guide for preparing and conducting clinical research study

IX. ONGOING REVIEW OF THE PROTOCOL

Continuing Review of a Protocol

Federal regulations require that an IRB shall conduct continuing review of human-subjects research at intervals appropriate to the degree of risk, but not less than once per year. The NIH MPA requires that the NIH IRB's review each protocol annually, regardless of whether the investigator intends to accrue new subjects or follow subjects already enrolled on the protocol. Depending on the degree of risk to subjects, the IRB may choose to review the protocol more frequently. The IRB must complete the continuing review and approval of the protocol before its anniversary date. The timely, scheduled IRB review of active protocols serves as an important mechanism by which the IRB fulfills its responsibility to protect the rights and welfare of human subjects.

Clinical Research Protocol: Continuing Review Application

Form NIH-1195-1, "Clinical Research Protocol: Continuing Review Application," is designed to carry the protocol through the yearly continuing review process (figure 13), and it captures and summarizes considerable information about changes made in the protocol since the last continuing review. The bottom of the form is a guide to the required signatures and dates by which to complete the continuing review process. The form is available from the Institute PC or the PCSC.

Figure 13: NIH-1195-1 -- Clinical Research Protocol: Continuing Review Application

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To accompany the completed NIH-1195-1 form, the PI must write a progress report, addressed to the IRB Chair, summarizing the progress of the protocol since the last continuing review. The report must include information on the numbers of women and minorities who have been enrolled on the protocol since its inception. PI's should keep records of all persons entered in their protocols, their medical record numbers, and their dates of entry. The progress report also should include an explanation for any "yes" responses on the NIH-1195-1 form and a discussion of scientific developments that bear on the protocol, especially those that alter the risks or hazards to research participants. Requirements for rewriting protocols at the time of the continuing review are determined by each IRB. A protocol may be rewritten to consolidate multiple amendments made to the protocol in a given time period, as defined by the IRB. The PI forwards the completed NIH-1195-1 form, the progress report, the protocol, the current consent and assent documents (electronic diskette and hard copy), and all pertinent reference materials to the Accountable Investigator, the Branch Chief or Department Head, and the Institute Clinical Director for their review and signature approval. The Clinical Director may withhold signature until notified of the action taken by the IRB. The continuing review package is then sent to the PC, who reviews it to verify that the NIH-1195-1 form is completed properly and all required documents are present. If the package is incomplete, the PC and the PI work together to address the deficiencies. Once the continuing review package is complete, the PC schedules it for IRB review.

An application for amending the radiation authorization must be submitted to the RSC and the IRB if there are changes to a protocol previously approved by the RSC. The RSC must review and approve protocol changes such as the administration of radiation, experimental design, and number of subjects studied. In addition, the RSC is required to review all protocols it authorizes every 3 years after the initial approval. The request for amendment or triennial review should be submitted simultaneously to the RSC and the appropriate IRB for concurrent review (see "Amendment and Triennial Reviews").

Continuing Review Process

The IRB reviews the scientific progress made in the protocol, the occurrence of unexpected events or problems in the subjects studied, and the rate of accrual of subjects. The protocol consent and assent documents are examined to ascertain that the information remains accurate. The IRB has the same five options for action on a continuing review package as on an initial review package:

  • Approval

    Approval (without stipulations) requires affirmative vote by a majority of the members present at the meeting. If the vote is not unanimous, the minority opinion must be recorded in, or attached to, the minutes when they are forwarded for final IRB review and approval. The PI may move forward with an approved protocol.

  • Approval with recommendations

    The IRB may approve a protocol with nonbinding recommendations. The PI must respond in writing to IRB recommendations, suggestions, and technical corrections. However, the PI may move forward with a protocol upon approval with recommendations.

  • Approval with stipulations

    The IRB may approve a protocol with specific conditions that must be met by the PI before proceeding with the protocol. The IRB will return the continuing review package to the PI, along with written notification identifying IRB action and specific requests for change. The PI may appeal to the IRB for reconsideration of one or more of the stipulations. However, investigators may not seek to reverse an IRB decision by submitting the same protocol to another NIH IRB. The PI is required to respond in writing to the IRB stipulations within 30 days. If the stipulations are not addressed within 30 days, the PI will have to resubmit the entire continuing review package for another review. The PI may not move forward with the protocol until the IRB stipulations have been adequately addressed and accepted by the IRB.

    Once the stipulations have been addressed as requested by the IRB, the PI should submit a "Response to IRB Stipulations" memorandum and two copies of the revised continuing review package to the PC for review and approval by the IRB Chair. Changes to the protocol or consent and assent documents should be highlighted in one copy of the revised continuing review package. Depending on the extent of the stipulations, the IRB Chair may review and approve the revised package without full committee review. The IRB minutes will specify whether stipulations are to be reviewed by the Chair, an IRB subcommittee, or the fully convened IRB.

  • Table

    The IRB agrees that approval cannot be granted until further information is provided or specific changes are made in the continuing review package. When the PI submits new information, the package is reviewed again by the full IRB.

  • Disapproval

    The IRB sends a notice to the PI identifying the reasons for disapproval of the protocol. Disapprovals are definitive. The PI may submit a new protocol that reflects due consideration of the reasons for disapproval of the old one.

Final approval of the continuing review package is indicated by the signature of the IRB Chair on the NIH-1195-1 form. The PC promptly forwards the original continuing review package, revised protocol, including consent and assent documents, the IRB minutes (if applicable), and all the correspondence to the PCSC.

Upon receipt of a completed continuing review package, a protocol specialist in the PCSC reviews the package to assure that all required documents are included, all elements and questions have been addressed, and all signatures and initials are present. Common deficiencies noted by the PCSC staff include failure of new AI's to initial the NIH-1195-1 form or protocol face sheet; missing Clinical Director initials for a cross-institutional AI; missing IRB minutes; or (in the case of IRB stipulations) a missing formal memorandum, titled "PI Response to IRB Stipulations." The protocol specialist works with the Institute PC, via telephone and electronic mail, to resolve any deficiencies promptly. However, it may be necessary to return the continuing review package if it requires major correction. Once the protocol review package has been determined complete, the protocol specialist abstracts and updates the protocol in the PROTRAK data base.

The protocol specialist then updates the protocol consent and assent documents on the intranet. The protocol specialist signs and dates the bottom of the NIH-1195-1 form, signifying that all tasks are completed. The PCSC retains the original NIH-1195-1 form, signed by all the required individuals and review bodies. Copies of the form are sent to the PI, the PC, and to the RSC, if applicable.

Continuing Review Notification Memorandums

The IRB must complete the continuing review and approval of the protocol before its anniversary date. Subjects cannot be accrued after the anniversary date unless the IRB has reviewed and approved the protocol. Furthermore, the research may be suspended or terminated.

The PCSC sends a "Continuing Review 1st Notice" to the PI and the PC 120 days before the anniversary date of the protocol. The notice reminds the PI of the upcoming anniversary date for the protocol and encourages the PI to begin the continuing review process to ensure that the protocol is approved on time. The PCSC sends a "Continuing Review 2nd Notice" to the PI and the PC 60 days before the anniversary date of the protocol.

It is the PI's responsibility to submit his or her protocol for continuing review promptly. The continuing review process may take some time, and the consequences of a delay – namely the suspension or termination of the protocol – may pose a significant inconvenience for the investigator. The PI should contact the PC to facilitate the continuing review process or to answer questions that arise.

Extensions

If the protocol is actively under review by the IRB at the time of its anniversary date, and the complete approval process is expected to take more than 30 days, the PI may request that the IRB Chair approve a formal extension of the continuing review due date. If the PCSC does not receive the completed review or a formal extension request from the IRB Chair within 30 days after the anniversary date, the protocol will be referred to the Institute Clinical Director for possible suspension or termination.

The PI must submit a written request for an extension to the IRB Chair. The request should include the duration of the requested extension, a justification for the extension, and whether or not protocol accrual will continue during the extension period. The convened IRB may grant an extension with continued patient accrual of up to 90 days beyond the anniversary date. Extensions longer than 90 days are at the discretion of the IRB Chair, and the protocol may not accrue new subjects during that time. Upon approval of the extension, the IRB Chair must send written notification to PCSC, which will modify the consent document to reflect the extent of the provisional approval. Upon final approval of the continuing review by the IRB, the PCSC will issue a new consent for the remaining part of the year not covered by the extension. Such extensions should be granted rarely, and only in those cases where the IRB decides that they will not affect the safety and welfare of the research subjects.

Amendment Review of a Protocol

From time to time, investigators amend some feature of their protocols; the PI should formally submit to the IRB a "Request for Amendment" memorandum, which should describe the amendment, the reason for the change, and record any untoward effects noted with the original protocol and any that may be expected because of the amendment. If several areas of the protocol are changed, the PI should highlight all changes on a copy of the current version of the protocol. Revised protocol consent and assent documents must accompany the memorandum if the proposed amendment changes the procedures or risks to subjects. All changes to the consent and assent documents must be documented in the memorandum, highlighted on a copy of the current consent and assent documents, and submitted electronically via diskette.

The PI forwards the "Request for Amendment" memorandum, the protocol, including consent and assent documents (if applicable), and all pertinent reference materials to the Institute Clinical Director for review and signature. If the proposed change is minor, the Institute Clinical Director may recommend to the IRB Chair that the amendment be approved by expedited review. If the PI, Institute Clinical Director, or IRB Chair considers the change more than minor or that it "materially affects risks to subjects," the amendment must be approved by the full IRB. Once the proposed amendment is approved by the Institute Clinical Director, the amendment review package is sent to the PC, who then schedules it for review by the full IRB or its Chair.

An application for amending the radiation authorization must be submitted to the RSC and the IRB if the procedures previously approved by the RSC change (see "Amendment and Triennial Reviews"). The request for amendment should be submitted simultaneously to the RSC and the appropriate IRB for concurrent review.

Investigators cannot initiate substantive changes in research activities during the period for which IRB approval has already been given without prior IRB review and approval – except when necessary for eliminating apparent immediate hazards to the research participant.

The amendment review package receives final IRB approval when it is signed by the IRB Chair. The PC promptly forwards to the PCSC the approval memorandum, signed by the Institute Clinical Director and the IRB Chair; original amendment review package; revised protocol, including consent and assent documents; IRB minutes (if applicable); and all correspondence.

Upon receipt of an amendment review package, a protocol specialist in the PCSC reviews it to assure that all required documents are included, all elements and questions have been addressed, and all signatures and initials are present. Common deficiencies noted by the PCSC staff include failure of new AI's to initial the amendment request or protocol face sheet; missing Clinical Director initials for a cross-institutional AI; no IRB minutes when the protocol is reviewed by the full IRB; or (in the case of IRB stipulations) a missing formal memorandum, titled "PI Response to IRB Stipulations." The protocol specialist works with the Institute PC, via telephone and electronic mail, to resolve any deficiencies promptly. However, it may be necessary to return the amendment review package if it requires major correction. Once the protocol review package has been determined complete, the protocol specialist abstracts and updates the protocol in the PROTRAK data base.

Once the amendment review package is complete, the protocol specialist assigns a letter to the approved amendment. Letters are sequentially assigned from A through Z. The protocol specialist enters the following data on the approval memorandum: PCSC completion date, amendment letter, quarter and fiscal year in which the protocol specialist completed the amendment, and protocol specialist's initials.

The PCSC staff initials and date, located on the approval memorandum, signify that all tasks are completed, at which time the proposed changes to the protocol and/or protocol consent and assent documents are in effect. The PCSC retains the original approval memorandum that was signed by the Institute Clinical Director and the IRB Chair. The PCSC staff sends copies of the approval memorandum to the PI, PC, RSC (if applicable), and the CC Pharmacy Department (if applicable).

Change of Principal or Medical Advisory Investigator

A change of PI or MAI may be requested by the new PI or the old PI by using the form NIH-2704, "Request for Change of Principal Investigator and/or Medical Advisor" (figure 14) or a "Request for Amendment" memorandum. The Institute Clinical Director must review such a request promptly because PI's and MAI's are the persons responsible for ensuring the well-being of the research participants. The Institute Clinical Director must certify that the training and experience of the new PI or MAI matches or exceeds that of the old PI or MAI. Signature of the Institute Clinical Director on the NIH-2704 form or the amendment approval memorandum signifies final approval of the change.

Figure 14: NIH-2704 -- Request for Change of Principal Investigator and/or Medical Advisor

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The approved NIH-2704 form or the approved "Request for Amendment" memorandum is forwarded to the PCSC, where the PROTRAK data base, protocol consent and assent documents, and the MIS are updated with the name of the new PI or MAI. The approved NIH-2704 form or "Request for Amendment" memorandum is retained in the PCSC.

Reporting Unanticipated Problems or Unexpected Harm

The PI must inform the IRB Chair promptly about unanticipated risks to research participants or others, or about unexpected serious harm to subjects. An investigational drug suspected of causing an adverse drug reaction must be reported to the appropriate persons (see "Reporting an Adverse Experience").

A written report of all unanticipated problems or unexpected harm should be submitted for evaluation to the appropriate IRB Chair, the Institute Clinical Director, the CC Director, and the CC Pharmacy Department (if an IND is suspected of causing an adverse experience). The written report may be included in an amendment prepared for review by the IRB requesting continuation of a protocol with amended procedures, consents, or subject populations. If the IRB Chair, Institute Clinical Director, or CC Director determines that the effects or information are sufficiently adverse, the protocol may be suspended or terminated.

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