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Technological Developments in Genetic Testing

Statement of

Mary Pendergast
Deputy Commissioner
Senior Advisor to the Commissioner
Food and Drug Administration
Department of Health and Human Services


the Subcommittee on Technology
House Committee on Science

September 17, 1996


Madame Chairman, Members of the Subcommittee, thank you for giving the Food and Drug Administration (FDA or the Agency) an opportunity to testify at this hearing. I am Mary K. Pendergast, Deputy Commissioner and Senior Advisor to the Commissioner. With me today is Dr. Bruce Burlington, Director of FDA's Center for Devices and Radiological Health.

The focus of this hearing, technological developments in genetic testing, and the questions raised concerning the quality, accuracy and use of the tests, are significant issues and of critical importance to FDA. For purposes of this hearing, I will focus on the principal scientific question posed by genetic testing, i.e., whether the genetic test is scientifically valid and the role FDA has in that determination.


Over the past two years, the Agency has met several times with Dr. Francis Collins, Director of the Human Genome Project at the National Institutes of Health, Dr. Neil A. Holtzman, Chair of the Task Force on Genetic Testing, and others to discuss the important and challenging medical and scientific issues surrounding genetic testing. These conversations have been very productive and useful, as we have grappled with whether, and to what extent, there should be oversight of genetic testing. There are no obvious, or easy, answers to those questions.


While there are many ethical, legal, psychological, and public policy issues raised by genetic testing, there are three principal questions that have been raised with respect to the performance of the tests themselves. These questions are critical to understanding what actions FDA has taken in the field of genetic testing.

  • Does the genetic test accurately provide information about a patient's health status? That is, is the genetic test useful to the patient and his/her physician?
  • Did the clinical laboratory performing the test run the test properly? Are we confident that the clinical laboratory got the correct answer actually determining the presence of absence of the gene?
  • Is there appropriate information available so that patients can be educated and counseled about the meaning of the genetic test?

The key question that FDA, Dr. Collins, members of the Task Force, and others, are all grappling with is who should decide the answers to those three questions. One thing is certain, there is no one group or entity -- whether inside or outside of government -- that has the full range of expertise and capacity to be seriously engaged in all three areas. Rather, we must look to strategic alliances, to partnerships, and to creative approaches in order to begin to resolve the questions posed by genetic testing.

The "who should decide" question is further compounded by the fact that genetic tests are used for a wide variety of different uses, and answers to those three questions may differ depending on the particular use of the genetic test. Thus, for example, genetic tests are used to collect ancillary information in patients with an established diagnosis of cancer for tumor subtype evaluation. In this context, the patient already has been diagnosed with a disease and the genetic test is used to optimize treatment for the disease.

Genetic tests also are used for diagnostic testing in a symptomatic individual and for in utero testing. When a person goes to see his or her doctor because of symptoms, the physician may use genetic tests to confirm or rule out certain diseases. In this instance, the information gained from the genetic test would have an immediate impact on both diagnosis and therapeutic decisions.

In the more complex situation, genetic tests also may be used to predict, in healthy individuals and fetuses, what their medical problems might be in the future. The test, instead of being used to support conclusions based on the physician's current assessment of the patient, is being used to predict, with variable certainty, future patient outcomes. Because of the latency between the genetic test and the expression of the disease, it may be decades before the accuracy of a predictive test can be assessed. Moreover, some of the tests are for diseases -- such as Alzheimer's -- that strike people of advanced age. If a genetic test says that someone has a gene associated with Alzheimer's disease and may get Alzheimer's disease many years from now, what can we say about the likely time course of the disease until onset and, indeed, the chances that it will ever occur in the person tested?

In addition, in many cases the first genetic testing and study is focused on families with a high incidence of a certain disease. It takes careful scientific study to learn whether the results of such tests are applicable to the general population. At present, scientists are studying whether the correlation between the BRAC1 gene and breast cancer seen in two dozen Ashkenazi Jewish families with strong histories of breast cancer is applicable to all women generally.

There is also the public policy question of whether genetic tests should be treated the same as, or differently than, other tests for the same condition or disease. For example:

  • Does it matter if you learn you have a genetic disease such as sickle cell anemia or cystic fibrosis through a test on a chemical or a protein in your body, or through a test on your DNA?
  • Is it more important for a genetic test to be better validated than a chemical test for the same disease?
  • Should genetic tests be performed by a clinical laboratory with higher quality testing services than those for chemical testing?


When scientists discuss the scientific validity of a genetic test, they are talking about two different things. First, they are trying to ascertain whether it is possible to actually test for a particular gene and its mutations, and get the answer right. This is called the analytical sensitivity and specificity of the test, and it addresses the question of how often there will be false positive and false negative test results for the presence or absence of the gene itself.

Second, and the more critical concern regarding the scientific validity of genetic testing, is the question of whether a particular gene and its mutations are related to a disease (i.e., whether the genetic test has clinical validity).

The mutation in a gene does not always predict disease in the tested individual. For example, Dr. Collins, Director of the Genome Project at the National Institutes of Health, led a team that discovered a specific gene mutation closely associated with cystic fibrosis. Although this was the most common mutation found in cystic fibrosis patients, wider implementation of the screening revealed several hundred other gene mutations. Some of these were associated with severe cystic fibrosis, but many others were found in healthy individuals. An accurate diagnosis of a gene mutation, therefore, may not be clinically relevant and may not determine who is "sick" or "well."

Because we do not know what a genetic test means in terms of the severity of disease that can be expected, genetic tests have significance for what it means to be "sick" or "well.". For example, let us say that a young man is tested and told that he has a gene associated with polycystic kidney disease. But perhaps that young man has a variant of the disease that is mild and he would have lived a full life without noticing any symptoms of the disease. If no genetic test had been performed, he would have felt "well" because he never had any symptoms that interfered with his life; he would not have been "sick." But, by performing the genetic test, the person is now a person with a disease, i.e., a "sick" person.

Thus, we cannot simply intuit that a gene and its mutation are associated with a disease; rather, the correlation between gene and disease requires the collection and analysis of scientific data. Thus, there are several critical questions, including:

  • Who should gather the data and who should analyze it?
  • Should the data be gathered before or after taking the test to market?
  • Does the amount of data needed depend on the severity of the disease or on whether the data is used for an immediate diagnosis or for the prediction of future events?
  • Is it possible to put a test on the market for some uses (e.g., immediate diagnosis and treatment), but require additional data for a different use (e.g., widespread screening and prediction)?
  • If there are simple things you can do to avoid the impact of the disease, such as diet or exercise, should more allowance be given for error and less data than if disease avoidance would require the taking an important life step -- such as a prophylactic mastectomy or chemoprophylaxis because of a prediction of breast cancer, forgoing children because of the risk for Huntington's Disease, or terminating a pregnancy because of a risk of congenital birth defects.
  • What warnings do we owe the public? Is cautionary labeling such as, "the meaning of these test results is not yet known," be used in situations where the data is incomplete or insufficient?
  • How can we create incentive systems to get to the correct answers?


To date, FDA has minimal involvement with genetic testing, although there are a few areas where the FDA has had some activity. Although genetic molecular diagnostic technology has been applied to a number of products, particularly in the area of testing for infectious diseases, only two companies have had approved genetic markers for malignancy, one for lymphomas and one for leukemia.

Investigational Therapeutic Products Using Genetic Tests As Diagnostic Criteria

Currently before FDA are a small number of requests by researchers to treat patients with genetic diseases by novel therapies involving cells and gene therapy products. The scientific validity of genetic tests comes into play in two ways through gene therapy protocols.

First, because of the highly experimental nature of the protocols, you should not treat a person for a genetic disease unless you know that the person actually has the disease. Genetic tests are sometimes part of the entry criteria for the gene therapy trial. Thus, the analytical sensitivity and specificity of the test directly influences the validity and appropriateness of the involvement of the patient in the experiment. Stated another way, the scientific validity of a genetic test used for entry into a study is paramount in assuring that the patient will actually have the otherwise untreatable disease.

This issue was brought into sharp focus this past year when FDA authorized several risky protocols involving the use of gene therapy to be performed on fetuses with known genetic diseases. In one case, one of our scientists had questions as to whether the genetic tests were predictive. She had another test with more predictive qualities performed and learned that the fetus did not have the genetic disease and the risky gene therapy was avoided.

In another case, the sponsor wanted to treat fetuses with all forms of a disease, andrenoleukodystrophy, in which there can be irreversible brain damage. The problem is that the disease has variable outcomes ranging from irreversible brain damage to essentially normal (an asymptomatic state). A scientist with FDA worked with the sponsors to limit the studies to only those fetuses with the irreversible disease.

Second, in the field of gene therapy sometimes the genetic test will play a role in the design of the therapy for the disease. FDA recently authorized a proposal to use a normal BRCA1 gene to treat patients with ovarian cancer with a diagnosed mutation in the BRAC1 gene. In other experimental protocols, a number of cystic fibrosis patients have been treated with the normal gene CFTR (cystic fibrosis transmembrane conductance receptor). All patients had the delta 508 mutation that had been clearly linked with cystic fibrosis disease. Thus, the quality of the treatment is often dependent on the quality of the test.

Because of the importance of the analytical and clinical validity of genetic tests used as a prelude to gene therapy, FDA has asked sponsors of gene therapy to provide the agency with information that would establish the quality of their genetic tests.

FDA's Proposal to Regulate Analyte Specific Reagents

Because the vast majority of genetic tests offered in the United States today are offered by either clinical or research laboratories which have made up their own tests, the use of these in-house developed genetic tests raise many of the questions raised by other laboratory practices. These genetic tests have thus been considered by the agency as part of its review of laboratory testing programs generally.

Clinical and research laboratories often develop and prepare their own tests that are intended to diagnose various medical conditions, using ingredients that they frequently purchase from biological or chemical suppliers. The ingredients and other materials used in developing these tests may be divided into two groups. The first group is referred to as "general purpose reagents," which include the laboratory apparatus, collection systems, and chemicals used broadly in a wide variety of tests. The second group is composed of chemicals or antibodies that may be thought of as the "active ingredients" of a test and which are useful only in testing for one specific disease or condition. Because, in laboratory terms, the chemical you are doing the analysis for is called the "analyte," these active ingredients are referred to as "analyte specific reagents" (ASRs). These in-house developed tests (sometimes referred to as "home brew" tests) include a wide variety of tests used in the diagnosis of infectious diseases, cancer, genetic, and various other conditions.

FDA currently regulates the safety and effectiveness of diagnostic tests that are traditionally manufactured and commercially marketed as finished products pursuant to our authority under the medical device laws. The in-house developed tests, however, have not been actively regulated by the FDA, and the ingredients used in them generally are not produced under FDA assured manufacturing quality control.

Because there are no controls over the analyte specific reagents used in the diagnostic tests, neither patients nor practitioners have assurance that all ingredients in the laboratory-developed tests are of high quality and capable of producing consistent results.

FDA has been concerned that, because these ASRs are of unpredictable quality, the present situation poses a range of risks to the public health. For tests with impact principally on the individual, inaccurate diagnoses can result in poor patient care and increased health care cost. In addition, as a matter of public health, if a test for HIV, tuberculosis, or another infectious disease is wrong, the society, not just the patient, can suffer because the patient can unwittingly pass the disease on to others.

Therefore, on March 14, 1996 the agency proposed a regulation under its medical device authorities that would require, among other things, that:

  1. . ASRs be made under good manufacturing practices;

    . ASRs be used to create in-house tests only by laboratories certified as "high complexity laboratories" under the Clinical Laboratories Improvement Amendments of 1988;

  2. . notice be provided to users of the ASRs that their scientific validity was not reviewed by FDA.

(61 Fed. Reg. 10484). Under this proposed rule, for most tests, including genetic tests, the FDA would not do any assessment as to whether any particular test offered by any laboratory had any analytical or clinical validity. Rather, the proposed rule is intended to limit the use of ASRs to laboratories that are required under CLIA to do their own analytical validation, and to keep the quality of the reagents consistent, so that if a laboratory has developed a test that has analytical utility, then the test will not be rendered meaningless by poor quality reagents.

The Agency's proposed rule does not address whether any genetic test might be clinically valid, i.e., that it might accurately forecast a person's disease state. The proposed rule reserved more rigorous effectiveness requirements only for tests that diagnose contagious conditions likely to result in fatal outcomes (e.g., HIV and tuberculosis), and tests used to determine the safe use of blood and blood products, safeguarding the blood supply. The proposed rule also would not regulate the claims made by the testing companies, clinical laboratories or physicians for the use of the tests, although it does require that there be a disclaimer that the test has not been reviewed by the FDA.

As part of that ASR rulemaking, the agency asked the public to comment on whether there should be any further regulatory requirements imposed on the ASRs used for human genetic testing, and whether distinctions could be made depending on the type of genetic test that was offered. Specifically, the agency asked whether more stringent controls, if thought necessary, could be limited to "only those ASR's used in tests intended for use in overtly healthy people to identify a genetic predisposition to a dementing disease, or to fatal or potentially fatal medical disorders (e.g., cancers or Alzheimer's disease), in situations where penetrance is poorly defined or variable and latency is long (five years or longer)."

The comments to the proposed rule were mixed. Some commentators supported the ASR proposed rule, with its limited oversight of the ASRs used in genetic testing. Other commentators -- including a majority of the members on the Task Force on Genetic Testing -- favored a more extensive regulatory approach for genetic tests. The agency is reviewing the comments received.


Although I have focused my remarks on the analytical and clinical validity of genetic testing, I would like to briefly address the issue of laboratory competence. The uncertainties surrounding the validity of genetic tests are magnified because genetic testing is very complex and requires extreme care, and there are few laboratories which have extensive experience in performing DNA analyses. If history is any guide, without some type of quality control system in place, many, if not most, of the laboratories that offer these tests will perform them competently, but some will not. We, collectively, need to learn from all of the various ways laboratories and other diagnostic providers have had oversight in the past -- under such models as the Clinical Laboratories Improvement Amendments of 1988 and the Mammography Quality Standards Act. We need to look at the problems and successes under these models to determine a model of oversight that might be the most appropriate for this new technology.


At present, we estimate that there are dozens of companies or laboratories offering hundreds of different genetic tests to the public and it is projected that this number will grow substantially. In order to avoid the disruption of patient care, implementation of any regulatory oversight would have to be phased in over time.

Implementation of any additional regulatory oversight also would cost money, both for the group(s) doing the regulating, and for those who are regulated. We need to consider what are the harms that are to be avoided -- the confusion, false fears, improper treatments, unnecessary expenses, stigmatization, etc. -- and how much we, as a society, are willing to pay to avoid those harms? If the FDA is to do any of the additional regulating, we would have to evaluate how these concerns fit with other concerns facing the agency, e.g., product approval and regulation, infectious disease transmission through foods, blood, and tissues, and examine how do the harms from inaccurate genetic testing stack up against those other priorities. If additional oversight is mandated, there is the question of resources and how to pay for the oversight. Industry involved in this field have expressed fears that new proposals for regulation would increase their costs thus stifling innovation and investment. Any new proposals to regulate this rapidly growing important technology would have to take these issues and concerns into consideration.


The future faced by the Human Genome Project is filled with both great hope and some trepidation. The FDA is carefully considering what, if any, additional role it should play in the oversight of genetic testing. To that end, the agency looks forward to the guidance on these issues which will be offered by you, and by the Task Force on Genetic Testing which will be presented to the Secretary of the Department of Health and Human Services.

Thank you again for the opportunity to testify, I will be glad to answer any questions.