Federal Register / Vol. 70, No. 25 / Tuesday, February 8, 2005 / Notices 6693

incentive for their time. A total of 432 

participants will be involved. This will 

be a one time (rather than annual) 

collection of information. 

FDA estimates the burden of this 

collection of information as follows:

TABLE 1—ESTIMATED ANNUAL REPORTING BURDEN1

No. of

Respondents

Annual Frequency

per Response

Total Annual

Responses

Hours per

Response Total Hours 

800 (screener) 1 800 .017 14

432 (survey) 1 432 .33 143

Total 157

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

Dated: February 1, 2005.

Jeffrey Shuren,

Assistant Commissioner for Policy.

[FR Doc. 05–2419 Filed 2–7–05; 8:45 am]

BILLING CODE 4160–01–S

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES

Food and Drug Administration

[Docket No. 2005N–0038]

Reporting of Adverse Events to 

Institutional Review Boards; Public 

Hearing

AGENCY: Food and Drug Administration, 

HHS.

ACTION: Notice of public hearing; request 

for comment.

SUMMARY: The Food and Drug 

Administration (FDA) is announcing a 

public hearing to consider the process 

by which institutional review boards 

(IRBs) obtain and review information on 

adverse events that occur during the 

conduct of clinical investigations. FDA 

is increasingly aware of concerns within 

the IRB community that the process is 

burdensome, inefficient, and not as 

effective as it should be in providing 

IRBs the information they need to 

ensure that the rights and welfare of 

human subjects are protected during the 

course of a clinical study. The purpose 

of the hearing is to solicit information 

and views from interested persons on 

issues and concerns regarding the 

submission of adverse events to and 

their review by IRBs. FDA is seeking 

general information about the nature of 

the problem and possible solutions, 

responses to specific questions (see 

section III of this document), and any 

other pertinent information stakeholders 

would like to share.

Date and Time: The public hearing 

will be held on March 21, 2005, from 9 

a.m. to 5 p.m. Submit written or 

electronic notices of participation by 

4:30 p.m. on March 4, 2005. Submit 

written and electronic comments by 

April 21, 2005.

Location: The public hearing will be 

held at the Advisors and Consultants 

Staff Conference Room, 5630 Fishers 

Lane, Rockville, MD 20857.

Addresses: Written or electronic 

notices of participation should be 

submitted to the Division of Dockets 

Management (HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852, e-mail: 

FDADockets@oc.fda.gov; or on the 

Internet at http://

www.accessdata.fda.gov/scripts/oc/

dockets/meetings/meetingdocket.cfm. 

Written or electronic comments should 

be submitted to http://

www.accessdata.fda.gov/scripts/oc/

dockets/commentdocket.cfm or to the 

Division of Dockets Management (see 

Addresses above).

Contacts: Nancy L. Stanisic, Center 

for Drug Evaluation and Research (HFD–

1), Food and Drug Administration, 5600 

Fishers Lane, rm. 9–64, Rockville, MD 

20857, 301–827–1660, FAX: 301–443–

9718, e-mail: stanisicn@cder.fda.gov.

For Registration and/or to participate 

in the meeting: Because of limited 

seating, we recommend that persons 

interested in attending the meeting 

register at http://

www.accessdata.fda.gov/scripts/oc/

dockets/meetings/meetingdocket.cfm. 

Registration will be accepted on a firstcome, first-served basis.

The procedures governing the hearing 

are found in part 15 (21 CFR part 15). 

If you wish to make an oral presentation 

during the open public comment period 

of the hearing, you must state your 

intention on your registration form (see 

Addresses). To participate, submit your 

name, title, business affiliation, address, 

telephone, fax number, and e-mail 

address. You should also submit a 

written statement at the time of 

registration for each discussion question 

you wish to address, the names and 

addresses of all individuals that plan to 

participate, and the approximate time 

requested to make your presentation. 

Individuals who have registered to make 

an oral presentation will be notified of 

the scheduled time for their 

presentation prior to the hearing. 

Depending on the number of 

presentations, FDA may need to limit 

the time allotted for each presentation. 

Presentations will be limited to the 

questions and subject matter identified 

in section III of this document. 

Presenters should submit two copies of 

each presentation given. All participants 

are encouraged to attend the entire day.

If you need special accommodations 

due to a disability, please inform the 

registration contact person when you 

register.

SUPPLEMENTARY INFORMATION:

I. Background

Clinical investigations regulated by 

FDA under sections 505(i) (drugs and 

biologics) and 520(g) (medical devices) 

of the Federal Food, Drug, and Cosmetic 

Act (21 U.S.C. 355(i) and 360j(g)) must 

be reviewed and approved by an IRB in 

a manner consistent with the 

requirements of 21 CFR part 50 and part 

56 (21 CFR part 56). To approve a 

proposed clinical investigation, IRBs 

must determine, among other things, 

that the risks to subjects are minimized; 

the risks are reasonable in relation to 

anticipated benefits (if any); the 

selection of subjects is equitable; and 

the informed consent process is 

adequate for the anticipated study 

population and appropriately 

documented (see § 56.111).

After their initial review and approval 

of a clinical study, IRBs are required to 

conduct continuing review of the study 

at intervals appropriate to the degree of 

risk presented by a study (at least 

annually) (§ 56.109(f)). IRBs are required 

to follow written procedures for 

continuing review of research and for 

determining which studies require 

review more often than annually 

(§ 56.108(a)), and must maintain records 

of continuing review activities 

(§ 56.115(a)(3)).

6694 Federal Register / Vol. 70, No. 25 / Tuesday, February 8, 2005 / Notices 

1July 8, 2004, letter from Ernest D. Prentice, Chair 

of SACHRP to The Honorable Tommy Thompson, 

Secretary of Health and Human Services concerning 

SACHRP recommendations to improve human 

research protections.

Under existing regulations for drugs 

and biologics, investigators are required 

to promptly report to an IRB all 

unanticipated problems involving risk 

to human subjects or others (§ 312.66 

(21 CFR 312.66)). Under this reporting 

requirement, IRBs receive many reports 

of adverse events from clinical 

investigators. Under existing regulations 

for medical devices, IRBs receive 

information about unanticipated 

adverse device effects from investigators 

and sponsors. Investigators are required 

to submit to the IRB and the sponsor a 

report of any unanticipated adverse 

device effect occurring during an 

investigation as soon as possible, and in 

no event later than 10 days after the 

investigator learns of the effect 

(§ 812.150(a)(1) (21 CFR 812.150(a)(1))), 

and sponsors are required to report the 

results of an evaluation of a reported 

effect to reviewing IRBs and 

investigators within 10 working days 

after the sponsor receives notice of the 

effect (§ 812.50(b)(1)). In addition, IRBs 

are required to follow written 

procedures to ensure that there is 

prompt reporting to the IRB, appropriate 

institutional officials, and FDA of any 

unanticipated problems involving risks 

to human subjects or others 

(§ 56.108(b)).

The regulations describing IRB 

responsibilities in part 56 and the 

regulations describing sponsor and 

investigator responsibilities in parts 312 

and 812, were implemented at a time 

when most clinical studies were 

conducted at a single site or a small 

number of sites. In the intervening 

years, the number of multicenter studies 

has grown substantially. There are many 

more studies with very large numbers of 

study sites, including trials with both 

foreign and domestic sites. FDA is 

increasingly aware of significant 

concerns and confusion within the IRB 

community about the way IRBs obtain 

and review adverse event information 

during the course of a clinical study, 

particularly in the context of a large 

multicenter study.

A. Volume of Adverse Event Reports

The rapid growth in the number of 

clinical research programs in recent 

years has led to a situation in which 

many IRBs receive large volumes of 

information, including a multitude of 

individual adverse event reports. In a 

recent letter, the Department of Health 

and Human Services Secretary’s 

Advisory Committee on Human 

Research Protections (SACHRP letter) 

noted that some institutions are 

receiving in excess of 12,000 adverse 

event reports per year.1 The clinical 

significance and relevance of reported 

events can vary considerably. FDA is 

aware that IRBs receive reports of events 

that range from serious to relatively 

minor, and that in some cases both 

anticipated and unanticipated events 

are reported. FDA is also aware that 

IRBs receive adverse event reports from 

other studies using the same drug, but 

not necessarily under the same 

conditions (e.g., different doses, 

durations of therapy, diseases, or 

subpopulations).

The prevalence of large, multicenter 

trials further contributes to the volume 

of adverse event reports to IRBs. 

Sponsors of investigations of drugs and 

biological products are required to 

notify all participating investigators of 

any adverse experience associated with 

the use of a drug that is both serious and 

unexpected and any finding from tests 

in laboratory animals that suggests a 

significant risk for human subjects 

(§ 312.32(c)(1)). Investigators typically 

forward copies of such reports to their 

IRBs, and also forward additional 

sponsor reports that do not meet these 

criteria. Thus an IRB for a single study 

site commonly receives reports of 

adverse events and other information 

from all study sites.

B. Quality of Adverse Events 

Information

Another significant concern is that 

individual adverse event reports 

submitted to IRBs are often not 

sufficiently informative to permit IRBs 

to assess the implications of reported 

events for study subjects. The SACHRP 

letter concluded that adverse event 

reports ‘‘seldom contain adequate 

information.’’

Considerable variation exists among 

reports in the amount of detail and 

quality of information provided. For 

example, in blinded studies, reports 

might not disclose the treatment the 

subject received (i.e., whether the 

subject received the study drug, an 

active control, or placebo). In addition, 

it may be difficult for IRBs to review 

and interpret the significance of large 

volumes of individual adverse event 

reports received in isolation 

(unaggregated and unanalyzed) at 

sporadic intervals over the course of 

study.

II. Purpose and Scope of the Hearing

This hearing is intended to provide 

the IRB community, sponsors, 

investigators, data monitoring 

committees, individuals who have 

participated in clinical studies, and 

other interested parties an opportunity 

to discuss their experiences and 

concerns about the process by which 

IRBs obtain and review information 

about adverse events, and to share their 

ideas about how the process might be 

improved to best meet the purposes of 

IRB review—to protect human subjects. 

FDA is not seeking comment on how to 

interpret the existing regulations in 

parts 56, 312, and 812 requiring the 

reporting of ‘‘unanticipated problems 

involving risk to human subjects or 

others’’ at this time. Instead, given the 

role of IRB’s, FDA is asking what 

information about adverse events is 

necessary or useful for IRBs to consider 

in how to best protect human subjects, 

and is asking what the best process is 

for submitting such information. FDA 

hopes to obtain information that will 

help it develop strategies, such as 

guidance or a change to the regulations, 

to address the identified concerns.

III. Issues for Discussion

FDA is interested in hearing about the 

experiences of IRBs, investigators, 

sponsors, data monitoring committee, 

individuals who have participated in 

clinical studies, and other affected 

parties concerning the reporting of 

adverse events to IRBs and how IRBs 

evaluate such reports.

In the conduct of a clinical trial, the 

following parties have responsibilities 

related to identifying, evaluating, 

reporting, and analyzing adverse events:

• Clinical investigators

Clinical investigators have the 

responsibility of identifying adverse 

events associated with a drug, biologic, 

or device, evaluating and documenting 

the occurrence of such events, and 

making required safety reports. For drug 

and biologics trials, the investigator 

must report to the sponsor any adverse 

effect that may reasonably be regarded 

as caused by, or probably caused by, a 

drug (§ 312.64(b)) or biologic. The 

investigator must also report to the IRB 

all unanticipated problems involving 

risk to human subjects (§ 312.66). In a 

multicenter trial, the investigator at a 

site may also serve as a conduit to the 

site IRB for reports of serious, 

unexpected adverse events occurring at 

other study sites because he or she 

received reports of such events from the 

sponsor (§ 312.32(c)). For medical 

device trials, the investigator must 

report to the sponsor and reviewing IRB 

any unanticipated adverse device effects 

occurring during an investigation 

§ 812.150(b)(1).

• Sponsors

Federal Register / Vol. 70, No. 25 / Tuesday, February 8, 2005 / Notices 6695

Trial or study sponsors are required to 

monitor their trials and provide 

required safety reports (§ 312.32). 

Sponsors of drug or biologics trials must 

report to FDA and clinical investigators 

any adverse experience associated with 

the use of the drug that is both serious 

and unexpected or any finding from 

tests in laboratory animals that suggests 

a significant risk for human subjects 

(§ 312.32). Sponsors are also required to 

submit to FDA annual reports, a 

component of which contains summary 

information about adverse events 

(§ 312.33). Sponsors of medical device 

trials are required to report the results 

of evaluations unanticipated adverse 

device effects to FDA and all reviewing 

IRBs (§ 812.150(b)(1)).

• FDA

FDA reviews safety reports, and 

annual reports of adverse events to 

determine whether there is new 

information that affects its original 

evaluation of the reasonableness of the 

risk to study subjects.

• Data Monitoring Committee (DMC)

In large phase 3 trials, there may also 

be a DMC (sometimes referred to as a 

data and safety monitoring board or 

DSMB) that conducts periodic review of 

accumulating data from an ongoing trial 

to assess whether the study continues to 

be safe and scientifically valid. DMCs 

report their analyses to the sponsor or 

an independent steering committee set 

up by the sponsor.

• IRBs

IRBs are responsible for performing a 

continuing review of ongoing research 

at appropriate intervals (at least 

annually) (§ 56.109(f)). IRBs must have 

written procedures to ensure prompt 

reporting to the IRB, appropriate 

institutional officials, and FDA of any 

unanticipated problems involving risk 

to human subjects or others 

(§ 56.108(b)).

FDA would like to understand better 

how the IRB’s responsibility with 

respect to adverse events fits with the 

roles of these other parties and how the 

process for reporting adverse events to 

IRBs can be improved to better enable 

IRBs to meet their obligation to protect 

the rights and welfare of human 

subjects. FDA would like interested 

parties to address the following issues 

and questions:

1. The role of IRBs in the review of 

adverse event information from ongoing 

clinical trials.

Given the number of parties with 

responsibilities related to adverse events 

that occur during the course of a clinical 

trial, what role should IRBs play in the 

review of adverse events information 

from an ongoing clinical trial? How does 

that role differ from the current role of 

IRBs? Should IRB responsibilities for 

multi-site trials differ from those for 

single-site trials? If so, how should they 

differ?

2. The types of adverse events about 

which IRBs should receive information.

Based on your view of the role of IRBs 

in the review of adverse event 

information from ongoing clinical trials, 

what types of adverse events should an 

IRB receive information about, and what 

types of information need not be 

provided to IRBs? For example, should 

IRBs generally receive information only 

about adverse events that are both 

serious and unexpected? Are there 

circumstances under which IRBs should 

receive information about adverse 

events that are not both serious and 

unexpected (e.g., if the information 

would provide a basis for changing the 

protocol, informed consent, or 

investigator’s brochure)? In a 

multicenter study, should the criteria 

for reporting adverse events to an IRB 

differ, depending on whether the 

adverse events occur at the IRB’s site or 

at another site?

3. Approaches to providing adverse 

events information to IRBs.

There seems to be a general consensus 

in the IRB community that adverse 

event reports submitted individually 

and sporadically throughout the course 

of a study without any type of 

interpretation are ordinarily not 

informative to permit IRBs to assess the 

implications of reported events for 

study subjects (see, e.g., the SACHRP 

letter, NIH Regulatory Burden v. Human 

Subjects Protection—Workgroups 

Report, available at http://

grants2.nih.gov/grants/policy/

regulatoryburden/

humansubjectsprotection.htm, which 

states that data that are neither 

aggregated nor interpreted do ‘‘not 

provide useful information to allow the 

IRB to make an informed judgment on 

the appropriate action to be taken, if 

any.’’). What can be done to provide 

IRBs adverse event information that will 

enable them to better assess the 

implications of reported events for 

study subjects? For example, if prior to 

submission to an IRB, adverse event 

reports were consolidated or aggregated 

and the information analyzed and/or 

summarized, would that improve an 

IRB’s ability to make useful 

determinations based on the adverse 

event information it receives? If so, what 

kinds of information should be included 

in consolidated reports? And when 

should consolidated reports be provided 

to IRBs (e.g., at specified intervals, only 

when there is a change to the protocol, 

informed consent, or investigator’s 

brochure due to adverse events 

experience)? Who should provide such 

reports? Should the approach to 

providing IRB’s adverse event reports be 

the same for drugs and devices?

IV. Notice of Hearing Under Part 15

The Commissioner of FDA is 

announcing that the public hearing will 

be held in accordance with part 15. The 

hearing will have a presiding officer, 

who will be accompanied by senior 

management from the Center for 

Biologics Evaluation and Research, the 

Center for Drug Evaluation and 

Research, the Center for Devices and 

Radiological Health, and the agency’s 

Good Clinical Practice Program.

Persons who wish to participate in the 

part 15 hearing must file a written or 

electronic notice of participation with 

the Division of Dockets Management 

(see Addresses). To ensure timely 

handling, any outer envelope should be 

clearly marked with the docket number 

listed in brackets in the heading of this 

document along with the statement 

‘‘IRB-Adverse Event Reporting.’’ Groups 

should submit two written copies. The 

notice of participation should contain 

the person’s name, address, telephone 

number, affiliation, if any; the sponsor 

of the presentation (e.g., the 

organization paying travel expenses or 

fees), if any; a brief summary of the 

presentation (including the specific 

discussion questions that will be 

addressed); and the approximate 

amount of time requested for the 

presentation. The agency requests that 

interested persons and groups having 

similar interests consolidate their 

comments and present them through a 

single representative. After reviewing 

the notices of participation and 

accompanying information, FDA will 

schedule each appearance and notify 

each participant by telephone of the 

time allotted to the person and the 

approximate time the person’s oral 

presentation is scheduled to begin. If 

time permits, FDA may allow interested 

persons attending the hearing who did 

not submit a written or electronic notice 

of participation in advance to make an 

oral presentation at the conclusion of 

the hearing. The hearing schedule will 

be available at the hearing. After the 

hearing, the hearing schedule will be 

placed on file in the Division of Dockets 

Management under the docket number 

listed in brackets in the heading of this 

document.

Under § 15.30(f), the hearing is 

informal, and the rules of evidence do 

not apply. No participant may interrupt 

the presentation of another participant. 

Only the presiding officer and panel 

members may question any person 

6696 Federal Register / Vol. 70, No. 25 / Tuesday, February 8, 2005 / Notices 

during or at the conclusion of each 

presentation.

Public hearings under part 15 are 

subject to FDA’s policy and procedures 

for electronic media coverage of FDA’s 

public administrative proceedings (part 

10, subpart C (21 CFR part 10, subpart 

C)). Under § 10.205, representatives of 

the electronic media may be permitted, 

subject to certain limitations, to 

videotape, film, or otherwise record 

FDA’s public administrative 

proceedings, including presentations by 

participants.

Any persons requiring special 

accommodations to attend the hearing 

should contact Nancy L. Stanisic (see 

Contacts).

To the extent that the conditions for 

the hearing, as described in this notice, 

conflict with any provisions set out in 

part 15, this notice acts as a waiver of 

those provisions as specified in 

§ 15.30(h).

V. Request for Comments

Interested persons may submit to the 

Division of Dockets Management (see 

Addresses) written or electronic notices 

of participation and comments for 

consideration at the hearing. To permit 

time for all interested persons to submit 

data, information, or views on this 

subject, the administrative record of the 

hearing will remain open following the 

hearing. Persons who wish to provide 

additional materials for consideration 

should file these materials with the 

Division of Dockets Management. You 

should annotate and organize your 

comments to identify the specific 

questions to which they refer (see 

section III of this document). Two 

copies of any mailed comments are to be 

submitted, except that individuals may 

submit one copy. Comments are to be 

identified with the docket number 

found in brackets in the heading of this 

document. Received comments may be 

seen in the Division of Dockets 

Management between 9 a.m. and 4 p.m., 

Monday through Friday. Transcripts of 

the hearing also will be available for 

review at the Division of Dockets 

Management.

VI. Transcripts

The hearing will be transcribed as 

stipulated in § 15.30(b). The transcript 

of the hearing will be available 30 days 

after the hearing on the Internet at http:/

/www.fda.gov/ohrms/dockets, and 

orders for copies of the transcript can be 

placed at the meeting or through the 

Freedom of Information Staff (HFI–35), 

Food and Drug Administration, 5600 

Fishers Lane, rm. 12A–16, Rockville, 

MD 20857, at a cost of 10 cents per page.

Dated: February 2, 2005.

Jeffrey Shuren,

Assistant Commissioner for Policy.

[FR Doc. 05–2300 Filed 2–7–05; 8:45 am]

BILLING CODE 4160–01–S

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES

Food and Drug Administration

[Docket No. 2004D–0422]

Guidance for Industry: Animal Drug 

Sponsor Fees Under the Animal Drug 

User Fee Act; Availability

AGENCY: Food and Drug Administration, 

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug 

Administration (FDA) is announcing the 

availability of a guidance for industry 

(#173) entitled ‘‘Guidance for Industry: 

Animal Drug Sponsor Fees Under the 

Animal Drug User Fee Act (ADUFA).’’

This guidance describes how FDA 

intends to implement the Federal Food, 

Drug, and Cosmetic Act (the act) as it 

relates to animal drug sponsor fees.

DATES: Comments on agency guidance 

documents are welcome at any time.

ADDRESSES: Submit written comments 

to the Division of Dockets Management 

(HFA–305), Food and Drug 

Administration, 5630 Fishers Lane, rm. 

1061, Rockville, MD 20852. Submit 

electronic comments on the guidance 

via the Internet at http://www.fda.gov/

dockets/ecomments. Comments should 

be identified with the full title of the 

guidance and the docket number found 

in brackets in the heading of this 

document. See the SUPPLEMENTARY

INFORMATION section for electronic 

access to the guidance document.

Submit written requests for single 

copies of the guidance to the 

Communications Staff (HFV–12), Center 

for Veterinary Medicine, Food and Drug 

Administration, 7519 Standish Pl., 

Rockville, MD 20855. Send one selfaddressed adhesive label to assist that 

office in processing your requests.

FOR FURTHER INFORMATION CONTACT:

David Newkirk, Center for Veterinary 

Medicine (HFV–100), Food and Drug 

Administration, 7500 Standish Pl., 

Rockville, MD 20855, 301–827–6967, email: dnewkirk@cvm.fda.gov.

SUPPLEMENTARY INFORMATION:

I. Background

FDA is announcing the availability of 

a guidance for industry (#173) entitled 

‘‘Guidance for Industry: Animal Drug 

Sponsor Fees Under the Animal Drug 

User Fee Act.’’ ADUFA requires FDA to 

assess and collect user fees for certain 

applications, products, establishments, 

and sponsors. This guidance represents 

FDA’s current thinking on how it 

intends to implement the animal drug 

sponsor fee provision of ADUFA.

In the Federal Register of September 

28, 2004 (69 FR 57941), FDA published 

a notice of availability for a draft of the 

guidance, giving interested persons 

until October 28, 2004, to comment. 

FDA received one comment on the draft 

guidance. No substantive changes were 

made in finalizing this guidance 

document.

II. Paperwork Reduction Act of 1995

FDA concludes that this guidance 

contains no collections of information. 

Therefore, clearance by the Office of 

Management and Budget under the 

Paperwork Reduction Act of 1995 is not 

required.

III. Significance of Guidance

This level 1 guidance is being issued 

consistent with FDA’s good guidance 

practices regulation (21 CFR 10.115). 

This guidance represents the agency’s 

current thinking on the topic. It does not 

create or confer any rights for or on any 

person and does not operate to bind 

FDA or the public. An alternate method 

may be used as long as it satisfies the 

requirements of applicable statutes and 

regulations.

IV. Comments

As with all FDA’s guidances, the 

public is encouraged to submit written 

or electronic comments with new data 

or other new information pertinent to 

this guidance. FDA periodically will 

review the comments in the docket and, 

where appropriate, will amend the 

guidance. The agency will notify the 

public of any substantive amendments 

through a document in the Federal 

Register.

Interested persons may submit to the 

Division of Dockets Management (see 

ADDRESSES) written or electronic 

comments on the guidance at any time. 

Submit a single copy of electronic 

comments or two paper copies of any 

mailed comments, except that 

individuals may submit one paper copy. 

Comments should be identified with the 

docket number found in brackets in the 

heading of this document. A copy of the 

document and received comments are 

available for public examination in the 

Division of Dockets Management 

between 9 a.m. and 4 p.m., Monday 

through Friday.