Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules 28301

whichever occurs later, and thereafter at

intervals not to exceed 3,000 landings,

inspect the wing front attachments (both the

wing sides and fuselage sides) in accordance

with Socata Service Bulletin No. SB 10–081–

57, Amendment 1, dated August 1996.

(b) For all affected airplanes, accomplish

the following on the wing front attachments

on the wing sides:

(1) If no cracks are found on the wing front

attachments on the wing sides during any

inspection required by paragraph (a) of this

AD, upon accumulating 12,000 landings on

these wing front attachments or within the

next 100 landings after the effective date of

this AD, whichever occurs later, and

thereafter at intervals not to exceed 6,000

landings provided no cracks are found during

any inspection required by paragraph (a) of

this AD, incorporate Modification Kit OPT10

911000 in accordance with Socata Technical

Instruction No. 9110, which incorporates the

following pages:

Pages Revision

level Date

0 and 1 ......... Amendment January 31,

1992.

2 through 11 Original Issue October

1985.

(2) If a crack(s) is found on the wing front

attachments on the wing sides during any

inspection required by paragraph (a) of this

AD, prior to further flight, incorporate

Modification Kit OPT10 911000 in

accordance with Socata Technical Instruction

No. 9110. Incorporate this kit at intervals not

to exceed 6,000 landings thereafter provided

no cracks are found during any inspection

required by paragraph (a) of this AD.

(c) For Models TB9 and TB10 airplanes,

with a serial number in the range of 1

through 399, or with a serial number of 413;

that do not have either Socata Service Letter

(SL) 10–14 incorporated or Socata

Modification Kit OPT10 908100

incorporated, accomplish the following on

the wing front attachments on the fuselage

sides:

(1) If no cracks are found on the wing front

attachments on the fuselage sides during any

inspection required by paragraph (a) of this

AD, upon accumulating 6,000 landings on

these wing front attachments or within the

next 100 landings after the effective date of

this AD, whichever occurs later, and

thereafter at intervals not to exceed 12,000

landings provided no cracks are found during

any inspection required by paragraph (a) of

this AD, incorporate Modification Kit OPT10

919800 in accordance with Socata Technical

Instruction of Modification OPT10 9198–53,

dated October 1994.

(2) If a crack(s) is found on the wing front

attachments on the fuselage sides during any

inspection required by paragraph (a) of this

AD, prior to further flight, incorporate

Modification Kit OPT10 919800 in

accordance with Socata Technical Instruction

of Modification OPT10 9198–53, dated

October 1994. Incorporate this kit at intervals

not to exceed 12,000 landings thereafter

provided no cracks are found during any

inspection required by paragraph (a) of this

AD.

(d) For Models TB9 and TB10 airplanes,

with a serial number in the range of 1

through 399, or with a serial number of 413;

that have either Socata Service Letter (SL)

10–14 incorporated or Socata Modification

Kit OPT10 908100 incorporated, accomplish

the following on the wing front attachments

on the fuselage sides:

(1) If no cracks are found on the wing front

attachments on the fuselage sides during any

inspection required by paragraph (a) of this

AD, upon accumulating 12,000 landings on

these wing front attachments or within the

next 100 landings after the effective date of

this AD, whichever occurs later, and

thereafter at intervals not to exceed 12,000

landings provided no cracks are found during

any inspection required by paragraph (a) of

this AD, incorporate Modification Kit OPT10

919800 in accordance with Socata Technical

Instruction of Modification OPT10 9198–53,

dated October 1994.

(2) If a crack(s) is found on the wing front

attachments on the fuselage sides during any

inspection required by paragraph (a) of this

AD, prior to further flight, incorporate

Modification Kit OPT10 919800 in

accordance with Socata Technical Instruction

of Modification OPT10 9198–53, dated

October 1994. Incorporate this kit at intervals

not to exceed 12,000 landings thereafter

provided no cracks are found during any

inspection required by paragraph (a) of this

AD.

(e) For Models TB9 and TB10 airplanes,

with a serial number in the range of 400

through 412, or with a serial number in the

range of 414 through 9999; accomplish the

following on the wing front attachments on

the fuselage sides:

(1) If no cracks are found on the wing front

attachments on the fuselage sides during any

inspection required by paragraph (a) of this

AD, upon accumulating 12,000 landings on

these wing front attachments or within the

next 100 landings after the effective date of

this AD, whichever occurs later, and

thereafter at intervals not to exceed 12,000

landings provided no cracks are found during

any inspection required by paragraph (a) of

this AD, incorporate Modification Kit OPT10

908100 in accordance with Socata Technical

Instruction of Modification OPT10 9181–53,

Amendment 2, dated October 1994.

(2) If a crack(s) is found on the wing front

attachments on the fuselage sides during any

inspection required by paragraph (a) of this

AD, prior to further flight, incorporate

Modification Kit OPT10 908100 in

accordance with Socata Technical Instruction

of Modification OPT10 9181–53, Amendment

2, dated October 1994. Incorporate this kit at

intervals not to exceed 12,000 landings

thereafter provided no cracks are found

during any inspection required by paragraph

(a) of this AD.

Note 3: ‘‘Unless already accomplished’’

credit may be used if the kits that are

required by paragraphs (c)(1), (d)(1), and

(e)(1) of this AD are aleady incorporated on

the applicable airplanes. As specified in the

AD, repetitive incorporation of these kits

would still be required at intervals not to

exceed 12,000 landings provided no cracks

are found.

(f) Special flight permits may be issued in

accordance with sections 21.197 and 21.199

of the Federal Aviation Regulations (14 CFR

21.197 and 21.199) to operate the airplane to

a location where the requirements of this AD

can be accomplished.

(g) An alternative method of compliance or

adjustment of the initial or repetitive

compliance times that provides an equivalent

level of safety may be approved by the

Manager, Small Airplane Directorate, FAA,

1201 Walnut, suite 900, Kansas City,

Missouri 64106. The request shall be

forwarded through an appropriate FAA

Maintenance Inspector, who may add

comments and then send it to the Manager,

Small Airplane Directorate.

Note 4: Information concerning the

existence of approved alternative methods of

compliance with this AD, if any, may be

obtained from the Small Airplane

Directorate.

(h) Questions or technical information

related to the service information referenced

in this AD should be directed to the

SOCATA—Groupe AEROSPATIALE, Socata

Product Support, Aeroport Tarbes-OssunLourdes, B P 930, 65009 Tarbes Cedex,

France; telephone: 33–5–62–41–76–52;

facsimile: 33–5–62–41–76–54; or the Product

Support Manager, SOCATA Aircraft, North

Perry Airport, 7501 Pembroke Road,

Pembroke Pines, Florida 33023; telephone:

(954) 893–1400; facsimile: (954) 964–1402.

This service information may be examined at

the FAA, Central Region, Office of the

Regional Counsel, Room 1558, 601 E. 12th

Street, Kansas City, Missouri.

Note 5: The subject of this AD is addressed

in French AD 94–264(A), dated December 7,

1994.

Issued in Kansas City, Missouri, on May

14, 1998.

Michael Gallagher,

Manager, Small Airplane Directorate, Aircraft

Certification Service.

[FR Doc. 98–13653 Filed 5–21–98; 8:45 am]

BILLING CODE 4910–13–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 315 and 601

[Docket No. 98N–0040]

Regulations for In Vivo

Radiopharmaceuticals Used for

Diagnosis and Monitoring

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA), in response to

the requirements of the Food and Drug

Administration Modernization Act of

1997 (FDAMA), is proposing to amend

the drug and biologics regulations by

adding provisions that would clarify the

evaluation and approval of in vivo
28302 Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules

radiopharmaceuticals used in the

diagnosis or monitoring of diseases. The

proposed regulations would describe

certain types of indications for which

FDA may approve diagnostic

radiopharmaceuticals. The proposed

rule also would include criteria that the

agency would use to evaluate the safety

and effectiveness of a diagnostic

radiopharmaceutical under the Federal

Food, Drug, and Cosmetic Act (the act)

and the Public Health Service Act (the

PHS Act).

DATES: Submit comments on this

proposed rule on or before August 5,

1998. Submit written comments on the

information collection provisions by

June 22, 1998. See section IV of this

document for the proposed effective

date of a final rule based on this

document.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857. Submit

comments of the information collection

provisions to the Office of Information

and Regulatory Affairs, OMB, New

Executive Office Bldg., 725 17th St.

NW., Washington, DC 20503, Attn: Desk

Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Dano B. Murphy, Center for Biologics

Evaluation and Research (HFM–17),

Food and Drug Administration, 1401

Rockville Pike, Rockville, MD 20852–

1448, 301–827–6210; or Brian L.

Pendleton, Center for Drug Evaluation

and Research (HFD–7), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–594–5649.

SUPPLEMENTARY INFORMATION:

I. Introduction

Radiopharmaceuticals are used for a

wide variety of diagnostic, monitoring,

and therapeutic purposes. Diagnostic

radiopharmaceuticals are used to image

or otherwise identify an internal

structure or disease process, while

therapeutic radiopharmaceuticals are

used to effect a change upon a targeted

structure or disease process.

The action of most

radiopharmaceuticals is derived from

two components: A nonradioactive

delivery component, i.e., a carrier and/

or ligand; and a radioactive imaging

component, i.e., a radionuclide.

Nonradioactive delivery ligands and

carriers are usually peptides, small

proteins, or antibodies. The purpose of

ligands and carriers is to direct the

radionuclide to a specific body location

or process. Once a radiopharmaceutical

has reached its targeted location, the

radionuclide component can be

detected. The imaging component

usually is a short-lived radioactive

molecule that emits radioactive decay

photons having sufficient energy to

penetrate the tissue mass of the patient.

The emitted photons are detected by

specialized devices that generate images

of, or otherwise detect, radioactivity,

such as nuclear medicine cameras and

radiation detection probe devices.

On November 21, 1997, the President

signed FDAMA into law. Section

122(a)(1) of FDAMA directs FDA to

issue proposed and final regulations on

the approval of diagnostic

radiopharmaceuticals within specific

timeframes. As defined in section 122(b)

of FDAMA, a radiopharmaceutical is an

article ‘‘that is intended for use in the

diagnosis or monitoring of a disease or

a manifestation of a disease in humans

* * * that exhibits spontaneous

disintegration of unstable nuclei with

the emission of nuclear particles or

photons[,] or * * * any nonradioactive

reagent kit or nuclide generator that is

intended to be used in the preparation

of any such article.’’ Section

122(a)(1)(A) of FDAMA states that FDA

regulations will provide that, in

determining the safety and effectiveness

of a radiopharmaceutical under section

505 of the act (for a drug) (21 U.S.C.

355) or section 351 of the PHS Act (for

a biological product) (42 U.S.C. 262), the

agency will consider the proposed use

of the radiopharmaceutical in the

practice of medicine, the

pharmacological and toxicological

activity of the radiopharmaceutical

(including any carrier or ligand

component), and the estimated absorbed

radiation dose of the

radiopharmaceutical.

FDAMA requires FDA to consult with

patient advocacy groups, associations,

physicians licensed to use

radiopharmaceuticals, and the regulated

industry before proposing any

regulations governing the approval of

radiopharmaceuticals. Accordingly, in

the Federal Register of February 2, 1998

(63 FR 5338), FDA published a

notification of a public meeting entitled

‘‘Developing Regulations for In Vivo

Radiopharmaceuticals Used for

Diagnosis and Monitoring.’’ The notice

invited all interested persons to attend

the meeting, scheduled for February 27,

1998, and to comment on how the

agency should regulate

radiopharmaceuticals. In particular,

FDA invited comment on the following

topics: (1) The effect of the use of a

radiopharmaceutical in the practice of

medicine on the nature and extent of

safety and effectiveness evaluations; (2)

the general characteristics of a

radiopharmaceutical that should be

considered in the preclinical and

clinical pharmacological and

toxicological evaluations of a

radiopharmaceutical (including the

radionuclide as well as the ligand and

carrier components); (3) determination

and consideration of a

radiopharmaceutical’s estimated

absorbed radiation dose in humans; and

(4) the circumstances under which an

approved indication for marketing

might refer to manifestations of disease

(biochemical, physiological, anatomic,

or pathological processes) common to,

or present in, one or more disease states.

Approximately 50 individuals from

industry, academic institutions,

professional medical organizations, and

patient advocacy groups attended the

February 27, 1998, public meeting and/

or submitted comments in response to

the notice. FDA has considered all of

these comments in drafting this

proposed rule.

The proposed rule applies to the

approval of in vivo

radiopharmaceuticals (both drugs and

biologics) used for diagnosis and

monitoring. The proposed regulations

will not apply to radiopharmaceuticals

used for therapeutic purposes. The

regulations include a definition of

diagnostic radiopharmaceuticals (which

includes radiopharmaceuticals used for

monitoring) and provisions that address

the following aspects of diagnostic

radiopharmaceuticals: (1) General

factors to be considered in determining

safety and effectiveness, (2) possible

indications for use, (3) evaluation of

effectiveness, and (4) evaluation of

safety.

To establish these regulations, FDA

proposes to add a new part 315 to title

21 of the Code of Federal Regulations

(CFR) and to rename subpart D and add

§§ 601.30 through 601.35 in part 601 (21

CFR part 601). These new provisions

would complement and clarify existing

regulations on the approval of drugs and

biologics in parts 314 (21 CFR parts 314)

and 601, respectively. In addition to

these regulatory changes, FDA is in the

process of revising and supplementing

its guidance to industry on product

approval and other matters related to

the regulation of diagnostic

radiopharmaceutical drugs and

biologics. This guidance will address

the application of the proposed rule.

FDA will make such guidance available

in draft form for public comment in

accordance with the agency’s Good

Guidance Practices (see 62 FR 8961,

February 27, 1997).

Positron emission tomography (PET)

drugs are a particular type of

radiopharmaceutical. Section 121 of

FDAMA addresses these products
Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules 28303

separately from other diagnostic

radiopharmaceuticals and requires FDA

to develop appropriate approval

procedures and current good

manufacturing practice requirements for

PET products within the next 2 years.

Although FDA expects the standards for

determining the safety and effectiveness

of diagnostic radiopharmaceuticals set

forth in this proposed rule to apply to

PET diagnostic products under the

approval procedures that FDA intends

to develop for those products, the

agency will address this issue when it

publishes its proposal on PET drugs.

II. Description of the Proposed Rule

The proposed rule would add a new

part 315 to the CFR containing

provisions on radiopharmaceutical

drugs subject to section 505 of the act

that are used for diagnosis and

monitoring. Corresponding provisions

applicable to radiopharmaceutical

biological products subject to licensure

under section 351 of the PHS Act would

be set forth in revised subpart D of part

601. Both proposed regulations are

discussed in the following section of

this document.

A. Scope

Proposed §§ 315.1 and 601.30 define

the scope of the diagnostic

radiopharmaceutical provisions, i.e.,

that they apply only to

radiopharmaceuticals used for diagnosis

and monitoring and not to

radiopharmaceuticals intended for

therapeutic uses. FDA intends that these

regulations will apply only to diagnostic

radiopharmaceuticals that are

administered in vivo. In vitro diagnostic

products generally are regulated as

medical devices under the act, although

they may also be biological products

subject to licensure under section 351 of

the PHS Act (see 21 CFR 809.3(a)).

Some radiopharmaceuticals may have

utility as both diagnostic and

therapeutic drugs or biologics. When a

particular radiopharmaceutical drug or

biologic is proposed for both diagnostic

and therapeutic uses, FDA will evaluate

the diagnostic claims under the

provisions in part 315 (for drugs) or

subpart D of part 601 (for biologics) and

evaluate the therapeutic claims under

the regulations applicable to other drug

or biologic applications.

B. Definition

The proposed ruling in §§ 315.2 and

601.31 would include a definition of

‘‘diagnostic radiopharmaceutical’’ that

is identical to the definition of

‘‘radiopharmaceutical’’ in section 122(b)

of FDAMA. Thus, a ‘‘diagnostic

radiopharmaceutical’’ would be defined

as an article that is intended for use in

the diagnosis or monitoring of a disease

or a manifestation of a disease in

humans; and that exhibits spontaneous

disintegration of unstable nuclei with

the emission of nuclear particles or

photons; or any nonradioactive reagent

kit or nuclide generator that is intended

to be used in the preparation of such

article. FDA interprets ‘‘disease or a

manifestation of a disease’’ to include

conditions that may not ordinarily be

considered diseases, such as essential

thrombocytopenia and bone fractures. In

addition, FDA interprets the definition

as including articles that exhibit

spontaneous disintegration leading to

the reconstruction of unstable nuclei

and the subsequent emission of nuclear

particles or photons.

C. General Factors Relevant to Safety

and Effectiveness

In §§ 315.3 and 601.32, FDA proposes

to incorporate in its regulations the

requirement in section 122 of FDAMA

that the agency consider certain factors

in determining the safety and

effectiveness of diagnostic

radiopharmaceuticals under section 505

of the act or section 351 of the PHS Act.

These factors are as follows: (1) The

proposed use of a diagnostic

radiopharmaceutical in the practice of

medicine; (2) the pharmacological and

toxicological activity of a diagnostic

radiopharmaceutical, including any

carrier or ligand component; and (3) the

estimated absorbed radiation dose of the

diagnostic radiopharmaceutical. Other

sections of the proposed regulations

describe how the agency will assess

these factors. In addition, FDA intends

to provide further information in

guidance to industry.

D. Indications

In §§ 315.4(a) and 601.33(a), FDA

proposes to specify some of the types of

indications for which the agency may

approve a diagnostic

radiopharmaceutical. These categories

of indications are as follows: (1)

Structure delineation; (2) functional,

physiological, or biochemical

assessment; (3) disease or pathology

detection or assessment; and (4)

diagnostic or therapeutic management.

Approval may be possible for claims

other than those listed. (In these and

other provisions on diagnostic

radiopharmaceuticals in the proposed

rule, the terms ‘‘indication,’’ ‘‘indication

for use,’’ and ‘‘claim’’ have the same

meaning and are used interchangeably.)

A diagnostic radiopharmaceutical that

is intended to provide structural

delineation is designed to locate and

outline anatomic structures. For

example, a radiopharmaceutical might

be developed to distinguish a structure

that cannot routinely be seen by any

other imaging modality, such as a drug

designed to image the lymphatics of the

small bowel.

A diagnostic radiopharmaceutical that

is intended to provide a functional,

physiological, or biochemical

assessment is used to evaluate the

function, physiology, or biochemistry of

a tissue, organ system, or body region.

Functional, physiological, and

biochemical assessments are designed to

determine if a measured parameter is

normal or abnormal. Examples of a

functional or physiological assessment

include the determination of the cardiac

ejection fraction, myocardial wall

motion, and cerebral blood flow.

Examples of a biochemical assessment

include the evaluation of sugar, lipid,

protein, or nucleic acid synthesis or

metabolism.

A diagnostic radiopharmaceutical that

is intended to provide disease or

pathology detection or assessment

information assists in the detection,

location, or characterization of a specific

disease or pathological state. Examples

of this type of diagnostic

radiopharmaceutical include a

radiolabeled monoclonal antibody used

to attach to a specific tumor antigen and

thus detect a tumor and a peptide that

participates in an identifiable

transporter function associated with a

specific neurological disease.

A diagnostic radiopharmaceutical that

is intended to assist in diagnostic or

therapeutic patient management

provides imaging, or related,

information leading directly to a

diagnostic or therapeutic patient

management decision. Examples of this

type of indication include: (1) Assisting

in a determination of whether a patient

should undergo a diagnostic coronary

angiography or will have predictable

clinical benefit from a coronary

revascularization, and (2) assisting in a

determination of the resectability of a

primary tumor.

Proposed §§ 315.4(b) and 601.33(b)

reflect the intent of section 122(a)(2) of

FDAMA, which states that in

appropriate cases, FDA may approve a

diagnostic radiopharmaceutical for an

indication that refers to ‘‘manifestations

of disease (such as biochemical,

physiological, anatomic, or pathological

processes) common to, or present in,

one or more disease states.’’ Where a

diagnostic radiopharmaceutical is not

intended to provide disease-specific

information, the proposed indications

for use may refer to a process or to more

than one disease or condition. This

would allow FDA to approve a product
28304 Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules

for an indication (e.g., delineation of a

particular anatomic structure or

functional assessment of a specific

organ system) that would encompass

manifestations of disease that are

common to multiple disease states. An

example of a manifestation that is

common to multiple diseases is tumor

metastases to the liver caused by various

malignancies.

E. Evaluation of Effectiveness

The specific criteria that FDA would

use to evaluate the effectiveness of a

diagnostic radiopharmaceutical are

stated in proposed §§ 315.5(a) and

601.34(a). These provisions state that

FDA assesses the effectiveness of a

diagnostic radiopharmaceutical by

evaluating its ability to provide useful

clinical information that is related to its

proposed indication for use. The nature

of the indication determines the method

of evaluation, and because an

application may include more than one

type of claim, FDA might need to

employ multiple evaluation criteria.

FDA would require that any such claim

be supported with information

demonstrating that the potential benefit

of the diagnostic radiopharmaceutical

outweighs the risk to the patient from

administration of the product.

Under proposed §§ 315.5(a)(1) and

601.34(a)(1), a claim of structure

delineation would be established by

demonstrating the ability of a diagnostic

radiopharmaceutical to locate and

characterize normal anatomic

structures. In §§ 315.5(a)(2) and

601.34(a)(2), FDA proposes that a claim

of functional, physiological, or

biochemical assessment would be

established by demonstrating that the

diagnostic radiopharmaceutical could

reliably measure the function or the

physiological, biochemical, or

molecular process. A reliable

measurement would need to be

supported by studies in normal and

abnormal patient populations,

consistent with the proposed claim and

would require a qualitative or

quantitative understanding of how the

measurement varies in normal and

abnormal subjects.

The agency proposes, in §§ 315.5(a)(3)

and 601.34(a)(3), that a claim of disease

or pathology detection or assessment

would be established by demonstrating

in a defined clinical setting that the

diagnostic radiopharmaceutical had

sufficient accuracy in identifying or

characterizing the disease or pathology.

The term ‘‘accuracy’’ refers to the

diagnostic performance of the product

as measured by factors such as

sensitivity, specificity, positive

predictive value, negative predictive

value, and reproducibility of test

interpretation. The term ‘‘sufficient

accuracy’’ means accuracy that is good

enough to indicate that the product

would be useful in one or more clinical

settings. FDA believes that the data

demonstrating accuracy must be

obtained from patients in a clinical

setting(s) reflecting the proposed

indication(s). For example, if a claim is

for diagnosis of tumor in patients with

a negative computed tomography (CT)

scan for disease and a borderline serum

carcinoembryonic antigen (CEA), the

accuracy of the diagnostic

radiopharmaceutical should be assessed

in such patients rather than only in

patients with CT-diagnosed disease or

high serum CEA.

Under proposed §§ 315.5(a)(4) and

601.34(a)(4), for a claim of diagnostic or

therapeutic patient management, the

applicant must establish effectiveness

by demonstrating in a defined clinical

setting that the test is useful in such

patient management. For example, an

imaging agent might be studied in a

manner that would demonstrate its

usefulness in directing local excision of

cancer-laden lymph nodes and sparing

a wide area of nondiseased lymphatic

tissue.

In §§ 315.5(a)(5) and 601.34(a)(5),

FDA proposes that, for claims that do

not fall within the indication categories

in §§ 315.4 and 601.33, the applicant

may consult with the agency on how to

establish effectiveness.

Proposed §§ 315.5(b) and 601.34(b)

specify that the accuracy and usefulness

of diagnostic information provided by a

diagnostic radiopharmaceutical must be

determined by comparison with a

reliable assessment of actual clinical

status. To obtain such a reliable

assessment, a diagnostic standard or

standards of demonstrated accuracy

must be used, if available. An example

of such a standard is a tissue biopsy

confirmation of a site of a diagnostic

radiopharmaceutical localization. If an

accurate diagnostic standard is not

available, the actual clinical status must

be established in some other manner,

such as through patient followup.

FDA intends to develop a guidance

document that will provide more

detailed guidance to industry on the

types of clinical investigations that

would meet regulatory requirements for

obtaining approval for particular types

of indications for diagnostic

radiopharmaceuticals. The guidance

may address such matters as appropriate

clinical endpoints and suitable

diagnostic standards. For indications

that are common to multiple disease

states, the guidance may address

clinical trial design and statistical

analysis considerations for patient

populations that provide a range of

representative disease processes.

F. Evaluation of Safety

FDA’s proposed approach to the

evaluation of the safety of diagnostic

radiopharmaceuticals is set forth in

§§ 315.6 and 601.35. Proposed

§§ 315.6(a) and 601.35(a) state that the

safety assessment of a diagnostic

radiopharmaceutical includes, among

other things, the following: The

radiation dose; the pharmacology and

toxicology of the radiopharmaceutical,

including any radionuclide, carrier, or

ligand; the risks of an incorrect

diagnostic determination; the adverse

reaction profile of the drug; and results

of human experience with the

radiopharmaceutical for other uses.

In §§ 315.6(b) and 601.35(b), FDA

proposes that the assessment of the

adverse reaction profile of a diagnostic

radiopharmaceutical (including the

carrier or ligand) include, but not be

limited to, an evaluation of the

product’s potential to elicit the

following: (1) Allergic or

hypersensitivity responses, (2)

immunologic responses, (3) changes in

the physiologic or biochemical function

of target and non-target tissues, and (4)

clinically detectable signs or symptoms.

Proposed §§ 315.6(c)(1) and

601.35(c)(1) state that FDA may require,

among other information, the following

types of preclinical and clinical data to

establish the safety of a diagnostic

radiopharmaceutical: (1) Pharmacology

data, (2) toxicology data, (3) a clinical

safety profile, and (4) a radiation safety

assessment. Other information that may

be required to establish safety includes

information on chemistry,

manufacturing, and controls.

Under proposed §§ 315.6(c)(2) and

601.35(c)(2), the amount of new safety

data required would depend on the

characteristics of the diagnostic

radiopharmaceutical and available

information on the safety of the product

obtained from other studies and uses.

This information might include, but

would not be limited to, the dose, route

of administration, frequency of use,

half-life of the ligand or carrier, half-life

of the radionuclide of the product, and

results of preclinical studies on the

product. Proposed §§ 315.6(c)(2) and

601.35(c)(2) further states that FDA will

categorize diagnostic

radiopharmaceuticals based on defined

characteristics that relate to safety risk

and will specify the amount and type of

safety data appropriate for each

category. The paragraph states, as an

example, that required safety data

would be limited for diagnostic
Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules 28305

1Medical and Healthcare Marketplace Guide,

Dorland’s Biomedical, sponsored by Smith Barney

Health Care Group, 13th ed., 1997 to 1998.

radiopharmaceuticals with wellestablished low-risk profiles.

Proposed §§ 315.6(d) and 601.35(d)

discusses the radiation safety

assessment that will be required for a

diagnostic radiopharmaceutical. FDA

proposes that the applicant for approval

of a diagnostic radiopharmaceutical

establish the radiation dose of the

product by radiation dosimetry

evaluations in humans and appropriate

animal models. Such evaluations must

consider dosimetry to the total body, to

specific organs or tissues, and, as

appropriate, to target organs or target

tissues. FDA notes that the use of

occupational radiation dosimetry limits

is not required in performing such

evaluations. The maximum tolerated

dose of the diagnostic

radiopharmaceutical need not be

established.

FDA intends to provide guidance on

safety assessments for diagnostic

radiopharmaceuticals. Such guidance

may include a classification of

diagnostic radiopharmaceuticals based

on quantity administered, adverse event

profile, and proposed patient

population. The guidance would allow

the safety information required to meet

regulatory requirements to vary

according to the class of the

radiopharmaceutical. The guidance will

also address evaluations of radiation

dosimetry.

III. Analysis of Economic Impacts

FDA has examined the impact of the

proposed rule under Executive Order

12866, under the Regulatory Flexibility

Act (5 U.S.C. 601–612), and under the

Unfunded Mandates Reform Act (Pub.

L. 104–114). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages, distributive

impacts and equity). Under the

Regulatory Flexibility Act, unless an

agency certifies that a rule will not have

a significant economic impact on a

substantial number of small entities, the

agency must analyze significant

regulatory options that would minimize

any significant economic impact of a

rule on small entities. The Unfunded

Mandates Reform Act requires (in

section 202) that agencies prepare an

assessment of anticipated costs and

benefits before proposing any mandate

that results in an expenditure by State,

local, and tribal governments, in the

aggregate, or by the private sector, of

$100 million in any 1 year.

The agency has reviewed this

proposed rule and has determined that

the rule is consistent with the principles

set forth in the Executive Order and in

these two statutes. FDA finds that the

rule will not be a significant rule under

the Executive Order. Further, the agency

finds that, under the Regulatory

Flexibility Act, the rule will not have a

significant economic impact on a

substantial number of small entities.

Also, since the expenditures resulting

from the standards identified in the rule

are less than $100 million, FDA is not

required to perform a cost/benefit

analysis according to the Unfunded

Mandates Reform Act.

The proposed rule clarifies existing

FDA requirements for the approval and

evaluation of drug and biological

products already in place under the act

and the PHS Act. Existing regulations

(parts 314 and 601) specify the type of

information that manufacturers are

required to submit in order for the

agency to properly evaluate the safety

and effectiveness of new drugs or

biological products. Such information is

usually submitted as part of a new drug

application (NDA) or biological license

application or as a supplement to an

approved application. The information

typically includes both nonclinical and

clinical data concerning the product’s

pharmacology, toxicology, adverse

events, radiation safety assessments,

chemistry, and manufacturing and

controls.

The proposed regulation recognizes

the unique characteristics of diagnostic

radiopharmaceuticals and sets out the

agency’s approach to the evaluation of

these products. For certain diagnostic

radiopharmaceuticals, the proposed

regulation may reduce the amount of

safety information that must be obtained

by conducting new clinical studies. This

would include approved

radiopharmaceuticals with wellestablished low-risk safety profiles

because such products might be able to

use scientifically sound data established

during use of the radiopharmaceutical

to support the approval of a new

indication for use. In addition, the

clarification achieved by the proposed

rule is expected to reduce the costs of

submitting an application for approval

of a diagnostic radiopharmaceutical by

improving communications between

applicants and the agency and by

reducing wasted effort directed toward

the submission of data that is not

necessary to meet the statutory approval

standard.

Manufacturers of in vitro and in vivo

diagnostic substances are defined by the

Small Business Administration as small

businesses if such manufacturers

employ fewer than 500 employees. The

agency finds that only 2 of the 8

companies that currently manufacture

or market radiopharmaceuticals have

fewer than 500 employees. 1 Moreover,

the proposed rule would not impose any

additional costs but, rather, is expected

to reduce costs for manufacturers of

certain diagnostic radiopharmaceuticals,

as discussed previously. Therefore, in

accordance with the Regulatory

Flexibility Act, FDA certifies that this

rule will not have a significant

economic impact on a substantial

number of small entities.

IV. Proposed Effective Date

FDA proposes that any final rule that

may issue based on this proposal

become effective 30 days after the date

of its publication in the Federal

Register.

V. Environmental Impact

The agency has determined under 21

CFR 25.24(h) 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.

VI. The Paperwork Reduction Act of

1995

This proposed rule contains

information collection provisions that

are subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995

(44 U.S.C. 3501–3520). A description of

these provisions is shown below with

an estimate of the annual reporting

burden. Included in the estimate is the

time for reviewing the instructions,

searching existing data sources,

gathering and maintaining the data

needed, and completing and reviewing

each collection of information.

FDA invites comments on: (1)

Whether the proposed collection of

information is necessary for the proper

performance of FDA’s functions,

including whether the information will

have practical utility; (2) the accuracy of

FDA’s estimate of the burden of the

proposed collection of information,

including the validity of the

methodology and assumptions used; (3)

ways to enhance the quality, utility, and

clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.
28306 Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules

Title: Regulations for In Vivo

Radiopharmaceuticals Used for

Diagnosis and Monitoring.

Description: FDA is proposing

regulations for the evaluation and

approval of in vivo

radiopharmaceuticals used for diagnosis

and monitoring. The proposed rule

would clarify existing FDA

requirements for approval and

evaluation of drug and biological

products already in place under the

authorities of the act and the PHS Act.

Those regulations, which appear in

primarily at parts 314 and 601, specify

the information that manufacturers must

submit to FDA for the agency to

properly evaluate the safety and

effectiveness of new drugs or biological

products. The information, which is

usually submitted as part of an NDA or

new biological license application or as

a supplement to an approved

application, typically includes, but is

not limited to, nonclinical and clinical

data on the pharmacology, toxicology,

adverse events, radiation safety

assessments, and chemistry,

manufacturing and controls. The

content and format of an application for

approval of new drugs and antibiotics

are set out in § 314.50 and for new

biological products in § 601.25. Under

the proposed regulation, information

required under the act and the PHS Act

and needed by FDA to evaluate safety

and effectiveness would still need to be

reported.

Description of Respondents:

Manufacturers of in vivo

radiopharmaceuticals used for diagnosis

and monitoring.

To estimate the potential number of

respondents that would submit

applications or supplements for

diagnostic radiopharmaceuticals, FDA

used the number of approvals granted in

fiscal year 1997 (FY 1997) to

approximate the number of future

annual applications. In FY 1997, FDA

approved seven diagnostic

radiopharmaceuticals and received one

new indication supplement; of these,

three respondents received approval

through the Center for Drug Evaluation

and Research and five received approval

through the Center for Biologics

Evaluation and Research. The annual

frequency of responses was estimated to

be one response per application or

supplement. The hours per response

refers to the estimated number of hours

that an applicant would spend

preparing the information referred to in

the proposed regulations. The time

needed to prepare a complete

application is estimated to be

approximately 10,000 hours, roughly

one-fifth of which, or 2,000 hours, is

estimated to be spent preparing the

portions of the application that are

affected by these proposed regulations.

The proposed rule would not impose

any additional reporting burden beyond

the estimated current burden of 2,000

hours because safety and effectiveness

information is already required by

preexisting regulations (parts 314 and

601). In fact, clarification by the

proposed regulation of FDA’s standards

for evaluation of diagnostic

radiopharmaceuticals is expected to

streamline overall information

collection burdens, particularly for

diagnostic radiopharmaceuticals that

may have well-established low-risk

safety profiles, by enabling

manufacturers to tailor information

submissions and avoid conducting

unnecessary clinical studies. The

following table indicates estimates of

the annual reporting burdens for the

preparation of the safety and

effectiveness sections of an application

that are imposed by existing regulations.

The burden totals do not include an

increase in burden because no increase

is anticipated. This estimate does not

include the actual time needed to

conduct studies and trials or other

research from which the reported

information is obtained. FDA invites

comments on this analysis of

information collection burdens.

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

315.4, 315.5, and 315.6 3 1 3 2,000 6,000

601.33, 601.34, and 601.35 5 1 5 2,000 10,000

Total 8 8 16,000

1There are no capital costs or operating and maintenance costs associated with this collection of information.

Interested persons and organizations

may submit comments on the

information collection requirements of

this proposed rule by June 22, 1998, to

Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., Washington,

DC 20503, Attn: Desk Officer for FDA.

At the close of the 30-day comment

period, FDA will review the comments

received, revise the information

collection provisions as necessary, and

submit these provisions to OMB for

review. FDA will publish a notice in the

Federal Register when the information

collection provisions are submitted to

OMB, and an opportunity for public

comment to OMB will be provided at

that time. Prior to the effective date of

the proposed rule, FDA will publish a

notice in the Federal Register of OMB’s

decision to approve, modify, or

disapprove the information collection

provisions. An 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.

VII. Request for Comments

Interested persons may, on or before

August 5, 1998, submit to the Dockets

Management Branch (address above)

written comments on 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

21 CFR Part 315

Biologics, Diagnostic

radiopharmaceuticals, Drugs.

21 CFR Part 601

Administrative practice and

procedure, Biologics, Confidential

business information.

Therefore, under the Federal Food,

Drug, and Cosmetic Act, the Public

Health Service Act, the Food and Drug

Modernization Act, and under authority

delegated to the Commissioner of Food

and Drugs, it is proposed that 21 CFR

chapter I be amended as follows:

1. Part 315 is added to read as follows:
Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules 28307

PART 315—DIAGNOSTIC

RADIOPHARMACEUTICALS

Sec.

315.1 Scope.

315.2 Definition.

315.3 General factors relevant to safety and

effectiveness.

315.4 Indications.

315.5 Evaluation of effectiveness.

315.6 Evaluation of safety.

Authority: 21 U.S.C. 321, 331, 351, 352,

353, 355, 356, 357, 371, 374, 379e; sec. 122,

Pub. L. 105–115, 111 Stat. 2322 (21 U.S.C.

355 note).

§ 315.1 Scope.

The regulations in this part apply to

radiopharmaceuticals intended for in

vivo administration for diagnostic and

monitoring use. They do not apply to

radiopharmaceuticals intended for

therapeutic purposes. In situations

where a particular radiopharmaceutical

is proposed for both diagnostic and

therapeutic uses, the

radiopharmaceutical shall be evaluated

taking into account each intended use.

§ 315.2 Definition.

For purposes of this part, diagnostic

radiopharmaceutical means:

(a) An article that is intended for use

in the diagnosis or monitoring of a

disease or a manifestation of a disease

in humans; and that exhibits

spontaneous disintegration of unstable

nuclei with the emission of nuclear

particles or photons; or

(b) Any nonradioactive reagent kit or

nuclide generator that is intended to be

used in the preparation of such article

as defined in paragraph (a) of this

section.

§ 315.3 General factors relevant to safety

and effectiveness.

FDA’s determination of the safety and

effectiveness of a diagnostic

radiopharmaceutical shall include

consideration of the following:

(a) The proposed use of the diagnostic

radiopharmaceutical in the practice of

medicine;

(b) The pharmacological and

toxicological activity of the diagnostic

radiopharmaceutical (including any

carrier or ligand component of the

diagnostic radiopharmaceutical); and

(c) The estimated absorbed radiation

dose of the diagnostic

radiopharmaceutical.

§ 315.4 Indications.

(a) For diagnostic

radiopharmaceuticals, the categories of

proposed indications for use include,

but are not limited to, the following:

(1) Structure delineation.

(2) Functional, physiological, or

biochemical assessment.

(3) Disease or pathology detection or

assessment.

(4) Diagnostic or therapeutic patient

management.

(b) Where a diagnostic

radiopharmaceutical is not intended to

provide disease-specific information,

the proposed indications for use may

refer to a process or to more than one

disease or condition.

§ 315.5 Evaluation of effectiveness.

(a) The effectiveness of a diagnostic

radiopharmaceutical is assessed by

evaluating its ability to provide useful

clinical information related to its

proposed indications for use. The

method of this evaluation will vary

depending upon the proposed

indication(s) and may use one or more

of the following criteria:

(1) The claim of structure delineation

is established by demonstrating the

ability to locate and characterize normal

anatomical structures.

(2) The claim of functional,

physiological, or biochemical

assessment is established by

demonstrating reliable measurement of

function(s) or physiological,

biochemical, or molecular process(es).

(3) The claim of disease or pathology

detection or assessment is established

by demonstrating in a defined clinical

setting that the diagnostic

radiopharmaceutical has sufficient

accuracy in identifying or characterizing

the disease or pathology.

(4) The claim of diagnostic or

therapeutic patient management is

established by demonstrating in a

defined clinical setting that the test is

useful in diagnostic or therapeutic

patient management.

(5) For a claim that does not fall

within the indication categories

identified in § 315.4, the applicant or

sponsor should consult FDA on how to

establish the effectiveness of the

diagnostic radiopharmaceutical for the

claim.

(b) The accuracy and usefulness of the

diagnostic information shall be

determined by comparison with a

reliable assessment of actual clinical

status. A reliable assessment of actual

clinical status may be provided by a

diagnostic standard or standards of

demonstrated accuracy. In the absence

of such diagnostic standard(s), the

actual clinical status shall be

established in another manner, e.g.,

patient followup.

§ 315.6 Evaluation of safety.

(a) Factors considered in the safety

assessment of a diagnostic

radiopharmaceutical include, among

others, the following: The radiation

dose; the pharmacology and toxicology

of the radiopharmaceutical, including

any radionuclide, carrier, or ligand; the

risks of an incorrect diagnostic

determination; the adverse reaction

profile of the drug; and results of human

experience with the

radiopharmaceutical for other uses.

(b) The assessment of the adverse

reaction profile includes, but is not

limited to, an evaluation of the potential

of the diagnostic radiopharmaceutical,

including the carrier or ligand, to elicit

the following:

(1) Allergic or hypersensitivity

responses.

(2) Immunologic responses.

(3) Changes in the physiologic or

biochemical function of the target and

non-target tissues.

(4) Clinically detectable signs or

symptoms.

(c) (1) To establish the safety of a

diagnostic radiopharmaceutical, FDA

may require, among other information,

the following types of data:

(i) Pharmacology data.

(ii) Toxicology data.

(iii) Clinical adverse event data.

(iv) Radiation safety assessment.

(2) The amount of new safety data

required will depend on the

characteristics of the product and

available information regarding the

safety of the diagnostic

radiopharmaceutical obtained from

other studies and uses. Such

information may include, but is not

limited to, the dose, route of

administration, frequency of use, halflife of the ligand or carrier, half-life of

the radionuclide, and results of

preclinical studies. FDA will categorize

diagnostic radiopharmaceuticals based

on defined characteristics relevant to

risk and will specify the amount and

type of safety data appropriate for each

category. For example, for a category of

radiopharmaceuticals with a wellestablished low-risk profile, required

safety data will be limited.

(d) The radiation safety assessment

shall establish the radiation dose of a

diagnostic radiopharmaceutical by

radiation dosimetry evaluations in

humans and appropriate animal models.

Such an evaluation must consider

dosimetry to the total body, to specific

organs or tissues, and, as appropriate, to

target organs or target tissues. The

maximum tolerated dose need not be

established.

PART 601—LICENSING

2. The authority citation for part 601

is revised to read as follows:

Authority: 21 U.S.C. 321, 351, 352, 353,

355, 360, 360c–360f, 360h–360j, 371, 374,
28308 Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules

379e, 381; 42 U.S.C. 216, 241, 262, 263; 15

U.S.C. 1451–1461; sec. 122, Pub. L. 105–115,

111 Stat. 2322 (21 U.S.C. 355 note).

§ 601.33 [Redesignated as § 601.28]

3. Section 601.33 Samples for each

importation is redesignated as § 601.28

and transferred from subpart D to

subpart C, and the redesignated section

heading is revised to read as follows:

§ 601.28 Foreign establishments and

products: samples for each importation.

* * * * *

4. Subpart D is amended by revising

the title and adding §§ 601.30 through

601.35 to read as follows:

Subpart D—Diagnostic

Radiopharmaceuticals

Sec.

601.30 Scope.

601.31 Definition.

601.32 General factors relevant to safety

and effectiveness.

601.33 Indications.

601.34 Evaluation of effectiveness.

601.35 Evaluation of safety.

Subpart D—Diagnostic

Radiopharmaceuticals

§ 601.30 Scope.

This subpart applies to

radiopharmaceuticals intended for in

vivo administration for diagnostic and

monitoring use. It does not apply to

radiopharmaceuticals intended for

therapeutic purposes. In situations

where a particular radiopharmaceutical

is proposed for both diagnostic and

therapeutic uses, the

radiopharmaceutical shall be evaluated

taking into account each intended use.

§ 601.31 Definition.

For purposes of this subpart,

diagnostic radiopharmaceutical means:

(a) An article that is intended for use

in the diagnosis or monitoring of a

disease or a manifestation of a disease

in humans; and that exhibits

spontaneous disintegration of unstable

nuclei with the emission of nuclear

particles or photons; or

(b) Any nonradioactive reagent kit or

nuclide generator that is intended to be

used in the preparation of such article

as defined in paragraph (a) of this

section.

§ 601.32 General factors relevant to safety

and effectiveness.

FDA’s determination of the safety and

effectiveness of a diagnostic

radiopharmaceutical shall include

consideration of the following:

(a) The proposed use of the diagnostic

radiopharmaceutical in the practice of

medicine;

(b) The pharmacological and

toxicological activity of the diagnostic

radiopharmaceutical (including any

carrier or ligand component of the

diagnostic radiopharmaceutical); and

(c) The estimated absorbed radiation

dose of the diagnostic

radiopharmaceutical.

§ 601.33 Indications.

(a) For diagnostic

radiopharmaceuticals, the categories of

proposed indications for use include,

but are not limited to, the following:

(1) Structure delineation.

(2) Functional, physiological, or

biochemical assessment.

(3) Disease or pathology detection or

assessment.

(4) Diagnostic or therapeutic patient

management.

(b) Where a diagnostic

radiopharmaceutical is not intended to

provide disease-specific information,

the proposed indications for use may

refer to a process or to more than one

disease or condition.

§ 601.34 Evaluation of effectiveness.

(a) The effectiveness of a diagnostic

radiopharmaceutical is assessed by

evaluating its ability to provide useful

clinical information related to its

proposed indications for use. The

method of this evaluation will vary

depending upon the proposed

indication and may use one or more of

the following criteria:

(1) The claim of structure delineation

is established by demonstrating the

ability to locate and characterize normal

anatomical structures.

(2) The claim of functional,

physiological, or biochemical

assessment is established by

demonstrating reliable measurement of

function(s) or physiological,

biochemical, or molecular process(es).

(3) The claim of disease or pathology

detection or assessment is established

by demonstrating in a defined clinical

setting that the diagnostic

radiopharmaceutical has sufficient

accuracy in identifying or characterizing

the disease or pathology.

(4) The claim of diagnostic or

therapeutic patient management is

established by demonstrating in a

defined clinical setting that the test is

useful in diagnostic or therapeutic

patient management.

(5) For a claim that does not fall

within the indication categories

identified in § 601.33, the applicant or

sponsor should consult FDA on how to

establish the effectiveness of the

diagnostic radiopharmaceutical for the

claim.

(b) The accuracy and usefulness of the

diagnostic information shall be

determined by comparison with a

reliable assessment of actual clinical

status. A reliable assessment of actual

clinical status may be provided by a

diagnostic standard or standards of

demonstrated accuracy. In the absence

of such diagnostic standard(s), the

actual clinical status shall be

established in another manner, e.g.,

patient followup.

§ 601.35 Evaluation of safety.

(a) Factors considered in the safety

assessment of a diagnostic

radiopharmaceutical include, among

others, the following: The radiation

dose; the pharmacology and toxicology

of the radiopharmaceutical, including

any radionuclide, carrier, or ligand; the

risks of an incorrect diagnostic

determination; the adverse reaction

profile of the drug; and results of human

experience with the

radiopharmaceutical for other uses.

(b) The assessment of the adverse

reaction profile includes, but is not

limited to, an evaluation of the potential

of the diagnostic radiopharmaceutical,

including the carrier or ligand, to elicit

the following:

(1) Allergic or hypersensitivity

responses.

(2) Immunologic responses.

(3) Changes in the physiologic or

biochemical function of the target and

non-target tissues.

(4) Clinically detectable signs or

symptoms.

(c) (1) To establish the safety of a

diagnostic radiopharmaceutical, FDA

may require, among other information,

the following types of data:

(i) Pharmacology data.

(ii) Toxicology data.

(iii) Clinical adverse event data.

(iv) Radiation safety assessment.

(2) The amount of new safety data

required will depend on the

characteristics of the product and

available information regarding the

safety of the diagnostic

radiopharmaceutical obtained from

other studies and uses. Such

information may include, but is not

limited to, the dose, route of

administration, frequency of use, halflife of the ligand or carrier, half-life of

the radionuclide, and results of

preclinical studies. FDA will categorize

diagnostic radiopharmaceuticals based

on defined characteristics relevant to

risk and will specify the amount and

type of safety data appropriate for each

category. For example, for a category of

radiopharmaceuticals with a wellestablished low-risk profile, required

safety data will be limited.

(d) The radiation safety assessment

shall establish the radiation dose of a
Federal Register / Vol. 63, No. 99 / Friday, May 22, 1998 / Proposed Rules 28309

1 In this notice, the term ‘‘land-based nonroad’’

and ‘‘nonroad’’ refers to the land-based CI engines

and equipment regulated under 40 CFR part 89. It

does not include locomotive engines.

2See 62 FR 54694 (October 21, 1997) and 62 FR

50152 (September 24, 1997).

3A copy of MARPOL 73/78 Annex VI and the

associated NOX Technical Code is available in this

docket.

diagnostic radiopharmaceutical by

radiation dosimetry evaluations in

humans and appropriate animal models.

Such an evaluation must consider

dosimetry to the total body, to specific

organs or tissues, and, as appropriate, to

target organs or target tissues. The

maximum tolerated dose need not be

established.

Dated: April 15, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98–13797 Filed 5–20–98; 11:44 am]

BILLING CODE 4160–01–F

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 89

[FRL–6014–4]

RIN 2060–AH65

Control of Emissions of Air Pollution

from New CI Marine Engines at or

Above 37 Kilowatts

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Advance notice of proposed

rulemaking.

SUMMARY: EPA is issuing this Advance

Notice of Proposed Rulemaking

(ANPRM) to invite comment from all

interested parties on EPA’s plans to

propose emission standards and other

related provisions for new propulsion

and auxiliary marine compressionignition (CI) engines at or above 37

kilowatts (kW). This action supplements

an earlier action for these engines

initiated as part of an overall control

strategy for new spark-ignition (SI) and

CI marine engines (Notice of Proposed

Rulemaking (NPRM) published

November 9, 1994, modified in a

Supplemental Notice of Proposed

Rulemaking (SNPRM) published at

February 7, 1996). The engines covered

by today’s action are used for

propulsion and auxiliary power on both

commercial and recreational vessels for

a wide variety of applications including,

but not limited to, barges, tugs, fishing

vessels, ferries, runabouts, and cabin

cruisers. This document does not

address diesel marine engines rated

under 37 kW, which are included in a

proposed rulemaking for land-based

nonroad CI engines published at

September 24, 1997.

DATES: EPA requests comment on this

ANPRM no later than June 22, 1998.

Should a commenter miss the requested

deadline, EPA will try to consider any

comments received prior to publication

of the NPRM that is expected to follow

this ANPRM. There will also be

opportunity for oral and written

comment when EPA publishes the

NPRM.

ADDRESSES: Materials relevant to this

action are contained in Public Docket

A–97–50, located at room M–1500,

Waterside Mall (ground floor), U.S.

Environmental Protection Agency, 401

M Street, S.W., Washington, DC 20460.

The docket may be inspected from 8:00

a.m. until 5:30 p.m., Monday through

Friday. A reasonable fee may be charged

by EPA for copying docket materials.

Comments on this notice should be

sent to Public Docket A–97–50 at the

above address. EPA requests that a copy

of comments also be sent to Jean Marie

Revelt, U.S. EPA, 2565 Plymouth Road,

Ann Arbor, MI 48105.

FOR FURTHER INFORMATION CONTACT:

Margaret Borushko, U.S. EPA, Engine

Programs and Compliance Division,

(734) 214–4334.

SUPPLEMENTARY INFORMATION:

I. Purpose and Background

A. Purpose

Ground level ozone levels continue to

be a significant problem in many areas

of the United States. In the past, the

main strategy employed in efforts to

reduce ground-level ozone was

reduction of volatile organic compounds

(VOCs). In recent years, however, it has

become clear that NOX controls are

often a more effective strategy for

reducing ozone. As a result, attention

has turned to NOX emission controls as

the key to improving air quality in many

areas of the country. Building on the

emission standards for CI engines

promulgated in the early 1990s, EPA has

recently promulgated a new emission

control program for on-highway CI

engines and proposed a new program

for nonroad CI engines.1, 2 Both of these

programs contain stringent standards

that will greatly reduce NOx emissions

from these engines.

Similarly, particulate matter (PM) is

also a problem in many areas of the

country. Currently, there are 80 PM–10

nonattainment areas across the U.S.

(PM–10 refers to particles less than or

equal to 10 microns in diameter). PM,

like ozone, has been linked to a range

of serious respiratory health problems.

Levels of PM caused by mobile sources

are expected to rise in the future, due to

the predicted increase in the number of

individual mobile sources. Both of the

new emission programs referred to

above, for on-highway and nonroad CI

engines, are anticipated to reduce

ambient PM levels, either through a

reduction in directly emitted particulate

matter or through a reduction in indirect

(atmospheric) PM formation caused by

NOX emissions.

Domestic and ocean-going CI marine

engines account for approximately 4.5

percent of total mobile source NOx

emissions nationwide. However,

because of the nature of their operation,

the contribution of these engines to NOX

levels in certain port cities and coastal

areas is much higher. To address these

emissions, today’s action outlines a

control program for CI marine engines at

or above 37 kW that builds on EPA’s

programs for on-highway and landbased nonroad diesel engines identified

above, EPA’s recent locomotive rule,

discussed below, and the International

Convention on the Prevention of

Pollution from Ships (MARPOL 73/78),

Annex VI—Air Pollution developed by

the International Maritime Organization

(IMO).3 If the emission standards and

other requirements for those CI marine

engines that use the same technologies

reflected in EPA’s on-highway, landbased nonroad, or locomotive rules are

implemented as discussed in today’s

action, EPA would expect to see NOX

and PM reductions on a per-engine basis

comparable to those achieved by

engines subject to those rules. The

numerical levels that EPA is considering

applying to very large CI marine engines

were intended by IMO to result in a 30

percent NOX reduction. EPA continues

to investigate IMO’s anticipated

reductions for those engines, based on

the age and other characteristics of the

U.S. fleet.

B. Statutory Authority

Section 213(a) of the Clean Air Act

(CAA) directs EPA to: (1) conduct a

study of emissions from nonroad

engines and vehicles; (2) determine

whether emissions of carbon monoxide

(CO), oxides of nitrogen (NOX), and

volatile organic compounds (VOCs,

including hydrocarbons (HC)) from

nonroad engines and vehicles are

significant contributors to ozone or CO

in more than one area which has failed

to attain the national ambient air quality

standards (NAAQS) for ozone or CO;

and (3) if nonroad emissions are

determined to be significant, regulate

those categories or classes of new