E9-4971. 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

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 April 9, 2009.

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 0910-0581. Also include the FDA docket number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT:

Jonna Capezzuto,Office of Information Management (HFA-710), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-796-3794.

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 an ongoing clinical trial. The DMC advises the sponsor regarding the continuing safety of current participants and those yet to be recruited, as well as the continuing validity and scientific merit of the trial.

FDA's guidance 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 and describes certain reporting and recordkeeping responsibilities, including the following: (1) Sponsor notification to the DMC regarding waivers, (2) DMC reports of meeting minutes to the sponsor, (3) sponsor reports to FDA on DMC recommendations related to safety, (4) standard operating procedures (SOPs) for DMCs, and (5) DMC meeting records.

1. Sponsor Notification to the DMC Regarding Waivers

The sponsor must report to FDA serious unexpected adverse events in drugs and biologics trials (§ 312.32 (21 CFR 312.32)) and unanticipated adverse events in the case of device trials under (§ 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.

2. DMC Reports of Meeting Minutes to the Sponsor

The agency recommends in the guidance that the DMC 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.

3. 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)) 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.”

4. SOPs for DMCs

In the guidance, we recommend 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 study statistician takes on the responsibility for interim analysis and reporting to the DMC; and
• Minimize the risks of bias that arise when the primary study 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.

5. 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))).

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.

Reporting and Recordkeeping 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 Drug 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. 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. 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 meeting records should be maintained per clinical trial.

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

The information collection provisions in the guidance for §§ 312.30 (21 CFR 312.30), 312.32, 312.38 (21 CFR 312.38), 312.55 (21 CFR 312.55), and 312.56 have been approved under OMB control no. 0910-0014; § 314.50 has been approved under OMB control no. 0910-0001; and §§ 812.35 (21 CFR 812.35) and 812.150 have been approved under OMB control no. 0910-0078.

In the Federal Register of October 8, 2008 (73 FR 58970), FDA published a 60-day notice requesting public comment on the information collection provisions. No comments were received.

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

Table 1.—Estimated Annual Reporting Burden¹

Section of Guidance/Reporting Activity	No. of Respondents	Annual Frequency per Response	Total Annual Responses	Hours Per Response	Total Hours
4.4.1.2. Sponsor notification to the DMC regarding waivers	1	1	1	.25	.25
4.4.3.2. DMC reports of meeting minutes to the sponsor	370	2	740	1	740
5. Sponsor reporting to FDA on DMC recommendations related to safety	37	1	37	.5	18.5
Total					758.75
1 There are no capital costs or operating and maintenance costs associated with this collection of information.

Table 2.—Estimated Annual Recordkeeping Burden¹

Recordkeeping Activity	No. of Recordkeepers	Annual Frequency per Recordkeeping	Total Annual Records	Hours Per Record	Total Hours
4.1. and 6.4 SOPs for DMCs	37	1	37	8	296
4.4.3.2. DMC meeting records	370	1	370	2	740
Total					1,036
1 There are no capital costs or operating and maintenance costs associated with this collection of information.

Dated: March 3, 2009.

Jeffrey Shuren,

Associate Commissioner for Policy and Planning.