[Federal Register Volume 67, Number 202 (Friday, October 18, 2002)]
[Notices]
[Pages 64393-64397]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-26617]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 02N-0296]


Agency Information Collection Activities; Submission for OMB 
Review; Comment Request; Investigational New Drug Regulations

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that the 
proposed collection of information listed below has been submitted to 
the Office of Management and Budget (OMB) for review and clearance 
under the Paperwork Reduction Act of 1995.

DATES: Submit written comments on the collection of information by 
November 18, 2002.

ADDRESSES: Submit written comments on the collection of information to 
the Office of Information and Regulatory Affairs, OMB, New Executive 
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: 
Stuart Shapiro, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information 
Resources Management (HFA-250), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-1482.

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Investigational New Drug (IND) Regulations--Part 312 (21 CFR Part 
312)--(OMB Control Number 0910-0014)--Extension

    FDA is requesting OMB approval for the reporting and recordkeeping 
requirements contained in the FDA regulation ``Investigational New Drug 
Application'' part 312 (21 CFR part 312). This regulation implements 
provisions of section 505(i) of the Federal Food, Drug, and Cosmetic 
Act (the act) (21 U.S.C. 355(i)) to issue regulations under which the 
clinical investigation of the safety and effectiveness of unapproved 
new drugs and biological products can be conducted.
    FDA is charged with implementing statutory requirements that drug 
products marketed in the United States be shown to be safe and 
effective, properly manufactured, and properly labeled for their 
intended uses. Section 505(a) of the act provides that a new drug may 
not be introduced or delivered for introduction into interstate 
commerce in the United States unless FDA has previously approved a new 
drug application (NDA). FDA approves an NDA only if the sponsor of the 
application first demonstrates that the drug is safe and effective for 
the conditions prescribed, recommended, or suggested in the product's 
labeling. Proof must consist, in part, of adequate and well controlled 
studies, including studies in humans, that are conducted by qualified 
experts. The IND regulations establish reporting requirements that 
include an initial application as well as amendments to that 
application, reports on significant revisions of clinical investigation 
plans, and information on a drug's safety or effectiveness. In 
addition, the sponsor is required to give FDA an annual summary of the 
previous year's clinical experience. Submissions are reviewed by 
medical officers and other agency scientific reviewers assigned 
responsibility for overseeing the specific study. The IND regulations 
also contain recordkeeping requirements that pertain to the 
responsibilities of sponsors and investigators. The detail and 
complexity of these requirements are dictated by the scientific 
procedures and human subject safeguards that must be followed in the 
clinical tests of investigational new drugs.
    The IND information collection requirements provide the means by 
which FDA can: (1) Monitor the safety of ongoing clinical 
investigations; (2) determine whether the clinical testing of a drug 
should be authorized; (3) ensure production of reliable data on the 
metabolism and pharmacological action of the drug in humans; (4) obtain 
timely information on adverse reactions to the drug; (5) obtain 
information on side effects associated with increasing doses; (6) 
obtain information on the drug's effectiveness; (7) ensure the design 
of well-controlled, scientifically valid studies; (8) obtain other 
information pertinent to determining whether clinical testing should be 
continued and information related to the protection of human subjects. 
Without the information provided by industry in response to the IND 
regulations, FDA cannot authorize or monitor the clinical 
investigations which must be conducted before authorizing the sale and 
general use of new drugs. These reports enable FDA to monitor a study's 
progress, to assure subject safety, to assure that a study will be 
conducted ethically, and to increase the likelihood that the sponsor 
will conduct studies that will be useful in determining whether the 
drug should be marketed and available for use in medical practice.
    There are two forms that are required under part 312:
    Form FDA-1571--``Investigational New Drug Application.'' A person 
who intends to conduct a clinical investigation submits this form to 
FDA. It includes: (1) A cover sheet containing background information 
on the sponsor and investigator; (2) a table of contents; (3) an 
introductory statement and general investigational plan; (4) an 
investigator's brochure describing the drug substance; (5) a protocol 
for each planned study; (6) chemistry, manufacturing, and control 
information for each investigation; (7) pharmacology and toxicology 
information for each investigation; and (8) previous human experience 
with the investigational drug.
    Form FDA-1572--``Investigator Statement.'' Before permitting an 
investigator to begin participation in an investigation, the sponsor 
must obtain and record this form. It includes background information on 
the investigator and the investigation, and a general outline of the 
planned investigation and the study protocol.
    FDA is requesting OMB approval for the following reporting and 
recordkeeping requirements in part 312:

                    Table 1.--Reporting Requirements
------------------------------------------------------------------------
          21 CFR Section                        Explanations
------------------------------------------------------------------------
312.7(d)..........................  Applications for permission to sell
                                     an investigational new drug.
312.10(a).........................  Applications for waiver of
                                     requirements under part 312.
                                     Estimates for this requirement are
                                     included under Sec. Sec.  312.23
                                     and 312.31.

[[Page 64394]]

 
312.20(c).........................  Applications for investigations
                                     involving an exception from
                                     informed consent under Sec.  50.24
                                     (21 CFR 50.24). Estimates for this
                                     requirement are included under Sec.
                                      312.23.
312.23............................  INDs (content and format).
312.23(a)(1)......................     Cover sheet FDA-1571.
312.23(a)(2)......................     Table of contents.
312.23(a)(3)......................     Investigational plan for each
                                        planned study.
312.23(a)(5)......................     Investigator's brochure.
312.23(a)(6)......................     Protocols--Phase 1, 2, and 3.
312.23(a)(7)......................     Chemistry, manufacturing, and
                                        control information.
312.23(a)(7)(iv)(a),(b),(c).......     A description of the drug
                                        substance, a list of all
                                        components, and any placebo
                                        used.
312.23(a)(7)(iv)(d)...............     Labeling: Copies of labels and
                                        labeling to be provided each
                                        investigator.
312.23(a)(7)(iv)(e)...............     Environmental impact analysis
                                        regarding drug manufacturing and
                                        use.
312.23(a)(8)......................     Pharmacological and toxicology
                                        information.
312.23(a)(9)......................     Previous human experience with
                                        the investigational drug.
312.23(a)(10).....................     Additional information.
312.23(a)(11).....................     Relevant information.
312.23(f).........................     Identification of exception from
                                        informed consent.
312.30............................  Protocol amendments.
312.30(a).........................     New protocol.
312.30(b).........................     Change in protocol.
312.30(c).........................     New investigator.
312.30(d).........................     Content and format.
312.30(e).........................     Frequency.
312.31............................  Information amendments.
312.31(b).........................     Content and format.
                                       Chemistry, toxicology, or
                                        technical information.
312.32............................  Safety reports.
312.32(c)(1)......................     Written reports to FDA and to
                                        investigators.
312.32(c)(2)......................     Telephone reports to FDA for
                                        fatal or life-threatening
                                        experience.
312.32(c)(3)......................     Format or frequency.
312.32(d).........................     Follow up submissions.
312.33............................  Annual reports.
312.33(a).........................     Individual study information.
312.33(b).........................     Summary information.
312.33(b)(1)......................     Adverse experiences.
312.33(b)(2)......................     Safety report summary.
312.33(b)(3)......................     List of fatalities and causes of
                                        death.
312.33(b)(4)......................     List of discontinuing subjects.
312.33(b)(5)......................     Drug action.
312.33(b)(6)......................     Preclinical studies and findings.
312.33(b)(7)......................     Significant changes.
312.33(c).........................     Next year general investigational
                                        plan.
312.33(d).........................     Brochure revision.
312.33(e).........................     Phase I protocol modifications.
312.33(f).........................     Foreign marketing developments.
312.35............................  Treatment use of investigational new
                                     drugs.
312.35(a).........................     Treatment protocol submitted by
                                        IND sponsor.
312.35(b).........................     Treatment IND submitted by
                                        licensed practitioner.
312.36............................  Requests for emergency use of an
                                     investigational new drug.
312.38(b) and (c).................  Notification of withdrawal of an
                                     IND.
312.42(e).........................  Sponsor requests that a clinical
                                     hold be removed and submits a
                                     complete response to the issues
                                     identified in the clinical hold
                                     order.
312.44(c) and (d).................  Opportunity for sponsor response to
                                     FDA when IND is terminated.
312.45(a) and (b).................  Sponsor request for or response to
                                     inactive status determination of an
                                     IND.
312.47(b).........................  ``End-of-Phase 2'' meetings and
                                     ``Pre-NDA'' meetings.
312.53(c).........................  Investigator information.
                                       Investigator report (Form FDA-
                                        1572) and narrative;
                                        Investigator's background
                                        information; phase 1 outline of
                                        planned investigation; and phase
                                        2 outline of study protocol;
                                        financial disclosure
                                        information.
312.54(a) and (b).................  Sponsor submissions concerning
                                     investigations involving an
                                     exception from informed consent
                                     under Sec.  50.24.
312.55(b).........................  Sponsor reports to investigators on
                                     new observations, especially
                                     adverse reactions and safe use.
                                     Only ``new observations'' are
                                     estimated under this section;
                                     investigator brochures are included
                                     under Sec.  312.23.
312.56(b), (c), and (d)...........  Sponsor monitoring of all clinical
                                     investigations, investigators, and
                                     drug safety; notification to FDA.
312.58(a).........................  Sponsor's submission of records to
                                     FDA on request.
312.64............................  Investigator reports to the sponsor.

[[Page 64395]]

 
312.64(a).........................     Progress reports.
312.64(b).........................     Safety reports
312.64(c).........................     Final reports.
312.64(d).........................     Financial disclosure reports.
312.66............................  Investigator reports to
                                     Institutional Review Board.
                                     Estimates for this requirement are
                                     included under Sec.  312.53.
312.70(a).........................  Investigator disqualification;
                                     opportunity to respond to FDA.
312.83............................  Sponsor submission of treatment
                                     protocol. Estimates for this
                                     requirement are included under Sec.
                                     Sec.  312.34 and 312.35.
312.85............................  Sponsors conducting phase 4 studies.
                                     Estimates for this requirement are
                                     included under Sec.  312.23, and
                                     under 21 CFR 314.50, 314.70, and
                                     314.81 in 0910-0001.
312.110(b)........................  Request to export an investigational
                                     drug.
312.120(b) and (c)(2).............  Sponsor's submission to FDA for use
                                     of foreign clinical study to
                                     support an IND.
312.120(c)(3).....................  Sponsor's report to FDA on findings
                                     of independent review committee on
                                     foreign clinical study.
312.130(d)........................  Request for disclosable information
                                     for investigations involving an
                                     exception from informed consent
                                     under Sec.  50.24.
------------------------------------------------------------------------


                  Table 2.--Recordkeeping Requirements
------------------------------------------------------------------------
          21 CFR Section                        Explanations
------------------------------------------------------------------------
312.52(a).........................  Transfer of obligations to a
                                     contract research organization.
312.57(a) and (b).................  Sponsor recordkeeping.
312.59............................  Sponsor recordkeeping of disposition
                                     of unused supply of drugs.
                                     Estimates for this requirement are
                                     included under Sec.  312.57.
312.62(a).........................  Investigator recordkeeping of
                                     disposition of drugs.
312.62(b).........................  Investigator recordkeeping of case
                                     histories of individuals.
312.160(a)(3).....................  Records maintenance: Shipment of
                                     drugs for investigational use in
                                     laboratory research animals or in
                                     vitro tests.
312.160(c)........................  Shipper records of alternative
                                     disposition of unused drugs.
------------------------------------------------------------------------

    In tables 3 through 5 of this document, the estimates for ``number 
of respondents,'' ``number of responses per respondent,'' and ``total 
annual responses'' were obtained from the Center for Drug Evaluation 
and Research (CDER) and the Center for Biologics Evaluation and 
Research (CBER) reports and data management systems for submissions 
received in 2001 and from other sources familiar with the number of 
submissions received under part 312. The estimates for ``hours per 
response'' were made by CDER and CBER individuals familiar with the 
burden associated with these reports and from estimates received from 
the pharmaceutical industry. Although the number of submissions may 
fluctuate, e.g., due to the addition of respondents not previously 
required to comply with part 312 or due to the normal variation in 
annual submissions, this variable is not reflected in the burden totals 
because the overall rate of submissions are not expected to change 
significantly over the next few years. In the Federal Register of July 
22, 2002 (67 FR 47811), the agency requested comments on the proposed 
collection of information. No comments were received on that request.

                                    Table 3.--Estimated Annual Reporting and Recordkeeping Burden for Human Drugs\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                           Number of
                                                      Number of         [chyph]Responses       Total Annual
                 21 CFR Section                   [chyph]Respondents          per            [chyph]Responses    Hours per Response      Total Hours
                                                                       [chyph]Respondent
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.7(d)                                                      5                    1.4                  7                   24                  168
312.23(a) through (f)                                     1,506                    1.2              1,872                1,600            2,995,200
312.30(a) through (e)                                     1,050                   15               15,705                  284            4,460,220
312.31(b)                                                 1,037                    8                8,375                  100              837,500
312.32(c) and (d)                                           546                   22.6             12,366                   32              395,712
312.33(a) through (f)                                     1,608                    2.6              4,202                  360            1,512,720
312.35(a) and (b)                                             1                    1                    1                  300                  300
312.36                                                      281                    1                  302                   16                4,832
312.38(b) and (c)                                           466                    1.3                608                   28               17,024
312.42(e)                                                    63                    1.2                 78                  284               22,152
312.44(c) and (d)                                            40                    1                   42                   16                  672
312.45(a) and (b)                                           244                    1.4                355                   12                4,260
312.47(b)                                                   130                    1.8                233                  160               37,280
312.53(c)                                                20,428                    1               20,428                   80            1,634,240
312.54(a) and (b)                                             1                    1                    1                   48                   48
312.55(b)                                                   388                  435              168,775                   48            8,101,200

[[Page 64396]]

 
312.56(b), (c), and (d)                                       2                    1                    2                   80                  160
312.58(a)                                                    75                    4.2                322                    8                2,576
312.64(a) through (d)                                    11,574                    3               34,722                   24              833,328
312.70(a)                                                     2                    1                    2                   40                   80
312.110(b)                                                   32                    8.1                261                   75               19,575
312.120(b) and (c)(2)                                       180                    2                  361                  168               60,548
312.120(c)(3)                                                 2                    2                    4                   40                  160
312.130(d)                                                    4                    1                    4                    8                   32
312.52(a)                                                 1,104                   3 .1              3,495                    2                6,990
312.57(a) and (b)                                         1,104                   34.5             38,088                  100            3,808,800
312.62(a)                                                 9,522                    2               19,044                   40              761,760
312.62(b)                                                 9,522                   10               95,220                   40            3,808,800
312.160(a)(3)                                               301                    1.4                425                     .5                213
312.160(c)                                       ...................               1.4                425                     .5.               213
Total                                            ...................  ...................  ...................  ...................      29,326,763
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.


                                              Table 4.--Estimated Annual Reporting Burden for Biologics\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                        No. of Responses       Total Annual          Hours per
                 21 CFR Section                   No. of Respondents      per Response       [chyph]Responses     [chyph]Responses       Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.7(d)                                                     22                    1.4                 31                   24                  744
312.10(a)                                                     9                    7.9                 71                   40                2,840
312.23(a) and (f) and 312.120(b), (c)(2), and               376                    1.4                535                1,600              856,000
 (c)(3)
312.30(a) through (e)                                       724                    5.6              4,038                  284            1,146,792
312.31(b)                                                   268                    9.0              2,399                  100              239,900
312.32(c) and (d) and 312.56(c)                             334                   12.8              4,261                   32              136,352
312.33(a) and (f) and 312.56(c)                             614                    2.6              1,615                  350              565,250
312.35(a) and (b)                                             1                    1                    1                  300                  300
312.36                                                       19                    4                   76                   16                1,216
312.38(b)                                                   172                    2.1                358                   28               10,024
312.38(c)                                                   172                    2.1                358                  160               57,280
312.44(c) and (d)                                             0                    0                    0                    0                    0
312.45(a) and (b)                                            70                    1.7                120                   12                1,440
312.47(b)                                                    60                    1.1                 68                  160               10,880
312.53(c)                                                   322                    5.9              1,904                   80              152,320
312.54(a) and (b)                                             0                    0                    0                    0                    0
312.55(b)                                                   139                    2.4                331                   48               15,888
312.56(b) and (d)                                            12                    1.7                 20                   80                1,600
312.58(a)                                                    19                    1                   19                    8                  152
312.64(a) and (d)                                         5,713                    1                5,713                   24              137,112
312.110(b)                                                    9                    2.4                 22                   75                1,650
312.130(d)                                                    1                    1                    1                    0.5                  0.5
Total                                            ...................  ...................  ...................  ...................       3,337,740.5
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.


                                            Table 5.--Estimated Annual Recordkeeping Burden for Biologics\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                       No. of           Annual Frequency       Total Annual          Hours per
                21 CFR Section                  [chyph]Recordkeepers   per Recordkeeping         Records        [chyph]Recordkeeper      Total Hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
312.52(a) recordkeeping                                     113                    1                  113                    5                  565
312.57(a) and (b) recordkeeping                           1,432                    2                2,859                  100              285,900
312.62(a) recordkeeping                                   5,713                    1                5,713                   40              228,520
312.62(b) recordkeeping                                   5,713                   12.5             71,355                   40            2,854,200
312.160(a) recordkeeping                                  1,432                    7.5             10,708                    0.5              5,354
312.160(c) recordkeeping                                  1,432                    2.5              3,573                    0.5              1,786.5
Total biologics recordkeeping hours             ....................  ...................  ...................  ...................       3,376,325.5
Total biologics burden hours                    ....................  ...................  ...................  ...................       3,337,740.5
Subtotal                                        ....................  ...................  ...................  ...................       6,714,066
Human Drugs                                     ....................  ...................  ...................  ...................      29,326,763

[[Page 64397]]

 
Biologics                                       ....................  ...................  ...................  ...................       6,714,066
Total                                           ....................  ...................  ...................  ...................      36,040,829
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.


    Dated: October 11, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-26617 Filed 10-17-02; 8:45 am]
BILLING CODE 4160-01-S