[Federal Register Volume 64, Number 155 (Thursday, August 12, 1999)]
[Notices]
[Pages 44019-44023]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-20846]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 99N-1010]


Agency Information Collection Activities; Submission for OMB 
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 the 
proposed collection of information listed below has been submitted to 
the Office of Management and Budget (OMB) for review and clearance 
under the Paperwork Reduction Act of 1995 (the PRA).

DATES: Submit written comments on the collection of information by 
September 13, 1999.
ADDRESSES: Submit written comments on the collection of information to 
the Office of Information and Regulatory Affairs, OMB, New Executive 
Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 20503, Attn: 
Wendy Taylor, Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT: Karen L. Nelson, Office of Information 
Resources Management (HFA-250), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-827-1482.
SUPPLEMENTARY INFORMATION: In compliance with section 3507 of the PRA 
(44 U.S.C. 3507), FDA has submitted the following proposed collection 
of information to OMB for review and clearance.

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

    FDA is requesting OMB approval for the reporting and recordkeeping 
requirements contained in FDA's regulation ``Investigational New Drug 
Application'' part 312 (21 CFR part 312). This regulation implements 
provisions of section 505(i) of the Federal Food, Drug, and Cosmetic 
Act (the act) (21 U.S.C. 355(i)) to issue regulations under which the 
clinical investigation of the safety and effectiveness of unapproved 
new drugs and biological products can be conducted.
    FDA is charged with implementing statutory requirements that drug 
products marketed in the United States be shown to be safe and 
effective, properly manufactured, and properly labeled for their 
intended uses. Section 505(a) of the act provides that a new drug may 
not be introduced or delivered for introduction into interstate 
commerce in the United States unless FDA has previously approved a new 
drug application (NDA). FDA approves an NDA only if the sponsor of the 
application first demonstrates that the drug is safe and effective for 
the conditions prescribed, recommended, or suggested in the product's 
labeling. Proof must consist, in part, of adequate and well-controlled 
studies, including studies in humans, that are conducted by qualified 
experts. The IND regulations establish reporting requirements that 
include an initial application as well as amendments to that 
application, reports on significant revisions of clinical investigation 
plans, and information on a drug's safety or effectiveness. In 
addition, the sponsor is required to give FDA an annual summary of the 
previous year's clinical experience. Submissions are reviewed by 
medical officers and other agency scientific reviewers assigned 
responsibility for overseeing the specific study. The IND regulations 
also contain recordkeeping requirements that pertain to the 
responsibilities of sponsors and investigators. The detail and 
complexity of these requirements are dictated by the

[[Page 44020]]

scientific procedures and human subject safeguards that must be 
followed in the clinical tests of investigational new drugs.
    The IND information collection requirements provide the means by 
which FDA can: (1) Monitor the safety of ongoing clinical 
investigations; (2) determine whether the clinical testing of a drug 
should be authorized; (3) ensure production of reliable data on the 
metabolism and pharmacological action of the drug in humans; (4) obtain 
timely information on adverse reactions to the drug; (5) obtain 
information on side effects associated with increasing doses; (6) 
obtain information on the drug's effectiveness; (7) ensure the design 
of well-controlled, scientifically valid studies; (8) obtain other 
information pertinent to determining whether clinical testing should be 
continued and information related to the protection of human subjects. 
Without the information provided by industry in response to the IND 
regulations, FDA cannot authorize or monitor the clinical 
investigations which must be conducted 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: 
(1) A cover sheet containing background information on the sponsor and 
investigator, (2) a table of contents, (3) an introductory statement 
and general investigational plan, (4) an investigator's brochure 
describing the drug substance, (5) a protocol for each planned study, 
(6) chemistry, manufacturing, and control information for each 
investigation, (7) pharmacology and toxicology information for each 
investigation, and (8) previous human experience with the 
investigational drug.
     Form FDA-1572-- ``Investigator Statement.'' Before permitting an 
investigator to begin participation in an investigation, the sponsor 
must obtain and record this form. It includes background information on 
the investigator and the investigation, and a general outline of the 
planned investigation and the study protocol.
     FDA is requesting OMB approval for the following reporting and 
recordkeeping requirements in part 312:

                    Table 1.--Reporting Requirements
------------------------------------------------------------------------
            21 CFR Section                        Explanations
------------------------------------------------------------------------
 312.7(d)............................  Applications for permission to
                                        sell an investigational new
                                        drugs.
 312.10(a)...........................  Applications for waiver of
                                        requirements under part 312.
                                        Only emergency requests are
                                        estimated under this section;
                                        other requests are included
                                        under Secs.  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..............................  IND's (content and format).
 312.23(a)(1)........................  Cover sheet FDA-1571.
 312.23(a)(2)........................  Table of contents.
 312.23(a)(3)........................  Investigational plan for each
                                        planned study.
 312.23(a)(5)........................  Investigator's brochure.
 312.23(a)(6)........................  Protocols--Phase 1, 2, and 3.
 312.23(a)(7)........................  Chemistry, manufacturing, and
                                        control information.
 312.23(a)(7)(iv)(a), (b), and (c)...  A description of the drug
                                        substance, a list of all
                                        components, and any placebo
                                        used.
 312.23(a)(7)(iv)(d).................  Labeling--copies of labels and
                                        labeling to be provided each
                                        investigator.
 312.23(a)(7)(iv)(e).................  Environmental impact analysis
                                        regarding drug manufacturing and
                                        use.
 312.23(a)(8)........................  Pharmacological and toxicology
                                        information.
 312.23(a)(9)........................  Previous human experience with
                                        the investigational drug.
 312.23(a)(10).......................  Additional information.
 312.23(a)(11).......................  Relevant information.
 312.23(f)...........................  Identification of exception from
                                        informed consent.
 312.30..............................  Protocol amendments.
 312.30(a)...........................  New protocol.
 312.30(b)...........................  Change in protocol.
 312.30(c)...........................  New investigator.
 312.30(d)...........................  Content and format.
 312.30(e)...........................  Frequency.
 312.31..............................  Information amendments.
 312.31(b)...........................  Content and format.
   ..................................  Chemistry, toxicology, or
                                        technical information.
 312.32..............................  Safety reports.
 312.32(c)(1)........................  Written reports to FDA and to
                                        investigators.
 312.32(c)(2)........................  Telephone reports to FDA for
                                        fatal or life-threatening
                                        experience.
 312.32(c)(3)........................  Format or frequency.
 312.32(d)...........................  Followup submissions.
 312.33..............................  Annual reports.
 312.33(a)...........................  Individual study information.
 312.33(b)...........................  Summary information.
 312.33(b)(1)........................  Adverse experiences.
312.33(b)(2).........................  Safety report summary.
312.33(b)(3).........................  List of fatalities and causes of
                                        death.
312.33(b)(4).........................  List of discontinuing subjects.

[[Page 44021]]

 
312.33(b)(5).........................  Drug action.
312.33(b)(6).........................  Preclinical studies and findings.
312.33(b)(7).........................  Significant changes.
 312.33(c)...........................  Next year general investigational
                                        plan.
 312.33(d)...........................  Brochure revision.
 312.33(e)...........................  Phase I protocol modifications.
 312.33(f)...........................  Foreign marketing developments.
 312.35..............................  Treatment use of investigational
                                        new drugs.
 312.35(a)...........................  Treatment protocol submitted by
                                        IND sponsor.
 312.35(b)...........................  Treatment IND submitted by
                                        licensed practitioner.
 312.36..............................  Requests for emergency use of an
                                        investigational new drugs.
 312.38(b) and (c)...................  Notification of withdrawal of an
                                        IND.
 312.44(c) and (d)...................  Opportunity for sponsor response
                                        to FDA when IND is terminated.
 312.45(a) and (b)...................  Sponsor request for or response
                                        to inactive status determination
                                        of an IND.
 312.47(b)...........................  ``End-of-Phase 2'' meetings and
                                        ``Pre-NDA'' meetings.
 312.53(c)...........................  Investigator information.
                                        Investigator report (Form FDA-
                                        1572) and narrative;
                                        Investigator's background
                                        information; Phase 1 outline of
                                        planned investigation; and Phase
                                        2 outline of study protocol;
                                        financial disclosure
                                        information.
 312.54(a) and (b)...................  Sponsor submissions concerning
                                        investigations involving an
                                        exception from informed consent
                                        under Sec.  50.24.
 312.55(b)...........................  Sponsor reports to investigators
                                        on new observations, especially
                                        adverse reactions and safe use.
                                        Only ``new observations'' are
                                        estimated under this section;
                                        investigator brochures are
                                        included under Sec.  312.23.
 312.56(b), (c), and (d).............  Sponsor monitoring of all
                                        clinical investigations,
                                        investigators, and drug safety;
                                        notification to FDA.
 312.58(a)...........................  Sponsor's submission of records
                                        to FDA on request.
 312.64..............................  Investigator reports to the
                                        sponsor.
 312.64(a)...........................  Progress reports.
 312.64(b)...........................  Safety reports.
 312.64(c)...........................  Final reports.
 312.64(d)...........................  Financial disclosure reports.
 312.66..............................  Investigator reports to
                                        Institutional Review Board.
                                        Estimates for this requirement
                                        are included under Sec.  312.53.
 312.70..............................  Investigator disqualification;
                                        opportunity to respond to FDA.
                                        Estimates for this requirement
                                        are not included in the
                                        estimates for part 312.
 312.83..............................  Sponsor submission of treatment
                                        protocol. Estimates for this
                                        requirement are included under
                                        Secs.  312.34 and 312.35.
 312.85..............................  Sponsors conducting phase 4
                                        studies. Estimates for these
                                        postmarketing studies are not
                                        included in the estimates for
                                        part 312.
 312.110(b)..........................  Request to export an
                                        investigational drug.
 312.120(b) and (c)(2)...............  Sponsor's submission to FDA for
                                        use of foreign clinical study to
                                        support an IND.
 312.120(c)(3).......................  Sponsor's report to FDA on
                                        findings of independent review
                                        committee on foreign clinical
                                        study.
 312.130(d)..........................  Request for disclosable
                                        information for investigations
                                        involving an exception from
                                        informed consent under Sec.
                                        50.24.
------------------------------------------------------------------------


                  Table 2.--Recordkeeping Requirements
------------------------------------------------------------------------
            21 CFR Section                        Explanations
------------------------------------------------------------------------
 312.52(a)...........................  Transfer of obligations to a
                                        contract research organization.
 312.57(a) and (b)...................  Sponsor recordkeeping.
 312.59..............................  Sponsor recordkeeping of
                                        disposition of unused supply of
                                        drugs. Estimates for this
                                        requirement are included under
                                        Sec.  312.57.
 312.62(a)...........................  Investigator recordkeeping of
                                        disposition of drugs.
 312.62(b)...........................  Investigator recordkeeping of
                                        case histories of individuals.
 312.160(a)..........................  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 May 6, 1999 (64 FR 24402), the agency 
requested comments on the proposed collections of information. No 
comments were received.

[[Page 44022]]



                         Table 3.--Estimated Annual Reporting Burden for Human Drugs\1\
----------------------------------------------------------------------------------------------------------------
                                                     No. of
                                       No. of       Responses   Total Annual    Hours per
          21 CFR Section             Respondents       Per        Responses     Response         Total Hours
                                                   Respondent
----------------------------------------------------------------------------------------------------------------
312.7(d)                                 7             1             7            24               168
312.10(a)                                0             0             0             0                 0
312.23(a) and (f)                    1,601             1.25      1,996         1,600         3,193,600
312.30(a) through (e)                  918            14.85     13,629           284         3,870,636
312.31(b)                              760             8.87      6,738           100           673,800
312.32(c) and (d)                      459            14.33      6,576            32           210,432
312.33(a) through (f)                1,841             2.35      4,318           350         1,511,300
312.35(a) and (b)                        1             1             1           300               300
312.36                                 643             1.2         720            16            11,520
312.38(b)                              621             1.24        773            28            21,644
312.38(c)                              621             1.24        773           160           123,680
312.44(c) and (d)                      710             1.10        780            16            12,480
312.45(a) and (b)                      294             1.32        389            12             4,668
312.47(b)                              252             1           252           160            40,320
312.53(c)                            4,500             1         4,500            80           360,000
312.54(a) and (b)                        4             1             4            48               192
312.55(b)                            4,500             1         4,500            48           216,000
312.56(b), (c), and (d)                  5             1             5            80               400
312.58(a)                              337             1           337             8             2,696
312.64(a) through (d)                8,200             1         8,200            24           196,800
312.110(b)                             150             2           303            75            22,725
312.120(b) and (c)(2)                  100             2           200           168            33,600
312(c)(3)                              100             2           200            40             8,000
312.130(d)                               4             1             4             8                32
Total Reporting Burden                                                                       10,514,993
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                       Table 4.--Estimated Annual Recordkeeping Burden for Human Drugs\1\
----------------------------------------------------------------------------------------------------------------
                                              Annual
     21 CFR Section           No. of       Frequency per   Total Annual      Hours per          Total Hours
                           Recordkeepers   Recordkeeping      Records      Recordkeeper
----------------------------------------------------------------------------------------------------------------
312.52(a)                     360               1             360               2                 720
312.57(a) and (b)           4,000               2.05        8,200             100             400,000
312.62(a)                   8,200               1           8,200              40             328,000
312.62(b)                   8,200              12.2       100,000              40             328,000
312.160(a)                  3,400               7.35       25,000          30 min               1,700
312.160(c)                  3,400               2.35        8,000          30 min               1,700
Total Recordkeeping                                                                         1,060,120
 Burden
Human Drugs Total Burden                                                                   11,575,113
 Hours
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                          Table 5.--Estimated Annual Reporting Burden for Biologics\1\
----------------------------------------------------------------------------------------------------------------
                                                       No. of
           21 CFR Section                No. of       Responses   Total Annual    Hours per       Total Hours
                                       Respondents  Per Response    Responses     Response
----------------------------------------------------------------------------------------------------------------
312.7(d)                                   9             1.3          12            24              288
312.10(a)                                  1             1             1            40               40
312.23(a) and (f) and 312.120(b),        278             1.8         492         1,600          787,200
 (c)(2), and (c)(3)
312.30(a) and (e)                        975             6.5       6,411           284         1,820,724
312.31(b)                                975             9.2       9,005           100          900,500
312.32(c) and (d) and 312.56(c)          602             6.7       4,034            32          129,088
312.33(a) and (f) and 312.56(c)        1,253             1.6       1,989           350          696,150
312.35(a) and (b)                          1             1             1           300              300
312.36                                    22             5.5         122            16            1,952
312.38(b)                                128             1.7         212            28            5,936
312.38(c)                                128             1.7         212           160           33,920
312.44(c) and (d)                         55             1.9         107            16            1,712
312.45(a) and (b)                         74             1.4         105            12            1,260
312.47(b)                                150             1.8         274           160           43,840
312.53(c)                                672             6.6       4,421            80          353,680
312.54(a) and (b)                          4             1             4            48              192
312.55(b)                                374             6.1       2,288            48          109,824
312.56(b) and (d)                         12             1.6          20            80            1,600
312.58(a)                                 10             1            10             8               80
312.64(a) and (d)                      5,014             1         5,014            24          120,336

[[Page 44023]]

 
312.110(b)                                10             1.3          13            75              975
312.130(d)                                 1             1             1             0.5              0.5
Total Reporting Burden                                                                        5,009,597.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                        Table 6.--Estimated Annual Recordkeeping Burden for Biologics\1\
----------------------------------------------------------------------------------------------------------------
                                              Annual
     21 CFR Section           No. of       Frequency per   Total Annual      Hours per          Total Hours
                           Recordkeepers   Recordkeeping      Records      Recordkeeper
----------------------------------------------------------------------------------------------------------------
312.52(a)                      27               2.5            67               5                 135
312.57(a) and (b)           1,253               2           2,506             100             125,300
312.62(a)                   5,014               1           5,014              40             200,560
312.62(b)                   8,200              12.2        100,000             40             328,000
312.160(a)                  3,400               7.35       25,000          30 min               1,700
312.160(c)                    320               1             320               0.5               160
Total Biologics                                                                               655,855
 Recordkeeping Hours
Total Biologics Burden                                                                      5,665,452.5
 Hours
Total Human Drugs Burden                                                                   11,575,113
 Hours
Total Combined Burdens                                                                     17,240,565.5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


    Dated: August 6, 1999
William K. Hubbard,
Senior Associate Commissioner for Policy, Planning, and Legislation.
[FR Doc. 99-20846 Filed 8-11-99; 8:45 am]
BILLING CODE 4160-01-F