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

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