[Federal Register: July 31, 2000 (Volume 65, Number 147)]
[Proposed Rules]
[Page 46674-46677]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr31jy00-33]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 315 and 601
[Docket No. 98D-0785]
Revised Draft Guidance for Industry on Developing Medical Imaging
Drugs and Biologics; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Availability of guidance.
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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a revised draft guidance for industry entitled
``Developing Medical Imaging Drugs and Biological Products.'' FDA has
revised the draft guidance issued on October 14, 1998, in response to
comments from industry and other interested persons. The revised draft
guidance is intended to assist developers of drug and biological
products used for medical imaging in conducting the clinical
investigations of, and submitting various types of applications for,
such products. The revised draft guidance also provides
[[Page 46675]]
information on how the agency will interpret and apply provisions in
FDA's final rule on in vivo radiopharmaceuticals used for diagnosis and
monitoring.
DATES: Submit written comments on the revised draft guidance by
September 29, 2000. General comments on agency guidance documents are
welcome at any time.
ADDRESSES: Submit written requests for single copies of the revised
draft guidance to the Drug Information Branch (HFD-210), Center for
Drug Evaluation and Research (CDER), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, or the Office of Communication,
Training, and Manufacturers Assistance (HFM-40), Center for Biologics
Evaluation and Research (CBER), 1401 Rockville Pike, Rockville, MD
20852-1448, FAX 888-CBERFAX or 301-827-3844. Send two self-addressed
adhesive labels to assist either office in processing your request. See
the Supplementary Information section for electronic access to the
revised draft guidance. Submit written comments to the Dockets
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers
Lane, rm. 1061, Rockville, MD 20852. Requests and comments should be
identified with the docket number found in brackets in the heading of
this document.
FOR FURTHER INFORMATION CONTACT:
    Robert K. Leedham, Jr., 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), Food and Drug Administration, 1401 Rockville Pike, Rockville, MD
20852-1448, 301-827-5097.
SUPPLEMENTARY INFORMATION:
I. Description of the Guidance
    In the Federal Register of October 14, 1998 (63 FR 55067), FDA
published a notice announcing the availability of a draft guidance for
industry entitled ``Developing Medical Imaging Drugs and Biological
Products.'' The draft guidance is intended to assist developers of drug
and biological products used for medical imaging in planning and
coordinating the clinical investigations of, and submitting various
types of applications for, such products. The draft guidance also
provides information on how the agency will interpret and apply
provisions in the final rule, published in the Federal Register of May
17, 1999 (64 FR 26657), on the evaluation and approval of in vivo
radiopharmaceuticals used in the diagnosis and monitoring of diseases.
The final rule describes certain types of indications for which FDA
will approve diagnostic radiopharmaceuticals and lists factors that the
agency will consider in evaluating the safety and effectiveness of a
diagnostic radiopharmaceutical drug or biological product under the
Federal Food, Drug, and Cosmetic Act (the act) or the Public Health
Service Act (the PHS Act), respectively.
    The draft guidance applies to medical imaging agents that are used
for diagnosis and monitoring and that are administered in vivo. Such
agents include contrast agents used with medical imaging techniques
such as radiography, computed tomography, ultrasonography, and magnetic
resonance imaging, as well as radiopharmaceuticals used with imaging
procedures such as single-photon emission computed tomography and
positron emission tomography. The draft guidance is not intended to
apply to possible therapeutic uses of these agents or to in vitro
diagnostic products.
    In a document published in the Federal Register of January 5, 1999
(64 FR 457), FDA reopened the comment period on the draft guidance
until February 12, 1999. In another document published in the Federal
Register of February 16, 1999 (64 FR 7561), FDA extended the comment
period until April 14, 1999.
    FDA received numerous written comments on the medical imaging draft
guidance. In addition, the agency held public meetings on January 25
and March 26, 1999, to discuss various issues concerning the draft
guidance.
II. Revisions to the Draft Guidance
    In response to comments and on its own initiative, FDA has made
several revisions to the medical imaging draft guidance. The revisions
include substantive changes as well as relatively minor clarifications
of terms and provisions. Following is a brief summary of the most
significant revisions that FDA has made to the draft guidance.
A. Clinical Safety Assessments: Group 1 and Group 2 Agents
    In accordance with several comments, FDA has redefined the category
of medical imaging agents--Group 1 agents--that may be able to undergo
a more focused clinical safety evaluation during development (i.e., a
complete standard clinical safety evaluation may not be necessary). The
revisions make it possible for more medical imaging agents to be
eligible for Group 1 status than under the previous definition.
    A principal change in Group 1 criteria is substitution of a no-
observed-adverse-effect level (NOAEL) in place of a no-observed-effect-
level (NOEL) in evaluations of the safety margin. An applicant will not
be asked to demonstrate a NOEL that is at least 1,000 times greater
than the maximal dose and dosage to be used in human studies, as stated
in the original draft guidance. Instead, the NOAEL in expanded-acute,
single-dose toxicity studies and safety pharmacology studies in
suitable animal species should be at least 100 times greater than the
maximal dose and dosage to be used in human studies. The NOAEL in
short-term, repeated-dose toxicity studies should be at least 25 times
greater than the maximal dose and dosage for humans.
    The revised draft guidance also specifies when FDA will make Group
1 designations. Group 1 designations based on the safety margin will be
made at the end of phase 1, after animal studies and initial human
trials have been completed. Group 1 designations based on documented
history of extensive clinical use without observed safety issues may
occur at any time during drug development.
B. Blinded Imaging Evaluations
    In response to concerns raised about blinding procedures discussed
in the original draft guidance, FDA has substantially revised the
recommendations on blinded imaging evaluations. The revised draft
guidance states that either a fully blinded image evaluation or an
image evaluation blinded to outcome by independent readers generally
should serve as the principal image evaluation for demonstration of
efficacy to support approval of a medical imaging agent. The revised
draft guidance also notes that such image evaluations may be performed
through sequential unblinding.
C. Endpoints in Trials of Medical Imaging Agents
    The revised draft guidance includes a more detailed discussion of
the use of primary endpoints in clinical trials designed to establish
or support the efficacy of a medical imaging agent. The revised draft
guidance clarifies that such primary endpoints usually should be
related directly to clinically meaningful objectives. The revised draft
guidance notes that image interpretations often have clinical
implications that may be incorporated into the primary endpoint in
clinical trials on the efficacy of a medical imaging agent. The revised
[[Page 46676]]
draft guidance also explains when objective imaging features,
subjective image assessments, and clinical outcomes may be appropriate
for use as primary imaging endpoints.
D. Other Issues on Imaging Conditions and Image Evaluations
    FDA has made several other changes to the provisions in the
original draft guidance on special considerations in the clinical
evaluation of efficacy. These include the following: (1) Clarifying the
steps in the evaluation of medical images (distinguishing between the
assessment of objective image features and the interpretation of
findings on an image); (2) providing a revised explanation of
independent image evaluations; (3) suggesting when offsite and onsite
image evaluations may be appropriate; (4) adding a discussion of the
use of protocol and nonprotocol images in evaluating efficacy; and (5)
clarifying the recommendations on separate or combined image
evaluations.
E. Clinical Usefulness
    FDA has revised the discussion of demonstrating the effectiveness
of a medical imaging agent by evaluating its ability to provide useful
clinical information related to its proposed indication. The revised
draft guidance clarifies the ways in which a sponsor may establish the
clinical usefulness of its product, depending on the specific
indication. The agency also has provided several examples of how
clinical usefulness should be established for different types of
indications and under different circumstances.
III. Statement of Guidance Practices
    This Level 1 draft guidance is being issued consistent with FDA's
good guidance practices (62 FR 8961, February 27, 1997). It represents
the agency's current thinking on the development of medical imaging
drugs and biological products. The revised draft guidance does not
create or confer any rights for or on any person and does not operate
to bind FDA or the public. An alternative approach may be used if such
approach satisfies the requirements of the applicable statutes,
regulations, or both.
IV. Request for Comments
    Interested persons may submit to the Dockets Management Branch
(address above) written comments on the revised draft guidance document
by September 29, 2000. Two copies of any comments are to be submitted,
except that individuals may submit one copy. Comments should be
identified with the docket number found in brackets in the heading of
this document. The revised draft guidance document and received
comments may be seen in the Dockets Management Branch between 9 a.m.
and 4 p.m., Monday through Friday.
V. Electronic Access
    Persons with access to the Internet may obtain the revised draft
guidance at http://www.fda.gov/cder/ guidance/index.htm or http://
www.fda.gov/cber/guidelines/ index.htm.
VI. The Paperwork Reduction Act of 1995
    This draft guidance contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). A description of these provisions is provided in the following
paragraphs with an estimate of the annual reporting burden. Included in
the estimate is the time for reviewing the instructions, searching
existing data sources, gathering and maintaining the data needed, and
completing and reviewing each collection of information.
    FDA invites comment on the following: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection on respondents, including
through the use of automated collection techniques, when appropriate,
and other forms of information technology.
    Title: Draft Guidance for Industry on Developing Medical Imaging
Drugs and Biological Products.
    Description: FDA is issuing a revised draft guidance on the
development of medical imaging drugs and biological products. The draft
guidance is intended to assist developers of drug and biological
products used for medical imaging in planning and coordinating the
clinical investigations of, and submitting various types of
applications for, such products. The draft guidance provides
information on how the agency will interpret and apply provisions of
the existing regulations regarding the content and format of an
application for approval of a new drug (21 CFR 314.50) and the content
of a biological product application (21 CFR 601.25). The draft guidance
also provides information on how the agency will interpret and apply
the final rule on the evaluation and approval of in vivo
radiopharmaceuticals used for diagnosis and monitoring (64 FR 26657).
The final rule, by adding part 315 (21 CFR part 315), clarifies
requirements for the evaluation and approval of drug and biological
radiopharmaceuticals under the authority of the act and the PHS Act.
    Existing regulations, which appear primarily in parts 314 and 601
(21 CFR parts 314 and 601), specify the information that manufacturers
must submit so that FDA may properly evaluate the safety and
effectiveness of new drugs and biological products. This information is
usually submitted as part of a new drug application (NDA) or a
biologics license application, or as a supplement to an approved
application. Part 315 contains regulations that clarify what
information is relevant for diagnostic radiopharmaceuticals. This
revised draft guidance supplements these regulations. Under part 315
and the revised draft guidance, information required under the act and
the PHS Act to establish safety and effectiveness would still have to
be reported.
    Description of Respondents: Manufacturers of medical imaging drugs
and biological products, including contrast drug products and
diagnostic radiopharmaceuticals.
    Burden Estimate: The final rule on in vivo radiopharmaceuticals
used for diagnosis and monitoring set forth an estimated annual
reporting burden on the industry that would result from that rulemaking
(64 FR 26657 at 26667). OMB has approved this collection of information
until July 31, 2002, under OMB control number 0910-0409. This revised
draft guidance on the development of medical imaging drugs and
biological products is in part intended to explain how FDA will
interpret and apply the final rule. Thus, the estimated annual
reporting burden of the draft guidance is the same as that of the final
rule, with one change. In addition to the diagnostic
radiopharmaceuticals that are the subject of the final rule, the
revised draft guidance also addresses the development of contrast drug
products, which FDA evaluates and approves under part 314, but which
are not affected by the final rule.
    Table 1 provides an estimate of the annual reporting burden for
contrast drug products. FDA estimates that the potential number of
respondents who would submit applications or supplements for contrast
drug products would be one. Although FDA did not approve any NDA's for
contrast drugs
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(there are no biological contrast drug products) in fiscal year 1999,
for purposes of estimating the annual reporting burden, the agency
assumes that it will approve one contrast drug each fiscal year. The
annual frequency of responses for contrast drugs is estimated to be one
response per application or supplement. The hours per response, which
is the estimated number of hours that an applicant would spend
preparing the information to be submitted for a contrast drug in
accordance with this draft guidance, is estimated to be approximately
2,000 hours.
    The revised draft guidance would not impose any additional
reporting burden because safety and effectiveness information is
already required by existing regulations. In fact, clarification by the
revised draft guidance of FDA's standards for evaluation of medical
imaging drugs and biological products is expected to reduce the overall
burden of information collection. FDA received no comments on the
analysis of information collection burdens stated in the notice of
availability of the original draft guidance published on October 14,
1998. FDA invites comments on this revised analysis of information
collection burdens.
                                 Table 1.--Estimated Annual Reporting Burden \1\
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                                                      Annual
                                      No. of      Frequency  per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
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Contrast Drugs..................        1               1               1           2,000           2,000
Total...........................                                                                    2,000
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
    In compliance with section 3507(d) of the PRA (44 U.S.C. 3507(d)),
the agency has submitted the information collection provisions of this
revised draft guidance to OMB for review. Interested persons are
requested to send comments on this information collection by August 30,
2000, to the Office of Information and Regulatory Affairs, OMB, New
Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC
20503, Attn: Wendy Taylor, Desk Officer for FDA.
    Dated: July 20, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-19176 Filed 7-28-00; 8:45 am]
BILLING CODE 4160-01-F