[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\
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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
