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U.S. Department of Energy ORDER
DOE O 443.1 Washington, D.C.

SUBJECT: PROTECTION OF HUMAN SUBJECTS

1. OBJECTIVE. To establish Department of Energy (DOE) procedures and responsibilities for
implementing the policy and requirements set forth in 10 CFR Part 745, Protection of Human
Subjects, and in DOE P 443.1, POLICY ON THE PROTECTION OF HUMAN SUBJECTS.

2. CANCELLATION. This Order cancels DOE Order 1300.3, PROTECTION OF HUMAN
SUBJECTS, dated 8-23-90.

3. APPLICABILITY.

a. DOE Elements. The provisions of this Order apply to all DOE elements.

b. DOE Contractors/Financial Assistance Recipients. The provisions of this Order apply to
DOE contractors including the National Nuclear Security Administration (NNSA), and
financial assistance recipients, as provided by law and/or contract or financial assistance
agreements, and as implemented by the cognizant contracting officer. The Contractor
Requirements Document (CRD), Attachment 1, sets forth requirements to be applied to
DOE managing and operating (M&O) contractors with respect to all human subjects
research conducted by anyone under the M&O contract. DOE non-M&O contractors
and financial assistance recipients performing DOE-funded research that is subject to 10
CFR Part 745 and/or 45 CFR Part 46 must also be made subject to requirements 4d
through 4f of this Order.

4. REQUIREMENTS.

a. Approvals. No research involving human subjects conducted with DOE funding, at DOE
institutions, or by DOE personnel may be initiated without both a project assurance and
approval by the cognizant Institutional Review Board (IRB) in accordance with 10 CFR
745.103. The assurance may be either an approved single project assurance (SPA) or
multiple project assurance (MPA) obtained from the Department of Health and Human
Services (DHHS) or the DOE Human Subjects Research Program Manager (SC-72).

b. Solicitations. Any solicitation for research involving human subjects must indicate the
requirement for compliance with this Order, 10 CFR PART 745, and 45 CFR PART 46.

c. Requirements Document. Any DOE contract or financial assistance agreement involving
human subjects research must require compliance with this Order, 10 CFR PART 745, and
45 CFR PART 46. See also Contractor Requirements Document (Attachment 1).

d. Notification. SC-72 must be notified of any new solicitation or proposal involving human
subjects research (including personally identifiable information or materials) that addresses

(1) an institution without an established IRB;

(2) a foreign country;

(3) a potential for significant controversy (e.g., negative press or reaction from
stakeholder or oversight groups);

(4) research subjects in a protected class; or

(5) the generation or use of classified or sensitive unclassified information.

e. Reporting. Human subjects research projects must be reported annually to the DOE
Human Subjects Research Projects Database, in accordance with directions and schedules
provided by SC-72.

f. Waivers. Requests for waivers from the requirements of 10 CFR Part 745 or this Order
must be submitted to SC-72 in writing. A waiver may be granted provided that it is not
prohibited by law and does not present an undue risk to the health and safety of workers or
research volunteers. Waiver decisions must set forth in writing the basis for granting or
denying the request.

g. Protected Classes. Research involving pregnant or lactating women, children, prisoners, or
the mentally disabled must be conducted in accordance with 45 CFR Part 46 Subparts B,
C, and D.

h. Non-compliance. SC-72 must be notified of any known or potential incidents of non-
compliance with requirements of this Order, 10 CFR Part 745, 45 CFR Part 46, or any
approved plan for correcting a non-compliance.

5. RESPONSIBILITIES.

a. Director of the Office of Science (SC-1).

(1) Implements 10 CFR Part 745 within the Department in accordance with policy
established by the Secretary and DOE P 443.1.

(2) Determines what constitutes DOE-related human subjects research.

(3) Ensures implementation of human research subject protection.

b. DOE Human Subjects Research Program Manager (SC-72).

(1) Develops and implements procedures for the DOE human subjects research
program.

(2) Prepares and updates guidance to be followed for obtaining approval for human
subjects research.

(3) Approves human subjects research assurances.

(4) Reviews/approves local plans to correct any noncompliance with applicable human
subjects research requirements, or to mitigate adverse study events.

(5) Provides advice and guidance on evolving DOE and national bioethics and regulatory
issues regarding human research subjects protection and helps identify and resolve
program/project concerns.

(6) Develops and implements educational programs on bioethics and human research
subjects protection requirements, practices, and procedures for DOE, DOE
contractor personnel, financial assistance recipients, and the public.

(7) Regularly conducts institutional performance reviews to assess compliance with
human research subjects protection requirements.

(8) Serves as the Chair of the DOE Human Subjects Working Group and as the official
DOE representative to groups with bioethics and human subjects research interests.

(9) Reviews and approves requests for waivers to requirements of 10 CFR Part 745 and
satisfies the advance notice and publication requirements of 10 CFR Part 745.101(i)
prior to granting any waiver.

(10) Concurs in human subjects research provisions in interagency agreements.

c. Program Secretarial Officers (PSOs), NNSA Administrators and Heads of Field
Organizations (HFOs) or their Designees.

(1) Ensure that all proposals for research, studies, tests, surveys, surveillance, or other
data collection are reviewed to identify research involving human subjects. Refer any
questions or uncertainties regarding the applicability of human research subjects
protection requirements to such proposals to SC-72 for resolution and determination.

(2) Ensure that solicitations, contracts, and financial assistance agreements involving
human subjects research include the appropriate human research subjects protection
requirements and that the contracting officer is advised of projects involving such
human subjects research. [It is recommended that the OSC Face Sheet for Grant
Applications (DOE F 4650.2), Attachment 2, be used in place of the standard
Federal face sheet (SF 424, Application for Federal Assistance) referenced in 10
CFR 600.10. DOE F 4650.2 contains questions for the applicant to answer on the
involvement of human subjects in the DOE-funded research while SF 424 does not
solicit such information.]

(3) Ensure their staffs and subordinate field elements comply with the requirements of this
Order.

(4) Ensure their staffs and subordinate field elements implement the procedures
established by SC-72.

(5) Promptly notify SC-72 of known or potential adverse events and issues of non-
compliance with this Order, 10 CFR Part 745, and 45 CFR Part 46 Subparts B, C,
and D. Submit proposed corrective action for approval to SC-72 and implement
approved corrective actions.

(6) Promptly consult with SC-72 regarding human subjects research issues and concerns.

(7) Actively participate in human research subjects protection educational programs.

(8) Periodically conduct self-assessments to ensure compliance with the requirements of
this Order.

(9) At their discretion, conduct further review and approve or disapprove research that
has been approved by the IRB. (Note: PSOs, NNSA Administrators, HFOs, or
their designees may not approve human subjects research that has not been approved
by an IRB.) (See 10 CFR Part 745.112.)

(10) Oversee the administration of human research subjects protection programs of
contractors and financial assistance recipients under their cognizance to ensure
compliance with applicable human research subjects protection requirements.

(11) Involve SC-72 in negotiating those portions of interagency agreements that address
human subjects research.

(12) Appoint a point of contact for interacting with SC-72 on program-related and/or
Department-wide issues.

6. DEFINITIONS.

a. Assurance. The written documentation, satisfactory to the Secretary of Energy, required
from the prospective performing institution, that ensures institutional compliance with and
implementation of DOE or DHHS regulations for the protection of human research
subjects. A single project assurance (SPA) is a commitment to comply with human
research subjects protection requirements during the conduct of a specific project by a
particular investigator. SPAs must be renewed annually. A multiple project assurance
(MPA) is a compliance commitment by an institution covering all research involving human
research subjects conducted at that institution, irrespective of the investigator. The
institution's first DOE MPA will be awarded for a 3-year period. Subsequent renewals of
the DOE MPA may be granted for 5-year periods. An institution's DHHS SPA or MPA
will be accorded the same acceptance and responsibilities as those granted by DOE. (See
10 CFR Part 745.103 and the DOE Human Subjects Research Handbook.)

b. Adverse Effect. A direct result of an administered research protocol (e.g., negative or
deleterious drug reaction, collateral damage to the human subject.)

c. Adverse Event. A result surrounding or indirectly related to the entire research process
(e.g., mishaps, mistakes, incorrect dosage administered, reconsideration of human subject
involvement.)

d. DOE Human Subjects Research Database. A compilation of summary information, which
is available on the DOE website at: http://www.doe.eml.gov/hsrd/, updated annually, on
every human subjects research project conducted by DOE personnel, with DOE funding,
or at DOE institutions or facilities.

e. Human subjects. Living individual(s) about whom an investigator conducting research
obtains (1) data through intervention or interaction with the individual or (2) personally
identifiable information or materials.

f. Institution. Any public or private entity or agency (including Federal, State, and other
agencies). For DOE, this term refers to laboratories and other facilities managed by DOE,
DOE contractors, or DOE financial assistance recipients.

g. Institutional Review Board (IRB). A committee or board instituted by the institution,
approved by DOE or DHHS under an SPA or MPA, and charged with the responsibility
for review of research activities involving human subjects in accordance with 10 CFR Part
745.

h. Research. A systematic investigation, including research development, testing, and
evaluation, designed to develop or contribute to generalizable knowledge.

7. REFERENCES.

a. DOE P 443.1, POLICY ON THE PROTECTION OF HUMAN SUBJECTS, dated
05-15-00, which defines the DOE policy for the protection of human subjects in research
activities.

b. 10 CFR Part 745, Protection of Human Subjects, which sets out Federal requirements
for DOE for the protection of human subjects involved in research activities.

c. DOE Human Subjects Research Handbook, Office of Health and Environmental Research,
Second Edition, 1996.

d. 45 CFR Part 46, Protection of Human Subjects, Subparts B, C, and D, which sets out
DOE-prescribed DHHS requirements for protected classes of human research subjects.

e. 5 United States Code 552, The Freedom of Information Act (Public Law 89-487 as
amended), which establishes the right of citizens to request information from Federal
agencies and establishes a framework of procedures to implement this right.

f. 5 United States Code 552a, Privacy Act of 1974 (Public Law 93-549), as amended,
which establishes requirements for the collection, maintenance, and dissemination of
personal information by Federal agencies.

g. DOE O 481.1, WORK FOR OTHERS (Non-Department of Energy Funded Work),
dated 9-30-96, which establishes the policy, responsibilities, and procedures for authorizing
and administering non-DOE funded work performed under DOE contracts.

h. DOE M 481.1-1, REIMBURSABLE WORK FOR NON-FEDERAL SPONSORS
PROCESSES MANUAL, dated 9-30-96, which describes the process to be used in
performing Work for Others projects for non-Federal sponsors.

i. DOE O 412.1, WORK AUTHORIZATION SYSTEM, dated 4-20-99, which provides
the policy, responsibilities, and procedures for authorizing and administering DOE-funded
work performed under DOE contracts.

j. 10 CFR Part 600, DOE Financial Assistance Rules, which provides the policies and
procedures for administration and management of all DOE financial assistance activities.

k. 10 CFR Part 602, Epidemiology and Other Health Studies Financial Assistance, which
sets forth the policies and procedures applicable to the award and administration of financial
assistance agreements and cooperative agreements for health-related research,
education/training, conferences, communication, and related activities.

l. 10 CFR Part 605, Office of Science Financial Assistance Program, which provides
policies and procedures for the administration and management of basic and applied
research financial award agreements awarded by the Office of Science.

8. CONTACT. Questions regarding this Order should be addressed to the Program Manager,
DOE Human Subjects Research Program, at the Office of Science, telephone 301-903-4731.
Information about the DOE human subjects research protection program may be found at
http://www.er.doe.gov/production/ober/humsubj/.

BY ORDER OF THE SECRETARY OF ENERGY:

T.J. GLAUTHIER
Deputy Secretary

CONTRACTOR REQUIREMENTS DOCUMENT

DOE O 443.1, PROTECTION OF HUMAN SUBJECTS

The following requirements must be incorporated by reference into management and operating (M&O)
contracts with the potential to involve human subjects research.

1. Ensure that the DOE Human Subjects Research Program Manager (SC-72) is notified of any
new human subjects research project involving

a. an institution without an established IRB;

b. a foreign country;

c. the potential for significant controversy (e.g., negative press or reaction from stakeholder or
oversight groups);

d. research subjects in a protected class; or

e. the generation or use of classified or sensitive unclassified information.

2. Ensure that research involving human subjects conducted at the contractor-operated institution,
with the contractor's DOE-contract funding, or by contractor personnel is conducted in
accordance with the applicable requirements of 10 CFR Part 745 and 45 CFR Part 46.

3. Ensure that contractor-issued solicitations or proposals for research, studies, tests, surveys,
surveillance, or other data collection are reviewed to identify research involving human subjects.

4. Ensure no research involving human subjects conducted at the contractor-operated institution,
with the contractor's DOE-contract funding, or by contractor personnel is initiated without prior
institutional review board (IRB) approval under the terms of an approved assurance covering the
research. For research involving current or former DOE employees or DOE contractor
employees at DOE sites or facilities, either the IRB or the assurance must be approved by SC-
72.

5. Apply for SC-72 approval of any single project assurance (SPA) or multiple project assurance
(MPA), with notice to the cognizant DOE Program Secretarial Officer (PSO), NNSA
Administrators or Head of Field Organization (HFO).

6. Ensure research is reviewed at intervals appropriate to the degree of risk, but not less than once
per year, to determine whether test subjects are at risk and if they are, whether the risk is
reasonable in relation to anticipated benefits.

7. Periodically conduct self-assessments to ensure compliance with the Human Subjects Research
Program procedures and other requirements.

8. Prepare and submit an annual report for the DOE Human Subjects Research Database in
accordance with directions and schedules provided by SC-72 and the contracting officer.

9. Report the following to SC-72 (and any designated PSO, NNSA Administrators or HFO point
of contact):

a. any adverse events, unanticipated risks, or complaints about the research, and a description
of any corrective actions taken and/or to be taken;

b. any changes in the IRB membership;

c. any suspension or termination of IRB approval of research;

d. any significant non-compliance with Human Subjects Research Program procedures or
other requirements.

(The adverse effects of any study are to be reported to the IRB for evaluation for further action
with SC-72, the PSO, the NNSA Administrators and the HFO, if necessary.)

10. Submit requests for waivers from these requirements in writing, through the designated cognizant
PSO, NNSA Administrators or HFO point of contact) to SC-72, with appropriate justification.

11. Actively participate in human subjects research educational programs.

DOE F 4650.2

Department of Energy

OMB Control No.

(10-99)

Office of Science (SC)
1910-1400

(All Other Editions Are Obsolete)

(OMB Burden Disclosure

Face Page

Statement on Back)

TITLE OF PROPOSED RESEARCH:

1.
CATALOG OF FEDERAL DOMESTIC ASSISTANCE #:
8.
ORGANIZATION TYPE:

81.049

Local Govt.

State Govt.

Non-Profit

Hospital

2.
CONGRESSIONAL DISTRICT:

Indian Tribal Govt.
Individual

Applicant Organization's District:

Other

Inst. of Higher Educ.

Project Site's District:

For-Profit

Small Business
Disadvan. Business

3.
I.R.S. ENTITY IDENTIFICATION OR SSN:

Women-Owned

8(a)

9.
CURRENT DOE AWARD # (IF APPLICABLE):

4.
AREA OF RESEARCH OR ANNOUNCEMENT TITLE/#:

10.
WILL THIS RESEARCH INVOLVE:

10A
Human Subjects
No

If yes,

5.
HAS THIS RESEARCH PROPOSAL BEEN SUBMITTED

Exemption No.

TO ANY OTHER FEDERAL AGENCY?

IRB Approval Date

Yes

Assurance of Compliance No:

10B
Vertebrate Animals No
If yes,

PLEASE LIST:

IACUC Approval Date

Animal Welfare Assurance No:

6.
DOE/SC PROGRAM STAFF CONTACT (if known):

11.
AMOUNT REQUESTED FROM DOE FOR ENTIRE

PROJECT PERIOD $

7.
TYPE OF APPLICATION:

12.
DURATION OF ENTIRE PROJECT PERIOD:

New

Renewal

Continuation
Revision

Mo/day/yr.

Supplement

13.
REQUESTED AWARD START DATE

15.
PRINCIPAL INVESTIGATOR/PROGRAM DIRECTOR

(Mo/day/yr.)

NAME, TITLE, ADDRESS, AND PHONE NUMBER

14.
IS APPLICANT DELINQUENT ON ANY FEDERAL DEBT?

Yes (attach an explanation)
No

16.
ORGANIZATION'S NAME, ADDRESS AND CERTIFYING

REPRESENTATIVE'S NAME, TITLE, AND PHONE NUMBER

SIGNATURE OF PRINCIPAL INVESTIGATOR/

SIGNATURE OF ORGANIZATION'S CERTIFYING

PROGRAM DIRECTOR

REPRESENTATIVE

Date

PI/PD ASSURANCE: I agree to accept responsibility for the scientific conduct of the project and to
CERTIFICATION & ACCEPTANCE: I certify that the statements herein are true and complete to the

provide the required progress reports if an award is made as a result of this submission. Willful

best of my knowledge, and accept the obligation to comply with DOE terms and conditions if an

provision of false information is a criminal offense. (U.S. Code, Title 18, Section 1001).

award is made as the result of this submission. A willfully false certification is a criminal offense.

(U.S. Code, Title 18, Section 1001).

NOTICE FOR HANDLING PROPOSALS

This submission is to be used only for DOE evaluation purposes and this notice shall be affixed to any reproduction or abstract thereof. All Government and non-Government personnel handling this submission shall

exercise extreme care to ensure that the information contained herein is not duplicated, used, or disclosed in whole or in part for any purpose other than evaluation without written permission except that if an

award is made based on this submission, the terms of the award shall control disclosure and use. This notice does not limit the Government's right to use information contained in the submission if it is obtainable

from another source without restriction. This is a Government notice, and shall not itself be construed to impose any liability upon the Government or Government personnel for any disclosure or use of data

contained in this submission.

PRIVACY ACT STATEMENT

If applicable, you are requested, in accordance with 5 U.S.C., Sec. 562A, to voluntarily provide your Social Security Number (SSN). However, you will not be denied any right, benefit, or privilege provided by

law because of a refusal to disclose your SSN. We request your SSN to aid in accurate identification, referral and review of applications for research/training support for efficient management of Office of Energy

Research grant/contract programs.