[Federal Register Volume 62, Number 171 (Thursday, September 4, 1997)]
[Proposed Rules]
[Pages 46686-46695]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-23449]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 884

[Docket No. 97N-0335]


Obstetric and Gynecologic Devices: Reclassification of Medical 
Devices Used for In Vitro Fertilization and Related Assisted 
Reproduction Procedures

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
reclassify instrumentation intended for use in in vitro fertilization 
(IVF) and related assisted reproduction procedures from class III to 
class II. FDA is also proposing to reclassify assisted reproduction 
microscopes and microscope accessories from class III to class I and to 
exempt this device from the requirement of premarket notification. This 
reclassification is being proposed on the Secretary of Health and Human 
Services' own initiative, based on new information. This action is 
being taken under the Federal Food, Drug, and Cosmetic Act (the act), 
as amended by the Medical Device Amendments of 1976 (the 1976 
amendments) and the Safe Medical Devices Act of 1990 (the SMDA).

DATES: Written comments by December 3, 1997. FDA proposes that any 
final regulation based on this proposal become effective 30 days after 
its date of publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Elisa D. Harvey, Center for Devices 
and Radiological Health (HFZ-470), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-594-1180.

SUPPLEMENTARY INFORMATION:

I. Background

A. Regulatory Authorities

    The act (21 U.S.C. 201 et seq.), as amended by the 1976 amendments 
(Pub. L. 94-295) and the SMDA (Pub. L. 101-629), established a 
comprehensive system for the regulation of medical devices intended for 
human use. Section 513 of the act (21 U.S.C. 360c) established three 
categories (classes) of devices, depending on the regulatory controls 
needed to provide reasonable assurance of their safety and 
effectiveness. The three categories of devices are: Class I (general 
controls), class II (special controls), and class III (premarket 
approval).
    Under section 513 of the act, devices that were in commercial 
distribution before May 28, 1976 (the date of enactment of the 
amendments), generally referred to as preamendments devices, are 
classified after FDA has: (1) Received a recommendation from a device 
classification panel (an FDA advisory committee); (2) published the 
panel's recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    Devices that were not in commercial distribution prior to May 28, 
1976, generally referred to as postamendments devices, are classified 
automatically by statute (section 513(f) of the act) into class III 
without any FDA rulemaking process. Those devices remain in class III 
and require premarket approval, unless and until FDA issues an order 
finding the device to be substantially equivalent, under section 513(i) 
of the act, to a predicate device that does not require premarket 
approval. The agency determines whether new devices are substantially 
equivalent to previously offered devices by means of premarket 
notification procedures in section 510(k) of the act (21 U.S.C. 360(k)) 
and part 807 (21 CFR part 807).
    Section 513(f)(2) of the act provides that FDA may initiate the 
reclassification of a device classified into class III under section 
513(f)(1) of the act, or the manufacturer or importer of a device may 
petition the agency to reclassify the device into class I or class II. 
FDA's regulations in Sec. 860.134 (21

[[Page 46687]]

CFR 860.134) set forth the procedures for the filing and review of a 
petition for reclassification of such class III devices. In order to 
change the classification of the device it is necessary that the 
proposed new class have sufficient regulatory controls to provide 
reasonable assurance of the safety and effectiveness of the device for 
its intended use. FDA relied upon ``valid scientific evidence,'' as 
defined in section 513(a)(3) of the act and 21 CFR 860.7(c)(2), in the 
classification process to determine the level of regulation for 
devices. For the purpose of reclassification, the valid scientific 
evidence upon which the agency relied must be publicly available. 
Publicly available information excludes trade secret and/or 
confidential information, e.g., the contents of premarket approval 
applications (PMA's) (see section 520(c) of the act (21 U.S.C. 
360j(c)).
    Section 513(d)(2)(A) of the act authorizes FDA to exempt, by 
regulation, a generic type of class I device from, among other things, 
the requirement of premarket notification in section 510(k) of the act 
after stating the reasons for making such a requirement inapplicable. 
Such an exemption permits manufacturers to introduce into commercial 
distribution generic types of devices without first submitting a 
premarket notification to FDA. If FDA has concerns about certain types 
of changes to a particular class I device, the agency may grant a 
limited exemption from premarket notification for that generic type of 
device.

B. Regulatory History of the Devices

    Devices specifically intended for IVF and embryo transfer (ET) were 
developed and studied after enactment of the 1976 amendments. The first 
premarket notification submission (510(k)) for a device with an IVF 
indication for use was submitted to FDA in 1986. FDA found this device, 
and several subsequent to it, not substantially equivalent to 
preamendments devices because the IVF indication for use constituted a 
new intended use for these devices. Consequently, these devices were 
classified into class III by statute.
    On January 29, 1988, FDA convened the Obstetrical and Gynecological 
Devices Panel (the Panel), an FDA advisory committee, to identify and 
discuss medical devices used for IVF or gamete intrafallopian transfer 
(GIFT), and to identify the data required for the evaluation of safety 
and effectiveness, in order to assist FDA in developing a regulatory 
strategy for medical devices used for IVF and related assisted 
reproductive technology (ART) procedures (Ref. 12). The Panel 
considered a wide variety of medical devices already being used by IVF 
clinics. Besides the overall quality and sterility of these devices, 
the Panel focused on one key concern that applied to many of the 
devices used for IVF, namely possible material toxicity of the device 
to gametes or embryos. The Panel agreed with many of the guest speakers 
that there was a general need to evaluate many of these IVF devices 
using the mouse embryo assay (MEA).
     The MEA had been shown to be highly predictive of material safety. 
The Panel discussed what devices should be subjected to a variety of 
test regimens. The Panel agreed that, in general, IVF had been shown to 
be safe and effective for properly selected patients, and that many of 
the generic types of devices used in IVF/ART procedures could be 
adequately regulated by special controls. The Panel believed that each 
generic type of device used for IVF/ET was a candidate for 
reclassification if certain recognized testing, specifications, and/or 
labeling requirements were imposed.
    Reclassification of devices can be initiated following a petition 
from a manufacturer, and FDA encouraged interested manufacturers to do 
so following the 1988 Panel meeting. However, no such petition was 
submitted to FDA, and devices intended for use in IVF remained in class 
III. Use of IVF/ART procedures in the United States continued to grow. 
A variety of assisted reproduction technologies and procedures, 
including IVF/ET and GIFT, are now considered the standard of care for 
treatment of infertility in a selected population of patients (Refs. 1, 
6, 8, 17, 18, 20, 32, and 35).
    On October 21, 1995, FDA reconvened the Panel to reconsider the 
safety and effectiveness of these devices (Ref. 13). At the October 
1995 meeting, the Panel considered a new list of generic device names 
and identifications. FDA asked for scientific and clinical input on 
important design, manufacture, and use characteristics of these devices 
(Ref. 7). After presentations by FDA-invited guest speakers, industry, 
and professional societies, the Panel reviewed the background materials 
on these devices and made suggestions about appropriate testing 
requirements for each.
    The individual devices used for IVF/ET, such as oocyte retrieval 
needles, reproductive media, labware, and ET catheters, each perform a 
part of a multistaged procedure. The ultimate success of the assisted 
reproduction procedure (pregnancy) depends on the safety and 
effectiveness of each individual medical device used, as well as 
operating procedures within the IVF clinic and patient selection/
exclusion criteria. The 1988 and 1995 Panels agreed that premarket 
approval is not necessary to provide reasonable assurance of the safety 
and effectiveness of the individual medical devices used for IVF/ET.
    In accordance with section 513(f) of the act and Sec. 860.134, 
based on new information with respect to the device, FDA, on its own 
initiative, is proposing to reclassify the following instrumentation 
for assisted reproduction: (1) Needles; (2) catheters; (3) accessories; 
(4) microtools; (5) micropipette fabrication instruments; (6) 
micromanipulators and microinjectors; (7) labware; (8) water and water 
purification systems; and (9) reproductive media and supplements, from 
class III to class II when intended for the uses specified below in the 
device description section. Additionally, in accordance with section 
513(f) of the act and Sec. 860.134, based on new information with 
respect to the device, FDA, on its own initiative, is proposing to 
reclassify the assisted reproduction microscopes and microscope 
accessories from class III to class I when intended to enlarge images 
of gametes or embryos. Furthermore, FDA is proposing to exempt assisted 
reproduction microscopes and microscope accessories used for IVF and 
related assisted reproduction procedures from premarket notification 
requirements.
    Consistent with the act and the regulation, and because the Panel 
had been consulted earlier in the process and offered input on 
appropriate design and test requirements, FDA did not refer the 
proposed reclassification back to the Panel for its recommendation on 
the requested change in classification.

II. Device Descriptions

    The following is a list of medical devices, with their respective 
identifications, covered by this reclassification. It is important to 
note that these requirements apply only to products that are intended 
for use in assisted reproduction. General purpose devices (e.g., 
incubators, freezers, and water purification systems), which are not 
intended for use in assisted reproduction, are not subject to the 
regulatory controls described later in this proposed rule.
    1. Assisted reproduction needles: Assisted reproduction needles are 
devices used to either obtain gametes from the body, or introduce 
gametes, zygote(s), preembryo(s), and/or embryo(s) into the body. This 
generic

[[Page 46688]]

type of device may include a single or double lumen needle and 
component parts, including needle guides such as those used with 
ultrasound.
    2. Assisted reproduction catheters: Assisted reproduction catheters 
are devices used to introduce or remove gametes, zygote(s), 
preembryo(s), and/or embryo(s) into or from the body. This generic type 
of device may include catheters, cannulae, introducers, dilators, 
sheaths, and component parts.
    3. Assisted reproduction accessories: Assisted reproduction 
accessories are a group of devices used during assisted reproduction 
procedures, in conjunction with assisted reproduction needles and/or 
assisted reproduction catheters to aspirate, incubate, infuse, and/or 
maintain temperature. This generic type of device may include:
    (a) Powered aspiration pumps, used to provide low flow, 
intermittent vacuum for the aspiration of eggs (ova).
    (b) Syringe pumps (powered or manual), used to activate a syringe 
to infuse or aspirate small volumes of fluid during assisted 
reproduction procedures.
    (c) Collection tube warmers, used to maintain the temperature of 
egg (oocyte) collection tubes at or near body temperature. A dish/
plate/microscope stage warmer is a device used to maintain the 
temperature of the egg (oocyte) during manipulation.
    (d) Embryo incubators, used to store and preserve gametes and/or 
embryos at or near body temperature.
    (e) Cryopreservation instrumentation and devices, used to contain, 
freeze, and maintain gametes and/or embryos at an appropriate freezing 
temperature.
    4. Assisted reproduction microtools: Assisted reproduction 
microtools are pipettes or other devices used in the laboratory to 
denude, micromanipulate, hold or transfer human gametes, or embryos for 
assisted hatching, intracytoplasmic sperm injection (ICSI), embryo 
biopsy, or other assisted reproduction methods, including 
preimplantation diagnosis.
    5. Assisted reproduction micropipette fabrication instruments: 
Assisted reproduction micropipette fabrication devices are instruments 
intended to pull, bevel, or forge a micropipette or needle for ICSI, 
IVF, or other similar procedures.
    6. Assisted reproduction micromanipulators and microinjectors: 
Assisted reproduction micromanipulators are devices intended to control 
the position of an assisted reproduction microtool. Assisted 
reproduction microinjectors include any device intended to control 
aspiration or expulsion of the contents of an assisted reproduction 
microtool.
    7. Assisted reproduction labware: Assisted reproduction labware 
consists of laboratory equipment or supplies intended to prepare, 
store, manipulate, or transfer human gametes or embryos for IVF or 
other assisted reproduction techniques. These include syringes, IVF 
tissue culture dishes, IVF tissue culture plates, pipette tips, dishes, 
plates, and other vessels that come into physical contact with gametes, 
embryos, or tissue culture media.
    8. Assisted reproduction water and water purification systems: 
Assisted reproduction water purification systems are devices intended 
to generate high quality sterile, pyrogen-free, distilled, deionized 
water for reconstitution of media used for aspiration, incubation, 
transfer or storage of gametes or embryos for IVF or other assisted 
reproduction procedures. They may also be intended as the final rinse 
for labware or other assisted reproduction devices that will contact 
the gametes or embryos. This device also includes bottled water that is 
specifically intended for reconstitution of media used for aspiration, 
incubation, transfer or storage of gametes or embryos for IVF or other 
assisted reproduction procedures.
    9. Reproductive media and supplements: Reproductive media ad 
supplements are products that are used for assisted reproduction 
procedures. Media include liquid and powder versions of carious 
substances that come in direct physical contact with human gametes or 
embryos (including oil used to cover the media) for the purposes of 
preparation, maintenance, transfer or storage, and supplements include 
specific reagents added to media to enhance specific properties of the 
media (e.g., proteins, sera, antibiotics, etc.).
    10. Assisted reproduction microscopes and microscope accessories: 
Assisted reproduction microscopes and microscope accessories (excluding 
microscope stage warmers, which are classified under Assisted 
Reproduction Accessories) are optical instruments used to enlarge 
images of gametes or embryos. Variation of microscopes and microscope 
accessories used for these purposes would include phase contrast 
microscopes, fluorescence microscopes, dissecting microscopes, and 
inverted stage microscopes.

III. Proposed Reclassification

    FDA is proposing that assisted reproduction: (1) Needles; (2) 
catheters; (3) accessories; (4) microtools; (5) micropipette 
fabrication instruments; (6) micromanipulators and microinjectors; (7) 
labware; (8) water and water purification systems; and (9) reproductive 
media and supplements; with the intended uses specified in section II 
of this document, be reclassified from class III to class II. FDA 
believes that class II, with the following special controls, would 
provide reasonable assurance of the safety and effectiveness of these 
devices: (1) The MEA (see Davidson et al., 1988 (Ref. 4); May, 1996 
(Ref. 10)); (2) endotoxin testing (see Nagata and Shirakawa, 1996; and 
United States Pharmacopeia (USP), 23d ed. (Ref. 10)); (3) design 
specifications; (4) labeling; (5) clinical studies; and (6) voluntary 
standards (College of American Pathologists (CAP) Reproductive 
Laboratory Accreditation Program (Ref. 16), Society for Assisted 
Reproductive Technology (SART, Refs. 22 through 31)). In addition, FDA 
is developing a policy addressing regulation of tissue culture media 
for a variety of in vivo applications, including assisted reproduction. 
Guidance for performance and labeling of such products, based on 
differing claims, is being evaluated with input from industry. For 
general claims, it is expected that minimum performance data (based on 
toxicologic, microbiologic, and chemical studies) will be required. 
More specific clinical claims will require additional data.
    FDA also proposes that assisted reproduction microscopes and 
microscope accessories used for IVF and related assisted reproduction 
procedures be reclassified from class III to class I. FDA believes that 
class I general controls are sufficient to provide reasonable assurance 
of the safety and effectiveness of these devices. Furthermore, FDA is 
proposing to exempt assisted reproduction microscopes and microscope 
accessories from premarket notification requirements.

IV. Risks to Health

    Because the inception of IVF and related ART procedures in the 
early 1980's, a wealth of literature regarding the safety and 
effectiveness of this technology has become available (Refs. 1, 5, 6, 
8, 11, 18, 20, 22 through 30, 35, 37, and 38). The long history of use 
of devices for assisted reproduction and the large amount of published 
literature have demonstrated that the potential risks from use of these 
devices are now well-known and extensively documented. The following is 
a summary of the overall general potential risks that may be associated 
with the use of assisted reproduction devices to the gametes or embryo 
and the patient,

[[Page 46689]]

including background information, and identification of the general or 
special controls that FDA believes address each risk. The risks may or 
may not apply to each individual device. Risks to health with the 
devices mentioned in section II of this document may involve trauma or 
damage to the patient (see discussion below), to gametes or embryos.

A. Gamete or Embryo Damage

    Gamete or embryo damage could occur which would render them viable 
but damaged, or nonviable. This could occur with the knowledge of the 
gynecologist, so that affected gametes or embryos would not be used in 
the procedures, or without the knowledge of the gynecologist, in which 
case damaged or nonviable gametes or embryos could be used in assisted 
reproductive procedures. This could result in cycles lost or potential 
development of damaged embryos, which may result in later loss of 
pregnancy or congenital defects. Nevertheless, if recommended testing 
procedures are followed, there is reasonable assurance that the risk of 
damage to gametes or embryos is small. The assisted reproduction 
devices most likely to present this risk are assisted reproduction 
needles, assisted reproduction catheters, assisted reproduction 
accessories, assisted reproduction microtools, assisted reproduction 
micromanipulators and microinjectors, and reproductive media and 
supplements. The special controls for these devices that would mitigate 
this risk would be the MEA, device sterilization validation, water 
quality testing, design specifications, labeling, and voluntary 
standards (in which techniques for using these devices are described).

B. Pain

    The incidence of pain or discomfort associated with assisted 
reproduction procedures has been estimated at 0 to 11.6 percent (Refs. 
2 and 9), depending on the specific procedure or part of the procedure 
being done. Typically it is associated with percutaneous abdominal 
needle puncture for oocyte retrieval, and it may be tolerable to the 
patient. In the event that the pain is intolerable, it may be mitigated 
by the use of local anesthetic. The assisted reproduction devices most 
likely to present this risk are assisted reproduction needles and 
assisted reproduction catheters. The special controls for these devices 
that would mitigate this risk would be labeling (specifically, 
instructions for use), design specifications, and voluntary standards 
(in which techniques for using these devices are described).

C. Hematuria

    The incidence of hematuria has been estimated at 0.4 to 13.3 
percent (Refs. 2, 9, 19, 34, and 39). This may occur due to the 
aspiration needle penetrating a filled bladder, and it may be 
accompanied by extravasation of urine or transient dysuria. These are 
short-term problems that typically resolve spontaneously within 24 
hours. The assisted reproduction devices most likely to present this 
risk are assisted reproduction needles and assisted reproduction 
catheters. The special controls for these devices that would mitigate 
this risk would be labeling (specifically, instructions for use), 
design specifications and voluntary standards (in which techniques for 
using these devices are described).

D. Infection (Uterine, Urinary Tract Infection (UTI), Exacerbation of 
Pelvic Inflammatory Disease (PID), and Cystitis)

    The incidence of infection occurring as a consequence of an 
assisted reproduction procedure has been estimated at 0.5 to 6.9 
percent (Refs. 2, 9, 19, 34, and 39). If a needle puncture traverses 
the bladder, cystitis is a possible sequela. Infection may be 
introduced via needle puncture, or the use of any contaminated 
(unsterile) device, as well as by lack of adherence to strict sterile 
technique. For these reasons, antibiotics are prophylactically 
administered. These complications can also be minimized with close 
attention to sterile technique and careful screening for preexisting 
active or latent pelvic infections. The assisted reproduction devices 
most likely to present this risk are assisted reproduction needles, 
assisted reproduction catheters, assisted reproduction accessories, 
assisted reproduction microtools, assisted reproduction 
micromanipulators and microinjectors, and reproductive media and 
supplements. The special controls for these devices that would mitigate 
this risk would be the MEA, endotoxin testing, device sterilization 
validation, water quality testing, design specifications, labeling, and 
voluntary standards (in which techniques for using these devices are 
described).

E. Bleeding

    The incidence of bleeding during assisted reproduction procedures 
has been estimated at 3.5 to 17 percent (Refs. 2, 9, 19, 34, and 39), 
and typically is associated with transvaginal oocyte retrieval or 
trauma secondary to insertion of a catheter through the cervix. 
Bleeding can usually be easily controlled with direct pressure. The 
assisted reproduction devices most likely to present this risk are 
assisted reproduction needles and assisted reproduction catheters. The 
special controls for these devices that would mitigate this risk would 
be design specifications, labeling, and voluntary standards (in which 
techniques for using these devices are described).

F. Puncture of Blood Vessels, Uterus, or Bowel

    The incidence of inadvertent puncture of intra- or retro-abdominal 
structures is estimated at 0.2 to 5.1 percent for blood vessels, 0.9 to 
1.9 percent for bowel, and 1.9 to 2.6 percent for the uterus (Refs. 2, 
9, 19, 34, and 39). This can occur during oocyte retrieval procedures 
and is most often due to incorrect needle placement or inadequate 
knowledge of pelvic and abdominal anatomy by the operator. Incidence of 
these complications is minimized with increasing experience of the 
operator. Should any of these adverse events occur, surgical correction 
may be necessary to avoid further complications. The assisted 
reproduction devices most likely to present this risk are assisted 
reproduction needles and assisted reproduction catheters. The special 
controls for these devices that would mitigate this risk would be 
design specifications, labeling, and voluntary standards (in which 
techniques for using these devices are described).

G. Other (Ectopic Pregnancy, Multiple Gestation, or Chromosomal and 
Congenital Abnormalities)

    Ectopic pregnancy, multiple gestation, or chromosomal and 
congenital abnormalities are also risks of assisted reproduction 
procedures, though not specifically related to any device. Rather, the 
occurrence of these events is related more to the inherent risk of 
assisted reproduction procedures in general, patient factors, and the 
specific clinical practices employed. Nevertheless, special controls of 
labeling and voluntary standards will help to ensure that the user 
includes appropriate patient education that informs patients of these 
risks as well as the specific procedures to be performed and devices to 
be used.
    SART collects data from all of its members annually on success 
rates and the incidence of adverse events such as those listed above. 
According to SART's 1996 report (Ref. 30), the incidence of ectopic 
pregnancy following assisted reproduction procedures has

[[Page 46690]]

consistently remained in the range of 0.6 to 1.3 percent of all 
transfers performed (approximately 4 percent of established 
pregnancies) in the United States for several years. This is somewhat 
higher than the incidence of ectopic pregnancies (around 1.7 percent) 
in the general U.S. population (Ref. 15). The increased incidence of 
ectopic pregnancy following IVF procedures correlates strongly with 
tubal damage, which is a major cause of infertility in IVF patients. 
Other potential but less substantiated causes of ectopic pregnancy 
include the use of clomiphene, or ET techniques that use high 
intrauterine positioning of the catheter tip (near the tubal ostium) or 
large amounts of fluid. Heterotopic (simultaneous intrauterine and 
extrauterine) pregnancies are also a known complication following 
assisted reproductive procedures (Ref. 33) with an estimated incidence 
of up to 1.4 percent of pregnancies in IVF patients, compared to the 
general population's rate of 0.003 to 0.038 percent (Ref. 31). Risk 
factors for this complication also include tubal pathology and 
replacement of multiple embryos, as well as the other previously 
mentioned factors. Early transvaginal sonography has greatly improved 
the ability to detect ectopic or heterotopic pregnancies with nearly 
100 percent sensitivity and specificity. The assisted reproduction 
devices most likely to present this risk are assisted reproduction 
needles and assisted reproduction catheters. The special controls for 
these devices that would mitigate this risk would be design 
specifications, labeling, and voluntary standards (in which techniques 
for using these devices are described).
    Multiple gestation is the most common complication of assisted 
reproductive procedures, and it is obviously related to the number of 
embryos transferred per procedure or cycle, as well as the efficiency 
of implantation at a particular IVF facility. In the general U.S. 
population, twinning occurs in about 1.2 percent of deliveries, and 
triplets constitute 0.01 to 0.02 percent. The incidence of twins 
following assisted reproductive procedures ranges from about 20 to 35 
percent, and 2 to 6 percent for triplets or higher order births. (Refs. 
27 through 30). Risks associated with multiple gestation include 
increased chance of prematurity, increased perinatal morbidity and 
mortality, and increased maternal risks such as gestational 
hypertension (Ref. 1). These risks are not related per se to the 
medical devices used in accomplishing the procedure, but the practice 
of implanting multiple embryos to maximize the chance of achieving 
pregnancy. Various approaches to dealing with this problem have been 
suggested, including limiting the number of transferred zygotes or 
embryos to three or four, cryopreservation techniques for preserving 
extra zygotes or embryos for future use, and selective embryo reduction 
techniques. Early ultrasonographic monitoring of IVF patients provides 
the best method for documenting and following multiple gestation 
pregnancies in order to best treat these patients.
    SART estimates with its data from 1996 (Ref. 30) that the incidence 
of birth defects is between 1.8 to 2.7 percent of neonates, which 
approximate those seen in the general U.S. population (Ref. 3), 
especially when adjusted for maternal age. Because the incidence of 
these abnormalities increased with maternal age, this rate would be 
expected due to the advanced age of many IVF patients. This one factor 
accounts for most abnormalities, although other potential procedure-
related causes could be defects induced through ovulation stimulation, 
in vitro manipulations of gametes, or the lack of elimination of 
abnormal gametes via normal biological mechanisms.

V. Summary of Reasons for Reclassification

    FDA believes that the instrumentation for assisted reproduction: 
(1) Needles; (2) catheters; (3) accessories; (4) microtools; (5) 
micropipette fabrication; (6) micromanipulators and microinjectors; (7) 
labware; (8) water and water purification systems; and (9) reproductive 
media and supplements should be classified into class II because 
special controls, in addition to general controls, can provide 
reasonable assurance of the safety and effectiveness of the devices, 
and there is sufficient information to establish special controls to 
provide such assurance. FDA believes that general controls alone are 
not sufficient to provide reasonable assurance of the safety and 
effectiveness of these devices.
    FDA believes that assisted reproduction microscopes and microscope 
accessories should be classified into class I because general controls 
would provide reasonable assurance of safety and effectiveness. 
Furthermore, FDA is proposing to exempt assisted reproduction 
microscopes and microscope accessories used for IVF and related 
assisted reproduction procedures from premarket notification 
requirements. These devices do not have a significant history of false 
or misleading claims or risks associated with their inherent 
characteristics such as device design or materials. In addition, the 
characteristics of these devices necessary for their safe and effective 
performance are well established.

VI. Summary of Data Upon Which the Reclassification is Based

    The number of IVF and other assisted reproduction procedures 
performed annually in the United States has grown considerably in 
recent years. In 1994, the most recent year from which statistics are 
available, about 33,000 IVF cycles were initiated, with approximately 
9,500 live-birth deliveries (Ref. 30).
    Success rates for standard IVF procedures have increased somewhat 
between 1991 and 1994, from about 15 to 21 percent per cycle initiated 
(see Table 1), while tubal transfer techniques such as GIFT and zygote 
intrafallopian transfer (ZIFT) have somewhat higher success rates in 
the range of 28 percent (Refs. 27 through 30). These include 
micromanipulation techniques such as ICSI, which is successful in 
treating male factor infertility, and assisted hatching. No consensus 
exists as to the explanation for the difference in success rates, but 
these techniques do reflect different patient populations and 
diagnostic categories. About 250 ART programs report data to a registry 
of SART (Ref. 30), published annually in Fertility and Sterility (Refs. 
22 through 30). Data reporting is mandatory for SART membership, and it 
is believed that most programs in the United States doing ART are 
reporting their data to SART.
    Adverse outcomes, such as ectopic pregnancy, pregnancy loss, 
stillbirth, and structural or functional anomalies, have remained 
steady over the period of 1991 to 1994. Ectopic pregnancy rates are 
about 1.5 to 4.0 percent of established pregnancies, or 0.6 to 1.3 
percent of ET's done. Pregnancy loss, most of which occurs during the 
first trimester, has remained around 20 percent. Stillbirths comprise 
approximately 1 percent of clinical pregnancies established, and 
congenital anomalies make up approximately 2 percent of neonatal 
outcomes. The incidence of prematurity was not recorded. The incidence 
of multiple gestations, a common feature of ART, was recorded, with 60 
to 67 percent (depending on the particular ART technique used) of 
births being singleton deliveries, about 29 percent of births being 
twin gestations, about 5 percent being triplet gestations, and less 
than 1 percent of multiple births being

[[Page 46691]]

quadruplets or greater (Refs. 27 through 30).
    The potential health benefit to be derived from the use of assisted 
reproductive devices is considerable. Infertility, defined as the 
inability to become pregnant within 1 year, is common in the United 
States today. Estimates range from 8.5 percent to 14 percent in couples 
over 30 years of age. IVF, an assisted reproductive technique wherein 
oocytes are retrieved from the ovaries and fertilized extracorporeally 
with subsequent embryo replacement (Ref. 1), was developed to treat 
infertility. In 1981, Elizabeth Carr became the first child born in the 
United States using IVF technology (Norfolk, VA). Since then, the 
number of IVF clinics in the United States has grown so that today 
approximately 250 specialized IVF clinics report their results to the 
SART registry. The use of these devices and their associated techniques 
provides the chance for restoration of reproductive function to those 
who would otherwise remain infertile (Ref. 25). Many advances have been 
made in assisted reproductive technology over the past two decades 
which have permitted treatment for more patients, including the ability 
to place oocyte aspiration needles transvaginally under ultrasonic 
guidance. This increases the ease and accuracy of the procedure and 
decreases procedure time and patient discomfort. It also decreases or 
avoids risks associated with general anesthesia and laparotomy or 
laparoscopy.

                                         Table 1.--ART Success Rates\1\                                         
----------------------------------------------------------------------------------------------------------------
                               1991                   1992                   1993                   1994        
----------------------------------------------------------------------------------------------------------------
Cycles Initiated\2\                                                                                             
IVF                          24,671 (15.2)          29,404 (16.8)          33,543 (18.3)          33,700 (20.7) 
GIFT\3\                       5,452 (26.6)           5,767 (26.3)           4,992 (28.1)           4,214 (28.4) 
ZIFT\3\                       2,104 (19.7)           1,993 (22.8)           1,792 (24.4)             926 (29.1) 
Combination                     714 (19.3)             791 (27.9)             882 (27.8)             550 (29.7) 
Frozen ET\3\                  4,838 (11.1)           5,814 (13.9)           6,869 (13.3)           7,046 (15.4) 
Donor Oocytes                 1,107 (25.6)           2,032 (31.3)           2,766 (30.2)           3,119 (46.8) 
                                                                                                                
Total Deliveries                  5,699                  7,355                  8,741                  9,573    
Number of Programs                  215                    249                    267                    249    
----------------------------------------------------------------------------------------------------------------


                                         Table 2.--ART Adverse Events\1\                                        
----------------------------------------------------------------------------------------------------------------
                                             1991               1992               1993               1994      
----------------------------------------------------------------------------------------------------------------
Ectopic Pregnancies\4\                                                                                          
IVF                                           223 (5.8)          272 (4.9)          288 (4.4)          246 (3.9)
GIFT                                           44 (2.9)           61 (3.6)           61 (4.0)           45 (3.2)
ZIFT                                           20 (4.5)           20 (3.9)           13 (2.8)            9 (3.1)
Combination                                    10 (4.5)           10 (3.9)           15 (5.3)            5 (2.7)
Frozen ET                                      28 (2.2)            2 (3.2)           10 (5.0)           17 (1.5)
Donor Oocytes                                     Nr\5\                 NR                 NR                 NR
                                                                                                                
Pregnancy Loss (% of clinical                                                                                   
 pregnancies)                                                                                                   
IVF                                                  20                 20                 19                 19
GIFT                                                 22                 22                 20                 22
ZIFT                                                 19                 15                 20                 16
Combination                                          39                 17                 20                 15
Frozen ET                                            19                 15                 20                 15
Donor Oocytes                                        23                 25                 20                 19
                                                                                                                
Stillbirths (% of clinical                                                                                      
 pregnancies)                                                                                                   
IVF                                                 0.5                1.0                1.1                1.4
GIFT                                                1.0                0.6                1.1                1.0
ZIFT                                                 NR                 NR                 NR                 NR
Combination                                          NR                 NR                 NR                 NR
Frozen ET                                            NR                 NR                 NR                 NR
Donor Oocytes                                       0.3                  0                 NR                 NR
                                                                                                                
Anomalies\6\                                                                                                    
IVF                                            57 (1.5)          109 (1.9)          164 (2.3)          174 (2.7)
GIFT                                           17 (1.1)           41 (2.4)           19 (1.2)           25 (1.8)
ZIFT                                            4 (0.8)           14 (2.5)           20 (2.8)            7 (2.4)
Combination                                          NR                 NR                 NR           26 (2.1)
Frozen ET                                       1 (2.0)            0 (0.0)           32 (3.1)                 NR
Donor Oocytes                                   5 (0.8)                 NR           18 (1.7)           34 (2.6)
----------------------------------------------------------------------------------------------------------------
\1\ See references 26 through 29.                                                                               
\2\ In parentheses = % deliveries per retrieval.                                                                
\3\ GIFT = gamete intrafallopian transfer; ZIFT = zygote intrafallopian transfer; ET = embryo transfer.         
\4\ In parentheses = % of established pregnancies.                                                              
\5\ NR = none reported.                                                                                         
\6\ In parentheses = defects/100 neonates.                                                                      


[[Page 46692]]

    These data compare to recent ectopic pregnancy rates of 
approximately 1.7 percent of all pregnancies (Ref. 15), overall 
(preclinical, clinical, and stillbirth) pregnancy loss rates of 
approximately 25 percent (Ref. 1), and an incidence of anomalies 
(congenital defects) of approximately 2 percent of all births in the 
general U.S. population (Ref. 3).

VII. Special Controls

    The following special controls are proposed for the assisted 
reproduction devices being proposed for reclassification into class II. 
These must be addressed, where appropriate, in any 510(k) premarket 
notification submitted to FDA.

A. Guidance Document

     FDA plans to develop a guidance document that would address the 
following:
1. Mouse Embryo Assay (Davidson et al., 1988 (Ref. 4); May, J. V., 1996 
(Ref.10))
    The MEA should be used for toxicity and functionality testing of 
reproductive media, labware, and other devices coming into contact with 
gametes and/or embryos (Refs. 4 and 10). The rationale for requiring 
this test as a special control for class II assisted reproduction 
devices is that it is a good surrogate indicator of potential toxicity 
of materials used in assisted reproduction devices to gametes and/or 
embryos. Both one-cell and two-cell assays are used, and these are 
identical except that one-cell embryos are flushed from the mouse 
oviduct earlier than two-cell embryos. There are advantages to either 
test. Some believe that a two-cell MEA is preferable because it assures 
that one is testing a viable cleaving embryo from the onset. If 
cleaving does not proceed to the expanding or hatching blastocyst 
stage, then the test material is suspect for toxicity to the embryo. A 
one-cell MEA may not be as reassuring because lack of cleavage may be 
due either to embryo toxicity or to an intrinsically compromised 
embryo. The two-cell MEA is also easier to use because of timing of 
oviductal flushing and the fact that the embryos release easily from 
their mass of cumulus cells. Others believe that one-cell embryos are 
more sensitive to toxic conditions and better represent the actual 
conditions of IVF and embryo development than the two-cell embryo. 
Whether a one-cell or two-cell MEA is used, the bioassay should 
duplicate, as closely as possible, the procedures used for human IVF, 
including the acquisition, maintenance, culture, transfer (relocation), 
and cryopreservation of embryos (Refs. 4 and 10). FDA will not dictate 
to the manufacturer which MEA should be used during the manufacture of 
a particular product, or even whether any MEA is used. Rather, if the 
MEA is used, the manufacturer should provide clear information to the 
user about how the assay was performed and the assay results, both on 
the label and in the labeling. If no MEA is used, then this information 
must also be clearly provided to the user.
2. Endotoxin Testing (Nagata and Shirakawa, 1996 (Ref. 14); USP, 23d 
ed., 1995 (Ref. 36))
    The rationale for requiring endotoxin testing as a special control 
for class II assisted reproduction devices is that it will provide a 
mechanism for ensuring that devices coming into contact with gametes, 
embryos, and/or the patient have been tested for levels of endotoxin 
released from gram-negative bacteria, which is the major pyrogen of 
concern. Of primary concern, endotoxin can be harmful to embryos and 
thus potentially affect development of the embryo, implantation, and 
pregnancy rates (Ref. 14). An established USP endotoxin assay using the 
limulus amebocyte lysate (LAL) test (Ref. 36) must be performed on any 
device, including needles, catheters, labware, water (including bottled 
water or water purification systems), and media.
3. Sterilization Validation
    The rationale for requiring sterilization validation as a special 
control for class II assisted reproduction devices is that it will 
provide a mechanism for ensuring that devices coming into contact with 
gametes and/or embryos are sterile to a sterility assurance level (SAL) 
of 10-6. Established sterilization validation testing must 
be performed on all devices according to American Association Medical 
Instrumentation (AAMI) guidelines.
4. Water Quality (May, J. V., 1996 (Ref. 10))
    The rationale for requiring this test as a special control for 
class II assisted reproduction devices is that water quality is 
critically important to successful assisted reproductive technology 
procedures (Ref. 10). Water used to reconstitute reproductive media and 
to wash and rinse labware, whether generated in-house using 
purification systems or obtained in bottled form from vendors, should 
be sterile, pyrogen-free, type I reagent grade (CAP or American Society 
for Testing Materials (ASTM)) or greater. Water purification systems 
typically can generate even purer water with increased resistivity (18 
megohm) relative to type I water. For general laboratory use, type II 
and higher can be used. Any item coming into contact with human gametes 
or embryos should have a final rinse with type I water or better. As 
stated earlier, general purpose water purification systems, not 
intended for use in assisted reproduction, will not be affected by this 
proposed rule.
5. Design Specifications
    Particular design specifications may be identified for each type of 
device that assure minimally acceptable standards. The rationale for 
including design specifications as a special control for class II 
assisted reproduction devices is that it will help to reduce the 
incidence of adverse events such as bleeding, pain, or perforation that 
could be due to suboptimal device design. For example, assisted 
reproduction needles may be specified to be 16 to 18 gauge, 22 to 23 
centimeters long, 45 to 60 degree beveled stainless steel and sterile 
to assure safe and adequate access to ovarian follicles.
6. Labeling
    Specific labeling that identifies the intended use, indication for 
use, contraindications, precautions, warnings, and instructions for use 
will be required. The rationale for including labeling as a special 
control for class II assisted reproduction devices is that it will 
ensure that devices are used properly, that the user is adequately 
informed, that the intended use of the device is clearly understood, 
and that claims by the manufacturer do not exceed the intended use of 
the device. For instance, assisted reproduction catheters will require 
labeling that specifies its intended use as ``For transvaginal 
retrieval of oocytes,'' or ``For delivery of embryos into the fallopian 
tube.'' Labeling will also indicate whether a one-cell or two-cell MEA, 
or no assay at all, was performed.
7. Clinical Studies
    Certain device designs may not conform to conventional 
configurations used in assisted reproduction today, e.g., a specially-
configured ET catheter. Although the device designs envisioned for this 
special control do not raise new types of safety and effectiveness 
questions, additional testing may be necessary to validate clinical 
performance.

[[Page 46693]]

B. Voluntary Standards (CAP) Reproductive Laboratory Accreditation 
Program (Ref. 15), SART, Refs. 22 through 31))

    The rationale for including voluntary standards by CAP and SART as 
a special control for class II assisted reproduction devices is that 
these organizations have already identified many important standards 
regarding various aspects of assisted reproduction, including 
recommended tests and equipment, as well as acceptable techniques in 
the use of many assisted reproduction devices. Voluntary standards 
issued by individual laboratories, and both CAP and SART, address many 
aspects of the use of these devices for assisted reproduction 
techniques, including water quality, type of laboratory equipment to be 
used, and various quality control techniques including MEA previously 
identified (Refs. 10, 11, 16, 21, 37, and 38). For example, CAP 
conducts comprehensive inspections of reproductive laboratories for 
quality assurance and control measures, specimen (sperm, oocytes, and 
embryos) handling and processing, documentation, equipment, reagents, 
personnel, glassware washing, communications, and laboratory safety 
(Ref. 16). SART publishes guidelines for human embryology and andrology 
laboratories (Ref. 31), and maintains an annually updated data base 
from all of its members (the great majority of IVF programs in the 
United States have membership in SART) on all assisted reproduction 
procedures conducted in the United States (Refs. 22 through 30). 
Statistics on the total numbers of ART procedures are kept, including 
IVF, GIFT, ZIFT, donated oocytes, frozen ET's, and micromanipulation 
procedures (e.g., ICSI, subzonal sperm insertion, assisted hatching). 
Outcome data on total numbers of clinical pregnancies, deliveries, and 
multiple gestations, as well as adverse events such as ectopic 
pregnancy, abortion, stillbirth, and congenital abnormalities are 
gathered.
    Significant available literature has established the reasonable 
safety and effectiveness of assisted reproduction devices, and the 
potential complications. In addition, the preexisting recommendations 
(Ref. 16) already put in place by CAP Reproductive Laboratory 
Accreditation Program and SART (Refs. 22 through 31) provide excellent 
and comprehensive guidelines on the proper use of these devices and 
data reporting required by its members.
    FDA believes that general controls and the special controls 
proposed for these devices are sufficient to provide reasonable 
assurance that these devices are safe and effective for their intended 
use.

VIII. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday:
    1. Adashi, E. Y., J. A. Rock, and Z. Rosenwaks, Reproductive 
Endocrinology, Surgery and Technology, Lippincott-Raven, 
Philadelphia, 1996.
    2. Ashkenazi, J. et al., ``Abdominal Complications Following 
Ultrasonically Guided Percutaneous Transvesical Collection of 
Oocytes for In Vitro Fertilization,'' Journal of In Vitro 
Fertilization and Embryo Transfer, 4(6):316-318, 1987.
    3. Behrman, R. E., and R. M. Kliegman, Nelson Essentials of 
Pediatrics, 2d ed., W. B. Saunders, Philadelphia, p. 175, 1993.
    4. Davidson, A. et al., ``Mouse Embryo Culture as Quality 
Control for Human In Vitro Fertilization: The One-Cell Versus the 
Two-cell Model,'' Fertility and Sterility, 49(3):516-521, 1988.
    5. Davis, O. K., and Z. Rosenwaks, ``In Vitro Fertilization,'' 
Infertility: Evaluation and Treatment, edited by W. R. Keye and R. 
J. Chang, Saunders, pp. 759-771, 1994,
    6. DeCherney, A. H., ``In Vitro Fertilization and Embryo 
Transfer: A Brief Overview,'' Yale Journal of Biology and Medicine, 
59:409-414, 1986.
    7. Letter from FDA to Manufacturers of Medical Devices Used for 
IVF/ET, September 1995.
    8. Kerin, J. F. et al., ``The Way Forward for In Vitro 
Fertilization in Man,'' Journal of Reproduction and Fertility, 
Supplement, 36:161-172, 1988.
    9. Lenz, S., and J. G. Lauritsen, ``Ultrasonically Guided 
Percutaneous Aspiration of Human Follicles Under Local Anesthesia: A 
New Method of Collecting Oocytes for In Vitro Fertilization,'' 
Fertility and Sterility, 38(6):673-677, 1982.
    10. May, J. V., Recommendations to the FDA Obstetrics and 
Gynecology Devices Panel for Safety and Efficacy Parameters for 
Assisted Reproduction Labware and Reproductive Media, personal 
communication to Mike Kuchinski, 1996.
    11. May, J. V., and K. Hanshew, ``Organization of the In Vitro 
Fertilization/Embryo Transfer Laboratory,'' CRC Handbook of the 
Laboratory Diagnosis and Treatment of Infertility, pp. 291-327.
    12. Minutes, Obstetrics and Gynecology Devices Panel meeting, 
January 29, 1988.
    13. Minutes, Obstetrics and Gynecology Devices Panel meeting, 
October 23, 1995.
    14. Nagata, Y., and K. Shirakawa, ``Setting Standards for the 
Levels of Endotoxin in the Embryo Culture Media of Human In Vitro 
Fertilization and Embryo Transfer,'' Fertility and Sterility, 
65(3):614-619, 1996.
    15. Nederlof, K. P., H. W. Lawson, A. F. Saftlas, H. K. Atrash, 
and E. L. Finch, ``Ectopic Pregnancy Surveillance, United States, 
1970-1987,'' Morbidity and Mortality Weekly Reports (MMWR), 39(SS-
4):9-17, 1990.
    16. Inspection Checklist Section XC: Reproductive Laboratory, 
College of American Pathologists, Reproductive Laboratory 
Accreditation Program, pp. 1-50, 1993.
    17. Palermo, G. D. et al., ``Intracytoplasmic Sperm Injection: A 
Powerful Tool to Overcome Fertilization Failure,'' Fertility and 
Sterility, 65(5):899-908, 1996.
    18. Paulson, R. J., ``In Vitro Fertilization and Other Assisted 
Reproduction Techniques,'' Journal of Reproductive Medicine, 
38(4):261-268, 1993.
    19. Riddle, A. F. et al., ``Two Years Experience of Ultrasound-
Directed Oocyte Retrieval,'' Fertility and Sterility, 48(3):454-458, 
1987.
    20. Seibel, M. M., ``A New Era in Reproductive Technology: In 
Vitro Fertilization Gamete Intrafallopian Transfer, and Donated 
Gametes and Embryos,'' New England Journal of Medicine, 
318(313):828-834, 1988.
    21. Seifer, D. B., ``Suggested Safety and Efficacy Parameters 
for FDA Reclassification Guidelines,'' personal communication to 
Colin Pollard, 1996.
    22. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``In Vitro Fertilization/Embryo Transfer in the 
United States: 1985 and 1986 Results From the National IVF-ET 
Registry,'' Fertility and Sterility, 49(2):212-215, 1988.
    23. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``In Vitro Fertilization/Embryo Transfer in the 
United States: 1985 and 1986 Results From the National IVF-ET 
Registry,'' Fertility and Sterility, 51(1):13-19, 1988.
    24. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``In Vitro Fertilization/Embryo Transfer in the 
United States: 1988 Results From the National IVF-ET Registry,'' 
Fertility and Sterility, 53(1):13-20, 1990.
    25. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``In Vitro Fertilization/Embryo Transfer in the 
United States: 1989 Results From the National IVF-ET Registry,'' 
Fertility and Sterility, 55(1):14-23, 1991.
    26. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``In Vitro Fertilization/Embryo Transfer in the 
United States: 1990 Results From the National IVF-ET Registry,'' 
Fertility and Sterility, 57(1):15-24, 1992.
    27. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``Assisted Reproductive Technology in the United 
States and Canada: 1991 Results From the Society for Assisted 
Reproductive Technology Generated From The American Fertility 
Society Registry,'' Fertility and Sterility, 59(5):956-962, 1993.
    28. Society for Assisted Reproductive Technology, The American 
Fertility Society ``Assisted Reproductive Technology in the United 
States and Canada: 1992 Results Generated From The American 
Fertility Society/Society for Assisted Reproductive Technology 
Registry,'' Fertility and Sterility, 62(6):1121-1128, 1994.
    29. Society for Assisted Reproductive Technology, The American 
Fertility Society,

[[Page 46694]]

``Assisted Reproductive Technology in the United States and Canada: 
1993 Results Generated From The American Fertility Society/Society 
for Assisted Reproductive Technology Registry,'' Fertility and 
Sterility, 64(1):13-21, 1995.
    30. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``Assisted Reproductive Technology in the United 
States and Canada: 1994 Results Generated From The American 
Fertility Society/Society for Assisted Reproductive Technology 
Registry,'' Fertility and Sterility, 66(5):697-705, 1996.
    31. Society for Assisted Reproductive Technology, The American 
Fertility Society, ``Guidelines for Human Embryology and Andrology 
Laboratories,'' Fertility and Sterility, 58(4) Supplement 1:1S-16S, 
1992.
    32. Surrey, E. S., and J. F. Kerin, ``Extended Techniques in 
Assisted Reproductive Technologies,'' Infertility: Evaluation and 
Treatment, edited by W. R. Keye and R. J. Chang, Saunders, pp. 788-
797, 1994.
    33. Tal, J. et al., ``Heterotropic Pregnancy After Ovulation 
Induction and Assisted Reproductive Technologies: A Literature 
Review from 1971 to 1993,'' Fertility and Sterility, 66(1):1-12, 
1996.
    34. Tan, S. L. et al., ``Surgical Techniques of Oocyte 
Collection and Embryo Transfer,'' British Medical Bulletin, 
46(3):628-642, 1990.
    35. Trounson, A., ``Recent Progress in Human In Vitro 
Fertilization and Embryo Transfer,'' Developmental Biology, chapter 
5, pp. 149-186, 1986.
    36. United States Pharmacopeia, 23d ed., National Formulary, 
vol. 18, Bacterial Endotoxins Test, No. 85, pp. 1696-1697, 1995.
    37. Utian, W. H. et al., ``Implementation of an In Vitro 
Fertilization Program,'' Journal of In Vitro Fertilization and 
Embryo Transfer, 1(1):72-75, 1984.
    38. Veeck, L. L., ``The Gamete Laboratory: Design, Management 
and Techniques,'' Infertility: Evaluation and Treatment, edited by 
W. R. Keye and R. J. Chang, Saunders, pp. 798-820, 1994.
    39. Wikland, M. et al., ``Collection of Human Oocytes By the Use 
of Sonography,'' Fertility and Sterility, 39(5):603-608, 1983.

IX. Proposed Effective Date

    The agency proposes that any final rule based on this proposal 
become effective 30 days after its date of publication in the Federal 
Register.

X. Environmental Impact

    The agency has determined under 21 CFR 25.24(e)(2) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

XI. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Pub. L. 104-121), and the Unfunded Mandates Reform Act of 1995 
(Pub. L. 104-4)). Executive Order 12866 directs agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The agency believes that this proposed rule is consistent with 
the regulatory philosophy and principles identified in the Executive 
Order and so is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Reclassification of these devices from class III to 
class II and class I will relieve all manufacturers of the device of 
the cost of complying with the premarket approval requirements in 
section 515 of the act (21 U.S.C. 360e). Because reclassification will 
reduce regulatory costs with respect to this device, it will impose no 
significant economic impact on any small entities, and it may permit 
small potential competitors to enter the marketplace by lowering their 
costs. The Commissioner of Food and Drugs therefore certifies that this 
proposed rule, if issued, will not have a significant economic impact 
on a substantial number of small entities. In addition, this proposed 
rule will not impose costs of $100 million or more on either the 
private sector or State, local, and tribal governments in the 
aggregate, and therefore a summary statement of analysis under section 
202(a) of the Unfunded Mandates Reform Act of 1995 is not required.

XII. Submission of Comments

    Interested persons may, on or before December 3, 1997, submit to 
the Dockets Management Branch (address above) written comments 
regarding this proposal. Two copies of any comments are to be submitted 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the office above 
between 9 a.m. and 4 p.m., Monday through Friday.

List of Subjects in 21 CFR Part 884

    Medical devices.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 884 be amended as follows:

PART 884--OBSTETRICAL AND GYNECOLOGICAL DEVICES

    1. The authority citation for 21 CFR part 884 continues to read as 
follows:

    Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j, 
371).

    2. Subpart G, consisting of Secs. 884.6100 through 884.7000 is 
added to read as follows:

Subpart G--Assisted Reproduction Devices

Sec.
884.6100   Assisted reproduction needles.
884.6200   Assisted reproduction catheters.
884.6300   Assisted reproduction accessories.
884.6400   Assisted reproduction microtools.
884.6500   Assisted reproduction micropipette fabrication 
instruments.
884.6600   Assisted reproduction micromanipulators and 
microinjectors.
884.6700   Assisted reproduction labware.
884.6800   Assisted reproduction water and water purification 
systems.
884.6900   Reproductive media and supplements.
884.7000   Assisted reproductive microscopes and microscope 
accessories.

Subpart G--Assisted Reproduction Devices


Sec. 884.6100  Assisted reproduction needles.

    (a) Identification. Assisted reproduction needles are devices used 
to obtain gametes or introduce gametes, zygote(s), preembryo(s), and/or 
embryo(s) into the body. This generic type of device may include a 
single or double lumen needle and component parts, including needle 
guides such as those used with ultrasound.
    (b) Classification. Class II (special controls) (premarket 
notification guidance and voluntary standards).


Sec. 884.6200  Assisted reproduction catheters.

    (a) Identification. Assisted reproduction catheters are devices 
used to introduce or remove gametes, zygote(s), preembryo(s), and/or 
embryo(s) into or from the body. This generic type of device may 
include catheters, cannulae, introducers, dilators, sheaths, and 
component parts.
    (b) Classification. Class II (special controls) (premarket 
notification guidance and voluntary standards).


Sec. 884.6300  Assisted reproduction accessories.

    (a) Identification. Assisted reproduction accessories are a group 
of devices used during assisted reproduction procedures, in conjunction 
with assisted reproduction needles and/

[[Page 46695]]

or assisted reproduction catheters, to aspirate, incubate, infuse, and/
or maintain temperature. This generic type of device may include:
    (1) Powered aspiration pumps, used to provide low flow, 
intermittent vacuum for the aspiration of eggs (ova).
    (2) Syringe pumps (powered or manual), used to activate a syringe 
to infuse or aspirate small volumes of fluid during assisted 
reproduction procedures.
    (3) Collection tube warmers, used to maintain the temperature of 
egg (oocyte) collection tubes at or near body temperature. A dish/
plate/microscope stage warmer is a device used to maintain the 
temperature of the egg (oocyte) during manipulation.
    (4) Embryo incubators, used to store and preserve gametes and/or 
embryos at or near body temperature.
    (5) Cryopreservation instrumentation and devices, used to contain, 
freeze and maintain gametes and/or embryos at an appropriate freezing 
temperature.
    (b) Classification. Class II (special controls) (premarket 
notification guidance and voluntary standards).


Sec. 884.6400  Assisted reproduction microtools.

    (a) Identification. Assisted reproduction microtools are pipettes 
or other devices used in the laboratory to denude, micromanipulate, 
hold or transfer human gametes or embryos for assisted hatching, 
intracytoplasmic sperm injection (ICSI), embryo biopsy or other 
assisted reproduction methods, including preimplantation diagnosis.
    (b) Classification. Class II (special controls) (premarket 
notification guidance and voluntary standards).


Sec. 884.6500  Assisted reproduction micropipette fabrication 
instruments.

    (a) Identification. Assisted reproduction micropipette fabrication 
devices are instruments intended to pull, bevel, or forge a 
micropipette or needle for intracytoplasmic sperm injection (ICSI), in 
vitro fertilization (IVF), or other similar procedures.
    (b) Classification. Class II (special controls) (premarket 
notification guidance and voluntary standards).


Sec. 884.6600  Assisted reproduction micromanipulators and 
microinjectors.

    (a) Identification. Assisted reproduction micromanipulators are 
devices intended to control the position of an assisted reproduction 
microtool. Assisted reproduction microinjectors are any device intended 
to control aspiration or expulsion of the contents of an assisted 
reproduction microtool.
    (b) Classification. Class II (special controls).


Sec. 884.6700  Assisted reproduction labware.

    (a) Identification. Assisted reproduction labware consists of 
laboratory equipment or supplies intended to prepare, store, 
manipulate, or transfer human gametes or embryos for in vitro 
fertilization (IVF) or other assisted reproduction techniques. These 
include syringes, IVF tissue culture dishes, IVF tissue culture plates, 
pippette tips, dishes, plates, and other vessels that come into 
physical contact with gametes, embryos or tissue culture media.
    (b) Classification. Class II (special controls).


Sec. 884.6800  Assisted reproduction water and water purification 
systems.

    (a) Identification. Assisted reproduction water purification 
systems are devices specifically intended to generate high quality 
sterile, pyrogen-free, distilled, deionized water for reconstitution of 
media used for aspiration, incubation, transfer or storage of gametes 
or embryos for in vitro fertilization (IVF) or other assisted 
reproduction procedures. It may also be intended as the final rinse for 
labware or other assisted reproduction devices that will contact the 
gametes or embryos. This also includes bottled water ready for 
reconstitution available from a vendor that is specifically intended 
for reconstitution of media used for aspiration, incubation, transfer 
or storage of gametes or embryos for IVF or other assisted reproduction 
procedures.
    (b) Classification. Class II (special controls).


Sec. 884.6900  Reproductive media and supplements.

    (a) Identification. Reproductive media and supplements are products 
that are used for assisted reproduction procedures. Media include 
liquid and powder versions of various substances that come in direct 
physical contact with human gametes or embryos (including water, or oil 
used to cover the media) for the purposes of preparation, maintenance, 
transfer or storage, and supplements are specific reagents added to 
media to enhance specific properties of the media (e.g., proteins, 
sera, antibiotics, etc.).
    (b) Classification. Class II (special controls) (premarket 
notification guidance and voluntary standards).


Sec. 884.7000  Assisted reproductive microscopes and microscope 
accessories.

    (a) Identification. Assisted reproduction microscopes and 
microscope accessories (excluding microscope stage warmers, which are 
classified under Assisted Reproduction Accessories) are optical 
instruments used to enlarge images of gametes or embryos. Variations of 
microscopes and accessories used for these purposes would include phase 
contrast microscopes, fluorescence microscopes, dissecting microscopes, 
and inverted stage microscopes.
    (b) Classification. Class I. The device is exempt from the 
premarket notification procedures in subpart E of part 807 of this 
chapter.

    Dated: August 26, 1997.
D. B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 97-23449 Filed 9-2-97; 8:45 am]
BILLING CODE 4160-01-F