Federal Register, Volume 63 Issue 99 (Friday, May 22, 1998)

[Federal Register Volume 63, Number 99 (Friday, May 22, 1998)]
[Proposed Rules]
[Pages 28301-28309]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-13797]

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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.

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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

[[Page 28302]]

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 Secs. 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

[[Page 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 Secs. 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 Secs. 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 Secs. 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 Secs. 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 Secs. 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

[[Page 28304]]

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 Secs. 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 Secs. 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 Secs. 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 Secs. 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 Secs. 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 Secs. 315.5(a)(5) and 601.34(a)(5), FDA proposes that, for
claims that do not fall within the indication categories in Secs. 315.4
and 601.33, the applicant may consult with the agency on how to
establish effectiveness.
Proposed Secs. 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 Secs. 315.6 and 601.35.
Proposed Secs. 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 Secs. 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 Secs. 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 Secs. 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 Secs. 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

[[Page 28305]]

radiopharmaceuticals with well-established low-risk profiles.
Proposed Secs. 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 well-
established 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.
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\1\ Medical and Healthcare Marketplace Guide, Dorland's
Biomedical, sponsored by Smith Barney Health Care Group, 13th ed.,
1997 to 1998.
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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.

[[Page 28306]]

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 Sec. 314.50 and for new biological
products in Sec. 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 Burden^{1
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Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
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
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\1\There 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:

[[Page 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).

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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.

Sec. 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 Sec. 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.

Sec. 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, half-life 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 well-established 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,

[[Page 28308]]

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).

Sec. 601.33 [Redesignated as Sec. 601.28]

3. Section 601.33 Samples for each importation is redesignated as
Sec. 601.28 and transferred from subpart D to subpart C, and the
redesignated section heading is revised to read as follows:

Sec. 601.28 Foreign establishments and products: samples for each
importation.

* * * * *
4. Subpart D is amended by revising the title and adding
Secs. 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

Sec. 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.

Sec. 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.

Sec. 601.32 General factors relevant to safety and effectiveness.

Sec. 601.33 Indications.

Sec. 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 Sec. 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.

Sec. 601.35 Evaluation of safety.

[[Page 28309]]

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}