Marshall University

Huntington, WV

SUBJECT: Types of Research and Types of Reviews Conducted by the Institutional Review Board (IRB)

PURPOSE: To define the different types of research and to explain the various types of research activities conducted at this facility and the three types of reviews the IRB may conduct in considering the research activities.

POLICY: To ensure that the appropriate type of IRB review is conducted within the constraints of the federal regulations and the facility’s policies and procedures.

SCOPE: This policy covers all research protocols conducted within the auspices of this IRB.

RESPONSIBILITIES:

The IRB Chairperson is responsible for ensuring that the appropriate type of review is conducted within all federal regulations and facility’s policies and procedures.

The IRB Members are responsible for ensuring the reviews are conducted appropriately, ethically, and within the constraints of the federal regulations and station policies.

The Principal Investigator (PI) is responsible for ensuring that every research subject’s rights, welfare and safety are protected. He is responsible for the protocol design, which must minimize risks to subjects while maximizing benefits. The PI must ensure that all members of the research team always comply with the findings, determinations, and requirements of the IRB. He must also ensure the adequacy of both the informed consent process, regardless of which members of the research team are authorized to actually obtain and document consent.

The IRB Coordinator is responsible for maintaining documentation of the activities of the IRB and reporting the information at the next IRB meeting.

Definitions:

a. Human Subject Research - Under this organization's policy Human Subject Research is defined as

1. Any activity that meets the DHHS definition of "research" and involves "human subjects" as defined by the DHHS regulations; OR

2. any activity that meets the FDA definition of "research" and involves "human subjects" as defined by the FDA regulations.

b. Research - the Department of Health and Human Services (HHS) and the FDA both have definitions of human subject research:

(HHS) a systematic investigation, including research development, testing, and evaluation, designed to develop or contribute to generalized knowledge.
(FDA) any experiment that involves a test article and one or more human subjects, and that either must meet the requirements for prior submission to the Food and Drug Administration or whose data will be submitted to or held for inspection by FDA. There are two types of activities that must meet the requirements for prior submission to the Food and Drug Administration. These are:

1. Any use of a drug, other than the use of a marketed drug in the course of medical practice.

2. Any activity that evaluates the safety or effectiveness of the medical device.

c. Human subject - the Department of Health and Human Services (HHS) and the FDA both have definitions of a human subject:

(HHS) a living individual about whom an investigator (whether professional or student) conducting research obtains: (1) data through intervention or interaction with the individual, or (2) identifiable private information.
(FDA) human subject means an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. A subject may be either a healthy individual or a patient. In the case of research involving medical devices, a human subject includes an individual on whose specimen a medical device is used.

d. Private information - includes information that an individual can reasonably expect will not be made public, and information about behavior that an individual can reasonably expect will not be observed or recorded. Private information must be individually identifiable.

e. Identifiable - means that the identity of the individual is or may readily be ascertained by the investigator or associated with the information.

f. Adverse Event (AE) - is any reaction or undesirable event that occurs in conjunction with the use of a drug, biologic product, diagnostic agent, medical device, experimental procedure, or even accepted medical treatment (if part of a research protocol), whether or not the event is considered related to the drug treatment or procedures. Such events may be psychological, emotional, social or physical and include any illness, sign, symptom, or clinically significant laboratory test abnormality that has appeared or worsened during the course of the experimental study regardless of causal relationship to the drugs and procedures under study. For observational studies (e.g. chart reviews, data base studies, surveys), deaths, life-threatening events or hospitalizations need not be reported as AEs. Any AE directly or indirectly related to the study, such as loss of confidentiality or emotional trauma are still reportable. In addition, reports of subjects having complaints about the experimental procedures or about the conduct of the investigators may be reported as AEs.

g. Case Studies/Presentations - Case studies/presentations which are published and/or presented at national or regional meetings are often not considered human subject research if the case is limited to a description of the clinical features and/or outcome of a single patient and do not contribute to generalizable knowledge (Note: a comparison of case studies would qualify as human subject research). In this situation, no IRB notification or classification should be required since it is not human research for IRB purposes. Of course, if an investigator is unsure whether an activity is human research or not, he/she should contact the Office of Research Integrity (304) 696-7320 for a judgment on that point.

I. TYPES OF RESEARCH

The following are examples of various types of research; however, not all of these types of research are conducted at this facility.

(1) Clinical Research involves research (a) to increase scientific understanding about normal or abnormal physiology, disease states, or development and (b) to evaluate the safety, effectiveness or usefulness of a medical product, procedure, or intervention. Vaccine trials, medical device research, and cancer research are, for example all types of clinical research.

(2) Behavioral and Social Sciences Research involving human subjects focuses on individual and group behavior, mental processes, or social constructs and usually generates data by means of surveys, interviews, observations, studies of existing records, and experimental designs involving exposure to some type of stimulus or environmental intervention.

(3) Epidemiological Research targets specific health outcomes, interventions, or disease states and attempts to reach conclusions about cost-effectiveness, efficacy, efficiency, interventions, or delivery of services to affected populations. Some epidemiological research is conducted through surveillance, monitoring, and reporting programs; whereas, other epidemiological research may employ retrospective review of medical, public health, or other records.

(4) Repository Research, Tissue Banking, and Databases. Research utilizing stored data or materials (i.e., cells, tissues, fluids, and body parts) from individually identifiable living persons qualifies as human subject research, and requires IRB review.

(5) Quality Assurance/Quality Improvement Activities. Quality assurance activities attempt to measure the effectiveness of programs or services. Such activities may constitute human subject research, and require IRB review, if they are designed or intended to develop or contribute to generalizable knowledge and involve human subjects. Quality assurance activities that are designed solely for internal program evaluation purposes, with no external application or generalization, will probably not require IRB review. Individuals who incorrectly determine or assume that an activity is not human subject research will be considered noncompliant with the federal regulations. Where there is any doubt about whether an activity is human subject research the activity should be submitted to the IRB for a determination. Only the IRB can make an authoritative determination about whether an activity is human subject research.

(6) Pilot Studies involving human subjects require IRB review.

(7) Human Genetic Research. Genetic studies include but are not limited to: (a) pedigree studies (to discover the pattern of inheritance of a disease and to catalogue the range of symptoms involved); (b) positional cloning studies (to localize and identify specific genes); (c) DNA diagnostic studies (to develop techniques for determining the presence of specific DNA mutations); (d) gene transfer research (to develop treatments for genetic disease at the DNA level); (e) longitudinal studies to associate genetic conditions with health, health care, or social outcomes; and (f) gene frequency studies. The primary risks involved in the first three types of genetic research are risks of social and psychological harm, rather than risks of physical injury. Genetic studies that generate information about subjects' personal health risks can provoke anxiety and confusion, damage familial relationships, and compromise the subjects' insurability and employment opportunities. For many genetic research protocols, these psychosocial risks can be significant enough to warrant careful IRB review and discussion. Those genetic studies limited to the collection of family history information and blood drawing are not automatically classified as "minimal risk" studies qualifying for expedited IRB review. Confidentiality is a major concern in determining if minimal risk is involved. The IRB must consider if informed consent from third parties can be waived and if so, document that reasoning in the IRB minutes. In most cases waiver of consent may be appropriate.

(8) Studies of Investigational Drugs or Biologics. The FDA requires various stages of human subject research to ensure that drugs and biologics are both safe and effective for the proposed use. This safety and efficacy data may eventually be used in marketing materials or on the drug’s label or patient insert.

Phase One Drug Trials. Phase 1 drug trials include the initial introduction of an investigational new drug into humans. These studies are typically closely monitored and conducted with healthy volunteers; sometimes, where the drug is intended for use in patients with a particular disease, however, such patients may participate as subjects. Phase 1 trials are designed to determine the metabolic and pharmacological actions of the drug in humans, the side effects associated with increasing doses (to establish a safe dose range), and, if possible, to gain early evidence of effectiveness; they are typically closely monitored. The ultimate goal of Phase 1 trials is to obtain sufficient information about the drug’s pharmacokinetics and pharmacological effects to permit the design of well-controlled sufficiently valid Phase 2 studies. Other examples of Phase 1 studies include studies of drug metabolism, structure activity relationships, and mechanisms of actions in humans, as well as studies in which investigational drugs are used as research tools to explore biological phenomena or disease processes. The total number of subjects involved in Phase 1 investigations is generally in the range of 20-80.

Phase Two Drug Trials. Phase 2 trials include controlled clinical studies conducted to evaluate the drug’s effectiveness for a particular indication in patients with the disease or condition under study, and to determine the common short-term side effects and risks associated with the drug. These studies are typically well controlled, closely monitored, and conducted with relatively larger numbers of subjects (100-300).

Phase Three Drug Trials. Phase 3 drug trials involve the administration of a new drug to a larger number of patients in different clinical settings to determine its safety, effectiveness, and appropriate dosage. They are performed after preliminary evidence of effectiveness has been obtained, and are intended to gather necessary additional information about effectiveness and safety for evaluating the overall benefit-risk relationship of the drug, and to provide an adequate basis for physician labeling. In Phase 3 studies, the drug is used in the way it would be administered when marketed. When these studies are completed and the sponsor believes that the drug is safe and effective under specific conditions, the sponsor applies to the FDA for approval to market the drug. Phase 3 trials usually involve several hundred to several thousand patient-subjects. These studies are conducted with large groups of subjects (1,000-3,000).

Phase Four Drug Trials. Concurrent with marketing approval, the FDA may seek agreement from the sponsor to conduct certain post-marketing (Phase 4) studies to delineate additional information about the drug’s risks, benefits, and optimal use. These studies could include, but would not be limited to, studying different doses or schedules of administration than were used in Phase 2 studies, use of the drug in other patient populations or other stages of the disease, or use of the drug over a longer period of time.

PROCEDURE:

All human subject research conducted at Marshall University or by Marshall University employees or agents or otherwise under the auspices of Marshall University must be prospectively reviewed. The IRB Chairman (or a designee who is an IRB member) will determine if studies qualify for an exempted or expedited review. The chairperson retains the right to require a convened review for exempted or expedited studies when warranted by the nature of the research. Regardless of the type of review the investigator is notified in writing of the IRB’s determinations.

Epidemiological Research - epidemiological research that involves aggregate examination of data without individually identifiable information is generally not human subjects research. If the PI is in doubt as to whether or not their study is human subjects research he/she should submit an abstract to the IRB#1 Chair for a determination.

Repository Research, Tissue Banking, and Databases. In the event, when data or materials are stored in a bank or repository for use in future research projects, the IRB will review the protocol detailing any repository policies and procedures for obtaining, storing, and sharing its resources, for verifying informed consent provisions, and for protecting subjects’ privacy and maintaining the confidentiality of data. The IRB will establish standard operating procedures and then determine the parameters under which the repository may share its data or materials with or without IRB review of individual research protocols.

II. TYPES OF REVIEWS

The IRB conducts three types of reviews: (1) Exempt, (2) Convened, or (3) Expedited.

EXEMPT REVIEW

The Exempt determination will be made by the IRB Chair or his/her designee. To obtain exempt status the research activity must meet one of the below listed categories.

(1) Research conducted in established or commonly accepted educational settings, involving normal educational practices, such as:

(a) research on regular and special education instructional strategies, or

(b) research on the effectiveness of or the comparison among instructional techniques, curricula, or classroom management methods.

(The research cannot involve prisoners as participants. The research cannot be FDA-regulated)

(2) Research involving the use of educational tests (e.g., cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures or observation of public behavior, unless:

(a) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifiers linked to the subjects; and

(b) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability, or be damaging to the subjects' financial standing, employability, or reputation.

If the research is VA-regulated,

- If any disclosure of the human participants' responses outside the research could reasonably place the participants at risk of loss of

insurability, information obtained is recorded in such a manner that human participants can be identified, directly or through

identifiers linked to the participants

(If the research involves children as participants, it cannot involve survey or interview procedures. If the research involves children as participants and observation of public behavior, the investigators may not participate in the activities being observed. The research cannot involve prisoners as participants. The research cannot be FDA-regulated.)

(3) Research involving the use of educational tests (e.g., cognitive, diagnostic, aptitude, achievement), survey procedures, interview procedures, or observation of public behavior that is not exempt under paragraph (2)(b) above if:

(a) The human subjects are elected or appointed public officials or candidates for public office; or

(b) federal statute(s) require(s) without exception that the confidentiality of the personally identifiable information will be maintained throughout the research and thereafter.

(The research cannot involve prisoners as participants. The research cannot be FDA-regulated)

(4) Research, involving the collection or study of existing data, documents, records, pathological specimens, or diagnostic specimens, if these sources are publicly available or if the information is recorded by the investigator in such a manner that subjects cannot be identified, directly or through identifiers linked to the subjects.

(The data being gathered must exist at the time the research is proposed. The research cannot involve prisoners as participants. The research cannot be FDA-regulated)

(5) Research and demonstration projects which are conducted by or subject to the approval of department or agency heads, and which are designed to study, evaluate, or otherwise examine:

(a) public benefit or service programs;

(b) procedures for obtaining benefits or services under those programs;

(d) possible changes in methods or levels of payment for benefits or services under those programs.

(The research must be conducted pursuant to specific federal statutory authority. The research must have no statutory requirements for IRB review. The research must not involve significant physical invasions or intrusions upon the privacy interests of participant. The research must have authorization or concurrence by the funding agency. The research cannot involve prisoners as participants. The research cannot be FDA-regulated)

(6) Taste and food quality evaluation and consumer acceptance studies,

(a) if wholesome foods without additives are consumed; or

(b) if a food is consumed that contains a food ingredient at or below the level and for a use found to be safe, or agricultural chemical or environmental contaminant at or below the level found to be safe by the Food and Drug Administration (FDA) or approved by the Environmental Protection Agency (EPA) or the Food Safety and Inspection Service of the U.S. Department of Agriculture. This also applies to FDA regulated research.

(The research cannot involve prisoners as participants.)

CONVENED REVIEW

A convened review is utilized for research activities/protocols when they do not meet the criteria for either exempt or expedited review. The IRB conducts initial and continuing reviews of all non-exempt research at convened meetings at which a majority of the members are present, unless the research falls into one or more of the categories appropriate for expedited review. A majority of the IRB members, including at least one member whose primary concerns are in non-scientific areas must be present to conduct a convened meeting. For research to be approved, it must receive the approval of a majority of those members present at the meeting where a quorum is present. A quorum is met when a majority of the voting members are in attendance.

For VAMC research, the IRB is required to determine whether the medical record has to be flagged to protect the participant's safety by indicating participation in the study and the source of more information on the study. The IRB may not want to require the medical record to be flagged when:

Participation in the study involves only only one encounter.
Participation in the study involves the use of a questionnaire.
Previously collected biological specimens, or if the identification as a participant in a particular study (if the study was not greater than minimal risk) will place the participant at greater than minimal risk.

Additional considerations for continuing review in multi-center trials monitored by DSMB, sponsors, or other similar monitoring boards.

The IRB may rely on a current statement from a Data Safety Monitoring Board (DSMB) or sponsor indicating that it has reviewed study-wide adverse events, interim findings, and any recent literature that may be relevant to the research, in lieu of requiring that this information be submitted directly to the IRB. The IRB will receive and review reports of local, on-site adverse events and unanticipated problems involving risks to subjects or others and any other information needed to ensure that its continuing review is substantive and meaningful.

INITIAL AND CONTINUING EXPEDITED REVIEW

The IRB may use the expedited review procedure to review either or both of the following:

(1) Some or all of the research appearing on the list titled "Categories of Research That May be Reviewed by The Institutional Review Board (IRB) Through and Expedited Review Procedure" and found by the reviewer(s) to involve no more than minimal risk,

(2) Minor changes in previously approved research during the period (of 1 year or less) for which approval is authorized.

Minimal risk means that the probability and magnitude of harm or discomfort in the research are not greater in and of themselves than those encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Research that is no greater than minimal risk may be eligible for expedited review, waiver or alteration of informed consent requirements, or waiver of the requirement to obtain written documentation of consent. Waiver of informed consent is not generally appropriate for FDA regulated test articles.

Minor change is one that makes no substantial alteration in

(1) the level of risks to subjects;

(2) the research design or methodology;

(3) the number of subjects enrolled in the research;

(4) the qualifications of the research team;

(5) the facilities available to support safe conduct of the research; or

(6) the addition of procedures not included in categories (1)-(7) of research that can be reviewed using an expedited procedure;

(7) any other factor, which would warrant review of the proposed changes by the convened IRB.

NOTE: Research that requires any invasive procedure, except venipuncture, is regarded as involving more than minimal risk and hence is not appropriate for expedited review.

PROCEDURE:

Under an expedited review procedure, the IRB Chairperson or his designee may carry out the review. The IRB Chairperson can utilize the CV's or resumes of the IRB members to help in the determination of whether an IRB member is experienced. The designated reviewer must have experience in, knowledge of, or may hold a particular board certification in a related field. In reviewing the research, the reviewers may exercise all of the authorities of the IRB except that the reviewers may not disapprove the research. A research activity may be disapproved only after review by a convened board.

In reviewing protocols for expedited review, the chairperson or his designee must remain cognizant of protocols where there is a greater than minimal risk that may result in an invasion of privacy or breach of confidentiality. Protocols are not approved through expedited procedures where the identification of the subjects would reasonably place them at risk of criminal/civil liability or damage the subjects financially, damage their employability, insurability, reputation, or be stigmatizing. Any research activity requiring a survey that is likely to cause stress in the subject, or places respondents at more than minimal risk, may require a convened review. The chairperson retains the right to require a convened review when warranted by the nature of the research.

Investigators must report to the IRB any proposed changes in the IRB-approved research, including proposed changes in informed consent documents. No changes may be initiated without prior approval of the IRB, except where necessary to eliminate apparent immediate hazards to subjects. The FDA can restrict, suspend, or terminate the IRB's use of the expedited review procedure when necessary to protect the rights or welfare of subjects.

The investigator must complete the IRB Protocol Application Packet, which includes a checkbox to request expedited status. The IRB Chairman or his designee reviews the protocol to ascertain if the protocol meets the definition of expedited status. The Chairman indicates on the Expedited Checklist Form under which category the protocol meets expedited status. If the protocol does not meet expedited status, the Chairman brings the protocol to the convened IRB. A list of all approved expedited protocols are reviewed and placed in the IRB minutes. Documentation for expedited reviews are maintained in IRB records and include the category and circumstances that justify using expedited procedures. The investigator is notified in writing of the final decision. Approved expedited review satisfies the conditions (1) for a minor change, or (2) involves minimal risk.

Expedited Initial and Continuing Review:

The IRB may utilize expedited procedures for the initial or continuing review of research as long as the research fits one (or more) of the following expedited categories::

a. Initial Review:

The following criteria apply to all categories:

The research presents no greater than minimal risks to subjects
The research includes reasonable and appropriate protections so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal, if the identification of the participants or their responses will reasonably place them at risk of criminal or civil liability or be damaging to their financial standing, employability, insurability, reputation, or be stigmatizing.
The research is not classified

(1) Clinical studies of drugs and medical devices only when condition (a) or (b) is met:

(a) Research on drugs for which an investigational new drug application (21 CFR Part 312) is not required. (Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review.)

(b) Research on medical devices for which (i) an investigational device exemption application (21 CFR 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.

(2) Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows:

(a) From healthy, non-pregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more frequently than 2 times per week; or

(b) From other adults and children, considering the age, weight, and health of the subjects, the collection procedure, the amount of blood to be collected, and the frequency with which it will be collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week.

(3) Prospective collection of biological specimens for research purposes by noninvasive means.

Examples: (a) hair and nail clippings in a non-disfiguring manner; (b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; (c) permanent teeth if routine patient care indicates a need for extraction; (d) excreta and external secretions (including sweat); (e) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue; (f) placenta removed at delivery; (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; (h) supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques; (i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; (j) sputum collected after saline mist nebulization.

(4) Collection of data through noninvasive procedures (not involving general anesthesia or sedation) routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. Where medical devices are employed, they must be cleared/approved for marketing. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications.)

Examples: (a) physical sensors that are applied either to the surface of the body or at a distance and do not involve input of significant amounts of energy into the subject or an invasion of the subject’s privacy; (b) weighing or testing sensory acuity; (c) magnetic resonance imaging; (d) electrocardiography, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography; (e) moderate exercise, muscular strength testing, body composition assessment, and flexibility testing where appropriate given the age, weight, and health of the individual.

(5) Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis). (Note: Some research in this category may be exempt from the DHHS regulations for the protection of human subjects at 45 CFR 46.101(b)(4). This listing refers only to research that is not exempt.)

(6) Collection of data from voice, video, digital, or image recordings made for research purposes.

(7) Research on individual or group characteristics or behavior (including, but not limited to, research on perception, cognition, motivation, identity, language, communication, cultural beliefs or practices, and social behavior) or research employing survey, interview, oral history, focus group, program evaluation, human factors evaluation, or quality assurance methodologies. (Note: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.)

b. Continuing Review:

The following criteria apply to all categories:

The research presents no greater than minimal risks to subjects (does not apply to category (8) (b)).
The research includes reasonable and appropriate protections so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal, if the identification of the participants or their responses will reasonably place them at risk of criminal or civil liability or be damaging to their financial standing, employability, insurability, reputation, or be stigmatizing (does not apply to category (8) (b)).
The research is not classified

(8) Continuing review of research previously approved by the convened IRB as follows:

(a) Where (i) the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects; or

(b) Where no subjects have been enrolled and no additional risks have been identified; or

(9) Continuing review of research, not conducted under an investigational new drug application or investigational device exemption where categories two (2) through eight (8) do not apply but the IRB has determined and documented at a convened meeting that the research involves no greater than minimal risk and no additional risks have been identified.

When expedited review is used for initial or continuing review, the re-review must take place within the IRB’s approval period. During the time-course of continuing review, the approval of a protocol due to a minor change in expedited review to the protocol is permitted but does not alter the original period of approval.

Protocol changes or amendments can be reviewed through convened or expedited review. The changes or amendments can only be implemented after the investigator has received written notification of IRB approval. The IRB will determine what information must be conveyed to the human subjects. The investigator must communicate, in writing, any changes or amendments identified by the IRB to the human subject in a timely manner.

Criteria for Requiring Review More Often Than Annually. The IRB will require review more often than annually when any of the following are true:

Procedures not before used in humans.
More than minimal risk to vulnerable populations with no prospect of direct benefit.
A high likelihood that participants will die due to the research procedures.
Any other reason for which the IRB wants closer monitoring.

In specifying an approval period of less than 1 year, the IRB may define the period with either a time interval or a maximum number of subjects, (i.e., after 3 months or after three subjects). The IRB will determine the time interval or number of subject and the IRB minutes will clearly reflect these determinations regarding risk and approval period.

To Approve the Research Activity

To approve a research activity, the IRB must comply with the following regulatory criteria:

(a) In order to approve research covered by these regulations the IRB shall determine that all of the following requirements are satisfied:

(1) Risks to subjects are minimized: (i) By using procedures which are consistent with sound research design and which do not unnecessarily expose subjects to risk, and (ii) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.

(2) Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies that subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (for example, the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.

(3) Selection of subjects is equitable. In making this assessment the IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons.

(4) Informed consent will be sought from each prospective subject or the subject's legally authorized representative, in accordance with and to the extent required by part 21 CFR §50.20, 21 CFR §46.116, and 38 CFR §16.116.

(5) Informed consent will be appropriately documented, in accordance with and to the extent required by 21 CFR §50.27, 21 CFR §46.117, and 38 CFR §16.117.

(6) Where appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.

(7) Where appropriate, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data.

(b) When some or all of the subjects, such as children, prisoners, pregnant women, handicapped, or mentally disabled persons, or economically or educationally disadvantaged persons, are likely to be vulnerable to coercion or undue influence additional safeguards have been included in the study to protect the rights and welfare of these subjects.

(c) In order to approve research in which some or all of the subjects are children, an IRB must determine that all research is in compliance with part 21 CFR §50, subpart D.

Outcomes of IRB Review

The IRB will notify investigators in writing of its determinations. The IRB actions, upon review of research, include the following:

(1) Approved with no changes (or no additional changes). The research may proceed.

(2) Approvable with minor changes to be reviewed by the IRB Chair or a voting IRB member(s) designated by the Chair. Such minor changes must be clearly delineated by the IRB so the investigator may simply concur with the IRB’s stipulations. Changes that involve more than simple concurrence must return to the IRB for review. The research may proceed after the required changes are verified and the designated reviewer approves the protocol.

(3) Approvable with substantive changes to be reviewed by the convened IRB. The research may proceed only after the convened IRB has reviewed and approved the required changes to the research.

(4) Deferred pending receipt of additional substantive information. The IRB determines that it lacks sufficient information about the research to proceed with its review. The research may not proceed until the convened IRB has approved a revised application incorporating all necessary information.

(5) Disapproved. The IRB has determined that the research cannot be continued to be conducted at Marshall University or by employees or agents of Marshall University or otherwise under the auspices of the Marshall University. The protocol immediately must be terminated.

Continuing Review of All Research Activities

All research activities will be subject to a continuing review at intervals no less than every year to ensure compliance. In order for continuing review to be substantive and meaningful, full-convened reviews will require an evaluation and review of all materials as performed in the initial review. Expedited reviews will be evaluated to ensure that the protocol continues to meet the expedited criteria, as appropriate. In the event, the protocol no longer meets the definition of exempt or expedited as previously determined, the protocol must be submitted for a full-convened review.

Continuing review is required to occur as long as the research remains active for long-term follow-up of participants, even when the research is permanently closed to the enrollment of new participants and all participants have completed all research-related interventions. Continuing review is also required to occur when the remaining research activities are limited to collection of private identifiable information.

Five Year Resubmission of All Research Activities

In addition to the annual Continuing Review, all research activities will be subject to a total resubmission every five years to ensure compliance. Full-convened reviews will require an evaluation and review of all materials as performed in the initial review. Expedited and Exempt reviews will be evaluated to ensure that the protocol meets the exempt or expedited criteria, as appropriate. In the event, the protocol no longer meets the definition of exempt or expedited as previously determined, the protocol must be submitted for a full-convened review.

Expiration of Approval Period

The expiration date is the first day that the protocol is no longer approved. The expiration date is calculated as follows:

If the research is approved by a convened IRB or approved with modifications with subsequent approval of responsive materials by the expedited procedure, the expiration date is the date of the convened IRB meeting plus the approval interval. (Example: If approved with modification by the convened IRB on 3/5/2007 for one year and granted final approval by the IRB chair on 3/19/2007, the expiration date is 3/5/2008.)
If the research is approved with modifications with subsequent approval of responsive materials by the convened IRB, the expiration date is the date of the last convened IRB meeting plus the approval interval. (Example: If approved with modifications by convened IRB on 3/5/2007 for one year and granted final approval by the convened IRB on 3/19/2007, the expiration date is 3/19/2008.)
If the research is approved using the expedited procedure, the expiration date is the date of approval plus the approval interval. (Example: If approved by the IRB chair using the expedited procedure on 3/5/2007 for one year, the expiration date is 3/5/2008.)

The IRB approval period for research may extend no more than one year after the convened IRB meeting at which the research was last approved, or the date of the expedited review process if expedited review was performed. The regulations permit no grace period to this 1-year requirement.

Research that continues after the approval period expires is research conducted without IRB approval and the investigator will be subject to disciplinary action. Research that does not receive IRB continuing review and approval prior to the end of the stipulated approval period becomes expired. All research activities must stop, including recruitment, enrollment, interventions, interactions, and data analysis. If an investigator believes that currently enrolled participants will be harmed by stopping interventions, the investigator must provide a list of such participants and the reasons why participation in the research should continue. The IRB chair, and in the case of VA research the IRB chair in consultation with the VA Medical Director, will determine which participants may continue because of an over-riding safety concern or ethical issue involved such that it was in the best interests of individual participants to continue participating in the research interventions or interactions. Under no circumstances will investigators be allowed to enroll new participants into expired research.

For VAMC Research that has expired before the continuing review was completed the following is required:

The biomedical IRB must notify investigators to immediately submit to the IRB Chair a list of participants for who stopping research activities would cause harm.
Prompt reporting of the expiration to the sponsor.

Suspension or Termination of IRB Approval of Research

45 CFR §46.113 states the following:

"An IRB shall have authority to suspend or terminate approval of research that is not being conducted in accordance with the IRB's requirements or that has been associated with unexpected serious harm to subjects. Any suspension or termination of approval shall include a statement of the reasons for the IRB's action and shall be reported promptly to the investigator, appropriate institutional officials, and the department or agency head."

Any suspensions and terminations by someone other than the convened IRB must be reported to and reviewed by the convened IRB.

Definitions:

Suspension of previously approved research. Suspension of IRB approval: An action taken by the IRB to temporarily or permanently withdraw approval for some or all research activities short of permanently withdrawing approval for all research activities