Agency information collection activities: Proposed collection; comment request,

[Federal Register: July 22, 2002 (Volume 67, Number 140)]

[Notices]

[Page 47811-47816]

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

[DOCID:fr22jy02-86]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 02N-0296]

Agency Information Collection Activities; Proposed Collection; Comment Request; Investigational New Drug Regulations

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

[[Page 47812]]

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 September 20, 2002.

ADDRESSES: Submit electronic comments on the collection of information to http://www.accessdata.fda.gov/scripts/oc/dockets/edockethome.cfm. Submit written comments on the collection of information to the Dockets Management Branch (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 Information Resources Management (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: (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--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 investigational new drug application (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; 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: (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.

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Table 1.--Reporting Requirements

21 CFR Section

Explanations

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 Secs. 312.23 and 312.31. 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.

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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. 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 Secs. 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.

Table 2.--Recordkeeping Requirements

21 CFR Section

Explanations

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.

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.

Table 3.--Estimated Annual Reporting and Recordkeeping Burden for Human Drugs\1\

Number of Number of Responses Total Annual 21 CFR Section

Respondents

per Respondent

Responses

Hours per Response Total Hours

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

8,101,200 312.56(b), (c), and (d)

2

1

2

80

160

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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

\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\

No. of Responses Total Annual 21 CFR Section

No. of Respondents per Response

Responses Hours per Responses Total Hours

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

\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\

No. of

Annual Frequency Total Annual

Hours per 21 CFR Section

Recordkeepers per Recordkeeping

Records

Recordkeeper

Total Hours

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 Biologics

6,714,066

[[Page 47816]]

Total

36,040,829

\1\There are no capital costs or operating and maintenance costs associated with this collection of information.

Dated: July 15, 2002. Margaret M. Dotzel, Associate Commissioner for Policy.

[FR Doc. 02-18318Filed7-19-02; 8:45 am]

BILLING CODE 4160-01-S