[Federal Register Volume 84, Number 29 (Tuesday, February 12, 2019)]
[Notices]
[Pages 3462-3467]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-01962]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-N-1721]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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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 March 
14, 2019.

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: 202-395-7285, or emailed to [email protected]. All 
comments should be identified with the OMB control number 0910-0014. 
Also include the FDA docket number found

[[Page 3463]]

in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: JonnaLynn Capezzuto, Office of 
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-3794, 
[email protected].

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 Application--21 CFR Part 312

OMB Control Number 0910-0014-Extension

    This information collection supports FDA regulations in 21 CFR part 
312 covering Investigational New Drugs. Part 312 implements provisions 
of section 505(i) of the Federal Food, Drug, and Cosmetic Act (FD&C 
Act) (21 U.S.C. 355(i)) requiring FDA 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 ensure 
drug products marketed in the United States are shown to be safe and 
effective, properly manufactured, and properly labeled for their 
intended uses. Section 505(a) of the FD&C Act provides that a new drug 
may not be introduced or delivered for introduction into interstate 
commerce in the United States unless FDA has previously approved a new 
drug application (NDA). FDA approves an NDA only if the sponsor of the 
application first demonstrates that the drug is safe and effective for 
the conditions prescribed, recommended, or suggested in the product's 
labeling. Proof must consist, in part, of adequate and well-controlled 
studies, including studies in humans, that are conducted by qualified 
experts.
    The investigational new drug application (IND) regulations under 
part 312 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. The regulations also include recordkeeping requirements 
pertaining to the disposition of drugs, records pertaining to 
individual case histories, and certain other documentation verifying 
the fulfillment of responsibilities by clinical investigators.
    Submissions are reviewed by medical officers and other Agency 
scientific reviewers assigned responsibility for overseeing a specific 
study. The details 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 monitor the clinical investigation of the safety and 
effectiveness of unapproved new drugs and biological products, 
including the following: (1) Monitor the safety of ongoing clinical 
investigations; (2) determine whether the clinical testing of a drug 
should be authorized; (3) ensure production of reliable data on the 
metabolism and pharmacological action of the drug in humans; (4) obtain 
timely information on adverse reactions to the drug; (5) obtain 
information on side effects associated with increasing doses; (6) 
obtain information on the drug's effectiveness; (7) ensure the design 
of well-controlled, scientifically valid studies; and (8) obtain other 
information pertinent to determining whether clinical testing should be 
continued and information related to the protection of human subjects. 
Without the information provided by industry as required under the IND 
regulations, FDA cannot authorize or monitor the clinical 
investigations that must be conducted before authorizing the sale and 
general use of new drugs. These reports enable FDA to monitor a study's 
progress, to ensure the safety of subjects, to ensure 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.
    To assist respondents with certain reporting requirements under 
part 312, we have developed two forms: Form FDA 1571 entitled, 
``Investigational New Drug Application (IND)'' and Form FDA 1572 
entitled, ``Statement of Investigator.'' Anyone who intends to conduct 
a clinical investigation must submit Form FDA 1571 as instructed. The 
reporting elements include: (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 is executed and submitted 
by the IND sponsor before an investigator may participate in an 
investigation. It includes background information on the investigator 
as well as the investigation, and a general outline of the planned 
investigation and study protocol.
    In the Federal Register of October 4, 2018 (83 FR 50102) FDA 
published a 60-day notice requesting public comment on the proposed 
collection of information. We received one comment. The comment did not 
pertain to the regulations or estimates provided in the 60-day notice 
requesting that OMB extend its approval for the information collection 
in these regulations. Rather, the comment discussed issues that 
pertained to Docket No. FDA-2010-D-0503 for the ``Guidance for Clinical 
Investigators, Sponsors, and Institutional Review Boards (IRBs): 
Investigational New Drug Applications (INDs)--Determining Whether Human 
Research Studies Can Be Conducted Without an IND.'' Accordingly, we 
have submitted the comment to Docket No. FDA-2010-D-0503.
    FDA estimates the burden of this collection of information as 
follows:

                      Table 1--Estimated Annual Reporting Burden for Human Drugs (CDER) \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
         21 CFR section              Number of     responses per   Total annual   Average burden    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
Sec.   312.2(e); Requests for                400               1             400              24           9,600
 FDA advice on the applicability
 of part 312 to a planned
 clinical investigation.........
Sec.   312.8; Requests to charge              74            1.23              91              48           4,368
 for an investigational drug....
Sec.   312.10; Requests to waive              86            1.84             158              24           3,792
 a requirement in part 312......

[[Page 3464]]

 
Sec.   312.23(a) through (f);              2,187             1.7           3,718           1,600       5,948,800
 IND content and format
 (including Form FDA 1571)......
Sec.   312.30(a) through (e);              4,418            5.52          24,387             284       6,925,908
 Protocol amendments............
Sec.   312.31(b); Information              6,691            3.32          22,214             100       2,221,400
 amendments.....................
Sec.   312.32(c) and (d); IND                867           15.78          13,681              32         437,792
 safety reports.................
Sec.   312.33(a) through (f);              3,376            2.86           9,655             360       3,475,800
 IND annual reports.............
Sec.   312.38(b) and (c);                    930            1.61           1,497              28          41,916
 Notifications of withdrawal of
 an IND.........................
Sec.   312.42; Sponsor requests              198            1.38             273             284          77,532
 that a clinical hold be
 removed, including sponsor
 submission of a complete
 response to the issues
 identified in the clinical hold
 order..........................
Sec.   312.44(c) and (d);                     12            1.16              14              16             224
 Sponsor responses to FDA when
 IND is terminated..............
Sec.   312.45(a) and (b);                    231            1.84             425              12           5,100
 Sponsor requests for or
 responses to an inactive status
 determination of an IND by FDA.
Sec.   312.47; Meetings,                     122            1.51             184             160          29,440
 including ``End-of-Phase 2''
 meetings and ``Pre-NDA''
 meetings.......................
Sec.   312.54(a); Sponsor                     15             2.4              36              48           1,728
 submissions to FDA concerning
 investigations involving an
 exception from informed consent
 under Sec.   50.24.............
Sec.   312.54(b); Sponsor                      2               1               2              48              96
 notifications to FDA and others
 concerning an IRB determination
 that it cannot approve research
 because it does not meet the
 criteria in the exception from
 informed consent in Sec.
 50.24(a).......................
Sec.   312.56(b), (c), and (d);            6,100               7          42,700              80       3,416,000
 Sponsor notifications to FDA
 and others resulting from: (1)
 The sponsor's monitoring of all
 clinical investigations and
 determining that an
 investigator is not in
 compliance with the
 investigation agreements; (2)
 the sponsor's review and
 evaluation of the evidence
 relating to the safety and
 effectiveness of the
 investigational drug; and (3)
 the sponsor's determination
 that the investigational drug
 presents an unreasonable and
 significant risk to subjects...
Sec.   312.58(a); Sponsor's                   73               1              73               8             584
 submissions of clinical
 investigation records to FDA on
 request during FDA inspections.
Sec.   312.70; During the                      4               1               4              40             160
 disqualification process of a
 clinical investigator by FDA,
 the number of investigator
 responses or requests to FDA
 following FDA's notification to
 an investigator of its failure
 to comply with investigation
 requirements...................
Sec.   312.110(b)(4) and (b)(5);              11           26.28             289              75          21,675
 Written certifications and
 written statements submitted to
 FDA relating to the export of
 an investigational drug........
Sec.   312.120(b); Submissions             1,414            8.62          12,189              32         390,048
 to FDA of ``supporting
 information'' related to the
 use of foreign clinical studies
 not conducted under an IND.....
Sec.   312.120(c); Waiver                     35            2.34              82              24           1,968
 requests submitted to FDA
 related to the use of foreign
 clinical studies not conducted
 under an IND...................
Sec.   312.130; Requests for                   3               1               3               8              24
 disclosable information in an
 IND and for investigations
 involving an exception from
 informed consent under Sec.
 50.24..........................
Sec.  Sec.   312.310(b) and                  935            2.77           2,590               8          20,720
 312.305(b); Submissions related
 to expanded access and
 treatment of an individual
 patient........................
Sec.   312.310(d); Submissions               480            2.15           1,032              16          16,512
 related to emergency use of an
 investigational new drug.......
Sec.  Sec.   312.315(c) and                  118            2.52             297             120          35,640
 312.305(b); Submissions related
 to expanded access and
 treatment of an intermediate-
 size patient population........
Sec.   312.320(b); Submissions                10            12.9             129             300          38,700
 related to a treatment IND or
 treatment protocol.............
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............      23,125,527
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


[[Page 3465]]


                    Table 2--Estimated Annual Recordkeeping Burden for Human Drugs (CDER) \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                    Average burden
         21 CFR section              Number of      records per    Total annual         per         Total hours
                                   recordkeepers   recordkeeper       records      recordkeeping
----------------------------------------------------------------------------------------------------------------
Sec.   312.52(a); Sponsor                  1,300               1           1,300               2           2,600
 records for the transfer of
 obligations to a contract
 research organization..........
Sec.   312.57; Sponsor                    13,000               1          13,000             100       1,300,000
 recordkeeping showing the
 receipt, shipment, or other
 disposition of the
 investigational drug and any
 financial interests............
Sec.   312.62(a); Investigator            13,000               1          13,000              40         520,000
 recordkeeping of the
 disposition of drugs...........
Sec.   312.62(b); Investigator            13,000               1          13,000              40         520,000
 recordkeeping of case histories
 of individuals.................
Sec.   312.160(a)(3); Records                547            1.43             782          * 0.50             391
 pertaining to the shipment of
 drugs for investigational use
 in laboratory research animals
 or in vitro tests..............
Sec.   312.160(c); Shipper                   547            1.43             782          * 0.50             391
 records of alternative
 disposition of unused drugs....
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............       2,343,382
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
* 30 minutes.


               Table 3--Estimated Annual Third-Party Disclosure Burden for Human Drugs (CDER) \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
         21 CFR section              Number of      disclosures    Total annual   Average burden    Total hours
                                    respondents   per respondent    disclosures   per disclosure
----------------------------------------------------------------------------------------------------------------
Sec.   312.53(c); Investigator             1,732            7.94          13,752              80       1,100,160
 reports submitted to the
 sponsor, including Form FDA
 1572, curriculum vitae,
 clinical protocol, and
 financial disclosure...........
Sec.   312.55(a); Investigator               995               4           3,980              48         191,040
 brochures submitted by the
 sponsor to each investigator...
Sec.   312.55(b); Sponsor                    995               4           3,980              48         191,040
 reports to investigators on new
 observations, especially
 adverse reactions and safe use.
Sec.   312.64; Investigator               13,000               1          13,000              24         312,000
 reports to the sponsor,
 including progress reports,
 safety reports, final reports,
 and financial disclosure
 reports........................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............       1,794,240
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                       Table 4--Estimated Annual Reporting Burden for Biologics (CBER) \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
         21 CFR section              Number of     responses per   Total annual   Average burden    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
Sec.   312.2(e); Requests for                217            1.18             256              24           6,144
 FDA advice on the applicability
 of part 312 to a planned
 clinical investigation.........
Sec.   312.8; Requests to charge              20            1.50              30              48           1,440
 for an investigational drug....
Sec.   312.10;Requests to waive                2               1               2              24              48
 a requirement in part 312......
Sec.   312.23(a) through (f);                335            1.35             452           1,600         723,200
 IND content and format.........
Sec.   312.30(a) through (e);                694            5.84           4,053             284       1,151,052
 Protocol amendments............
Sec.   312.31 (b); Information                77            2.43             187             100          18,700
 amendments.....................
Sec.   312.32(c) and (d); IND                161            8.83           1,422              32          45,504
 Safety reports.................
Sec.   312.33(a) through (f);                745            2.14           1,594             360         573,840
 IND Annual reports.............
Sec.   312.38(b) and (c);                    134            1.69             226              28           6,328
 Notifications of withdrawal of
 an IND.........................
Sec.   312.42; Sponsor requests               67            1.30              87             284          24,708
 that a clinical hold be
 removed, including sponsor
 submission of a complete
 response to the issues
 identified in the clinical hold
 order..........................
Sec.   312.44(c) and (d);                     34            1.15              39              16             624
 Sponsor responses to FDA when
 IND is terminated..............
Sec.   312.45(a) and (b);                     55            1.38              76              12             912
 Sponsor requests for or
 responses to an inactive status
 determination of an IND by FDA.
Sec.   312.47; Meetings,                      88            1.75             154             160          24,640
 including ``End-of-Phase 2''
 meetings and ``Pre-NDA''
 meetings.......................
Sec.   312.53(c); Investigator               453            6.33           2,867              80         229,360
 reports submitted to the
 sponsor, including Form FDA
 1572, curriculum vitae,
 clinical protocol, and
 financial disclosure...........

[[Page 3466]]

 
Sec.   312.54(a); Sponsor                      1               1               1              48              48
 submissions to FDA concerning
 investigations involving an
 exception from informed consent
 under Sec.   50.24.............
Sec.   312.54(b); Sponsor                      1               1               1              48              48
 notifications to FDA and others
 concerning an IRB determination
 that it cannot approve research
 because it does not meet the
 criteria in the exception from
 informed consent in Sec.
 50.24(a).......................
Sec.   312.55(a); Number of                  239            1.91             456              48          21,888
 investigator brochures
 submitted by the sponsor to
 each investigator..............
Sec.   312.55(b); Number of                  243            4.95           1,203              48          57,744
 sponsor reports to
 investigators on new
 observations, especially
 adverse reactions and safe use.
Sec.   312.56(b), (c), and (d);              108            2.21             239              80          19,120
 Sponsor notifications to FDA
 and others resulting from: (1)
 The sponsor's monitoring of all
 clinical investigations and
 determining that an
 investigator is not in
 compliance with the
 investigation agreements; (2)
 the sponsor's review and
 evaluation of the evidence
 relating to the safety and
 effectiveness of the
 investigational drug; and (3)
 the sponsor's determination
 that the investigational drug
 presents an unreasonable and
 significant risk to subjects...
Sec.   312.58(a); Number of                    7               1               7               8              56
 sponsor's submissions of
 clinical investigation records
 to FDA on request during FDA
 inspections....................
Sec.   312.64; Number of                   2,728            3.82          10,421              24         250,104
 investigator reports to the
 sponsor, including progress
 reports, safety reports, final
 reports, and financial
 disclosure reports.............
Sec.   312.70; During the                      5               1               5              40             200
 disqualification process of a
 clinical investigator by FDA,
 the number of investigator
 responses or requests to FDA
 following FDA's notification to
 an investigator of its failure
 to comply with investigation
 requirements...................
Sec.   312.110(b)(4) and (b)(5);              18               1              18              75           1,350
 Number of written
 certifications and written
 statements submitted to FDA
 relating to the export of an
 investigational drug...........
Sec.   312.120(b); Number of                 280            9.82           2,750              32          88,000
 submissions to FDA of
 ``supporting information''
 related to the use of foreign
 clinical studies not conducted
 under an IND...................
Sec.   312.120(c); Number of                   7            2.29              16              24             384
 waiver requests submitted to
 FDA related to the use of
 foreign clinical studies not
 conducted under an IND.........
Sec.   312.130; Number of                    350            1.34             469               8           3,752
 requests for disclosable
 information in an IND and for
 investigations involving an
 exception from informed consent
 under Sec.   50.24.............
Sec.   312.310(b) and                         78            1.08              84               8             672
 312.305(b); Number of
 submissions related to expanded
 access and treatment of an
 individual patient.............
Sec.   312.310(d);Number of                   76            2.76             210              16           3,360
 submissions related to
 emergency use of an
 investigational new drug.......
Sec.   312.315(c) and                          9               1               9             120           1,080
 312.305(b); Number of
 submissions related to expanded
 access and treatment of an
 intermediate-size patient
 population.....................
Sec.   312.320(b); Number of                   1               1               1             300             300
 submissions related to a
 treatment IND or treatment
 protocol.......................
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............       3,254,606
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.


                     Table 5--Estimated Annual Recordkeeping Burden for Biologics (CBER) \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of                    Average burden
         21 CFR section              Number of      records per    Total annual         per         Total hours
                                   recordkeepers   recordkeeper       records      recordkeeping
----------------------------------------------------------------------------------------------------------------
Sec.   312.52(a); Sponsor                     75            1.40             105               2             210
 records for the transfer of
 obligations to a contract
 research organization..........
Sec.   312.57; Sponsor                       335            2.70             904             100          90,400
 recordkeeping showing the
 receipt, shipment, or other
 disposition of the
 investigational drug, and any
 financial interests............

[[Page 3467]]

 
Sec.   312.62(a); Investigator               453               1             453              40          18,120
 recordkeeping of the
 disposition of drugs...........
Sec.   312.62(b); Investigator               453               1             453              40          18,120
 recordkeeping of case histories
 of individuals.................
Sec.   312.160(a)(3); Records                111            1.40             155           * 0.5              78
 pertaining to the shipment of
 drugs for investigational use
 in laboratory research animals
 or in vitro tests..............
Sec.   312.160(c); Shipper                   111            1.40             155           * 0.5              78
 records of alternative
 disposition of unused drugs....
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............         127,006
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
* 30 minutes.

    Because we have received an increased number of IND submissions 
since the last OMB approval of the information collection, we have 
increased our estimate of the associated burden accordingly.

    Dated: February 6, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-01962 Filed 2-11-19; 8:45 am]
BILLING CODE 4164-01-P