46686 Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules

under paragraph (a) of this section and

does not change the amount to be

deducted from the family benefit or

payment. The increase is simply added

to what amount, if any, is payable. If a

new beneficiary becomes entitled to

monthly benefits on the same earnings

record after the increase, the amount of

the reduction is redistributed among the

new beneficiaries entitled under section

202 of the Act and deducted from their

current benefit rate.

(k) Effect of changes in the amount of

the workers’ compensation/public

disability benefit or payment. Any

change in the amount of the workers’

compensation/public disability benefit

or payment received will result in a

recalculation of the reduction under

paragraph (a) of this section and,

potentially, an adjustment in the

amount of such reduction. For those

individuals described in paragraph

(a)(1) of this section who do not meet

the conditions specified in paragraph

(a)(2) of this section, any increased

reduction will be imposed effective with

the month after the month the

Commissioner received notice of the

increase in the workers’ compensation

benefit or payment (it should be noted

that only workers’ compensation can

cause this reduction). Adjustments due

to a decrease in the amount of the

workers’ compensation/public disability

benefit or payment will be effective with

the actual date the decreased amount

was effective. For individuals described

in paragraph (a)(2) of this section, any

increase or decrease in the reduction

will be imposed effective with the

actual date of entitlement to the new

amount of the workers’ compensation/

public disability benefit or payment.

(l) Redetermination of benefits—(1)

General. In the second calendar year

after the year in which reduction under

this section in the total of an

individual’s benefits under section 223

of the Act and any benefits under

section 202 of the Act based on his or

her wages and self-employment income

was first required (in a continuous

period of months), and in each third

year thereafter, the amount of those

benefits which are still subject to

reduction under this section are

redetermined. The redetermination will

be made unless it results in any

decrease in the total amount of benefits

payable under title II of the Act on the

basis of the workers’ wages and selfemployment income. The redetermined

benefit is effective with the January

following the year in which the

redetermination is made.

(2) * * *

(i) The ratio of the average of the total

wages (as defined in § 404.1048(c)) of all

persons for whom wages were reported

to the Secretary of the Treasury or his

delegate for the calendar year before the

year in which the redetermination is

made, to the average of the total wages

of all persons reported to the Secretary

of the Treasury or his delegate for

calendar year 1977 or, if later, the

calendar year before the year in which

the reduction was first computed (but

not counting any reduction made in

benefits for a previous period of

disability); and

* * * * *

[FR Doc. 97–23506 Filed 9–3–97; 8:45 am]

BILLING CODE 4190–29–P

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.

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 § 860.134 (21
Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules 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 § 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 § 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
46688 Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules

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,
Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules 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 shortterm 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
46690 Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules

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
Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules 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 RATES1

1991 1992 1993 1994

Cycles Initiated2

IVF 24,671 (15.2) 29,404 (16.8) 33,543 (18.3) 33,700 (20.7)

GIFT3 5,452 (26.6) 5,767 (26.3) 4,992 (28.1) 4,214 (28.4)

ZIFT3 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 ET3 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 EVENTS1

1991 1992 1993 1994

Ectopic Pregnancies4

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 Nr5 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

Anomalies6

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)

1See references 26 through 29.

2 In parentheses = % deliveries per retrieval.

3GIFT = 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.
46692 Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules

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 twocell 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.
Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules 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,
46694 Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules

‘‘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

§§ 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

§ 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).

§ 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).

§ 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/
Federal Register / Vol. 62, No. 171 / Thursday, September 4, 1997 / Proposed Rules 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).

§ 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).

§ 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).

§ 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).

§ 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).

§ 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, pyrogenfree, 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).

§ 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).

§ 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

DEPARTMENT OF THE INTERIOR

Office of Surface Mining Reclamation

and Enforcement

30 CFR Part 934

[ND–032–FOR; Amendment No. XXII]

North Dakota Regulatory Program

AGENCY: Office of Surface Mining

Reclamation and Enforcement, Interior.

ACTION: Proposed rule; reopening and

extension of public comment period on

proposed amendment.

SUMMARY: The Office of Surface Mining

Reclamation and Enforcement (OSM) is

announcing receipt of a revision to a

previously proposed amendment to the

North Dakota regulatory program

(hereinafter, the ‘‘North Dakota

program’’) under the Surface Mining

Control and Reclamation Act of 1977

(SMCRA). The revision for North

Dakota’s proposed rules pertain to

individual civil penalties. The

amendment is intended to revise the

North Dakota program to be consistent

with the corresponding Federal

regulations.

DATES: Written comments must be

received by 4:00 p.m., m.d.t., September

19, 1997.

ADDRESSES: Written comments should

be mailed or hand delivered to Guy

Padgett at the address listed below.

Copies of the North Dakota program,

the proposed revision to the proposed

amendment, the proposed amendment,

and all written comments received in

response to this document will be

available for public review at the

addresses listed below during normal

business hours, Monday through Friday,

excluding holidays. Each requester may

receive one free copy of the proposed