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Andrology Lab Corner |
,
From the * Departments of Surgery (Urology),
Obstetrics and Gynecology, and
Physiology, University of Utah School of
Medicine, Salt Lake City, Utah.
| Correspondence to: Douglas T. Carrell, PhD, HCLD, Division of Urology, Room 3B208, University of Utah School of Medicine, 50 N Medical Dr, Salt Lake City, UT 84132 (e-mail: dcarrell{at}med.utah.edu). |
| Received for publication May 16, 2002; accepted for publication May 16, 2002. |
Assisted reproduction laboratories now stand at an intersection in the process of federal regulation. The Clinical Laboratory Improvement Act of 1988 (CLIA 88) has caused significant operating changes for many assisted reproduction laboratories, including the initiation of proficiency testing (PT) and quality improvement programs. However, for many laboratories, the changes have been made solely or primarily to pass an accreditation inspection, rather than as an actual impetus to laboratory improvement. Other laboratories, including physician office laboratories (POLs), have continued to operate without regard to the requirements of CLIA 88, with no apparent repercussions. These 2 factors have increased cynicism and have led many lab directors to consider laboratory regulation not only burdensome and ineffective, but also unfair to those attempting to meet the requirements of CLIA 88.
While still in the midst of implementing CLIA 88, new changes are on the horizon. The ability of individual laboratories to effectively and productively deal with the increasing role of laboratory regulation will not only be necessary for laboratory survival, but will also ultimately shape the quality of service provided by the laboratory as well as the public's perception of the ART industry in general. The purpose of this report was to briefly review the history and intent of regulations affecting ART laboratories and to highlight current proposals and actions that may soon apply to ART laboratories.
Federal Regulation History—Clinical Laboratory Improvement Act
of 1967
Accuracy of laboratory results is inherently important to laboratory
management. Although internal PT has been in place in some laboratories
throughout much of the history of laboratory medicine, modern PT began in the
mid-1940s by the private sector in the Philadelphia area attempting to improve
accuracy among clinical laboratories in that region
(Sunderman, 1992). The utility
of external PT services was quickly apparent, which spurred the development of
the College of American Pathologists (CAP) in 1946. The CAP was instrumental
in establishing nationwide annual surveys to monitor the accuracy of assays
and to establish and assess standards of laboratory work
(Sunderman, 1992).
Federal regulation of clinical laboratories began in 1966 when regulations were established with regard to personnel standards for laboratories that participated in the Medicare and Medicaid programs (Hinkel, 1992). Governmental oversight of clinical laboratories was dramatically strengthened with the passage of the Clinical Laboratory Improvement Act of 1967 (CLIA 67). The Secretary of the US Department of Health, Education, and Welfare, Wilbur Cohen, and the director of the US Communicable Disease Center (later to become the Center for Disease Control), Dr. D. J. Spencer, testified before the House Committee on Interstate and Foreign Commerce that laboratory accuracy was suboptimal and in need of regulation. Their testimony indicated that significant error rates in laboratory testing reached as high as 25%. To dramatize their assessment of the situation, their testimony also included a case report of a patient who lost her breast due to a lab error (Mahkorn, 1995). Although several pathologists submitted refuting testimony, CLIA 67 was passed with mandates requiring minimum performance standards for clinical laboratories engaged in interstate commerce (Laessig et al, 1992; Sunderman, 1992; Mahkorn, 1995). The standards included licensure of the laboratories and enrollment and "successful" participation in state-operated or state-approved PT programs (Hinkel, 1992; Laessig et al, 1992).
The utility of CLIA 67 and available PT programs in improving the quality of service provided by laboratories is debatable. Several proficiency studies were conducted between 1970 and 1990 assessing the impact of federal regulations on clinical laboratory performance. Those studies generally showed no differences in the accuracy of PT results between regulated and independent labs (Boone, 1992). Although exact data are not available, it is doubtful that CLIA 67 affected many fertility-related laboratories. Most ART laboratories at that time were specialty labs, not involved in the care of Medicare or Medicaid patients. With the exception of endocrine PT, available PT did not include programs for andrology-related services.
Clinical Laboratory Improvement Amendment of 1988
The second major attempt at the regulation of medical laboratories was
initiated to a large extent by the press. The Wall Street Journal
issued a front-page report on November 2, 1987, describing errors that
resulted in missed or delayed diagnoses of cervical cancer and reported the
death of a patient due to a misread Pap smear. A wave of other press reports
followed, and the government responded
(BeSaw, 1995;
Mahkorn, 1995;
Born and Thran, 1998). The
Clinical Laboratory Improvement Amendment of 1988 (CLIA 88) was enacted as a
federal measure to improve the quality and consistency of laboratory testing
(Byrd, 1994;
Hurst et al, 1998). The intent
of CLIA 88 (which was implemented in 1992) was to protect patients from
unqualified or unscrupulous laboratories. One of the radical differences
between CLIA 67 and CLIA 88 was the application of CLIA 88 to all clinical
laboratories, including POLs (Bachner,
1998; Hurst et al,
1998).
CLIA 88 identified 3 levels of laboratory testing: waived, moderate complexity, and high complexity. The classification of any given test was based on the risk of harm to patients, the likelihood of erroneous results, and the simplicity of testing. Any test defined as moderate or high complexity required that the laboratory meet the regulatory requirements of CLIA 88, which included a quality assurance (QA) program, specific personnel standards, and quality control (QC) measures. More than 75% of laboratory testing was defined in the "high- or moderate-complexity" testing category and subsequently came under regulation (Gerrity, 1993; Born and Thran, 1998). Facilities that perform moderate- or high-complexity testing were also mandated to undergo registration and periodic on-site inspections. Importantly, each laboratory must also engage in an approved PT program and ensure the reliability of the testing equipment and assays (Born and Thran, 1998).
The facilities most directly affected by the passage of CLIA 88 were the POLs and small private laboratories (Gerrity, 1993). Some argue, both positively and negatively, that these facilities were targeted by CLIA 88, with the aim that the management expertise and added expenses needed to meet minimum requirements of CLIA 88 made the limited testing provided by most POLs impractical and cost-ineffective. Centers for Disease Control and Prevention (CDC) data indicate POL tests dropped from a projected 2.7 billion to 294 million as a result of CLIA 88 (Born and Thran, 1998). A survey of 797 POLs reported that more than 64% eliminated some or all in-office lab testing directly due to CLIA 88, with even more dramatic decreases in rural locations (Born and Thran, 1998). A survey of physicians in Texas indicated that 58% reduced or eliminated their office laboratories (BeSaw, 1995). A Commission on Laboratory Accreditation (COLA) onsite survey of 562 laboratories found that many POLs that previously performed only 1 or 2 high-complexity tests had discontinued testing rather than face CLIA 88 requirements (Kroger, 1994).
Occupational Safety and Health Administration 1989
The Occupational Safety and Health Administration (OSHA) subsequently
proposed rules in 1989, also implemented in 1992, to protect the health care
worker from bloodborne disease. The political impetus for the OSHA regulations
was partially due to the acquired immunodeficiency syndrome epidemic. The OSHA
regulations are applicable to any health care facility
(Tokarski, 1990;
Gerrity, 1993). Implementation
of OSHA standards included the design and actualization of an
infection-control plan, providing employees with the opportunity for free
hepatitis B vaccination, the availability of personal protective equipment
suitable for every aspect of an employee's job responsibilities, and a
directive to improve the handling and disposal of infectious waste
material.
The Fertility Clinic Success Rate and Certification Act of 1992
The Fertility Clinic Success Rate and Certification Act (also known as the
Wyden bill, or HR4773) was signed into law in October 1992 after 4 years of
collaborative work between Congressman Ron Wyden, the American Fertility
Society (AFS, now the American Society of Reproductive Medicine, ASRM), and
the Society for Assisted Reproductive Technology (SART). Congressman Wyden
began the initiative in response to complaints from consumers regarding the
lack of open and reliable pregnancy success rate information. A second impetus
during that same period was a report in Fertility and Sterility,
published in November 1987, that highlighted the exploitation of the infertile
couple (Blackwell et al, 1987;
Gerrity, 1993; Lawrence and Rosenwaks, 1993;
Wilcox, 1996). Sensing the
inevitability of regulatory legislation, the AFS and the SART became involved
in the legislative process, hoping to gain the respect and credibility of the
profession, to improve chances of insurance reimbursement for ART procedures,
and to lobby for restoring federal funding for IVF research. It was during
this time that the AFS and the CAP formed a joint laboratory accreditation
program for the ART laboratory, the Reproductive Laboratory Accreditation
Program (RLAP) (Visscher,
1991; Lawrence and Rosenwaks,
1993; Adamson,
2000).
Prior to the passing of the Wyden bill, the Senate Committee on Labor and Human Resources concluded that the infertility service field lacked performance standards and a credentialing process. As additional support for the bill, the Federal Trade Commission also testified about several enforcement actions it had taken against providers of infertility services because of the providers' misleading advertising and promotional materials (Brown and Paine, 1993). Again, the media was prominent in highlighting the concerns of patients, not only with regard to misleading pregnancy rate information but also with respect to cases of inappropriate patient care.
The Wyden bill was designed to address the laboratory aspects of ART programs by creating a set of model laboratory protocols and procedures for use in the laboratory accreditation process. It also requires ART programs to provide statistics on pregnancy rates for public use on a yearly basis. The bill was enacted in October 1994, and since that time, all ART programs have been required to report their pregnancy success rates to the CDC through SART (Brown and Paine, 1993; Lawrence and Rosenwaks, 1993). Membership in SART is dependent on participation in the reporting program. Largely because of the input of SART, the measure did not intend to create barriers to improvements of, or research on, infertility treatments or to dictate which patients physicians accept for ART procedures (Brown and Paine, 1993).
The Current State of the Implementation of Regulations
Practical problems and limitations in effectively implementing CLIA 88 have
been addressed and resolved to different degrees. At the time of the enactment
of CLIA 88, there was no approved PT program for andrology procedures, nor was
there specialized training or courses for certification in andrology or gamete
cryobiology (Byrd, 1992).
Additionally, many IVF and andrology laboratories lacked effective and
efficient QC measures (Byrd,
1992). Lastly, the regulations on personnel education and
training, at both the director and technician levels, have caused difficult
and sensitive obstacles. While these and other areas may still be problematic
in some laboratories, practices, policies, and procedures have been developed
to overcome the difficulties and effectively comply with CLIA 88. Those
measures have included industry-wide improvements, including the usage of
publications such as the World Health Organization manuals, which provide a
more standard base for the development of an internal and external QC program,
and expanded and improved PT programs. Perhaps most importantly, the changes
also include intralaboratory implementation of effective QC measures,
technician training and monitoring programs, and improvements in sample
identification and documentation.
The voluntary aspect of the Wyden bill (HR4773) prevents assurance to patients that all ART laboratories in the United States meet minimum standards of QC and QA (Consumer Reports, 1996; Pool, 1996). There are no penalties to clinics or laboratories for failure to report pregnancy rates to SART, other than to be listed as a nonparticipating ART program. CLIA 88 does carry penalties; however, enforcement has not been strict. Without strict enforcement of the regulations, it is not unusual for patients to attend ART programs not in compliance with the HR4773 or CLIA 88 (Consumer Reports, 1996; Pool, 1996; Wilcox, 1996). Lastly, another disadvantage of the HR4773 is that the information provided to the public reflects data that are 2 to 3 years old (Wiczyk, 1998).
A number of organizations have received federal authorization to implement the inspection, licensing, and accreditation of andrology and IVF laboratories, including the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), the CAP, the COLA, state regulatory agencies, and the American Association of Tissue Banks (AATB) (Lawrence and Rosenwaks, 1993; Chang, 1994; Pool, 1997).
JCAHO accreditation is accepted in 41 states and territories in lieu of state- or territory-managed inspection and accreditation programs and services a broad range of health care providers. The flexibility of their scoring guidelines provides the opportunity to meet required laboratory standards in the manner most appropriate to the individual laboratory setting; however, as the commission doesn't have its own PT program, laboratories must subscribe to a program independently (Chang, 1994).
The CAP is a not-for-profit organization that presently certifies approximately 4500 clinical laboratories (Visscher, 1991). Because the CAP has received a deemed status under CLIA 88, laboratories inspected and accredited through the CAP/AFS RLAP meet all the requirements of CLIA 88, OSHA, and other applicable federal regulations (Visscher, 1991; Chang, 1994). It is considered by some to be the best laboratory inspecting organization in the country (Visscher, 1991; Neff and Speicher, 1992; Pool, 1996).
The COLA is a nonprofit peer-review accrediting program for the POL and has been approved by the Health Care Financing Administration for CLIA certification purposes (Kroger, 1994). This commission is developing an inspection program that will be aimed at smaller volume andrology laboratories (Byrd, 1994). Accreditation for laboratories involved in cryopreservation and storage of gametes is possible through the AATB; however, as of October 2001, only 9 reproductive tissue banks were accredited (Critser, 1998; Centola, 2002). Lastly, laboratories may also be accredited by deemed state agencies, such as in New York, which have a deemed status.
In 1997, it was estimated that about 35% (116 out of an estimated 325 reproductive laboratories) were accredited through the CAP/ASRM RLAP program (Pool, 1997). Of 232 polled ART facilities in 1998, 26.3% of the respondents indicated the embryo laboratory was not currently accredited, licensed, or certified by an organization or agency (Smith, 2000). SART currently estimates that there are approximately 400 IVF laboratories in the United States (personal communication). It is more difficult to ascertain the number of independent, non-IVF-affiliated andrology laboratories, but it is likely that the number is significant, thereby increasing the number of ART laboratories to significantly greater than 400. The RLAP currently reports the participation of 220 laboratories in RLAP, with an estimate of approximately 50 in the JCAHO accreditation program (personal communication). It is doubtful that the COLA, state accreditation programs, and the AATB account for the majority of the remaining laboratories, therefore supporting the observation that numerous laboratories remain unaccredited.
The Practical Results of Current Regulations
The intent of CLIA 88 and OSHA legislation was to promote the accuracy and
reproducibility of results, high standards of lab performance, and a safe work
environment, and ultimately, to enhance the quality of patient care
nationwide. However, many in the medical profession have condemned CLIA 88 as
government regulation at its worst and an unnecessary expense that would
ultimately compromise the quality of patient care
(BeSaw, 1995;
Findlay, 1995). In 1994, the
Medical Laboratory Observer conducted a national survey in which two thirds of
the respondents indicated that CLIA 88 had failed to improve the quality of
patient care, and instead, had adversely affected the clinical laboratory
profession (Jahn, 1994;
Born and Thran, 1998). The
reasons for that conclusion are diverse, but they include increased costs,
ineffective additional paperwork, and frivolous and illogical requirements
that are perceived to be irrelevant to laboratory function.
Many leaders of organized medicine, including the leaders of the CAP and other societies, have opposed CLIA as an unwarranted intervention by the federal government into the traditional practice of medicine and the patient-physician relationship (Bachner, 1998). Those conclusions have been reinforced by surveys that have shown mixed results in the effectiveness of CLIA 88 on improving patient care and clinical performance (Neff and Speicher, 1992; Gerrity, 1993; BeSaw, 1995; Consumer Reports, 1996; Pool, 1996; Wilcox, 1996; Bachner, 1998; Hurst et al, 1998). It will be important and interesting to again survey laboratory directors once a reasonable period of time has passed after CLIA compliance by laboratories.
Although the regulations have undoubtedly influenced the operation of most ART laboratories, whether the regulations have significantly improved patient care is still debated (Gerrity, 1993; Lawrence and Rosenwaks, 1993; Pool, 1997). One recent study analyzed live birth rates of CAP/ASRM-accredited ART labs to the birth rates of non-CAP/ASRM accredited labs and found that accreditation was not associated with higher pregnancy rates (Smith, 2000). That study may indicate several possible problems with the accreditation process, including ineffectiveness of the parameters evaluated in the inspection process or ineffectiveness of the laboratory in applying the measures in a meaningful manner. As most RLAP inspectors have experienced, it is certainly possible to pass an accreditation inspection without serious, meaningful, or effective application of the principles covered in the inspection checklist. Also, many inspectors have observed that laboratories undergoing an initial inspection often demonstrate less actual focus on the use of the CLIA 88 regulations to facilitate real laboratory quality improvement than is observed in subsequent inspections. Therefore, improvements in the accreditation process can certainly be made, but it is imperative that participating laboratories also focus on actual quality improvement rather than accreditation itself.
Data from the CAP laboratory management index program on 73 labs enrolled in the program between 1994 and 1999 indicate a substantial and statistically significant increase in labor productivity, attributed to the increased throughput per hour employed (not to staff working longer hours) observed during the 6-year study period (Valenstein et al, 2001). In addition, data from a widespread compilation of information from over 17000 unique testing sites and more than 1.2 million PT event scores for 1994 demonstrated there was a consistent difference in PT performance depending on the type of facility performing the analysis. Traditional testing sites (hospital and independent lab) achieved higher rates of satisfactory performance than newly regulated, alternative testing sites. This increase in performance (with declining PT error rates) was attributed to laboratory improvement rather than CLIA regulations (Stull et al, 1998).
Because ART laboratories, both andrology and IVF, have historically been removed from traditional clinical laboratory management, PT or surveying mechanisms have not previously been in place to allow a comparison of laboratory accuracy before and after CLIA 88. One could certainly argue that because some PT is now available, evidence exists that the regulations have been beneficial. Although the potential benefits derived from the regulations may take longer to be realized in ART laboratories than in laboratories specializing in other areas, the process has certainly been stimulated by the regulations.
Confusion has surrounded the applicability of CLIA 88 to embryology laboratories. The application of complexity models of CLIA 88 would seemingly indicate that embryology procedures are high-complexity procedures. Additionally, any sperm analysis by the IVF laboratory would classify the laboratory as falling under the rules of CLIA 88. However, at this point, embryology laboratories are considered to be in a gray area and not subject to CLIA 88, as long as the laboratory is not involved in high-complexity sperm evaluation as part of the IVF procedure (Pool, 1996). This ruling has been the subject of legal actions.
In March 2000, a suit filed by the American Association of Bioanalysts (AAB) attempting to force the inclusion of IVF laboratories under CLIA 88 regulations was dismissed. The suit was dismissed on technical issues, not on the merits of the AAB suit. The ruling indicated that a final ruling on the issue from the Department of Health and Human Services was forthcoming; however, no final ruling has yet been issued. However, many IVF laboratories have undergone accreditation inspections. Some embryology laboratories have been inspected and accredited as a subspecialty laboratory under hospital or university medical center JCAHO inspection, and many have been inspected and accredited under the CAP/ASRM RLAP program (Gerrity, 1993; Consumer Reports, 1996; Pool, 1996).
Proposed Food and Drug Administration Regulations
In 1997, the Food and Drug Administration (FDA) issued a proposed rule for
new requirements of regulation of cellular and tissue-based products,
including the registration of facilities that process, procure, store, or
distribute human tissues. This proposal included reproductive tissue banks for
the first time (Centola,
2002). The 1997 rule was intended to be the first of 3 proposed
regulations. Subsequent proposals were issued in 1999 and 2001 for suitability
determination and good tissue practices. The FDA cites authority under the
Public Health Service Act (PHS Act, section 361), enabling the agency to make
and enforce regulations necessary to prevent the introduction, transmission,
or spread of communicable diseases between the states (Federal Register,
1999,
2001a;
Zoon, 2001). The FDA indicates
the rulings will only exert the type of government regulation necessary to
protect the public health (Federal
Register, 2001a). The FDA has concluded that since reproductive
biology laboratories work with human tissues and products in the form of
semen, oocytes, and embryos, all of which are capable of transmitting disease,
the regulations will apply to all reproductive facilities, with very few
exceptions. The FDA considers voluntary regulation in this field inadequate
(Federal Register, 2001a).
In January 2001, the FDA released a final rule on the registration and listing proposal. Essentially, all reproductive facilities, except for those that provide only immediate transfer into a sexually intimate partner and a private physician who only thaws donor samples for insemination (not processing), are required to register with the FDA (Federal Register, 2001b; Zoon, unpublished data). In addition, CLIA certification is required. The FDA estimates there are approximately 400 ART facilities and 110 sperm banks active in the United States and that each will need to register. Mandatory registration is necessary by April 2003, although voluntary registration is currently being accepted (Wells, unpublished data). The main impact on reproductive laboratories for registration and listing is estimated to be staff time (Federal Register, 2001b). It has been proposed that a central database, established as part of the registration process, may be useful in measuring artificial insemination outcomes and other large-scale questions (Critser, 1998).
The proposal for donor suitability, the second of the 3 phases of regulatory action, was issued in 1999 and encompasses donor screening and donor testing (Federal Register, 1999). The proposal, as it is now written, will increase the number of transmittable diseases that are required to be screened in a prospective donor. For the first time, donors of gametes and embryos are included in the regulations, and the quarantine of oocytes and embryos is proposed. The FDA has no data on current screening practices in ART laboratories but estimates that 100% of IVF facilities involved in egg donation and 80% of sperm banks will need additional screening and testing of donors to meet the new criteria. In a survey of ART facilities conducted by the CDC in 1998, all but one laboratory reported that they perform gamete or embryo cryopreservation, and 83% of the respondents reported that they perform embryo cryopreservation (CDC, 1999). Therefore, they conclude that their proposal for the cryopreservation and quarantine of donated oocytes and embryos would not be outside the capabilities of most IVF laboratories (Federal Register, 1999). This issue will surely be debated in the period remaining before implementation.
The FDA defines donor screening as a review of relevant medical records for information about the donor that might indicate past or present infections or genetic risk factors. Donor testing is subsequently defined as the actual performance of laboratory tests on a specimen collected from the donor to determine whether the donor has been exposed to or is infected with a disease agent. As part of donor screening, the FDA will require a documented dialogue with the potential donor, which will include a review of relevant medical records by qualified personnel and screening for transmissible spongiform encephalopathies, human immunodeficiency virus (HIV), hepatitis B and hepatitis C, xenotransplantation (including intimate contact with a xenotransplant recipient), other sexually transmitted diseases, and genitourinary diseases (Federal Register, 1999). All testing will need to be performed with FDA-approved and -licensed tests, the exceptions being chlamydia and gonorrhea (there is not currently an approved FDA test). Testing includes HIV (types 1 and 2), hepatitis B core antibody, hepatitis C antibody, syphilis (in the form of Treponema pallidum), human T-lymphotropic virus I/II, and cytomegalovirus (Federal Register, 1999).
Additional requirements include stringent documentation and record handling. The retention of records is set for a minimum of 10 years. All products must clearly be identified as "in quarantine" for the duration of storage in the quarantine period. Documentation must be shipped with all samples and must include a determination of the suitability of the donor, as well as relevant medical records. The name and address of the gamete bank must be clearly visible. If any product is shipped without complete screening and testing, labeling must clearly indicate the sample has not been evaluated for infectious substances (Federal Register, 1999). Other labels would be required for tissues banked for autologous transplantation to help minimize the risk of inadvertent allogeneic administration (Federal Register, 1999).
The proposal for implementation of good tissue practices, the third phase of FDA regulation, was released in early 2001. This ruling will be the final phase of the comprehensive plan for regulation of human cells and tissues. There are no exceptions to this rule. The establishment of a "quality program" and subsequent audits are addressed in this proposal (Federal Register, 2001a). Functions of the quality program include requirements that procedures be established and maintained, that the analysis be appropriate and relevant to the product, that appropriate corrective actions be taken and documented, that the personnel be properly trained and educated, that appropriate monitoring systems be established and maintained, and that a system for record maintenance be established. There would need to be documentation of evaluations, investigations, and product deviations. Also, audits would need to be conducted, as well as any other actions necessary to ensure compliance with the program (Federal Register, 2001a).
Conclusions
While the debate over the effectiveness of government regulations in
improving patient care will surely continue, the reality of the current
situation is that the degree of regulation will continue to increase. During
this period, it is important to remember that the benefits of the regulatory
process are not only measured in immediate changes in pregnancy rates or assay
reliability, but also in changes in personnel attitudes, development of
industry-wide programs to assist in laboratory improvement, and establishment
of intralaboratory quality improvement programs that may require extended time
frames to yield the desired results.
Ultimately, the attitude of individual ART laboratories will affect their ability to use the regulations as a means of improving patient services. While ART laboratories may have had a delayed initiation to the regulatory process, many ART laboratories have effectively improved their laboratories by implementation of the principles underlying the accreditation inspection checklists. The current lack of compliance by some laboratories is not only unfair to patients and compliant laboratories, it also threatens the benefit of improved public perception that the ART industry hopes to achieve as a result of the oversight and improved QC emphasis provided by the current regulations. Since governmental oversight will likely never effectively enforce the current regulations, creative measures of improved self-regulation may be needed.
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