Genetic tests need oversight

April 1, 2013

FDA committees are examining DTC genetic tests that make medical claims

The availability of genetic and genomic tests is increasing at a rapid rate. The website currently lists more than 2,700 inherited genetic disorders for which tests are available, and the number of available tests for inherited disorders increases at an annual rate of 25%, based on the data available on

However, this figure does not include genetic tests for acquired disorders such as cancer, nor does it include genomic assays. Although no comparable comprehensive database exists for this group of tests, the Association for Molecular Pathology (AMP) maintains a directory that lists several hundred available tests for cancers and infectious diseases. Therefore, it is not unreasonable to estimate that more than 3,000 clinical genetic and genomic tests are currently available.

One of the factors contributing to the explosion of available tests is the relative lack of regulatory oversight of genetic testing in the United States.  And when that happens, patients can be harmed. In the worst-case scenario, patients with cancer can die because they are treated with ineffective drugs based on the results of gene-based tests that later prove to be unreliable, or, conversely, they could be denied treatment with a potentially beneficial drug based on a test that suggests the drug won’t work.

One of the areas of greatest expansion in genetic and genomic testing has been in the development of tests marketed directly to consumers (direct-to-consumer or DTC). These tests, which can be ordered by individuals over the telephone or internet without the involvement of their doctor, claim to provide genetic information about a wide range of medical and nonmedical issues. For example, DTC tests might include carrier tests for common genetic diseases (for example, cystic fibrosis), predisposition tests for a wide range of chronic conditions (for example, heart disease, diabetes, etc.) and tests that provide information about how an individual’s genes affect their response to drugs (pharmacogenetic or pharmacogenomic interactions).

Other tests may include ancestry testing, which claim to predict the global origin of an individual’s ancestors. The issue with many DTC genetic tests in particular is that the evidence and the science behind the tests are very limited. And so while there may be one or at most a few studies regarding a particular genetic association, the evidence is not robust enough to make predictive conclusions for any given person.

As a result, physicians, payers, and patients are confused about what the test results do and don’t mean, and what to do with the information. For example, a patient may choose unwisely not to follow screening guidelines for colon cancer because a DTC test suggested a lower-than-average risk for colon cancer.

The American College of Medical Genetics and Genomics (ACMG) asserts that the self-ordering of DTC genetic tests by patients over the telephone or the internet and the use of these kits are potentially harmful. ACMG is concerned that patients may use the tests inappropriately, misinterpret or ignore the results, or fail to follow up with their healthcare providers. Even worse, test results may be inaccurate, causing patients undue anxiety.

Such a situation occurred in 2010 after 23andMe reportedly mailed inaccurate test results to 96 customers. The company attributed the mix-up to a laboratory error. As a result of this mishap, the FDA issued warning letters to the company and four of its competitors. The FDA previously had issued a similar warning letter to another company that marketed an at-home saliva collection kit, which was intended to report personal genetic health disposition results for more than 70 health conditions, including pharmacogenetics, propensity for complex disease, and carrier status. The warning letters in their entirety appear on the FDA website.

The FDA contended that DTC genetic kits met the definition of a device as defined in section 201(h) of the Federal Food Drug and Cosmetic Act since they are “intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body.”

At the present time, the FDA regulates genetic test kits as in vitro diagnostic devices (IVDs) when the components of the test are bundled together, labeled for a certain use, and distributed to a laboratory as a single unit. The FDA requires such test kits to undergo premarket review prior to commercial distribution to demonstrate their safety and efficacy. The genetic tests in question did not undergo such an examination before marketed to consumers.

The FDA also maintains narrower oversight of the active ingredients of laboratory-developed genetic tests that are performed by certified laboratories. These components, known as “analyte-specific reagents” or ASRs, may be sold only to those laboratories that have been certified to perform high complexity tests and must be labeled in accordance with FDA requirements.

The FDA took further action in July 2010 when it held public meetings to discuss how to improve FDA oversight of laboratory-developed tests (LDTs) in the future. LDT is an inclusive term used to describe in vitro diagnostic tests that are manufactured by and performed in the same laboratory. Originally planned as a category for simple, single-analyte tests that are easily replicated in other labs, LDTs now include certain genetic and molecular tests that require complex interpretation and often lead patients to make important decisions about their health care.

For example, the Oncotype DX breast cancer assay is an LDT that is designed to provide women with guidance on the use of adjuvant chemotherapy following breast cancer. The test is based on the expression of 21 genes in breast cancer tumor tissue and requires a proprietary algorithm to convert the results to a score, known as the recurrence score (RS), that predicts the risk of cancer recurrence. The intention is that women and their doctors will use this information to decide if adjuvant chemotherapy is warranted. Consequently, serious medical decisions are being made on the basis of this test that has been subjected to minimal regulatory oversight. The same situation exists for an increasing number of genetic and genomic tests designated as LDTs.

The purpose of the FDA-sponsored meeting was to seek public input on issues and concerns related to LDT oversight. The meeting addressed patient considerations, challenges for laboratories, DTC marketing of tests, and education and outreach. At that meeting, the FDA asserted that it was “working toward a reasonable and fair approach to regulation that can give patients and doctors confidence in these tests and facilitate progress in personalized medicine.”

Subsequent meetings of FDA Advisory Committees were convened to elicit expert opinion and input on scientific issues concerning DTC genetic tests that make medical claims. At its March 2011 Advisory Committee meeting, the FDA contended that it was working with genetic-testing companies to come into compliance with FDA regulations for medical devices and it sought input on three issues:

  • Pros/cons of DTC genetic testing without clinician involvement;

  • Risks/mitigations for incorrect, misunderstood test results; and

  • Appropriate scientific evidentiary standards for testing.

Where do we stand today? Nearly three years after issuing warning letters and holding public meetings, the FDA is still in the process of drafting guidance on DTC genetic tests, which had not been released as of the time of writing of this article.

 With any type of genetic or molecular testing, but especially with those marketed directly to consumers, there needs to be a level of regulatory oversight that ensures that the test does what it says it will do and predicts what it says it will predict. The results of these tests are often intended to specifically guide therapy and to promote use of novel technologies as clinical diagnostics. Without an appropriate level of oversight by the FDA or other organization, payers, providers, and consumers need guidance to understand the scientific evidence surrounding these tests and to determine when and for whom they should be used.

There is no argument that knowledge of genetics has the potential to rapidly revolutionize medical understanding of a disease state and improve treatment and patient outcomes. This science is moving forward quickly, as we gain more information about genes and their variants, both benign and deleterious. Patients should not have to pay the price, however, when a lack of regulatory oversight enables companies to rush genetic tests to market without proper evidence of their analytical validity, clinical validity, and clinical utility. Nor should payers be put into a position to reimburse for a test that may do nothing for the patient or, worse, do more harm than good.

Winifred S. Hayes is president and CEO, Hayes Inc. Diane Allingham-Hawkins, PhD, FCCMG, FACMG, is director of the Hayes Genetic Test Evaluation Program