[Federal Register Volume 74, Number 27 (Wednesday, February 11, 2009)]
[Notices]
[Pages 6889-6894]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-2846]



[[Page 6889]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2009-N-0030]


Agency Information Collection Activities; Proposed Collection; 
Comment Request; Investigational New Drug Regulations

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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

SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information, 
including each proposed extension of an existing collection of 
information, and to allow 60 days for public comment in response to the 
notice. This notice solicits comments on requirements under which the 
clinical investigation of the safety and effectiveness of unapproved 
new drugs and biological products can be conducted.

DATES: Submit written or electronic comments on the collection of 
information by April 13, 2009.

ADDRESSES: Submit electronic comments on the collection of information 
to http://www.regulations.gov. Submit written comments on the 
collection of information to the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. All comments should be identified with the docket 
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Elizabeth Berbakos, Office of 
Information Management (HFA-710), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-796-3792.

SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal 
agencies must obtain approval from the Office of Management and Budget 
(OMB) for each collection of information they conduct or sponsor. 
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 
1320.3(c) and includes agency requests or requirements that members of 
the public submit reports, keep records, or provide information to a 
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) 
requires Federal agencies to provide a 60-day notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, 
before submitting the collection to OMB for approval. To comply with 
this requirement, FDA is publishing notice of the proposed collection 
of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (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 of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

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

    FDA is requesting OMB approval for the reporting and recordkeeping 
requirements contained in FDA's regulations ``Investigational New Drug 
Application'' in part 312 (21 CFR part 312). Part 312 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 Investigational New Drug (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 do the following: (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; and (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 prior to authorizing the sale 
and general use of new drugs. These reports enable FDA to monitor a 
study's progress, assure subject safety, assure that a study will be 
conducted ethically, and 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:
    The first form is Form FDA-1571--``Investigational New Drug 
Application.'' A person who intends to conduct a clinical investigation 
submits this form to FDA. It includes the following information: (1) A 
cover sheet containing background information on the sponsor and 
investigator; (2) a table of contents; (3) an introductory

[[Page 6890]]

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.
    The second form is 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 and Recordkeeping Requirements in 21 CFR Part 312
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                         REPORTING REQUIREMENTS
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          21 CFR Section                        Requirements
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312.7(d)..........................  Applications for permission to sell
                                     an investigational new drug
 
 
312.80............................  Charging for investigational drugs
                                     under an IND
 
 
312.10............................  Applications for waiver of
                                     requirements under part 312; as
                                     indicated in Sec.   312.10(a),
                                     estimates for this requirement are
                                     included under Sec.  Sec.   312.23
                                     and 312.31. In addition, separate
                                     requests under Sec.   312.10 are
                                     estimated in table 2 of this
                                     document.
 
 
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)
  (a)(1)..........................    Cover sheet FDA-1571
  (a)(2)..........................    Table of contents
  (a)(3)..........................    Investigational plan for each
                                    planned study
  (a)(5)..........................    Investigator's brochure
  (a)(6)..........................    Protocols--Phases 1, 2, and 3
  (a)(7)..........................    Chemistry, manufacturing, and
                                    control information
  (a)(7)(iv)(a), (b), and (c).....    A description of the drug
                                    substance, a list of all components,
                                    and any placebo used
  (a)(7)(iv)(d)...................    Labeling: Copies of labels and
                                    labeling to be provided each
                                    investigator
  (a)(7)(iv)(e)...................    Environmental impact analysis
                                    regarding drug manufacturing and use
  (a)(8)..........................    Pharmacological and toxicology
                                    information
  (a)(9)..........................    Previous human experience with the
                                    investigational drug
  (a)(10).........................    Additional information
  (a)(11).........................    Relevant information
  (f).............................    Identification of exception from
                                    informed consent
 
 
312.30............................  Protocol amendments
  (a).............................    New protocol
  (b).............................    Change in protocol
  (c).............................    New investigator
  (d).............................    Content and format
  (e).............................    Frequency
 
 
312.31............................  Information amendments
  (b).............................    Content and format
                                    Chemistry, toxicology, or technical
                                     information
 
 
312.32............................  Safety reports
  (c)(1)..........................    Written reports to FDA and to
                                    investigators
  (c)(2)..........................    Telephone reports to FDA for fatal
                                    or life-threatening experience
  (c)(3)..........................    Format or frequency
  (d).............................    Followup submissions
 
 
312.33............................  Annual reports
  (a).............................    Individual study information
  (b).............................    Summary information
  (b)(1)..........................    Adverse experiences
  (b)(2)..........................    Safety report summary
  (b)(3)..........................    List of fatalities and causes of
                                    death
  (b)(4)..........................    List of discontinuing subjects
  (b)(5)..........................    Drug action
  (b)(6)..........................    Preclinical studies and findings
  (b)(7)..........................    Significant changes
  (c).............................    Next year general investigational
                                    plan
  (d).............................    Brochure revision
  (e).............................    Phase I protocol modifications
  (f).............................    Foreign marketing developments
 
 
312.35............................  Treatment use of investigational new
                                     drugs
  (a).............................    Treatment protocol submitted by
                                    IND sponsor
  (b).............................    Treatment IND submitted by
                                    licensed practitioner
 
 

[[Page 6891]]

 
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
 
 
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
  (a).............................    Progress reports
  (b).............................    Safety reports
  (c).............................    Final 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 in
                                     0910-0014, and Sec.  Sec.   314.50,
                                     314.70, and 314.81 in 0910-0001
 
 
312.110(b)........................  Request to export an investigational
                                     drug
 
 
312.120...........................  Submissions related to foreign
                                     clinical studies not conducted
                                     under an IND
 
 
312.130(d)........................  Request for disclosable information
                                     for investigations involving an
                                     exception from informed consent
                                     under Sec.   50.24
------------------------------------------------------------------------


------------------------------------------------------------------------
                       RECORDKEEPING REQUIREMENTS
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          21 CFR Section                        Requirements
------------------------------------------------------------------------
312.52(a).........................  Transfer of obligations to a
                                     contract research organization
 
 
312.57............................  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
 
 
312.120(d)........................  Recordkeeping requirements for
                                     submissions related to foreign
                                     clinical studies not conducted
                                     under an IND; estimates for this
                                     requirement are included under Sec.
                                       312.57
 
 
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
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[[Page 6892]]

    In tables 2 and 3 of this document, the estimates for ``No. of 
Respondents,'' ``No. 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 
2007 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.
    FDA estimates the burden of this collection of information as 
follows:

               Table 2--Estimated Annual Reporting Burden for Human Drugs and Biologics (CDER)\1\
----------------------------------------------------------------------------------------------------------------
                         No. of        No. of Responses     Total Annual        Hours per
  21 CFR Section      Respondents       per Respondent       Responses           Response         Total Hours
----------------------------------------------------------------------------------------------------------------
312.7(d)                          28               1.58                 44                 24              1,056
----------------------------------------------------------------------------------------------------------------
312.10                             4                  1                  4                 10                 40
----------------------------------------------------------------------------------------------------------------
312.23(a) through              2,496               1.26              3,156              1,600          5,049,600
 (f)
----------------------------------------------------------------------------------------------------------------
312.30(a) through              2,030               8.91             18,079                284          5,134,436
 (e)
----------------------------------------------------------------------------------------------------------------
312.31(b)                        153               2.97                454                100             45,400
----------------------------------------------------------------------------------------------------------------
312.32(c) and (d)                985              23.06             22,713                 32            726,816
----------------------------------------------------------------------------------------------------------------
312.33(a) through              2,564               2.34              5,994                360          2,157,840
 (f)
----------------------------------------------------------------------------------------------------------------
312.35(a) and (b)                  9               1.11                 10                300              3,000
----------------------------------------------------------------------------------------------------------------
312.36                           525               1.23                645                 16             10,320
----------------------------------------------------------------------------------------------------------------
312.38(b) and (c)                654               1.34                874                 28             24,472
----------------------------------------------------------------------------------------------------------------
312.42(e)                        149               1.10                164                284             46,576
----------------------------------------------------------------------------------------------------------------
312.44(c) and (d)                159               1.13                179                 16              2,864
----------------------------------------------------------------------------------------------------------------
312.45(a) and (b)                254               1.43                362                 12              4,344
----------------------------------------------------------------------------------------------------------------
312.47(b)                        281                1.8                529                160             84,640
----------------------------------------------------------------------------------------------------------------
312.53(c)                        900              26.51             23,855                 80          1,908,400
----------------------------------------------------------------------------------------------------------------
312.54(a) and (b)                  1                  1                  1                 48                 48
----------------------------------------------------------------------------------------------------------------
312.55(b)                        985              2,306          2,271,300                 48        109,022,400
----------------------------------------------------------------------------------------------------------------
312.56(b), (c),                   18                  1                 18                 80              1,440
 and (d)
----------------------------------------------------------------------------------------------------------------
312.58(a)                         91               4.10                373                  8              2,984
----------------------------------------------------------------------------------------------------------------
312.64                       141,393                  1            141,393                 24          3,393,432
----------------------------------------------------------------------------------------------------------------
312.70(a)                          4                1.5                  6                 40                240
----------------------------------------------------------------------------------------------------------------
312.110(b)                        23              18.26                420                 75             31,500
----------------------------------------------------------------------------------------------------------------
312.120\2\                       115                  5                575                 32             18,400
----------------------------------------------------------------------------------------------------------------
312.130(d)                         3                  1                  3                  8                 24
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\1\ There are no capital and startup, or operation, maintenance, and purchase costs associated with the
  collection of information requirements.
\2\ Section 312.120 includes the burden estimate for both CDER and CBER.


             Table 3--Estimated Annual Recordkeeping Burden for Human Drugs and Biologics (CDER)\1\
----------------------------------------------------------------------------------------------------------------
                           No. of         No. of Records      Total Annual       Hours per
   21 CFR Section      Recordkeepers     per Recordkeeper       Records            Record         Total Hours
----------------------------------------------------------------------------------------------------------------
312.52(a)                          683                  1                683                2              1,366
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312.57                              75             485.28             36,396              100          3,639,600
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312.62(a)                       14,732                  1             14,732               40            589,280
----------------------------------------------------------------------------------------------------------------
312.62(b)                      147,320                  1            147,320               40          5,892,800
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[[Page 6893]]

 
312.160(a)(3)                      547                1.4                782               .5                391
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312.160(c)                         547                1.4                782               .5                391
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\1\ There are no capital and startup, or operation, maintenance, and purchase costs associated with the
  collection of information requirements.


                       Table 4--Estimated Annual Reporting Burden for Biologics (CBER)\1\
----------------------------------------------------------------------------------------------------------------
                         No. of        No. of Responses     Total Annual        Hours per
  21 CFR Section      Respondents       per Respondent       Responses          Responses         Total Hours
----------------------------------------------------------------------------------------------------------------
312.7(d)                          12                1.1                 13                 24                312
----------------------------------------------------------------------------------------------------------------
312.23(a) through                168                1.5                256              1,600            409,600
 (f)\2\
----------------------------------------------------------------------------------------------------------------
312.30(a) through                372                6.4              2,369                284            672,796
 (e)
----------------------------------------------------------------------------------------------------------------
312.31(b)\2\                     703                7.7              5,417                100            541,700
----------------------------------------------------------------------------------------------------------------
312.32(c) and (d)                175               14.6              2,563                 32             82,016
----------------------------------------------------------------------------------------------------------------
312.33(a) through                512                2.3              1,168                360            420,480
 (f)
----------------------------------------------------------------------------------------------------------------
312.35(a) and (b)                  1                  1                  1                300                300
----------------------------------------------------------------------------------------------------------------
312.36                            10                  4                 40                 16                640
----------------------------------------------------------------------------------------------------------------
312.38(b) and (c)                 81                1.5                120                 28              3,360
----------------------------------------------------------------------------------------------------------------
312.42(e)                         74                1.5                108                284             30,672
----------------------------------------------------------------------------------------------------------------
312.44(c) and (d)                 34                1.1                 39                 16                624
----------------------------------------------------------------------------------------------------------------
312.45(a) and (b)                 41                1.4                 59                 12                708
----------------------------------------------------------------------------------------------------------------
312.47(b)                         31                1.2                 37                160              5,920
----------------------------------------------------------------------------------------------------------------
312.53(c)                        243               4.95              1,203                 80             96,240
----------------------------------------------------------------------------------------------------------------
312.54(a) and (b)                  1                  1                  1                 48                 48
----------------------------------------------------------------------------------------------------------------
312.55(b)                         42                  1                 43                 48              2,064
----------------------------------------------------------------------------------------------------------------
312.56(b), (c),                   10                1.6                 16                 80              1,280
 and (d)
----------------------------------------------------------------------------------------------------------------
312.58(a)                          7                  1                  7                  8                 56
----------------------------------------------------------------------------------------------------------------
312.64                         2,728               3.82             10,411                 24            249,864
----------------------------------------------------------------------------------------------------------------
312.70(a)                          5                  1                  5                 40                200
----------------------------------------------------------------------------------------------------------------
312.110(b)                        18                  1                 18                 75              1,350
----------------------------------------------------------------------------------------------------------------
312.130(d)                         1                  1                  1                  8                  8
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital and startup, or operation, maintenance, and purchase costs associated with the
  collection of information requirements.
\2\ The reporting requirement for Sec.   312.10 is included in the estimates for Sec.  Sec.   312.23 and 312.31.


                     Table 5--Estimated Annual Recordkeeping Burden for Biologics (CBER)\1\
----------------------------------------------------------------------------------------------------------------
                          No. of         Annual Frequency       Total Annual       Hours per
  21 CFR Section      Recordkeepers      per Recordkeeping        Records            Record        Total Hours
----------------------------------------------------------------------------------------------------------------
312.52(a)                          52                   1.4                 73                2              146
----------------------------------------------------------------------------------------------------------------
312.57                            168                  3.05                512              100           51,200
----------------------------------------------------------------------------------------------------------------
312.62(a)                       2,560                     1              2,560               40          102,400
----------------------------------------------------------------------------------------------------------------
312.62(b)                       2,560                    10             25,600               40        1,024,000
----------------------------------------------------------------------------------------------------------------
312.160(a)(3)                      55                   1.4                 77              0.5             38.5
----------------------------------------------------------------------------------------------------------------

[[Page 6894]]

 
312.160(c)                         55                   1.4                 77              0.5             38.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital and startup, or operation, maintenance, and purchase costs associated with the
  collection of information requirements.


Table 6--Totals for Estimated Annual Reporting and Recordkeeping Burdens
                            for CDER and CBER
Reporting Burden                     130,190,510
------------------------------------------------------------------------
Recordkeeping                        11,301,652
------------------------------------------------------------------------
Total                                141,492,162
------------------------------------------------------------------------


    Dated: February 4, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-2846 Filed 2-10-09; 8:45 am]
BILLING CODE 4160-01-S