Regulation of assisted reproductive technologies in the United States
2002; Elsevier BV; Volume: 78; Issue: 5 Linguagem: Inglês
10.1016/s0015-0282(02)04199-7
ISSN1556-5653
Autores Tópico(s)Assisted Reproductive Technology and Twin Pregnancy
ResumoThere is a widely perceived notion that assisted reproductive technology (ART) is not regulated in the United States. This current perception has developed for a number of reasons. In the United States, ART has been characterized by the absence of a socialized healthcare system, lack of centralized government or financial oversight, and the proliferation of a large number of clinics to meet market demand. Although some of these clinics are based in universities, which are operated under state oversight, and some are in private academic centers, many function as private medical practices. Second, there is no statutory national body, such as the Reproductive Technology Accreditation Committee (RTAC) in Australia, or the Human Fertilization and Embryology Authority (HFEA) in England, to oversee these programs (1Approaches to ART oversight: what's best in the U.S.? Washington, D.C.: Centers for Disease Control Conference Summary, 12–13 February. 1998; Google Scholar). Third, highly publicized incidents of illegal, immoral, irresponsible, and unethical behavior have occurred in the United States in the past few years. Extensive media exposure of physicians using their own semen for patient insemination, theft of patient eggs, proposals for human cloning, the use of stem cells for research, exorbitant sums of money paid to egg donors, and septuplet and octuplet births have received wide media attention. As a result, the perception is that these events represent the norm, rather than anomalous incidents. Fourth, the rapid pace of scientific advances in ART has led to the use of new techniques such as cryopreservation of eggs, intracytoplasmic sperm injection (ICSI), embryo hatching, sex selection, cytoplasmic transfer, and preimplantation genetic diagnosis in patients before large, well-designed clinical trials have confirmed their safety and efficacy. This has led to criticisms of experimenting on humans in an irresponsible fashion. Furthermore, the political climate surrounding abortion—and, by extension, embryo research, stem cells, and somatic cell nuclear transfer—has, until now, resulted in a vacuum of governmental involvement in ART research. Finally, the media has perpetuated the current perception of an uncontrolled industry. Yet, despite its shortcomings, the current regulatory status of ART in the United States is far from laissez faire. Perspective is needed on the issues related to current and potential regulation of ART in the United States. Professional societies and individuals involved with ART have worked with federal and state governments and with professional and other organizations to develop an improved process that should ensure higher quality care, protect the public interest, and create public confidence in ART services. The federal government has several mandatory regulations affecting medicine in general, which also affect the clinical practice of ART. These include the Clinical Laboratory Improvement Amendments of 1988 (CLIA 88), which mandate, among many other requirements, certain standards for andrology laboratories and also cover those that provide ART services. Strict compliance with standards and on-site inspections are required. The Centers for Medicare and Medicaid Services (CMS), formerly Health Care Financing Administration (HCFA), is responsible for approving diagnostic and procedural coding terminology and the resource-based relative value studies (RBRVS) units that determine reimbursement for ART procedures. The Food and Drug Administration (FDA) also has numerous regulations affecting the use of the pharmaceutical products used in ART. On the state level, a license to practice medicine is required to practice ART, and inappropriate activities in ART clinics can and have been investigated by state licensing bodies. Most ART practitioners are certified by the American Board of Obstetrics and Gynecology, and many by the Reproductive Endocrinology Subspecialty Board. However, neither is required to practice ART. Facilities in which ART is practiced, such as hospitals, operating rooms, and procedure rooms, are also strictly licensed and inspected. At the university level, regulations for clinical research and ethics are in place to protect patients, physicians, and the institutions. Locally, county medical societies, hospitals, and health maintenance organizations (HMOs) usually oversee the practice of medicine and deal with the clinical, financial, and ethical issues brought to them by patients, physicians, or others. The most visible and important ART-specific regulation that has been developed in the United States is the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA), sponsored by congressman Ron Wyden (2The Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102-493).Google Scholar). This law requires that "each ART program shall annually report to the Secretary through the Centers for Disease Control and Prevention (CDC) pregnancy success rates achieved by such program through each assisted reproductive technology and the identity of each embryo laboratory used by such program, and whether the laboratory is certified or has applied for such certification." The law calls for the Secretary to consult with appropriate consumer and professional organizations in developing definitions. It also calls for the CDC "to develop a model program for the certification of embryo laboratories … to be carried out by the States. In developing the certification program, the Secretary may not establish any regulation, standard or requirement which has the effect of exercising supervision or control over the practice of medicine in ART programs." The law also calls for the Secretary, through the CDC, to promulgate criteria and procedures for the approval of accreditation organizations to inspect and certify embryo laboratories. The Secretary will also evaluate annually the performance of each accreditation organization. States, or accrediting organizations that issue a certification to an embryo laboratory, also have the right to revoke or suspend the license. The FCSRCA also requires the CDC to publish annually and distribute to the states and to the public the statistics on pregnancy success rates, the programs that have failed to report, and the status of the embryo laboratory's certification. The Secretary may require the payment of fees for the purpose of, and in an amount sufficient to cover the cost of, administering the FRSRCA. The current status of this law is as follows. The law has been enacted and over 95% of ART programs in the country annually report their results to the CDC through the Society for Assisted Reproductive Technology (SART), which has a contract with the CDC to collect these data. Those few programs that elect not to report have their names listed as "non-reporters" in the CDC publication. In 1997, for the first time, the 1995 results were posted on the Internet. Results for 1996 through 1999 are also posted. Also, in 1997 on-site validation inspections were initiated by SART, sometimes with CDC observers, to ensure the accuracy of the data that were reported through SART to the CDC. Thirty clinics of the approximately 370 in the United States had an on-site validation inspection. Programs are selected for a validation inspection based on those with highest and lowest success rates, as well as randomly. (Further comment on the FRSRCA will be made later in this paper.) In addition to the FCSRCA, the National Institutes of Health (NIH) has multiple regulations governing research in reproductive medicine. These laws are also frequently considered in non-NIH funded research. The federal and state governments have also passed laws regarding certain aspects of ART. For example, federal law and several state laws prohibit cloning a human; compensating a gestational carrier is prohibited in Michigan; and cryopreservation is limited in Louisiana. New York State requires licensure of ART laboratories, and California requires a provisional license (3Rules and Regulations of the State of New York, Part 52 of Title 10 (Health). Tissue Banks and Non-transplant Anatomic Banks. State of New York Department of Health, Albany, New York1992Google Scholar, 4California Health and Safety Code. Division 2, Chapter 4.1: Tissue Banks. State of California, Department of Health Services, Berkeley, CA1992Google Scholar). At the university level, many state universities have laws specifically preventing the use of, or research in, certain ART technologies, and ethical oversight by appropriate committees is mandatory for any reproductive research. The Federal Trade Commission (FTC) has regulations regarding truth in advertising and marketing. A number of ART programs in the United States have been investigated by the FTC for making claims about their pregnancy success rates that could not be substantiated by their clinical data. For example, when clinics advertise their success rates, the FTC has required that they must disclose the numerator and the denominator used in their calculations when such advertised rates are not based on initiated cycles and live births. The FTC has the authority to, and has in the past, publicized these transgressions and issued cease and desist orders. They also can impose punitive sanctions such as fines. Working conditions for clinic employees are regulated by the Occupational Safety and Hazard Act (OSHA), which has numerous strict requirements regulating employees in all medical practices, including ART. These regulations can and are enforced by on-site inspections. State regulations also require a license for business, which includes ART clinics. In local communities, cities and towns require commercial licenses, have building codes for facilities, and have other regulations that affect ART clinics. Other mandatory nonmedical regulations include insurance company, HMO, and other healthcare organization requirements. In early 1999, Tufts Health Plan in Boston deselected three of nine ART providers based on criteria Tufts Health Plan had set, which included number of physicians, percentage of reproductive endocrinologists, and success rates. Physicians must also follow federal and state laws the same as nonphysicians. Another most interesting development was the finding by the United States Supreme Court in the case Bragdon v. Abbott in June 1998, interdicta, that infertility is a major life activity as defined by the Americans with Disabilities Act (ADA). The short and long-term impact of this finding is as yet unknown, but class action lawsuits based on this finding are in process. The Equal Employment Opportunity Commission (EEOC) also found in a New York case that failure to provide infertility benefits is discriminatory, although the finding in this case was changed on appeal. National ramifications of these legal and regulatory cases are still being determined in subsequent cases. As noted above, andrology laboratories are covered under CLIA 88, and when these same laboratories also perform portions of the ART procedure, that portion falls under CLIA 88. The Centers for Medicare and Medicaid Services (CMS) also develops the diagnostic, procedural, and billing codes on a national basis for laboratories. Other national organizations that regulate ART laboratories include the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). This commission has the authority and does inspect some ART laboratories that are located in hospitals. Some states also have mandatory regulations involving ART laboratories. New York State inspects laboratories, and California ART laboratories currently are provisionally licensed under the California Tissue Bank Licensure Laws (3Rules and Regulations of the State of New York, Part 52 of Title 10 (Health). Tissue Banks and Non-transplant Anatomic Banks. State of New York Department of Health, Albany, New York1992Google Scholar, 4California Health and Safety Code. Division 2, Chapter 4.1: Tissue Banks. State of California, Department of Health Services, Berkeley, CA1992Google Scholar). The history of ART research regulations in the United States has been political and complex. Prior to 1993, federal policy required review and approval of research involving ART by an ethical advisory board (EAB), which had been established in 1975 to oversee research in reproduction. In 1979, the EAB released a report supporting ART research. However, because of the politics surrounding abortion, a chair for the committee could not be agreed upon; thus, the EAB was disbanded in 1980. From 1980 to 1993 federal policy required review and approval of ART research by a board that did not exist. As a result, no research was approved for federal funding. Recognizing this problem, the federal government established the Human Embryo Research Panel, which in 1993 recommended that some research be acceptable (for example, embryo research up to 14 days) and that other research not be acceptable (for example, cloning). President Clinton immediately tabled this report for further study. Following review, in 1994 a limited approach was taken to the report and a law was passed with a provision not to support "the creation of human embryos for research purposes." Following further study, in 1996 President Clinton signed a "continuing resolution" that banned federal funding for human embryo research. However, in 1999 the NIH initiated requests for proposals (RFP) for reproductive research that could involve embryos; however, embryos could not be created for the research and had to be obtained in the course of clinical care. Such research has to meet very rigorous NIH research guidelines, but represents increasing recognition of the potential widespread benefits of research in this area. In July 2001, President George W. Bush promulgated regulations under which stem cell research could receive federal funding in the United States. Somatic cell nuclear transfer (SCNT) has more commonly been termed "cloning" by the media. Since Dolly the cloned sheep came on the international scene in 1997, several controversial bills have been introduced but not passed regarding SCNT. At the height of the controversy over Dolly, Congress came very close to passing restrictive legislation regarding SCNT, but this was forestalled by giving the FDA authority to oversee such programs. In 2001, the House of Representatives approved a ban of both reproductive SCNT ("cloning" of a person) as well as therapeutic SCNT (the production of cells and tissue for the purpose of research and treatment of diseases). The Senate did not pass the bill, so no legislation has yet to result. Senate legislation of this issue has come forward in 2002, but the outcome of the various proposals is currently unknown. In the interim, the FDA has claimed authority, and has instructed all ART laboratories that FDA permission to perform any type of SCNT is required through the submission of a New Drug Application (NDA). At this time no NDAs have been approved and there is strong indication that the FDA will not give approval for any type of SCNT research. This requirement does not necessarily prevent private entities from performing such research, but federal legislation potentially could. Regulation of genetics is rapidly becoming an integral aspect of regulation of ART. The federal Department of Health and Human Services (DHHS) has oversight authority of genetic tests through the Centers for Disease Control (CDC), Food and Drug Administration (FDA), Centers for Medicare and Medicaid Services (CMS) and Office for Human Research Protection (OHRP). The Clinical Laboratories Improvement Act (CLIA) provides laboratory oversight. The National Institutes of Health (NIH) and other agencies support genetics research activities. The Secretary's Advisory Committee on Genetic Testing (SACGT) made recommendations in 2000 regarding criteria to assess genetic tests, classification of tests into scrutiny levels, data collection, confidentiality, oversight mechanisms, institution review boards, informed consent, transition of genetic tests to clinical use, orphan diseases, social and ethical concerns, current genetic tests, and regulation enforcement (http://www4.od.nih.gov/oba/sacgt.htm). The Health Care Portability and Accountability Act of 1996 restricts use of genetic test data by health insurers; and Equal Opportunity Commission guidelines prohibit employment discrimination based on genetic tests. Additionally, there is a prohibition on human embryo research (Public Health Service Act (42 U.S.C. 289g(b)). State health agencies have an oversight role in genetic testing including licensure of personnel and facilities and quality assurance activities under the CLIA program. Some states have additional regulations. The federal government has numerous regulations regarding research involving human subjects that apply regardless of the funding source. Institutional review board (IRB) approval is needed if human research projects are federally funded or will be submitted to the FDA. Written consent of the research participants is always required. The Department of Health and Human Services (DHHS) requires review and approval of research involving human subjects prior to funding by federal agencies. Additionally, university institutional oversight requires that regulations be adhered to and that IRB approval be obtained for research projects. Numerous initiatives have been taken by professional societies associated with ART in the United States. The American Society for Reproductive Medicine (ASRM) was founded in 1944 and has been actively involved in research, education, and setting standards for practice in reproductive medicine, including ART. Founded in 1987, SART is an affiliate society of the ASRM; it published 1989 clinic-specific success rates on a voluntary basis, and has continued annual publication since then. Both SART and ASRM worked with congressman Wyden to support the FCSRCA, which passed in 1992 (2The Fertility Clinic Success Rate and Certification Act of 1992 (Public Law 102-493).Google Scholar). With the College of American Pathologists, SART and ASRM also developed the CAP/ASRM Reproductive Laboratory Accreditation Programs (RLAP) (5The College of American Pathologists/American Society for Reproductive Medicine Reproductive laboratory accreditation program. Northfield, IL: College of American Pathologists, 1996.Google Scholar). The RLAP includes strict standards collaboratively developed by professionals in the field in 1992, and on-site laboratory inspections by CAP/ASRM/RLAP inspectors. Over 200 SART clinics have now been accredited on a voluntary basis by this national accrediting body. As a result of changes in SART bylaws, in December 1998 accreditation became mandatory for all SART programs; programs must apply for accreditation to CAP/ASRM, JCAHO, or the state of New York. Those IVF clinics that do not become accredited or do not apply for accreditation lose their membership in SART. At this time essentially all SART clinics have completed accreditation or are in the process of completing accreditation. The American Association of Bioanalysts (AAB) has a proficiency testing service that is approved by CLIA. The AAB also supports CLIA coverage of embryology laboratories, and has a grandfather provision for embryology laboratory directors who do not have doctoral degrees. The ASRM and SART have collaboratively developed professional society guidelines and practice standards, shown in Table 1 (6American Society for Reproductive Medicine and Society for Assisted Reproductive Technology. Birmingham, AL.Google Scholar).TABLE 1ASRM and SART guidelines and practice standards.•Minimum standards for IVF (1984)•Minimum standards for GIFT (1988)•Revised minimum standards for IVF, GIFT, and related procedures (1990)•Guidelines for human embryology and andrology laboratories (1992)•Guidelines for practice, including gamete donation (1993)•Statement on intracytoplasmic sperm injection (1994)•Guidelines for the provision of infertility services (1996)•Elements to be considered in obtaining informed consent for ART (1997)•Induction of ovarian follicle development and ovulation with exogenous gonadotropins (1998)•Guidelines for number of embryos transferred (1998)•Guidelines for gamete and embryo donation (1998)•Revised minimum standards for in vitro fertilization, gamete intrafallopian transfer, and related procedures (1998)•Position statement on nurses performing limited ultrasound in a gynecology/infertility setting (1997)•Intravenous immunoglobulin (IVIG) and recurrent spontaneous pregnancy loss (1998)•Guidelines on number of embryos to transfer (1999)•Antiphospholipid antibodies do not affect IVF success (1999)•Who is to report ART cycles (1999)•Optimal evaluation of the infertile female (2000)•The role of assisted hatching in IVF: a review of the literature (2000)•Repetitive oocyte donation (2000)•Does intracytoplasmic sperm injection (ICSI) carry inherent genetic risks? (2000)•Blastocyst production and transfer in clinical assisted reproduction (2001)•Salpingectomy for hydrosalpinx prior to IVF (2001)•Preimplantation genetic diagnosis (2001) Adamson. Regulation of ART in the U.S. Fertil Steril 2002. Open table in a new tab Adamson. Regulation of ART in the U.S. Fertil Steril 2002. The American College of Obstetricians and Gynecologists (ACOG) has also developed technical bulletins and practice opinions on ART procedures (Table 2) (7American College of Obstetricians and Gynecologists. Washington, DC.Google Scholar).TABLE 2ACOG technical bulletins and practice opinions.•Technical bulletin on infertility (1989)•Technical bulletin on new reproductive technologies (1990)•Technical bulletin male infertility (1990)•Practice opinion on ZIFT (1993)•Technical bulletin male infertility (1994)•Practice opinion on use of frozen sperm (1994) Adamson. Regulation of ART in the U.S. Fertil Steril 2002. Open table in a new tab Adamson. Regulation of ART in the U.S. Fertil Steril 2002. Recognizing the social context in which ART must be practiced, ASRM, SART, and ACOG have not confined their concerns regarding ART just to the clinical and laboratory practice of medicine. Considerable time, effort, and expertise have been devoted to developing ethical guideline initiatives that have created standards for self-regulation. Because most practitioners follow these guidelines, they have been important in directing the ethical practice of ART (Table 3) (6American Society for Reproductive Medicine and Society for Assisted Reproductive Technology. Birmingham, AL.Google Scholar, 7American College of Obstetricians and Gynecologists. Washington, DC.Google Scholar).TABLE 3Professional society ethical guidelines.•ASRM and SART: Ethical considerations of the assisted reproductive technologies (1986, 1988, 1990, 1994, 1997) ◦1994 report with complete statements on over 29 topics◦1997 report with statements on: -disposition of abandoned embryos-oocyte donation to postmenopausal women-embryo splitting for infertility treatment-the use of fetal oocytes in assisted reproduction-posthumous reproduction-ASRM and SART: Ethical issues with respect to specific ART practices including IVF, GIFT, ZIFT, gamete donation, surrogacy, cryopreservation of embryos, and research•ASRM and SART: Guidelines addressing quality assurance and formation of public policy ◦Definition of "experimental" (1993)◦Definition of "infertility" (1993)•ACOG committee on ethics and opinions on IVF (1986), surrogacy (1990) and research on preimplantation embryos (1993)•The National Advisory Board on Ethics in Reproduction (NABER) [Originally organized through the cooperative efforts of ACOG and ASRM in 1991, then became independently incorporated and funded and had broad representation before disbanding in 1998 because of lack of funding]: Informed consent and the use of gametes and embryos for research (1997) ◦ASRM and SART: Shared-risk or refund programs in assisted reproduction (1998)◦Guidelines for advertising by ART programs (1998, 1999)◦Sex selection and preimplantation genetic diagnosis (1999)◦Financial incentives in recruitment of oocyte donors (2000)◦Human somatic cell nuclear transfer—cloning (2000)◦Preconception gender selection for nonmedical reasons (2001) Adamson. Regulation of ART in the U.S. Fertil Steril 2002. Open table in a new tab Adamson. Regulation of ART in the U.S. Fertil Steril 2002. Recommendations are that preimplantation genetic diagnosis (PGD) to prevent transmission of serious genetic disease, including by sex selection, is ethically acceptable, sex selection during IVF for nonmedical reasons should not be encouraged, initiation of IVF with preimplantation genetic diagnosis solely for the purpose of sex selection should be discouraged, and further studies of the consequences of sex selection are needed. The use of somatic cell nuclear transfer for reproduction or producing a "clone" is strongly opposed, whereas the use of SCNT for therapeutic purposes is supported under rigorous research guidelines and oversight. The past 4 years have seen a dramatic increase in the pace at which ASRM and SART have been working with other organizations, especially the CDC and RESOLVE, to enhance the collecting, analyzing, and publishing of clinic-specific success rates (8Chapko K.M Weaver M.R Chapko M.K Pasta D Adamson G.D Stability of in vitro fertilization-embryo transfer success rates from the 1989, 1990, and 1991 clinic-specific outcome assessments.Fertil Steril. 1995; 64: 757-763PubMed Scopus (9) Google Scholar, 9Centers for Disease Control and PreventionReporting pregnancy success rates from assisted reproductive technology programs. 1997; (62CFR45259, 26 August)Google Scholar). Through its registry committee, SART has completely reviewed and refined all of the variables that are collected for the annual report. In addition, a survey of SART members has been taken to help improve the data definition and collection process. Also, the turnaround time for publication of the report has been significantly reduced. Prospective reporting of data is already in place, with full compliance expected in the very near future. In 1998 SART and ASRM, along with the CDC, developed an on-site validation program (6American Society for Reproductive Medicine and Society for Assisted Reproductive Technology. Birmingham, AL.Google Scholar). Twenty-five programs were inspected in 1998 and 30 more programs were inspected in 1999, 2000, and 2001. These programs are selected based on the lowest and highest success rates in the country as well as a random selection of programs of varying size that do not fall into these categories. Careful review and evaluation of the on-site validation program is ongoing under the validation committee of SART. Funding for publication and validation has been committed by the CDC. Approximately $200,000 annually has been committed in the contract that SART has to collect and validate the data. At this time the funding covers primarily the validation program. The cost of collecting the data is almost entirely borne by SART and its member programs, and by extension their patients. Both the CDC and SART have begun publishing results of clinical research based on the collected data. To ensure patient confidentiality, these data have been accorded the highest possible confidentiality status (known as 308D). Only the CDC and SART members have access to the data. For SART members to have such access, there are strict confidentiality and research requirements, the violation of some of which may result in civil and criminal penalties. Furthermore, all patients undergoing ART must agree to have their individual cycle data submitted through SART to the CDC. In 1998 the CDC published their Proposed Model Program for the Certification of Embryo Laboratories as required by the FCSRCA (10Implementation of the Fertility Clinic Success Rate and Certification Act of 1992: Proposed model program for the certification of embryo laboratories; notice. Federal Register 63(215); 6 November 1998 (60178-60189).Google Scholar). This model program was implemented by publication in the Federal Register in 1998 and has been distributed to all states in the hope and expectation that the states can use it to draft their own requirements. California is one state that currently is considering further regulation of ART and is reviewing the model program to assist in development of its legislation. It is also expected that this model program will be used on a national level to help determine guidelines for oversight of ART. The FDA has recently proposed regulations that will affect ART (11Establishment registration and listing for manufacturers of human cellular and tissue-based products. Federal Register 63(93); 14 May 1998 (26744–26755).Google Scholar). The purpose of their proposal is "to establish a unified registration and product listing system for establishments that manufacture human cellular and tissue-based products" (11Establishment registration and listing for manufacturers of human cellular and tissue-based products. Federal Register 63(93); 14 May 1998 (26744–26755).Google Scholar). It is expected that all ART clinics will be registered with the FDA beginning in 2003. The FDA is also concerned with qualification of donors, especially with respect to infectious disease testing and suitability of donor screening. They are also concerned with the handling, storage, and identification of reproductive tissue. The FDA's other areas of interest are product factors, including transmission of communicable disease, the processing of cells and tissue, clinical saf
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