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 Department of Health and Human Services Food and Drug Administration [Docket No. FDA-2014-N-1721]
 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 regulations under which the clinical investigation of the safety and effectiveness of unapproved new drugs and biological products can be conducted.
 DATES: Submit either electronic or written comments on the collection of information by January 5, 2015.
 ADDRESSES: Submit electronic comments on the collection of information to 
                        *http://www.regulations.gov.*
                         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: FDA PRA Staff, Office of Operations, Food 
                        ( print page 65664)
                        and Drug Administration, 8455 Colesville Rd., COLE-14526, Silver Spring, MD 20993-0002, 
                        *PRAStaff@fda.hhs.gov.*


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 (IND) Regulations—21 CFR Part 312 (OMB Control Number 0910-0014)—Extension FDA is requesting OMB approval for the reporting and recordkeeping requirements contained in FDA regulations entitled “Investigational New Drug Application” in 21 CFR part 312 (part 312). Part 312 implements provisions of section 505(i) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(i)) (the FD&C Act) 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 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 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 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; (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 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 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. 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. I. Reporting Requirements 21 CFR 312.2(e)—Requests for FDA advice on the applicability of part 312 to a planned clinical investigation. 21 CFR 312.6—Labeling of an investigational new drug. Estimates for the information collection in this requirement are included under § 312.23(a)(7)(iv)(
                    *d*). 21 CFR 312.8—Charging for investigational drugs under an IND. 21 CFR 312.10—Applications for waiver of requirements under part 312. As indicated in § 312.10(a), estimates for the information collection in this requirement are included under §§ 312.23 and 312.31. In addition, other waiver requests under § 312.10 are estimated in table 1. 21 CFR 312.20(c)—Applications for investigations involving an exception from informed consent under § 50.24 (21 CFR 50.24). Estimates for the 
                    ( print page 65665)
                    information collection in this requirement are included under § 312.23. 21 CFR 312.23—IND (content and format). .23(a)(1)—Cover sheet FDA-1571. .23(a)(2)—Table of Contents. .23(a)(3)—Investigational plan for each planned study. .23(a)(5)—Investigator's brochure. .23(a)(6)—Protocols—Phase 1, 2, and 3. .23(a)(7)—Chemistry, manufacturing, and control information. .23(a)(7)(iv)(
                    *a*),(
                    *b*),(
                    *c*)—A description of the drug substance, a list of all components, and any placebo used. .23(a)(7)(iv)(
                    *d*)—Labeling: Copies of labels and labeling to be provided each investigator. .23(a)(7)(iv)(
                    *e*)—Environmental impact analysis regarding drug manufacturing and use. .23(a)(8)—Pharmacological and toxicology information. .23(a)(9)—Previous human experience with the investigational drug. .23(a)(10)—Additional information. .23(a)(11)—Relevant information. .23(f)—Identification of exception from informed consent. 21 CFR 312.30—Protocol amendments. .30(a)—New protocol .30(b)—Changes in protocol .30(c)—New investigator. .30(d)—Content and format. .30(e)—Frequency. 21 CFR 312.31—Information amendments. .31(b)—Content and format. —Chemistry, toxicology, or technical information. 21 CFR 312.32—Safety reports. .32(c)(1)—Written reports to FDA and to investigators. .32(c)(2)—Telephone reports to FDA for fatal or life-threatening experience. .32(c)(3)—Format or frequency. .32(d)—Followup submissions. 21 CFR 312.33—Annual reports. .33(a)—Individual study information. .33(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. .33(c)—Next year general investigational plan. .33(d)—Brochure revision. .33(e)—Phase I protocol modifications. .33(f)—Foreign marketing developments. 21 CFR 312.38(b) and (c)—Notification of withdrawal of an IND. 21 CFR 312.41—Comment and advice on an IND. Estimates for the information collection in this requirement are included under § 312.23. 21 CFR 312.42—Sponsor requests that a clinical hold be removed, and submits a complete response to the issues identified in the clinical hold order. 21 CFR 312.44(c) and (d)—Opportunity for sponsor response to FDA when IND is terminated. 21 CFR 312.45(a) and (b)—Sponsor request for, or response to, an inactive status determination of an IND. 21 CFR 312.47—Meetings, including “End-of-Phase 2” meetings and “Pre-NDA” meetings. 21 CFR 312.48—Dispute resolution. Estimates for the information collection in this requirement are included under § 312.47. 21 CFR 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. 21 CFR 312.54(a) and (b)—Sponsor submissions concerning investigations involving an exception from informed consent under § 50.24. 21 CFR 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. 21 CFR 312.56(b), (c), and (d)—Sponsor monitoring of all clinical investigations, investigators, and drug safety; notification to FDA and others. 21 CFR 312.58(a)—Sponsor's submission of records to FDA on request. 21 CFR 312.64—Investigator reports to the sponsor. .64(a)—Progress reports. .64(b)—Safety reports .64(c)—Final reports. .64(d)—Financial disclosure reports. 21 CFR 312.66—Investigator reports to institutional review board (IRB). Estimates for the information collection in this requirement are included under § 312.53. 21 CFR 312.70—Investigator disqualification; opportunity to respond to FDA. 21 CFR 312.83—Sponsor submission of treatment protocol. Estimates for this requirement are included under § 312.320. 21 CFR 312.85—Sponsors conducting phase 4 studies. Estimates for the information collection in this requirement are included under § 312.23, and under §§ 314.50, 314.70, and 314.81 in OMB control number 0910-0001. 21 CFR 312.110(b)—Requests to export an investigational drug. 21 CFR 312.120—Submissions related to foreign clinical studies not conducted under an IND. 21 CFR 312.130—Requests for disclosable information in an IND and from investigations involving an exception from informed consent under § 50.24. 21 CFR 312.310(b); 312.305(b)—Submissions related to expanded access and treatment of an individual patient. 21 CFR 312.310(d)—Submissions related to emergency use of an investigational new drug. 21 CFR 312.315(c); 312.305(b)—Submissions related to expanded access and treatment of an intermediate-size patient population. 21 CFR 312.320—Submissions related to a treatment IND or treatment protocol. II. Recordkeeping Requirements 21 CFR 312.52(a)—Transfer of obligations to a contract research organization. 21 CFR 312.57—Sponsor recordkeeping on the investigational drug. 21 CFR 312.59—Sponsor recordkeeping of disposition of unused supply of drugs. Estimates for the information collection in this requirement are included under § 312.57. 21 CFR 312.62(a)—Investigator recordkeeping of disposition of drugs. 21 CFR 312.62(b)—Investigator recordkeeping of case histories of individuals. 21 CFR 312.120(d)—Recordkeeping requirements for submissions related to foreign clinical studies not conducted under an IND. Estimates for the information collection in this requirement are included under § 312.57. 21 CFR 312.160(a)(3)—Records pertaining to the shipment of drugs for investigational use in laboratory research animals or in vitro tests. 21 CFR 312.160(c)—Shipper records of alternative disposition of unused drugs. FDA estimates the burden of this collection of information as follows:
                    ( print page 65666) Table 1—Estimated Annual Reporting Burden for Human Drugs 1
21 CFR Section
Number of
                             respondents
Number of 
                             responses per respondent
Total annual responses
Average
                             burden per  
                             response
Total hours312.2(e),  Requests for FDA advice on the applicability of part 312 to a planned clinical investigation
800
1
800
24
19,200312.8,  Requests to charge for an investigational drug
56
1.25
70
48
3,360312.10,  Requests to waive a requirement in part 312
50
1.76
88
24
2,112312.23(a) through (f),  IND content and format (including Form FDA 1571)
1,689
1.57
2,648
1,600
4,236,800312.30(a) through (e),  Protocol amendments
3,739
5.77
21,588
284
6,130,992312.31(b),  Information amendments
4,537
3.39
15,377
100
1,537,700312.32(c) and (d),  IND Safety reports
755
24.28
18,332
32
586,624312.33(a) through (f),  IND Annual reports
2,877
2.76
7,953
360
2,863,080312.38(b) and (c),  Notifications of withdrawal of an IND
862
1.54
1,328
28
37,184312.42,  Sponsor requests that a clinical hold be removed, including sponsor submission of a complete response to the issues identified in the clinical hold order
158
1.30
205
284
58,220312.44(c) and (d),  Sponsor responses to FDA when IND is terminated
12
1
12
16
192312.45(a) and (b),  Sponsor requests for or responses to an inactive status determination of an IND by FDA
260
1.73
451
12
5,412312.47,  Meetings, including “End-of-Phase 2” meetings and “Pre-NDA” meetings
225
1.86
419
160
67,040312.53(c),  Investigator reports submitted to the sponsor, including Form FDA 1572, curriculum vitae, clinical protocol, and financial disclosure. (Third party disclosure)
1,444
8.38
12,087
80
966,960312.54(a),  Sponsor submissions to FDA concerning investigations involving an exception from informed consent under 21 CFR 50.24
7
5
35
48
1,680312.54(b),  Sponsor 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 § 50.24(a). (Includes third party disclosure)
7
1
7
48
336312.55(a),  Investigator brochures submitted by the sponsor to each investigator. (Third party disclosure)
590
3.50
2,067
48
99,216312.55(b),  Sponsor reports to investigators on new observations, especially adverse reactions and safe use. (Third party disclosure)
590
3.50
2,067
48
99,216312.56(b), (c), and (d),  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. (Includes third party disclosure)
3,584
6.52
23,355
80
1,868,400312.58(a),  Sponsor's submissions of clinical investigation records to FDA on request during FDA inspections
60
1
60
8
480312.64,  Investigator reports to the sponsor, including progress reports, safety reports, final reports, and financial disclosure reports.  (Third party disclosure)
1,444
1
1,444
24
34,656312.70,  During the 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
4
1
4
40
160312.110(b)(4) and (b)(5),  Written certifications and written statements submitted to FDA relating to the export of an investigational drug
11
26.28
289
75
21,675312.120(b),  Submissions to FDA of “supporting information” related to the use of foreign clinical studies not conducted under an IND
1,414
8.63
12,198
32
390,336312.120(c),  Waiver requests submitted to FDA related to the use of foreign clinical studies not conducted under an IND
35
2.34
82
24
1,968312.130, Requests for disclosable information in an IND and for investigations involving an exception from informed consent under § 50.24
3
1
3
8
24( print page 65667)312.310(b) and 312.305(b), Submissions related to expanded access and treatment of an individual patient
228
1.76
401
8
3,208312.310(d),  Submissions related to emergency use of an investigational new drug
410
2.19
899
16
14,384312.315(c) and 312.305(b),  Submissions related to expanded access and treatment of an intermediate-size patient population
44
7.07
311
120
37,320312.320(b),  Submissions related to a treatment IND or treatment protocol
12
12.67
152
300
45,600Total




19,134,0391
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 Table 2—Estimated Annual Recordkeeping Burden for Human Drugs1
21 CFR Section
Number of 
                             recordkeepers
Number of records per recordkeeper
Total annual records
Average burden per recordkeeping
Total hours312.52(a), Sponsor records for the transfer of obligations to a contract research organization
335
1.50
503
2
1,006312.57, Sponsor recordkeeping showing the receipt, shipment, or other disposition of the investigational drug, and any financial interests
1,689
1
1,689
100
168,900312.62(a), Investigator recordkeeping of the disposition of drugs
1,444
1
1,444
40
57,760312.62(b), Investigator recordkeeping of case histories of individuals
1,444
1
1,444
40
57,760312.160(a)(3), Records pertaining to the shipment of drugs for investigational use in laboratory research animals or in vitro tests
547
1.40
782
0.50 (30 minutes)
391312.160(c) Shipper records of alternative disposition of unused drugs
547
1.40
782
0.50 (30 minutes)
391Total




286,1901
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 Table 3—Estimated Annual Reporting Burden for Biologics1
21 CFR section
Number of 
                             respondents
Number of 
                             responses per  
                             respondent
Total annual responses
Average 
                             burden per  
                             response
Total hours312.2(e), Requests for FDA advice on the applicability of part 312 to a planned clinical investigation
217
1.18
255
24
6,120312.8, Requests to charge for an investigational drug
20
1.50
30
48
1,440312.10, Requests to waive a requirement in part 312
2
1
2
24
48312.23(a) through (f), IND content and format
335
1.35
452
1,600
723,200312.30(a) through (e), Protocol amendments
694
5.84
4,050
284
1,150,200312.31(b), Information amendments
77
2.43
187
100
18,700312.32(c) and (d), IND Safety reports
161
8.83
1,421
32
45,472312.33(a) through (f), IND Annual reports
745
2.14
1,595
360
574,200312.38(b) and (c), Notifications of withdrawal of an IND
134
1.69
227
28
6,356312.42, Sponsor requests that a clinical hold be removed, including sponsor submission of a complete response to the issues identified in the clinical hold order
67
1.30
87
284
24,708312.44(c) and (d), Sponsor responses to FDA when IND is terminated
34
1.15
39
16
624312.45(a) and (b), Sponsor requests for or responses to an inactive status determination of an IND by FDA
55
1.38
76
12
912312.47, Meetings, including “End-of-Phase 2” meetings and “Pre-NDA” meetings
88
1.75
154
160
24,640312.53(c), Investigator reports submitted to the sponsor, including Form FDA-1572, curriculum vitae, clinical protocol, and financial disclosure
453
6.33
2,869
80
229,520( print page 65668)312.54(a), Sponsor submissions to FDA concerning investigations involving an exception from informed consent under § 50.24
1
1
1
48
48312.54(b), Sponsor 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 § 50.24(a)
1
1
1
48
48312.55(a), Number of investigator brochures submitted by the sponsor to each investigator
239
1.91
457
48
21,936312.55(b), Number of sponsor reports to investigators on new observations, especially adverse reactions and safe use
243
4.95
1,203
48
57,744312.56(b), (c), and (d), 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
108
2.21
239
80
19,120312.58(a), Number of sponsor's submissions of clinical investigation records to FDA on request during FDA inspections
7
1
7
8
56312.64, Number of investigator reports to the sponsor, including progress reports, safety reports, final reports, and financial disclosure reports
2,728
3.82
10,411
24
249,864312.70, During the 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
5
1
5
40
200312.110(b)(4) and (b)(5), Number of written certifications and written statements submitted to FDA relating to the export of an investigational drug
18
1
18
75
1,350312.120(b), Number of submissions to FDA of “supporting information” related to the use of foreign clinical studies not conducted under an IND
280
9.82
2,750
32
88,000312.120(c), Number of waiver requests submitted to FDA related to the use of foreign clinical studies not conducted under an IND
7
2.29
16
24
384312.130, Number of requests for disclosable information in an IND and for investigations involving an exception from informed consent under § 50.24
350
1.34
470
8
3,760312.310(b) and 312.305(b), Number of submissions related to expanded access and treatment of an individual patient
78
1.08
84
8
672312.310(d), Number of submissions related to emergency use of an investigational new drug
76
2.76
210
16
3,360312.315(c) and 312.305(b), Number of submissions related to expanded access and treatment of an intermediate-size patient population
9
1
9
120
1,080312.320(b), Number of submissions related to a treatment IND or treatment protocol
1
1
1
300
300Total




3,254,0621
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 Table 4—Estimated Annual Recordkeeping Burden for Biologics1
21 CFR Section
Number of 
                             recordkeepers
Number of records per recordkeeper
Total annual records
Average burden per recordkeeping
Total hours312.52(a), Sponsor records for the transfer of obligations to a contract research organization
75
1.40
105
2
210( print page 65669)312.57, Sponsor recordkeeping showing the receipt, shipment, or other disposition of the investigational drug, and any financial interests
335
2.70
904
100
90,400312.62(a), Investigator recordkeeping of the disposition of drugs
453
1
453
40
18,120312.62(b), Investigator recordkeeping of case histories of individuals
453
1
453
40
18,120312.160(a)(3), Records pertaining to the shipment of drugs for investigational use in laboratory research animals or in vitro tests
111
1.40
155
0.50 (30 minutes)
78312.160(c), Shipper records of alternative disposition of unused drugs
111
1.40
155
0.50 (30 minutes)
78Total




127,0061
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 Dated: October 31, 2014. Leslie Kux, Assistant Commissioner for Policy.


[FR Doc. 2014-26304 Filed 11-4-14; 8:45 am] BILLING CODE 4164-01-P