[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<SUP>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.

    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. 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.


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.

    (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

[[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