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22.1 Research with Human Subjects

22.1.1 Policy

It is the policy of the Laboratory to implement the principles and regulations formulated and overseen by the Office of Human Research Protection (OHRP) within the Department of Health and Human Services (HHS) for research projects involving human subjects.

22.1.2 LBNL Support Organizations

Human and Animal Regulatory Committees Office
Human Subjects Committee

22.1.3 Implementation

It is the responsibility of the Laboratory to maintain an agreement by which Laboratory projects may be reviewed and certified in accordance with HHS principles and regulations. Investigators are responsible for safeguarding the welfare, privacy, and rights of human subjects who take part in their research experiments and for observing both the letter and the spirit of the HHS regulations.

22.1.3.1 Human Subjects Committee

LBNL’s Institutional Review Board (IRB) is the Human Subjects Committee (HSC) and it is fully empowered to review and certify Laboratory projects. The HSC holds Federalwide Assurance for Protection of Human Subjects (FWA) #00006253 from OHRP.

22.1.3.2 Human Subject Involvement

All proposed research projects that involve human subjects must be reviewed to determine risk. Human subject involvement includes:

The use of personally identifiable human-derived data or cultures of human cells.
Projects in which the investigator is the only subject.
Projects involving intentional modification of an individual’s or a group of individuals’ environment, for example through installation of devices in homes.
Information sought indirectly such as through observation.
Information sought directly through an interview or questionnaire.
Collaborative studies in which materials or information are collected at another institution and sent to researchers at the Laboratory.
Requests from third parties for information concerning the individuals in question, whether through access to files or data banks or through direct inquiry.
Donation of tissues, organs, fluids, or other bodily material.
Physical participation in an activity.

If the human subject involvement in a research project satisfies certain criteria, it may be categorized as qualified for exempt, expedited, or full board review. In all cases, the project must still be submitted for review by the HSC. Human subject involvement must be documented for every project and grant application. It must be reviewed even if the proposed involvement appears to be similar to a previously approved project. Research involving vulnerable subjects always requires a full review.

22.1.3.3 Review and Approval Procedures

All research projects involving human subjects require prior review and formal approval by an Institutional Review Board. The purpose of this review is to determine whether risks to subjects are minimized, whether the risks to subjects are reasonable in relation to the anticipated benefits of the research, whether the selection of subjects is equitable, whether adequate provision has been made to obtain and document informed consent, and whether there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data. Risk is defined as exposure to the possibility of harm, whether physical, psychological, sociological, economic, or other, to a participant in a research activity. Research is defined as a systematic investigation designed to develop or contribute to generalizable knowledge. This definition extends to pilot studies. Except in extraordinary cases, the researcher must obtain the informed consent of a subject to participate in research. Research involving vulnerable subjects requires special care in design and review.

Projects that involve human subjects must not be initiated until the appropriate HSC approval has been received.

The HSC meets monthly and as needed. Human subject protocols should be submitted to the HSC twelve days prior to its meeting date. Final HSC review takes anywhere from two to seven weeks from the time of submission. Full board review projects take longer, minimal risk expedited and exempt studies typically have a much faster route to approval.

Most funding agencies require that certification of human subjects approval be submitted prior to receipt of any awarded funds. The National Institutes of Health (NIH), for example, now requires submission of IRB approval dates during the Just-In-Time period. Human subjects review should be requested when a research proposal is being prepared, since delays sometimes occur before final approval can be granted. Annual reviews are required for continuing projects.

22.1.3.4 Authority to Suspend or Terminate Approval of Research

Under the FWA, the Laboratory, upon recommendation by the Committee, has the authority and the responsibility to suspend or terminate research that is not being conducted in accordance with HSC decisions, conditions, and requirements or that has been associated with unexpected serious harm to subjects.

In the case of suspension of research, study activities must not resume until the Committee has assurance that the appropriate corrective actions have been implemented. Institutional management at Berkeley Lab cannot reinstate research that has been suspended by the HSC, however they can choose to suspend or terminate a study for another reason regardless of HSC approval.

The reporting requirements for issues and concerns that might involve suspension or termination of research are as follows:

The HSC must report information concerning noncompliance by Berkeley Lab research investigators, injuries to subjects, and unanticipated problems involving risk to OHRP and the Institutional Official.
If the HSC suspends or terminates approval of research, the Committee must include a statement of the reason for the action and must report the action promptly to the research investigator, the Berkeley Lab Director, and the OHRP.
The Laboratory has an institutional responsibility to inform the DOE Human Subjects Program Manager and the Field Office. If the research is funded by DOE, the Laboratory must inform the appropriate Program Secretarial Office; if funded by a non-DOE agency or source, the Berkeley Lab Sponsored Projects Office must be informed.

Call the LBNL Human and Animal Regulatory Committees Office at (510) 486-6005 for information on human subjects research.

22.1.4 Standards

10 CFR Part 745, The Common Rule for Human Subjects Research
DOE Order 443.1C, Policy on the Protection of Human Subjects
DOE Order 481.1E Chg 1, Strategic Partnership Projects

22.1.5 References

Office of Human Research Protections, https://www.hhs.gov/ohrp/
DOE Human Research Protection Program, https://www.energy.gov/science/ber/biological-and-environmental-research

22.2 Research with Radioactive Drugs

22.2.1 Policy

It is the policy of the Laboratory to implement the regulations and policies of the Food and Drug Administration (FDA) for the use of radioactive drugs in human subjects.

22.2.2 LBNL Support Organizations

Human and Animal Regulatory Committees Office
Radioactive Drug Research Committee

22.2.3 Implementation

It is the responsibility of the Laboratory to review and approve protocols for the use of radioactive drugs in human subjects in accordance with FDA regulations and policies. Investigators are responsible for indicating in their protocol submission to the HSC that the study uses radioactive drugs and completing the corresponding sections, so that the proper channels of review can be completed. (See Section 22.1, Research with Human Subjects, for information on the HSC.)

22.2.4 Radioactive Drug Research Committee

The Laboratory maintains a Radioactive Drug Research Committee (RDRC) in compliance with FDA regulations (21 CFR 363.1.) The LBNL RDRC is identified as RDRC #38. The RDRC meets quarterly, or more often as required. In addition to its FDA-mandated responsibilities, the RDRC is required by the Laboratory to review the doses of all experimental radiopharmaceuticals, that are not under review by the FDA (e.g. as an IND), administered to human subjects at the Laboratory.

22.2.5 Review and Approval

For approval purposes, a radiopharmaceutical falls into one of three classifications: experimental, under investigational new drug permit, or commercially available. Basic research involving human use of experimental radiocompounds must be approved by the Laboratory RDRC. Investigators are responsible for filing an Investigational New Drug (IND) application with the FDA for qualifying radiopharmaceuticals; such applications are not reviewed by the RDRC. Human subjects protocols involving the use of IND-covered or commercially available radiopharmaceuticals are not reviewed by the RDRC but are reviewed for human subjects approval, as described in Section 22.1, Research with Human Subjects. However, the HSC may request an advisory review of any such uses for the purpose of consultation at any time during the review of the research.

Protocols calling for the use of an experimental radioactive drug in humans must be submitted at least 90 days in advance of the required approval date. The RDRC reviews the protocol to ensure that pharmacological and radiation doses lie within federal guidelines, that the radiation exposure is justified by the benefits of the research, and that the study meets certain other requirements in investigator expertise and radiation safety.

Per FDA regulations, the HSC must vote to fully approve the protocol as described in Section 22.1, Research with Human Subjects, before the RDRC can convene and vote on it. Often studies will be reviewed by both committees in parallel, however, to ensure that the final approved protocol will be acceptable to both groups without further revision.

Investigators using experimental radioactive drugs must file form FDA 2915 annually with the RDRC. Quarterly reporting is additionally required in the form of spreadsheets detailing the work performed during the previous quarter.

Call the LBNL Human and Animal Regulatory Committees Office at (510) 486-6005 for information on radioactive drug research.

22.2.6 Standards

10 CFR Part 745, The Common Rule for Human Subjects Research
21 CFR 361.1, Radioactive Drugs for Certain Research Uses
DOE Order 1300.3, Policy on the Protection of Human Subjects
DOE Order 4300.2C, Work for Others

22.2.7 References

The Radioactive Drug Research Committee: Human Research Without an Investigational New Drug Application, Guidance for Industry and Researchers, FDA
Research with Radioactive Drugs in Human Subjects, LBNL Policy in the RPM

22.3 Research with Animals

22.3.1 Policy

It is the policy of the Laboratory that all research involving animals performed at or funded through the Laboratory shall be conducted in accordance with the Public Health Service’s Policy on Humane Care and Use of Laboratory Animals (PHS Policy).

22.3.2 LBNL Support Organizations

Human and Animal Regulatory Committees Office
Animal Welfare and Research Committee

22.3.3 Implementation

It is the responsibility of the Laboratory to ensure that all animal work sponsored or conducted by Berkeley Lab be reviewed and approved in accordance with PHS Policy. Investigators are accountable for the protection of research animals in their care from the earliest stages of planning until a study is completed.

22.3.3.1 Responsibilities

The Laboratory is responsible for:

Complying with the Animal Welfare Act, PHS Policy, and other applicable federal and state statutes and regulations relating to the care and use of laboratory animals.
Ensuring that all research involving animals is conducted in accordance with the Guide for the Care and Use of Laboratory Animals (The Guide).
Maintaining full accreditation of the laboratory animal program from AAALAC International.
Maintaining an approved Animal Welfare Assurance (AWA) with the Office of Laboratory Animal Welfare (OLAW) of the NIH.
Maintaining registration as a research facility with the United States Department of Agriculture’s (USDA) Animal and Plant Health Inspection Services (APHIS).

Investigators are responsible for:

Following the procedures laid out in their approved animal use protocol, taking proper care of laboratory animals used in experiments, and maintaining full approval of their animal use protocols.
Ensuring that all staff, students, or visitors using animals under their aegis are following an approved protocol and are properly trained to perform the procedures involved.
Promoting good science through the responsible, judicious use of laboratory animals in research, teaching, or testing.

22.3.3.2 Animal Welfare and Research Committee

The Animal Welfare and Research Committee (AWRC) was formed at the Laboratory in 1975 in accordance with federal statutes and regulations. The AWRC is an Institutional Animal Care and Use Committee (IACUC) with OLAW Animal Welfare Assurance #A3054-01. The AWRC meets monthly, or more often, as required.

The AWRC is responsible for:

Ensuring that all animal research conducted at LBNL complies with the Assurance.
Reviewing all Laboratory projects involving animals at least annually.
Reviewing all aspects of the animal care program, and inspecting the animal colony and its satellite facilities at least once every 6 months, and submitting a report to the Institutional Official.
Reviewing concerns involving the care and use of animals at Berkeley Lab.

22.3.3.3 Protocol Requirements

All research projects involving live vertebrate animals or vertebrate animal tissues or products require prior review and formal approval by the AWRC.

Researchers are responsible for submitting a complete animal use protocol to AWRC for experiments using live vertebrate animals.

The AWRC is responsible for determining whether the activity is in compliance with the following requirements:

Procedures that involve live animals must avoid or minimize discomfort, distress, and pain to the animals, consistent with sound research design.
Any procedure that may cause more than momentary or slight pain or distress to the animals must be performed with appropriate sedation, analgesia, or anesthesia. These measures must not be omitted unless there is justification for scientific reasons. If so, investigators are responsible for putting the justification in writing for approval in the animal protocol.
Animals that would otherwise experience severe or chronic pain or distress that cannot be relieved must be painlessly euthanized at the end of the procedure or, if appropriate, during the procedure, unless adequately justified in the animal use protocol.
Investigators must explain the significance of the research and the need to use animals to achieve the stated research goals in terms understandable to a nonscientist. The proposed research must not duplicate existing data.
The number of animals proposed for use in an experiment must be justified on the basis of sound research design.
The living conditions of the animals must be appropriate for their species and contribute to their health and comfort. The housing, feeding, and care of the animals must be directed by a veterinarian. All conditions should conform to the specifications of The Guide.
Medical care for animals by a qualified veterinarian must be available on an as-needed basis.
Personnel conducting procedures on the animals must be appropriately qualified and trained in those procedures.
Knowledge of protocol procedures, Laboratory guidelines, and training must be documented for all study personnel listed on the protocol.
Investigators and their staff may be expected to demonstrate their skill or training in the presence of the Attending Veterinarian or their designee.
Methods of euthanasia used must be consistent with the American Veterinary Medical Association (AVMA) guidelines for the euthanasia of animals, unless a deviation is justified in writing as necessary to prevent an adverse impact on the research.

22.3.3.4 Special Use Protocols

There are three special use protocols that may be obtained to allow limited animal use:

Collaborative
Shipping
Facility use

Collaborative protocols enable an investigator to acquire and analyze the tissues or products of experimental animals held by another investigator either at the Laboratory or at another institution.

Shipping protocols allow a Laboratory investigator to send animals to another facility and to receive animals at the Laboratory from another facility.

Facility use protocols allow an investigator from another institution to use the specialized equipment available at the Laboratory.

Collaborative, shipping, and facility use protocols must be reviewed to ensure that the investigator from an outside institution is operating under a protocol approved by an IACUC with a current Assurance. In general, if an outside institution does not have a current Assurance, a full animal use protocol must be filed with the AWRC.

22.3.3.5 Approval Procedures

Requests for approval of projects involving animals must be submitted to the AWRC at least two weeks before the proposed use of the animals.

Many funding agencies require that certification of AWRC approval be submitted during the Just-In-Time phase prior to receiving an award. To avoid delays in a grant proposal’s funding, certification of animal use protocol approval should be obtained as early as is reasonable in the process of proposal submission and review.

Projects that involve animals must not be initiated until the appropriate animal use protocol has received AWRC approval.

Annual reviews by the AWRC are required for continuing projects. The researcher holding the protocol is responsible for submitting renewals in a timely fashion, and for ceasing animal use under protocols which have expired.

All requisite forms and implementing procedures can be found in the Berkeley Lab Guidelines for Vertebrate Animal Use and are available through the AWRC office.

22.3.3.6 Authority to Suspend or Terminate Approval of Research

Under the Assurance to the National Institutes of Health (NIH), the Laboratory, upon recommendation by the Committee, has the authority and responsibility to suspend or terminate research that is not being conducted in accordance with AWRC decisions, conditions, and requirements. In addition, United States Department of Agriculture regulations stipulate that research activities may be suspended if the standards for animal welfare, care and housing, or mitigation of pain and distress are not being met.

In case of suspension of research, research must not resume until the Committee has assurance that the appropriate corrective actions have been implemented.

The reporting requirements for issues and concerns that might involve suspension or termination of research are as follows.

The AWRC must report information concerning noncompliance by research investigators to the NIH OLAW.
If the AWRC suspends or terminates approval of research, the Committee must include a statement of the reason for the action and must report the action promptly to the research investigator, the researcher’s Division Director, to Berkeley Lab Sponsored Projects Office, and to OLAW.

Call the LBNL Human and Animal Regulatory Committees Office at (510) 486-6758 or (510) 486-5399 for information on animal use approval.

22.3.4 Standards

9 CFR, United States Department of Agriculture Animal Welfare Regulations
7 U.S.C1. 2131-2157, The Animal Welfare Act

22.3.5 References

PHS Policy on Humane Care and Use of Laboratory Animals
U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training
USDA APHIS’s Animal Welfare Act and Animal Welfare Regulations (The “Blue Book”)
Guide for the Care and Use of Laboratory Animals
AVMA Guidelines for the Euthanasia of Animals: 2020 Edition
Berkeley Lab Guidelines for Vertebrate Animal Use, https://commons.lbl.gov/display/harc/Animal+Use+Guidelines

22.4 Glossary

22.4.1 Research With Human Subjects

A human subject is a living person about whom an investigator conducting research: (1) obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (2) obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.

Informed consent is consent to participate in research based on a full and complete understanding of the research and any attendant risk.

An Institutional Review Board is a board or committee duly authorized by a federal assurance to review human subjects use.

Vulnerable subjects are subjects especially susceptible to coercion or undue influence (including, but not limited to, adults with diminished decision-making capacity, children, elderly, those with health conditions, non-English speakers, prisoners and parolees, ethnic or racial minorities, and the socioeconomically disadvantaged).

22.4.2 Research With Radioactive Drugs

An experimental radioactive drug is a radioactive drug used to obtain basic information regarding the metabolism of the drug or regarding human physiology, pathophysiology, or biochemistry, but not intended for immediate therapeutic, diagnostic, or similar purposes.

An investigational new drug is a drug product for human use covered by an investigational new drug permit from the Food and Drug Administration.

A radioactive drug is any radioactive compound or isotope which is intended for use in humans.

A Radioactive Drug Research Committee is a committee duly authorized by the Food and Drug Administration to review the use of experimental radioactive drugs.

22.4.3 Research With Animals

Animal use is the use of a live vertebrate animal or the product of a live vertebrate animal for research purposes.

An Institutional Animal Care and Use Committee is a committee duly authorized under federal regulations to review and approve animal use.

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The ES&H Manual is moving to the EHS Website!New address for this chapter: ehs.lbl.gov/pub3000/ch22

Chapter 22

RESEARCH WITH HUMAN AND ANIMAL SUBJECTS

Contents