An MD&DI May 1998 Column
The new president of the European Diagnostic Manufacturers Association discusses the challenges ahead as gene technology advances into the next millennium.
Every day, headlines in the world's major newspapers and magazines herald the advent of the genetic age. Whether it's coverage of "Dolly," the cloned sheep, discovery of the latest gene responsible for breast cancer or hair loss, or the imposing questions of ethics and costs surrounding genetic testing, patients, medical professionals, health service providers, and insurers are keenly aware that genetic testing is not a pipe dream but a reality, although at this point there are more questions than answers.
Genetic testing promisesor threatensto advance medicine by a quantum leap to the essence of each unique human being: the human genome. The great challenge for this health-care revolution will be how to educate people so they are knowledgeable enough to apply their understanding of complex issues surrounding genetic technology to make life-affecting decisions.
As a physician, I firmly believe that medical professionals should continue to lead the way in the decision process for patients. However, the increased complexity behind genetic information calls for a greater understanding of the issues. Although device manufacturers may feel somewhat removed from genetic discussions such as this one, they must consider potential component needs of genetic researchers and thus encourage their own R&D teams to keep up to date on such needs as well as on other health-care related issues. Physicians must likewise ensure that patients receive complete, unbiased information regardless of an insurer's desire to save money by limiting treatment options and that patients be forewarned that optional genetic test results might lead to discrimination. Only by working together can wephysicians, patients, and manufacturersmeet the new millennium with greater hope for medical advancement.
Genetic testingin vitro analysis of human nucleic acids or their productsis not really new. The newer technologies that detect nucleic acid sequencessuch as gene probe technology, polymerase chain reaction (PCR), and chip technologycan, however, provide more specific information about genes than traditional methods such as chromosome analysis and phenotype analysis. The latter is based on an observable physical characteristic rather than genetic information (genotype). Although much controversy surrounds the use of genetic testing, the potential for abuse of genetic information is no more or less than that of other medical information. The question is: Does the superior diagnostic capability of genetic testing outweigh the potential for abuse? I believe the answer is yes. However, we must diligently develop standards concerning the use of genetic testing.
The accumulation of genetic information is increasing at an amazing pace. The European Bioinformatics Institute (Cambridge, UK), for example, is adding new DNA sequences to its public database at a rate of one per minute. The resultant knowledge will affect our lives and much of our economyfrom employment to insurance, lifestyle to health-care managementfor years to come. The in vitro diagnostics (IVD) industry is at the forefront of these changes in health care.
The development of genomic technologies into clinical practice applications will produce far-reaching effects in the field of IVDs. New technologies that have already been launched into the marketplace and those in advanced stages of development will affect future IVD business more dramatically than has any other achievement within this field during the past 50 years. Work with sophisticated new diagnostic testing has already been performed in many areas, including the following:
- Revolutionizing infectious disease diagnostics to detect distinct or specific sequences in certain organisms such as pathogenic bacteria or viruses.
- Detecting mutations of known human DNA/RNA sequences (genes), which can be used to diagnose predispositions to common disorders, inherited diseases, or different types of cancer as well as indicate the prognosis of malignant diseases.
- Addressing special concerns such as bacterial and viral drug resistance.
Major pharmaceutical companies have announced stepped-up plans to begin a series of collaborations and acquisitions on a scale never before seen in genetic research. The driving forces behind these new corporate conglomerations are the multitude of scientific breakthroughs bringing together gene-sleuthing and high-speed computerized chemistryand the mammoth associated costs. Most large pharmaceutical and diagnostic companies have major gene probe research under way, in which the probe is DNA prepared and marked to distinguish genes or their mutations; automation of gene probe technology is taking place in both clinical chemistry and infectious disease fields.
Many people in the scientific and medical community predict that most monogenetic diseases will be diagnosed via molecular levels by the year 2005. About one-quarter of the 4000 known inherited diseases can already be analyzed this way. Tests are available for various infectious diseases, some types of cancer, and genetically inherited diseases such as Huntington's chorea, Duchenne's muscular dystrophy, and cystic fibrosis.
Our ability to market tests based on the new advances depends on developing technological applications that make testing and results interpretation more convenient, easy to perform, and accurate. For instance, the upcoming miniaturized chip technology will make tests more convenient for patients, physicians, and lab professionals because it will require smaller amounts of specimen and reagent. Less waste means tests are also more environmentally friendly.
Diagnostic chips for certain applications are already on the market for determining HIV resistance, locating mutations in the tumor suppressor gene p53, as well as for finding polymorphisms within the p450 gene to determine individual patient response to various drugs.
Gene probe technology may be the largest single sector of IVDs in the future. The projected numbers vary, but the growth potential is clear. Investment analysts Cowen & Co. project that sales for gene probe and chip technology will rise from the current $125 million to $600 million by the year 2000 and reach $2 billion by 2004. The 1997 Genesis Report predicts that the chip-based diagnostics market will account for $2.7 billion worldwide by 2005. A Frost & Sullivan report projects an enormous jump in DNA testing from $200 million in 1996 to $740 million in 2000 and $1.4 billion in 2003. Furthermore, Wall Street and London stock analysts predict that the greatest market potential for chip technology will be in infectious disease and cancer detection as well as genetic screening.
So far, commercialization of such technology has focused on creating tests to detect the cause of diseases so that appropriate drugs or therapy can be developed and administered. The more controversial field of testing for the potential onset of diseases has, in many cases, been avoided, mainly for this simple reason: if we can't treat or cure a disease, why detect it in the first place? Practical concerns surround the use of test results to discriminate against people applying for insurance coverage because of their potentially higher risk of contracting a certain disease. This is particularly problematic because many people who have a gene that has been linked to a specific cancer, for example, never develop the disease.
In the United States, most life insurance companies usually won't cancel a person's coverage if he or she contracts a disease during the life of the policy, but they may not extend coverage to certain applicants for fear of affecting their actuarial rates. For example, individuals applying for health or life insurance are often required to undergo a blood test, which can detect HIV antibodies in the blood or through genotype analysis with DNA probes using PCR technology. HIV carriers are often denied coverage.
Individual states regulate insurance company coverage; under the terms of state legislation, companies are not required to accept individuals who fail to meet their underwriting guidelines. Some states, such as New York, don't allow coverage to be rejected based on medical history. Furthermore, a 1997 U.S. federal law requires that, after all other forms of insurance are exhausted, the states must provide minimal coverage to individuals with costly, long-term conditions. A state may require private companies to unconditionally offer this basic coverage or may run a program through its government.
On the positive side, heightened surveillance because of a known increased risk for a disease and the resulting early detection and treatment can often increase the odds for a cure or at least lengthen life. However, in many situations, genetic testing results provide more questions than answers. Predisposition or susceptibility testing for incurable diseases as well as preimplantation or prenatal genetic testing raise major ethical, legal, and social concerns.
For example, breast cancer testing in the United States and Europe has been controversial. The first gene responsible for hereditary breast cancer, BRCA1, was identified in 1994 on chromosome 17. Only 15 months later, a second gene, BRCA2, was detected on chromosome 13. Inherited breast cancer accounts for about 5 to 10% of all breast cancers. The prevalence of BRCA1 is estimated to be 1 in 800 women, and mutations in both genes play a role in about two-thirds of breast cancer patients. Physicians' and patients' expectations were high that a key to better understanding of all breast cancers had been found.
But those expectations were not totally fulfilled. With today's test, negative results may bring at least temporary relief, and for those in whom mutations in the BRCA genes are detected, frequent and early screening may detect early signs of cancer when it can more likely be eradicated.
But there are many negatives as well. Hundreds of sequence variations exist in both genes, and the detection of one specific mutation is insufficient for conclusive diagnosis. Full-length sequencing of BRCA1 and BRCA2 is time consuming and expensive. Available tests cost $500 to $2400, depending on whether the test is for a specific mutation or an entire gene sequence.
A strong argument against commercial testing is that risk estimates are still vague. Some mutations seem to be less penetrant than others; therefore, BRCA mutations are found in individuals without a family history of breast cancer. How does one react, then, to the news of carrying BRCA mutations? Even prophylactic surgery will not eliminate the risk of developing breast or ovarian cancer. It's also unknown how additional genes and environmental factors alter the risk of breast cancer development. The greatest danger, then, to finding that one carries a BRCA mutated gene is the potential discrimination by employers and insurance companies.
The reductionist conclusion that mutations in gene X cause disease Y is just not valid. Although these developments have heightened the population's general awareness about gene technology and its potential uses, many complex issues still need to be ironed out before patients can acquire the benefits of this technology.
The Brussels-based European Diagnostic Manufacturers Association (EDMA) advocates the following tenets:
- To use genetic testing only when prior written informed consent has been obtained from the patient.
- To view genetic testing as part of the established process of gaining medical information and therefore to support individual countries and European legislation to protect an individual's right to confidentiality of all medical information, not just genetic data.
- To actively participate in efforts to improve public knowledge and understanding of genetic testing.
- To work with laboratory professionals and the wider medical community to ensure that comprehensive genetic counseling is provided to the patient, including full disclosure of expected and actual test results, alternatives to the test, and therapeutic and preventive options after testing.
- To repudiate misuse of prenatal and infant genetic testing for possible selection purposes based on criteria of medically irrelevant information or so-called socially unacceptable characteristics; to allow genetic testing and screening only when timely medical benefit may come to a child via preventive measures and therapies or early diagnosis; to defer testing if the benefit will not accrue until adulthood (e.g., if the child is a carrier of adult-onset diseases).
Ethical questions point to the need for extensive information and education programs for patients and the general population. Controversial points surrounding genetic testing issues need careful consideration, such as the extent of our ability to prevent the particular disease being tested for; the ethics involving the notification of patients about a potential, but unproven, disease risk based on fragmented knowledge; whether people's desire to know their genetic risk is worth the price of the possible resultant stress and anxiety; and the nature and degree of interaction between genetic background and environmental exposure.
No current overall consensus exists concerning genetic testing. The Advisory Committee on Genetic Testing within the United Kingdom's Department of Health has set up an independent parliamentary committee to oversee genetic testing concerns, but this is a minute step within the industry. Greater agreement and effort is needed throughout the industry. The following five principles can be used as a basis for working toward a consensus on genetic testing. They are: autonomy, privacy, justice, equity, and quality. Those individuals responsible for legislating or running the health-care industry need to respect individuals' autonomy by allowing them to make their own decisions based on full disclosure of all information and implications concerning genetic testing; prohibit all communication to third parties without the written consent of those affected by such disclosures; see that particularly vulnerable groups (incompetent adults, minors, future generations) receive justice by only being tested when medically necessary and that their test results won't be used for discriminatory purposes; make testing available to individuals of all financial and social backgrounds; and set standards for all tests, laboratories, and personnel and monitor them to ensure that standards are upheld.
With medical diagnosis and treatment increasingly moving from phenotype- to genotype-based decisions, medicine in the new millennium will be more personalized than ever. The most effective treatment options will rely increasingly on medical solutions using state-of-the-art diagnostic technologies. In addition, new treatments will be found for old problems. Some of these treatments may differ for patients with dissimilar genetic characteristics, and some of them may be applied before the onset of a disease to help maintain health.
Professor Uwe Bicker, MD, PhD, is president of the European Diagnostic Manufacturers Association (Brussels), executive chairman, Dade Behring, Inc. (Deerfield, IL), and a member of the board, Hoechst Marion Roussel AG (Frankfurt).