[Federal Register Volume 64, Number 94 (Monday, May 17, 1999)]
[Rules and Regulations]
[Pages 26657-26670]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-12320]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 315 and 601

[Docket No. 98N-0040]
RIN 0910-AB52


Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis 
and Monitoring

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing regulations 
on the evaluation and approval of in vivo radiopharmaceuticals used in 
the diagnosis and monitoring of diseases. FDA is issuing these 
regulations in accordance with the Food and Drug Administration 
Modernization Act of 1997 (the Modernization Act). These regulations 
are intended to clarify existing regulations applicable to the approval 
of radiopharmaceutical drugs and biologics under the Federal Food, 
Drug, and Cosmetic Act (the act) and the Public Health Service Act (the 
PHS Act).

EFFECTIVE DATE: Effective July 16, 1999.

FOR FURTHER INFORMATION CONTACT: Patricia Y. Love, Center for Drug 
Evaluation and Research (HFD-160), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-7510; or George Q. Mills, 
Center for Biologics Evaluation and Research (HFM-573), 1401 Rockville 
Pike, Rockville, MD 20852-1448, 301-827-5097.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of May 22, 1998 (63 FR 28301), FDA 
published a proposed rule to implement section 122 of the Modernization 
Act (Pub. L. 105-115). Section 122(a)(1) of the Modernization Act 
directs FDA to issue proposed and final regulations on the approval of 
radiopharmaceuticals intended for use in diagnosing or monitoring a 
disease or a manifestation of disease in humans. The proposed 
regulations apply to the approval of in vivo radiopharmaceuticals (both 
drugs and biologics) used for diagnosis and monitoring.
    The preamble to the proposed rule noted that FDA was 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, and stated that such guidance 
would address the application of the proposed rule. In the Federal 
Register of October 14, 1998 (63 FR 55067), FDA announced the 
availability of a draft guidance for industry entitled ``Developing 
Medical Imaging Drugs and Biologics'' (medical imaging draft guidance). 
The guidance, when completed, will assist developers of drug and 
biological products used for medical imaging, including 
radiopharmaceuticals used in disease diagnosis, in planning and 
coordinating the clinical investigations of, and submitting various 
types of applications for, such products. The guidance will also 
provide information on how the agency will interpret and apply 
provisions in the final rule on diagnostic radiopharmaceuticals.
    In the Federal Register of January 5, 1999 (64 FR 457), FDA 
reopened until February 12, 1999, the comment period on the medical 
imaging draft guidance. In the Federal Register of February 16, 1999 
(64 FR 7561), the agency further extended the comment period to April 
14, 1999.
    Several of the comments on the proposed rule on diagnostic 
radiopharmaceuticals addressed issues that are also relevant to the 
medical imaging draft guidance. In FDA's responses to the comments set 
forth in section III of this document, the agency refers to relevant 
portions of the draft guidance that interpret and apply provisions of 
the regulations on diagnostic radiopharmaceuticals. In finalizing the 
medical imaging guidance, FDA will carefully consider all comments 
received on the proposed rule that are relevant to issues addressed in 
the draft guidance.

II. Highlights of the Final Rule

    In accordance with section 122 of the Modernization Act, the final 
rule adds new regulations pertaining to the review and approval of in 
vivo radiopharmaceuticals used for diagnosis and monitoring. The new 
regulations in part 315 (21 CFR part 315) and part 601 (21 CFR part 
601) (Secs. 601.30 through 601.35)) complement and clarify existing 
regulations on the approval of drugs and biologics in part 314 (21 CFR 
part 314) and part 601, respectively. The regulations include a 
definition of diagnostic radiopharmaceuticals and

[[Page 26658]]

provisions that address the following aspects of these products: (1) 
General factors to be considered in determining safety and 
effectiveness, (2) proposed indications for use, (3) evaluation of 
effectiveness, and (4) evaluation of safety.
    FDA revised the proposed rule in response to comments received on 
the proposal. Proposed Secs. 315.4(b) and 601.33(b) were revised to 
clarify that where a diagnostic radiopharmaceutical is not intended to 
provide disease-specific information, the proposed indications for use 
may refer to a biochemical, physiological, anatomical, or pathological 
process or to more than one disease or condition.
    FDA also revised the provisions on the evaluation of effectiveness 
of a diagnostic radiopharmaceutical. The agency revised proposed 
Secs. 315.5(a)(1) and (a)(2) and 601.34(a)(1) and (a)(2) to state that 
claims of structure delineation and of functional, physiological, or 
biochemical assessment must be demonstrated in a defined clinical 
setting that is appropriate for the intended clinical benefit (as is 
the case with claims of: (1) Disease or pathology detection or 
assessment and (2) diagnostic or therapeutic patient management). In 
addition, FDA revised Secs. 315.5(a)(1) and 601.34(a)(1) to state that 
a structure delineation claim involves an ability ``to locate 
anatomical structures and to characterize their anatomy,'' rather than 
an ability ``to locate and characterize normal anatomical structures.''
    FDA also revised the provisions on the evaluation of the safety of 
a diagnostic radiopharmaceutical. Proposed Secs. 315.6(a) and 601.35(a) 
were revised to add to the factors that FDA will consider in assessing 
the safety of a diagnostic radiopharmaceutical the results of any 
previous human experience with the carrier or ligand of a 
radiopharmaceutical when the same chemical entity as the carrier or 
ligand has been used in a previously studied product. Similarly, the 
agency revised Secs. 315.6(c)(2) and 601.35(c)(2) to specify that the 
amount of new safety data required to be submitted for a particular 
diagnostic radiopharmaceutical will depend on the characteristics of 
the product and available information on the safety of not only the 
diagnostic radiopharmaceutical itself but also its carrier or ligand. 
These sections were also revised to state that the safety information 
that FDA may require may include the results of clinical studies, in 
addition to the results of preclinical studies. Additionally, these 
sections were revised to clarify that the agency will establish 
categories of diagnostic radiopharmaceuticals based on defined risk 
characteristics and, upon reviewing a particular diagnostic 
radiopharmaceutical's relevant product characteristics and safety 
information, will place the radiopharmaceutical into the appropriate 
safety risk category. FDA also deleted the requirements in proposed 
Secs. 315.6(d) and 601.35(d) on the tests that must be included in a 
radiation dosimetry evaluation of a diagnostic radiopharmaceutical 
(i.e., dosimetry to total body, to specific organs or tissues, and, as 
appropriate, to target organs or tissues) in favor of addressing this 
matter in the medical imaging guidance.
    Finally, FDA made minor editorial changes to the final rule in 
response to the President's June 1, 1998, memorandum on plain language 
in government writing.

III. Responses to Comments on the Proposed Rule

    FDA received nine written comments on the proposed rule. The 
comments were submitted by manufacturers, trade associations, 
universities, and a health care organization.

A. General Responses

    1. One comment expressed support for the intent of the proposed 
regulations, but it questioned how FDA could develop acceptable 
indications, as well as safety and effectiveness criteria for 
radiopharmaceuticals, without doing the same for all diagnostic drugs 
and biologics. The comment maintained that while radiopharmaceuticals 
may be a unique ``chemical'' class, they are part of the 
``therapeutic'' class of diagnostic agents used for medical imaging. 
The comment further contended that because the proposed regulations on 
diagnostic radiopharmaceuticals were designed to clarify FDA's 
expectations and might reduce the cost of developing these products, 
adoption of these regulations would create a competitive disadvantage 
for companies developing nonradiopharmaceutical products for the same 
indications and efficacy endpoints.
    Section 122(a)(1) of the Modernization Act directs FDA to develop 
regulations specifically governing the approval of diagnostic 
radiopharmaceuticals. It does not direct the agency to establish new 
approval procedures that would apply to all in vivo diagnostic agents, 
including radiopharmaceuticals and contrast agents. Consequently, as 
stated in Secs. 315.1 and 601.30, the final rule applies to 
radiopharmaceuticals intended for in vivo administration for diagnostic 
and monitoring use; it does not apply to radiopharmaceuticals intended 
for therapeutic use or to nonradiopharmaceutical products. FDA will 
consider whether it should develop similar regulations for 
nonradiopharmaceutical diagnostic agents in the future.
    However, FDA agrees with the comment that there are common 
principles in developing diagnostic imaging products. FDA's medical 
imaging draft guidance addresses such matters as conducting clinical 
studies and submitting applications for all medical imaging drugs and 
biologics, not just diagnostic radiopharmaceuticals. In doing so, the 
draft guidance elaborates on the concepts set forth in the proposed 
rule on diagnostic radiopharmaceuticals. Consequently, although the 
final rule applies only to diagnostic radiopharmaceuticals, FDA is 
proposing in the medical imaging draft guidance that the principles set 
forth in this final rule should apply to all medical imaging drugs and 
biologics, including contrast agents.

B. Definition

    Proposed Secs. 315.2 and 601.31 defined a diagnostic 
radiopharmaceutical as an article that is intended for use in the 
diagnosis or monitoring of a human disease or manifestation of disease 
and that exhibits spontaneous disintegration of unstable nuclei with 
the emission of nuclear particles or photons. The definition also 
included any nonradioactive reagent kit or nuclide generator that is 
intended to be used in the preparation of a previously defined article.
    2. One comment, noting that three of the four indication categories 
under proposed Secs. 315.4 and 601.33 did not include the word 
``diagnostic,'' asked whether the regulations should state a definition 
of ``radiopharmaceutical'' rather than ``diagnostic 
radiopharmaceutical'' to be consistent with section 122 of the 
Modernization Act.
    Although section 122(b) of the Modernization Act includes a 
definition of ``radiopharmaceutical'' rather than ``diagnostic 
radiopharmaceutical,'' the term applies only to radiopharmaceuticals 
``intended for use in the diagnosis or monitoring of a disease or a 
manifestation of a disease in humans * * *.'' Consequently, FDA states 
in Secs. 315.1 and 601.30 that the regulations in part 315 and part 
601, subpart D, respectively, apply to radiopharmaceuticals intended 
for diagnostic and monitoring use and not to radiopharmaceuticals 
intended for therapeutic purposes. FDA believes that

[[Page 26659]]

the definition and use of the term ``diagnostic radiopharmaceutical'' 
in these regulations are consistent with the Modernization Act and the 
scope of these regulations. Although three of the four categories of 
indications do not include the word ``diagnostic,'' it is clear from 
the context of the regulations that each of the categories applies to 
diagnostic or monitoring indications and not to therapeutic 
indications.
    3. Two comments asked that FDA clarify a statement in the preamble 
to the proposed rule (63 FR 28301 at 28303) that the definition of 
diagnostic radiopharmaceutical includes articles that exhibit 
spontaneous disintegration leading to reconstruction of unstable nuclei 
and the subsequent emission of nuclear particles or photons.
    Proposed Secs. 315.2 and 601.31 defined a diagnostic 
radiopharmaceutical as an article ``that exhibits spontaneous 
disintegration of unstable nuclei with the emission of nuclear 
particles or photons * * *.'' This definition is identical to the 
definition of ``radiopharmaceutical'' in section 122(b) of the 
Modernization Act. FDA was concerned that this definition might be 
interpreted as excluding an article that exhibits spontaneous 
disintegration leading to the reconstruction of unstable nuclei and the 
subsequent emission of nuclear particles or photons (i.e., the electron 
capture process of decay). Therefore, the agency stated in the preamble 
that it interprets the definition of ``radiopharmaceutical'' in section 
122(b) of the Modernization Act and ``diagnostic radiopharmaceutical'' 
in proposed Secs. 315.2 and 601.31 as including such an article. This 
statement was intended to clarify that diagnostic radiopharmaceuticals 
include articles with unstable nuclei that do not initiate decay by 
spontaneous disintegration but by spontaneous incorporation of an 
electron into the nucleus, bonding with a proton to form a neutron. 
This is followed by neutrino emission from the nucleus and both x-ray 
and Auger electron emissions from the electron shells. Iodine-123 is an 
example of a radionuclide that decays in this manner.

C. Indications

    Proposed Secs. 315.4(a) and 601.33(a) specified the following 
categories of indications for which FDA may approve a diagnostic 
radiopharmaceutical: (1) Structure delineation; (2) functional, 
physiological, or biochemical assessment; (3) disease or pathology 
detection or assessment; and (4) diagnostic or therapeutic patient 
management.
    4. One comment, referring to examples of structural delineation and 
functional/physiological/biochemical assessment indications provided in 
the preamble to the proposed rule, requested that FDA provide examples 
of actual claim language and primary endpoints of adequate and well 
controlled clinical trials for drugs with such types of indications.
    FDA does not believe that it would be appropriate to suggest 
potential language for indications for use or primary clinical 
endpoints outside of the context of evaluating a specific diagnostic 
radiopharmaceutical for a desired indication. However, the medical 
imaging draft guidance provides examples of products with such 
categories of indications and discusses the kinds of claim statements 
that may be permitted in promotional materials for such products. The 
draft guidance also provides examples of the types of endpoints that 
are appropriate for clinical studies on medical imaging drugs and 
biologics.
    5. One comment stated that the distinction between the disease 
detection and patient management categories of indications in proposed 
Secs. 315.4(a)(3) and (a)(4) and 601.33(a)(3) and (a)(4) was vague and 
asked whether the former category allowed for use of the phrase ``as an 
aid in the diagnosis of [a specific disease].'' The comment further 
stated that the difference between the two categories appeared to be 
related to the ability to provide diagnostic information and/or lead to 
a decision on patient management. However, the comment found it 
difficult to understand how a diagnostic radiopharmaceutical could 
characterize a specific disease as described in the preamble (63 FR 
28301 at 28303) and not be of diagnostic value (i.e., fall within the 
diagnostic or therapeutic patient management indication category).
    FDA agrees that there is a need to further clarify the distinction 
between the disease or pathology detection and assessment indication 
category and the diagnostic or therapeutic patient management 
indication category. A disease or pathology detection or assessment 
claim is established by demonstrating that a diagnostic 
radiopharmaceutical provides clinically useful information that can 
assist in the detection, localization, or characterization of a 
specific disease or pathological state in a defined clinical setting. 
However, the way that the information affects patient management is 
implied and may not be directly studied. The phrases ``as an aid in'' 
or ``as an adjunct to'' may be appropriate for this type of indication. 
On the other hand, a diagnostic or therapeutic patient management claim 
is established by explicitly demonstrating a radiopharmaceutical's 
ability to provide imaging or related information that leads directly 
to an appropriate diagnostic or therapeutic management decision for 
patients in a defined clinical setting. FDA will revise the medical 
imaging draft guidance to further distinguish disease/pathology 
detection and assessment indications from patient management 
indications.
    6. One comment, stating that reliance on patient management for a 
diagnostic claim might be unfounded, asked what indication language FDA 
might approve for a diagnostic radiopharmaceutical if there were no 
approved therapy for treating a specific disease.
    A diagnostic or patient management decision need not necessarily 
relate to the use of an approved drug product or therapy. Therefore, 
the absence of an approved therapy for a particular disease would not 
necessarily mean that FDA would not approve a diagnostic 
radiopharmaceutical with an indication for diagnostic or therapeutic 
management of patients with that disease. However, the applicant would 
need to demonstrate that its product has some clinical value. For 
example, in a situation in which two disorders are difficult to 
distinguish but a treatment exists for only one of the two, a 
radiopharmaceutical might be used to distinguish between the two 
disorders, thereby directly affecting subsequent patient management. In 
addition, a diagnostic radiopharmaceutical could have clinical 
usefulness in providing disease progression information about an 
untreatable disease; a patient management claim might be appropriate if 
such information were shown to directly affect some aspect of patient 
management (e.g., symptomatic treatment, avoidance of unnecessary 
treatment). As with all diagnostic radiopharmaceuticals for which a 
patient management indication is sought, FDA would need to determine 
whether the proposed clinical studies on the product included endpoints 
for assessing the appropriateness of patient management or clinical 
outcomes. The medical imaging draft guidance provides further 
clarification on the indications that may be appropriate for a 
diagnostic radiopharmaceutical under these circumstances.
    7. Two comments expressed concern that FDA might narrowly interpret 
the diagnostic or therapeutic patient management indication category, 
noting that the two examples provided in the preamble involved 
indications dealing

[[Page 26660]]

with initial patient management, i.e., deciding therapeutic course. The 
comments sought confirmation that this indication category would 
include diagnostic radiopharmaceuticals used in followup patient 
management, i.e., monitoring response to therapy.
    Although the two examples in the proposed rule related to initial 
patient management rather than monitoring response to therapy, FDA 
affirms that the diagnostic or therapeutic patient management 
indication category includes drugs used to monitor patient response to 
therapy if the response to therapy has direct implications for 
subsequent patient management. Possible diagnostic or therapeutic 
patient management indications might include diagnostic evaluation, use 
of a nonregulated therapy such as surgery, and other significant 
aspects of how a patient is treated. For example, a diagnostic 
radiopharmaceutical might be used to evaluate whether therapy for a 
malignancy is causing tumor regression if that information directly 
affects subsequent patient management decisions. A patient management 
indication also might be appropriate for a radiopharmaceutical that 
provides a convenient, well tolerated, accurate test that has been 
shown to effectively replace a more cumbersome or risky standard 
battery of tests, regardless of the availability of therapy.
    8. Proposed Secs. 315.4(b) and 601.33(b) stated that where a 
diagnostic radiopharmaceutical is not intended to provide disease-
specific information, the proposed indications for use might refer to a 
process or to more than one disease or condition. One comment stated 
that this provision properly implements the special rule in section 
122(a)(2) of the Modernization Act that a radiopharmaceutical may be 
approved for indications referring to manifestations of disease (such 
as biochemical, physiological, anatomical, or pathological processes) 
common to, or present in, one or more disease states. However, the 
comment asked that the phrase ``biochemical, physiological, anatomical, 
or pathological'' be added before the word ``process'' to eliminate the 
possibility that ``process'' might be construed as referring to a 
diagnostic procedure.
    FDA agrees with the comment and has revised Secs. 315.4(b) and 
601.33(b) accordingly.

D. Evaluation of Effectiveness

    In proposed Secs. 315.5 and 601.34, FDA set forth the specific 
criteria that the agency would use to evaluate the effectiveness of a 
diagnostic radiopharmaceutical. The proposed rule stated that 
effectiveness would be assessed by evaluating the ability of the 
diagnostic radiopharmaceutical to provide useful clinical information 
related to the proposed indications for use. The method of this 
evaluation would vary depending on the proposed indication.
    9. One comment maintained that the proposed rule should have 
detailed the differences between diagnostic radiopharmaceuticals and 
conventional, nonradioactive drugs as a basis for a different 
regulatory treatment. For example, the comment stated that adequate and 
well controlled investigations are not applicable to diagnostic 
radiopharmaceuticals and that specific studies involving each 
potentially applicable disease state should not be required for such 
drugs. The comment argued that ``proof of principle'' is all that has 
been required by the Atomic Energy Commission (AEC) and that use of 
this standard would be a good way to implement the requirements of the 
Modernization Act.
    Section 122(a)(1)(A) of the Modernization Act directs FDA to 
develop regulations for determining the safety and effectiveness of 
diagnostic radiopharmaceuticals under section 505 of the act (21 U.S.C. 
355) and section 351 of the PHS Act (42 U.S.C. 262); it does not exempt 
diagnostic radiopharmaceuticals from the requirements of those 
statutory provisions. Under section 505(d)(5) of the act, FDA may 
refuse to approve a new drug application (NDA) if, among other things, 
there is a lack of substantial evidence that the drug will have the 
effect it purports or is represented to have under the conditions of 
use in its proposed labeling. ``Substantial evidence'' is defined as 
adequate and well controlled investigations, including clinical 
investigations, by qualified experts, on the basis of which such 
experts may fairly and responsibly conclude that the drug will have its 
intended effect. Under section 351 of the PHS Act, FDA approves a 
biologics license application (BLA) on, among other things, a 
demonstration that the biological product is safe, pure, and potent. 
Potency has long been interpreted to include effectiveness ``as 
indicated by appropriate laboratory tests or by adequately controlled 
clinical data obtained through the administration of the product in the 
manner intended'' (21 CFR 600.3(s)). FDA believes that the standard of 
substantial evidence is appropriate for use in evaluating the 
sufficiency of evidence of effectiveness submitted in a BLA (see FDA's 
guidance for industry entitled ``Providing Clinical Evidence of 
Effectiveness for Human Drugs and Biological Products,'' May 1998). For 
these reasons, FDA may not establish regulations for diagnostic 
radiopharmaceuticals that exempt such drugs and biologics from the 
statutory requirements.
    The ``proof of principle'' concept noted by the comment was used by 
the Nuclear Regulatory Commission (NRC), the successor agency to the 
AEC. The NRC licenses persons who use nuclear materials. NRC standards 
are directed exclusively at radiological health and safety. The NRC 
focuses on ensuring an adequate level of radiation protection without 
regard to whether a radiopharmaceutical actually works. Because it is 
FDA's statutory responsibility to determine the safety and 
effectiveness of drug products, the NRC's standards are not relevant to 
the approval of diagnostic radiopharmaceuticals under the act. Proof of 
principle, e.g., the metabolic, pharmacokinetic, and pharmacological 
database on a diagnostic radiopharmaceutical, is only part of the drug 
development process. This information alone is insufficient to meet the 
requirements in the act and in FDA regulations on safety and 
effectiveness and on product labeling statements regarding such matters 
as safe use, the adverse event profile, and clinical use information.
    10. One comment maintained that because statements in the preamble 
describing the structure delineation and functional/physiological/
biochemical assessment indication categories do not mention clinical 
benefit, unlike the descriptions of the other two categories, FDA 
should state that a demonstration of ``traditional'' clinical utility 
or benefit is not required for diagnostic radiopharmaceuticals with 
these types of indications. However, the comment noted that this 
interpretation contradicted the statement in proposed Secs. 315.5(a) 
and 601.34(a) that the effectiveness of a diagnostic 
radiopharmaceutical is assessed by evaluating its ability to provide 
``useful clinical information'' concerning its proposed indications. 
The comment stated that it was unclear how one could provide useful 
clinical information related to a proposed indication for use that 
would not be of diagnostic or patient management value. Alternatively, 
the comment asked that FDA provide an example of a drug that 
demonstrates clinical utility but does not aid in diagnosis or 
contribute to patient management.
    Although not explicitly stated in the preamble discussion on 
indication categories, a demonstration of clinical

[[Page 26661]]

benefit, i.e., ability to provide useful clinical information related 
to proposed indications for use, is required for approval of all types 
of diagnostic radiopharmaceuticals under Secs. 315.5(a) and 601.34(a). 
The indication categories are intended to describe the types of 
clinically useful information that could be derived from an imaging 
study, and the type of indication for a particular product is related 
to the type of clinical trial designs that are used in the clinical 
studies. The draft medical imaging guidance further addresses these 
matters.
    It is indeed possible for a diagnostic radiopharmaceutical to 
provide useful clinical information without directly being effective 
for detecting or assessing a disease or aiding patient management. For 
example, a diagnostic radiopharmaceutical might be used to locate and 
outline a normal parathyroid gland; while this information might not 
directly result in disease diagnosis and might not be demonstrated to 
improve patient management, it could indirectly assist a physician in 
planning and performing surgery to remove a mass in the thyroid gland.
    11. Proposed Secs. 315.5(a)(1) through (a)(5) and 601.34(a)(1) 
through (a)(5) set forth the criteria for demonstrating effectiveness 
with respect to particular categories of indications. A structure 
delineation claim would be established by demonstrating the ability of 
the diagnostic radiopharmaceutical to locate and characterize normal 
anatomical structures. A claim of functional, physiological, or 
biochemical assessment would be established by demonstrating reliable 
measurement of functions or physiological, biochemical, or molecular 
processes. A claim of disease or pathology detection or assessment 
would be established by demonstrating in a defined clinical setting 
that the diagnostic radiopharmaceutical has sufficient accuracy in 
identifying or characterizing a disease or pathology. A claim of 
diagnostic or therapeutic patient management would be established by 
demonstrating in a defined clinical setting that the test is useful in 
diagnostic or therapeutic management of patients.
    One comment suggested that the word ``normal'' be deleted from 
proposed Secs. 315.5(a)(1) and 601.34(a)(1) because 
radiopharmaceuticals with structure delineation indications are used to 
locate and characterize structures that may be normal or abnormal, and 
in some cases they may be used to help determine the abnormal 
appearance of a structure.
    FDA agrees to delete the word ``normal'' from Secs. 315.5(a)(1) and 
601.34(a)(1) because a structure delineation claim may be appropriate 
for a diagnostic radiopharmaceutical that is used to determine the 
anatomical appearance of a structure even when the anatomy is abnormal. 
However, to clarify FDA's intent as to what is needed to demonstrate a 
structure delineation claim, the agency is further revising these 
provisions to state that a claim of structure delineation is 
established by demonstrating the ability to locate anatomical 
structures and to characterize their anatomy. FDA recognizes the need 
to clarify when a structure delineation claim is appropriate rather 
than a claim in one of the other indication categories. The agency will 
consider revising the medical imaging draft guidance to further explain 
the scope of permissible structure delineation claims.
    12. One comment maintained that the information provided by 
radiopharmaceuticals with functional, physiological, or biochemical 
assessment indications may be either quantitative, semiquantitative, or 
qualitative. To prevent Secs. 315.5(a)(2) and 601.34(a)(2) from being 
interpreted as permitting only quantitative measurement of function or 
process in establishing a functional, physiological, or biochemical 
assessment claim, the comment requested that the phrase ``quantitative, 
semi-quantitative, or qualitative'' be added before the word 
``measurement.''
    FDA agrees with the comment that a diagnostic radiopharmaceutical 
with a functional, physiological, or biochemical assessment indication 
may be established through either a quantitative, semi-quantitative, or 
qualitative measurement of a function or process. However, the agency 
concludes that it is not necessary to revise Secs. 315.5(a)(2) and 
601.34(a)(2) as requested because these provisions do not require any 
specific type of measurement.
    13. One comment asked FDA to confirm that claims involving 
structure delineation or physiological assessment would not require 
evaluation in a defined clinical setting under proposed 
Secs. 315.5(a)(1) and (a)(2) and 601.34(a)(1) and (a)(2), as would be 
required for disease detection and patient management claims under 
proposed Secs. 315.5(a)(3) and (a)(4) and 601.34(a)(3) and (a)(4). In 
particular, the comment asked whether, if a sponsor could demonstrate 
unequivocally a diagnostic radiopharmaceutical's ability to quantitate 
nucleic acid synthesis (one of the preamble's examples of a biochemical 
assessment indication), FDA would require the sponsor to demonstrate 
such effectiveness in a clinically relevant setting or patient 
population.
    FDA believes that to demonstrate that a diagnostic 
radiopharmaceutical has the ability to provide useful clinical 
information in accordance with Secs. 315.5(a) and 601.34(a), the drug 
must be evaluated in a defined clinical setting, regardless of its 
proposed indication. Consequently, FDA has revised Secs. 315.5(a)(1) 
and (a)(2) and 601.34(a)(1) and (a)(2) to specify that structure 
delineation and functional, physiological, or biochemical assessment 
claims, like disease detection and patient management claims, must be 
demonstrated in a defined clinical setting. The medical imaging draft 
guidance provides further discussion and explanation of the defined 
clinical setting. Claims involving structure delineation or 
physiological assessment must be evaluated under a clinical protocol 
and require a population from a clinically relevant setting. Regarding 
the hypothetical situation posed by the comment, even if a sponsor were 
able to demonstrate unequivocally that a diagnostic radiopharmaceutical 
was able to quantitate nucleic acid synthesis, the sponsor would have 
to demonstrate the usefulness of the imaging information in a 
clinically relevant setting. The clinical setting might be broad, 
demonstrating the common value of nucleic acid synthesis. 
Alternatively, the clinical studies might involve patients with a need 
for a particular type of evaluation (e.g., radionuclide ejection 
fraction) regardless of the underlying disease.
    14. Under proposed Secs. 315.5(b) and 601.34(b), the accuracy and 
usefulness of diagnostic information provided by a diagnostic 
radiopharmaceutical would be determined by comparison with a reliable 
assessment of actual clinical status, which could be provided by a 
diagnostic standard or standards of demonstrated accuracy. One comment 
maintained that these sections should be deleted because the act does 
not require either accuracy or usefulness. The comment stated that 
practitioners determine the accuracy and usefulness of a diagnostic 
radiopharmaceutical and that this information may be found in peer-
reviewed literature, in the United States Pharmacopoeia Drug 
Information, and at professional and continuing medical education 
meetings. The comment added that accuracy and usefulness were never a 
part of the AEC process.

[[Page 26662]]

    FDA declines the request to delete Secs. 315.5(b) and 601.34(b). 
Although section 505(d) of the act and section 351 of the PHS Act do 
not specifically require that a new drug or biologic be shown to be 
``accurate'' and ``useful,'' they do authorize FDA, as noted 
previously, to refuse to approve an application if there is a lack of 
substantial evidence that the product will have the effect it purports 
or is represented to have under the proposed conditions of use, based 
on an evaluation of well controlled clinical trials on the product. The 
statistical assessment of such trials includes accuracy; the clinical 
assessment considers the usefulness of the diagnostic information in 
the studied clinical setting and the proposed indication. FDA 
acknowledges that in the practice of medicine physicians may obtain 
information about a particular diagnostic radiopharmaceutical from 
numerous sources, including the published literature, and they may make 
diagnosis and treatment decisions on the basis of such information. 
Such literature typically becomes available after a product is 
marketed. However, a diagnostic radiopharmaceutical may not be marketed 
unless the agency determines, on the basis of data from clinical trials 
and other information, that the drug is safe and effective under 
section 505 of the act or section 351 of the PHS Act, and that 
determination must include the accuracy and usefulness of the product.

E. Evaluation of Safety

    Proposed Secs. 315.6(a) and 601.35(a) listed the factors that FDA 
would consider in assessing the safety of a diagnostic 
radiopharmaceutical. These factors include 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 drug's adverse reaction 
profile; and results of human experience with the drug for other uses.
    15. One comment maintained that there is no ``pharmacology and 
toxicology of the radiopharmaceutical, including any radionuclide, 
carrier, or ligand,'' as stated in proposed Secs. 315.6(a) and 
601.35(a).
    FDA disagrees with the comment. The agency is aware of specific 
diagnostic radiopharmaceuticals, ligands, and carriers that have been 
shown to have a pharmacological or toxicological effect on the human 
body. For example, biological antibodies used in radiopharmaceuticals 
have demonstrated pharmacological and immunologic activity. In 
addition, as the development of radiopharmaceuticals increasingly 
focuses on receptors and metabolic processes, ligands (either 
synthesized peptides or antibodies) could have agonist or antagonist 
activity at nanomolar levels.
    16. One comment asked why the safety of a diagnostic 
radiopharmaceutical might relate to the pharmacological action of its 
ligand rather than an observed adverse event, suggesting that a 
deleterious pharmacological action would be manifested as an adverse 
event.
    The pharmacological action of a diagnostic radiopharmaceutical's 
ligand directly affects the sponsor's plan for detecting adverse events 
associated with the administration of a radiopharmaceutical. Without 
knowledge of the pharmacological action, the sponsor's selected time 
intervals for monitoring (e.g., immediate reactions, 7- to 10-day 
reactions, 3- to 6-month reactions) may not allow for observation, 
detection, and reporting of adverse events that occur during other time 
intervals. Also, some adverse events are not reported by patients and 
may not be suggested by animal studies; they may be identified only by 
physical examination (e.g., detection of nystagmus by cranial nerve 
examination). In addition, if the pharmacological action of the ligand 
is not known, the sponsor may not determine and use the appropriate 
modality (e.g., clinical evaluation, laboratory assessment, 
radiographic imaging) to monitor adverse events. For example, in a 
radiopharmaceutical that binds irreversibly to activated platelet 
receptors, a pharmacology evaluation would demonstrate an inhibition of 
platelet aggregation. Subsequent clinical studies should evaluate the 
bleeding time and potential drug interaction with treatments that 
prolong bleeding. Therefore, it is appropriate to include both the 
pharmacology and toxicology of a diagnostic radiopharmaceutical 
(including any radionuclide, carrier, or ligand) as well as the drug's 
adverse reaction profile as separate factors to consider in evaluating 
the safety of a diagnostic radiopharmaceutical.
    17. One comment stated that FDA should delete the risks of an 
incorrect diagnostic determination as a factor in assessing the safety 
of a diagnostic radiopharmaceutical. The comment maintained that such 
risks depend on physician competence, patient cooperation, equipment 
quality, and other factors that are not characteristics of a diagnostic 
radiopharmaceutical, and that such a provision does not appear in the 
act.
    FDA disagrees with the proposed deletion. The risk of an incorrect 
diagnostic determination is an independent factor to be considered in 
evaluating the safety of a diagnostic radiopharmaceutical under section 
505 of the act or section 351 of the PHS Act. For example, a new 
diagnostic radiopharmaceutical might produce images and clinical 
information that require additional physician knowledge and competence 
for adequate interpretation or that might suggest an incorrect 
diagnosis even though interpreted by a well trained physician. 
Misinterpretation of the diagnostic images in such circumstances might 
pose a significant threat to the health of patients.
    18. One comment stated that a diagnostic radiopharmaceutical's 
adverse reaction profile should not be considered because it is 
generally nonexistent, nonspecific, or trivial.
    FDA disagrees with the comment. It is possible for a diagnostic 
radiopharmaceutical to have a specific and significant adverse reaction 
profile. Examples are the development of angina after the injection of 
a synthetic radiopharmaceutical to evaluate myocardial perfusion and 
the immune system response to the administration of a radiolabeled 
small peptide or antibody. The production of a human antimurine 
antibody has been demonstrated in response to both first administration 
as well as multiple administrations of a murine antibody. The 
production of the immune response to the administration of the murine 
antibody has elicited life-threatening anaphylactoid responses. 
Therefore, a diagnostic radiopharmaceutical's adverse reaction profile 
is a relevant factor to consider in assessing the drug's safety.
    19. Two comments addressed the proposed safety assessment factor 
concerning ``the results of human experience with the 
radiopharmaceutical for other uses.'' One comment found this factor to 
be confusing and asked that FDA explain the phrase and provide some 
examples. Another comment agreed with the proposed rule that, when an 
applicant is seeking approval for a new indication for a previously 
approved radiopharmaceutical, the clinical data in the approved 
application and postmarketing experience with that product should be 
considered in assessing the safety of that radiopharmaceutical for the 
proposed new use. However, the comment maintained that human safety 
data on a

[[Page 26663]]

ligand or carrier used in a radiopharmaceutical may be important even 
though the radiopharmaceutical has not been previously approved. The 
comment stated that the radionuclide component of a radiopharmaceutical 
may have a long history of use in other radiopharmaceuticals and that 
most radiopharmaceutical issues (other than radiation dosimetry issues) 
will arise from the potential pharmacological or toxicological 
properties of the compound used in the carrier or ligand, about which 
there may be relevant safety information from use in marketed products. 
Therefore, the comment recommended that the following factor be added 
to the end of Secs. 315.6(a) and 601.35(a):
    the results of previous human experience with the ligand or 
carrier component (if any) of the radiopharmaceutical where 
essentially the same chemical entity as the ligand or carrier has 
been used in a previously approved product (e.g., as the ligand or 
carrier in another diagnostic or therapeutic radiopharmaceutical or 
as the active ingredient in a nonradioactive product for therapeutic 
use).
    FDA believes that human experience with a diagnostic 
radiopharmaceutical for previously approved uses (or even uses that 
have been studied but are unapproved) could provide important 
information about the safety of that radiopharmaceutical for a proposed 
new use. For example, the agency would review the safety experience of 
technetium-99m (Tc-99m) pyrophosphate used in bone imaging if a sponsor 
submitted an application for approval of that drug for a new 
indication, such as imaging of myocardial infarction. FDA agrees with 
the comment that the results of any human experience with the carrier 
or ligand of a diagnostic radiopharmaceutical, as used in a previously 
studied product (either as a ligand or carrier in a radiopharmaceutical 
or as an active ingredient in a nonradioactive drug product), should be 
considered in assessing the safety of a diagnostic radiopharmaceutical. 
Therefore, FDA has revised Secs. 315.6(a) and 601.35(a) accordingly. 
However, the agency believes that this human experience must involve 
the exact chemical entity as the carrier or ligand of the diagnostic 
radiopharmaceutical undergoing safety assessment, rather than 
``essentially the same chemical entity'' as the comment recommended. 
(For purposes of part 315 and subpart D of part 601, the terms 
``carrier'' and ``ligand'' collectively refer to the entire 
nonradionuclidic portion of a diagnostic radiopharmaceutical.)
    20. Proposed Secs. 315.6(b) and 601.35(b) stated that the 
assessment of a diagnostic radiopharmaceutical's adverse reaction 
profile includes, but is not limited to, an evaluation of the potential 
of the drug (including its carrier or ligand) to elicit allergic or 
hypersensitivity responses, immunologic responses, changes in the 
physiologic or biochemical function of target and nontarget tissues, 
and clinically detectable signs or symptoms. One comment stated that 
although allergic and immunologic responses may be an issue with 
foreign proteins, a determination of antibody production in a small 
number of subjects would be enough to determine whether such responses 
are common.
    FDA disagrees with the comment. The agency believes that there 
should be adequate clinical experience with a diagnostic 
radiopharmaceutical to identify uncommon as well as common allergic and 
immunologic responses to the radiopharmaceutical. Data on a small 
number of subjects generally are insufficient to identify an uncommon 
but potentially life-threatening adverse reaction.
    21. One comment recommended adding the words ``Clinically 
significant'' before ``Changes in the physiologic or biochemical 
function of the target and nontarget tissues'' in proposed 
Secs. 315.6(b)(3) and 601.35(b)(3) because such changes are relevant to 
assessing a diagnostic radiopharmaceutical's adverse reaction profile 
only when they are clinically significant. As an example, the comment 
stated that the process by which a radiopharmaceutical binds to an 
intended receptor on a cell surface might be regarded as a change in 
the biochemical function of the target tissue even though the change 
has no potential to adversely affect safety and has no other clinical 
significance. The comment contended that its suggested revision would 
be consistent with a statement in the agency's medical imaging draft 
guidance (i.e., that localization of a medical imaging drug in a target 
organ or tissue is not considered to have a biological effect unless it 
produces demonstrable perturbation).
    FDA declines to revise Secs. 315.6(b)(3) and 601.35(b)(3) as 
recommended. The agency believes that the potential of a product to 
change the physiologic or biochemical function of target and nontarget 
tissues should be evaluated. The clinical significance of any detected 
functional change should be assessed. If the functional change has 
little or no clinical significance, it likely will not affect the 
diagnostic radiopharmaceutical's adverse reaction profile.
    22. One comment stated that the references to changes in the 
physiologic or biochemical function of target and nontarget tissues and 
to clinically detectable signs and symptoms should be deleted because 
such events do not occur (or not to any significant extent) with 
diagnostic radiopharmaceuticals.
    FDA disagrees with the comment. FDA's experience with evaluating 
the safety of radiopharmaceuticals has demonstrated that the 
physiologic and biological function of target and nontarget tissues may 
be affected by the administration of a radiopharmaceutical. For 
example, as noted previously, the administration of a radiolabeled 
antibody can produce a strong immune system response. Moreover, changes 
in target and nontarget tissues can sometimes result in clinically 
detectable signs and symptoms, such as the anaphylactoid response 
discussed previously. Therefore, FDA may need information on a 
radiopharmaceutical's potential to produce changes in the physiologic 
or biochemical function of tissues as well as clinically detectable 
signs and symptoms to accurately assess the drug's adverse reaction 
profile.
    23. Proposed Secs. 315.6(c)(1) and 601.35(c)(1) stated that, among 
other information, FDA may require the following types of data to 
establish the safety of a diagnostic radiopharmaceutical: Pharmacology 
data, toxicology data, clinical adverse event data, and a radiation 
safety assessment. One comment maintained that pharmacology, 
toxicology, and clinical adverse event data are for the most part not 
relevant due to the minute mass of the radiopharmaceutical.
    FDA disagrees with the comment. Diagnostic radiopharmaceuticals 
differ widely in mass, and the pharmacological and toxicological 
effects of a diagnostic radiopharmaceutical are not necessarily related 
to the mass of the drug product. However, the mass of a diagnostic 
radiopharmaceutical may be a relevant factor in FDA's determination of 
the type of pharmacology, toxicology, clinical adverse event 
monitoring, and radiation safety data needed to establish the safety of 
a diagnostic radiopharmaceutical.
    24. Proposed Secs. 315.6(c)(2) and 601.35(c)(2) stated that the 
amount of new safety data required for a diagnostic radiopharmaceutical 
would depend on the characteristics of the product and available 
information on the safety of the diagnostic radiopharmaceutical 
obtained from other studies and uses. Included among such information 
would be the dose, route of

[[Page 26664]]

administration, frequency of use, half-life of the ligand or carrier, 
half-life of the radionuclide, and results of preclinical studies. FDA 
would categorize diagnostic radiopharmaceuticals based on defined 
characteristics relevant to risk and would specify the amount and type 
of safety data appropriate for each category. For example, required 
safety data would be limited for a category of radiopharmaceuticals 
with a well established, low-risk profile.
    One comment contended that these provisions fail to address the 
possibility of a reduction in required safety data for previously 
unapproved radiopharmaceuticals. The comment stated that where 
preexisting data demonstrate a history of safe use of a carrier or 
ligand of a diagnostic radiopharmaceutical, such information should 
permit a reduction in the amount of new safety data that the sponsor 
must provide. Therefore, the comment recommended that the phrase ``or 
its carrier or ligand component'' be added following 
``radiopharmaceutical'' in Secs. 315.6(c)(2) and 601.35(c)(2).
    FDA agrees with the comment that such prior data may permit a 
reduction in the amount of new safety data that a sponsor may need to 
provide and has revised these sections accordingly.
    25. One comment noted that ``results of preclinical studies,'' but 
not clinical studies, is listed among the kinds of information on the 
safety of a diagnostic radiopharmaceutical that might be used to 
determine the amount of new safety data required in an application. The 
comment argued that clinical information may also be important to 
consider in determining what new safety data is needed. Such clinical 
information could include data on a diagnostic radiopharmaceutical 
approved for a different indication, on a carrier or ligand that has a 
history of use as a carrier or ligand in an approved 
radiopharmaceutical or as the active ingredient in a therapeutic 
product, or from Phase 1 studies on the drug that is the subject of the 
pending application. Although the comment recognized that the list of 
information on the safety of a diagnostic radiopharmaceutical in 
proposed Secs. 315.6(c)(2) and 601.35(c)(2) was not exclusive, the 
comment believed that failure to explicitly include the results of 
clinical studies might dissuade sponsors from providing FDA with useful 
clinical information early in the clinical development program for the 
drug.
    FDA agrees with the comment and has revised these sections 
accordingly.
    26. One comment agreed with FDA's proposal to define a category of 
low-risk radiopharmaceuticals that would be subject to reduced safety 
requirements. The comment stated that FDA should provide in a guidance 
document a description of the low-risk category, criteria for 
eligibility, and types of safety data required for products in this 
category. The comment contended that the medical imaging draft guidance 
does not specify the different safety requirements for Group 1 and 
Group 2 medical imaging drugs beyond stating that reduced safety 
monitoring is appropriate for Phase 2 and 3 studies on Group 1 drugs.
    FDA agrees with the comment and will consider revising the medical 
imaging draft guidance to further address the type of safety 
information that may be appropriate for Group 1 and Group 2 medical 
imaging drugs.
    27. One comment asked that proposed Secs. 315.6(c)(2) and 
601.35(c)(2) be revised to clarify that, even for radiopharmaceuticals 
that do not fall within a low-risk category, FDA will consider existing 
information and determine on an ad hoc basis the amount of new safety 
data that is required for a particular diagnostic radiopharmaceutical 
product.
    FDA has revised Secs. 315.6(c)(2) and 601.35(c)(2) to clarify the 
agency's approach to determining the amount of new safety data that 
will be required for a particular diagnostic radiopharmaceutical. As 
stated in revised Secs. 315.6(c)(2) and 601.35(c)(2), FDA will consider 
certain product characteristics and available safety information 
obtained from other studies and uses in determining the amount of new 
safety information that is needed for each drug. The information that 
FDA may review includes, but is not limited to, the following: The 
dose, route of administration, and frequency of use of the diagnostic 
radiopharmaceutical; the half-life of the ligand, carrier, and 
radionuclide; and results of clinical studies. In the medical imaging 
guidance, FDA will establish categories of diagnostic 
radiopharmaceuticals based on defined characteristics relevant to 
safety risk and will specify the amount and type of safety data that is 
appropriate for each category (e.g., required safety data may be 
limited for diagnostic radiopharmaceuticals with a well established, 
low-risk profile). Based on its review of the previously listed product 
characteristics and safety information, FDA will place each diagnostic 
radiopharmaceutical into the appropriate safety risk category.
    28. One comment stated that the regulation should specify a 
procedure by which a sponsor may provide FDA with information on the 
basis of which the agency can categorize a diagnostic 
radiopharmaceutical according to new safety data required. The comment 
maintained that this would enable manufacturers to make product 
development decisions with the assurance that a categorization process 
will be available and applied consistently. The comment recommended 
that the categorization procedure provide for the following: (1) 
Sponsor submission of a request for low-risk designation at a meeting 
prior to the submission of an investigational new drug application 
(IND) or any subsequent time; (2) FDA designation of the product as low 
risk if the sponsor submits preclinical data, clinical data, and/or 
other information demonstrating that the radiopharmaceutical possesses 
the characteristics of a low-risk category drug; and (3) FDA action on 
a designation request within 30 days of submission.
    FDA agrees that there should be a standard procedure that the 
sponsor of a diagnostic radiopharmaceutical may follow to request that 
the agency assign the radiopharmaceutical to a particular safety risk 
category. FDA also agrees that such procedure should specify, among 
other things, when a request for categorization may be made and the 
information that should be submitted with a request. However, FDA 
believes that it is more practical to address this matter in the 
medical imaging guidance rather than in regulations.
    29. One comment requested that proposed Secs. 315.6(c)(2) and 
601.35(c)(2) be revised to clarify that a diagnostic 
radiopharmaceutical that has not been previously approved may be 
eligible for low-risk categorization. The comment noted that this would 
allow low-risk categorization of a previously unapproved 
radiopharmaceutical when (1) there is a history of safe use of the 
radiopharmaceutical's ligand or carrier or (2) the sponsor submits 
sufficient preclinical and toxicology data on the radiopharmaceutical 
itself.
    FDA agrees that, under Secs. 315.6(c)(2) and 601.35(c)(2), a 
diagnostic radiopharmaceutical that has not been previously approved 
may be eligible for placement in a low-risk category under certain 
circumstances, such as those suggested by the comment. However, FDA 
finds it unnecessary to revise these sections of the regulations to 
specifically refer to diagnostic radiopharmaceuticals that have not 
been previously approved because the rule does not address the approval 
status of the radiopharmaceuticals. The agency intends to revise the 
medical imaging draft guidance to clarify that even a diagnostic 
radiopharmaceutical that has

[[Page 26665]]

not been previously approved may, under certain circumstances, fall 
within a low-risk category.
    30. Proposed Secs. 315.6(d) and 601.35(d) stated that a radiation 
safety assessment would establish the radiation dose of a diagnostic 
radiopharmaceutical by radiation dosimetry evaluations in humans and 
appropriate animal models. In making such an evaluation, dosimetry to 
the total body, to specific organs or tissues, and, if appropriate, to 
target organs or tissues must be considered, although the maximum 
tolerated dose need not be established.
    One comment stated that a radiation safety assessment should 
usually consist of an estimate of radiation absorbed dose in a few 
normal subjects and that there is no need for subjects with renal or 
hepatic insufficiency or other diseases. The comment maintained that 
precise dosimetry is usually unnecessary, especially for Tc-99m agents, 
because absorbed doses are insignificant. The comment added that even 
though some radionuclides may give selected organ doses that are not 
insignificant, such doses are low and have not been associated with any 
hazard.
    FDA does not agree that it is unnecessary to measure dosimetry and 
to assess the radiation safety of a diagnostic radiopharmaceutical. FDA 
agrees that current knowledge suggests that absorbed radiation doses 
from some diagnostic radiopharmaceuticals are not significant. However, 
as the comment notes, the experience with dosimetry and radiation 
safety demonstrates that this is not true for all diagnostic 
radiopharmaceuticals. Because the agency does not know the future 
significance of the absorbed radiation dose of a particular diagnostic 
radiopharmaceutical, current standardized dosimetry measurements are 
needed for all diagnostic radiopharmaceuticals. These standardized 
dosimetry measurements ensure that the absorbed radiation dose of a 
particular diagnostic radiopharmaceutical is recorded in a standardized 
procedure and that the current known risk of radiation injury from the 
radiopharmaceutical is as low as possible.
    31. There were three comments on evaluation of radiation dosimetry. 
Two comments objected to the use of dosimetry to the total body because 
it assumes uniform, homogenous distribution of a radiopharmaceutical 
throughout the body. The comments contended that this is inaccurate 
because diagnostic radiopharmaceuticals must localize in certain organs 
or tissues to be clinically useful and because essentially all 
diagnostic radiopharmaceuticals undergo some type of elimination from 
the body that leads to concentration in the kidneys/urinary tract or 
liver/biliary tract/gastrointestinal tract. The comments maintained 
that because diagnostic radiopharmaceuticals are heterogeneously 
concentrated in various organs and tissues having different 
radiosensitivities, the radiation safety assessment should consider 
radiation absorbed doses for all organs and tissues in conjunction with 
their relative radiosensitivities using a so-called ``effective dose'' 
calculation.
    FDA acknowledges that a diagnostic radiopharmaceutical is not 
distributed uniformly throughout the body but rather localizes in 
particular organs or tissues. Although FDA agrees that effective dose 
is a relevant measure of dosimetry, the measurement of total body 
dosimetry also may provide relevant information in some settings. FDA 
believes that each sponsor should use dosimetry measurements that are 
appropriate for a particular diagnostic radiopharmaceutical in the 
defined clinical setting, whether this requires measurement of 
dosimetry to the total body, to specific organs or tissues, and/or to 
target organs or tissues. However, FDA concludes that it is more 
appropriate to address this matter in the medical imaging guidance 
rather than the regulations so that dosimetry evaluations of diagnostic 
radiopharmaceuticals may better reflect developments in 
radiopharmaceutical science. Consequently, the agency is deleting the 
sentence in proposed Secs. 315.6(d) and 601.35(d) specifying what must 
be considered in a radiation dosimetry evaluation.
    32. A third comment on evaluation of radiation dosimetry noted that 
the ``Guideline for the Clinical Evaluation of Radiopharmaceutical 
Drugs'' states that organ and tissue dosimetries are required only in 
preclinical studies; for clinical studies, dosimetry calculations 
should be made only on the primary organ(s) of interest and should 
follow the system specified by the Medical Internal Radiation Dose 
Committee of the Society of Nuclear Medicine. The comment recommended 
that the final rule include similar recommendations. The comment also 
maintained that the final rule must distinguish preclinical from 
clinical expectations.
    FDA believes that the appropriate design of the preclinical and 
clinical dosimetry studies for determining radiation dosimetry must be 
based on the characteristics of the radiopharmaceutical, e.g., 
biodistribution, pharmacological actions, and clearance pathways. FDA 
intends to address in the medical imaging guidance the preclinical and 
clinical dosimetry measurements that are considered currently 
appropriate for different types of diagnostic radiopharmaceuticals. 
Therefore, FDA declines to include in the regulations specific methods 
or models of dosimetry or to distinguish between the preclinical and 
clinical dosimetry requirements in the regulations.
    33. There were two comments on maximum tolerated dose. One comment 
found the statement that the maximum tolerated dose need not be 
established to be ``curious'' because the maximum tolerated radiation 
dose was established decades ago. One comment asked that FDA clarify 
whether the phrase refers to the maximum tolerated dose associated with 
adverse events and laboratory abnormalities or to the maximum tolerated 
dose based on radiation dosimetry.
    By stating in Secs. 315.6(d) and 601.35(d) that the maximum 
tolerated dose need not be established, FDA is simply clarifying that 
there is no need to determine the maximum tolerated dose of radiation 
as part of the radiation dosimetry evaluation.

IV. Analysis of Economic Impacts

    FDA has examined the impact of the final 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. 104-4). 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 final rule and has determined that it 
is consistent with the principles set forth in the Executive Order and 
in these two statutes. FDA finds that, while the rule

[[Page 26666]]

will not be an economically significant rule, it is a significant 
regulatory action as described in section 3 paragraph (f)(4) of 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 final 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 so that the agency may properly evaluate the safety and 
effectiveness of new drugs or biological products. Such information is 
usually submitted as part of an NDA, BLA, or 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 final 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 final regulation may reduce the 
amount of safety information that an applicant must obtain 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 final 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 diagnostic radiopharmaceuticals 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 final rule would not 
impose any additional costs but, rather, might reduce the clinical 
costs associated with the existing regulations by clarifying data 
submission requirements. One comment stated that the regulatory costs 
currently associated with developing new radiopharmaceuticals have made 
it difficult for more than two small entities to stay in business. 
While the agency is not aware of any safe and effective 
radiopharmaceuticals that have been prevented from entering the 
marketplace, it believes that this rule might reduce costs and 
therefore benefit small entities. 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.
---------------------------------------------------------------------------

    \1\ Medical & Healthcare Marketplace Guide, 13th ed., Dorland's 
Directories, 1997.
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V. The Paperwork Reduction Act of 1995

    This final 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 (PRA) (44 U.S.C. 3501-3520). The 
title, description, and the respondent description of the information 
collection provisions are 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.
    Title: Regulations for In Vivo Radiopharmaceuticals Used for 
Diagnosis and Monitoring.
    Description: FDA is finalizing regulations for the evaluation and 
approval of in vivo radiopharmaceuticals used for diagnosis and 
monitoring. The final rule clarifies 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 primarily in 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 BLA, 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 a new drug are set out in 
Sec. 314.50 and for a new biological product in Sec. 601.2. Under part 
315 and Secs. 601.30 through 601.35 of part 601, information required 
under the act and the PHS Act, and needed by FDA to evaluate the safety 
and effectiveness of in vivo radiopharmaceuticals, will still need to 
be reported.
    Description of Respondents: Manufacturers of in vivo 
radiopharmaceuticals used for diagnosis and monitoring.
    As required by section 3506 (c)(2)(B) of the PRA, FDA provided an 
opportunity for public comment on May 22, 1998 (63 FR 28301), on the 
information collection provisions of the proposed rule. FDA received 
one comment on the information collection provisions. The comment 
stated that use of the figure of seven approved diagnostic 
radiopharmaceuticals in fiscal year 1997 (FY 1997) resulted in a very 
low estimate of the expected number of future annual applications. The 
comment suggested that 50 applications would be a more appropriate 
figure.
    Based on 5 years of experience, FDA believes that the estimate of 
the number of applications for approval of in vivo diagnostic 
radiopharmaceuticals is a reasonable one. In FY 1992 to 1997, FDA 
approved 13 in vivo diagnostic radiopharmaceuticals. In FY 1998, only 
one such product was approved. The agency does not expect an increase 
in applications for approval of diagnostic radiopharmaceuticals in the 
near future. Although sponsors may submit higher numbers of IND's for 
diagnostic radiopharmaceuticals each year, the annual number of NDA's, 
abbreviated new drug applications, and BLA's approved is small. FDA 
therefore declines to change its estimate.
    In a notice of action on the proposed rule dated July 17, 1998, OMB 
stated that it had concerns about the utility and burden of the 
information collected to demonstrate the safety and effectiveness of a 
new diagnostic radiopharmaceutical or of a new indication for use of an 
approved diagnostic radiopharmaceutical. OMB maintained that the burden 
and utility of this information collection should be assessed in light 
of public comments on the proposed rule and that FDA should 
specifically address such comments in the preamble to the final rule.
    Section 122 of the Modernization Act directs FDA to develop 
regulations on the approval of diagnostic radiopharmaceuticals under 
section 505 of the act. As discussed previously, FDA

[[Page 26667]]

received only one comment on the information collection provisions of 
the proposed rule. None of the manufacturers of diagnostic 
radiopharmaceuticals who submitted comments on the proposed rule 
questioned the need for the submission of information to demonstrate 
the safety and effectiveness of a product to obtain marketing approval. 
Rather, their comments primarily sought clarification or proposed minor 
modification of the proposed regulations.
    To estimate the potential number of respondents that would submit 
applications or supplements for diagnostic radiopharmaceuticals, FDA 
used the number of approvals granted in 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 required 
by the final regulations. Based on FDA's experience, the agency 
estimates the time needed to prepare a complete application for a 
diagnostic radiopharmaceutical 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 
final regulations. The final rule would not impose any additional 
reporting burden for safety and effectiveness information on diagnostic 
radiopharmaceuticals beyond the estimated current burden of 2,000 hours 
because safety and effectiveness information is already required by 
Sec. 314.50 under OMB control number 0910-0001 and Sec. 601.2 under OMB 
control number 0910-0124. In fact, clarification in the final rule 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, 
Secs. 314.50 and 601.2. 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.

                                 Table 1.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                                                    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
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.

    The information collection provisions of the final rule have been 
submitted to OMB for review. Prior to the effective date of the final 
rule, FDA will publish a notice in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection provisions in the final rule. 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.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(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.

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 Administration 
Modernization Act, and under authority delegated to the Commissioner of 
Food and Drugs, 21 CFR chapter I is amended to read as follows:
    1. Part 315 is added to read as follows:

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, 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 must 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.

[[Page 26668]]

Sec. 315.3  General factors relevant to safety and effectiveness.

    FDA's determination of the safety and effectiveness of a diagnostic 
radiopharmaceutical includes 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; and
    (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 biochemical, physiological, anatomical, or pathological 
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 varies 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 in a defined clinical setting the ability to locate 
anatomical structures and to characterize their anatomy.
    (2) The claim of functional, physiological, or biochemical 
assessment is established by demonstrating in a defined clinical 
setting 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 is 
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 must 
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:
    (1) The radiation dose;
    (2) The pharmacology and toxicology of the radiopharmaceutical, 
including any radionuclide, carrier, or ligand;
    (3) The risks of an incorrect diagnostic determination;
    (4) The adverse reaction profile of the drug;
    (5) Results of human experience with the radiopharmaceutical for 
other uses; and
    (6) Results of any previous human experience with the carrier or 
ligand of the radiopharmaceutical when the same chemical entity as the 
carrier or ligand has been used in a previously studied product.
    (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 nontarget tissues, and
    (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, and
    (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, and its carrier or 
ligand, 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 clinical and preclinical studies. FDA will 
establish categories of diagnostic radiopharmaceuticals based on 
defined characteristics relevant to risk and will specify the amount 
and type of safety data that are appropriate for each category (e.g., 
required safety data may be limited for diagnostic radiopharmaceuticals 
with a well established, low-risk profile). Upon reviewing the relevant 
product characteristics and safety information, FDA will place each 
diagnostic radiopharmaceutical into the appropriate safety risk 
category.
    (d) Radiation safety assessment. The radiation safety assessment 
must establish the radiation dose of a diagnostic radiopharmaceutical 
by radiation dosimetry evaluations in humans and appropriate animal 
models. 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:  15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353, 
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216, 
241, 262, 263; 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 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 revised 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.


[[Page 26669]]



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 must be evaluated taking 
into account each intended use.


Sec. 601.31  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. 601.32  General factors relevant to safety and effectiveness.

    FDA's determination of the safety and effectiveness of a diagnostic 
radiopharmaceutical includes 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; and
    (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 biochemical, physiological, anatomical, or pathological 
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 varies 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 in a defined clinical setting the ability to locate 
anatomical structures and to characterize their anatomy.
    (2) The claim of functional, physiological, or biochemical 
assessment is established by demonstrating in a defined clinical 
setting 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 is 
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 must 
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:
    (1) The radiation dose;
    (2) The pharmacology and toxicology of the radiopharmaceutical, 
including any radionuclide, carrier, or ligand;
    (3) The risks of an incorrect diagnostic determination;
    (4) The adverse reaction profile of the drug;
    (5) Results of human experience with the radiopharmaceutical for 
other uses; and
    (6) Results of any previous human experience with the carrier or 
ligand of the radiopharmaceutical when the same chemical entity as the 
carrier or ligand has been used in a previously studied product.
    (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 nontarget tissues, and
    (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:
    (A) Pharmacology data,
    (B) Toxicology data,
    (C) Clinical adverse event data, and
    (D) 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, and its carrier or 
ligand, 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 clinical and preclinical studies. FDA will 
establish categories of diagnostic radiopharmaceuticals based on 
defined characteristics relevant to risk and will specify the amount 
and type of safety data that are appropriate for each category (e.g., 
required safety data may be limited for diagnostic radiopharmaceuticals 
with a well established, low-risk profile). Upon reviewing the relevant 
product characteristics and safety information, FDA will place each 
diagnostic radiopharmaceutical into the appropriate safety risk 
category.
    (d) Radiation safety assessment. The radiation safety assessment 
must establish the radiation dose of a diagnostic radiopharmaceutical 
by radiation dosimetry evaluations in humans and appropriate animal 
models. The maximum tolerated dose need not be established.


[[Page 26670]]


    Dated: April 16, 1999.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 99-12320 Filed 5-14-99; 8:45 am]
BILLING CODE 4160-01-F