20992 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

agency may not conduct or sponsor, and

a person is not required to respond to,

a collection of information unless it

displays a currently valid OMB control

number. OMB has now approved the

information collection and has assigned

OMB control number 0910–0338. The

approval expires on March 31, 2003. A

copy of the supporting statement for this

information collection is available on

the Internet at http://www.fda.gov/

ohrms/dockets.

Dated: April 12, 2000.

William K. Hubbard,

Senior Associate Commissioner for Policy,

Planning, and Legislation.

[FR Doc. 00–9714 Filed 4–18–00; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 98D–0969]

Risk Assessment of the Public Health

Impact of Streptogramin Resistance in

Enterococcus faecium Attributable to

the Use of Streptogramins in Animals;

Request for Comments and for

Scientific Data and Information

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice; request for comments

and for scientific data and information.

SUMMARY: The Food and Drug

Administration (FDA), Center for

Veterinary Medicine (CVM), is

announcing plans to develop a

prototypic risk assessment (RA) model

that accounts for the transfer of

resistance determinants from bacteria in

food-producing animals to bacteria in

humans. The agency requests comments

on their approach to the RA model and

requests that scientific data and

information relevant to the conduct of

the RA be submitted. This model will be

applied to assess the association

between the development of

streptogramin (quinupristin/dalfopristin

(QD)) resistant Enterococcus faecium in

humans and the use of virginiamycin in

food-producing animals. The center will

attempt to use the RA model to quantify

the human health impact attributable

both to direct acquisition of resistant E.

faecium from food-producing animals

and to the transfer of resistance

determinants from E. faecium in foodproducing animals to E. faecium in

humans.

DATES: Submit written comments,

scientific data, and information by June

19, 2000.

ADDRESSES: Single copies of ‘‘A

Proposed Framework for Evaluating and

Assuring the Human Safety of the

Microbial Effects of Antimicrobial New

Animal Drugs Intended for Use in FoodProducing Animals’’ (hereinafter

referred to as the Framework Document)

is discussed in the SUPPLEMENTARY

INFORMATION section of this document

and may be obtained by writing to the

Communications Staff (HFV–12), Center

for Veterinary Medicine, Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855. Send one selfaddressed adhesive label to assist the

office in processing your request. This

document is also available through

CVM’s homepage on the Internet at

http://www.fda.gov/cvm/fda/mappgs/

antitoc.html. Submit written comments,

scientific data, and information to the

Dockets Management Branch (HFA–

305), Food and Drug Administration,

5630 Fishers Lane, rm. 1061, Rockville,

MD 20852.

FOR FURTHER INFORMATION CONTACT:

Nicholas E. Weber, Center for Veterinary

Medicine (HFV–150), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–827–6986,

FAX 301–594–2298, or e-mail

nweber@cvm.fda.gov.

SUPPLEMENTARY INFORMATION:

I. Background

In theFederal Register of January 6,

1999 (64 FR 887), FDA published a

notice of availability of a discussion

paper (the Framework Document). This

Framework Document sets out a

conceptual risk-based process for

evaluating the microbial safety of

antimicrobial drugs intended for use in

food-producing animals. The proposed

RA furthers the tenets of the Framework

Document by developing a RA model to

quantify the potential human health

impact of resistant bacteria acquired

from animals via food.

Thus, CVM proposes to conduct its

second antimicrobial resistance RA. A

draft of CVM’s first antimicrobial

resistance RA model and associated

documents are available on CVM’s

homepage on the Internet at http://

www.fda.gov/cvm/fda/mappgs/ra/

risk.html. The first RA modeled the

human health impact of

fluoroquinolone resistant

Campylobacter infections associated

with the consumption of chicken. CVM

proposes to develop a second RA that

will account for both the acquisition of

resistant bacteria and the transfer of

resistance determinants from bacteria in

food-producing animals to bacteria in

humans. This model will be applied to

assess the association between the

presence of streptogramin (QD) resistant

Enterococci faecium in humans and the

use of streptogramins (virginiamycin) in

food-producing animals as an example

of risk attributed to transference of

resistance determinants.

In September 1999, FDA’s Center for

Drug Evaluation and Research approved

SynercidTM, a streptogramin (QD), for

use in human medicine for treatment of

vancomycin resistant E. faecium (VREF)

bacteremias as well as for treatment of

Staphylococcus aureus and

Streptococcus pyogenes skin and soft

tissue infections. At the current time,

QD is considered to be the last line of

therapy for VREF. Another

streptogramin, virginiamycin, has been

used in food-producing animals for 26

years. The initial approval was for

chickens, but virginiamycin was

subsequently approved for use in

turkeys, swine, and most recently in

cattle. This RA will seek to quantify the

public-health risk attributable to the use

of virginiamycin in food-producing

animals. Enterococcus faecium that

develop resistance due to exposure to

virginiamycin also demonstrate reduced

susceptibility to QD. These resistant

strains of E. faecium can contaminate

meat products and thereby enter the

human intestine. It is thought that these

resistant strains contaminating meat

products may cause problems for the

human in two major ways: By becoming

host-adapted or by transferring

resistance determinants to endogenous

human E. faecium.

It is generally believed that the

indigenous intestinal microflora of

healthy humans inhibit colonization by

bacteria from exogenous sources. In the

case of illness requiring antibiotic

therapy however, associated

perturbations due to drug treatment may

result in colonization by organisms not

included in the flora of healthy

individuals. This scenario could result

in the intestinal colonization and

proliferation of antibiotic resistant

bacteria from the external environment.

Enterococcal infections comprise 20 to

30 percent of over 2 million hospitalacquired infections per year in the

United States (Ref. 1). VREF infections

are almost exclusively hospital

infections and account for about 14

percent of all enterococcal infections,

although this varies widely (5 to 70

percent) from hospital to hospital,

according to hospital vancomycin use,

teaching versus nonteaching hospital

status, and hospital size (number of

beds) (Refs. 1 and 2). This translates to

about 70,000 VREF infections per year

which will most likely be treated with

QD . Among VREF bacteremic patients

treated with QD, emerging resistance

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 20993

has been documented in about 4 percent

of cases (Ref. 3).

QD is a mixture of streptogramin A

(SA) and streptogramin B (SB)

compounds. Resistance to Type B

streptogramins is widespread among

enterococci and other organisms. SB

resistance is due to hydrolysis of the

antibiotic mediated by the vgb gene (Ref.

4), or more commonly, by ribosomal

methylation mediated by the ermB gene

product (Ref. 5). Expression of erm

confers collateral resistance to

macrolides, lincosamides, and

streptogramin B (MLSB) antimicrobials.

Expression of SB resistance

determinants is not sufficient to confer

resistance either to SA or to the

combination of compounds (Ref. 6). SA

resistance has been linked to two genes

in E. species, satA (Ref. 7) and satG (Ref.

8). These genes encode related enzymes

that inactivate the drug by acetylation,

and expression imparts resistance to the

mixture of SA and SB. Both genes have

been found on plasmids and shown to

be transferable in vitro to susceptible

strains. However, a number of SA

resistant enterococci carry neither locus

(Ref. 9), indicating that the complete

complement of streptogramin resistance

determinants has not been identified in

enterococci.

Data on the prevalence of QD

resistance in hospitals, the environment,

and the community is sparse. QDresistant E. faecium has been detected in

the stools of healthy adults in the

community. Because these individuals

had not received QD therapy, some have

assumed that the resistant strain entered

the human population from an

agricultural food production

environment where virginiamycin is

used or, possibly, following exposure to

other drugs that conferred crossresistance to streptogramins.

The prevalence of streptogramin

resistant enterococci in the animal

production environment and on animal

derived food is largely unknown. For

the purpose of this RA, data on human

exposure to enterococci through the

food supply and the rate at which these

organisms possess determinants

conferring resistance to streptogramin

antibiotics is critical. Preliminary data

collected on isolates from the poultry

production environment suggest that

about 65 percent of E. faecium are

resistant to streptogramins (MIC≥4μg

mg/ml) (Ref. 10). Data on the prevalence

of these organisms and their antibiotic

resistance phenotypes associated with

retail products are very limited but

critical to the RA process.

II. Objectives of the Risk Assessment

FDA is planning to conduct a RA of

the potential harm to hospitalized

patients by E. faecium resistant to the

streptogramin combination drug (QD)

associated with the use of virginiamycin

in food-producing animals. A RA is a

systematic and comprehensive

collection and analysis of information

that promotes an understanding of the

interactions of various factors in a

complex situation and provides a basis

for making decisions. One goal of this

RA is to organize a broad array of

information and to study the complex

set of interactions necessary to review

the current uses of virginiamycin and

their impact on public health in an

effort to make sound science-based

decisions. An underlying goal of this RA

is to provide experience and a method

for modeling risk involving transfer of

resistance determinants from strains of

bacteria found in food-producing

animals to those found in people. It is

anticipated that the RA will reveal data

gaps and help guide the industry, FDA,

and related agencies in setting research

priorities.

III. Risk Assessment Plan

FDA’s RA plan will attempt to

determine the relationship between the

use of virginiamycin in food-producing

animals, and the development and

dissemination of QD-resistant E.

faecium in contaminated meat products.

Examination of this relationship will be

used to describe health effects in

humans resulting from exposure to meat

contaminated with QD resistant E.

faecium. To accurately assess human

exposure to QD-resistant E. faecium

from contaminated meat, the RA will

seek and analyze the following four

types of information concerning the

epidemiology of foodborne QD-resistant

E. faecium. Information concerning the

molecular epidemiology and associated

carriage of resistance determinants of E.

faecium with respect to the on-farm

environment, carcass/retail meat

contamination, other foods, and to the

human community (both within and

outside of the hospital setting) will be

collected and analyzed.

1. Concerning the on-farm component

of the RA, CVM will analyze

epidemiological evidence pertaining to

the following areas in each animal

species studied: The prevalence of E.

faecium colonization, the proportion of

animals exposed to virginiamycin, the

rate of selection of QD resistance in E.

faecium, the emergence and

dissemination of QD resistance

determinants in virginiamycin exposed

live animals and in their environment

(including the level of fecal shedding).

2. The RA will also seek to collect and

analyze information on the frequency of

occurrence of post-slaughter

contamination with QD resistant E.

faecium to include carcass and retail

sampling, and, where data are available,

the impact of other agricultural sources

of QD resistant E. faecium on food

products destined for human

consumption. Modeling may be used

when data are collected at slaughter and

retail outlets to estimate actual human

exposure.

3. Human exposure is a function of

QD-resistant E. faecium prevalence in

the food supply and the consumption

patterns of the population. The level of

QD-resistant E. faecium contamination

of meat destined for human

consumption is very critical exposure

information. Thus, the RA will evaluate

information on the level of QD-resistant

E. faecium in retail meat classes where

data are available and combine this

information with food consumption

patterns. The RA will then produce

estimates of QD-resistant E. faecium gut

flora colonization likely given the levels

of meat consumption by different

subpopulations.

4. The RA will include an

examination of the number of people

who may enter the hospital colonized

with QD-resistant E. faecium, and the

proportion of those who are likely to

develop VREF infections and require

QD treatment. In addition, the RA will

seek to evaluate the rate of emergence of

QD-resistant E. faecium in the hospital

environment and its dissemination

within the hospital setting.

The RA process will seek to quantify

the risk associated with virginiamycin

use in animals utilizing data and

information in a number of areas

including: Prevalence of QD-resistant E.

faecium pre- and post-slaughter

contamination; molecular epidemiology

of E. faecium carriage of resistance

determinants in animal, community,

and human clinical isolates;

epidemiology of community and

hospital sources of QD-resistant E.

faecium; and prevalence of QD-resistant

VREF infections, and molecular

fingerprinting and epidemiology of QD

resistance transfer to VREF in humans.

All uncertainties and assumptions will

be identified and documented. The RA

process will also include an evaluation

of the adequacy of current scientific

knowledge, data, and information. This

will be used to suggest where future

research could be directed to reduce the

uncertainty in the risk estimate.

20994 Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices

IV. Data and Information Requested

FDA requests comments on the RA

approach outlined in the RA plan and

the submission of any information

relevant to the RA. The purpose of the

request for comments and data is to

gather relevant information from a broad

base of stakeholders to help the agency

develop a science-based RA model.

While some preliminary data are

available, as indicated in section I of

this document, the agency specifically

requests data that would help to

quantify the steps outlined in section III

of this document. A list of requested

information is presented below;

however, the list is not exhaustive, and

the agency encourages submission of

any additional data relevant to this RA.

The requested information includes, but

is not limited to the following:

1. The prevalence of E. faecium and

the prevalence of QD resistant E.

faecium among all E. faecium in foodproducing animals;

2. Virginiamycin use information,

including the proportion of foodproducing animals in each class that

receive virginiamycin;

3. The prevalence of carcasses

contaminated with E. faecium and

among those, the prevalence of

carcasses contaminated with QDresistant E. faecium;

4. Procedures during slaughtering and

food processing which modify

enterococcal contamination and load on

the carcass or product;

5. The prevalence and load of QDresistant E. faecium in humans in the

community acquired from contaminated

meat products of each class;

6. Consumption and food preparation

patterns that would aid in apportioning

potential E. faecium ingestion among

chicken, turkey, pork, beef, and other

sources;

7. The prevalence of colonization by

E. faecium and infection rates due to E.

faecium in humans, for: (a) All E.

faecium, (b) vancomycin resistant E.

faecium, (c) QD-resistant E. faecium,

and (d) QD-resistant/vancomycin

resistant E. faecium;

8. The rate at which QD resistance

and vancomycin resistance will be

transferred among E. faecium in

humans;

9. The enterococcal disease infection

rate among humans harboring

vancomycin resistant E. faecium;

10. Genetic fingerprinting for

molecular epidemiology of E. faecium

strains and details of the mechanisms of

associated resistance, including gene

identification; and

11. Other pertinent data.

FDA’s CVM requests that reports of

data include a description of the

population from which samples were

taken and a description of sampling and

culture procedures used. All prevalence

information or rates need to be provided

with numerators and denominators.

Likewise, count data is most useful if it

is provided with information about the

distribution of counts, such as with a

range or with the mean and standard

deviation. For the RA to become a

useful regulatory tool for protection of

public health in the United States, it

must be based on good quality,

contemporaneous data gathered in the

United States, or from populations

demonstrated to be representative of the

U.S.-population.

FDA believes that the credibility and

validity of the RA requires that the

process for the conduct of the RA be

transparent, and all data and

information evaluated in the context of

the RA and utilized in the RA should be

publicly available. Accordingly, any

data or information submitted in

response to this document should be in

a form that permits public disclosure.

Submitters of data and information

should not mark any information as

‘‘Confidential’’ and should fully expect

that any data or information submitted

will be made available to the public.

Questions regarding the public

availability of data and information

submitted in response to this document,

including questions on maintaining

confidentiality while maximizing the

utility of the data, should be directed to

the contact person above.

As noted, the purpose of this request

for data is to gather relevant information

to facilitate a valid RA of the human

health impact attributable both to direct

acquisition of resistant E. faecium from

food-producing animals and to the

transfer of resistance determinants from

E. faecium in food-producing animals to

E. faecium in humans. The larger goal

is the development of a prototype

quantitative RA model that incorporates

a segment modeling the transfer of

resistance determinants from animal

bacteria to human bacteria. This model

along with CVM’s first quantitative

antimicrobial RA model for acquisition

of resistant food-borne bacteria will be

used to help the agency make

appropriate risk management decisions

about the use of antimicrobials in foodproducing animals. Accordingly, it is

acceptable that data submitted in

response to this document be ‘‘blinded’’

in the sense that the data need not

identify the particular manufacturer,

animal producer, or processor that was

the source of the samples underlying the

results. However, the agency must be

assured of the validity of the study

design and data.

The RA team plans to present a

summary of responses to this document

as part of the completed RA document.

Comments and scientific data and

information should be addressed to the

Dockets Management Branch (address

above) and identified with the docket

number found in brackets in the

heading of this document. Received

materials may be seen in the Dockets

Management Branch between 9 a.m. and

4 p.m., Monday through Friday.

V. 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. The Centers for Disease Control and

Prevention National Nosocomial Infections

Surveillance (NNIS) System, NNIS Report,

data summary from October 1986 to April

1996, issued May 1996, American Journal of

Infection Control, 24(5), pp. 380–388, 1996.

2. Moellering, R. C., P. K. Linden, J.

Reinhardt, E. A. Blumberg, et al., ‘‘The

Efficacy and Safety of Quinupristin/

dalfopristin for the Treatment of Infections

Caused by Vancomycin-resistant

Enterococcus faecium,’’ Synercid Emergency

Use Study Group, Journal of Antimicrobial

Chemotherapy, 44(2), pp. 251–261, 1999.

3. Huycke, M., D. Sahm, and M. Gilmore,

‘‘Multiple-Drug Resistant Enterococci: The

Nature of the Problem and an Agenda for the

Future,’’ Emerging Infectious Diseases, 4(2),

pp. 239–249, 1998.

4. Jensen, L. B., A. M. Hammerum, F. M.

Aerestrup, A. E. Van Den Gofaard, and E. E.

Stobberingh, ‘‘Occurrence of satA and vgb

Genes in Streptogramin-resistant

Enterococcus faecium Isolates of Animal and

Human Origins in The Netherlands,’’

Antimicrobial Agents and Chemotherapy,

vol. 42, pp. 3330–3331, 1998.

5. Leclercq, R., and P. Courvalin, ‘‘Bacterial

Resistance to Macrolide, Lincosamide, and

Streptogramin Antibiotics by Target

Modification,’’ Antimicrobial Agents and

Chemotherapy, 35(7), pp. 1267–1272, 1991.

6. Bozdogan, B., and R. Leclercq, ‘‘Effects

of Genes Encoding Resistance to

Streptogramins A and B on the Activity of

Quinupristin-Dalfopristin Against

Enterococcus faecium,’’Antimicrobial Agents

and Chemotherapy, 43(11), pp. 2720–2725,

1999.

7. Rende-Fournier, R., R. Leclercq, M.

Galimand, J. Duval, and P. Courvalin,

‘‘Identification of the satA Gene Encoding a

Streptogramin A Acetyltransferase in

Enterococcus faecium BM4145,’’

Antimicrobial Agents and Chemotherapy,

37(10), pp. 2119–2125, 1993.

8. Werner, G., and W. Witte,

‘‘Characterization of a New Enterococcal

Gene, satG, Encoding a Putative

Acetyltransferase Conferring Resistance to

Streptogramin A Compounds,’’ Antimicribial

Agents and Chemotherapy, 43(7), pp. 1813–

1814, 1999.

Federal Register / Vol. 65, No. 76 / Wednesday, April 19, 2000 / Notices 20995

9. Soltani, M., D. Beighton, J. PhilpottHoward, N. Woodford, ‘‘Mechanisms of

Resistance to Quinupristin-dalfopristin

among Isolates of Enterococcus Faecium from

Animals, Raw Meat, and Hospital Patients in

Western Europe,’’ Antimicrobial Agents and

Chemotherapy, 44(2), pp. 433–436, 2000.

10. English, L. L., J. R. Hayes, D. G. White,

S. W. Joseph, L. E. Carr, and D. D. Wagner,

‘‘Antibiotic Susceptibility Profiles of

Enterococcus Isolates from the Poultry

Production Environment,’’ Abstract J17, 2000

FDA Science Forum FDA and the Science of

Safety: New Perspectives, p. 73, 2000.

Dated: April 11, 2000.

Margaret M. Dotzel,

Acting Associate Commissioner for Policy.

[FR Doc. 00–9696 Filed 4–14–00; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket Nos. 00D–1086, 00D–1087, 00D–

1088, 00D–1089, 00D–1090, and 00D–1091]

Guidance Documents for Premarket

Notification (510(k)) Submissions for

Six Devices; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

availability of six guidance documents.

These six guidance documents are

intended to serve as special controls for

six devices that FDA has proposed

previously to reclassify from class III

(premarket approval) to class II (special

controls). Elsewhere in this issue of the

Federal Register, FDA is reopening the

comment period on the proposed

reclassification of the six devices and

one other device. FDA is now inviting

comment on these guidance documents

because they were not available for

comment at the time of the publication

of the proposed reclassification (64 FR

12774, March 15, 1999).

DATES: Submit written comments by

July 18, 2000.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 5630 Fishers Lane, rm.

1061, Rockville, MD 20852. Comments

should be identified with the docket

number for the appropriate guidance

document found in the SUPPLEMENTARY

INFORMATION section. Submit written

requests for single copies on a 3.5′′

diskette of one or more of these

guidance documents to the Division of

Small Manufacturers Assistance (HFZ–

220), Center for Devices and

Radiological Health, Food and Drug

Administration, 1350 Piccard Dr.,

Rockville, MD 20850. Send two selfaddressed adhesive labels to assist that

office in processing your request, or fax

your request to 301–443–8818. See the

SUPPLEMENTARY INFORMATION section for

information on electronic access to the

guidance documents.

FOR FURTHER INFORMATION CONTACT:

Joseph M. Sheehan, Center for Devices

and Radiological Health (HFZ–215),

Food and Drug Administration, 1350

Piccard Dr., Rockville, MD 20850, 301–

827–2974.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of March 15,

1999, FDA published a proposed rule to

reclassify 38 preamendments class III

devices into class II and to establish

special controls for these devices. FDA

invited interested persons to comment

on the proposed rule by June 14, 1999.

FDA received one request to reopen

the comment period for six devices. The

request noted that FDA had not made

the guidance documents that were

proposed as special controls for these

six devices available for comment

through FDA’s Good Guidance Practices

(GGP’s) (62 FR 8961, February 27, 1997).

The request further noted that it was

impossible to comment on the proposed

reclassification without the guidance

documents being available. Therefore,

the requester asked that FDA extend the

comment period until at least 90 days

after the guidance documents are

publicly available. FDA agreed with the

request. FDA also identified three

additional devices for which the agency

had not issued the guidance documents

proposed as special controls in

accordance with the GGP policy.

The agency is announcing the

availability of the following six

guidance documents (each with a

separate docket number) for six of these

nine devices. In the near future, FDA

will announce the availability of two

guidance documents that will address

the other three devices.

The six guidance documents, with

their docket numbers, and Facts-onDemand (FOD) numbers are as follows:

Guidance document Docket No. FOD No. 21 CFR Section Device name

Guidance for the Submission of Research and Marketing Applications for

Permanent Pacemaker Leads and for

Pacemaker Lead Adaptor 510(k) Submissions.

00D–1086 372 870.3260 Pacemaker lead adaptor.

Guidance Document for Vascular Prostheses 510(k) Submissions.00D–1087 1357 870.3450 Vascular graft prosthesis of less than 6

millimeter diameter.

Guidance for Annuloplasty Rings 510(k)

Submissions.

00D–1088 1358 870.3800 Annuloplasty ring.

Guidance for Extracorporeal Blood Circuit Defoamer 510(k) Submissions.00D–1089 1632 870.4230 Cardiopulmonary bypass defoamer.

Guidance for Cardiopulmonary Bypass

Arterial Line Blood Filter 510(k) Submissions.

00D–1090 1622 870.4260 Cardiopulmonary bypass arterial line

blood filter.

Guidance for Cardiopulmonary Bypass

Oxygenators 510(k) Submissions.

00D–1091 1361 870.4360 Cardiopulmonary bypass oxygenators.

These guidance documents represent

the agency’s current thinking on

premarket notifications for these

devices. These guidance documents do

not create or confer any rights for or on

any person and do not operate to bind

FDA or the public. An alternative

approach may be used if such approach

satisfies the applicable statute,

regulations, or both. Under FDA’s GGP

policy, each of these guidance

documents is a Level 2 guidance.