Chapter 22

RESEARCH WITH
HUMAN AND
ANIMAL SUBJECTS

Contents

Approved by Christine Byrne
Revised 12/01


22.1 Research with Human Subjects
22.1.1 Policy
22.1.2 LBNL Support Organizations

22.1.3 Implementation

22.1.3.1 Human Subjects Committees
22.1.3.2 Human Subject Involvement

22.1.3.3 Review and Approval Procedures

22.1.3.4 Authority to Suspend or Terminate Approval of Research

22.1.4 Standards
22.1.5 References
22.2 Research with Radioactive Drugs

22.2.1 Policy
22.2.2 LBNL Support Organizations

22.2.3 Implementation

22.2.4 Radioactive Drug Research Committee

22.2.5 Review and Approval

22.2.6 Standards

22.2.7 References

22.3 Research with Animals

22.3.1 Policy
22.3.2 LBNL Support Organizations

22.3.3 Implementation

22.3.3.1 Responsibilities
22.3.3.2 Animal Welfare and Research Committee

22.3.3.3 Protocol Requirements

22.3.3.4 Special Use Protocols

22.3.3.5 Approval Procedures

22.3.3.6 Authority to Suspend or Terminate Approval of Research
22.3.4 Standards
22.3.5 References
22.4 Glossary

22.4.1 Research With Human Subjects
22.4.2 Research With Radioactive Drugs

22.4.3 Research With Animals

NOTE:
. . . . . Denotes a new section.
. . . . . . . . Denotes the beginning of changed text within a section.
. . . . . . . . Denotes the end of changed text within a section.

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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 by the Department of Health and Human Services (DHHS) 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 DHHS 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 DHHS regulations.

    22.1.3.1 Human Subjects Committees

    The Laboratory has a long-standing agreement with the UC Berkeley Committee for Protection of Human Subjects (CPHS) to review and certify Laboratory projects. CPHS is an Institutional Review Board with DHHS Multiple Project Assurance #M-1349.

    The Berkeley Lab Human Subjects Committee (HSC) is responsible for pre-reviewing and approving all Laboratory projects. Requests for approval go to the Berkeley Lab HSC and not to the CPHS on campus.

    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.
  • 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 declared exempt from further review. This does not mean that review of the project is not required. 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 subjects are at risk, whether the potential benefits of the research outweigh the risk, and whether adequate provision has been made to obtain informed consent. Risk is defined as exposure to the possibility of harm, whether physical, psychological, sociological, or other, to a participant in a research activity. Research is defined as a systematic investigation designed to contribute to scientific 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 CPHS approval has been received.

    Both the HSC and the CPHS meet monthly. The HSC meetings are scheduled for timely submission to the CPHS for its agenda deadline.

    Human subject protocols should be submitted to the HSC two weeks prior to its meeting date. Final CPHS review generally takes about seven weeks from the time of submission.

    Many funding agencies require that certification of human subjects approval be submitted with the grant proposal. The National Institutes of Health (NIH) allows a grace period of 60 days following the proposal submission date. 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 DHHS Assurance of Compliance for Protection of Human Subjects, the Laboratory, upon recommendation by the Committees, has the authority and the responsibility to suspend or terminate research that is not being conducted in accordance with CPHS decisions, conditions, and requirements or that has been associated with unexpected serious harm to subjects.

    In the case of suspension of research, research must not resume until the Committees have 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 CPHS must report information concerning noncompliance by Berkeley Lab research investigators, injuries to subjects, and unanticipated problems involving risk to the DHHS Office for Protection from Research Risks (OPRR). If the CPHS 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 OPRR. 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) 486-5507 for information on human subjects research.

    22.1.4 Standards

  • 10 CFR Part 745, The Common Rule for Human Subjects Research
  • DOE Order 1300.3, Policy on the Protection of Human Subjects
  • DOE Order 4300.2C, Work for Others
  • 22.1.5 References

  • Protecting Human Subjects at the Department of Energy, DOE Human Subjects Handbook
  • Guidelines of the Committee for Protection of Human Subjects, Berkeley Campus (CPHS), September 1996 (or most recent annual update)
  • 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 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 Food and Drug Administration regulations and policies. Investigators are responsible for obtaining the appropriate approval to use a radioactive drug in a human subject prior to requesting protocol approval from the HSC. (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 Food and Drug Administration 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 radiopharmaceuticals 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 Food and Drug Administration 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.

    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.

    Protocols approved by the RDRC are automatically forwarded for human subjects approval, as described in Section 22.1, Research with Human Subjects.

    Investigators using experimental radioactive drugs must additionally file form FDA 2914 quarterly with the RDRC.

    Call the LBNL Human and Animal Regulatory Committees Office at (510) 486-5507 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

  • Guidelines of the Committee for Protection of Human Subjects, Berkeley Campus (CPHS), September 1996 (or most recent annual update)
  • 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.

    22.3.2 LBNL Support Organizations

  • Human and Animal Regulatory Committees Office
  • Animal Welfare and Research Committee
  • 22.3.3 Implementation

    22.3.3.1 Responsibilities

    The Laboratory is responsible for:

  • Complying with the Animal Welfare Act and other federal statutes and regulations relating to animals.
  • Ensuring that all research involving animals is conducted in accordance with the Public Health Service’s Guide for Care and Use of Laboratory Animals.
  • Maintaining full accreditation of the Laboratory animal colony from the American Association for the Accreditation of Laboratory Animal Care (AAALAC).
  • Maintaining an approved Assurance of Compliance (Assurance) with Public Health Service Policy on Humane Care and Use of Laboratory Animals with the Office for Protection from Research Risks (OPRR) of the NIH.
  • 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.
  • Exercising extreme care in observing the letter and the spirit of the Assurance.
  • 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 with OPRR Multiple Project 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 twice a year.
  • 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, including a description of the sources used to determine that no alternatives to this procedure exist.
  • 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.
  • 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 or other scientist trained and experienced in the proper care, handling, and use of the species being maintained or studied. All conditions should conform to the specifications of the Guide for the Care and Use of Laboratory Animals.
  • Medical care for animals by a qualified veterinarian must be available on an as-needed basis.
  • Personnel conducting procedures on the animals must be qualified and trained in those procedures.
  • Knowledge of protocol procedures, Laboratory guidelines, and training must be documented on a Protocol Personnel Form.
  • Investigators and their staff may be expected to demonstrate their skill or training in the presence of an AWRC representative.
  • Methods of euthanasia used must be consistent with the recommendations of the Euthanasia Review Panel of the American Veterinary Medical Association (AVMA). These methods must not be omitted unless there is justification for scientific reasons. If so, investigators are responsible for putting the justification in writing.
  • 22.3.3.4 Special Use Protocols

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

  • Exempt
  • Collaborative
  • Shipping
  • Facility use
  • Exempt protocols allow the acquisition and analysis of tissues from public sources such as abattoirs.

    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.

    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 institutional animal care and use committee 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 four weeks before the proposed use of the animals.

    Many funding agencies require that certification of AWRC approval be submitted with the proposal. NIH allows a grace period of 60 days following the proposal submission date. To avoid delays in a grant proposal review and funding, certification of animal use protocol approval should be obtained by the time a proposal is submitted to the sponsoring agency.

    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 OPRR. 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 the OPRR.

    Call the LBNL Human and Animal Regulatory Committees Office at (510) 486-5507 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

  • Guide for the Care and Use of Laboratory Animals, U.S. Public Health Service
  • Berkeley Lab Guidelines for Vertebrate Animal Use
  • 22.4 Glossary

    22.4.1 Research With Human Subjects

    A human subject is a living person about whom a researcher obtains (1) data through intervention or interaction or (2) identifiable private information.

    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, the mentally or physically infirm, children, the illiterate, prisoners and parolees, addicts, and the poor).

    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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