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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, Agency, or we) 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: Submit written comments (including recommendations) on the collection of information by March 21, 2022.
 ADDRESSES: To ensure that comments on the information collection are received, OMB recommends that written comments be submitted to 
                        *https://www.reginfo.gov/​public/​do/​PRAMain.*
                         Find this particular information collection by selecting “Currently under Review—Open for Public Comments” or by using the search function. The OMB control number for this information collection is 0910-0014. Also include the FDA docket number found in brackets in the heading of this document.
 FOR FURTHER INFORMATION CONTACT: Domini Bean, Office of Operations, Food and Drug Administration, Three White Flint North, 10A-12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-5733, 
                        *PRAStaff@fda.hhs.gov*.


SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has submitted the following proposed 
                    ( print page 9059)
                    collection of information to OMB for review and clearance. Investigational New Drug Application Regulations—21 CFR part 312 OMB Control Number 0910-0014—Revision This information collection supports implementation of provisions of section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) and of the licensing provisions of the Public Health Service Act (42 U.S.C. 201 
                    *et seq.*) that govern investigational new drugs and investigational new drug applications (INDs). Implementing regulations are found in part 312 (21 CFR part 312), and provide for the issuance of guidance documents (see § 312.145 (21 CFR 312.145)) to assist persons in complying with the applicable requirements. The information collection applies to all clinical investigations subject to section 505 of the FD&C Act and include the following types of INDs: An Investigator IND is submitted by a physician who both initiates and investigates, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug or an approved product for a new indication or in a new patient population.
                Emergency Use IND allows FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with § 312.23 or § 312.20 (21 CFR 312.23 or 312.20). It is also used for patients who do not meet the criteria of an existing study protocol or if an approved study protocol does not exist.
                Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and FDA's review takes place. There are two IND categories: Commercial and research (non-commercial). General IND requirements include submitting an initial application as well as amendments to that application; submitting reports on significant revisions of clinical investigation plans; submitting information to the clinical trials data bank (
                    *https://clinicaltrials.gov*) established by the National Institutes of Health/National Library of Medicine, including expanded information on certain clinical trials and information on the results of these clinical trials; and reporting information on a drug's safety or effectiveness. In addition, sponsors are required to provide to FDA an annual summary of the previous year's clinical experience. The regulations also include recordkeeping requirements regarding the disposition of drugs, records regarding individual case histories, and certain other documentation verifying clinical investigators' fulfillment of responsibilities. Form FDA 1571 entitled “Investigational New Drug Application (IND)” and Form FDA 1572 entitled “Statement of Investigator,” were developed to assist respondents with the information collection and provide for uniform reporting of required data elements. The information is required to be submitted electronically. Individuals who are interested in receiving printed forms may send an email request to the FDA Forms Manager at 
                    *formsmanager@OC.FDA.GOV.*
                     Fees may apply. Sponsors (including sponsor-investigators) interested in filing or updating a research IND may use a new web-based interface developed for use by mobile device or desktop to help in completing Form FDA 1571. The web-based interface also allows respondents to electronically submit completed Form FDA 1571 and associated files. For more information regarding Forms FDA 1571 and 1572 visit 
                    *https://www.fda.gov/​news-events/​expanded-access/​how-complete-form-fda-1571-and-form-fda-1572.* Human drug, biological product, and device product submissions must be accompanied by Form FDA 3674, as discussed in the guidance document entitled “Form FDA 3674—Certifications To Accompany Drug, Biological Product, and Device Applications/Submissions” (updated November 2017), available from our website at 
                    *https://www.fda.gov/​regulatory-information/​search-fda-guidance-documents/​form-fda-3674-certifications-accompany-drug-biological-product-and-device-applicationssubmissions.*
                     The guidance document provides procedural instruction on completing and submitting required information to FDA. As communicated in the instructions, the certification must accompany the application or submission and be included at the time of submission to FDA. Regulations in part 312, subpart B, specify content and format requirements for applications, amendments, annual reporting, and withdrawals, including content and format requirements for protocol and information amendments. The regulations also explain phases of an investigation and set forth principles of IND submissions. Regulations in part 312, subpart C, describe administrative actions pertaining to respondents' requests for and responses to clinical holds, terminations, and inactive IND status determinations, as well as various types of meetings (for example, End-of-Phase 2 and Pre-new drug application (NDA) meetings). Regulations in part 312, subpart D, set forth sponsor and investigator responsibilities, including general responsibilities; transfer of obligations to a contract research organization; recordkeeping and record retention controls; reporting responsibilities; and responsibility for disposition of unused supply of investigational drug. The regulations also provide for investigator controls including review of ongoing investigations; compliance with requirements regarding the protection of human subjects and institutional review board assurance; and disqualification of clinical investigators. Regulations in part 312, subpart E, sets forth requirements applicable to drugs intended to treat life-threatening and severely debilitating illnesses. The regulations establish procedures to reflect that physicians and patients accept greater risk or side effects from products that treat life-threatening and severely debilitating illnesses than they would accept from products that treat less serious illnesses. The procedures also reflect the recognition that the benefits of the drug need to be evaluated in light of the severity of the disease being treated. Regulations in part 312, subpart F, include provisions pertaining to import and export requirements; foreign clinical studies not conducted under an IND; the disclosure of data and information in an IND; and the issuance of guidance documents. We are revising the information collection to account for burden that may be associated with recommendations found in Agency guidance documents. The guidance document entitled “Oversight of Clinical Investigations” (August 2013) communicates risk-based monitoring strategies and recommends plans for investigational studies of medical products, including human drug and biological products, medical devices, and combinations thereof. The guidance document is intended to enhance human subject protection and the quality of clinical trial data by focusing sponsor oversight on the most important aspects of study conduct and reporting. The guidance also communicates that sponsors can use a variety of approaches to fulfill( print page 9060)
                    responsibilities for monitoring clinical investigator conduct and performance in IND studies, and provides a description of strategies for monitoring activities to reflect a modern, risk-based approach. The guidance document recommends that respondents develop a written comprehensive monitoring plan and describes monitoring approaches for respondents to consider (Guidance Section IV.D.).
                The guidance document entitled “Pharmacogenomic Data Submissions” (March 2005) provides recommendations intended to assist sponsors submitting or holding INDs, NDAs, or biologics license applications (BLAs) with submission requirements for relevant data regarding drug safety and effectiveness (including §§ 312.22, 312.23, 312.31, 312.33, 314.50, 314.81, 601.2, and 601.12 (21 CFR 312.22, 312.23, 312.31, 312.33, 314.50, 314.81, 601.2 and 601.12)). Because the regulations were developed before the advent of widespread animal or human genetic or gene expression testing, the regulations do not specifically address when such data must be submitted. The guidance document includes content and format recommendations regarding pharmacogenomic data submissions. Although we have not received any pharmacogenomic submissions since 2013, we assume an average of 50 hours for preparing and providing information to FDA as recommended in the guidance and estimate one submission annually.
                The guidance document entitled “Adaptive Designs for Clinical Trials of Drugs and Biologics” (December 2019) was developed to assist sponsors and applicants submitting INDs, NDAs, BLAs, or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biologic. The guidance document describes important principles for designing, conducting, and reporting the results from an adaptive clinical trial, and advises sponsors on the types of information to submit to facilitate FDA evaluation of clinical trials with adaptive designs, including Bayesian adaptive and complex trials that rely on computer simulations for their design. The guidance document also helps to fulfill FDA Commitment Goals under the Prescription Drug User Fee Act pertaining to the enhancement of regulatory decision tools. The referenced guidance documents are available for download from our website at 
                    *https://www.fda.gov/​regulatory-information/​search-fda-guidance-documents*
                     and were issued consistent with § 312.145 to help respondents comply with requirements in part 312. In publishing the respective notices of availability for each guidance document, we included an analysis under the PRA and invited public comment on the associated information collection recommendations. In addition, all Agency guidance documents are issued in accordance with our Good Guidance Practice regulations in 21 CFR 10.115, which provide for public comment at any time. Regulations in part 312, subpart G, provide for drugs for investigational use in laboratory research animals or in vitro tests. In the 
                    **Federal Register**
                     of November 24, 2021 (86 FR 67060), we published a 60-day notice requesting public comment on the proposed collection of information. Although we received two general comments, neither discussed the four information collection topics solicited in our 60-day notice or suggested that we revise our burden estimate. We estimate the burden of this collection of information as follows: Table 1—Estimated Annual Reporting Burden for Biologics 1
21 CFR section; activity
Number of
                             respondents
Number of
                             responses per 
                             respondent
Total
                             annual 
                             responses
Average
                             burden per 
                             response
Total
                             hours**Subpart A—General Provisions: §§ 312.1 through 312.10**§ 312.2(e); requests for FDA advice on the applicability of part 312 to a planned clinical investigation
454
1.528
694
24
16,656§ 312.8; requests to charge for an investigational drug
14
1.64
23
48
1,104§ 312.10; waiver requests
5
1
5
24
120Subtotal Subpart A Center for Biologics Evaluation and Research (CBER)


722

17,880**Subpart B—Investigational New Drug Application (IND): §§ 312.20 through 312.38 (Including Forms FDA 1571, 1572, and 3674)**§ 312.23(a) through (f); IND content and format
2,075
3.382
7,018
300
2,105,400§ 312.30(a) through (e); protocol amendments
1,781
4.6692
8,316
284
2,361,744§ 312.31(b); information amendments
169
2.48
419
100
41,900§ 312.32(c) and (d); IND safety reports
224
10.59
2,372
32
75,904§ 312.33(a) through (f); IND annual reports
971
2.2739
2,208
360
794,880§ 312.38(b) and (c); notifications of withdrawal of an IND
712
3.057
2,177
28
60,956Subtotal Subpart B CBER


22,510

5,440,784**Subpart C—Administrative Actions: §§ 312.40 through 312.48**§ 312.42; clinical holds and requests for modification
154
1.65
254
284
72,136§ 312.44(c) and (d); sponsor responses to FDA when IND is terminated
86
1.22
105
16
1,680§ 312.45(a) and (b); sponsor requests for or responses to an inactive status determination of an IND by FDA
48
1.48
71
12
852§ 312.47; meetings, including “End-of-Phase 2” meetings and “Pre-NDA” meetings
157
1.80
283
160
45,280Subtotal Subpart C CBER


713

119,948( print page 9061)**Subpart D—Responsibilities of Sponsors and Investigators: §§ 312.50 through 312.70**§ 312.53(c); investigator reports submitted to the sponsor, including Form FDA 1572, curriculum vitae, clinical protocol, and financial disclosure
1,068
5.23
5,586
80
446,880§ 312.54(a); sponsor submissions to FDA concerning investigations involving an exception from informed consent under § 50.24
4
4.25
17
48
816§ 312.54(b); sponsor notifications to FDA and others concerning an institutional review board 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
48§ 312.55(a); number of investigator brochures submitted by the sponsor to each investigator
473
2.224
1,052
48
50,496§ 312.55(b); number of sponsor reports to investigators on new observations, especially adverse reactions and safe use
243
4.95
1,203
48
57,744§ 312.56(b), (c), and (d); review of ongoing investigations and associated notifications; sponsor notifications
915
2.948
2,698
80
215,840§ 312.58; inspection of records and reports by FDA
7
1
7
8
56§ 312.64; number of investigator reports to the sponsor, including progress reports, safety reports, final reports, and financial disclosure reports
2,728
3.816
10,411
24
249,864§ 312.70; disqualification of a clinical investigator by FDA
5
1
5
40
200Subtotal Subpart D CBER


20,980

1,021,944**Subpart F—Miscellaneous: §§ 312.110 through 312.145**§ 312.110(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
1,350§ 312.120(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
88,000§ 312.120(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
384§ 312.130; number of requests for disclosable information in an IND and for investigations involving an exception from informed consent under § 50.24
350
1.342
470
8
3,760Subtotal Subpart F CBER


3,254

93,494Total


48,179

6,694,0501
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 Table 2—Estimated Annual Recordkeeping Burden for Biologics 1
21 CFR section; activity
Number of
                             recordkeepers
Number of
                             records per 
                             recordkeeper
Total annual
                             records
Average
                             burden per 
                             recordkeeping
Total
                             hours**Subpart D—Responsibilities of Sponsors and Investigators: §§ 312.50 through 312.70**§ 312.52(a); sponsor records for the transfer of obligations to a contract research organization
94
2.26
212
2
424§ 312.57; sponsor recordkeeping showing the receipt, shipment, or other disposition of the investigational drug, and any financial interest
335
2.70
904
100
90,400§ 312.62(a); investigator recordkeeping of the disposition of drugs
453
1
453
40
18,120§ 312.62(b); investigator recordkeeping of case histories of individuals
453
1
453
40
18,120Subtotal Subpart D CBER


2,022

127,064( print page 9062)**Subpart G—Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests**§ 312.160(a)(3); records pertaining to the shipment of drugs for investigational use in laboratory research animals or in vitro tests
111
1.40
155
0.5 (30 minutes)
78§ 312.160(c) shipper records of alternative disposition of unused drugs
111
1.40
155
0.5 (30 minutes)
78Subtotal Subpart G CBER


310

156Total


2,332

127,2201
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 Table 3—Estimated Annual Reporting Burden for Human Drugs 1
21 CFR section; activity
Number of 
                             respondents
Number of
                             responses per 
                             respondent
Total annual responses
Average 
                             burden per  
                             response
Total hours**Subpart A—General Provisions**§ 312.2(e); requests for FDA advice on the applicability of part 312 to a planned clinical investigation
419
1
419
24
10,056§ 312.8; requests to charge for an investigational drug
25
1.28
32
48
1,536§ 312.10; requests to waive a requirement in part 312
68
1.5
102
24
2,448Subtotal Subpart A Center for Drug Evaluation and Research (CDER)


553

14,040**Subpart B—Investigational New Drug Application (IND)**§ 312.23(a) through (f); IND content and format (including Forms FDA 1571 and 3674)
4,886
1.4662
7,164
300
2,149,200§ 312.30(a) through (e); protocol amendments
11,847
3.2367
38,346
284.25
10,899,850§ 312.31(b); information amendments
8,094
3.30899
26,783
100
2,678,300§ 312.32(c) and (d); IND safety reports
892
15.848
14,137
32
452,384§ 312.33(a) through (f); IND annual reports
3,777
2.9097
10,990
360
3,956,400§ 312.38(b) and (c); notifications of withdrawal of an IND
1,549
1.834
2,841
28
79,548Subtotal Subpart B CDER


100,261

20,215,682**Subpart C—Administrative Actions: §§ 312.40 through 312.48**§ 312.42; clinical holds and requests for modifications
181
1.28
232
284
65,888§ 312.44(c) and (d); sponsor responses to FDA when IND is terminated
1
1
1
16
16§ 312.45(a) and (b); sponsor requests for or responses to an inactive status determination of an IND by FDA
213
1.72
367
12
4,404§ 312.47; meetings, including “End-of-Phase 2” meetings and “Pre-NDA” meetings
174
2.885
502
160
80,320Subtotal Subpart C CDER


1,102

150,628**Subpart D—Responsibilities of Sponsors and Investigators**§ 312.54(a); sponsor submissions to FDA concerning investigations involving an exception from informed consent under § 50.24
7
1.14
8
48
384§ 312.54(b); sponsor notifications to FDA and others concerning an institutional review board determination that it cannot approve research because it does not meet the criteria in the exception from informed consent in § 50.24(a)
2
1
2
48
96§ 312.56; review of ongoing investigations and associated notifications
4,570
5.4689
24,993
80
1,999,440§ 312.58; inspection of records and reports by FDA
73
1
73
8
584§ 312.70; disqualification of a clinical investigator by FDA.
5
1
5
40
200Subtotal Subpart D CDER


25,081

2,000,704( print page 9063)**Subpart F—Miscellaneous: §§ 312.110 through 312.145**§ 312.110(b)(4) and (b)(5); written certifications and written statements submitted to FDA relating to the export of an investigational drug
8
22.375
179
75
13,425§ 312.120(b); submissions to FDA of “supporting information” related to the use of foreign clinical studies not conducted under an IND
1,964
7.352
14,440
32
462,080§ 312.120(c); waiver requests submitted to FDA related to the use of foreign clinical studies not conducted under an IND
68
1.5
102
24
2,448§ 312.130; requests for disclosable information in an IND and for investigations involving an exception from informed consent under § 50.24
3
1
3
8
24§ 312.145; Guidance Documents:Oversight of Clinical Investigations (2013)
88
1.5
132
4
528Pharmacogenomic Data Submissions (2005)
1
1
1
50
50Adaptive Designs for Clinical Trials of Drugs and Biologics (2019)
55
4.727
260
50
13,000Subtotal Subpart F CDER


15,117

491,555Total


142,114

22,872,6091
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 Table 4—Estimated Annual Recordkeeping Burden for Human Drugs 1
21 CFR section; activity
Number of recordkeepers
Number of records per recordkeeper
Total annual records
Average burden per
                             recordkeeping
Total hours**Subpart D—Responsibilities of Sponsors and Investigators**§ 312.52(a); transfer of obligations to a contract research organization
466
3.107
1,448
300
434,400§ 312.57; records showing the receipt, shipment, or other disposition of the investigational drug and any financial interests
13,000
1
13,000
100
1,300,000§ 312.62(a); records on disposition of drugs
13,000
1
13,000
40
520,000§ 312.62(b); records on case histories of individuals
2,192
6.587
14,439
40
577,560Subtotal Subpart D CDER


41,887

2,831,960**Subpart G—Drugs for Investigational Use in Laboratory Research Animals or In Vitro Tests**§ 312.160(a)(3); records pertaining to the shipment of drugs for investigational use in laboratory research animals or in vitro tests
547
1.43
782
0.50 (30 minutes)
391§ 312.160(c); shipper records of alternative disposition of unused drugs
547
1.43
782
0.50 (30 minutes)
391Subtotal


1,564

782Total


43,451

2,832,7421
                         There are no capital costs or operating and maintenance costs associated with this collection of information.
 The information collection reflects program changes and adjustments. We have revised the information collection to account for burden that may be incurred by respondents who choose to adopt or implement recommendations discussed in referenced Agency guidance documents intended to assist respondents in complying with regulatory requirements in part 312. We have also made adjustments to individual collection elements, specifically with regard to protocol amendments and emergency INDs for both human drugs and biological drugs. We attribute the increase for these elements to a corresponding increase in submissions since last OMB review and approval of the information collection and the ongoing public health emergency. Finally, we have removed burden we attribute to provisions in part 312, subpart I: Expanded Access to Investigational Drugs for Treatment Use and are revising OMB control number 0910-0814 to include burden associated with information collection applicable 
                    ( print page 9064)
                    to these regulatory provisions for efficiency of Agency operations. As a result of these cumulative changes and adjustments, the information collection reflects an overall decrease in both annual responses and burden hours. Dated: February 10, 2022. Lauren K. Roth, Associate Commissioner for Policy.


[FR Doc. 2022-03432 Filed 2-16-22; 8:45 am] BILLING CODE 4164-01-P