[Federal Register Volume 70, Number 196 (Wednesday, October 12, 2005)]
[Notices]
[Pages 59350-59355]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-20362]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2005N-0393]


Agency Information Collection Activities; Proposed Collection; 
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 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 December 12, 2005.

ADDRESSES: Submit electronic comments on the collection of information 
to:http://www.fda.gov/dockets/ecomments. 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: Karen Nelson, Office of Management 
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-1482.

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 the FDA regulation ``Investigational New Drug 
Application'' in 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

[[Page 59351]]

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. The first 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 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 required under part 312 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.
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                         REPORTING REQUIREMENTS
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          21 CFR Section                        Requirements
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.
 
 
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), (a)(7)(iv)(b),       A description of the drug
   and (a)(7)(iv)(c)                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.

[[Page 59352]]

 
  (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 an
                                    investigational new drug sponsor.
  (b).............................    Treatment investigational new drug
                                    application (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
                                     investigational new drug.
 
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 an investigational new
                                     drug is terminated.
 
312.45(a) and (b).................  Sponsor request for, or response to,
                                     inactive status determination of an
                                     investigational new drug.
 
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.
  (a).............................    Progress reports.
  (b).............................    Safety reports
  (c).............................    Final reports.
  (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 in OMB
                                     control number 0910-0014, and Sec.
                                     Sec.   314.50, 314.70, and 314.81
                                     (21 CFR 314.50, 314.70, and 314.81)
                                     in OMB control number 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. Estimates for this
                                     requirement are included under Sec.
                                      Sec.   312.23 and 312.30 in OMB
                                     control number 0910-0014, and Sec.
                                     Sec.   314.50, 314.60, and 314.70
                                     (21 CFR 314.60) in OMB control
                                     number 0910-0001.
 
312.120(c)(3).....................  Sponsor's report to FDA on findings
                                     of independent review committee on
                                     foreign clinical study. Estimates
                                     for this requirement are included
                                     under Sec.  Sec.   312.23 and
                                     312.30 in OMB control number 0910-
                                     0014, and Sec.  Sec.   314.50,
                                     314.60, and 314.70 in OMB control
                                     number 0910-0001.
 

[[Page 59353]]

 
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(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 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 
2004 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 and Recordkeeping Burden for Human Drugs\1\
----------------------------------------------------------------------------------------------------------------
                                                REPORTING BURDEN
-----------------------------------------------------------------------------------------------------------------
                                        No. of       No. of Responses  Total Annual   Hours per
          21 CFR Section             Respondents      per Respondent     Responses     Response     Total Hours
----------------------------------------------------------------------------------------------------------------
312.7(d)                                         9                1.4            13         24             7,488
----------------------------------------------------------------------------------------------------------------
312.23(a) through (f)                        1,245                1.3         1,597      1,600         2,555,200
----------------------------------------------------------------------------------------------------------------
312.30(a) through (e)                        1,257               13.3        16,687        284         4,739,108
----------------------------------------------------------------------------------------------------------------
312.31(b)                                    1,116                7.4         8,298        100           829,800
----------------------------------------------------------------------------------------------------------------
312.32(c) and (d)                              649               24.7        16,052         32           513,664
----------------------------------------------------------------------------------------------------------------
312.33(a) through (f)                        1,821                2.5         4,516        360         1,625,760
----------------------------------------------------------------------------------------------------------------
312.35(a) and (b)                                5                1.2             6        300             1,800
----------------------------------------------------------------------------------------------------------------
312.36                                         109                1.1           121         16             1,936
----------------------------------------------------------------------------------------------------------------
312.38(b) and (c)                              536                1.3           677         28            18,965
----------------------------------------------------------------------------------------------------------------
312.42(e)                                       97                1.2           118        284            33,512
----------------------------------------------------------------------------------------------------------------
312.44(c) and (d)                               44                1              45         16               720
----------------------------------------------------------------------------------------------------------------
312.45(a) and (b)                              185                1.5           271         12             3,252
----------------------------------------------------------------------------------------------------------------
312.47(b)                                      215                1.7           355        160            56,800
----------------------------------------------------------------------------------------------------------------
312.53(c)                                   21,194                1          21,194         80         1,695,520
----------------------------------------------------------------------------------------------------------------
312.54(a) and (b)                                0                0               0         48                 0
----------------------------------------------------------------------------------------------------------------
312.55(b)                                  807,400                1         807,400         48        38,755,200
----------------------------------------------------------------------------------------------------------------
312.56(b), (c), and (d)                         13                1              13         80             1,040
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[[Page 59354]]

 
312.58(a)                                       88                3.8           340          8             2,720
----------------------------------------------------------------------------------------------------------------
312.64(a) through (d)                       31,791                1          31,791         24           762,984
----------------------------------------------------------------------------------------------------------------
312.70(a)                                        4                1               4         40               160
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312.110(b)                                      33                8.3           276         75            20,700
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312.130(d)                                       5                1               5          8                40
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Total reporting burden                                                                                51,626,369
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                                              RECORDKEEPING BURDEN
-----------------------------------------------------------------------------------------------------------------
                                        No. of        No. of Records   Total Annual   Hours per
          21 CFR Section            Recordkeepers    per Recordkeeper     Records       Record      Total Hours
----------------------------------------------------------------------------------------------------------------
312.52(a)                                      335                1.5           488          2               976
----------------------------------------------------------------------------------------------------------------
312.57(a) and (b)                              335              119.8        40,148        100         4,014,800
----------------------------------------------------------------------------------------------------------------
312.62(a)                                   20,074                1          20,074         40           802,960
----------------------------------------------------------------------------------------------------------------
312.62(b)                                  200,740                1         200,740         40         8,029,600
----------------------------------------------------------------------------------------------------------------
312.160(a)(3)                                  372                1.5           542           .5             271
----------------------------------------------------------------------------------------------------------------
312.160(c)                                     372                1.5           542           .5             271
----------------------------------------------------------------------------------------------------------------
Total recordkeeping burden                                                                            12,848,878
==================================                  =============================================
----------------------------------------------------------------------------------------------------------------


                 Table 3.--Estimated Annual Reporting and Recordkeeping Burden for Biologics\1\
----------------------------------------------------------------------------------------------------------------
                                                REPORTING BURDEN
-----------------------------------------------------------------------------------------------------------------
                                        No. of       No. of Responses  Total Annual   Hours per
          21 CFR Section             Respondents      per Respondent     Responses     Response     Total Hours
----------------------------------------------------------------------------------------------------------------
312.7(d)                                        41                1.4            58         24             1,392
----------------------------------------------------------------------------------------------------------------
312.23(a) through (f) and                      433                1.3           557      1,808         1,007,056
 312.120(b), (c)(2), and (c)(3)
----------------------------------------------------------------------------------------------------------------
312.30(a) through (e)                          590                6.8         4,014        284         1,139,976
----------------------------------------------------------------------------------------------------------------
312.31(b)                                      263               29.3         7,700        100           770,000
----------------------------------------------------------------------------------------------------------------
312.32(c) and (d) and 312.56(c)                294               13.7         4,042         32           129,344
----------------------------------------------------------------------------------------------------------------
312.33(a) through (f) and                      647                2.3         1,473        360           530,280
 312.56(c)
----------------------------------------------------------------------------------------------------------------
312.35(a) and (b)                                1                1               1        300               300
----------------------------------------------------------------------------------------------------------------
312.36                                           6                1               6         16                96
----------------------------------------------------------------------------------------------------------------
312.38(b) and (c)                              117                1.3           153         28             4,284
----------------------------------------------------------------------------------------------------------------
312.42(e)                                       74                1.5           108        284            30,672
----------------------------------------------------------------------------------------------------------------
312.44(c) and (d)                               17                1.1            18         16               288
----------------------------------------------------------------------------------------------------------------
312.45(a) and (b)                               60                1.8           107         12             1,284
----------------------------------------------------------------------------------------------------------------
312.47(b)                                       43                1.5            66        160            10,560
----------------------------------------------------------------------------------------------------------------
312.53(c)                                      348                6.6         2,303         80           184,240
----------------------------------------------------------------------------------------------------------------

[[Page 59355]]

 
312.54(a) and (b)                                1                1               1         48                48
----------------------------------------------------------------------------------------------------------------
312.55(b)                                      138                2.5           347         48            16,656
----------------------------------------------------------------------------------------------------------------
312.56(b) and (d)                               14                1.6            23         80             1,840
----------------------------------------------------------------------------------------------------------------
312.58(a)                                        8                1               8          8                64
----------------------------------------------------------------------------------------------------------------
312.64(a) through (d)                        6,003                3.5        21,185         24           508,440
----------------------------------------------------------------------------------------------------------------
312.70(a)                                        6                1               6         40               240
----------------------------------------------------------------------------------------------------------------
312.110(b)                                      21                1              21         75             1,575
----------------------------------------------------------------------------------------------------------------
312.130(d)                                       1                1               1          8                 8
----------------------------------------------------------------------------------------------------------------
Total reporting burden                                                                                 4,338,643
----------------------------------------------------------------------------------------------------------------


 
                                              RECORDKEEPING BURDEN
-----------------------------------------------------------------------------------------------------------------
                                      No. of        Annual Frequency   Total Annual   Hours per
         21 CFR Section           Recordkeepers    per Recordkeeping      Records       Record      Total Hours
----------------------------------------------------------------------------------------------------------------
312.52(a)                                    139                  1.4           200          2               400
----------------------------------------------------------------------------------------------------------------
312.57(a) and (b)                            433                  2.6         1,114        100           111,400
----------------------------------------------------------------------------------------------------------------
312.62(a)                                  5,570                  1           5,570         40           222,800
----------------------------------------------------------------------------------------------------------------
312.62(b)                                  5,570                 10          55,700         40         2,228,000
----------------------------------------------------------------------------------------------------------------
312.160(a)(3)                                146                  1.4           211          0.5           105.5
----------------------------------------------------------------------------------------------------------------
312.160(c)                                   146                  1.4           211          0.5           105.5
----------------------------------------------------------------------------------------------------------------
Total recordkeeping burden                                                                             2,562,811
================================                                                     ============
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


 Table 4.--Estimated Annual Reporting and Recordkeeping Burden for Human
                         Drugs and Biologics\1\
 
Total human drugs burden hours..........................------64,475,247
Total biologics burden hours............................       6,901,454
 
Total burden hours......................................      71,376,701
------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs
  associated with this collection of information.


    Dated: October 3, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-20362 Filed 10-11-05; 8:45 am]
BILLING CODE 4160-01-S