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 Department of Health and Human Services Food and Drug Administration [Docket No. 2005N-0393]
 AGENCY: Food and Drug Administration, HHS.
 ACTION: Notice.
 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 
                    ( print 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.**
REPORTING REQUIREMENTS21 CFR Section
Requirements312.7(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 §§ 312.23 and 312.31.312.20(c)
Applications for investigations involving an exception from informed consent under § 50.24 (21 CFR 50.24). Estimates for this requirement are included under § 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*), and (a)(7)(iv)(
                            *c*)
A description of the drug 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.( print 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 § 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 § 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 § 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 §§ 312.34 and 312.35.312.85
Sponsors conducting phase 4 studies.  Estimates for this requirement are included under § 312.23 in OMB control number 0910-0014, and §§ 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 §§ 312.23 and 312.30 in OMB control number 0910-0014, and §§ 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 §§ 312.23 and 312.30 in OMB control number 0910-0014, and §§ 314.50, 314.60, and 314.70 in OMB control number 0910-0001.( print page 59353)312.130(d)
Request for disclosable information for investigations involving an exception from informed consent under § 50.24.
 RECORDKEEPING REQUIREMENTS21 CFR Section
Requirements312.52(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 § 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 BURDEN21 CFR Section
No. of 
                             Respondents
No. of Responses 
                             per Respondent
Total Annual 
                             Responses
Hours per 
                             Response
Total Hours312.7(d)
9
1.4
13
24
7,488312.23(a) through (f)
1,245
1.3
1,597
1,600
2,555,200312.30(a) through (e)
1,257
13.3
16,687
284
4,739,108312.31(b)
1,116
7.4
8,298
100
829,800312.32(c) and (d)
649
24.7
16,052
32
513,664312.33(a) through (f)
1,821
2.5
4,516
360
1,625,760312.35(a) and (b)
5
1.2
6
300
1,800312.36
109
1.1
121
16
1,936312.38(b) and (c)
536
1.3
677
28
18,965312.42(e)
97
1.2
118
284
33,512312.44(c) and (d)
44
1
45
16
720312.45(a) and (b)
185
1.5
271
12
3,252312.47(b)
215
1.7
355
160
56,800312.53(c)
21,194
1
21,194
80
1,695,520312.54(a) and (b)
0
0
0
48
0312.55(b)
807,400
1
807,400
48
38,755,200312.56(b), (c), and (d)
13
1
13
80
1,040( print page 59354)312.58(a)
88
3.8
340
8
2,720312.64(a) through (d)
31,791
1
31,791
24
762,984312.70(a)
4
1
4
40
160312.110(b)
33
8.3
276
75
20,700312.130(d)
5
1
5
8
40Total reporting burden
51,626,369
 RECORDKEEPING BURDEN21 CFR Section
No. of 
                             Recordkeepers
No. of Records 
                             per Recordkeeper
Total Annual 
                             Records
Hours per 
                             Record
Total Hours312.52(a)
335
1.5
488
2
976312.57(a) and (b)
335
119.8
40,148
100
4,014,800312.62(a)
20,074
1
20,074
40
802,960312.62(b)
200,740
1
200,740
40
8,029,600312.160(a)(3)
372
1.5
542
.5
271312.160(c)
372
1.5
542
.5
271Total recordkeeping burden
12,848,878Human drugs total burden hours
64,475,2471
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 **Table 3.—Estimated Annual Reporting and Recordkeeping Burden for Biologics**1
REPORTING BURDEN21 CFR Section
No. of 
                             Respondents
No. of Responses 
                             per Respondent
Total Annual 
                             Responses
Hours per 
                             Response
Total Hours312.7(d)
41
1.4
58
24
1,392312.23(a) through (f) and 312.120(b), (c)(2), and (c)(3)
433
1.3
557
1,808
1,007,056312.30(a) through (e)
590
6.8
4,014
284
1,139,976312.31(b)
263
29.3
7,700
100
770,000312.32(c) and (d) and 312.56(c)
294
13.7
4,042
32
129,344312.33(a) through (f) and 312.56(c)
647
2.3
1,473
360
530,280312.35(a) and (b)
1
1
1
300
300312.36
6
1
6
16
96312.38(b) and (c)
117
1.3
153
28
4,284312.42(e)
74
1.5
108
284
30,672312.44(c) and (d)
17
1.1
18
16
288312.45(a) and (b)
60
1.8
107
12
1,284312.47(b)
43
1.5
66
160
10,560312.53(c)
348
6.6
2,303
80
184,240( print page 59355)312.54(a) and (b)
1
1
1
48
48312.55(b)
138
2.5
347
48
16,656312.56(b) and (d)
14
1.6
23
80
1,840312.58(a)
8
1
8
8
64312.64(a) through (d)
6,003
3.5
21,185
24
508,440312.70(a)
6
1
6
40
240312.110(b)
21
1
21
75
1,575312.130(d)
1
1
1
8
8Total reporting burden
4,338,643
 RECORDKEEPING BURDEN21 CFR Section
No. of 
                             Recordkeepers
Annual Frequency 
                             per Recordkeeping
Total Annual 
                             Records
Hours per 
                             Record
Total Hours312.52(a)
139
1.4
200
2
400312.57(a) and (b)
433
2.6
1,114
100
111,400312.62(a)
5,570
1
5,570
40
222,800312.62(b)
5,570
10
55,700
40
2,228,000312.160(a)(3)
146
1.4
211
0.5
105.5312.160(c)
146
1.4
211
0.5
105.5Total recordkeeping burden
2,562,811Total biologics burden hours
6,901,4541
                         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
64,475,247Total biologics burden hours
6,901,454Total burden hours
71,376,7011
                         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