Clinical Research Operations

Medical Oncology Branch (MOB) and Affiliates Scientific Review

Purpose: To identify the processes and standards for scientific review and approval of new clinical research and proposed protocol amendments within the MOB and Affiliates to ensure that:

1) CCR clinical trials are scientifically rigorous, include sound design, rationale, biostatistical foundation, and

2) Are nationally relevant, likely to accrue targeted population(s) and make important contributions to the field.

The final responsibility for scientific review lies with the MOB Branch Chief. The scientific knowledge of the members of the MOB Scientific Review Committee (SRC) justifies its expertise in reviewing clinical trials in the research realm of medical/hematologic oncology.

Definition: For this document, the following definitions apply: 1. Chair (upper case) is the position held by the head of the MOB SRC. 2. chair (lower case) is anyone who serves as the chair for a given SRC meeting.

STEP 1: Protocols Must Undergo Comprehensive Scientific Review by a Protocol Committee with Requisite Scientific Knowledge Prior to NCI IRB Submission

A. Medical Oncology Branch (MOB) Scientific Review Committee (SRC) approval must be obtained for all new MOB and affiliate protocols and amendments with major scientific changes, prior to submission to the Institutional Review Board (IRB), according to the criteria outlined in the CCR-MOB Protocol Assessment Checklist.

B. There are two stages of review in MOB CCR, NCI:

1. Concept Review:
   • Concept review permits feedback on a clinical trial before a full protocol is written.
   • Concept forms will be reviewed for the scientific question and rationale, importance of the research question, experimental design, resources required and innovation of the correlative studies. If CCR resources are required in addition to branch resources, funding approval from the Scientific Director will be obtained prior to submission to the IRB.
2. Protocol Review:
   • Protocol review permits feedback on the complete clinical trial plan prior to ethics review by the IRB.
   • A complete protocol is reviewed in entirety for scientific design, statistical section, procedures, agents, and correlative studies. A Strategic Alignment Questionnaire must be submitted with every protocol and included in the documentation.

C. At the conclusion of the Scientific Review in MOB, a CCR-MOB Protocol Assessment Checklist will be completed.

D. Principal investigators can visit the NCI Medical Oncology Branch Web site to obtain information about the concept review and protocol review processes within the MOB. A Protocol Review process tutorial is also available.

E. A protocol review will be conducted for adherence to regulatory requirements and adherence to NCI/CCR administrative guidelines. Protocol support staff will review and revise the documents for editorial, administrative and regulatory changes, if needed.

STEP 2: Concepts for New Protocols Will Be Reviewed by the Branch Prior to Protocol Review

A. Concept Review Committee:

1. At a minimum, a concept review meeting is held every other Friday from 2:00 - 4:00 pm.
2. Meetings are open to Branch Chiefs, senior staff, invited guests and fellows, and research team members for all concepts under review.
3. The Concept Form submission deadline is midnight the Tuesday one week before the study concept meeting date.
4. The submitted version will be distributed to SRC members at least 7 days prior to the concept review meeting; revisions will not be accepted after this date. Concepts will also be distributed to the Branch Chief of the Pharmacy Department, Clinical Center (CC); Laboratory of Pathology, CCR; and the Statistician, Biostatistics and Data Management Section, CCR.
5. The investigator will bring PowerPoint slides on a USB "thumb drive" for a 10-minute presentation for viewing during the investigator’s presentation of the concept.

B. Concept Review Committee Meeting Procedures:

1. The Chair/Deputy Chair or designee conducts the Concept Review meetings on Friday (dates subject to change) from 2:00 - 4:00 pm in the Clinical Center (Building 10), Conference Room 13S235A. A protocol review may follow concept reviews (http://medicaloncology.cancer.gov/index.php/scientific-review/clinical-trials/index.htm), if scheduled.
2. Voting members consist of the MOB and affiliate senior staff, including Staff Clinicians, Investigators, Senior Investigators, Senior Clinicians or Staff Scientists in MOB and the affiliate lab/branch clinical programs, and a member of the Laboratory of Pathology, CCR.
3. Concept review actions require the presence of a quorum, defined as representatives from at least four (4) labs or branches.
4. Protocol support staff will prepare hard copies of the concept to be distributed at the meeting.

C. Concept Review Process:

1. Primary and two senior Secondary Reviewers will be assigned.
   • The Chair/Deputy Chair will assign a primary reviewer,a secondary reviewer, and a third reviewer PI mentor with a fellow (who will present the review). All senior staff are invited to review the concept applications.
   • Selection of reviewers is based on the expertise and availability of the senior staff members.
     • Primary and secondary reviewers may not have a conflict-of-interest (COI) or be an Associate Investigator (AI) on the clinical trial under review.
   • Ad hoc reviewers may be assigned if additional expertise is needed, at the discretion of the Chair/Deputy Chair.
   • In general, statisticians will not attend the meeting, but will provide input prior to the meeting, and review meeting minutes. Pharmacy will provide feedback regarding cost shift for study agents.
2. Concept Meeting Conduct
   • The principal investigator must be present and participate in the discussion, answer questions and receive constructive feedback. In the event the principal investigator cannot attend, the review will be rescheduled.
   • The principal investigator (with mentee when applicable) will present a 10-minute overview of the trial with emphasis on rationale and feasibility.
   • Primary and two secondary reviewers present their recommendations and topics for discussion.
   • The principal investigator (and designee) may respond to questions and participate in the discussion.
3. Concept Approval Process
   • At the completion of the discussion, all associate investigators on the protocol should leave the conference room during the vote.
   • Members attending the meeting will vote using anonymous paper ballet; options include:
     • Approved (with recommendations) - The Committee recommends approval but requests the PI revise according to recommendations. The investigator incorporates recommendations into drafting a full protocol for Protocol Review.
       
     • Approved (with stipulations) - The Committee recommends approval but requests the PI revise according to the stipulations. The investigator responds in writing to the stipulations and provides documents for review by the Chair/Deputy Chair prior to drafting a full protocol for Protocol Review.
       
     • Deferred - Resubmit to the Concept Review Committee for a focused review
       In this case, the Committee makes the decision that the concept application needs significant scientific revision and will need to be resubmitted for a focused review by the Concept Review Committee. The PI responds in writing to the stipulations and presents the response at the focused re-review.
       
     • Disapproved - Disapproved concepts may be appealed through discussion with the MOB Branch Chief, and if not resolved, appealed to the NCI CCR Scientific Director.

STEP 3: Documentation of Concept Review Process

A. Primary and secondary reviewers will e-mail written comments to the MOB Protocol Support Office no later than 5:00 pm the next business day following the Concept Review meeting.

B. Any Committee member or research team member may provide written comments, which must be submitted no later than 5:00 pm the next business day.

C. The minute taker will compile the minutes within 3 business days.

D. Minutes will be sent for review to the Chair, primary and secondary reviewers, pharmacy and statistician prior to final approval and distribution.

E. Written feedback will be submitted to the PI within 5 business days after the review, through the Chair and Branch Chief, MOB.

STEP 4: New Protocols Will Be Reviewed by the Review Committee Prior to IRB Submission

A. Standing Protocol Review Committee Meetings:

1. The Chair/Deputy Chair or designee conducts the Protocol Review meetings on Friday (dates subject to change) from 2:00 - 4:00 pm in the Clinical Center (Building 10) Conference room 13S235A. The protocol review may follow concept reviews (http://medicaloncology.cancer.gov/index.php/scientific-review/clinical-trials/index.htm), if scheduled.
2. The meetings are open to the MOB and affiliate Principal Investigators, invited guests and their research staff.
3. Voting members consist of the MOB and affiliate senior staff, including Staff Clinicians, Investigators, Senior Investigators, Senior Clinicians or Staff Scientists in MOB and the affiliate lab/branch clinical programs and a member of the Laboratory of Pathology, NCI.
4. Protocol review actions require the presence of a quorum, defined as representatives from at least four (4) labs or branches.
5. All voting members attending the meeting are permitted to vote.

B. Protocol Review Process:

1. Each protocol is assigned one primary and two secondary reviewers, the selection of which is based on the expertise and availability of the senior staff member.
   • Primary and secondary reviewers may not have conflict-of-interest (COI) or be an Associate Investigator (AI) on the clinical trial under review.
   • Ad hoc reviewers may be assigned at the discretion of the Chair/Deputy Chair.
2. Protocol documents will also be distributed to the Branch Chief of the Pharmacy Department, CC; Laboratory of Pathology, CCR; and the Statistician, Biostatistics and Data Management Section, CCR.
3. In order to submit a protocol to the Committee for Review, the following applicable items must be in place:
   • Complete draft protocol, including NIH-specific appendix, if applicable
   • Tech Transfer Agreement, if applicable
   • Radiation Safety input, if applicable.
   • Strategic Alignment Questionnaire
   • Any protocol requiring CCR resources must have approval of funds from the Scientific Director prior to submission to the IRB.
4. Complete draft protocols are sent to the following review groups as appropriate:
   • Radiation Safety Committee
   • DEC
   • OBA/IBC
   • FDA (if investigator-sponsored IND)
5. The Chair/Deputy Chair, primary and secondary reviewers, senior staff, and statistician review the protocol for scientific rationale, feasibility, and programmatic goals (See CCR-MOB Protocol Assessment Checklist). In general, administrative aspects, grammatical corrections, or syntax suggestions should not be part of the protocol review, and will be corrected by the staff in the Protocol Support Office.

C. Receipt of Protocol Documents:

1. The protocol submission deadline is midnight Tuesday the week before the protocol review.
2. Senior staff will receive an electronic copy of the protocol being reviewed at least 5 business days prior to each protocol review meeting.
3. The document(s) for Protocol Review will be uploaded into iRIS, with notification of key affected individuals/groups, and must include a complete protocol document with attendant figures, tables, and appendices, and a SRC Strategic Alignment Questionnaire.
4. Staff attending the Review Meeting are responsible for bringing their own paper copies of the electronically distributed protocol documents.
5. Primary and secondary reviewers will e-mail written comments to the MOB Protocol Support Office no later than 5:00 pm the next business day following the Protocol Review meeting.
6. Any Committee member or research team member may provide written comments, submitted no later than 5:00 pm the next business day.

D. Protocol Review Meeting Process:

1. The principal investigator must be present and participate in the discussion, answer questions and receive constructive feedback. In the event the principal investigator cannot attend, the review will be rescheduled.
2. All associate investigators on the protocol should leave the conference room during the vote.
3. Members attending the meeting will vote using anonymous paper ballet; options include:
   • Approved (May have stipulations/recommendations); resubmit for review by Chair - The SRC recommends approval pending PI response to any stipulations/recommendations. The investigator’s response must be returned to the SRC for review and approval by the Chair/Deputy Chair and/or Branch Chief.
   • Approved with stipulations; resubmit for Committee review - In this case the SRC makes the decision that the protocol needs significant scientific revision and will need to be resubmitted to the SRC for full review. In theory this should occur rarely if protocols are adequately vetted at the concept stage.
4. Decisions will be made by majority vote. The Chair will break a tie vote. The decision will be forwarded to the MOB Branch Chief as a recommendation of the Committee, although the MOB Branch Chief has the final approval for Protocol Review. Appeal of any MOB Branch Chief decision can be made to the Scientific Director, NCI. In the event the Branch Chief is the PI of the protocol under review, the final approval will be performed by the Scientific Director CCR, NCI.

STEP 5: The Protocol Review Process Will Be Documented

A. Meeting Outcome:

1. Minutes of the proceedings will be recorded including the time, date, names of all attendees, and decision (per above) including votes for, against and abstain. These will be uploaded electronically into IRiS.
2. Reviewer comments must be received by the PSO by 5:00 pm the next business day following the meeting to be incorporated into the minutes.
3. Minutes will be sent for review to the Chair, primary and secondary reviewers, pharmacy and statistician prior to final approval and distribution.
4. The final minutes (approved by the Branch Chief and Chair) and a track-changed protocol (if changes suggested by the PSO) will be uploaded into iRIS within 5 business days after the review.

B. PI Responses and Re-review:

1. The principal investigator or designee must respond in writing to the SRC stipulations/recommendations (unless advised otherwise) to the PSO within 10 business days. A written exception for an extension describing extenuating circumstances may be requested from the Branch Chief, who may grant up to seven (7) additional business days.
2. PSO staff forward the investigator’s response to the Chair, primary and secondary reviewers, and statistician and pharmacist for review and approval. The primary and secondary reviewers, statistician and pharmacist must respond within one (1) business day to the PSO indicating an approval or disapproval.
3. In the event a primary or secondary reviewer or statistician disagrees with the investigator’s response, the reviewer’s comments are routed to the Chair for evaluation.
4. Following approval/disapproval by the reviewers, the investigator’s response (and reviewer’s response, if any) is forwarded to the MOB Branch Chief for review.
5. If the response is approved by reviewers, Chair and MOB Branch Chief, the documents are distributed to the PI in iRIS within 5 business days.
6. If additional changes to the protocol are required, the Chair will submit a response to the PI via iRIS within 5 business days.

C. Approval/Disapproval Process:

1. Within three (3) business days of receipt, the MOB Branch Chief will review and approve or disapprove the protocol, including the investigator’s response memo. This approval must be co-signed by the Chair and indicates that adequate resources are available to appropriately conduct the proposed study. The Chair and/or Deputy Chair will be the co-signatory.
2. In the event the protocol PI is the Branch Chief, the Scientific Director is the approval signatory.
3. After MOB Branch Chief approval is received, the principal investigator and designee(s) will receive notification from iRIS of approval and may then proceed to submission to the Institutional Review Board (IRB).
4. In the event the Committee or MOB Branch Chief disapproves protocol, the PI may appeal the decision through additional discussion with their Branch Chief initially, followed by discussion with the Scientific Director if resolution is not achieved. The PSO will be contacted by the Chair or Branch Chief and advised about the outcome of the discussion.

STEP 6: Combined Concept/Protocol Review Procedures

A. Protocols that meet the following criteria may undergo a combined Concept/Protocol review:

1. The complete protocol (except for the NCI-specific appendix) has been written and approved by a third party, i.e. cooperative group studies, ongoing pharmaceutical trials.
2. The complete protocol, consent and NCI-specific information is submitted for the review.
3. Specimen procurement protocols or protocols conducting retrospective analysis of stored specimens or existing data may be submitted directly to the MOB Review process for combined review, at the PI’s discretion.

B. Protocols undergoing combined review will be evaluated according to the same criteria as required for Concept and Protocol Review.

C. Members attending the meeting will vote using anonymous paper ballet; options include:

• Approved (with recommendations/stipulations) - The Committee recommends approval but requests the PI revise according to the stipulations/recommendations. The investigator responds in writing to the stipulations and provides documents for review by the Chair/Deputy Chair prior to submission to the IRB.
• Deferred: Resubmit to the Review Committee for a focused review - In this case, the Committee makes the decision that the application needs significant scientific revision and will need to be resubmitted for a focused review by the Review Committee. The PI responds in writing to the stipulations and presents the response at the focused re-review.

D. Appeal: In the event the Committee or MOB Branch Chief disapproves protocol, the PI may appeal the decision through additional discussion with their Branch Chief initially, followed by discussion with the Scientific Director if resolution is not achieved. The PSO will be contacted by the Chair or Branch Chief and advised about the outcome of the discussion.

STEP 7: IRB Submission and Review

A. Once approved by the Branch SRC, the PI will submit a copy of the response memo along with other pertinent protocol and consent documents to the NCI IRB via the Integrated Research Information System (iRIS) within 5 business days or by the next IRB deadline following the 5 business days; for review by the CCR Clinical Director.

STEP 8: Amendments with Substantive Scientific Changes Will Be Reviewed by the Statistician and Scientific Review Committee

A. Review of Amendments:
Amendments should be discussed with the Committee Chair to determine whether full Scientific Review is required using the following guidelines:

1. Scientific and/or statistical review at the discretion of the Chair:
   • A change in protocol primary objectives
   • Treatment or agent(s) change(s) that materially affect trial evaluation.
   • Change in trial design of more than trivial consequence. For example, adding arms or removing arms to a randomized or phase II trial, or changing stratification factors.
   • Adding additional patients to a phase II trial other than replacement of inevaluable patients.
   • Amendments returned by the Scientific Director and/or IRB for review by the SRC.
2. The following amendment changes do NOT require review by the statistician or SRC:
   • Adding cohorts to a phase I trial after failure to reach MTD.
   • Adding limited patients for more than anticipated inevaluable patients or to keep positive study open until implementation of a subsequent trial.
   • Minor changes considered administrative and/or of limited scientific concern.

STEP 9: Activities/Actions of the Clinical Trials Review Process Will Be Documented

A. Data documentation (metrics) will be available for evaluation of clinical trials review process.

B. Interdepartmental Communication reports will inform affected individuals/groups of new clinical trial efforts to allow for pre-planning.

CCR-MOB Protocol Assessment Checklist

View/print the CCR-MOB Protocol Assessment Checklist. (Word)