[Federal Register: October 18, 2002 (Volume 67, Number 202)]
[Notices]
[Page 64393-64397]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr18oc02-85]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. 02N-0296]
Agency Information Collection Activities; Submission for OMB
Review; 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 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.
DATES: Submit written comments on the collection of information by
November 18, 2002.
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:
Stuart Shapiro, 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 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--Part 312 (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'' 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 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 before 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
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21 CFR Section Explanations
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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.
[[Page 64394]]
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).
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),(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)......................... Follow up 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.
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 drug.
312.38(b) and (c)................. Notification of withdrawal of an
IND.
312.42(e)......................... Sponsor requests that a clinical
hold be removed and submits a
complete response to the issues
identified in the clinical hold
order.
312.44(c) and (d)................. Opportunity for sponsor response to
FDA when IND is terminated.
312.45(a) and (b)................. Sponsor request for or response to
inactive status determination of an
IND.
312.47(b)......................... ``End-of-Phase 2'' meetings and
``Pre-NDA'' meetings.
312.53(c)......................... Investigator information.
Investigator report (Form FDA-
1572) and narrative;
Investigator's background
information; phase 1 outline of
planned investigation; and phase
2 outline of study protocol;
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.
[[Page 64395]]
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(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, and
under 21 CFR 314.50, 314.70, and
314.81 in 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.
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.
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Table 2.--Recordkeeping Requirements
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21 CFR Section Explanations
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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.
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In tables 3 through 5 of this document, the estimates for ``number
of respondents,'' ``number 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 2001 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. Although the number of submissions may
fluctuate, e.g., due to the addition of respondents not previously
required to comply with part 312 or due to the normal variation in
annual submissions, this variable is not reflected in the burden totals
because the overall rate of submissions are not expected to change
significantly over the next few years. In the Federal Register of July
22, 2002 (67 FR 47811), the agency requested comments on the proposed
collection of information. No comments were received on that request.
Table 3.--Estimated Annual Reporting and Recordkeeping Burden for Human Drugs\1\
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Number of
Number of [chyph]Responses Total Annual
21 CFR Section [chyph]Respondents per [chyph]Responses Hours per Response Total Hours
[chyph]Respondent
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312.7(d) 5 1.4 7 24 168
312.23(a) through (f) 1,506 1.2 1,872 1,600 2,995,200
312.30(a) through (e) 1,050 15 15,705 284 4,460,220
312.31(b) 1,037 8 8,375 100 837,500
312.32(c) and (d) 546 22.6 12,366 32 395,712
312.33(a) through (f) 1,608 2.6 4,202 360 1,512,720
312.35(a) and (b) 1 1 1 300 300
312.36 281 1 302 16 4,832
312.38(b) and (c) 466 1.3 608 28 17,024
312.42(e) 63 1.2 78 284 22,152
312.44(c) and (d) 40 1 42 16 672
312.45(a) and (b) 244 1.4 355 12 4,260
312.47(b) 130 1.8 233 160 37,280
312.53(c) 20,428 1 20,428 80 1,634,240
312.54(a) and (b) 1 1 1 48 48
312.55(b) 388 435 168,775 48 8,101,200
[[Page 64396]]
312.56(b), (c), and (d) 2 1 2 80 160
312.58(a) 75 4.2 322 8 2,576
312.64(a) through (d) 11,574 3 34,722 24 833,328
312.70(a) 2 1 2 40 80
312.110(b) 32 8.1 261 75 19,575
312.120(b) and (c)(2) 180 2 361 168 60,548
312.120(c)(3) 2 2 4 40 160
312.130(d) 4 1 4 8 32
312.52(a) 1,104 3 .1 3,495 2 6,990
312.57(a) and (b) 1,104 34.5 38,088 100 3,808,800
312.62(a) 9,522 2 19,044 40 761,760
312.62(b) 9,522 10 95,220 40 3,808,800
312.160(a)(3) 301 1.4 425 .5 213
312.160(c) ................... 1.4 425 .5. 213
Total ................... ................... ................... ................... 29,326,763
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\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\1\
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No. of Responses Total Annual Hours per
21 CFR Section No. of Respondents per Response [chyph]Responses [chyph]Responses Total Hours
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312.7(d) 22 1.4 31 24 744
312.10(a) 9 7.9 71 40 2,840
312.23(a) and (f) and 312.120(b), (c)(2), and 376 1.4 535 1,600 856,000
(c)(3)
312.30(a) through (e) 724 5.6 4,038 284 1,146,792
312.31(b) 268 9.0 2,399 100 239,900
312.32(c) and (d) and 312.56(c) 334 12.8 4,261 32 136,352
312.33(a) and (f) and 312.56(c) 614 2.6 1,615 350 565,250
312.35(a) and (b) 1 1 1 300 300
312.36 19 4 76 16 1,216
312.38(b) 172 2.1 358 28 10,024
312.38(c) 172 2.1 358 160 57,280
312.44(c) and (d) 0 0 0 0 0
312.45(a) and (b) 70 1.7 120 12 1,440
312.47(b) 60 1.1 68 160 10,880
312.53(c) 322 5.9 1,904 80 152,320
312.54(a) and (b) 0 0 0 0 0
312.55(b) 139 2.4 331 48 15,888
312.56(b) and (d) 12 1.7 20 80 1,600
312.58(a) 19 1 19 8 152
312.64(a) and (d) 5,713 1 5,713 24 137,112
312.110(b) 9 2.4 22 75 1,650
312.130(d) 1 1 1 0.5 0.5
Total ................... ................... ................... ................... 3,337,740.5
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\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\1\
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No. of Annual Frequency Total Annual Hours per
21 CFR Section [chyph]Recordkeepers per Recordkeeping Records [chyph]Recordkeeper Total Hours
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312.52(a) recordkeeping 113 1 113 5 565
312.57(a) and (b) recordkeeping 1,432 2 2,859 100 285,900
312.62(a) recordkeeping 5,713 1 5,713 40 228,520
312.62(b) recordkeeping 5,713 12.5 71,355 40 2,854,200
312.160(a) recordkeeping 1,432 7.5 10,708 0.5 5,354
312.160(c) recordkeeping 1,432 2.5 3,573 0.5 1,786.5
Total biologics recordkeeping hours .................... ................... ................... ................... 3,376,325.5
Total biologics burden hours .................... ................... ................... ................... 3,337,740.5
Subtotal .................... ................... ................... ................... 6,714,066
Human Drugs .................... ................... ................... ................... 29,326,763
[[Page 64397]]
Biologics .................... ................... ................... ................... 6,714,066
Total .................... ................... ................... ................... 36,040,829
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
Dated: October 11, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-26617 Filed 10-17-02; 8:45 am]
BILLING CODE 4160-01-S