging in preemptive genetic counseling for each customer seeking whole classes or categories of genetic tests. Irrespective of whether such pre-testing genetic counseling would be desirable in the DTC context, at this point the resources simply do not exist to support such a model – there are simply not enough genetic counselors or other appropriately trained medical professionals. And as the cost of genomic data production continues to decline, demand for data is likely to continue to outpace the capacity of genetic testing providers – whether DTC or clinical – to provide that data alongside individualized genetic counseling.

Furthermore, given the Commission’s underlying concern that consumers will inappropriately lean upon DTC genetic information to make important medical and lifestyle choices, requiring DTC companies to provide detailed and personalized medical assessments to their customers seems an odd way to set consumer expectations for the appropriate use of DTC genetic information.

Technical Provisions. Sections 6 (Data protection), 7 (Sample handling) and 8 (Laboratory processes) provide useful guidelines for DTC service providers that seem likely to be supported – if not already adopted – by most responsible companies and would serve as a useful floor to ensure that consumers receive a high-quality genetic testing experience. Recommendations such as improved proficiency testing for genetic testing laboratories and more specific policies governing the treatment of an individual’s genetic data in the event of a bankruptcy have been made elsewhere and are likely to be widely supported by both companies and regulators.

Part III: What’s coming next?

In the “Purpose and Scope” section of the Principles (Section 1.1), the Commission writes that the “test provider should strive to provide a high-quality service that meets the expectations of the consumer whilst safeguarding their interests.” In focusing primarily on the desire to safeguard consumers’ interests – a desire that is manifest in standardized guidelines that attempt to bring the DTC companies closer in line with practices used in clinical genetic testing – the Commission has crafted Principles that, while comprehensive and ambitious in that regard, are likely to do much to frustrate the expectations and desires of many consumers if implemented to the letter.

Next week, we will take a closer look at just what these Principles, in conjunction with various other calls for increased oversight and a heightened focus on clinically relevant testing, might herald for the future of the DTC genomics industry. In the meantime, the Commission has prepared 11 consultation questions, many of which touch on the issues identified above, and we encourage our readers to provide their own take on the Principles both directly to the Commission (pdf) and in the comments below.

The workshop focused on a review of the “scientific foundation for using personal genomics in risk assessment and disease prevention,” developing five specific recommendations for the future development and use of personal genomics.

1. Develop and implement scientific standards for personal genomics. Of primary importance was the development of scientific benchmarks for evaluating personal genomics testing. Heavily emphasized was the need to establish standards for measuring the clinical validity (how well a genetic variant identifies or predicts an individual’s clinical status) and clinical utility (the health and other benefits of a test balanced against its harms or costs) of personal genomics tests. The importance of voluntary industry guidelines (pdf), randomized clinical trials and economic analysis of personal genomics testing were all discussed.

2. Develop and implement a multidisciplinary research agenda. The workshop recognized that this area is a meeting point for many disciplines, including, in addition to the obvious biological and medical fields, the fields of communication and behavioral and social sciences. There is a need for large-scale research projects to improve risk characterization, “especially of gene-gene and gene-environment interactions.” But there is also a need to study how the results of such research are publicly disseminated and become incorporated into the delivery of health services or the decision-making of individual consumers.

3. Enhance credible knowledge synthesis and dissemination of information to providers and consumers. Continuing with the theme of communicating knowledge to policy makers, health care providers and individuals, workshop participants noted that such communication needs to be timely and capable of “rapid turnaround” (given the pace of developments), based on standardized formats, and subject to agreed standards for what constitutes the “best available data.”

4. Link scientific research on validity and utility to evidence-based recommendations for use of personal genomic tests. One of the key issues for personal genomics, and particularly for direct-to-consumer (DTC) genomics companies, is when and how policymakers, clinicians and healthcare payors (including consumers) will determine that a personalized genomic test has demonstrated sufficient clinical validity and clinical utility to warrant its incorporation “into clinical practice and disease prevention.” Setting the bar for this “evidence threshold” at an appropriate height was another concern of the panel, and it noted that setting the bar too law resulted in the marketing and use of genomic tests without sufficient evidence of their clinical validity and/or utility, a common concern voiced by critics of the DTC genomics industry. Setting the bar too high, on the other hand, “may result in tests with high validity and utility but with lower financial incentive for innovation” which could, paradoxically, “lead to fewer developed tests and potentially diminished health benefits.…” The panel declined to offer its own suggestion for an appropriate evidence threshold, concluding only that the bar must be set by “independent panels that have no conflict of interest and use rigorous systematic evaluations,” such as those employed by EGAPP and USPSTF.

5. Consider the value of personal utility. Finally, the panel went out of its way to highlight the potential “personal utility” of genomic and genetic testing and services. Even in the absence of proven clinical or medical interventions, personal genomics information may have utility for individuals, including promoting improved comprehension of genetic information and the adoption of healthy lifestyle changes. As an example, the participants singled out the recent REVEAL Study conducted by Bob Green et al. that found, in the case of Alzheimer Disease (AD), that “even though there are no proven effective interventions to remediate” the risk of AD, providing participants with genetic information regarding that risk was found “to be useful by allowing them to prepare their families and arrange personal affairs including long-term care.”

DTC genomics companies have long trumpeted the personal utility of their products, often choosing to highlight the educational aspects of their services in the face of doubts about their clinical validity and/or utility. The workshop’s recommendation that these “perceptions of utility” be “scientifically supported” with “objective metrics” and “rigorous multidisciplinary observational studies and [randomized clinical trials],” if carried out, would be an acid test for the personal genomics industry and its claims of personal utility. Some of this work has already begun and, from an industry perspective, the preliminary results are encouraging. A recent study (the NIH Multiplex Initiative) of early adopters of genetic testing services similar to those provided by DTC companies found that such individuals “may be among the most motivated to take steps toward healthier lifestyles.”

Of course, no set of personal genomics recommendations would be complete without the obligatory ELSI nod: “these scientific standards have to be examined in the context of principles of population screening with full consideration of the ethical, legal and social, economic, and policy issues.” Ultimately, however, its encouraging to see such influential individuals in the field of personal genomics continuing to focus their attention on better understanding the science, utilization and effect of personal genomics. This initiative provides a useful counterbalance to calls for the preemptive regulation of a field that remains in its infancy.

The ACCP’s position paper faults a number of features of the current regime: (i) the FDA does not require premarket review of laboratory-developed tests; (ii) even if conducted in CLIA certified laboratories, the clinical validity of laboratory-developed tests (which includes most DTC genetic testing) is not regulated; (iii) there is no regulatory oversight system for advertising of DTC genetic tests; and (iv) the communication of DTC test results is not mediated through a trained clinician. The ACCP fears that consumers are insufficiently protected in the current unregulated environment, with the result that “at a population level, these collective [negative] experiences may give future genetic testing a poor reputation, and it consequently may not be trusted by consumers.” The ACCP further cautions that the “inequitable regulatory policy regarding laboratory-developed tests [may stifle] innovation in the creation of validated genetic tests.” The position paper does not state, or offer any data suggesting, that any such stigma currently attaches to genetic testing or that innovation is being stifled.

The ACCP recommends “the establishment of effective governmental oversight…soon” but does not specify exactly what that regulation should be. For instance, the position paper notes that CLIA certification of laboratories does not address the issue of clinical validation of genetic tests and that laboratory-developed tests (which includes most current DTC genetic tests) require no premarket review by the FDA. The FDA is already wrestling with this extremely complicated issue as it assess whether and how to regulate laboratory-developed tests employing multivariate index assays (pdf) (or IVDMIAs), but the statement offers no suggestions on how the FDA should balance the trade-offs inherent in such regulation.

One such trade-off is the difficult question of how to require clinical validity in the face of rapidly advancing knowledge without stifling innovation (a problem the ACCP’s position paper implicitly acknowledges). The statement’s clearest recommendation is that professional clinicians should be more involved in the process of communicating DTC genetic test results, particularly clinical or medical test results, thereby preserving “future utilization of pharmacogenetics testing to inform choices about medication use.” Few would argue the desirability of consumers receiving advice from appropriately trained clinicians, but there would be a lot of devil in the details of any attempt to dictate by law the scope of such involvement, including (i) distinguishing clinical or medical DTC genetic testing from recreational or informational testing and (ii) ensuring a supply of sufficiently trained professionals. The ACCP statement offers little assistance with those details.

The ACCP position statement is just the latest manifestation of a view that DTC genetic testing should be more highly regulated (see “In Search of a Coherent Framework: Options for FDA Oversight of Genetic Tests” (pdf) and the recently published House of Lords report on Genomic Medicine), with the most recent call to action coming from Genetic Alliance, which advocates a public, FDA-supervised registry of both DTC and laboratory genetic tests.

Most of the key players in the DTC genomics industry appear to at least agree on the need for self-regulation in the form of voluntary standards of conduct. 23andMe, deCODE, Navigenics, and others, as members of the Personalized Medicine Coalition, have proposed the development and communication of common standards regarding the scientific validity of genetic services available directly to consumers (pdf). And a recent study (the NIH Multiplex Initiative) of early adopters of genetic testing services similar to those provided by DTC companies found that those individuals “may be among the most motivated to take steps toward healthier lifestyles,” providing, as one reviewer puts it, “another reason to leave DTC gene-testing shops alone.”

The ACCP position paper raises several arguments in favor of state-supported or federally supported regulation in addition to improved industry self-regulation, including the risk that “poor consumer experiences [could] stigmatize[] the genetic testing field.” But what is missing from ACCP’s call for more robust state regulation is rigorous documentation of those “poor consumer experiences.” And it is missing because patient or consumer harms due to DTC genetic testing, although oft-alleged, have yet to be convincingly demonstrated. (Indeed, a common assumption of many in the medical community—that patients with incurable genetic diseases would be at risk of needless harm were they to be tested and confronted with their genetic status—has been called into question by a recent study suggesting that, at least in the case of Alzheimer’s disease, returning genetic test results to individuals does not cause any significant distress.)

Without convincing evidence of the harms of DTC genetic testing, it remains difficult to fully justify more rigorous governmental regulation, or to anticipate its content, structure or ultimate effect, which perhaps explains why such regulation continues to remain just over the horizon.