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Agency Information Collection Activities; Submission for Office of Management and Budget Review; Comment Request; Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees

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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 May 21, 2012.

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: 202-395-7285, or emailed to oira_submission@omb.eop.gov. All comments should be identified with the OMB control number 0910-0581. Also include the FDA docket number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT:

Ila S. Mizrachi, Office of Information Management, Food and Drug Administration, 1350 Piccard Dr., PI50-400B, Rockville, MD 20850, 301-796-7726, Ila.Mizrachi@fda.hhs.gov.

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.

Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees—(OMB Control Number 0910-0581)—Extension

Sponsors are required to monitor studies evaluating new drugs, biologics, and devices (21 CFR 312.50 and 312.56 for drugs and biologics, and 21 CFR 812.40 and 812.46 for devices). Various individuals and groups play different roles in clinical trial monitoring. One such group is a data monitoring committee (DMC), appointed by a sponsor to evaluate the accumulating outcome data in some trials. A clinical trial DMC is a group of individuals with pertinent expertise that reviews on a regular basis accumulating data from one or more ongoing clinical trials. The DMC advises the sponsor regarding the continuing safety of current trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.

The guidance document referenced in this document is intended to assist sponsors of clinical trials in determining when a DMC is needed for monitoring a study and how such committees should operate. The guidance addresses the roles, responsibilities, and operating procedures of DMCs, describes certain reporting and recordkeeping responsibilities, including the following: (1) Sponsor reporting to FDA on DMC recommendations related to safety; (2) standard operating procedures (SOPs) for DMCs; (3) DMC meeting records; (4) sponsor notification to the DMC regarding waivers; and (5) DMC reports based on meeting minutes to the sponsor.

1. Sponsor Reporting to FDA on DMC Recommendations Related to Safety

The requirement of the sponsor to report DMC recommendations related to serious adverse events in an expedited manner in clinical trials of new drugs (§ 312.32(c) (21 CFR 312.32(c))) would not apply when the DMC recommendation is related to an excess of events not classifiable as serious. Nevertheless, the Agency recommends in the guidance that sponsors inform FDA about all recommendations related to the safety of the investigational product whether or not the adverse event in question meets the definition of “serious.”

2. SOPs for DMCs

In the guidance, FDA recommends that sponsors establish procedures to do the following things:

  • Assess potential conflicts of interest of proposed DMC members;
  • Ensure that those with serious conflicts of interest are not included in the DMC;
  • Provide disclosure to all DMC members of any potential conflicts that are not thought to impede objectivity and, thus, would not preclude service on the DMC;
  • Identify and disclose any concurrent service of any DMC member on other DMCs of the same, related, or competing products;
  • Ensure separation, and designate a different statistician to advise on the management of the trial, if the primary trial statistician takes on the responsibility for interim analysis and reporting to the DMC; and
  • Minimize the risks of bias that are associated with an arrangement under which the primary trial statistician takes on the responsibility for interim analysis and reporting to the DMC, if it appears infeasible or highly impractical for any other statistician to take over responsibilities related to trial management.

3. DMC Meeting Records

The Agency recommends in the guidance that the DMC or the group preparing the interim reports to the DMC maintain all meeting records. This information should be submitted to FDA with the clinical study report (§ 314.50(d)(5)(ii) (21 CFR 314.50(d)(5)(ii)).

4. Sponsor Notification to the DMC Regarding Waivers

The sponsor must report to FDA certain serious and unexpected adverse events in drugs and biologics trials (§ 312.32) and unanticipated adverse device effects in the case of device trials (§ 812.150(b)(1) (21 CFR 812.150(b)(1)). The Agency recommends in the guidance that sponsors notify DMCs about any waivers granted by FDA for expedited reporting of certain serious events.

5. DMC Reports of Meeting Minutes to the Sponsor

The Agency recommends in the guidance that DMCs should issue a written report to the sponsor based on the DMC meeting minutes. Reports to the sponsor should include only those data generally available to the sponsor. The sponsor may convey the relevant information in this report to other interested parties, such as study investigators. Meeting minutes or other information that include discussion of confidential data would not be provided to the sponsor.

Description of Respondents: The submission and data collection recommendations described in this document affect sponsors of clinical trials and DMCs.

Burden Estimate: Table 1 of this document provides the burden estimate of the annual reporting burden for the information to be submitted in accordance with the guidance. Table 2 of this document provides the burden estimate of the annual recordkeeping burden for the information to be maintained in accordance with the guidance. Table 3 of this document provides the burden estimate of the annual third-party disclosure burden for the information to be submitted in accordance with the guidance.

Reporting, Recordkeeping, and Third-Party Disclosure Burdens: Based on information from FDA review divisions, FDA estimates there are approximately 740 clinical trials with DMCs regulated by the Center for Biologics Evaluation and Research, the Center for Drugs Evaluation and Research, and the Center for Devices and Radiological Health. FDA estimates that the average length of a clinical trial is 2 years, resulting in an annual estimate of 370 clinical trials. Because FDA has no information on which to project a change in the use of DMCs, FDA estimates that the number of clinical trials with DMCs will not change significantly in the next few years. For purposes of this information collection, FDA estimates that each sponsor is responsible for approximately 10 trials, resulting in an estimated 37 sponsors that are affected by the guidance annually.

Based on information provided to FDA by sponsors that have typically used DMCs for the kinds of studies for which this guidance recommends them, FDA estimates that the majority of sponsors have already prepared SOPs for DMCs, and only a minimum amount of time is necessary to revise or update them for use for other clinical studies. FDA receives very few requests for waivers regarding expedited reporting of certain serious events; therefore, FDA has estimated one respondent per year to account for the rare instance a request may be made. Based on FDA's experience with clinical trials using DMCs, FDA estimates that the sponsor on average would issue two interim reports per clinical trial to the DMC. FDA estimates that the DMCs would hold two meetings per year per clinical trial, resulting in the issuance of two DMC reports of meeting minutes to the sponsor. One set of both of the meeting records should be maintained per clinical trial.

The “Average Burden per Response” and “Average Burden per Recordkeeping” are based on FDA's experience with comparable recordkeeping and reporting provisions applicable to FDA regulated industry. The “Average Burden per Response” includes the time the respondent would spend reviewing, gathering, and preparing the information to be submitted to the DMC, FDA, or the sponsor. The “Average Burden per Recordkeeping” includes the time to record, gather, and maintain the information.

The information collection provisions in the guidance for 21 CFR 312.30, 312.32, 312.38, 312.55, and 312.56 have been approved under OMB control number 0910-0014; § 314.50 has been approved under OMB control number 0910-0001; and 21 CFR 812.35 and 812.150 have been approved under OMB control number 0910-0078.

In the Federal Register of December 22, 2011 (76 FR 79689), 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 1

Section of guidance/reporting activityNumber of respondentsNumber of responses per respondentTotal annual responsesAverage burden per responseTotal hours
5. Sponsor reporting to FDA on DMC recommendations related to safety371370.50 (30 minutes)18.5
Total18.5
1 There are no capital costs or operating and maintenance costs associated with this collection of information.

Table 2—Estimated Annual Recordkeeping Burden 1

Recordkeeping activityNumber of recordkeepersNumber of records per recordkeeperTotal annual recordsAverage burden per recordkeepingTotal hours
4.1. and 6.4 SOPs for DMCs371378296
4.4.3.2. DMC meeting records37013702740
Total1,036
1 There are no capital costs or operating and maintenance costs associated with this collection of information.

Table 3—Estimated Annual Third-Party Disclosure Burden 1

Section of guidance/reporting activityNumber of respondentsNumber of responses per respondentTotal annual responsesAverage burden per responseTotal hours
4.4.1.2. Sponsor notification to the DMC regarding waivers1110.25 (15 minutes)0.25
4.4.3.2. DMC reports of meeting minutes to the sponsor37027401740
Total740.25
1 There are no capital costs or operating and maintenance costs associated with this collection of information.

Dated: April 16, 2012.

Leslie Kux,

Assistant Commissioner for Policy.

[FR Doc. 2012-9533 Filed 4-19-12; 8:45 am]

BILLING CODE 4160-01-P