2011-11540. Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Investigational New Drug Regulations

AGENCY:

Food and Drug Administration, HHS.

ACTION:

Notice.

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 June 10, 2011.

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: [phone], or e-mailed to [e-mail]. All comments should be identified with the OMB control number 0910-0014. Also include the FDA docket number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT:

Elizabeth Berbakos, Office of Information Management, Food and Drug Administration, 1350 Piccard Dr., PI50-400B, Rockville, MD 20850, 301-796-3792, [e-mail].

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—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 regulations “Investigational New Drug Application” in part 312 (21 CFR part 312). Part 312 implements provisions of section 505(i) of the Federal Food, Drug, and Cosmetic Act (the FD&C 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 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 INDs.

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; 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 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:

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:

Reporting Requirements

21 CFR 312.2(e)—Requests for FDA advice on the applicability of part 312 to a planned clinical investigation.

21 CFR 312.8—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 this requirement are included under §§ 312.23 and 312.31. In addition, separate 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 this requirement are included under § 312.23.

21 CFR 312.23—INDs (content and format).

21 CFR 312.23(a)(1)—Cover sheet FDA-1571.

21 CFR 312.23(a)(2)—Table of Contents.

21 CFR 312.23(a)(3)—Investigational plan for each planned study.

21 CFR 312.23(a)(5)—Investigator's brochure.

21 CFR 312.23(a)(6)—Protocols—Phases 1, 2, and 3.

21 CFR 312.23(a)(7)—Chemistry, manufacturing, and control information.

21 CFR 312.23(a)(7)(iv)(a),(b),(c)—A description of the drug substance, a list of all components, and any placebo used.

21 CFR 312.23(a)(7)(iv)(d)—Labeling: Copies of labels and labeling to be provided each investigator.

21 CFR 312.23(a)(7)(iv)(e)—Environmental impact analysis regarding drug manufacturing and use.

21 CFR 312.23(a)(8)—Pharmacological and toxicology information.

21 CFR 312.23(a)(9)—Previous human experience with the investigational drug.

21 CFR 312.23(a)(10)—Additional information.

21 CFR 312.23(a)(11)—Relevant information.

21 CFR 312.23(f)—Identification of exception from informed consent.

21 CFR 312.30—Protocol amendments.

21 CFR 312.30(a)—New protocol.

21 CFR 312.30(b)—Change in protocol.

21 CFR 312.30(c)—New investigator.

21 CFR 312.30(d)—Content and format.

21CFR 312.30(e)—Frequency.

21 CFR 312.31—Information amendments.

21CFR 312.31(b)—Content and format.

—Chemistry, toxicology, or technical information.

21 CFR 312.32—Safety reports.

21 CFR 312.32(c)(1)—Written reports to FDA and to investigators.

21 CFR 312.32(c)(2)—Telephone reports to FDA for fatal or life-threatening experience.

21 CFR 312.32(c)(3)—Format or frequency.

21 CFR 312.32(d)—Follow up submissions.

21 CFR 312.33—Annual reports.

21 CFR 312.33(a)—Individual study information.

21 CFR 312.33(b)—Summary information.

21 CFR 312.33(b)(1)—Adverse experiences.

21 CFR 312.33(b)(2)—Safety report summary.

21 CFR 312.33(b)(3)—List of fatalities and causes of death.

21 CFR 312.33(b)(4)—List of discontinuing subjects.

21 CFR 312.33(b)(5)—Drug action.

21 CFR 312.33(b)(6)—Preclinical studies and findings.

21 CFR 312.33(b)(7)—Significant changes.

21 CFR 312.33(c)—Next year general investigational plan.

21 CFR 312.33(d)—Brochure revision.

21 CFR.312.33(e)—Phase I protocol modifications.

21 CFR.312.33(f)—Foreign marketing developments.

21 CFR 312.38(b) and (c)—Notification of withdrawal of an IND.

21 CFR 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.

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, inactive status determination of an IND.

21 CFR 312.47(b)—“End-of-Phase 2” meetings and “Pre-NDA” meetings.

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.

21 CFR 312.58(a)—Sponsor's submission of records to FDA on request.

21 CFR 312.64—Investigator reports to the sponsor.

21 CFR 312.64(a)—Progress reports.

21 CFR 312.64(b)—Safety reports.

21 CFR 312.64(c)—Final reports.

21 CFR 312.66—Investigator reports to Institutional Review Board. Estimates for this requirement are included under § 312.53.

21 CFR 312.70(a)—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 this requirement are included under § 312.23 in 0910-0014, and §§ 314.50, 314.70, and 314.81 in 0910-0001.

21 CFR 312.110(b)—Request to export an investigational drug.

21 CFR 312.120—Submissions related to foreign clinical studies not conducted under an IND.

21 CFR 312.130(d)—Request for disclosable information for 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 treatment IND or treatment protocol.

Recordkeeping Requirements

21 CFR 312.52(a)—Transfer of obligations to a contract research organization.

21 CFR 312.57—Sponsor recordkeeping.

21 CFR 312.59—Sponsor recordkeeping of disposition of unused supply of drugs. Estimates for 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 this requirement are included under § 312.57.

21 CFR 312.160(a)(3)—Records maintenance: 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.

In the tables below, the estimates for “No. of Respondents,” “Annual Frequency per Response,” 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 2007 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.

In the Federal Register of January 27, 2011 (76 FR 4914), FDA published a 60-day notice requesting public comment on the proposed collection of information. No comments were received.

FDA estimates the burden of this collection of information as follows:

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 (in hours) 2	Total hours
312.2(e)	455	1.03	469	24	11,256
312.8	30	1.13	34	48	1,632
312.10	4	1	4	10	40
312.23(a) through (f)	2,496	1.26	3,145	1,600	5,032,000
312.30(a) through (e)	2,030	8.91	18,087	284	5,136,708
312.31(b)	153	2.97	454	100	45,400
312.32(c) and (d)	985	23.06	22,714	32	726,848
312.33(a) through (f)	2,564	2.34	6,000	360	2,160,000
312.38(b) and (c)	654	1.34	876	28	24,528
312.42(e)	149	1.10	164	284	46,576
312.44(c) and (d)	44	1	45	16	704
312.45(a) and (b)	254	1.43	363	12	4,356
312.47(b)	281	1.8	506	160	80,960
312.53(c)	21,194	1	21,194	80	1,695,520
312.54(a) and (b)	0	0	0	48	0
312.55(b)	985	2,306	2,271,410	48	109,027,680
312.56(b), (c), and (d)	18	1	18	80	1,440
312.58(a)	91	4.10	373	8	2,984
312.64	31,791	1	31,791	24	762,984
312.70(a)	4	1	4	40	160
312.110(b)	23	18.26	420	75	31,500
312.120	115	5	575	32	18,400
312.130(d)	3	1	3	8	24
312.310(b) and 312.305(b)	988	1	988	8	7,904
312.310(d)	525	1.23	646	16	10,336
312.315(c) and 312.305(b)	68	1	68	120	8,160
312.320	9	1.11	10	300	3,000
Total					124,841,100
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
2 Burden estimates of less than 1 hour are expressed as a fraction of an hour in the format “[number of minutes per response]/60”.

Table 2—Estimated Annual Recordkeeping Burden for Human Drugs ¹

21 CFR Section	Number of recordkeepers	Number of records per recordkeeper	Total annual records	Average burden per recordkeeping (in hours) 2	Total hours
312.52(a)	335	1.5	503	2	1,006
312.57	75	485.28	36,396	100	3,639,600
312.62(a)	14,732	1	14,732	40	589,280
312.62(b)	147,320	1	147,320	40	5,892,800
312.160(a)(3)	547	1.4	766	30/60	383
312.160(c)	547	1.4	766	30/60	383
Total					10,123,452
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
2 Burden estimates of less than 1 hour are expressed as a fraction of an hour in the format “[number of minutes per response]/60”.

Table 3—Estimated Annual Reporting Burden for Biologics ¹

21 CFR Section	Number of respondents	Number of responses per respondent	Total annual responses	Average burden per response (in hours) 2	Total hours
312.7(d)	41	1.4	57	24	1,368
312.23(a) through (f) and 312.120(b), (c)(2), and (c)(3)	433	1.3	563	1,808	1,017,904
312.30(a) through (e)	590	6.8	4,012	284	1,139,408
312.31(b)	263	29.3	7,706	100	770,600
312.32(c) and (d) and 312.56(c)	294	13.7	4,028	32	128,896
312.33(a) through (f) and 312.56(c)	647	2.3	1,488	360	535,680
312.35(a) and (b)	1	1	1	300	300
312.36	6	1	6	16	96
312.38(b) and (c)	117	1.3	152	28	4,256
312.42(e)	74	1.5	111	284	31,524
312.44(c) and (d)	17	1.1	18	16	304
312.45(a) and (b)	60	1.8	108	12	1,296
312.47(b)	43	1.5	65	160	10,400
312.53(c)	348	6.6	2,297	80	183,760
312.54(a) and (b)	1	1	1	48	48
312.55(b)	138	2.5	345	48	16,560
312.56(b) and (d)	14	1.6	22	80	1,760
312.58(a)	8	1	8	8	64
312.64(a) through (d)	6,003	3.5	21,010	24	504,240
312.70(a)	6	1	6	40	240
312.110(b)	21	1	21	75	1,575
312.130(d)	1	1	1	8	8
Total					4,350,287
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
2 Burden estimates of less than 1 hour are expressed as a fraction of an hour in the format “[number of minutes per response]/60”.

Table 4—Estimated Annual Recordkeeping Burden for Biologics ¹

21 CFR Section	Number of recordkeepers	Number of records per recordkeeper	Total annual records	Average burden per recordkeeping (in hours) 2	Total hours
312.52(a)	139	1.4	195	2	390
312.57(a) and (b)	433	2.6	1,126	100	112,600
312.62(a)	5,570	1	5,570	40	222,800
312.62(b)	5,570	10	55,700	40	2,228,000
312.160(a)(3)	146	1.4	204	30/60	102
312.160(c)	146	1.4	204	30/60	102
Total					2,563,994
1 There are no capital costs or operating and maintenance costs associated with this collection of information.
2 Burden estimates of less than 1 hour are expressed as a fraction of an hour in the format “[number of minutes per response]/60”.

Dated: May 6, 2011.

Leslie Kux,

Acting Assistant Commissioner for Policy.