Introduction

*“Consider God’s handiwork; who can straighten what He hath made crooked?”* 
**“I not only think that we will tamper with Mother Nature, I think Mother wants us to.”**

Genetic testing holds promise as the either the most beneficial or the most destructive creation of the new millennium.  The consequences of genetic testing research are far-reaching, with the potential for finding cures to diseases such as cancer, or destroying an individual’s life by changing insurance ratings, employment opportunities, and reproductive decisions. The scientific, legal, socioeconomic, and ethical implications of genetic testing demand appropriate regulatory controls.  The responsibility of regulation falls on various governmental agencies, including the Food and Drug Administration (FDA).   However, the neophyte genetics industry, ever evolving through biotechnological developments, does not have sufficient safeguards to meet the challenges posed by the impending completion of the Human Genome Project.  Whether FDA is the appropriate regulatory body to solve these imminent problems is a question requiring a detailed exploration of genetic testing, the Human Genome Project, FDA’s history, current regulation of genetic testing, critiques of FDA involvement,  and alternative solutions.

Genetic Tests

Genetic tests can be utilized to determine a number of hereditary diseases.  Predictive genetic testing allows patients to check for the presence of genes that code for life-altering illnesses, and thus, may aid the patient in divining whether he will manifest the disease within his lifetime, or whether he is willing to pass the gene on to a child. Government officials define a genetic test as:

The analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations, phenotypes, or karyotypes for clinical purposes.  Such purposes include predicting risk of disease, identifying carriers, and establishing prenatal and clinical diagnosis or prognosis.  Prenatal, newborn and carrier screening, as well as testing in high risk families, are included.  Test for metabolites are covered only when they are undertaken with high probability that an excess or deficiency of the metabolite indicates the presence of heritable mutations in single genes.  Tests conducted purely for research are excluded from the definition, as are tests for somatic (as opposed to heritable) mutations, and testing for forensic purposes. 

The creation of genetic tests involve locating the gene that codes for the specific disease, and translating  that information into a test product.  Scientists are diligently working to find the link between genes and illness.  The speed at which this is accomplished will influence the need for regulation.  

History of the Human Genome Project

Today, the most controversial and well-publicized genetic event is the near-completion of the Human Genome Project, which will lead to the development of genetic tests and the possible discovery of cures for life-threatening illnesses.  The Human Genome Project results will impact how genetic testing is monitored and how much regulation will be needed. The potential impact of the Human Genome Project can be better understood by examining the science,  politics, and policy behind the enormous endeavor.

The Science Behind Genetic Testing

The complicated, yet fascinating science behind genetic testing and the Human Genome Project permits researchers to explore the code of human life and human disease.  The human genome is the entire complement of genetic material in a human cell. The genetic material is distributed among multiple chromosomes; the number of chromosomes typically is characteristic of the species.  Twenty-three sets of chromosomes contain all the genetic information comprising the human genome, which is preserved in trillions of body cells.  At a primary level, the genome consists of deoxyribonucleic acid (DNA), a polymer of repeating nucleotides which are comprised of a sugar (deoxyribose), a phosphate group, and one of four complementary nitrogenous bases.   Located on a chromosome, a DNA segment that directs the synthesis of a single type of protein constitutes a gene.  Genes, which code for hereditary traits, occupy only a small percent of the total genome.  Within each chromosome structure, two DNA strands intertwine to form the shape of a double helix and are held together by weak hydrogen bonds between the over three billion nucleotide pairs with complementary/ matching bases comprised of adenine (A) and thymine (T), or cytosine (C) and guanine (G).    The double helix resembles a twisted ladder with the DNA base pairs (G-C, A-T) forming the rungs of  the ladder.  When the ladder is pulled apart into single chains, a DNA marker containing the complementary base pair can be used to identify the base pair of the single chain, as each base pair on the marker will only bind to its complement on the chain.

The specificity of the base-pair linkages permits each strand of the double helix to serve as the template for a new, complementary strand.   Information from a double-stranded DNA is transferred  to a single-stranded ribonucleic acid (RNA)  through the process called transcription.   The information encoded on the RNA then plays a role in the formation of proteins, which may eventually lead to gene expression.  

Changes to amino acids and proteins may be manifested in diseases.  For example, sickle-cell anemia results from an amino acid change in the hemoglobin protein that transports oxygen in the blood.   In general, each protein is comprised of polypeptide chains, which in turn are the creation of 20 different kinds of amino acids, and are several hundred amino acids long.  Through the process of translation, the synthesis of a protein chain is determined through the sequencing of amino acids by a type of ribonucleic acid (RNA) known as messenger RNA (mRNA).  Translation is the conversion in the cell of the base sequence information in the mRNA into the amino acid sequence of a polypeptide.   In mRNA, which is similar to DNA in structure, the base uracil substitutes for the DNA base thymine and the sugar ribose substitutes for the DNA sugar deoxyribose.    In both DNA and RNA, a sequence of three bases, called a codon in mRNA, corresponds uniquely to a specific amino acid.   Each codon links to another form of RNA called transfer RNA (tRNA) containing the complementary three-based sequence.  The tRNA then transfers an amino acid to a growing protein chain.   

Hereditary traits are under the control of genes.  Genes give only the potential for the development of a particular physical manifestation of a genetic trait, or phenotype.  The extent to which a genetic constitution of an person, or genotype,  is manifested depends not only on interactions with other genes but also on environmental influences.    Genetic differences exist in humans in part due to alleles, or alternative forms of a gene, which occur in varying frequency among populations.  

The Challenge of Sequencing

Sequencing allows researchers to catalogue their discoveries and find relationships between genetic codes and disease. The sequencing of the genome is accomplished by plotting positions of normal and mutated genes on what is called a genetic linkage map.  Mutations can occur through mistakes in nucleotide coding, rearranged base pairs within a gene, insertion of new genetic information into the gene, deletion of part of the gene, or duplication of parts of the gene.   Disorders such as cystic fibrosis, sickle cell anemia, and Duchenne muscular dystrophy are caused by changes in only one gene and are thus labeled monogenic disorders.  Monogenic disorders are not significantly influenced by environmental factors.  Mutations in two or more genes which act in combination cause polygenic disorders.   Conditions such as diabetes and heart disease are caused by changes in several genes acting in combination with environmental factors and are labeled multifactorial.   

Genetic anomalies may occur during recombination. Genetic recombination, or crossing over, results from the exchange of chromosome parts between paired chromosomes during gamete production, or meiosis.  If a genetic variation is located near the gene with a disease-inducing mutation, the variation and the mutation will often be inherited together.  The closer the mutation and the marker variation are located physically, the stronger the likelihood of linked inheritance.  When two genes on a chromosome are located closely enough that the chances of being separated through genetic recombination are only one in a hundred, they are separated by one centimorgan. A genetic linkage map indicates for each chromosome the location of genes or other markers by measuring recombination frequency in centimorgans.  The terms “loci” or “locus” signifies the position of a gene on a genetic map.   Studying the frequency of marker separation during recombination allows scientists to map the relative position of the markers. 

Several paths to mapping the genome exist.  Methods to finding a particular sequence include: by location and cloning, by finding a linkage to an identified marker, or by using genetic probes.  Fluorescence in situ hybridization (FISH) probes are strands of DNA labeled with fluorescent dye molecules which bind to complementary chromosomal DNA, and therefore identify the position of target DNA sequences in relation to known sequences.  Restriction enzymes are DNA-splitting enzymes that selectively cut the double helix at a specific site, generally four or six nucleotides long.  For example, the restriction enzyme EcoRI recognizes and excises the DNA sequence GAATTC exclusively.   After slicing the DNA, scientists can then clone, or copy the fragments by using the reproductive processes of a host organism such as a bacterium.  

Another method of DNA amplification is the polymerase chain reaction (PCR), an enzymatic replication technique requiring an initiating step in which an enzyme completes the synthesis of a complementary strand, doubling the amount of DNA.  Multiple copies allow scientists to study fragments and overlaps in segments of chromosomes, eventually resulting in a ordered library of clones.  The collection of clones that contains at least one copy of every DNA sequence in the genome is called a genomic library.  DNA from the same genomic region of different people can yield dissimilar fragment sets of different lengths.  DNA fragments of different sizes are often separated and sorted by size through a process called gel electrophoresis. 

In gel electrophoresis, electrically charged molecules migrate through a gel under a static electric field.   Electrophoresis patterns can aid in sequencing and may be associated with variations of genetic traits.   Other approaches to mapping include the use of transposons, a genetic element with a well known DNA sequence that randomly inserts itself into DNA strands, thus allowing a marker for genetic sequencing.   Other methods also exist and new technologies are constantly developing. 

Defective genes cause approximately 5000 hereditary human diseases such as Huntington’s disease, and over 1,000 disorders have already been mapped to specific chromosome regions.  A single misplaced nucleotide among billions may lead to lethal ailments.  It is estimated that printing out the genome would result in several hundred volumes of information the size of a big-city phone book.   The connection between a newly identified human gene and a known health disorder can be established in some cases but more often clear links between the cloned genes and human diseases are elusive.   Once links are found, genetic testing and gene therapy have the potential for identifying, preventing, or even reversing the effects of a harmful gene.  “The techniques of biotechnology have broad implications for many industries, but perhaps promise the greatest innovations in the production of products regulated by FDA.” 

Birth of the Genome Project

The birth of the Human Genome Project led to the creation of numerous governmental and private organizations for the purpose of monitoring genetic testing and the potential consequences and successes of the Project.  In December 1984, a meeting jointly convened by the U.S. Department of Energy (DOE) and the International Commission for Protection Against Environmental Mutagens and Carcinogens first contemplated the sequencing of the human genome largely to research genetic mutations in survivors of atomic bombings.   The DOE, in 1986, announced the Human Genome Initiative in an effort to pursue greater knowledge of the human genome.   In 1988, the National Institutes of Health (NIH), which is part of the U.S. Department of Health and Human Services (DHHS or HHS) joined the Initiative.   James D. Watson, the Nobel Prize-winning geneticist, who co-postulated the double-helical model of DNA with Francis H.C. Crick in 1953, was appointed the head of the Human Genome Initiative in 1988.   The National Human Genome Research Institute (NHGRI) was created as a subdivision of the NIH in 1989.

The Human Genome Project officially began on 1 October 1990.  The DOE and the NIH developed a joint research plan for the genome program detailing specific goals for the following five years.  This collaborative effort strives to map all of the approximated 100,000 genes (gene sequence), and to obtain the complete sequence of the over three billion nucleotide pairs of the genome (genome sequence).  In 1993, the plan was updated to encompass plans for five years past the update.  New goals included genetically and physically mapping the genome, exploring the role of scientific training, investigating public access to research information, and paying close attention to ethical, legal, and social implications of research particularly with regard to privacy and use of genetic information.   Further DNA sequencing, the identification and location of genes and pursuing developments in technology, were other notable goals. 

The Division of Extramural Research (DER) is a unit within the NHGRI that, in cooperation with the Department of Energy,  administers the NIH’s role in the Human Genome Project. Having achieved all the major goals in the 1993 plan, the DER published a new five-year plan for achieving goals in the in Human Genome Project in October 1998.  DNA sequencing is the major emphasis of the 1998-2003 plan with a goal of completing the full genomic sequence by the end of 2003, two years ahead of previous projections.    Scientists hoped to finish a gene-rich one-third of the human genome sequence by the end of 2001.   The plan specifies seven other goal areas for 1998-2003, including 1) advancements in sequencing technology, 2) identifying human genome sequence variations, 3) improving technology for functional genomics, 4) exploring comparative genomics including completing the sequence of Drosophila (fruit-fly) and mouse genomes, 5) further studying ethical, legal, and social implications through the ELSI program, 6) improve information provided through bioinformatics support and computational biology resources, and 7) ensure training of scholars and scientists in genetics. 

In 1990, the Ethical, Legal, and Social Implications (ELSI) Research Program was established by the architects of the Human Genome Project as part of the Division of Extramural Research.   The ELSI Program is responsible for funding and managing grants and education projects that examine ethical issues at American research institutions. The ELSI Program addresses four priority areas of research: 1) privacy and fairness in the use and interpretation of genetic information, 2) clinical integration of new genetic technologies, 3) issues surrounding genetic research, and 4) public and professional education. 

The Task Force on Genetic Testing was created by the NIH-DOE ELSI group to review genetic testing in the United States and make recommendation to ensure the development of safe and effective genetic tests.   The Task Force defined safety and effectiveness to encompass validity and utility of genetic tests, their delivery in laboratories of assured quality, and their appropriate use by health providers and consumers.  

In September 1997, the Task Force on Genetic Testing issued its final report on promoting safe and effective genetic testing in the United States.  In the report, the Task Force suggested a framework for ensuring that tests meet safety and effectiveness requirements to reduce the possibility of premature clinical use.  The report emphasized the need for informed consent, advocated the respect of parental values in prenatal testing, discouraged the testing of children for adult onset diseases, urged protection of confidentiality, rejected all forms of genetic discrimination, and encouraged consumer involvement in policy making.   The Task Force called for the Secretary of DHHS to establish an advisory committee on genetic testing that would ensure that new genetic tests evidenced analytical validity,  clinical validity, and utility, that all stages of genetic testing in clinical laboratories met quality standards, that health providers were sufficiently competent in genetics, and that there would be expanded availability of tests for rare genetic diseases. 

The Task Force believed that institutional review boards (IRBs) are the most appropriate group to determine whether scientific protocols in predictive genetic test development were sufficient for the protection of human subjects and the validity and utility of data.  The Task Force urged IRBs to avoid all appearance of impropriety or actual conflicts of interest.  Tests must be conducted in labs certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) if the results are reported to patients or patient providers. The Task Force considered many options for requiring IRB approval including that FDA use its authority to require test developers to submit protocols to IRBs.    The Task Force recommended that FDA bring together consultants on genetic testing to provide guidance on genetic testing devices with single or multiple intended uses.  The Task Force found CLIA to be inadequate in ensuring the overall quality of genetic testing as the laws were not specifically designed for genetic tests. 

The report broke new ground on the policy front with its attention to market influences in genetic testing, however, it did not clearly delineate the role FDA should play in genetic testing regulation,  which may suggest that the Task Force is uncertain whether FDA is the correct regulatory body in this area.  As FDA would not exercise jurisdiction over tests marketed as commercial services, although FDA believes it could do so, but instead chooses to regulate testing kits marketed as products, which permits evasion of FDA oversight, the Task Force questioned the arbitrary distinction as a reflection on FDA’s regulatory competence. 

History of SACGT

   	The progress of the Human Genome Project prompted the creation of an exploratory group under the Secretary of Health for the purpose of monitoring the status of genetic testing and implementing suggestions. In June 1998, the Secretary of Health and Human Services, Donna Shalala,  chartered the Secretary's Advisory Committee on Genetic Testing (SACGT).  The SACGT was formed  in response to recommendations by the Task Force on Genetic Testing and the Joint NIH/DOE Committee to Evaluate the Ethical, Legal, and Social Implications (ELSI) Program of the Human Genome Project.  The recommendations included reviewing the benefits and challenges of genetic knowledge and genetic testing, and the need for policy making. The SACGT advises the government about all aspects of genetic testing, including the medical, ethical, legal, and social issues raised by genetic testing. The SACGT may review the development of guidelines,

“including criteria regarding the risks and benefits of genetic testing, to assist Institutional Review Boards in reviewing genetic testing protocols in both academic and commercial settings; the adequacy of regulatory oversight of genetic tests; provisions for assuring the quality of genetic testing laboratories; the need for mechanisms to track the introduction of genetic tests to enable accuracy and clinical effectiveness  over time to be evaluated; and safeguarding the privacy and confidentiality of genetic information and preventing discrimination and stigmatization based on genetic information.”

In June 1999, the SACGT was asked by Dr. David Satcher, Surgeon General, and Assistant Secretary for Health, to assess the adequacy of oversight of genetic tests in consultation with the public.   Based on consideration of public comment and analysis of the issues, the SACGT was asked to recommend options for additional oversight.  

After spending the summer and fall of 1999 designing a process to gather public commentary, the SACGT conducted a public consultation on the oversight of genetic tests from 1 December 1999 until 31 January 2000 through a Federal Register notice,  a public meeting on 27 January 2000, scholarly literature analysis, website feedback, and mailings to 2500 interested parties.  The SACGT provided the public with a summary of the current state of genetic testing and requested guidance on four main issues: 1) What criteria should be used to assess the benefits and risks of genetic tests?; 2) How can the criteria for assessing the benefits and risks of genetic tests be used to differentiate categories of tests?  What are the categories and what kind of mechanism could be used to assign tests to the different categories?; 3) What process should be used to collect, evaluate, and disseminate data on single tests or groups of tests in each category?;  4) What are the options for oversight of genetic tests and the advantages and disadvantages of each option?; and 5) What is an appropriate level of oversight for each category of genetic test?   Possibilities explored included “the strengthening and expansion of current CLIA or FDA regulations or voluntary standards and guidelines.” 

At the end of February 2000, the SACGT reviewed public comments and drafted preliminary recommendations.  Among the key preliminary recommendations were: additional oversight for all genetic tests; FDA should review all new genetic tests in proportion to the level of complexity of the tests while facilitating minimal time and costs of review; FDA should give added attention to predictive genetic tests for rare and untreatable diseases; the CLIA should be augmented to ensure better quality; and work with the CDC in increasing utility of genetic tests by more conclusive analysis of the relationship between the genetic anomaly and the disease. Also noted in the recommendation was that:  DHHS requires additional resources; the public should be involved especially to relieve fears of confidentiality and privacy breaches, discrimination in employment, and fears of diverse  populations; and the education of the public and health care providers is essential in the genetic testing process. SACGT committed itself to monitoring the progress of DHHS in implementing enhanced genetic testing oversight. The SACGT is scheduled to meet again in June 2000, at which time the SACGT will review new public commentary on the preliminary conclusions.  

Executive Action

In February 2000, following the SACGT public consultation, President Clinton issued an executive order prohibiting discrimination in federal employment based on genetic information. The action is in response to widespread fear that genetic information will be misused, studies of current genetic inquiries on job applications, and fear of taking genetic tests if the information could be made public.  The executive order generally sought to prohibit federal employers from requiring genetic tests as a condition of employment or using protected genetic information to deprive an employee of opportunities, and provide stringent privacy protections for genetic information used in medical research.   Subject to certain limited exceptions, protected genetic information includes genetic information about an individual, the individual’s family members, or the occurrence of disease in the family members.  Also, at the President’s request, DHHS will instruct FDA and NIH to review gene therapy guidelines and regulations specifically concerning informed consent requirements. 

The President also endorsed the Genetic Non-discrimination in Health Insurance and Employment Act of 1999, which would extend similar protections such as non-discrimination on the basis of genetic information for Americans seeking employment, promotion, or health insurance to the private sector and to individuals purchasing health insurance.  In 1996, President Clinton signed the Health Insurance Portability and Accountability Act (HIPAA), which prevents group health insurers from using genetic information to deny individuals health insurance benefits.

Open Genome

Today, the Human Genome Project is an international consortium of 16 institutions in France, Germany, Japan, Great Britain and the United States.   On 15 March 2000,  U.S. President Bill Clinton and Prime Minister Tony Blair of Great Britain announced a joint statement to make the results of human genome sequencing freely accessible to the scientific community world-wide.  The statement lauded researchers who have made their human genome information available to the public and urged other researchers to follow suit.  President Clinton noted that “the profits of human genome research are measured not in dollars but in the betterment of human life.”   Plans exist to publish a full genetic map on the world wide web by 2003.    The Clinton administration requested $448 million in federal funding for the Human Genome Project for the fiscal year 2001, resulting in a total U.S. expenditure of approximately $3 billion since the start of the project. 

Biotech stocks plunged after the announcement, some more than twenty percent.   Billions of dollars in market value were lost in the frantic sell-off of biotech stocks.     The Nasdaq composite index dropped over 200 points, its second-largest point loss ever as of that date.   Despite the drop, the biotech index still remains elevated this year.  Investment fears may be unwarranted as gene sequences can still be patented and the White House release did not challenge intellectual property rights for gene-based patents.  The genome sequence, on the other hand, which consists of the total DNA base pairings, cannot be patented and has “no commercial value.”   Even if the genome sequence is freely available, the gene sequences and the medical products derived from them can be patented, and thus yield considerable profit. Even when the genome sequence is known, it is difficult to locate the genes, and furthermore to link the genes with diseases.  

On April 5, 2000, Celera Genomics Corporation of Rockville, Maryland, announced that it had “completed the sequencing phase of one person’s genome,” although scientists were skeptical.  Celera, in collaboration with the Berkeley Drosophila Genome Project, had succeeded in the goal of mapping the genome of the fruit fly.  Celera further announced expectations that it would also complete sequencing of the mouse genome before the public consortium.  Celera’s stocks were positively affected following the announcements, but Celera still preferred not to make its results available to the public. 

On 29 March 2000, Dr. Francis Collins, the head of the Human Genome Project announced that two-thirds of the three billion letters that make up the human genome had been deciphered.   The international consortium expects to complete a working draft including 90 percent of the human DNA sequence by June 2000 and the final version before 2003.   The announcement was made at Bio2000, a gathering of over 10,000 people involved in the biotech industry.  The two billionth base pair was deposited earlier this month by the Wellcome Trust’s Sanger Center in Great Britain.  Sequencing of the DNA bases is progressing at the rate of 12,000 bases per minute.  New segments are deciphered and deposited in the GenBank, a public database of DNA sequences operated by the U.S. National Institutes of Health and updated each 24 hour period at the Web site: (http://www.ncbi.nlm.nih.gov/genome/seq). 

History of U.S. Drug Regulation & FDA

The history of FDA evidences broad-based regulatory experience. The progress of FDA regulatory policy indicates that FDA may be well suited to regulate genetic testing.  Congress has noted that the purpose and mission of FDA is to ensure that  “(1) food is safe, pure, and wholesome; (2) cosmetics are safe; (3) human and animal drugs biological products, and therapeutic devices are safe and effective; and (4) radiological products and use procedures do not result in unnecessary exposure to radiation.”  While encountering problems through the course of history, FDA has effectively strived to fulfill its purpose.

1902 Biologics Act & Pre Laws

The 1800s witnessed the passing of the federal Vaccine Act of 1813, which was repealed following an outbreak of smallpox in North Carolina leaving regulation to local authorities,  and also witnessed the regulation of drug imports for safety and purity in 1848.  The call for federal regulation was finally answered in the 1900s and led to the formation of the Food and Drug Administration as it is known today. Following the utilization of an diphtheria antitoxin which resulted in the death of children from tetanus in St. Louis, and the outbreak of tetanus in Camden, New Jersey resulting from contaminated smallpox vaccines, the Biologics Act was passed in 1902.  The act was the first statute worldwide to require a form of pre-market approval.   Following the re-enactment of the Biologics Act in 1944, the updated statute gave FDA authority to regulate biological products, including human blood products, vaccines, and biotech drugs.  

1906 Pure Food and Drugs Act
The Federal Food and Drugs Act of 1906 prohibited interstate commerce in misbranded and adulterated food and drugs but required no pre-market approval.    Drug standards were based on the United States Pharmacopoeia and the National Formulary, while food standards were generally divined.  Disclosure was required of the net weight of foods and the presence of narcotic drugs.  Violators could face criminal penalties. 

1938 Food, Drug & Cosmetic Act
Pre-market requirements were not seriously contemplated until a tragedy struck in 1937.  The S.E. Massengill Company marketed a drug called “Elixir Sulfanilamide” which was created to provide the drug sulfanilamide in liquid form.   Diethylene glycol, commonly known today as antifreeze, was used as a solvent.   Over 100 people, mostly children died from the drug. The only legal basis for FDA intervention was misbranding, as the term “elixir” was reserved only for alcohol solutions.   Following the public outcry after the incident, Congress enacted the 1938 Food, Drug and Cosmetic Act.   The main principles of the act had been drafted by FDA and were under contemplation for five years.  Pre-market notification was now required.  Cosmetics and medical devices were now regulated under the statute.  Expanded definitions of adulteration and misbranding and an enumerated list of prohibited acts also graced the statute.  Companies had to notify FDA that they intended to market a product, and 60 days after notification, the companies could market the product barring interference from FDA within that period.  

1962 Kefauver-Harris Amendments to FDC Act
The 1962 Amendments to the FDC Act followed the tragedy of the birth of children with focalmelia/peripheral neuritis to mothers who had taken the drug thalidomide.  The Congressional bill was enacted unanimously by the House of Representatives and the Senate.   The amendments changed the pre-market notification requirement to one of individual pre-market approval for the safety and effectiveness of each new drug.   Advertising of prescription drugs was now under the regulation of FDA. 

1976 Medical Device Amendments to the FD&C Act

The 1976 Medical Device Amendments enhanced FDA’s regulation of medical devices. Seizure of misbranded or adulterated devices without proof of interstate commerce was added and upheld.  Interstate commerce was presumed to exist under the amendments.  Export of medical devices that were not approved for use in the United States was permitted.   Devices in medical use prior to this law were grandfathered and exempted from premarket review.   Such devices are known as “predicate devices.” 

1983 Orphan Drug Act
The 1983 Orphan Drug Act established a regulatory status for and facilitated the production of drugs used in the treatment of rare diseases whose sales return cannot justify research expenditures.   The Act provides incentives for the development of orphan drugs through tax credits, FDA guidance, open labeling, and market exclusivity.  The Act was amended in 1985 to expand market exclusivity. 

1984 Drug Price Competition and Patent Term Restoration Act (Waxman-Hatch Act)
The 1984 Act helped companies to recoup the patent life lost in the long FDA approval process.  This made generic drugs easier to market.  Once a patent expired, generic drugs would meet FDA standards through a basic showing of bioequivalence which was a significantly faster and less expensive process.

1990 Safe Medical Device Act (SMDA)

The 1990 Safe Medical Device Act amended the definitions of “drug” and “device.”   This allowed FDA to regulate drug-device combination products according to their “primary mode of action.” 

1992 Prescription Drug User Fee Act  (PDUFA)
In an effort to supplement FDA’s budget, the 1992 Act was passed.  User fees were assessed on the industry for prescription drugs only which allowed for hundreds of additional medical reviewers and which cut approval time in half.  The Act was only authorized for a five year period, but was re-authorized in 1997.

1997 FDA Modernization Act  (FDAMA)

FDAMA extended the Drug User Fee Act of 1992 by another five years.  The Act codified FDA practice to increase patient access to experimental drugs and medical devices, accelerate review of important new medications, provide an expanded database on clinical trials, modernize regulation of biological products, and eliminate certain requirements.  The Act permit dissemination of information about unapproved uses of drugs and medical devices, however, a supplemental application on safety and effectiveness may be required.  Dissemination of economic information is regulated more closely.  The Act mandates special attention to higher risk devices while requirements for lower risk devices were relaxed.

FDA was not recognized in legislation until 1988, despite a long institutional history.  As FDA is a division of the HHS, formal legal responsibility for administering the FD&C Act and other FDA related statutes lies with the Secretary of HHS.  After 1988, FDA Commissioners have been appointed by the President with the advise and consent of the Senate.  Prior to 1988, the commissioner was appointed by the Secretary of HHS.  Despite FDA prominence, the agency ranks relatively low in the HHS hierarchy which may help to insulate it from political pressure.  FDA is comprised of five centers: the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Food Safety and Applied Nutrition (CFSAN), the Center for Devices and Radiological Health (CDRH), and the Center for Veterinary Medicine (CVM).

FDA REGULATION

FDA Device Classification
FDA divides medical devices into three review categories.   Class I devices are products of low risk which are subject to general controls to provide reasonable assurance of the safety and effectiveness of the device.  If insufficient information exists to provide reasonable assurance, but the device is not represented to be used in sustaining human life or is of substantial importance in preventing impairment of human health, and does not pose an unreasonable risk of illness or injury, the device may also be classified as a Class I device.  

Class II devices require additional special controls to assure adequate safety and effectiveness levels, including premarket notification (PMN). Special controls may consist of the “promulgation of performance standards, postmarket surveillance, patient registries, development and dissemination of guidelines..., submission of clinical data in premarket notification submissions,” and other actions deemed necessary by the Secretary of DHHS.   Special attention is given to devices for use in supporting or sustaining life.  
Class III devices require premarket approval (PMA).  Insufficient information exists for these devices to determine that the general controls of Class I devices or the special controls of Class II devices would provide reasonable assurance of safety and effectiveness.   Class III devices are purported to be for a supporting or life sustaining use, present a potential unreasonable risk of illness or injury, or are for uses which are of substantial importance in preventing impairment of human health. Class III devices require submission of PMAs unless “substantial equivalence” to a previously approved device can be established through the filing of a 510(k) notification. 

Oversight of Genetic Testing

Five DHHS organizations mainly provide oversight of genetic tests: the Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), Health Care Financing Administration (HCFA), Office for Protection from Research Risks (OPRR), and the National Institutes of Health (NIH) which does not serve a regulatory function but supports genetic research activities.   “Genetic tests are regulated at the Federal level through three mechanisms: 1) the Clinical Laboratory Improvement Amendments (CLIA); 2) the Federal Food, Drug, and Cosmetic Act; and 3) during investigational phases, regulations for the Protection of Human Subjects (45 CFR 46, 21 CFR 50, and 21 CFR 56).”  The SACGT’s public consultation document provides a brief summary of FDA’s role in the oversight of genetic tests. According to the report, all laboratory tests and their components are subject to FDA oversight under the Federal Food, Drug, and Cosmetic Act which regulates these tests as diagnostic devices, requiring premarket approval or FDA clearance for tests packaged and sold as kits to multiple laboratories.  

In Vitro Diagnostic Tests
Currently, genetic tests are received and reviewed by FDA in the same fashion as other in vitro diagnostic tests (IVDs).  

“In vitro diagnostic products” are those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.  These product are devices as defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the act), and may also be biological products subject to section 351 of the Public Health Service Act.

The Division of Clinical Laboratory Devices (DCLD), a unit within the CDRH of FDA is presently responsible for regulation of IVDs including devices used for genetic testing.  FDA regulatory system is based on the Medical Device Amendments of 1976 as modified in 1990 and 1997.  IVDs developed as kits or systems for use in multiple laboratories require FDA review before marketing in order to safeguard labeling and performance standards. 
As FDA’s regulatory review process is dictated by a product’s claims, a new genetic test that has the same intended use as a previously approved device may possibly by classified as a 510(k), class II device.  Additionally, a genetic test with a well established background evidenced by extensive literature or a clear standard of care for future medical use may sometimes be automatically classified into class II status per FDA Modernization Act of 1997. 

The premarket review is based on data submitted by sponsors to scientific reviewers at the DCLD,  and involves an analysis of the device’s sensitivity, specificity, and accuracy.  The vast majority of IVDs are reviewed as 510(k) submissions, merely necessitating the demonstration of substantial equivalence to a predicate device.  There is a 90 day review period. Good Manufacturing Practices (GMPs) are monitored by periodic field inspections, labels must clearly state “For In Vitro Diagnostic Use,” and premarket notification is required.  Depending on a manufacturer’s product claims and laboratory  methods, the required levels of performance in categories such as accuracy, repeatability, or clinical specificity may vary.   FDA premarket review of 510(k) submissions is completely based on data submitted by manufacturers or clinicians and do not encompass direct device testing by FDA. 

FDA requires additional review for devices in which the link between analytical and clinical performance has not yet been established.  New or high risk devices that are not comparable to predicate devices must attain premarket approval (PMA) through FDA determination that the device is safe and effective.   FDA reviews IVDs for clinical sensitivity, specificity, and analytical performance, although establishing measurements for safety and effectiveness remains a challenge to FDA.   “FDA review is predicated on three basic tenets: (a) identification of an up-front study design with a clear study hypothesis; (b) careful collection of data; and (c) use of appropriate statistical models for data interpretation.” 

High risk device requirements include completion of a premarket approval application, a showing that the device is safe and effective, a 180 day review period, and the label: “For In Vitro Diagnostic Use.” These requirements and GMPs are monitored by subjecting the product to premarket inspection and approval.   The safety of an IVD is based on the impact the information generated by the device has on patients, such as harm from false positive or false negative results, with the standard for effectiveness defined by federal code.  

Analyte Specific Reagents and Home Brews 

IVDs created as in-house tests, also known as “home-brew” tests, are considered medical devices, but historically have not been subject to premarket review under FDA’s discretion.  While FDA has always considered in-house tests to be medical devices subject to regulatory oversight, the agency chose on a discretionary basis not to use its authority in that area based on the protections offered by  the Health Care Financing Administration’s provisions under the CLIA of 1988.

Recently, FDA established a regulatory program for home-brew tests based on classifying the active ingredients of the tests as analyte specific reagents (ASRs) which are exempt from premarket review but subject to good manufacturing practice and labeling controls.   FDA action was prompted by a “growing trend in recent years for more sophisticated clinical laboratories to develop and prepare their own tests” using ingredients that they frequently purchase from biological or chemical suppliers for the purpose of diagnosing medical conditions.

“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.  It is this group of active ingredients that FDA is proposing to identify as ASR’s.  These in-house developed tests (sometimes referred to as “home brew” tests) include a wide variety 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. However, in-house developed tests have not been actively regulated by the Agency and the ingredients used in them generally are not produced under FDA assured manufacturing quality control.”

Through the introduction of the new category of IVDs labeled analyte-specific reagents (ASRs), FDA sought to provide additional controls to home-brew tests without requiring premarket review, in 1996.   FDA proposed a rule to classify/reclassify ASRs presenting a low risk into class I devices, to exempt these ASRs from PMN and 510(k) requirements, to designate these ASRs as restricted devices, to establish restrictions on their sale, labeling and distribution, and to retain high risk ASRs in class III (PMA).  In November 1997, FDA issued the final ruling based on those parameters, which covered both previously unclassified pre-1976 devices as well as post-1976 devices which fall under class III to achieve consistent regulation.    At the time of the final ruling, FDA did not plan “to regulate ASRs used in genetic testing differently from other restricted class I medical devices that are exempt from premarket notification requirements.”    FDA considered classifying a subset of ASRs used to develop predictive genetic tests under a heightened scrutiny in view of potential risks to patients, but declined to do so at the time as those particular ASRs were not “being commercially marketed independently of the tests”.  While FDA further considered designating ASRs that would be marketed independently for use in predictive tests of latent genetic conditions as class III, the Agency determined no logically distinguishing criteria or special issues to warrant more stringent regulatory controls. The ASR rule became effective in November of 1998.

Officially, ASRs are defined as “antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.”  

ASRs, with exceptions for reagents used to ensure public blood supply safety, are mostly exempt for premarket review requirements, although they are subject to performance standards under the CLIA and are subject to periodic field inspections to ensure compliance.  The restrictions on the sale, distribution, and use of ASRs were later finalized in the Code of Federal Regulations.  Advertising and promotional materials for ASRs must include the identity and purity of the ASR and identity of the analyte, a statement for class I exempt ASRs “Analyte Specific Reagent.  Analytical and performance characteristics are not established,” a statement for class II or III ASRs “Analyte Specific Reagent.  Except as a component of the approved/cleared test (name of approved/cleared test), analytical and performance characteristics are not established,” and cannot contain statements concerning clinical or analytical performance. 

Furthermore, the laboratory that develops a home-brew test using ASRs must inform the ordering person of test results by adding to the report: “This test was developed and its performance characteristics determined by (Laboratory Name). It has not been cleared or approved by the U.S. Food and Drug Administration.” ASRs that meet the class II or III definitions are reviewed as components of a test or kit if not marketed independently.  FDA effects a premarket review of the ASR and the test of which it is a component to find substantial equivalence or safety and effectiveness of class II and III ASRs.  The requirement is not applicable when test results are created using “the test that was cleared or approved in conjunction with review of the class II or III ASR.”  Regulation also prohibits direct marketing of “home brews” to consumers. 

Monitoring of Human Subjects

FDA and OPRR administer regulations governing the protection of human research subjects during the research phase of genetic testing.  While the OPRR handles subject in DHHS-funded projects, FDA oversees the protection of human subjects in trials of investigational drugs, devices, and biologics created for later commercial use.   Experimental protocols must be reviewed to ensure safety, and ensure cost-benefit analysis by a group’s Institutional Review Board (IRB). The requirement applies to trials developing tests for commercial use and those funded by DHHS agencies, but it does not yet apply to home brew genetic tests which are not currently subject to FDA’s enforcement authority.  “In a 1995 survey of biotechnology companies, the Task Force on Genetic Testing found that 46 percent of respondents did not routinely submit protocols to an IRB for any aspect of genetic test development.”

The basic HHS policy for the protection of human research subjects includes requirements of written assurances from the research institution such as a statement of principles governing the institution in protecting human subjects, the designation of an IRB, a list of IRB members, and written IRB procedures.

Clinical Laboratory Amendments
In 1988, Congress passed the Clinical Laboratory Improvement Amendments (CLIA) for the purpose of establishing quality standards for all laboratory testing.  Under CLIA, a laboratory is defined as a facility that performs lab testing on human-derived specimens for the purpose of assessing, diagnosing, or treating human health.  Costs of administering the CLIA program are covered by the regulated facilities themselves. 

Until recently,  laboratories that produced tests from ASR’s and offered them as laboratory services were regulated by HCFA under CLIA for compliance with general laboratory standards regarding quality control, quality assurance, personnel matters, and proficiency testing. The HCFA regulations, however, do not include the same product controls provided by FDA, and therefore, assurance that all ingredients in the laboratory developed tests are of high quality and capable of producing consistent results cannot be attained by either patients or practitioners.  FDA evidenced concern that the situation with respect to home-brew tests, in which the ingredients are of unpredictable quality as they are essentially unregulated, will potentially create a risk to the public health. FDA also demonstrated concern that an unpredictable business climate for manufacturers and suppliers would be created due to continuing uncertainties about the regulatory status of commercially marketed ASRs.  

In December 1999, the CDC, HCFA, and FDA issued a notice that the CDC was transferring the responsibility for the categorization of IVDs that were commercially marketed under CLIA to FDA.  The process of categorization involves assigning commercial clinical lab tests to one of the CLIA regulatory categories (waived, moderate complexity, high complexity).  CLIA criteria will not change, and all other CLIA responsibilities currently assigned to the CDC will remain with the CDC such as review of assays, test systems, and tests not commercially marketed as IVDs.

Originally, HCFA administered the CLIA program with the support of PHS.  In 1992, FDA was assigned the responsibility of categorizing the complexity of commercially marketed lab tests.  The responsibility switched to the CDC in 1994 for monetary reasons, and the re-transfer was contingent on FDA funding.  “The transfer will permit manufacturers of commercially marketed IVDs to submit premarket applications for products and requests for complexity categorizations of those products to one agency.  When the transfer is complete, FDA staff in CDRH will evaluate the appropriate complexity category as they review premarket submissions for clinical laboratory devices.  Products seeking a waiver categorization, devices exempt from premarket notification, and devices under premarket review by other FDA centers also will be processed by these FDA staff.”

The transfer of responsibility was expected to be completed by 31 January 2000. This seemingly inert action will allow FDA to gain more control over genetic tests while gaining knowledge of industry practice. FDA should now be able to directly ensure that IVDs have been meeting quality laboratory standards.  More stringent standards for IRBs and IRB review would also further these ends.

State and Federal Monitoring

State health agencies and laboratories perform various oversight roles in genetic testing, including the licensure of personnel and facilities that perform human genetic testing.   Quality assurance is monitored by state CLIA programs, deemed sufficiently equivalent to the Federal CLIA program, with some states such as New York requiring even higher standards than CLIA.  States also provide genetic services through maternal and child health programs. Furthermore, Congress and several state legislatures have enacted statutory non-discrimination acts in response to the potential risk of genetic discrimination.  As of 1999, there were approximately 30 different State laws dealing with genetic information and health insurance. 

The private sector develops laboratory and clinical guidelines in addition to providing oversight in conjunction with HCFA and the CDC for accreditation activities.  Other organizations such as the College of American Pathology (CAP), the National Committee on Clinical Laboratory Standards (NCCLS), the American College of Medical Genetics (ACMG), and various medical societies help to assure quality lab practices and ensure appropriate use of genetic tests. 

A Few Issues to be Considered in Current and Future Genetic Testing
Patients

Predictive genetic tests “may become the equivalent of biological tarot cards, subject, like the Tarot, to misinterpretation and over reliance.”  DNA tests often require biological specimens from both the patient and other biological relatives, which has profound psychological, social, and economic implications for all family members.  Physicians lack adequate training in the rapidly changing field of genetics, and thus recommendations that health care providers have sufficient knowledge of genetics and nondirective (allowing patients the autonomy to make difficult personal decisions) genetic counseling hold merit. 

The failure of legislators to clearly differentiate among various applications of genetic testing may result in  “well-intentioned efforts to offer privacy protections” that result in “imprecisely worded legislation that handicaps research and may, in the future, impede the optimal delivery of health care.”   Perhaps genetic data should be treated with the same legal status as other health care information, however, this only appears satisfactory if the level of general health care data privacy is heightened.  “The answer lies not in artificial and impractical segmentation of different categories of health-care information, but rather in providing far more robust protections for all medical data--irrespective of the category--and stringent and transparent regulatory standards for predictive tests as they are used by employers and insurers.”  

Laboratories 

Private laboratories and manufacturers may try to avoid routine FDA review processes by manufacturing and using their own reagents in-house, and selling test services through primary care providers. Presently, CLIA monitoring may not be sufficient to monitor these practices.  Furthermore, “the CLIA validity requirement is satisfied when a genetic test to determine the presence of a specific genetic alteration does so accurately, even though the test may offer no clinical predictability,” with the only patient-based safeguards at the human-trial phase through IRB monitoring.  Perhaps the lack of sufficient coverage is due to the fact that “at the time CLIA was written...DNA-related genetic testing was in its infancy and had not yet become a defined laboratory specialty.”  Recently however, an advisory committee was formed and asked by HHS to review genetic testing as part of CLIA.   The committee concluded that CLIA should include a “dedicated genetic testing section.” The committee’s recommendations may be implemented in the near future to give added protection to patients who receive genetic testing. 

Perceptions of FDA

FDA critics claim that the Agency’s resistance to work with the international scientific community, and the rapid expansion of the biotech industry will make it difficult for FDA to maintain the full range of expertise needed to adequately regulate genetic testing.   However, recent FDA actions contradict this assumption.  For example, FDA established the Molecular and Clinical Genetics Panel of the Medical Devices Advisory Committee to serve as a source of independent advice in the area of DNA-based testing in 1999. 

Answering SACGT’s Questions

Finding the answers to the questions posed in the SACGT’s Public Consultation will involve review of the effectiveness of current regulation.  Based on observations of the history of the Human Genome Project and intergovernmental regulation of genetic testing, criteria that should be used to assess the benefits and risks of genetic tests include clinical validity, clinical utility, (effectiveness at linking genes with disease, effectiveness at predicting the likelihood of illness to a degree beneficial to the patient), potential for social, physical, psychological, and economic harm to the patient, and the ability to monitor manufacturing and marketing practices.  

The assessment criteria and differentiation into test categories should be effected by FDA.  FDA currently has an effective process to differentiate medical devices on the basis of safety, which also encompasses a form of cost-benefit analysis through effectiveness requirements.  The device classification system already details levels of oversight appropriate for each product that has proven to be implementable and effective over time.  

Instead of replicating the already effective methods of FDA, the DHHS should expand FDA’s budget to acquire more personnel.  With the transfer of responsibility of CLIA oversight for IVDs to  FDA, there is even more reason for FDA to be the primary source of genetic test regulation.  With the completion of the Human Genome Project, it is likely that FDA will finally choose to use its regulatory power to more closely monitor home brew tests.  As was noted by FDA, at some time in the future, “the agency may reevaluate whether additional controls over the in-house tests developed by such laboratories may be needed to provide an appropriate level of consumer protection.  Such controls may be especially relevant as testing for the presence of genes associated with cancer or dementing diseases becomes more widely available.” 

Other DHHS agencies should continue to support FDA in helping to set standards for genetic test regulations. While working with other DHHS agencies, FDA could tap outside sources through the recently chartered genetics advisory panel to provide the agency with outside counsel on genetic testing issues.  Also, while FDA review of medical devices is often performed by FDA scientists and statisticians, outside scientific experts in various fields often serve as special governmental employees during the review process.   Oversight protections are also provided by professional organizations, state and federal authorities, and self-regulatory standards.   The legislature, with greater ability to determine constituent needs, may propose new legislation concerning informed consent, genetic education, counseling, and marketing controls.  FDA could also issue new rules to effect a form of heightened scrutiny for genetic tests.  However, if enough legislative and professional protections have been put in place, there may not be a need for scrutiny beyond the current FDA regime if home-brews are more closely monitored.  The length of time needed for FDA approval further allows for monitoring over time.

Conclusion:  Predicting the Genetic Makeup of FDA

The future of FDA regulation of genetic testing lacks clear definition.  It is difficult to predict to what extent FDA will eventually regulate genetic testing, although current trends may indicate increased regulation. The completion of the Human Genome Project creates a reality of problems once merely hypothesized.   Given the experienced history of  FDA, FDA’s system of classifying and monitoring medical devices, and the transfer of IVD CLIA responsibility to FDA, the Agency is in the best position to be the main source of genetic test regulation.  With the rapidly changing technological advancements propagated by the completion of the Human Genome Project, it seems likely that FDA will use the full force of its regulatory power according to the needs that arise.  Whether Mother Nature will be pleased that humans tamper with Her cannot be predicted by a genetic test, but will be evident in the consequences of genetic testing on the human race.