[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.
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\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
