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IRB-HSR > Protocol Review Process > Background

 

 

 

 

 

 

Protocol Review Process - Background

Introduction

The review of research at University of Virginia is conducted in accordance with:

  • the principles of the Belmont Report,
  • the federal regulations as published by Department of Health and Human Services (DHHS) and
  • the Food and Drug Administration (FDA).

In addition, the University of Virginia follows guidance issued by:

  • the Office of Human Research Protections (OHRP),
  • the National Institutes of Health (NIH),
  • and the FDA.

The IRB has sole authority at University of Virginia for the approval of research with human subjects.

In the case of a decision by the IRB to disapprove, suspend, or terminate a project, the AVRPGS or any other officer or agency of the University of Virginia , state government, or federal government may not reverse the decision.

IRB review applies to research conducted by faculty, students, staff, or agents of the University utilizing facilities or resources of UVA, as well as research conducted elsewhere by UVA personnel in connection with their institutional responsibilities.

The review requirements apply to all research conducted under the auspices of UVA, regardless of the funding source or University support or any research determined by the Institutional Official (IO).

The Institutional Review Board Review Process

The IRB is responsible for ensuring that all approved research complies with the letter and spirit of the human subject protections regulations, as well as the three principles previously defined in the Belmont Report:

  • respect for persons,
  • beneficence, and
  • justice.

The review will help ensure:

  • that investigators recruit subjects in an equitable, non-coercive manner,
  • that subjects are fully informed about the risks and benefits in participation, and
  • that subjects are not exposed to disproportionate risks.

The IRB has the authority to:

  • approve,
  • to require modifications in,
  • to defer actions when additional information is needed before approval can be given, and
  • to disapprove proposed human subjects research.

The IRB also has the authority to suspend or revoke its approval of on-going research.

In order to maintain a review process that is responsive to the concerns of all involved Federal regulations require that the IRB membership reflect:

  • experience,
  • expertise and diversity in academic, research and professional background,
  • racial and cultural heritage, and a
  • sensitivity to community attitudes.

When the IRB reviews research involving a vulnerable category of subjects, such as cognitively impaired individuals or prisoners, it is required to include one or more individuals qualified to represent that group, either through personal experience or experience working with that population.

Protocols are reviewed by IRB members whose knowledge best matches the expertise required for review of the protocol. If no IRB member has adequate knowledge or experience to review a given protocol, the IRB chair may elect to engage a consultant to conduct the review.

Failure to comply with IRB requirements is considered serious non-compliance (and may be misconduct) and may be subject to sanctions, including possible termination of all approved research.

Issues Considered by the Institutional Review Board

The Institutional Review Board will consider the following when reviewing requests to involve human subjects in research:

Study Design

The IRB will examine the study design insofar as it impacts the rights and welfare of the human subjects. The Office for Protection from Research Risks (now the Office for Human Research Protections) indicates in the Protecting Human Subjects: Institutional Review Board Guide Book that "...if a research study is so methodologically flawed that little or no reliable information will result, it is unethical to put subjects at risk or even inconvenience them through participation in such a study." Many experts agree that the IRB should approve only research that is both valid and of value. The IRB may request an expert consultant review or defer to scientific review committees, including the investigator's departmental review, in order to determine whether a study design places subjects at unnecessary risk. The federal regulations allow the IRB to approve a study design that involves deception or withholding of information, if the strategies are justified and the protocol provides for a post-study debriefing of the subjects.

Deception or Withholding Information

The basic principles that guide the ethical conduct of research, as previously outlined in Chapter 1, Introduction "The Foundations of 45 CFR 46: The Belmont Report" are (1) respect for subjects, (2) beneficence; and (3) justice. The requirements for complete informed consent strongly favor comprehensive, honest, and understandable disclosure of all elements of the subject's participation in research. There are times, however, especially in behavioral research, when investigators plan to withhold information about the real purpose of the study or purposely give subjects false information about some aspect of the research. As a result, the subject cannot give prospective fully informed consent. The use of deception or incomplete disclosure imposes special responsibilities on the investigator and the IRB. Occasionally, a study will involve degrees of deception. Minor deception, such as withholding specific points of interest in an attempt to prevent a bias in the results, can be acceptable, provided the subject is fully debriefed after participation. Risks stemming from major deception, such as leading the subject to believe that she/he has committed a crime or has a disease, must be clearly counterbalanced by the benefits of the research.

The Federal regulations do not allow the IRB to waive some or all of the elements of informed consent, including a fair and comprehensive description of all elements of the research, if the study involves more than minimal risk. In addition, the waiver of the elements of consent must not adversely affect the rights and welfare of subjects, and must be essential to the ability to carry out the research.

Incomplete disclosure or the use of deception cannot be used as a means to secure the participation of subjects in research. The IRB may not approve research that entails more than minimal risk and withholds information that is material to the subject's decision to participate in the study. The IRB is required to consider whether the withheld information would influence the decision of potential subjects to participate in the research. The IRB cannot approve a study that presents more than minimal risk where subjects are deceived or not given complete information that they would consider material to the decision to participate.

Use of Deception

The employment of deception by an investigator(s) for the purpose of securing subject participation and/or to prevent potentially biased reporting of data/information by the subject is permissible provided all of the following conditions exist:

  • Deception is necessary due to the lack of alternative procedures for data collection not involving deception;
  • The deceptive procedures will not place subjects at significant financial, physical, legal, psychological, or social risk;
  • The data collection/experiment will be followed by careful debriefing sessions whereby the subjects are fully informed of the nature and purpose of the deception; and
  • The procedures for deception must meet the guidelines established by the discipline of the investigator through its professional code of ethics.
Debriefing

In order for the IRB to adequately review the research, investigators should justify, in detail, in the protocol, the reasons for deceiving or withholding information from subjects, including an explanation of:

  • the necessity for deceiving subjects;
  • how potential benefits of the research justify the use of deception; and
  • how the investigators will conduct the debriefing.

In addition, investigators should include a debriefing script or statement that indicates the information subjects will receive regarding their participation in the research.

The IRB in collaboration with the investigator will determine whether subjects should be debriefed either after unwittingly participating in the research or after knowingly participating in research that involved deception.

The IRB may require debriefing when it contributes to the subject's welfare, i.e.,

  • when it corrects painful or stressful misperceptions, or
  • when it reduces pain, stress, or
  • anxiety concerning the subject's performance.

For example, if a subject is lead to believe through participation in deception research that she/he has committed a crime or has a disease, a debriefing session may correct the induced stress, pain, and/or anxiety.

Risks and Benefits

There are a number of steps discussed by the Federal regulations that the IRB must follow when assessing risks and benefits. The IRB is required to:

  • identify the risks associated with the research, as distinguished from the risks of therapies the subjects would receive even if not participating in the research;
  • determine that the risks will be minimized to the fullest extent possible;
  • identify the probable benefits to be derived from the research;
  • determine that the risks are reasonable in relation to the benefits to subjects, if any, and the importance of the knowledge to be gained;
  • assure that potential subjects will be provided with an accurate and fair description of the risks or discomforts and the anticipated benefits;
  • determine intervals for periodic review (no greater than annually), and, where appropriate, determine that adequate provisions are in place for monitoring the data collected and, if the subjects are likely to be members of vulnerable populations, determine that appropriate additional safeguards are in place to protect the rights and welfare of these subjects.

Because the IRB follows the above listed procedures, investigators should address these considerations in their protocol and consent form.

Considering Risk

Assessing risk is an important component of the review process. As stated earlier, one aspect is to ensure that risks have been minimized, risks are appropriate given the expected benefits, and benefits are maximized.

Each protocol submitted must information detailing how confidentiality is protected and, to the extent possible, risks are reduced to a minimum. This does not need to be complicated but should be appropriate for the risks associated with the study.

Considering Risk: Minimal Risk

An especially prominent concept is that of minimal risk. According to the federal regulations, a risk is minimal where the probability and magnitude of harm or discomfort anticipated in the proposed research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the performance of routine physical or psychology examinations or tests.

Considering Risk: Physical Risks

Some research presents risk of physical injury to subjects. Although most of these risks are transient, some adverse effects of study participation (especially those that result from medical procedures, drug research or device research) may result in permanent injury to subjects. For all research with the potential to do physical harm investigators are encouraged to think through all risk possibilities, however rare they may seem, so that they can be resolved quickly and effectively to minimize harm to subjects. By clearly detailing procedures to address situations of physical harm, the IRB can be assured that the investigator has made efforts to minimize physical risks to the greatest extent possible.

Considering Risk: Psychological Risks

Some research has the potential to cause undesired changes in thought processes and emotion including episodes of depression, confusion, and hallucination resulting from drugs, feelings of stress, guilt, and loss of self-esteem. As is the case with physical risks, these effects are usually transient. For all research with the potential to cause psychological harm investigators are encouraged to think through all risk possibilities, however rare, so that a course of action can be planned to quickly and effectively minimize the distress to subjects. By clearly detailing procedures to address situations of psychological harm, the IRB can be assured that the investigator has made efforts to minimize psychological risks to the greatest extent possible.

Considering Risk: Social, Legal and Economic Risks

Some research proposals involve the handling of sensitive information that may result in injury to subjects through a breach of confidentiality. These breaches may result in embarrassment within a subject's business or social group, loss of employment, or criminal prosecution. The IRB is especially concerned about information regarding drug and alcohol use, mental illness, sexual behavior, and illegal activities. For these situations, investigators should clearly detail strong precautions to ensure that the research does not cause social, legal or economic risks to the subjects.

Research may also pose direct economic risk to study subjects. Procedures billed to insurance companies may require a significant co-payment on behalf of subjects, insurance companies may refuse to pay for "investigational" therapies, subjects may be responsible for transportation costs, and subjects may lose wages during research participation. Investigators should attempt to minimize economic costs to subjects. If the research may involve additional actual costs to individuals, the anticipated costs should be described to subjects during the consent process.

Considering Risk: Drugs

The IRB is frequently called upon to consider protocols involving drugs that are in development and have yet to receive approval from the FDA, as well as those that have already been approved for specific indications by the FDA. Any research with a drug, whether approved or not, requires IRB approval. Drugs or drug combinations, that have not been approved, will require a specific IND number from the FDA. The IND number must be submitted to the IRB prior to the protocol being opened to enrollment.

Approved drugs being tested for unapproved indications may also require an IND or a specific waiver from the FDA of the requirement for an IND. An IND is required if the investigation involves a route of administration, a dosage level or use in a vulnerable subject population (e.g., children, prisoners, pregnant women and fetuses, etc.), or other factors that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug.

In considering drug studies, it should be indicated that drug studies have traditionally been divided into Phase I, II, III and IV. Knowing the phase of the trial helps the reviewer determine the adequacy of the consent form and the appropriateness of the protocol.

In addition to drug studies utilized for the development of new therapies, many volunteer studies may include drugs that are either waiting for approval or have been approved. The same rule concerning advertisements applies to these except an extra level of scrutiny should be applied to be certain that volunteers are drawn from an appropriate population.

An additional factor the reviewer must weigh is the role of placebo. The current custom at the University of Virginia IRB is to allow placebo studies, but to be certain that appropriate rescue procedures are in place if subjects are endangered. Specific psychiatric protocols may also require subject hospitalization and supervision by a separate team of physicians responsible for the clinical care rather the study investigator if withdrawal from normal drugs is deemed to be a potential risk to the subject or to society.

Considering Risk: Devices

Unless specifically exempt from FDA device regulations (e.g. an IDE application is not required (21CFR312) or the device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/ approved labeling), all devices are categorized as either significant risk (SR) or non-significant risk (NSR). While SR studies must be submitted to the FDA for an Investigational Device Exemption (IDE) and to the IRB, NSR studies are conducted following the FDA's "abbreviated requirements," and do not require an IDE. As a result, a critical part of the review process for IRB submissions involving devices is the determination if a device is considered significant risk or non-significant risk. When a research project involving a device is presented to the IRB as a NSR device, reviewers should consider if the device or the failure of the device poses a significant risk to the subject. Although the sponsor makes the initial determination regarding NSR versus SR, the IRB may differ in its assessment. The FDA has the authority to rule that a device is a SR device based on one IRB's view, and the sponsor is then obligated to inform all the institutions using the device that a judgment about the device being a NSR was in error. Because all SR devices are required to secure an IDE number, a protocol cannot be opened to enrollment if this is missing. If the IRB determines that a device proposed as NSR is more appropriately considered SR, the PI will notify the sponsor, who has the responsibility to contact the FDA to obtain an IDE.

For detailed information regarding the definition and differing requirements for SR and NSR devices, as well as a partial list of devices considered by the FDA as SR and NSR, please see the FDA Information Sheets on Medical Devices, that is available on the IRB Website.

In considering if a device is SR or NSR, a reviewer should

  • Consult the FDA list of SR and NSR devices,
  • Consider the proposed use of a given device in a study and risks that may be associated with it, and consider the innate risks and benefits, and how they compare to those of alternate devices or procedures. A reviewer should present his/her rationale to the IRB so that the minutes can document the decision.
Benefits

The benefits of research fall into two categories: benefits to individuals and benefits to society. Research frequently provides subjects with treatment, diagnosis or examination for an illness or abnormal condition. In these cases, the research involves evaluations that may benefit the subjects by ameliorating their condition or by providing a better understanding of their disorder. Investigators should clearly detail those potential benefits for the IRB in the protocol, and subjects in the consent form, while not over stating these benefits. The investigator should attempt to maximize benefits to the greatest extent possible for potential subjects.

Where research does not provide direct benefit to potential subjects, this should be clearly stated in the protocol and in the informed consent form.

Although research may not always provide a benefit to society, researchers are encouraged to design research projects so that information, in the form of generalizable knowledge, can contribute to societal benefit whenever possible. Investigators should clearly detail these potential benefits for the IRB in the protocol, and for subjects in the informed consent form, while not overstating these benefits. Research that does not provide benefit to individuals is required to provide a reasonable likelihood of resulting in benefits for society.

Equitable Selection of Subjects

The selection of subjects should be equitable and free of any coercion, both explicit and implied. The IRB will consider the purpose of the research and the setting of the research. The IRB will closely examine research involving vulnerable subject populations, such as children, prisoners, subjects with cognitive disorders, or economically or educationally disadvantaged subjects. Investigators should detail any extra precautions taken to safeguard the rights and welfare of subject populations.

Women and members of minority groups and their subpopulations must be included in all clinical research, unless a clear and compelling rationale and justification establishes to the satisfaction of the IRB that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances may be made based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research.

The inclusion of women and members of minority groups and their subpopulations must be addressed in developing a research design or contract proposal appropriate to the scientific objectives of the study/contract. The research plan/proposal should describe the composition of the proposed study population in terms of sex/gender and racial/ethnic group, and provide a rationale for selection of such subjects. Such a plan/proposal should contain a description of the proposed outreach programs for recruiting women and minorities as participants.

Identification of Subjects and Confidentiality

The IRB is required to review the method for prospective identification and recruitment of subjects. They will examine the means of identifying and contacting potential subjects and the methods for ensuring the subjects' privacy and confidentiality. Investigators are required to submit plans for ensuring the privacy and confidentiality of subjects.

The Informed Consent Process

The IRB will carefully review the informed consent process; when, where and how consent is obtained, and any provisions for the on-going consent of subjects. Generally, the IRB will not dictate the procedure to be used to obtain informed consent, but reserves the right to do so if deemed necessary.

Qualifications

Procedures requiring special skills on the part of the investigators, licensure, accreditation, and/or experience in qualifying the investigator for the performance of the proposed procedures are reviewed by the IRB. In addition, the IRB will consider the facilities and equipment used to conduct the research and maintain the rights and welfare of subjects.

Additional Review

The IRB will determine whether a project requires more than annual review and may require an appropriate monitoring procedure that could include monitoring of the consent process, observation of the research procedures and review of research related records. In some instances, the IRB may refer review of the research to an additional committee. However, final authority for additional review lies with the IRB.

Conflict of Interest

A conflict of interest refers to a divergence between an individual's personal financial, relational, or other interests and his/her professional obligations to the University of Virginia whether through teaching, involvement in research, contracting, purchasing, or performing other administrative duties such that an independent observer might reasonably determine that the individual's professional actions or decisions are adversely affected, distorted or otherwise compromised by the individual's personal interest. The term conflict of interest is broader and encompasses more professional activities than the term financial conflict of interest in research, defined below.

Financial Conflict of Interest in Research

Financial conflict of interest in research is the existence of a significant financial interest that an independent observer might reasonably determine could affect or compromise, or appears to affect or compromise, the design, conduct, reporting or management of research. The effect or compromise contemplated might relate to the collection, analysis, and interpretation of data, the hiring of staff, the procurement of materials, the sharing of results, the choice of protocol, the involvement or consenting of human participants, and/or the use of statistical methods.

Surveys, Questionnaires, Interview Materials, or other Testing Instruments

These materials may be in written or electronic format. If electronic, investigators should provide a hardcopy of the material. These materials should be reviewed to ensure that they adequately reflect the purpose and procedures in the study and handle sensitive issues appropriately. If the materials ask for information that, according to local law, would require reporting (e.g., elder or child abuse), the consent form should explain this exception to the promise of subject confidentiality. There are, however, a variety of psychological and other measures which are considered "standard" and, while they cannot be modified, reviewers should still indicate if use of a given measure is appropriate for a particular study. In particular, reviewers should consider if survey answers, if known, would impact a subject's reputation, insurability, etc.

The No Child Left Behind Act of 2001(Public Law 107-110) identified 8 categories of protected information for survey responses:

  • political affiliations of student or student's parent;
  • mental or psychological problems of student or student's family;
  • sex behavior or attitudes;
  • illegal, anti-social, self-incriminating or demeaning behavior;
  • critical appraisals of others with whom students have close family relationships;
  • legally recognized privileged or analogous relationships;
  • religious practices, affiliations or beliefs of student or student's parent; and
  • income.

Research involving any of the eight identified categories requires written parental informed consent prior to participation of a child, even if the research meets the exempt criteria.

Recruitment Tools

Recruitment tools (advertisements, etc.) are not approved or valid without an IRB approval stamp containing the approval and expiration dates. Only IRB approved advertisements may be used in the conduct of subject recruitment. Recruitment materials should be included with your initial and continuing review applications. If the material is not ready at the time of the initial application, investigators may submit the material as an amendment to an already approved project. Requests for approval of recruitment materials following initial IRB review of the protocol should allow sufficient time for any necessary revisions prior to publication. Advertisements, press releases, etc., may qualify for expedited review.

All recruitment materials are required to have IRB review and approval prior to implementation. The tools may not be used to recruit subjects until the investigator receives final IRB approval. Prior to use, each recruitment tool should have an approval and expiration date on the tool. Audio and video tools may be exempt from this requirement. When recruiting subjects from another institution with an IRB, investigators are required to gain IRB approval from that institution. In institutions without an IRB, investigators are required to obtain a letter of agreement on the facility's letterhead indicating the research can be conducted at the site and the agency or institution will review, abide by and comply with the procedures approved by the UVA IRB.

A recruitment tool informs potential subjects of a research activity and provides them with an opportunity to contact the researcher. A recruitment tool may include, but is not limited to, post-cards, flyers, advertisements, press releases, brochures, and postings on the Internet. Investigators are required to use the following guidelines when developing recruitment tools:

  • name and address of the clinical investigator and/or research facility (letterhead is acceptable)
  • the condition under study and/or the purpose of the research
  • in summary form, the criteria that will be used to determine eligibility for the study
  • a brief list of the benefits of study participation, (if any) i.e. a free health examination
  • time or other commitments required
  • the location of the research and the person or office to contact for further information
  • in drug or device studies, no clam should be made as to the superiority , safety or effectiveness of the drug or device. Proprietary names of study products may not be used.
  • do not provide excessive monetary or other incentives that could be interpreted as inappropriate or coercive.
  • are consistent with the protocol.

Due to contractual obligations, recruitment tools should not include any proprietary identifiers, contain therapeutic or outcome claims or mention the corporate sponsor by name.

See also additional information on recruiting and the advertising process.

*Taken from UVa IRB-HSR Research Guidance