Implementation of the Fertility Clinic Success Rate and Certification Act of 1992A Model Program for the Certification of Embryo Laboratories

SUMMARY: The Fertility Clinic Success Rate and Certification Act of

1992 (Pub. L. 102-493, 42 U.S.C. 263a-1 et seq.) requires that the

Secretary, HHS, through the CDC, develop a model program for the

certification of embryo laboratories, to be carried out voluntarily by

interested States.

This notice sets forth the model certification program

requirements, including definitions, administrative requirements, and

embryo laboratory standards. The model program incorporates comments

received by CDC on the proposed model certification program that was

published in the Federal Register on November 6, 1998 (63 FR 60178).

FOR FURTHER INFORMATION CONTACT: Robert Martin, Dr.P.H., Division of

Laboratory Systems, CDC, telephone (770) 488-8295

SUPPLEMENTARY INFORMATION:

Introduction

The Fertility Clinic Success Rate and Certification Act of 1992

(FCSRCA), Public Law 102-493 (42 U.S.C. 263a-1 et seq.), was intended

to provide the public with comparable information concerning the

effectiveness of infertility services and to assure the quality of such

services by providing for the certification of embryo laboratories.

Section 2 of the statute requires that the Secretary, HHS, through

the CDC, define pregnancy success rates, and seek public comment on the

proposed definitions. In addition, Section 2 requires each assisted

reproductive technology (ART) program to annually report its pregnancy

success rates to the CDC, along with the identity of each embryo

laboratory used by the program, and whether the laboratory is certified

under Section 3 or has applied for such certification. Section 2 was

addressed in a Federal Register notice published on August 26, 1997 (62

FR 45259).

Section 3(a) of the FCSRCA requires that the CDC ``develop a model

program for the certification of embryo laboratories * * * to be

carried out by the States.'' In developing the model certification

program, CDC is to consult with ``appropriate consumer and professional

organizations with expertise in using, providing, and evaluating

professional services and embryo laboratories associated with assisted

reproductive technology programs.''

Section 3(b) lists State officials who are to receive a description

of the model certification program, and requires that the Secretary

encourage States to adopt such a program.

Section 3(c) includes the requirements for administration of the

certification program by the States, with provisions for the inspection

and certification of embryo laboratories by States or approved

accreditation organizations, and the requirement for application to the

State by an embryo laboratory that seeks certification.

Section 3(d) specifies the embryo laboratory standards that are to

be in the model certification program. These include a standard to

assure consistent performance of laboratory procedures; a standard for

a quality assurance and quality control program; standards for the

maintenance of all laboratory records (including laboratory tests and

procedures performed, as well as personnel and equipment records); and

a standard for personnel qualifications.

Section 3(e) includes provisions for a State to adopt the model

certification program if it applies to the Secretary, and is approved,

and Section 3(f) allows for the use of accreditation organizations,

approved under the requirements described in Section 4, to inspect and

certify embryo laboratories in States that have adopted the program.

Section 3(g) requires that States which qualify to adopt the model

certification program conduct embryo laboratory inspections to

determine if the laboratories meet the requirements of the program.

Inspections are to be unannounced or be announced in circumstances in

which the likelihood of discovering deficiencies in the operations of

an embryo laboratory is not diminished. Section 3(g) also requires the

Secretary to seek public comment on the circumstances under which

announced inspections may be conducted. In addition, inspection results

(including deficiencies and any subsequent corrections to those

deficiencies) are to be reported and made available to the public.

Section 3(h) provides for the Secretary to conduct validation

inspections of embryo laboratories certified by a State or an approved

accreditation organization to determine if the laboratories are being

operated in accordance with the standards in the model certification

program. If a validation survey demonstrates that an embryo laboratory

is not in compliance with such standards, the statute specifies

requirements for notification of the State, or as applicable, the

accreditation organization. A subsequent investigation and inspection

of additional certified embryo laboratories are to be conducted to

determine if the State or accreditation organization is reliably

identifying laboratory deficiencies. The Secretary may revoke the

approval of the State certification program or accreditation

organization if requirements applicable to the program are not being

met.

Section 3(i) limits the Secretary in developing the model

certification program, and the States in adopting such program, from

establishing any regulation, standard, or requirement that has the

effect of exercising supervision or control over the practice of

medicine in ART programs.

Section 3(j) states that the Secretary may define the term of the

certification issued by a State or an accreditation organization in a

State, through the public comment process, and provides for application

for recertification to be submitted when there is a change in ownership

or administration of a certified embryo laboratory.

Section 4 calls for the Secretary, through the CDC, to promulgate

criteria and procedures for the approval and use of accreditation

organizations to inspect and certify embryo laboratories in States

which have adopted the model certification program, as well as in

States which have not adopted the program. The section also includes

provisions for annual evaluation of approved accreditation

organizations by the Secretary, through the inspection of a

representative sample of accredited embryo laboratories and other such

appropriate means.

Section 5 specifies the conditions under which a certification

issued by a State or an accreditation organization shall be revoked or

suspended, and the effect that such revocation or suspension would

impose on the certification and application for recertification of the

laboratory.

Section 6 mandates that the Secretary, through the CDC, annually

publish pregnancy success rates as reported by ART programs (Section

2); the names of ART programs that fail to report pregnancy success

rates; the identity and certification status of each embryo laboratory

located in a State which has adopted the model certification program;

the identity of each embryo laboratory in a State which has not

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adopted the certification program and which has been certified by an

approved accreditation organization; and in the case of an embryo

laboratory which is not certified, whether the laboratory has applied

for certification. The annual publication is to be distributed to

States and the public. This section was also addressed in the

previously mentioned Federal Register notice published on August 26,

1997 (62 FR 45259). The first report, 1995 Assisted Reproductive

Technology Success Rates: National Summary and Fertility Clinic

Reports, was published in December 1997. The second report, 1996

Assisted Reproductive Technology Success Rates: National Summary and

Fertility Clinic Reports, was published in February 1999. Copies of

these reports may be obtained by contacting CDC by calling 1-770-488-

5372 or via the Internet at www.cdc.gov/nccdphp/drh/art96/.

Section 7 authorizes the Secretary to charge sufficient fees to

cover the cost of administering the FCSRCA and authorizes States

adopting the certification program to charge sufficient fees to cover

the cost of administering their program.

Section 8 includes a definition of assisted reproductive technology

and provides for seeking public comment on any proposed expansion of

the definition.

Background

In accordance with the FCSRCA, in developing the model

certification program, the CDC consulted with individuals, professional

organizations and consumer groups with expertise and interest in ART.

The organizations represented reproductive medicine--the American

Society for Reproductive Medicine (ASRM) and the Society for Assisted

Reproductive Technology, laboratory professionals--the College of

American Pathologists (CAP) and the American Association of

Bioanalysts, and a consumer group that serves to educate the public on

infertility diagnosis and treatment--RESOLVE. The CDC also sought input

from State programs and Federal agencies with regulatory

responsibilities related to laboratory practice, tissue banking and

ART.

A useful example in developing the model certification program was

the voluntary Reproductive Laboratory Accreditation Program (RLAP)

developed jointly by the CAP and the ASRM, and administered by the CAP.

The CAP/ASRM RLAP currently provides oversight of at least one third of

embryo laboratories affiliated with ART programs and clinics in the

United States and served as the basis for many of the standards in the

proposed model program. Standards and guidelines from other

professional organizations, State, Federal, and international programs

were also used as resources, and the CDC made a number of site visits

to embryo laboratories to observe the daily operation of these

facilities. In addition, between November 1996 and August 1997, the CDC

held several work sessions with technical consultants to obtain

individual expert input on specific issues related to the embryo

laboratory and the model certification program, including personnel

qualifications and responsibilities, quality assurance and quality

control (quality management), recordkeeping, specific definitions as

they would apply to the model certification program, and State

administration of the program.

Subsequently, on November 6, 1998, the CDC published in the Federal

Register (63 FR 60178) a notice soliciting public comment on a proposed

model program for the certification of embryo laboratories. As

mentioned above, the FCSRCA required the Secretary to facilitate public

comment on specific aspects of the model certification program and the

definitions as they relate to the model. To ensure appropriate

consideration during the public comment period, the CDC highlighted the

following issues in the preamble to the proposed model program:

Based on the comments received during the previously

mentioned work sessions with technical consultants (63 FR 60170),

the proposed model's definitions for ``assisted reproductive

technology'' and ``embryo laboratory'', have been elaborated from

the definitions specified in the FCSRCA. The issue is whether the

revised definitions are appropriate and accurate for use in the

model certification program.

The proposed model permits announced initial and

routine inspections and unannounced inspections for complaint

investigations. The issues are under what circumstances should

announced inspections be permitted so as not to diminish the

likelihood of discovering deficiencies in the operation of an embryo

laboratory, and whether there are circumstances that should require

unannounced inspections.

The proposed model specifies a 2-year term for embryo

laboratory certification. The issue is whether this is an

appropriate period of time for the term of certification of a

laboratory (i.e., renew biennially).

In addition, we were interested in receiving comments on the

following issue which was not specifically addressed in the proposed

model certification program but could have been considered for

inclusion in the finalized model:

Proficiency testing (PT) currently available for the

embryo laboratory is limited to determining whether culture media

samples provided by the PT program are suitable for in vitro mouse

embryo culture. While the performance of PT is not required in the

proposed model, the model's standards do require a laboratory to

perform quality control procedures to monitor the reliability of the

ART procedures performed (including culture media checks). Equipment

and instrument maintenance and function checks are also required to

ensure their adequate performance. In addition, the laboratory must

track and evaluate procedural outcomes such as fertilization rates,

cleavage rates and embryo quality as a means of monitoring the

quality of the procedures and services provided by the laboratory.

The issue is whether these standards provide a sufficient means for

monitoring laboratory performance or if a standard requiring PT

should be included in the model.

During the 60-day comment period the public had the opportunity to

submit concerns and recommendations in response to the issues

highlighted above, as well as any other aspect of the proposed model

program. The letters we received provided helpful information for

finalizing the model certification program. A summary of the comments

and our responses to them are included below.

Other information that was useful in finalizing this model

certification program for embryo laboratories was data provided in a

Survey of Assisted Reproductive Technology Embryo Laboratory Procedures

and Practices, conducted under a CDC Task Order Contract with Research

Triangle Institute and performed by Analytical Sciences, Inc. The

purpose of this survey was to provide the CDC with an enumeration of

those ART embryo laboratory procedures and practices that are currently

in use. The final report of the survey was completed on January 29,

1999, and can be accessed via the Internet at www.phppo.cdc.gov/dls/

pdf/art/ARTsurvey.pdf. A copy of the report may also be obtained by

calling the CDC at (770) 488-8295.

Responses to Comments

In response to our request for comments to the proposed model

certification program, we received a total of 15 letters, four of which

were from professional organizations, one from a consumer advocacy

group, one from a manufacturer, and the rest from individuals employed

in embryo laboratories or affiliated with infertility clinics/programs.

The letters contained approximately 60 comments, 14 of which were in

response to the issues highlighted for consideration in the proposed

model program. Six of the commenters, which included two

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professional organizations, expressed support for and/or complimented

our efforts to develop a model certification program. There was no

opposition to the model in its entirety, but rather the respondents

provided comments on specific aspects of the proposed model. Comments

to the highlighted issues and additional comments are addressed below.

1. Are the revised definitions for ``assisted reproductive

technology'' and ``embryo laboratory'' appropriate and accurate for use

in the model certification program?

One commenter believed that the definition for ``assisted

reproductive technology'' was overly broad and could be interpreted as

including intra uterine insemination (IUI) and intra vaginal culture

(IVC), procedures which do not require the same level of quality

control, quality assurance, etc., as do other ART procedures. The

commenter suggested that the model be revised to contain new categories

for IUI and IVC with requirements consistent with the complexity level

of the procedures. Another commenter stated that while the term

``embryo laboratory'' is technically correct, these laboratories would

be more appropriately named ``embryology laboratories'' to reflect the

science of the work performed in them.

Response: The proposed definition for assisted reproductive

technology (ART) was based on the definition of ART provided in the

FCSRCA, which was modified for clarity based on the comments received

during our work sessions with technical consultants. We do not agree

with the comment that the ART definition is overly broad for use in the

model certification program. The definition appropriately and

accurately specifies ART as ``all clinical and laboratory treatments

which involve the handling of human oocyte and sperm, or embryos, with

the intent of establishing a pregnancy.'' The commenter's

interpretation is incorrect; IUI is not covered by this definition of

ART, as IUI is a procedure that involves the manipulation of sperm only

rather than oocytes and sperm. However, IVC is covered by the ART

definition, since it is a procedure in which oocytes and sperm are

mixed and incubated together. In addition, we disagree with this

commenter's viewpoint that IVC does not require the same level of

quality control or quality assurance as other ART laboratory

procedures. In performing IVC, oocytes and embryos must be accurately

identified just as they are for other ART laboratory procedures,

requiring qualified personnel with appropriate training and expertise,

written procedures and policies outlining criteria for the

identification of oocytes and embryos, etc., to ensure quality patient

care.

In response to the comment suggesting that the term ``embryology

laboratory'' be used in place of ``embryo laboratory'', we are

retaining ``embryo laboratory'' because it is the term used throughout

the statute (FCSRCA). Although embryology refers to the science of

studying the origin and development of an individual organism, in using

the term embryo, we are specifically referring to the intended goal of

the procedures performed in these laboratories--the manipulation of

human gametes to produce viable human embryos.

2. Under what circumstances should announced inspections be

permitted so as not to diminish the likelihood of discovering

deficiencies in the operation of an embryo laboratory, and are there

circumstances that should require unannounced inspections?

Five commenters, two of which were professional organizations,

expressed concern with the proposed model's option to permit

unannounced inspections for complaint investigations. The commenters

cited the potential for disrupting embryo laboratory procedures and

interfering with patient treatment. Maintaining patient confidentiality

during an inspection was also of concern. Three commenters suggested

providing the laboratory 48 hours notice to allow rescheduling of

patient procedures or other alternative measures to reduce the risk to

eggs, sperm and embryos. The consumer advocacy group supported

unannounced inspections if precautions are taken to prevent

interference with patient treatment and safeguard patient

confidentiality.

Response: We understand the commenters' concerns, and agree that

the nature of the work performed in embryo laboratories is delicate and

time sensitive, and that disruptions or delays in the process could

have deleterious effects. We also agree that maintaining patient

confidentiality during a laboratory inspection is of utmost importance.

When performing inspections, it is not the intent to disrupt the

laboratory's operations or divulge confidential patient information. In

general, Federal, State and professional accreditation organization

laboratory inspectors are health professionals with pertinent

education, qualifications, and experience. They receive special

training and are instructed to make every effort to avoid interrupting

the routine workflow when conducting an inspection. They are also aware

of the importance of safeguarding confidential patient information.

The proposed model program did not mandate that unannounced

inspections must be performed for complaint investigations, but it did

provide the State that chooses to adopt the model the option to do so.

We included this option so that investigations of complaints of truly

egregious behavior could be conducted immediately and unannounced. In

addition, this option would allow the State to incorporate embryo

laboratory inspections into an already existing laboratory or health

care facility regulatory program that may require unannounced complaint

inspections. Based on the comments we received, and because of the

unique nature of the procedures performed in embryo laboratories, we

agree that in some cases there may be a need to allow 48 hours notice

prior to conducting a complaint inspection. This could be done to give

the laboratory time to reschedule ART procedures, if necessary, and to

ensure that adequate staffing and the appropriate individuals are

available on the day of inspection. In addition, we do not believe that

a 48 hour notice would significantly diminish the likelihood of

discovering systemic deficiencies in a laboratory's operation.

Therefore, if a State determines that it is appropriate to provide some

advance notice of a complaint inspection, the model certification

program as written allows the State to provide the laboratory a 48 hour

notice.

3. Is two years an appropriate period of time for the term of

certification of a laboratory (i.e., renew biennially)?

Two individuals provided comments on the time period for the term

of certification. One of the commenters viewed a two year term as

reasonable. The other commenter suggested that three to five years

would be more appropriate as long as there was no significant change in

the laboratory's personnel, no change in the laboratory's location, or

no complaints registered against the laboratory.

Response: A two year term of laboratory certification is consistent

with other similar laboratory licensure or accreditation programs

currently in existence. Maintaining this consistency among programs may

allow for easier coordination of inspections if a laboratory

participates in more than one program offered by the same organization

or agency. For example, a facility that has both a clinical laboratory

and a reproductive laboratory accredited by the CAP may be able to have

a joint inspection for both of the programs. For this reason, we agree

with

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the commenter who stated that a two year term is reasonable, and have

not revised this requirement in the model certification program.

4. Do the proposed embryo laboratory standards provide a sufficient

means for monitoring laboratory performance or should a standard

requiring PT be included in the model?

Each of the four professional organizations commenting on the

proposed model addressed the issue of PT. Three of the organizations

did not support the inclusion of a PT requirement in the model

certification program. They did not believe appropriate PT was

available or could be developed and standardized due to the specimens

(human gametes and embryos) used in the embryo laboratory. They stated

this is especially true if the purpose of PT is to measure a

laboratory's performance by replicating ART laboratory procedures. One

organization strongly believed PT must be applied to embryo

laboratories as it is applied to laboratories performing clinical

laboratory testing; not doing so would undermine any potential

effectiveness of the model program.

Response: We agree that, at this time, the inclusion of PT in the

model certification program for embryo laboratories is not appropriate.

Proficiency testing monitors laboratory performance by comparing the

laboratory's evaluation or measurement of external samples that mimic

patient samples to known test results, or results obtained by

standardized methods. Proficiency testing results should be comparable

to results that would be obtained when testing similar patient samples.

Definitive PT programs are available for andrology procedures (sperm

counts and microscopic semen evaluations), however, the one program

currently available for embryo laboratories evaluates whether a

laboratory's bioassay system can detect toxicity in culture media

samples sent to the laboratory by the program. It does not test a

laboratory's ability to examine oocytes and embryos, or successfully

perform other embryo laboratory procedures. Standardized methods for

monitoring these laboratory procedures have not yet been developed, in

part due to the fact that the ultimate measure of the performance of

most embryo laboratory procedures is a viable human embryo.

Proficiency testing is only one measure of a laboratory's quality.

Other measures such as quality control, personnel standards, and

monitoring laboratory practices must also be considered in determining

the overall quality of laboratory performance. As mentioned in the

preamble to the proposed model, these measures are all included in the

model certification program. Since appropriate, standardized PT is not

available at this time for embryo laboratory procedures, we have not

included it in the model certification program. At such time as

definitive PT becomes available for embryo laboratory procedures,

States that adopt the model certification program or develop an

equivalent program should consider including it in their program as an

additional indicator of laboratory performance.

5. Additional comments.

Comment: One commenter requested clarification of what regulations

take priority, or must be met, when there is a conflict/difference

between Federal and State laboratory requirements.

Response: A laboratory must meet all applicable Federal, State and

local requirements, and when differences exist among regulations, the

laboratory must meet the most stringent requirement. By doing this, the

laboratory should meet corresponding regulations that are less

stringent.

Comment: One professional organization strongly urged the CDC to

approve accreditation organizations for embryo laboratory certification

purposes. The organization believes that CDC approval of the CAP/ASRM

Reproductive Laboratory Accreditation Program (RLAP) and others that

could be developed would be the best means to protect the public health

without creating overly burdensome and redundant regulation. An

additional commenter endorsed the existing CAP/ASRM RLAP as the means

to assure constructive assessment of embryologic methods and

improvement in the quality of ART programs.

Response: The CDC recognizes there are existing voluntary

accreditation programs currently available that provide oversight of

ART embryo laboratories and have had a positive impact on laboratory

quality without Federal oversight. These programs were reviewed and

served as examples in developing the model certification program for

embryo laboratories, and could provide an excellent resource for States

that wish to develop their own certification program. One such program

is the CAP/ASRM RLAP, mentioned above.

While we agree that Federal approval of an accreditation

organization(s) could be beneficial to laboratories in States which do

not adopt the model or have an equivalent certification program, as

explained below, this would go beyond the proposed model's

implementation plan which permits States to approve accreditation

organizations to certify laboratories within their respective State. As

stated earlier in the preamble, the FCSRCA authorizes the Secretary and

States to charge fees to cover the costs of the model certification

program. Since this is a voluntary program, and laboratories have not

indicated they would opt into such a self-supporting program, at this

time, the CDC is deferring the implementation of the approval and

subsequent monitoring of accreditation organizations to States that

choose to adopt the model certification program and wish to use an

accreditation organization for State certification purposes.

Although we have not officially approved any accreditation programs

or determined their equivalency to the model certification program, as

data become available, the CDC will publish the certification/

accreditation status of embryo laboratories affiliated with ART

programs or clinics in conjunction with future annual publications of

the ART Success Rates reports.

Comment: One commenter asserted that any fees charged for

certification must not be unduly excessive or burdensome to the

laboratory. The commenter suggested the cost of certification be

adjusted with respect to the laboratory's level of activity, i.e.,

higher volume laboratories should be charged more than smaller volume

laboratories. A professional organization commented that the Federal

government should share the costs of the certification and

accreditation programs.

Response: It will be up to each State that adopts the model program

to develop fee schedules and the methodology for determining fees

charged to the laboratory for certification. Many existing licensing/

certification programs do establish fees based on volume of testing or

number of procedures performed. The requirement that addresses fees at

Part II., B., 8. of the model certification program was included to

reiterate the FCSRCA's provision (Pub. L. 102-493, sec. 7) that allows

charging such fees necessary to recoup the cost of administering a

certification program.

To date, the Federal government has assumed the cost of

implementing the FCSRCA, in development of the laboratory standards and

administrative process for the model certification program for embryo

laboratories and publication of both the proposed and finalized model

programs. In addition, the CDC will distribute this model program to

State officials and health authorities as outlined in the statute and

will provide the certification/accreditation status of embryo

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laboratories affiliated with infertility clinics and ART programs in

its annual publication of ART Success Rates.

Comment: Two commenters expressed concern over the model's

administrative requirement for the State, or as applicable,

accreditation organization to make available to the public, upon

request, the laboratory's specific inspection findings, including

deficiencies identified and any subsequent corrections to those

deficiencies. One of the commenters believed this would discourage a

laboratory's participation in the voluntary certification program and

that the public would be unable to interpret the published inspection

findings.

Response: The requirement to make a laboratory's inspection

findings available to the public upon request was mandated by the

FCSRCA. This requirement is part of the overall effort in the

legislation to provide the public with consistently reliable and

comparable information about the effectiveness of infertility services

provided by ART clinics. It is one piece of the information that may be

used by consumers in choosing a clinic for ART services. We disagree

that this requirement would discourage laboratories that are

maintaining good laboratory practices from participation in the

voluntary model certification program. In fact, successful

participation in a voluntary program such as the model certification

program could be viewed as an asset for a laboratory or ART program

seeking new clients. We also disagree with the commenter that the

public would not be able to interpret inspection findings. The model

certification program requires States and accreditation organizations

to include the necessary explanatory information for the public to

interpret the findings.

Comment: Two professional organizations were concerned the model

did not sufficiently address due process procedures for laboratories

found to be out of compliance with the certification program's

standards.

Response: Due process procedures for laboratories that are not in

compliance with certification program requirements are not described in

the model program because such a process would be developed and

performed at the State level and may vary from State to State. The

reference to State development of due process procedures is found at

Part II., B., 7., a. of the model certification program.

Comment: One commenter disagreed with the model's proposed

guideline at Part III., A., that the laboratory employ one individual

for every 90-150 ART cycles performed by the laboratory annually. The

commenter suggested one individual for every 100 ART cycles is more

appropriate.

Response: We disagree. We included the recommended range as a

guideline for adequate staffing of a laboratory, recognizing that some

embryo laboratories do not provide as extensive service as others and

may not need as many employees. In addition, a laboratory's workload

may vary over time, and it may not be possible to keep the staffing

level at an exact number. By giving an appropriate range as a guideline

for staffing, we are providing some guidance for laboratories while

maintaining flexibility for the reasons stated above.

Comment: A few commenters promoted requiring board certification

for laboratory directors with a doctoral degree, with one of the

commenters stating, ``Board examinations are the only comprehensive

measure available of a candidate's command of a unified fund of

laboratory specific knowledge and are crucial in establishing a minimum

competence level for laboratory directorship in our field.'' One of the

commenters misinterpreted the requirements of the model, thinking it

would allow an individual with a doctoral degree in English (or other

non-science major) to qualify as a laboratory director.

Response: We agree it is beneficial for the director of the embryo

laboratory to be board certified, especially if that certification is

specific to reproductive laboratory science. However, we do not believe

it is the only way to ensure that a laboratory director is qualified

for this position. Therefore, while not making board certification a

requirement, we are adding language at Part III., A., 1., b.,

recommending board certification in embryology for doctoral scientist

laboratory directors.

In response to the commenter who misread the model certification

program requirements for a doctoral degree, Part I., Definitions,

specifies the earned doctoral degree must be in a chemical, physical,

biological or medical laboratory science. This would preclude an

individual with a doctoral degree in English or other nonscience from

fulfilling the qualification requirements for an embryo laboratory

director.

Comment: Several commenters, which included three professional

organizations provided their opinions on the use of documented hours of

training and numbers of ART cycles in an embryo laboratory as an

appropriate qualification requirement for laboratory personnel, in

particular the laboratory director. Reasons given by commenters for not

requiring a specific number of hours and/or cycles of training/

experience included the following:

Training should bear a logical relationship to the complexity of

procedures performed. Some ART laboratory procedures may require fewer

or greater number of repetitions to ensure competency, i.e.,

intracytoplasmic sperm injection (ICSI) requires more manipulation and

skill than in vitro fertilization (IVF) and should have a higher hour/

cycle requirement assigned;

The laboratory director should determine the adequacy of each

employee's training/experience and not be locked into requiring an

exact number of hours and/or cycles;

Consideration must be given to the laboratory director, who may not

always perform bench work;

The number of hours/cycles may be impossible to document if a

current laboratory director was trained several years in the past; and

Requiring the laboratory director to have 60 cycles of experience

in ART procedures including IUI, IVC, conventional IVF, gamete

intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT),

ICSI, and assisted hatching, etc., if these procedures are not offered

by a facility is unreasonable.

On the other hand, one professional organization stated that, for

laboratory directors, the number of ART laboratory cycles performed is

a better measure of training and experience than a specific number of

hours of training. This organization suggested 60 ART cycles and six

months full time in an IVF laboratory is sufficient training for

reproductive endocrinologists. Another professional organization agreed

if the laboratory director was performing bench work, a requisite

number of hours and cycles correlating with the skill level for a

specific procedure should be met. Both organizations stated the model

program should be flexible and accommodate future changes in embryo

laboratory procedures.

Response: Professional guidelines such as the ASRM's revised

minimum standards for IVF, GIFT, and related procedures (see

References) were a valuable resource in developing the model

certification program. The ASRM guidelines recommend the embryo

laboratory director or supervisor should have had at least six months

training and completed at least 60 ART procedures in a program that

performs at least 100 IVF procedures per year with a minimum annual 10%

IVF live birth rate per retrieval cycle. The ASRM defines an ART

procedure as ``a combination of the examination of

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follicular aspirates, insemination, documentation of fertilization and

preparation for embryo transfer.'' These guidelines also recommend that

embryo laboratory technologists have evidence of completion of 30

complete IVF procedures under continuous supervision of the laboratory

director or supervisor.

The ASRM recommendations for personnel training are similar to

those proposed in the model certification program. The model's proposed

training requirement for the laboratory director and supervisor of one

thousand hours of laboratory training is approximately equal to the

ASRM's requirement of six months of full-time (40 hour week) training.

The ASRM's recommendation for completion of 60 ART laboratory

procedures is synonymous with the model's requirement for ``performing,

at a minimum, each laboratory component of the human ART cycle 60

times''. For the reproductive biologist, the model program proposed to

require training that included performing the ART laboratory

procedure(s) to be performed in the laboratory, at a minimum, 30 times

under direct and constant supervision.

We do not agree with the commenters who recommended we not require

a specific number of hours of documented training, and/or performance

of a certain number ART laboratory procedures for laboratory director,

laboratory supervisor, or reproductive biologist. Although we recognize

it can be difficult to impose a blanket training requirement for the

skill level needed for a diverse group of laboratory procedures, we

believe the requirements in the model certification program are

consistent with the ASRM guidelines and appropriate (with minor

revisions) as minimum training requirements for the majority of ART

laboratory procedures and job duties to be performed by each respective

personnel category. We agree with the commenters who suggested some ART

laboratory procedures require more extensive technical skill and

manipulation (e.g., ICSI) and may need additional repetitions prior to

assuring competence of an individual. As stated in the model, it is the

responsibility of the laboratory director to ensure all personnel

receive appropriate training, and can demonstrate reliable performance

of procedures prior to working on patient specimens (Part III., A., 2.,

k.). If the director determines it is necessary to increase the number

of repetitions for some ART laboratory procedures, he or she should

require such for adequate personnel training.

For clarification of the requirements in the model certification

program and for consistency with the ASRM guidelines, we have replaced

the laboratory director requirement at Part III., A., 1., b., ii., and

c., ii., for at least ``1000 hours'' of documented training with ``six

months.'' In this same section, and at Part III., A., 3., b., ii., and

c., ii., we have substituted ``each ART laboratory procedure 60 times''

for ``each laboratory component of the human assisted reproductive

technology cycle 60 times.'' Although we have deleted the word

``human'' from this requirement, the model's definition for ART

laboratory procedures specifies these are ``all laboratory procedures

for the handling and processing of human oocytes and sperm, or embryos,

with the intent of establishing a pregnancy.''

In response to the comments regarding the role of the laboratory

director, as outlined in the model program, the laboratory director is

responsible for the overall operation, administration, and technical

and scientific oversight of the embryo laboratory. Although in some

laboratories this may not include day-to-day performance of ART

laboratory procedures, it does require the director to have knowledge

and technical skills pertaining to the ART laboratory procedures

selected/developed and performed in the facility. He or she must also

ensure all personnel receive appropriate training for the ART

laboratory procedures to be performed, and the laboratory supervisor is

technically qualified for that position. Based on these

responsibilities, we believe it is necessary for the laboratory

director to have at least six months training in an embryo laboratory,

and have performed each ART laboratory procedure at least 60 times as

part of the training process.

Since the laboratory supervisor is responsible for day-to-day

supervision and oversight of the embryo laboratory and may perform the

laboratory director responsibilities if authorized in writing by the

director, the model program also requires the supervisor to have

training which includes performing each ART laboratory procedure at

least 60 times. We note that in finalizing the model program, we have

clarified at Part III., A., 2., that the laboratory director may

delegate performance of his or her responsibilities to an individual

qualified as a laboratory supervisor or laboratory director.

In response to the commenter who was concerned about documentation

of an individual's training if that person had been working for a

number of years, the part of the training that may be difficult to

document would be the number of ART laboratory procedures performed by

that individual. In such cases, laboratory worksheets or logbooks, or

other forms of laboratory documentation showing completion of ART

laboratory procedures by a specific individual may be used as the

documentation that adequate training has been completed.

The commenter who interpreted the qualification requirements for

laboratory director as being 60 cycles of IUI, IVC, * * * etc.,

misinterpreted the model program. As explained above, the model

requires the laboratory director to perform at least 60 ART laboratory

procedures as part of his or her training. Performing medical

procedures that may be part of an ART cycle, such as IUI, GIFT, and

ZIFT is not required. ART laboratory procedures do include, but are not

limited to, ``the examination of follicular aspirates, oocyte

classification, sperm preparation, oocyte insemination, assessment of

fertilization, assessment of embryo development, preparation of embryos

for embryo transfer, and cryopreservation of specimens.'' We believe it

is appropriate for both the laboratory director and laboratory

supervisor to be trained in the performance of all of these procedures

to adequately carry out their duties and provide oversight of

reproductive biologists who are performing any of these procedures.

Although procedures such as ICSI, assisted hatching or other

micromanipulative techniques are laboratory procedures, they are

specific techniques for oocyte insemination and assessment of embryo

development. We would not expect the laboratory director and supervisor

to be trained in these specialized techniques, unless they perform them

in their laboratory.

Comment: One individual stated there should be a requirement for

the laboratory director and supervisor to each perform at least 25 ART

cycles per year.

Response: We agree with the commenter that, to maintain their

skills and expertise, embryo laboratory personnel performing ART

laboratory procedures should perform a minimum number of these

procedures on an annual basis. The ASRM guidelines, described in the

previous response, recommend each staff embryologist (including the

laboratory director or supervisor) perform at least 20 ART procedures a

year, in contrast to the 25 ART cycles suggested by the commenter. We

believe performance of a minimum of 20 ART laboratory procedures per

year is a reasonable number to recommend if an individual

[[Page 39380]]

performs ART laboratory procedures as part of his or her

responsibilities. Since it is consistent with what is recommended by

the ASRM professional guidelines, we are recommending at Parts III.,

1., d., ii. and 3., d., ii., for the laboratory director and laboratory

supervisor, that if the individual serving in either position performs

ART laboratory procedures in the laboratory, he or she should perform

each of these laboratory procedures at least 20 times annually. We have

also added a recommendation at Part III., 5., d., ii. that each

reproductive biologist perform each of the ART laboratory procedures he

or she performs in the laboratory at least 20 times annually.

Comment: One commenter was concerned the proposed model's personnel

qualification requirements fail to address formal and specific

education in reproductive medicine and promotes on-the-job training as

the only option to fulfill the educational requirement because the

model program would ``grandfather'' currently employed individuals who

do not have an appropriate college degree. The commenter asked that we

consider adding provisions that would allow formal education in

reproductive laboratory science as an option to on-the-job training. A

professional organization also suggested the proposed ``grandfather''

clauses at Part III., A., 3, c., and 5., c., include a minimum

educational standard, specifically a bachelor's degree for the

laboratory supervisor and an associate's degree for the reproductive

biologist.

Response: We agree with the commenter that it is appropriate to

include reproductive laboratory science in the list of acceptable

academic degrees for all categories of embryo laboratory personnel.

However, we do not agree that having this degree is sufficient to

delete the training or experience requirements for any of the personnel

categories. In this rapidly changing field, where accurate performance

of laboratory procedures is dependent on the skill and expertise of the

individual performing the procedures, we believe in addition to an

academic degree, it is critical to obtain adequate hands-on training

and experience prior to working with human gametes and embryos. This is

especially true for procedures that may differ significantly from one

laboratory to another.

We do not agree with the comment made by the professional

organization that minimum educational standards should be included in

the ``grandfather'' clauses at Part III., A., 3, c., and 5., c. of the

model certification program. In developing standards for this

relatively new area of laboratory technology, we do not wish to create

a situation where individuals who have been working in the field would

not meet the qualifications specified for their positions. In the model

certification program, we have specified educational requirements which

must be met by individuals who first become employed in an embryo

laboratory after the date of this Federal Register notice. For the

reason stated above, individuals serving in these positions on or

before July 20, 1999 who have the specified experience and/or training

requirements for their respective positions will be considered

qualified.

Comment: A professional organization and two individuals commented

on the proposed requirements for the laboratory director, supervisor

and reproductive biologist to obtain 12 contact hours of continuing

education per year in ART or clinical laboratory practice. While the

professional organization expressed the view that continuing education

for non-supervisory personnel as specified in the proposed model

program is acceptable, one of the individual commenters felt that 12

contact hours was excessive for non-supervisory personnel as well as

costly for the ART program. This commenter suggested reducing the

requirement to 12 contact hours every two years. The other individual

commenter noted the proposed requirement at Part III., A., 2., l., made

the laboratory director responsible for ensuring each employee obtain

the required continuing education. The commenter felt this should also

be the reproductive biologist's responsibility and that reading

appropriate literature should count as continuing education.

Response: We agree with the professional organization that in this

rapidly evolving field of science and technology, it is appropriate and

necessary for all levels of laboratory personnel to maintain current

knowledge and skills relevant to ART embryo laboratory procedures. We

do not believe requiring 12 contact hours of continuing education (CE)

on an annual basis is excessive. At the same time, we recognize there

may be some cost to the laboratory or individual to obtain the

continuing education. However, we believe the benefits outweigh the

costs, especially when there are a number of ways in which CE may be

provided, including video or audioconferencing seminars or self-study

educational materials. As the one commenter suggested, reading relevant

journal articles is another cost-effective way to obtain CE. However,

we note that to meet the model's CE requirement, the specific vehicle

used for earning CE contact hours must have been approved by an

approved continuing education provider such as the International

Association of Continuing Education and Training or other provider

specified by the State implementing the model certification program.

We agree that each reproductive biologist, as well as laboratory

supervisor, should be pro-active in obtaining appropriate CE. However,

as stated previously, it is the laboratory director who is ultimately

responsible for the overall operation, administration and technical and

scientific oversight of the laboratory. This includes employing

qualified personnel and ensuring they receive appropriate training and

continuing education to maintain and update their knowledge and skills

in ART and laboratory practice.

Comment: One commenter requested clarification of the proposed

requirements at Part III., B., 1., and C., 2., which require the

laboratory to have ``adequate'' space and ``sufficient'' equipment for

the type and volume of ART laboratory procedures performed.

Specifically, the commenter would like guidelines that address the

number of procedures per square foot of space and the number of

procedures per cell freezer, etc.

Response: Although we appreciate the commenter's suggestion to more

specifically define adequate space and sufficient equipment for an

embryo laboratory, we have not specified exact laboratory measurements

or numbers of required equipment in the model certification program in

an effort to allow flexibility in the configuration and arrangement of

laboratory facilities and equipment contained therein. Requirements may

differ depending on the number and types of procedures performed, and

the number of individuals that are employed by or using each

laboratory. As noted in the proposed model standards, the physical

space, utilities, and laboratory equipment must be able to accommodate

the volume of ART laboratory procedures performed at its busiest time,

in a manner that will reduce the potential for spilled, lost or

misplaced patient specimens while they are being handled or stored. The

laboratory must be secure and have limited access, and must include an

isolated area for performing sterile techniques under aseptic

conditions. The laboratory and administrative space must be

conveniently located, but separate from patient areas, and immediate

communication must be

[[Page 39381]]

possible with the oocyte retrieval and transfer room. As long as these

requirements can reasonably be met, the space and equipment are

considered adequate and sufficient.

Comment: Four individuals pointed out the proposed requirement at

Part III., B., 3., b., for animal specimens to be incubated separately

from human specimens would disallow the use of an incubator containing

human specimens when performing the mouse embryo bioassay for quality

control purposes.

Response: We agree with the commenters that the proposed

requirement noted above could be interpreted to prohibit quality

control procedures that require mouse embryos to be held in the same

incubator as human specimens. However, there are acceptable alternative

procedures (i.e., human sperm survival) that may be used for quality

control if a laboratory does not have access to a separate incubator

for checking media, glassware, pipettes, etc. The quality control for

an incubator itself includes monitoring temperature, humidity and gas

concentration, and does not require a bioassay to be performed.

Although not mentioned by commenters, the use of live cells,

tissues, organs from a nonhuman animal source transplanted or implanted

into a human, or used for ex vivo contact with human body fluids,

cells, tissues, organs that are subsequently given to a human recipient

(xenotransplantation), raises a major public health dilemma. In its

Guidance For Industry, Public Health Issues Posed by the Use of

Nonhuman Primate Xenografts in Humans (April 1999), The Food and Drug

Administration, in consultation with other Federal agencies, concluded

that further scientific research, evaluation and public discussion is

needed in order to obtain sufficient information to adequately assess

and potentially reduce the risks (particularly the transmission of

infectious agents) posed by the use of nonhuman primate cells, tissues

and organs. A Federal Advisory Committee on Xenotransplantation is

currently under development within the Department of Health and Human

Services to address these issues, conduct discussions, and make

recommendations regarding the use of nonhuman primate xenografts.

To assure consistency with applicable Federal, State or local

requirements as they are developed, we are revising the requirement at

Part III., B., 3. , to state, ``If live nonhuman animal cells, tissues,

and/or organs are used, all applicable Federal, State and local

regulations regarding their handling, storage and use must be met.'' We

believe this revision is appropriate and necessary in light of the

serious public health issues that need to be addressed with their use

in humans.

Comment: One commenter expressed concern with the proposed

requirement at Part III., C., 4., c., that states for oral requests for

changes to the original written or electronic request for an ART

laboratory procedure, the laboratory must receive written or electronic

documentation within 24 hours from the authorized person requesting the

change. The commenter states particularly in programs where the

physicians and/or laboratory staff have multiple work sites, it is

sometimes difficult to receive written confirmations within a 24-hour

time frame.

Response: It is critical for embryo laboratories to obtain written

or electronic orders for procedures to be performed and that these

orders are communicated clearly in a timely manner. This enables the

laboratory to ensure adequate and appropriate staffing for scheduled

procedures and, more importantly, it ensures that the patient's

specimens used in the ART embryo laboratory procedures are handled

appropriately. Some of the procedures are of a sensitive nature, and

the laboratory could be subject to liability if an unauthorized

laboratory procedure is accidentally performed due to miscommunication

or lack of communication. The model certification program requires a

written or electronic request by an authorized person prior to

performing any procedure. It is only when there is a change to the

original request that the model allows 24 hours for written or

electronic verification of the change. We do not agree with the

commenter that this time frame should be extended to 48 hours. In most

cases, it is desirable to have written or electronic verification of

revised orders at the time the decision is made to change the patient's

treatment protocol. Allowing 24 hours provides a minimal amount of

leeway for extenuating circumstances.

Comment: One commenter was confused by the proposed requirement at

Part III., C., 4., i., which states that clinical laboratory testing on

specimens obtained by the embryo laboratory must be performed in

accordance with the Clinical Laboratory Improvement Amendments of 1988

(CLIA) regulations.

Response: Examinations of materials derived from the human body to

provide information for the diagnosis, prevention, or treatment of

disease, or assessment of the health of human beings must be performed

in accordance with the regulations (42 CFR Part 493) implementing CLIA.

Examples of specimens that may be obtained by the embryo laboratory

that would be subject to the CLIA regulations include blood or serum

samples for endocrinology or hematology testing or microbiology culture

samples. If the embryo laboratory performs this testing it must have a

valid CLIA certificate for the testing to be performed, or if the

laboratory is in a CLIA-exempt State it must be licensed by the State

in which it is located. If the embryo laboratory refers specimens for

clinical laboratory testing, the testing must be performed by a

laboratory that meets the CLIA requirements. To clarify the requirement

at Part III., C., 4., i., we are specifying the purpose of clinical

laboratory testing is to ``provide information for the diagnosis,

prevention or treatment of disease, or assessment of the health of

human beings.''

Comment: One professional organization suggested the quality

control standards include an additional statement at Part III., C., 6.,

e., iv., that ``The use of blood-based media prepared in-house is not

recommended. However, if such products are used then * * *'' This

statement is to preface the proposed quality management requirement

that the laboratory test blood-based media supplements prepared in-

house for several communicable diseases.

Response: We agree with the commenter that it is not a recommended

practice for the laboratory to prepare blood-based media or a blood-

based media supplement that could potentially contain and transmit

communicable diseases. However, if blood-based media or supplements are

prepared in-house, blood from the donor(s) used to make the media/

supplement must be tested to ensure the donor(s) is negative/

nonreactive for significant disease agents. We have added language to

the requirement at Part III., C., 6., e., iv., to state that the in-

house preparation of blood-based media or a blood-based media

supplement is not recommended. In addition, we have clarified that the

blood donor(s) must be tested for the communicable diseases listed

using FDA licensed, approved or cleared tests for markers of these

diseases. Also, to maintain consistency with the FDA's requirements for

the testing of blood and tissue product donors, we have added human T-

cell lymphotrophic virus, Type II, to the communicable diseases listed

in this requirement.

Comment: One commenter recommended that the proposed quality

assurance requirement at Part III., C., 7.,

[[Page 39382]]

b., for the laboratory to track and evaluate procedural outcomes (e.g.,

fertilization rates and embryo quality) should be incorporated into the

current Society for Assisted Reproductive Technology (SART) reporting

computer program. The commenter believes capturing the data in the SART

program would help to reduce the amount of additional paperwork for the

laboratory.

Response: We recognize that for some laboratories, it may be

possible to maintain the data listed at Part III., C., 7., b. in a

database similar to that used by SART to collect data on ART programs

and clinics. However, we do not agree this should be required by the

model certification program for several reasons. First, the data

collected by SART is not specific to embryo laboratory activities, but

their data relates to clinical ART practices and pregnancy success

rates reported by ART programs/clinics. In addition, there are many

instances in which there is not a direct, one-to-one relationship

between ART programs/clinics and the embryo laboratories used by these

facilities, and not all ART programs report to SART. To meet the

standards in the model certification program, laboratories must record

and track the data described in the model. These data are part of the

laboratory's internal system to monitor the ongoing quality of its

activities.

Comment: One professional organization commented that the proposed

ten year period for record retention is excessive and should be reduced

to a five year period, while a consumer advocacy group felt indefinite

record-keeping should be considered since consumers of ART procedures

need to know if they, or their children, have ever had exposure to

contaminants through laboratory procedures.

Response: While we appreciate the consumer advocacy group's

concerns, requiring indefinite retention of all laboratory records

could be extremely burdensome for some laboratories. We proposed the

ten year period for record retention because it was consistent with

similar requirements mandated by the Food and Drug Administration for

human tissue intended for transplantation. We continue to believe this

time period is reasonable and have not changed the requirement in the

model certification program. However, we note that the 1998 Survey of

Assisted Reproductive Technology Embryo Laboratory Procedures and

Practices conducted by the CDC indicated the majority of embryo

laboratories are retaining most of their records indefinitely. If

consumers are concerned they may not have indefinite access to

pertinent laboratory records, it may be possible for them to request

the laboratory provide them with all relevant information at the time

of an ART procedure. The consumer could then maintain this information

for as long as desired.

Additional Revisions to the Proposed Model Certification Program

Although written comment was not received on the following, we are

making a few additional revisions to the administrative requirements

proposed in the model certification program for the reasons stated

below.

At Part II., B., 2., d., vi., we are extending the time

frame in which the approved accreditation organization must provide the

State advanced written notice of the effective date of any proposed

changes in the organization's requirements from ``at least 30 days'' to

``at least 60 days.'' We believe that this revision will provide the

State a more reasonable period of time to review the organization's

proposed changes for continued equivalency to the State's certification

program.

At Part II., B., 4., a., we are revising the language that

states ``Initial inspections are performed when the laboratory applies

for certification and may be performed for recertification after the

laboratory has had a change in ownership or administration,'' to

include a change in the laboratory's location. We believe a change in

the laboratory's location may require an onsite inspection to ensure

that the laboratory continues to meet the certification program's

requirements for adequate space and appropriate environmental

conditions. A conforming change is also being made at Part II., B., 3.,

ii., which requires the embryo laboratory to submit changes in its

ownership or administration to the State within 30 days of the change.

A Model Program for the Certification of Embryo Laboratories

With this publication, CDC has provided a model program for the

certification of embryo laboratories which incorporates the definitions

and laboratory standards called for in the FCSRCA and has included

administrative requirements for States which choose to adopt the model

program. CDC will distribute the model certification program to State

officials and health authorities as outlined in the statute, and

encourage their assistance in the State adopting the program.

As stated in the preamble to the proposed model certification

program, CDC will defer implementation of the approval of State

certification programs or accreditation organizations, as well as

Federal validation inspections of embryo laboratories certified by

States adopting the model or accredited by an accreditation program for

embryo laboratories. While Congress anticipated that the cost of

Federal and State monitoring and oversight of embryo laboratories would

be covered by the fees paid by participating laboratories,

participation by embryo laboratories is voluntary and laboratories not

willing to pay these fees would not be limited in their ability to

operate. To date, embryo laboratories have not indicated they would opt

into such a voluntary oversight program.

While the model certification program for embryo laboratories does

not provide for a Federal oversight role, we believe that this model

provides an excellent resource for States that wish to develop their

own programs and professional organizations with an interest in

establishing or adopting standards for the embryo laboratory. In

addition, as mentioned previously in this preamble, as the data become

available, the CDC will publish the certification/accreditation status

of embryo laboratories affiliated with ART programs or clinics in

conjunction with future annual publications of the ART Success Rates

reports.

Organization of the Model Certification Program

This notice describes a model certification program for embryo

laboratories and includes definitions (Part I), administrative

requirements (Part II), and embryo laboratory standards (Part III).

References are also provided as an addendum to this notice for

background and educational purposes.

Dated: July 14, 1999.

Thena M. Durham,

Acting Associate Director for Management and Operations, Centers for

Disease Control and Prevention.

A Model Certification Program for Embryo Laboratories

Contents

Part I. Definitions

Part II. Administrative Requirements

Part III. Embryo Laboratory Standards

Addendum References

Part I. Definitions

Accredited institution. A school or program which--

(a) Admits as a regular student only persons having a certificate

of graduation from a school providing secondary education, or the

recognized equivalent of such certificate;

[[Page 39383]]

(b) Is legally authorized within the State to provide a program of

education beyond secondary education;

(c) Provides an educational program for which it awards a

bachelor's degree or provides not less than a 2-year program which is

acceptable toward such a degree, or provides an educational program for

which it awards a master's or doctoral degree; and

(d) Is accredited by a nationally recognized accrediting agency or

association.

This definition includes any foreign institution of higher

education that HHS or its designee determines meets substantially

equivalent requirements.

Approved accreditation organization. An accreditation organization

that has formally applied for and received the State's approval based

on the organization's compliance with this model certification program

and other requirements as specified by the State.

ART. Assisted reproductive technology.

Assisted hatching. A micromanipulation technique which involves

making a small opening in the zona wall of the embryo to enhance

implantation.

Assisted reproductive technology. All clinical treatments and

laboratory procedures which include the handling of human oocytes and

sperm, or embryos, with the intent of establishing a pregnancy. This

includes, but is not limited to, in vitro fertilization, gamete

intrafallopian transfer, zygote intrafallopian transfer, embryo

cryopreservation, oocyte or embryo donation, and gestational surrogacy.

Assisted reproductive technology cycle. Any cycle in which (1) ART

has been used, (2) in which the woman has undergone ovarian stimulation

or monitoring with the intent of undergoing ART, (3) a woman has

donated oocytes, or (4) in the case of cryopreserved embryos, in which

embryos have been thawed with the intent of transfer. ART cycles can be

stimulated (use of ovulation induction) or unstimulated (natural

cycle).

Assisted reproductive technology laboratory procedures. All

laboratory procedures for handling and processing of human oocytes and

sperm, or embryos, with the intent of establishing a pregnancy. These

procedures include, but are not limited to, the examination of

follicular aspirates, oocyte classification, sperm preparation, oocyte

insemination, assessment of fertilization, assessment of embryo

development, preparation of embryos for embryo transfer, and

cryopreservation of specimens.

Assisted reproductive technology program or clinic. A legal entity

practicing under State law, recognizable to the consumer, that provides

ART to couples who have experienced infertility or are undergoing ART

for other reasons. This can be an individual physician or a group of

physicians who practice together, and share resources and liability.

Authorized person. An individual authorized under State law to

order ART procedures.

CDC. The Centers for Disease Control and Prevention.

CLIA. The Clinical Laboratory Improvement Amendments of 1988.

Certification. The certification of an embryo laboratory by a State

certification program or through accreditation by an approved

accreditation organization.

Certification program. The model certification program for embryo

laboratories described in this notice or a State certification program

for embryo laboratories which meets or exceeds the requirements of the

model certification program.

Cryopreservation. A technique to preserve biologic material through

freezing.

Doctoral scientist. An individual holding an earned doctoral degree

in a chemical, physical, biological, medical or reproductive laboratory

science from an accredited institution. As defined here, doctoral

scientist also includes individuals holding an earned doctoral degree

in veterinary medicine.

Embryo. The normal (2 pronuclei) fertilized egg that has undergone

one or more divisions.

Embryo laboratory. A facility in which human oocytes and sperm, or

embryos, are subject to ART laboratory procedures.

Embryo transfer. Introduction of an embryo(s) into a woman's uterus

after in vitro fertilization.

Fertilization. The penetration of the egg by the sperm and fusion

of genetic materials to result in the development of a fertilized egg

(or zygote).

Gamete intrafallopian transfer. An ART procedure that involves

removing eggs from the woman's ovary, combining them with sperm, and

immediately injecting the eggs and sperm into the fallopian tube.

Fertilization takes place inside the fallopian tube.

HHS. The U.S. Department of Health and Human Services, or its

designee.

Intracytoplasmic sperm injection. The placement of a single sperm

into the ooplasm of an oocyte by micro-operative techniques.

In vitro fertilization. A method of assisted reproduction that

involves removing eggs from a woman's ovaries, combining them with

sperm in the laboratory and, if fertilized, replacing the resulting

embryo(s) into the woman's uterus.

Laboratory. Unless otherwise specified in this notice, means embryo

laboratory.

Micromanipulation. Microtechniques such as intracytoplasmic sperm

injection and assisted hatching commonly used to overcome fertilization

disorders.

Oocyte. The female reproductive cell, also called an egg.

Physician. An individual with a doctor of medicine or doctor of

osteopathy degree who is licensed by the State to practice medicine or

osteopathy within the State in which the embryo laboratory is located.

Procedural outcome. The outcome of the ART laboratory procedure

performed e.g., fertilization assessment-the presence of two pronuclei

in the ooplasm.

Specimen. Human biologic material (includes human reproductive

tissue such as oocytes, sperm, zygotes and embryos).

Sperm. The male reproductive cell that has completed the process of

meiosis and morphological differentiation.

State. Includes, for purposes of this model certification program,

each of the 50 States, the District of Columbia, the Commonwealth of

Puerto Rico, the Virgin Islands, and other territories of the United

States, and a political subdivision of a State where the State, acting

pursuant to State law, has expressly delegated powers to the political

subdivision sufficient to authorize the political subdivision to act

for the State in enforcing requirements equal to or more stringent than

the model certification program.

Zygote. A normal (2 pronuclei) fertilized egg before cell division

begins.

Zygote intrafallopian transfer. Eggs are collected and fertilized,

and the resulting zygote is then transferred to the fallopian tube.

Part II. Administrative Requirements

A. Overview

The certification program for embryo laboratories is a model

program developed by the Centers for Disease Control and Prevention

(CDC) in accordance with Pub. L. 102-493 (42 U.S.C. 263a-1 et seq.) and

is to be administered by interested States.

[[Page 39384]]

B. Requirements for State Administration of the Model Certification

Program for Embryo Laboratories

The State may adopt and administer the model certification program

for embryo laboratories described in this notice or administer a State

certification program for embryo laboratories that meets or exceeds the

requirements of the model certification program, and must, at a

minimum, meet the following provisions--

1. Certification Under State Programs. A State may qualify to adopt

and administer the model certification program if the State submits an

attestation to the CDC, Public Health Practice Program Office, Division

of Laboratory Systems, 1600 Clifton Rd., Atlanta, GA 30333, providing--

a. Assurances that the certification program for embryo

laboratories administered by the State meets or exceeds the

requirements of the model certification program specified in this

notice.

b. An agreement that in administering the certification program, a

State will not establish any regulation, standard, or requirement which

has the effect of exercising supervision or control over the practice

of medicine in ART programs or clinics.

c. An agreement that the term of State certification/

recertification issued to an embryo laboratory is for a period of not

more than two years.

d. An agreement to investigate, when appropriate and to the extent

necessary, complaints received about an embryo laboratory certified

under the State's program.

e. An agreement to annually report to the CDC, Public Health

Practice Program Office, Division of Laboratory Systems, 1600 Clifton

Rd., Atlanta, GA 30333, the identity and certification status of each

embryo laboratory in the State as well as any such laboratory which has

applied for certification, and the ART programs or clinics with which

each embryo laboratory is associated, for annual publication by the

CDC.

f. Information about any proposed use and approval and revocation

of approval of accreditation organizations in accordance with

paragraphs 2. and 5. of this section.

g. An agreement to make such reports as the Secretary of the

Department of Health and Human Services (through the CDC) may require.

2. Use and Approval of Accreditation Organizations. Accreditation

organizations approved by the State may be used to inspect and accredit

embryo laboratories for the purpose of State certification and such

accreditation shall constitute certification. The criteria and

procedures used by the State to approve accreditation organizations

must include, at a minimum, the following:

a. The accreditation organization must provide assurances

satisfactory to the State that its standards and requirements for

accreditation of embryo laboratories meet or exceed the requirements of

the certification program;

b. The accreditation organization must, at a minimum, conduct

inspections of embryo laboratories in accordance with the requirements

under paragraph 4. of this section which includes making available to

the public, upon request, the specific findings (with any explanatory

information required to interpret the findings), including deficiencies

identified in an inspection, and any subsequent corrections to those

deficiencies, no later than 60 days after the date of the inspection;

c. The accreditation organization must agree to revoke or suspend a

laboratory's accreditation for one year, if the accreditation

organization finds, on the basis of inspections, that the owner or

operator of the laboratory, or any employee of the laboratory--

i. Has been guilty of misrepresentation in obtaining the

accreditation.

ii. Has failed to comply with any standards of the accreditation

program.

iii. Has refused a request of the accreditation organization or

State for permission to inspect the laboratory, its operations, and

records; and

d. The accreditation organization must agree to submit such reports

and maintain such records as the State, or HHS, may require, to

include, but not be limited to, the following:

i. Notification to the State of each newly accredited embryo

laboratory within the State within 30 days of the laboratory obtaining

accreditation;

ii. Notification to the State of any embryo laboratory within the

State that has its accreditation denied, suspended, withdrawn or

revoked, or that has had any other adverse action taken against it by

the accreditation organization within 30 days of the action taken;

iii. Notification to the State within 10 days of a deficiency

identified in any accredited embryo laboratory within the State where

the deficiency poses an immediate jeopardy to the laboratory's patients

or a hazard to the general public;

iv. Notification to the State if the accreditation organization

finds, on the basis of inspections, that the owner or operator of the

laboratory, or any employee of the laboratory--

A. Has been guilty of misrepresentation in obtaining the

accreditation.

B. Has failed to comply with any standards of the accreditation

program.

C. Has refused a request of the accreditation organization for

permission to inspect the laboratory, its operations, and records;

v. Provide inspection schedules as requested by the State for the

purpose of conducting onsite validation inspections of laboratories;

and

vi. Provide the State written notification at least 60 days in

advance of the effective date of any proposed changes in its

requirements.

3. Embryo Laboratory Application Requirements. The State must

provide for the submission of an application to the State by an embryo

laboratory requesting certification, in such form as may be specified

by the State. Such an application must include the following:

a. Assurances satisfactory to the State that the embryo laboratory

will be operated in accordance with the standards of the certification

program;

b. An agreement by the embryo laboratory to--

i. Annually report to the State the ART programs or clinics with

which the laboratory is associated.

ii. Submit changes in the ownership, administration, or location of

the laboratory to the State within 30 days of the change.

iii. Permit the State to conduct onsite inspections including, as

applicable, initial, routine, validation and complaint inspections,

upon presentation of identification to the owner, operator, or agent in

charge of the laboratory, during the laboratory's regular hours of

operation to determine compliance with the certification program.

iv. Permit the State to have access to all facilities, equipment,

materials, records, and information which the State requires to

determine if the laboratory is being operated in accordance with the

standards of the certification program.

v. Permit the State to copy any material, record, or information

inspected, or submit such, upon request by the State.

vi. Permit the State to make available, upon request, to the

public, the laboratory's specific inspection findings (with any

explanatory information required to interpret the findings), including

deficiencies identified in an inspection, and any subsequent

corrections to those deficiencies;

[[Page 39385]]

c. If the State allows certification of an embryo laboratory on the

basis of the laboratory's accreditation by an approved accreditation

organization (e.g., issues a certificate of accreditation), the

laboratory must, in addition to the requirements of subparagraphs 3.a.

and 3.b. of this section--

i. Submit proof of current accreditation.

ii. Permit the accreditation organization to have access to all

facilities, equipment, materials, records, and information which the

accreditation organization requires to determine if the laboratory is

being operated in accordance with the standards of the accreditation

organization program.

iii. Permit the accreditation organization to copy any material,

record, or information inspected, or submit such, upon request by the

accreditation organization.

iv. Permit the accreditation organization to make available, upon

request, to the public, the laboratory's specific inspection findings

(with any explanatory information required to interpret the findings),

including deficiencies identified in an inspection, and any subsequent

corrections to those deficiencies.

v. Agree to authorize the accreditation organization to submit to

the State or HHS such laboratory-specific information or reports as the

State or HHS may require; and

d. Such other information, agreements and assurances as the State

finds necessary.

4. Initial, Routine and Complaint Inspections. Inspections must be

conducted to determine if embryo laboratories applying for or renewing

their certification meet the requirements of the certification program.

In addition, inspections may be performed as part of the State's

investigation of complaints received about a certified embryo

laboratory. The inspections may be carried out by the State or, as

applicable, by an accreditation organization approved by the State in

accordance with paragraph 2. of this section.

a. Initial inspections for embryo laboratory certification must be

performed during the laboratory's regular hours of operation and may be

announced. Initial inspections are performed when the laboratory

applies for certification and may be performed for recertification

after the laboratory has had a change in ownership, administration, or

location.

b. Routine inspections for renewal of the laboratory's

certification must be performed biennially, during the laboratory's

regular hours of operation and may be announced.

c. Inspections to investigate complaints received by the State

about a laboratory may be performed unannounced, during the

laboratory's regular hours of operation.

d. Inspection of a laboratory may be made only upon the

presentation of identification to the owner, operator, or agent in

charge of the laboratory being inspected.

e. In conducting an inspection, the State or approved accreditation

organization must have access to all facilities, equipment, materials,

records, and information which the State or approved accreditation

organization requires to determine if the laboratory is being operated

in accordance with the standards of the certification program.

f. The State or approved accreditation organization may copy any

material, record, or information inspected or require it to be

submitted to the State or, as applicable, to the approved accreditation

organization.

g. The specific findings (with any explanatory information required

to interpret the findings), including deficiencies identified in an

inspection, and any subsequent corrections to those deficiencies must

be made available to the public upon request beginning no later than 60

days after the date of the inspection.

5. Validation Inspections. The State must annually evaluate the

performance of each approved accreditation organization by performing

validation inspections of a sufficient number of embryo laboratories

within the State accredited by the organization, to allow a reasonable

estimate of the performance of such organization.

a. The State may enter and inspect, during regular hours of

operation, embryo laboratories which have been accredited by an

approved accreditation organization for the purpose of determining

whether the laboratory is being operated in accordance with the

standards of the certification program.

b. A validation inspection of a laboratory may be announced and be

made only upon the presentation of identification to the owner,

operator, or agent in charge of the laboratory being inspected.

c. In conducting a validation inspection, the State must have

access to all facilities, equipment, materials, records, and

information which the State requires to determine if the laboratory is

being operated in accordance with the standards of the certification

program.

d. The State may copy any material, record, or information

inspected or require it to be submitted to the State.

e. If the State determines as a result of a validation inspection

that the embryo laboratory is not in compliance with the standards of

the certification program, the State must--

i. Notify the accreditation organization which accredited the

laboratory.

ii. Make available to the public the inspection findings (with any

explanatory information required to interpret the findings), including

deficiencies identified in the inspection, and any subsequent

corrections to those deficiencies.

iii. Conduct additional inspections of other embryo laboratories

accredited by the accreditation organization to determine if the

accreditation organization is reliably identifying the deficiencies of

the laboratories.

f. If the State determines that the accreditation organization has

not met the requirements of paragraph 2. of this section, the State may

(under such notice and hearing standards to be developed by the State)

revoke the approval of the accreditation program.

6. Revocation of an Accreditation Organization's State Approval. If

the State revokes approval of an accreditation organization under

subparagraph 5.f., of this section--

a. The State must notify each laboratory, accredited by the

organization under the State certification program, that it has revoked

its approval of the organization within 10 days of the revocation.

b. The certification of any embryo laboratory accredited by the

organization will continue in effect for 60 days after the laboratory

is notified by the State of the withdrawal of approval, except that the

State may extend the period during which the certification may remain

in effect if the State determines that the laboratory submitted an

application to another approved accreditation organization for

accreditation or to the State, as applicable, in a timely manner after

receipt of such notice.

7. Embryo Laboratory Certification Revocation and Suspension.

a. A certification issued by a State for an embryo laboratory must

be revoked or suspended if the State or, as applicable, approved

accreditation organization finds, on the basis of inspections and after

reasonable notice and opportunity for hearing (under such notice and

hearing standards to be developed by the State) to the owner or

operator of the laboratory, that the

[[Page 39386]]

owner or operator or any employee of the laboratory--

i. Has been guilty of misrepresentation in obtaining the

certification.

ii. Has failed to comply with any standards of the certification

program.

iii. Has refused a request of the State or approved accreditation

organization for permission to inspect the laboratory, its operations,

and records.

b. If the certification of an embryo laboratory is revoked or

suspended, the certification of the laboratory shall continue in effect

for 60 days after the laboratory receives notice of the revocation or

suspension, unless there is a finding that the laboratory's continued

operation may constitute a public health threat, in which case the

certification shall be immediately revoked or suspended.

c. If the certification of an embryo laboratory is revoked or

suspended, the laboratory may apply for recertification after one year

after the date of the revocation or suspension.

8. Fees. The State may require the payment of fees for the purpose

of, and in an amount sufficient to cover the costs of, administering

the certification program.

Part III. Embryo Laboratory Standards

A. Personnel Qualifications and Responsibilities

The embryo laboratory must have a sufficient number of individuals,

who meet the qualification requirements, to perform the functions

necessary to provide timely services appropriate for the size and

volume of the ART program(s) or clinic(s) served by the laboratory. As

a guideline, for every 90-150 ART cycles performed annually, the

laboratory should employ one individual who is capable of performing

all ART laboratory procedures provided by the embryo laboratory.

Regardless of workload, at a minimum, two qualified individuals should

be available to provide the appropriate laboratory services.

1. Laboratory Director Qualifications. The laboratory director must

be qualified to manage and direct the laboratory personnel and the

performance of ART laboratory procedures. The laboratory director

must--

a. Possess a current license as an embryo laboratory director

issued by the State in which the laboratory is located, if such

licensing is required.

b. Be a physician or a doctoral scientist with a broad knowledge of

the biochemistry, biology, and physiology of reproduction, and

laboratory operations including experimental design, statistics, and

problem solving. It is recommended that a doctoral scientist serving as

a laboratory director be board certified in embryology. In addition,

the laboratory director must meet the following:

i. Have two years documented pertinent experience in a laboratory

performing ART procedures. This experience should include familiarity

with laboratory quality control, sterile technique and cell culture;

and

ii. Have documented training of at least six months in an embryo

laboratory which includes performing, at a minimum, each ART laboratory

procedure 60 times.

Note: Documented experience and training may be acquired

concurrently.

c. If not qualified under paragraph 1.b. of this section, be the

director of an embryo laboratory on or before July 20, 1999 and meet

the following:

i. Have two years documented pertinent experience in a laboratory

performing ART procedures. This experience should include familiarity

with laboratory quality control, sterile technique and cell culture;

and

ii. Have documented training of at least six months in an embryo

laboratory which includes performing, at a minimum, each ART laboratory

procedure 60 times.

Note: Documented experience and training may be acquired

concurrently.

d. In addition to meeting the qualification requirements above--

i. Obtain at least 12 contact hours of continuing education

annually in assisted reproductive technology or clinical laboratory

practice; and

ii. If the individual serving as the laboratory director performs

ART laboratory procedures in the laboratory, it is recommended that he

or she performs each of these procedures at least 20 times annually.

2. Laboratory Director Responsibilities. The laboratory director is

responsible for the overall operation, administration, and technical

and scientific oversight of the embryo laboratory, including the

employment of personnel who are qualified to perform ART laboratory

procedures, and record and report procedural outcomes promptly,

accurately and proficiently. If the laboratory director delegates

performance of his or her responsibilities to an individual qualified

as an embryo laboratory director or laboratory supervisor, he or she

must do so in writing. The laboratory director remains responsible for

ensuring that all delegated duties are properly performed. The

laboratory director must--

a. Be accessible to the laboratory to provide on-site, telephone or

electronic consultation as needed.

b. Ensure that the physical plant (space, facilities and equipment)

and environmental conditions of the laboratory are appropriate for the

laboratory procedures performed and provide a safe environment in which

employees and other occupants are protected from physical, chemical,

electrical and biological hazards.

c. Establish and monitor a program to ensure that aseptic

conditions are maintained in the laboratory, as appropriate, for the

ART laboratory procedures to be performed.

d. Ensure that ART laboratory procedures selected or developed by

the laboratory are appropriate to provide quality patient care.

e. Ensure that adequate systems are in place to maintain patient

confidentiality throughout those parts of the ART process under the

laboratory's control.

f. Ensure that an approved procedure manual is available to all

personnel responsible for performing ART laboratory procedures.

g. Establish and monitor a quality management program to assure the

quality of laboratory services provided and to identify failures in

quality as they occur.

h. Ensure that all necessary corrective actions are taken,

documented and reviewed for effectiveness whenever failures in quality

are identified.

i. Provide consultation to physicians and others, as appropriate,

regarding the clinical significance of laboratory findings.

j. Employ a sufficient number of qualified personnel with the

appropriate education and documented experience or training to

supervise and perform the work of the laboratory. Written records of

the qualifications of all personnel must be maintained.

k. Ensure that all personnel receive appropriate training for the

ART laboratory procedures to be performed, and have demonstrated that

they can perform the procedures reliably prior to working on patients'

specimens. All training activities must be documented.

l. Ensure that all personnel acquire, on an annual basis, the

required number of continuing education contact hours. A record of each

employee's continuing education participation must be maintained.

m. Specify, in writing, the responsibilities and duties of each

person who performs ART laboratory procedures, identifying which

procedures each individual is

[[Page 39387]]

authorized to perform and whether supervision is required.

n. Ensure that policies and procedures are established for

monitoring each employee's continued competence to perform ART

laboratory procedures, and whenever necessary, provide remedial

training or additional continuing education to improve skills.

o. Ensure that performance evaluations for each employee are

performed and documented, at a minimum, annually.

3. Laboratory Supervisor Qualifications. The embryo laboratory must

have one or more qualified supervisors who, under the direction of the

laboratory director, provide day-to-day supervision of laboratory

personnel performing ART laboratory procedures. In the absence of the

director, the laboratory supervisor must be responsible for the proper

performance of all ART laboratory procedures. The laboratory supervisor

must--

a. Possess a current license issued by the State in which the

laboratory is located, if such licensing is required.

b. Meet the qualification requirements for an embryo laboratory

director under paragraph 1. of this section, or meet the following:

i. Have an earned master's or bachelor's degree in a chemical,

physical, biological, medical technology, clinical or reproductive

laboratory science from an accredited institution; and

ii. Have documented training which includes performing, at a

minimum, each ART laboratory procedure 60 times.

c. If not qualified under subparagraph 3.b. of this section, be the

supervisor of an embryo laboratory on or before July 20, 1999 and have

documented training which includes performing, at a minimum, each ART

laboratory procedure 60 times.

d. In addition to meeting the qualification requirements above--

i. Obtain at least 12 contact hours of continuing education

annually in assisted reproductive technology or clinical laboratory

practice. If also serving as the laboratory director, continuing

education obtained to meet the laboratory director qualification

requirements may be used to meet this requirement; and

ii. If the individual serving as the laboratory supervisor performs

ART laboratory procedures in the laboratory, it is recommended that he

or she performs each of these procedures at least 20 times annually.

4. Laboratory Supervisor Responsibilities. The laboratory

supervisor is responsible for day-to-day supervision or oversight of

the embryo laboratory operation and personnel performing ART laboratory

procedures. The laboratory supervisor must--

a. Be accessible to laboratory personnel at all times when ART

laboratory procedures are performed to provide on-site, telephone or

electronic consultation to resolve technical problems in accordance

with policies and procedures established by the laboratory director.

b. Provide day-to-day supervision of laboratory personnel

performing ART laboratory procedures.

c. Ensure direct and constant supervision of personnel undergoing

training in ART laboratory procedures to fulfill the qualification

requirements for a reproductive biologist.

d. Perform laboratory director responsibilities as authorized in

writing by the laboratory director.

5. Reproductive Biologist Qualifications. Each individual

performing ART laboratory procedures must--

a. Possess a current license issued by the State in which the

laboratory is located, if such licensing is required.

b. Meet the qualification requirements for an embryo laboratory

director under paragraph 1. of this section, laboratory supervisor

requirements under paragraph 3. of this section, or meet the following:

i. Have an earned bachelor's degree in a chemical, physical,

biological, medical technology, clinical or reproductive laboratory

science from an accredited institution; and

ii. Have documentation of training appropriate for the ART

laboratory procedure(s) to be performed before performing the

procedure(s) without direct and constant supervision on patient

specimens. Training must include performing the ART laboratory

procedure(s), at a minimum, 30 times under direct and constant

supervision.

c. If not qualified under subparagraph 5.b. of this section, be

performing ART laboratory procedures in an embryo laboratory on or

before July 20, 1999 and have documentation of training appropriate for

the ART laboratory procedure(s) to be performed before performing the

procedure(s) without direct and constant supervision on patient

specimens. Training must include performing the ART laboratory

procedure(s), at a minimum, 30 times under direct and constant

supervision.

d. In addition to meeting the qualification requirements above--

i. Obtain at least 12 contact hours of continuing education

annually in ART or clinical laboratory practice. If also serving as the

laboratory director or laboratory supervisor, continuing education

obtained to meet the laboratory director or laboratory supervisor

qualification requirements may be used to meet this requirement; and

ii. It is recommended that each reproductive biologist perform each

of the ART laboratory procedures he or she performs in the laboratory

at least 20 times annually.

6. Reproductive Biologist Responsibilities. The reproductive

biologist is responsible for performing ART laboratory procedures, and

recording and reporting procedural outcomes promptly, accurately and

proficiently. The reproductive biologist must--

a. Perform only those ART laboratory procedures that are authorized

by the laboratory director, and for which training has been documented.

If appropriate training has not been documented, perform ART laboratory

procedures only under direct and constant supervision.

b. Follow the laboratory's established policies and procedures for

performing ART laboratory procedures, and recording and reporting

procedural outcomes.

c. Adhere to the laboratory's quality management policies, document

all specimen and procedure management, quality control and quality

assurance activities, and equipment and instrument calibration,

function verification and maintenance performed.

d. Identify problems that may adversely affect the performance of

ART laboratory procedures and either immediately notify the laboratory

supervisor or director, or correct the problem(s) in accordance with

the laboratory's established policies and procedures and notify the

laboratory supervisor or director of the problem(s) and the corrective

action(s) taken.

e. Document all corrective actions taken when failures in quality

are identified.

B. Facilities and Safety

The embryo laboratory must provide adequate space and the

appropriate environmental conditions to ensure safe working conditions

and quality performance of ART laboratory procedures.

1. Requirements for Physical Space and Utilities. The laboratory

must be constructed and arranged so that--

a. The laboratory space, ventilation, and utilities are adequate

for the volume of ART laboratory procedures performed during peak

periods of activity.

[[Page 39388]]

b. ART laboratory procedures are carried out in a secure area with

access limited to authorized personnel.

c. Movement of patient specimens and traffic around sensitive work

areas is limited in order to reduce the potential for spilled or lost

specimens.

d. Incubator and storage space are configured to ensure positive

specimen identification and minimize the potential for errors due to

misplaced specimens or retrieval of the wrong specimen.

e. Activities requiring sterile technique such as the handling,

assessment and culturing of human oocytes and embryos, are performed

under aseptic conditions in an area that is physically isolated from

other laboratory activities.

f. All laboratory work areas (does not include administrative

areas) are easily washed and disinfected.

g. The laboratory and administrative space are conveniently

located, but are separate from patient areas.

h. Immediate communication can occur with the oocyte retrieval and

transfer room(s).

2. Safety Requirements. Safety precautions, policies, and

procedures must be established and posted, or readily available to all

personnel, to ensure protection from physical, chemical, electrical and

biological hazards.

a. All personnel must be knowledgeable about and abide by

applicable Federal, State and local regulations regarding protection

from physical, chemical, electrical and biological hazards.

b. Disposable materials should be used wherever possible for all

procedures that involve exposure to tissue and body fluids.

c. The laboratory must store and dispose of tissue, body fluids, or

other potentially biohazardous materials as outlined in Federal, State

and local regulations.

d. Toxic chemicals, including toxic cleaning materials, must be

used in a manner that is not harmful to patient specimens.

e. Radioisotopes must not be used in a laboratory that performs ART

procedures.

f. The laboratory must have an emergency plan appropriate for its

geographical location which specifies the actions to be taken to

protect employees, patients, visitors and specimens in case of a

natural disaster or other potentially devastating event.

3. Laboratory Animals/Nonhuman Animal Cells, Tissues, Organs.

a. If laboratory animals are used, all applicable Federal, State

and local regulations regarding animal care and use must be met.

b. If live nonhuman animal cells, tissues, and/or organs are used,

all applicable Federal, State and local regulations regarding their

handling, storage and use must be met.

C. Quality Management

The embryo laboratory must establish and follow written policies

and procedures for a comprehensive quality management program that is

designed to monitor and evaluate the ongoing and overall quality of the

ART laboratory procedures performed and services provided. All quality

management activities must be documented.

1. Procedure Manual. A written procedure manual including

instructions for all ART laboratory procedures performed must be

available in the embryo laboratory and followed by all laboratory

personnel. The written procedures must be in sufficient detail to

assure reproducibility and competence in the performance of the

laboratory procedures.

a. The procedure manual must include the following, when applicable

to the ART laboratory procedure performed:

i. Principle (scientific basis) of the ART laboratory procedure;

ii. Clinical significance of the ART laboratory procedure;

iii. Requirements for specimen collection and handling;

iv. Step-by-step instructions for performance of the ART laboratory

procedure;

v. Preparation of required reagents, culture media, solutions, or

other special supplies;

vi. Equipment and instrumentation required for the performance of

the procedure, including necessary function checks and calibration

protocols;

vii. Quality control procedures to be performed, including

frequency of control testing, and criteria for acceptability;

viii. Remedial action to be taken when function checks, calibration

or control results do not meet the laboratory's criteria for

acceptability;

ix. Calculations and interpretation of procedural outcomes,

including criteria for acceptable and unacceptable outcomes, and

procedural outcomes requiring special notification;

x. The laboratory's system for recording and reporting procedural

outcomes;

xi. Limitations in methodologies, including interfering substances

and precautions;

xii. Pertinent literature references;

xiii. Description of the course of action to be taken if required

equipment or instrumentation malfunctions or is inoperable;

xiv. Criteria for the referral or transfer of specimens to another

embryo laboratory for the performance of an ART laboratory procedure,

including procedures for specimen submission and handling; and

xv. Procedure for safe and appropriate specimen disposal.

b. Manufacturers' instrument/equipment manuals and package inserts

may be used, when applicable, to meet the requirements of this section.

i. Any of the items listed under subparagraph 1.a. of this section,

not provided by the manufacturer must be provided by the laboratory.

ii. Any modifications to, or deviations from, the manufacturer's

instructions, must be clearly documented and provided in the procedure

manual.

c. Appropriate reference materials (e.g., slides, pictures,

textbooks, etc.) should be available in the laboratory to allow, as

needed, comparison with patient specimens.

d. Procedures must initially be approved, signed and dated by the

laboratory director, and must thereafter, be reviewed by the laboratory

director on an annual basis.

e. Procedures must be re-approved, signed and dated if the

directorship of the laboratory changes.

f. Each change in a procedure must be approved, signed and dated by

the current laboratory director.

g. The laboratory must retain a copy of each procedure with the

dates of initial use and discontinuance in accordance with the

requirements of section D., Maintenance of Records, of this part.

2. Equipment and Instrument Maintenance/Calibration. The embryo

laboratory must perform and document equipment and instrument

maintenance and, as applicable, calibration, and function verification

that include(s) electronic, mechanical and operational checks necessary

for the proper performance of ART laboratory procedures. The laboratory

must--

a. Have sufficient equipment for the type and volume of ART

laboratory procedures performed, which may include but is not limited

to, incubators, freezers, refrigerators, hoods, thermometers,

centrifuges, microscopes, pipettes, and warming devices.

b. Establish and follow written policies and procedures for

equipment and instrument maintenance and, as applicable, calibration,

and function checks, that ensure proper performance of the equipment

and instruments used in ART laboratory procedures. The laboratory

must--

[[Page 39389]]

i. Define acceptable limits for equipment and instrument

maintenance and, as applicable, calibration, and function checks prior

to their use in ART laboratory procedures.

ii. Perform maintenance and, as applicable, calibration, and

function checks in accordance with the equipment/instrument

manufacturer's instructions and at the frequency required to ensure

adequate performance of the equipment and instruments used in ART

laboratory procedures.

iii. Monitor environmental conditions, using an independent

measuring device, in critical equipment, including but not limited to,

incubators, controlled-rate freezers and liquid nitrogen storage tanks,

at a frequency that ensures timely detection of conditions that are

deleterious to specimens. These conditions include, if applicable:

A. Temperature;

B. Humidity;

C. Gas concentration; and

D. Liquid nitrogen levels.

iv. Maintain an alarm system on critical equipment that will

immediately detect when pre-established limits for the environmental

conditions listed in subparagraph 2.b.iii. (excluding humidity), of

this section, are exceeded. The alarm system must be:

A. Checked periodically to ensure that it will be triggered when

preestablished limits for environmental conditions are exceeded; and

B. Monitored 24 hours a day in the laboratory or at a remote site.

v. Protect critical equipment and instrumentation from fluctuations

and interruptions in electrical current.

vi. Have available emergency back-up capability for critical

equipment, including but not limited to, incubators, refrigerators and

controlled-rate freezers.

vii. Document all maintenance, calibration, and function checks

performed.

c. Identify, investigate, and correct problems with equipment or

instrumentation that may adversely affect the performance of ART

laboratory procedures.

d. Document all corrective actions taken when problems with

equipment or instrumentation are identified.

3. Labeling, Handling, and Storage of Chemicals, Reagents,

Solutions, Culture Media, Materials and Supplies. The embryo laboratory

must label, handle and store chemicals, reagents, solutions, culture

media, materials and supplies in a manner that ensures their positive

identification, optimum integrity and appropriate reactivity in ART

laboratory procedures. The laboratory must--

a. Have a mechanism for ensuring sufficient chemicals, reagents,

solutions, culture media, materials and supplies for the type and

volume of ART laboratory procedures performed (e.g., inventory

maintenance program).

b. Define criteria that are essential for proper storage of

chemicals, reagents, solutions, and culture media, including the

following, as applicable:

i. Temperature;

ii. Humidity; and

iii. Other conditions necessary for proper storage.

c. Label all chemicals, reagents, solutions, and culture media to

indicate the following, as applicable:

i. Identity, and when significant, batch or lot number, titer,

strength, or concentration;

ii. Recommended storage conditions;

iii. Expiration date; and

iv. Other pertinent information required for proper use.

d. Verify that materials which come in contact with sperm, oocytes,

and embryos have been tested and found to be non-toxic to sperm,

oocytes, and embryos. Documentation supplied by the manufacturer may be

used to meet this requirement.

e. Maintain records documenting the batch or lot number, date of

receipt or preparation, and date placed in use, for all chemicals,

reagents, solutions, and culture media.

f. Prepare, store, and handle chemicals, reagents, solutions, and

culture media in a manner to ensure that they are not used when they

have exceeded their expiration date, have deteriorated, or are of

substandard quality.

4. Specimen and Procedure Management. The embryo laboratory must

have written protocols and criteria for the laboratory procedures

performed and employ and maintain a system that provides for proper

patient identification and preparation; specimen collection,

identification, and handling (transportation, processing, storage,

preservation); and accurate recording and reporting of laboratory

procedural outcomes.

a. The laboratory must have available and follow written policies

and procedures for each of the following:

i. Instructions for patient preparation, if applicable;

ii. Methods used for the positive identification of patients;

iii. Specimen collection;

iv. The labeling of patient specimens to ensure positive

identification from the time of specimen collection through final

disposition or disposal;

v. Criteria for maintaining specimen integrity and viability during

transport, storage and the performance of ART laboratory procedures

including, as applicable, requirements for:

A. Temperature;

B. Humidity; and

C. Gas concentration; and

vi. Criteria for specimen acceptability and, as appropriate,

instructions for special handling of suboptimal specimens.

b. The laboratory must have adequate systems in place to ensure

patient confidentiality throughout those parts of the ART process that

are under the laboratory's control.

c. The laboratory may perform ART laboratory procedures only at the

written or electronic request of an authorized person. Oral requests

for changes to the original written or electronic request must be

documented by the laboratory and followed by receipt of written or

electronic documentation from an authorized person within 24 hours of

the oral request. The patient's chart or medical record may be used for

written authorization, but must be available to the laboratory at the

time of the laboratory procedure. Written or electronic authorization

must include the following:

i. The patient's name and an unique identifier;

ii. When applicable, the partner's or donor's name or other unique

identifier;

iii. The name and address or other suitable identifiers of the

authorized person requesting the procedure, and the name of the

individual communicating the request;

iv. The procedure(s) to be performed;

v. The date(s) and time(s) the procedure(s) is to be performed; and

vi. Any additional information relevant and necessary to the

performance of the procedure(s) including verification of informed

patient consent, and as applicable, special handling instructions and

any instructions stipulated by the patient.

d. As applicable, the laboratory must establish and follow written

protocols, including documented criteria, for--

i. Evaluation and assessment of oocyte morphology and maturity,

fertilization, and embryo quality.

ii. Insemination schedule relative to oocyte maturity.

iii. Volume, numbers, and quality of sperm used for insemination of

each oocyte.

iv. Disposition of oocytes with an abnormal number of pronuclei.

v. Disposition of excess oocytes.

vi. The time period following insemination for examination of

oocytes to determine fertilization.

[[Page 39390]]

vii. Micromanipulation of oocytes and embryos.

viii. Re-insemination of oocytes.

ix. Cryopreservation of specimens.

x. Embryo transfer procedures, which include the following:

A. The length of time embryos are cultured prior to transfer;

B. The medium and protein supplementation used for transfer, as

applicable;

C. Disposition of excess embryos;

D. Types of catheters available, with circumstances for use of

each;

E. Method of transfer; and

F. Technique for post transfer catheter check.

e. The laboratory must maintain a record system, for each patient's

ART cycle, to ensure reliable identification and control of the

patient's specimens as they are received and the laboratory

procedure(s) performed. The record system must include documentation of

the information specified in subparagraph 4.c. of this section, and--

i. The laboratory accession number, or other unique identification

of the specimen.

ii. The date and time of specimen receipt into the laboratory and,

as applicable, the number of oocytes retrieved and assessment of each

oocyte or cumulus corona complex.

iii. The condition and disposition of all specimens including those

that do not meet the laboratory's criteria for acceptability.

iv. The records and dates of all laboratory handling and

procedures, including the following, as applicable:

A. Semen assessment before and after washing and concentration for

insemination;

B. Outcome of insemination or micromanipulation procedures (e.g.,

fertilization);

C. Outcome of any culture (e.g., cleavage);

D. Relative timing of protocol events (incubation hours, etc.);

E. Assessment of the developmental status and quality of all

embryos at transfer;

F. Verification that no embryos remain in the catheter following

completion of transfer;

G. The identity and lot numbers of the media and media supplements

used in each phase of the procedure; and

H. The identity of the laboratory personnel who handled the

specimens and performed the procedures.

f. The laboratory must have a mechanism in place for promptly

providing the authorized person who ordered the procedure a complete

summary of all procedural outcomes and the occurrence of any unusual or

abnormal events, including the condition and disposition of specimens

that do not meet the laboratory's criteria for acceptability.

g. The laboratory must have an accurate and reliable method of

tracking cryopreserved specimens ensuring positive identification of

each cryopreservation container. In addition, the cryopreservation

container must be labeled with the patient's name or unique identifier,

and the date the specimen(s) was frozen. All labeling must be of a

permanent nature. Documentation must be maintained in duplicate log

books or files for each liquid nitrogen storage tank and include the

following:

i. The patient's name or other unique identifier;

ii. A description of each cryopreservation container's contents;

iii. The freezing protocol used;

iv. Date frozen;

v. Type and location of cryopreservation container (e.g., straw,

vial); and

vi. Final disposition/disposal of the cryopreserved specimen(s).

h. If cryopreserved specimens are received from or transferred to

other facilities, the laboratory must have written policies and

procedures for the receipt/transfer of cryopreserved specimens.

Policies and procedures must include appropriate methods of

transportation and the method for verifying the identification and

number of cryopreservation containers received/transferred. In

addition, documentation of the freezing protocol used, and copies of

patient release forms and applicable log sheets must accompany the

cryopreserved specimens.

i. Clinical laboratory testing on specimens obtained by the embryo

laboratory to provide information for the diagnosis, prevention or

treatment of disease, or assessment of the health of human beings must

be performed in accordance with the regulations implementing CLIA at 42

CFR Part 493. In addition--

i. The referring embryo laboratory must not revise results or

information directly related to the interpretation of results provided

by the testing laboratory.

ii. The referring embryo laboratory may permit the testing

laboratory to send the test result(s) directly to the authorized person

who initially requested the testing. The embryo laboratory must retain

or be able to produce an exact duplicate of the testing laboratory's

report.

iii. The authorized person who orders a clinical laboratory test

must be notified by the referring embryo laboratory of the name and

address of the testing laboratory.

5. Method Validation. All ART procedures selected or established by

the embryo laboratory must be validated by the laboratory prior to

routine patient use. The laboratory must determine appropriate

performance measures and demonstrate that the procedure, when performed

by the laboratory's staff, meets or exceeds acceptable levels of

performance as defined by the laboratory. In addition, the laboratory

must periodically verify, through its quality management activities (as

specified in this part), each procedure's continued acceptable level of

performance. All validations must be documented.

6. Quality Control. The embryo laboratory must establish and follow

written quality control procedures at a frequency appropriate to

monitor the reliability of the ART laboratory procedures performed. All

quality control activities must be documented. The laboratory must--

a. Establish acceptability criteria for all quality control

procedures.

b. Perform and document the remedial action(s) taken when problems

are identified or quality control procedures do not meet the

laboratory's criteria for acceptability.

c. For each laboratory procedure performed and, as applicable,

culture media preparation--

i. Define and use the appropriate grade of water required.

ii. Periodically monitor water quality to ensure that its quality

continues to meet the laboratory's specifications for its intended use.

As applicable, adherence to manufacturers' storage and handling

requirements, and expiration dates may meet this requirement.

d. As applicable, have and follow a written procedure for the

preparation, washing and sterilization of glassware used in the

laboratory's procedures that includes the following:

i. Rinsing all washable glassware with distilled or deionized water

prior to drying; and

ii. If detergent is used, testing washed items for detergent

removal.

e. Have and follow a written procedure for the quality control of

culture media which includes a visual check for physical damage to the

media container and evidence of media contamination prior to its use

and--

i. For each batch of culture media prepared in-house, document the

quality of the media by testing--

A. pH.

B. Osmolality.

C. Culture suitability using an appropriate bioassay system.

[[Page 39391]]

ii. For each batch of commercially prepared culture media--

A. Verify and document the quality of the media with an appropriate

bioassay system. Documentation of quality control performed by the

manufacturer may meet this requirement.

B. Follow the manufacturer's specifications for using the media.

iii. Test and document the quality of any media supplementation

(e.g., protein), when appropriate, using a bioassay system.

iv. While the use of blood-based media or a blood-based media

supplement (e.g., human fetal cord serum) prepared in-house is not

recommended, if such media or supplements are prepared, the laboratory

must test blood from the donor(s) used to make the media/supplement

with a FDA licensed, approved, or cleared test and show the donor(s) to

be negative/nonreactive for the following communicable diseases prior

to use of the media/supplement:

A. Human immunodeficiency virus, Type 1 (e.g., anti-HIV-1);

B. Human immunodeficiency virus, Type 2 (e.g., anti-HIV-2);

C. Hepatitis B virus (e.g., HbsAg);

D. Hepatitis C virus (e.g., anti-HCV);

E. Human T-cell lymphotrophic virus, Types I and II (e.g., anti-

HTLV I/II); and

F. Such other diseases that may be later added to this list.

Note: A batch of media (solid, semi-solid, or liquid) consists

of all tubes, plates, or containers of the same medium prepared at

the same time in the laboratory; or, if received from an outside

source or commercial supplier, consists of all of the plates, tubes

or containers of the same medium that have the same lot numbers and

are received in a single shipment.

7. Quality Assurance. The embryo laboratory must establish and

follow written policies and procedures for a quality assurance program

to monitor the quality of services provided by the laboratory, and

resolve problems that are identified. The laboratory must have a

mechanism to evaluate the effectiveness of its policies and procedures;

identify and correct problems; and assure the adequacy and competency

of the staff. As necessary, the laboratory must revise its policies and

procedures based on the results of those evaluations. All quality

assurance activities must be documented.

a. The laboratory must have an ongoing mechanism for monitoring,

evaluating and revising, if necessary, based on the results of its

evaluations, the following:

i. The criteria established for patient identification and specimen

collection, identification, and handling;

ii. The information requested and maintained on each patient and

for each laboratory procedure performed for its completeness, relevance

and necessity;

iii. The timeliness and accuracy of recording and reporting

procedural outcomes;

iv. The accuracy and reliability of tracking cryopreserved

specimens;

v. The appropriate storage and retrieval of laboratory records such

as procedural outcomes, and other data recorded and maintained; and

vi. The corrective actions taken for--

A. Problems identified during the evaluation of equipment and

instrument maintenance, calibration, and function check data.

B. Problems identified during the evaluation of quality control

data.

C. Errors detected in patient or specimen identification and

handling.

D. Clerical or analytical errors detected in laboratory records.

b. The embryo laboratory must have an ongoing mechanism to--

i. Identify and evaluate laboratory procedural outcomes that appear

inconsistent with the patient or donor history.

ii. Track and evaluate laboratory procedural outcomes including,

but not limited to, fertilization rates, cleavage rates and embryo

quality.

iii. Maintain a file of adverse reactions occurring as a result of

errors made during the performance of ART laboratory procedures.

iv. Evaluate the effectiveness of its policies and procedures for

assuring employee competence in performing ART laboratory procedures.

v. Document problems that occur as a result of a breakdown in

communication between the laboratory and referring physicians or others

involved in the ART procedures, and take corrective actions to resolve

the problems and minimize future communications breakdowns.

vi. Assure that all complaints and problems reported to the

laboratory are documented. Investigations of complaints must be made,

when appropriate, and as necessary, corrective actions must be

instituted.

vii. Document and assess problems identified during quality

assurance reviews, and discuss them with the laboratory staff and, as

appropriate, referring physicians and others involved in the ART

procedures. The laboratory must take the necessary corrective actions

to prevent recurrences.

D. Maintenance of Records

The embryo laboratory must retain records of all of its policies

and procedures; personnel employment, training, evaluations and

continuing education activities; and quality management activities

specified in this part.

1. Record Format. Laboratory records must be accurate, indelible,

and legible. Records may be retained electronically, or as original

paper records, or as true copies such as photocopies, microfiche, or

microfilm.

2. Retention Period. Laboratory records must be retained in

accordance with time frames specified by applicable Federal, State and

local laws or for ten years beyond the date of final disposition or

disposal of all specimens obtained during each patient's ART cycle,

whichever is later. Records must be retained on site for two years.

Note: Transfer of cryopreserved specimens to another facility

constitutes final disposition for the transferring facility.

3. Record Retrieval. Laboratory records must be maintained in a

manner which ensures timely, accurate and reliable retrieval.

4. Laboratory Closure. In the event that the laboratory ceases

operation, the laboratory must make provisions for these records to be

maintained for the time frame required above.

Addendum

References

1. The American Association of Bioanalysts. Embryology and Andrology

Review Course. American Association of Bioanalysts, St. Louis,

Missouri, 1994.

2. The American Association of Tissue Banks. Standards for Tissue

Banking. The American Association of Tissue Banks, McLean, Virginia,

1996.

3. The American Society for Reproductive Medicine. Revised Minimum

Standards for In Vitro Fertilization, Gamete Intrafallopian

Transfer, and Related Procedures. Fertility and Sterility 1998; 70

(Suppl 2) :1S-5S.

4. Association of Clinical Embryologists. Accreditation Standards

and Guidelines for IVF Laboratories. Association of Clinical

Embryologists, London, England, 1996.

5. California Health and Safety Code, Division 2, Chapter 4.1--

Tissue Banks. State of California, Department of Health Services,

Berkeley, California, 1992.

6. Centers for Disease Control and Prevention. Reporting of

Pregnancy Success Rates from Assisted Reproductive Technology

Programs. 62 FR 45259, Aug. 26, 1997.

7. Centers for Disease Control and Prevention. Implementation of the

Fertility Clinic Success Rate and Certification Act of 1992;

Proposed Model Program for the Certification of Embryo Laboratories.

63 FR 60178, Nov. 6, 1998.

8. Code of Federal Regulations, Title 42, Chapter IV, Part 493--

Laboratory Requirements.

[[Page 39392]]

9. The College of American Pathologists/American Society for

Reproductive Medicine Reproductive Laboratory Accreditation Program.

The College of American Pathologists, Northfield, Illinois, 1996.

10. The Fertility Clinic Success Rate and Certification Act of 1992

(Public Law 102-493).

11. Guidance for Industry, Public Health Issues Posed by the Use of

Nonhuman Primate Xenografts in Humans. Food and Drug Administration,

Center for Biologics Evaluation and Research, April, 1999.

12. Keel BA and BW Webster. CRC Handbook of the Laboratory Diagnosis

and Treatment of Infertility. CRC Press, Inc., Boca Raton, Florida,

1990.

13. Rules 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 York, 1992.

14. Senate Report 102-452 on H.R. 4773. Fertility Clinic Success

Rate and Certification Act of 1992. 102d Congress, 2d Session, 1992.

15. Survey of Assisted Reproductive Technology Embryo Laboratory

Procedures and Practices. www.phppo.cdc.gov/dls/pdf/art/

ARTsurvey.pdf.

16. Veeck LL. The Gamete Laboratory: Design, Management and

Techniques. pp. 798--820 in: Infertility: Evaluation and Treatment.

Edited by WR Keye, RJ Chang, RW Rebar and MR Soules. WB Saunders,

Philadelphia, Pennsylvania, 1995.

[FR Doc. 99-18405 Filed 7-19-99; 11:53 am]

BILLING CODE 4163-18-P