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Part 4 – NGHS IRB Procedural Guidelines

Three Basic Definitions

Three definitions are required to determine if an activity must have IRB review. These three are important because they are in the following sentence.

All research involving humans as subjects conducted at or under the auspices of NGHS, is subject to the Program for Protection of Human Subjects and the policies and procedures established and implemented by the NGHS Institutional Review Board

The NGHS IRB requires justification for exclusion of some categories of subjects such as the elderly or very young or women of childbearing potential. Equitable selection requires consideration of the fairness of inclusion criteria and of exclusion criteria.

The NGHS IRB requires researchers to obtain a pregnancy test on potential participants, who could possibly be pregnant, prior to enrolling them in any protocol/study that precludes pregnant women.

If, after reading this section and these references, it is still unclear whether your project is subject to review by the NGHS IRB or not, you should err on the conservative side and ask the IRB for a determination.

Research

All "research" at NGHS needs IRB review. Two definitions of research are used. The first definition (45 CFR 46.102(x)) from DHHS applies to all federally funded studies or studies sponsored by a research base under a "Federal-Wide Assurance (FWA)". The second definition is from the FDA (21 CFR 56.102(c)) and applies to regulated test articles.

COMMON RULE 45 CFR 46.

FDA 21 CFR 56.

Researchmeans a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.

Activities that meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program that is considered research for other purposes. For example, some demonstration and service programs may include research activities.

"Clinical investigation" means 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 under section 505(i), 507(d), or 520(g) of the act, or need not meet the requirements for prior submission to the Food and Drug Administration under these sections of the act, but the results of which are intended to be later submitted to, or held for inspection by, the Food and Drug Administration as part of an application for a research or marketing permit. The term does not include experiments that must meet the provisions of Part 58, regarding nonclinical laboratory studies. The terms "research," "clinical research," "clinical study," "study," and "clinical investigation" are deemed to be synonymous for purposes of this part.


The difficult issues are those that are between practice and research. Innovation may be experimental but experimentation is not research. Experimentation ranges from altering a dose level to using a drug off-label to developing a new surgical procedure. Experimentation is under the jurisdiction of the medical staff and research is under the jurisdiction of the IRB. It is usually wise to subject experimental practices to research scrutiny.

Human Subject

The NGHS program and the IRB are concerned with the rights, safety and welfare of the human subject. Because of its "Federal-Wide Assurance", NGHS applies the DHHS and Common Rule definition that is far broader than, and is inclusive of, the FDA definition. This includes basic, applied, social science and medical research involving subjects, review of records and collection of biological specimens.

Common Rule 45 CFR 46.102(f)

FDA 21 CFR 56.

"Human subject" means a living individual about whom a researcher (whether professional or student) conducting research obtains:

• data through intervention or interaction with the individual, or

• identifiable private information.

INTERVENTION includes both physical procedures by which data are gathered (for example, venipuncture) and manipulations of the subject or the subject's environment that are performed for research purposes.

INTERACTION includes communication or interpersonal contact between researcher and subject

PRIVATE INFORMATION includes information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information which has been provided for specific purposes by an individual and which the individual can reasonably expect will not be made public (for example, a medical record). Private information must be individually identifiable (i.e., the identity of the subject is or may readily be ascertainable by the researcher or associated with the information) in order for obtaining the information to constitute research involving human subjects

"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 human or a patient.

 


Jurisdiction

"At or under the auspices of NGHS" refers to people, places or things done at or by or within NGHS.

 

Review Required

Review probably not required

Personnel

• Full time NGHS staff person

• Students

Private practice

Procedures

• the experimental procedure is to be done at NGHS

A standard fee-for service procedure requested by a private practice physician

 

An investigational drug must be administered to a person on a non-NGHS study if the person is hospitalized for another reason and if the IRB approval letter and consent form are presented to the IRB Chairman

Facility

• NGHS

 

Information

• Any use of NGHS medical records

• Any use of NGHS path specimens

 


IRB Review

The federal regulations allow some research to be exempt from IRB review, some to be reviewed by a specified expedited review process and the rest by full board. There are a couple of things to remember:

There is no such thing as an emergency in research! There are emergencies in the practice of medicine. Research is a pre-planned activity.

The IRB staff will help if possible. However, federal regulations, NGHS policies, and the amount of time in a workday restrain them.

Before review of new studies can occur the IRB Office must have on file for each ‘Principal Investigator’ and Sub/Co Investigator involved in the research/study the following:
  • Current Curriculum Vitae (CV) or Resume,
  • A signed "Investigator’s Manual Compliance Acknowledgement" from the NGHS IRB: Investigators’ Manual
  • A signed Conflict of Interest Statement
  • A copy of the NIH computer based training "Certificate of Completion" Contact the IRB Office for information regarding accessing the NIH site.

The NGHS IRB typically meets on the first Thursday of each month. A complete ‘Proposal Packet’ should be submitted to the IRB Office18 days prior to the IRB’s monthly meeting.

Proposal Packet Content:

  • NGHS IRB Review Application (Initial or Continuing): Form must be completely filled out and it must be signed. Questions may be answered "N/A" if appropriate. Note: If a proposal affects the workload or usual operating procedures of an NGHS department (i.e. Laboratory; Diagnostic Imaging, Pharmacy) it is the responsibility of the ‘Principal Investigator’ to make arrangements with the department(s) prior to submission of the application..
  • Protocol: A protocol is a cookbook for the conduct of a study. Using this set of instructions all members of the research team should have a good understanding of the study and the study should be replicable. An IRB approved document (i.e. protocol, consent form) is NEVER modified/revised/changed/etc. prior to submission to the IRB for review and approval.
  • Consent Document: This document is the primary means of giving information to the person considering becoming a subject. It should be written in the NGHS format. If non-English speaking individuals will be included in the study all foreign language versions of the consent document(s) should be included (see 45 CFR 46.117)
  • All supporting documents, including ( as appropriate):
    • Questionnaires
    • Interview guides
    • Investigators Brochure or Report of Prior Investigations
    • Text for all advertisements (websites, print & broadcast)
    • Recruitment materials (websites, print & broadcast)
    • Any other available appendices (e.g. schemas)
  • Grant Applications: Federally funded activities must be accompanied by a copy of the grant application. A grant application is a request for money and focuses on convincing a grant review panel of the value of the endeavor. A protocol sets out why and how a study will proceed and how subjects will be involved and protected. They serve different functions.
Full Board Review
All submissions will be considered for full board review unless the investigator requests and justifies another process (e.g. Expedited Review).

A ‘Proposal Packet’ will be distributed to each IRB member for review. Remember that the membership is diverse; there may be no board member conversant in your field. Your documentation must speak for itself.

To facilitate the review process, it is required that the PI and/or a representative with knowledge of the study attend the IRB meeting at which the new proposal will be reviewed. It is the PI’s responsibility to contact the IRB Office to make arrangements for meeting attendance. The PI must leavethe meeting prior to "calling the vote".

Facilitated Review

Facilitated review is Only used when the ‘IRB of Record’ is the NCI’s Central Institutional Review Board (CIRB). The IRB Chair and/or designee(s), appointed by the Chair, conducts the "facilitated review" and decides whether the submitted protocol and informed consent document are acceptable and appropriate in local context. The individual(s) conducting the "Facilitated Review" has the option to:

  • Approve – The reviewer accepts the CIRB approval "as is".
  • Approve Contingent – The reviewer accepts the CIRB approval with minimal modifications made before the research is implemented.
  • Send To Full Board – The reviewer decides not to accept the CIRB review and requires the protocol be submitted for full board review. The reviewer may not disapprove the study.

A decision to accept the CIRB approval means that NCI’s CIRB remains the "IRB of Record". Thus, the date of approval, the expiration date and the continuing review date will be the dates established by the CIRB.

Expedited Initial Review

An expedited application/review worksheet is allowed if two conditions are met:

  • the study meets the definition of "Minimal Risk", and
  • the study contains only procedures on the list of expedited procedures

The IRB Chairman or his/her designee will review the ‘Proposal Packet’ . Approval, when granted, is equivalent to full-board approval.

Exempt studies

It is NGHS policy that all studies that appear on the FDA exempt list shall be reviewed by the expedited review procedure.

Possible IRB Decisions 
Approval As Submitted

A formal approval letter signifies approval. When received the study has IRB approval to be initiated. (Other approvals may also be required so IRB approval may be insufficient by itself.)

Approvals may be granted for a maximum of one year. Although the IRB office will remind investigators, the responsibility for submission of a continuing review application rests with the investigator.

Approval Contingent

A contingent approval is NOT equivalent to an approval. Although the protocol is accepted, there are remaining questions or conditions (e.g. the consent form needs some correction). The IRB may delegate to the chair or another member the duty of reviewing the response. That person may remove the contingencies or may send the response back to full board. Return to full board is not required unless the reviewer is not satisfied.

Return For Clarification

Should the application/protocol/consent be so unclear that no decision is possible without making assumptions, it is returned with a summary of questions/comments needing clarification.

Attendance by the investigator or his/her designee to a regularly scheduled meeting of the IRB to provide clarification to questions/comments is welcome. It is the responsibility of the investigator or his/her designee to contact the IRB Office to make arrangements for IRB meeting attendance.

Applications for which no response has been received within 60 days will be returned without prejudice and will need to be re-submitted before the second review can occur.

Disapproval

The study/research activity may not be conducted. Prior to a final decision to disapprove, the IRB will put all concerns/questions relevant to the final decision in writing to the investigator (e.g. Study Returned For Clarification), and will seek and consider the investigator’s response.

Following the final decision with which an investigator disagrees, he or she may be assured of the right to make one further personal presentation to the IRB.

Following that presentation, if the investigator remains unhappy with the decision, he or she may make a presentation to the Director of Performance Improvement and or Vice President Professional Services for the sole purpose of informing them of the perceived problem.

The IRB disapproval may not be overturned by any other NGHS authority.

 Post Approval Activities

The IRB-Investigator relationship only begins with approval. There are several post-approval requirements. There is one primary over-riding rule: Never surprise the IRB!

Modifications

Once the IRB has approved a study it expects the study to be carried out exactly as approved. Changes to the protocol itself must be pre-approved by the IRB. Modifications made to the study, including major modifications, will not change the expiration date unless the IRB specifically designates a new date at the time the modification is reviewed. The IRB will attempt to refrain from requiring modifications mid-way through a protocol. However, if new information or insights necessitating changes become available then the IRB may deem it prudent to require protocol/study modifications.

1. Sudden Modification

A change to the protocol itself that is taken to reduce a risk of harm may be made without IRB approval. The investigator should submit the appropriate paper work to the IRB Office in order that the board can be informed of the modification at the IRB meeting following the modification.

2. Administrative Modification

A protocol change that does not alter any substance at all may be an administrative alteration. Such a change should involve no change affecting subjects and no change requiring a change of the consent document.

Administrative modifications should be sent to the IRB office along with appropriate paper work (e.g. Institutional Review Board: Protocol Modification Form) so that the board can be informed of the modification at the IRB meeting following the modification. A copy of the form reflecting IRB acknowledgement will be returned for the investigator’s file.

Examples of administrative modifications include:
• Memorandum explaining a study concept or other information; does not change study or consent
• Temporary or permanent closure built into the study design

3. Minor Modification

The chair, using the expedited review process, may review "Minor" modifications. Decisions available to the chair are: approval; approval contingent on a response; or, referral to full committee. The action will be reported at the next meeting. 21 CFR 46.220(b)(2)

Examples of minor modifications include:

  • addition of another site known to the reviewer
  • changes in wording of protocol or consent forms to clarify a concept
  • approval of advertisements
  • advertisements and other recruitment materials
  • small changes in compensation
  • grammatical or organizational changes in consent forms
  • a clarification of meaning
  • adding an investigator who has already been approved for another study if the study is in the same disciplinary area.
4. Major Modification

Major modifications will be circulated to all members and reviewed using the full board review procedures.
Examples of major modifications include:

  • changes in study design which may increase risk to participants
  • a substantive change in enrollment numbers
  • any application for which no clear rationale is given.
    21 CFR 46.113
Violations of Protocol

The IRB and the funding agency truly believe that the protocol is being conducted as approved. A protocol (original or modified) must be followed for each subject. However, both subjects and staff are human. Protocol violations are usually taken to accommodate the needs of an individual.

1. Deviations
  • A change made for an individual without any pre-consultation.
  • Deviations should be recorded immediately.
  • Any "substantive" deviation should be reported to the IRB within ten working days.

Example: The study requires the second dose to be 30 days after the first. On day 30 the subject has the flu and re-schedules for day 33.

2. Exceptions
  • A change that is approved by the sponsor ahead of time.
  • Exceptions should be documented in writing and logged immediately.
  • Any "substantive" exception should be reported to the IRB within ten working days.

Example: The study requires the second dose to be 30 days after the first. On day 15 the subject receives an all expense paid trip to Paris and asks to be re-scheduled for day 33. The sponsor grants permission.

Continuing Review

Periodic "check-in" with the IRB is a requirement. Federal regulations and FWA policy do not provide for exceptions to the requirement for continuing review. Therefore, failure by the Principal Investigator to ensure timely IRB review is a serious matter that may lead to suspension or termination of the protocol.

During a study many things can change such as the available alternatives, the standard of care, costs, laws or personnel. The primary question raised is whether, given what has occurred in the intervening time, the IRB would again approve the study. Appendix E provides an example of the "NGHS Continuing Review Application".

Timing: The maximum approval the IRB can grant is one year. It is expected to require more frequent reporting depending upon the level of risk or for any relevant reason. The approval letter/document will state the expiration date. It is the investigator’s responsibility to submit the continuing review application sufficiently in time to avoid a break in approval.

On the expiration date, IRB approval expires. The IRB chair and the IRB office are not allowed to extend. No intervention is allowed unless it would be unsafe to stop using the test article. Follow-up monitoring is allowed only for the continued safety of subjects.

Process: The application process is identical to the initial review application process. Expedited review is allowed if:

  • the initial review was by the expedited process,
  • the study is in the "follow-up only" phase in which the subjects are being monitored but there is no further intervention.

Questions: Relevant information would relate to what has happened since the last complete review.

  • Numbers: subjects screened, enrolled, completed, dropped, lost or other.
  • Adverse events: This is the time to generate a complete list by frequency and to highlight the serious events.
  • Problems faced: Have unexpected procedural issues come up?
  • Consent: How has the consent document worked? What questions were raised? Were there parts that were not understood or that could be improved?
  • External events: Has the standard of care changed? Have the costs and reimbursements stayed the same?

Completed Studies: When an approved research project is completed, the investigator must promptly notify the IRB and file with the IRB a "final report" which includes the information required for continuing review for the entire research project period.

Adverse Events (AE)

An adverse event is any experience during the course of the research project that, in the opinion of the investigator, was harmful to a participant, increased the risk of harm, or had an unfavorable impact on the risk/benefit ratio.

The Code of Federal Regulation (CFR 46-103) and the NGHS Program for the Protection of Human Subjects requires the reporting of all adverse events associated with NGHS, Inc. approved protocols. Two types of reports are submitted to the IRB:

  • Adverse Event Report: An internal report from an NGHS investigator.
  • Safety Report: Reports from other sites that are sent to the NGHS investigator by the sponsor or the FDA.
    A report summarizing information provided to the investigator via SRs will be submitted as a part of the materials required for continuing review.

    However, if at any time prior to a study’s expiration date, the study’s sponsor and/or the FDA issues an "Action Letter" related to any experimental/investigational component of a study requiring:
    • A change in the study’s protocol and/or Informed Consent Document; and/or,
    • Notification of the study’s participants of new information or insights necessitating changes,

the investigator is required to submit the SR(s) and the modification(s) to the IRB for review and approval prior to implementation.

All violations must be summarized on the continuing review application. Violations that affect the safety or well being of a subject or that occur with sufficient frequency must be reported to the IRB. Violations submitted to the IRB will be acknowledged. The chair is authorized to seek supplemental or clarifying information.

Types of Adverse Events Identified by NGHS IRB

Type

Adverse Event

 

Definition

Time Frame

For Reporting To IRB

Serious AE

An event that:

  • is fatal or life-threatening,
  • is permanently or significantly disabling,
  • requires or prolongs inpatient hospitalization
  • is a congenital anomaly, cancer, or overdose

Reported immediately to NGHS IRB; formal written notification to follow within 5 business days of the event’s occurrence/detection.

Unanticipated AE

An event that is:

  • not noted in the consent form or,if required, in the ‘Investigator’s Brochure, or
  • more serious than anticipated

Reported in writing within five (5) working days of the event’s occurrence/detection.

Expected AE

The occurrence of an event that is noted in:

  • the consent form or, if required,
  • the ‘Investigator’s Brochure

Reported in writing within ten (10) working days of the event’s occurrence/detection.


Principal Investigator’s Manual

Compliance Acknowledgement:

Please print complete print the acknowledgement page of this document, sign, date and forward the acknowledgement to the IRB Coordinator.

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