[Federal Register Volume 65, Number 147 (Monday, July 31, 2000)]
[Proposed Rules]
[Pages 46674-46677]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-19176]


=======================================================================
-----------------------------------------------------------------------

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Revised Draft Guidance for Industry on Developing Medical Imaging 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.

-----------------------------------------------------------------------

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availability of a revised draft guidance for industry entitled 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revised the draft guidance issued on October 14, 1998, in response to 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 The revised draft 
guidance is intended to assist developers of drug and biological 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 The revised draft guidance also provides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DATES: Submit written comments on the revised draft guidance by 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draft guidance to the Drug Information Branch (HFD-210), Center for 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revised draft guidance.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

[[Page 46677]]

(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\
----------------------------------------------------------------------------------------------------------------
                                                      Annual
                                      No. of      Frequency  per   Total Annual      Hours per      Total Hours
                                    Respondents      Response        Responses       Response
----------------------------------------------------------------------------------------------------------------
Contrast Drugs..................        1               1               1           2,000           2,000
Total...........................                                                                    2,000
----------------------------------------------------------------------------------------------------------------
\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