[Federal Register Volume 74, Number 88 (Friday, May 8, 2009)]
[Notices]
[Pages 21690-21696]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-10730]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

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


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Investigational New 
Drug Regulations

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Notice.

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

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

DATES: Fax written comments on the collection of information by June 8, 
2009.

ADDRESSES:  To ensure that comments on the information collection are 
received, OMB recommends that written comments be faxed to the Office 
of Information and Regulatory Affairs, OMB, Attn: FDA Desk Officer, 
FAX: 202-395-6974, or e-mailed to [email protected]. All 
comments should be identified with the OMB control number 0910-0014. 
Also include the FDA 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.

[[Page 21691]]


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 Regulations--OMB Control Number 0910-0014--
Extension

    FDA is requesting OMB approval for the reporting and recordkeeping 
requirements contained in the FDA 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 (21 U.S.C. 355(i)) (the act) 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 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; (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, 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 the following information: (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.
    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
------------------------------------------------------------------------
                         REPORTING REQUIREMENTS
-------------------------------------------------------------------------
          21 CFR Section                        Requirements
------------------------------------------------------------------------
 
312.7(d)..........................  Applications for permission to sell
                                     an investigational new drug
 
312.8.............................  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

[[Page 21692]]

 
  (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
 
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

[[Page 21693]]

 
  (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
-------------------------------------------------------------------------
          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
------------------------------------------------------------------------

    In the Federal Register of February 11, 2009 (74 FR 6889), FDA 
published a 60-day notice requesting public comment on the information 
collection provisions. No comments were received.
    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 21 CFR 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)
----------------------------------------------------------------------------------------------------------------

[[Page 21694]]

 
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
----------------------------------------------------------------------------------------------------------------
\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
----------------------------------------------------------------------------------------------------------------
312.57                              75             485.28             36,396              100          3,639,600
----------------------------------------------------------------------------------------------------------------
312.62(a)                       14,732                  1             14,732               40            589,280
----------------------------------------------------------------------------------------------------------------
312.62(b)                      147,320                  1            147,320               40          5,892,800
----------------------------------------------------------------------------------------------------------------
312.160(a)(3)                      547                1.4                782               .5                391
----------------------------------------------------------------------------------------------------------------
312.160(c)                         547                1.4                782               .5                391
----------------------------------------------------------------------------------------------------------------
\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)
----------------------------------------------------------------------------------------------------------------

[[Page 21695]]

 
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
----------------------------------------------------------------------------------------------------------------
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.


[[Page 21696]]


    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: May 1, 2009.
Jeffrey Shuren,
Associate Commissioner for Policy and Planning.
[FR Doc. E9-10730 Filed 5-7-09; 8:45 am]
BILLING CODE 4160-01-S