Funding | NIAAA

This guidance is intended to assist the NIAAA-supported extramural researchers in establishing and operating a Data and Safety Monitoring Board (DSMB) for clinical trials[1] funded by NIAAA.

The purpose of the DSMB is to provide oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of study data. The National Institutes of Health (NIH) strongly recommends data and safety monitoring in the form of a DSMB for all Phase III clinical trials.  For Phase I and Phase II clinical trials, a DSMB may be established if the principal investigator, their institution, or the clinical trial sponsor deems it necessary. For example, a Phase I or II clinical trial that has multiple clinical sites, is blinded (masked), is studying a particularly high-risk intervention(s), is involving a vulnerable population(s), or has a high probability of early termination for safety or efficacy, should consider establishing a DSMB.

Responsibilities of the Data and Safety Monitoring Board

The DSMB is responsible for reviewing study documentation (e.g., study protocol, the informed consent and other participant handouts, etc.) and ensuring that it has adequate information to assess the safety of the study participants and the efficacy of the intervention during both the treatment and follow-up periods.  A comprehensive description of the data and safety monitoring plan, including details about the DSMB composition, safety and operating procedures, frequency of DSMB monitoring (based on anticipated recruitment and/or identified safety concerns), and reporting requirements, should be outlined in the study protocol.  The DSMB must ensure that the data and safety monitoring plan is sufficient given the complexity of the study and patient population(s).

The DSMB shall evaluate participant safety data throughout the duration of the trial; evaluate the efficacy of the study intervention(s) at intervals specified in the DSMB charter (described below); and independently provide recommendations to the study sponsor to either continue, amend or terminate a clinical trial based on this information. The presence of early unanticipated therapeutic results, side effects, or adverse events are all reasons that a DSMB might recommend termination of a clinical trial early due to safety or efficacy matters.

In addition, the DSMB is responsible for monitoring the performance of each clinical site (e.g., protocol violations, improper participant enrollment criteria, slow accrual rate, low participation rate, failure of randomization, inadequate treatment adherence, inadequate follow-up rate, severely compromised validity).  The DSMB should independently make recommendations for improving the performance of the clinical trial or terminating the trial if it determines the study would be unable to provide useful data, regardless of modifications. A summary of each board meeting and the board recommendation(s) must be provided to the clinical trial sponsor for distribution to each participating clinical site.

Establishing a Data and Safety Monitoring Board

Board Membership

DSMBs are either appointed by NIAAA and act as an independent advisory group to the NIAAA Director, or are appointed locally for investigator-initiated studies[2].

In general, the DSMB voting members are appointed by the clinical trial sponsor or by the Principal Investigator. A DMSB may have as few as three voting members; however, the number of members and the specific composition of the Board will depend on the type and complexity of the clinical trial.  The DSMB composition should be multidisciplinary, including but not limited to clinical medicine (appropriate specialty), biostatistics, bioethics, pharmacology (if applicable), clinical trial methodologies, and other disciplines relevant to the study. For logistical reasons, the clinical trial sponsor or principal investigator may strive to have the fewest number of DSMB members possible while maintaining representation of all needed expertise. The DSMB may also include a patient advocate or a community representative who would bring the perspectives of the population under study but not be enrolled in the study.

DSMB members shall have no real or perceived conflicts of interest with the clinical trial, including any financial and/or scientific ties to the outcome of the study.  Individuals who are invited to serve on the DSMB should disclose in writing to the clinical trial sponsor or principal investigator any potential conflicts of interest, actual and perceived, and provide documentation of financial disclosures.  At the start of each new member's term, the individual should sign a confidentiality statement promising not to disclose any proprietary and nonproprietary data or deliberations of the DSMB.

The Chairperson of the DSMB should be selected among the voting members and have previous experience in monitoring clinical trials.  The Chairperson should be a good facilitator, communicator, and consensus builder.

An Executive Secretary may be designated to facilitate effective functioning of the DSMB. For locally-appointed boards, the DSMB Chairperson may designate the Executive Secretary, and in the case of NIAAA-appointed DSMBs, the Executive Secretary is either a NIAAA employee or a contractor with clinical trial expertise. The Executive Secretary may not vote or be present during closed or executive sessions of the DSMB, and must maintain all information reviewed, discussed and recorded during DSMB meetings with strict confidentiality.

Non-voting, non-member ex officio attendees may participate in DSMB meetings to provide information and answer questions as needed, e.g. research staff involved with the study.  Ex officio attendees must be limited in number and are not permitted to attend the closed or executive sessions of DSMB meetings.

Data and Safety Monitoring Board Charter

NIAAA recommends that DSMBs establish and operate under a written charter that includes well-defined standard operating procedures. The clinical trial sponsor or principal investigator may draft this charter and present it to the DSMB for agreement, or the DSMB may draft the charter with subsequent concurrence by the clinical trial sponsor or principal investigator.  The charter should at a minimum specify: the meeting schedule and format, the format for presentation of data, the individuals who may attend all or part of the DSMB meetings, the individuals who will have access to interim data, the method and timing for providing interim reports to the DSMB, procedures for assessing conflict of interest of potential DSMB members, and other issues relevant to committee operations.

Data and Safety Monitoring Board Meeting Schedule

The frequency and format of DSMB meetings depends on the nature and risk of the studies to be monitored. Meetings may be face-to-face or by teleconference. The Board shall have the option for expedited meetings to review unexpected Serious Adverse Events[3] or other urgent issues that may arise during the course of the trial. Unscheduled meetings may be recommended and initiated by the DSMB Chairperson, the clinical trial sponsor, or the principal investigator.  Clinical trial documentation and data should be available to the Board members at least two weeks prior to the meeting.

Conduct of the Meetings

DSMB meetings are generally divided into three sessions: open, closed and executive.

Open Session

The purpose of the open session is to provide relevant information to the Board about general aspects of the trial. The open session may focus on: the background of the study, the protocol, status of the study, problems with accrual and follow-up, baseline demographic data, compliance issues, frequency of adverse events[4], documentation of endpoints, data quality issues, flow of forms, data based protocol modification issues, external monitoring of coordinating center operations in multicenter trials, and any other study-related issues that can be discussed without reference to interim comparative results. The principal investigator, co-investigators, and statisticians may attend the open session and present information during the meeting.

For NIAAA-appointed boards, the number of coordinating center and NIAAA representatives in attendance should be limited as not to overwhelm free and open exchange among board members.

For locally-appointed DSMBs, NIAAA staff may participate as ex officio attendees unless the board chair decides that the presence of NIAAA staff may inhibit free and open discussion, or compromise the Board’s independence. The issue should be addressed in the DSMB charter. The NIAAA program official involved with the study should be informed of upcoming board meetings at least two weeks in advance, and receive the appropriate meeting materials at the same time as the Board members.

Closed Session

During the closed session, the DSMB reviews and votes on all issues.  This session is usually attended by the DSMB members only. The principal investigator or clinical trial sponsor may attend the closed session at the request of the DSMB. During the closed session, the discussions should focus on: treatment safety, efficacy data, whether the primary study question has been answered, the interim results by treatment arm (usually masked), determination of when study data may be released, review of requests for access to the results of the interim analysis, and results of Board actions and recommendations made in the previous meeting.

For NIAAA-appointed boards, NIAAA staff members involved in the conduct and oversight of the trial are not permitted to attend the closed session.

For locally-appointed boards, NIAAA staff may participate at the discretion of the DSMB Chair.

Executive Session

It is recommended that the DSMB have the option of conducting an executive session with DSMB members only. During these sessions, the Board may discuss any unmasked analysis of a blinded clinical trial and other sensitive issues related to the clinical trial. 

Data and Safety Monitoring Board Recommendations and Meeting Records

The DSMB should keep a record or minutes of all meetings.  Minutes of open session discussions should be kept separately from the minutes of closed and executive session discussions. The Executive Secretary is responsible for preparing the open session meeting minutes. The Board Chairperson should prepare the meeting minutes from the closed and executive sessions and distribute only to the other Board members.

The DSMB shall provide a meeting report to the clinical trial sponsor or principal investigator that includes the Board’s recommendation(s) and sufficient information to explain the rationale for any recommended changes. The report should also include the minutes of the open session. Meeting minutes of the closed or executive session should not be included, but rather a statement that a closed/executive session was held.  The draft report shall be reviewed, edited, and finalized by all Board members, and signed by the Board Chairperson prior to issuance to the clinical trial sponsor or principal investigator.

Scope of Data Monitoring

The precise nature of the data to be monitored and the analyses used by the DSMB will depend on the design of the study and the issues of concern to the Board. The primary source of the data should be case report forms developed for each protocol. Data regarding severe adverse events should be supplemented with additional detailed information from study investigators.  Specific types of data that DSMBs are required to monitor include:

Study Admission Data

Monitoring of admission data should include the number of subjects requesting participation in the study, number of subjects screened, and number of subjects admitted to the study. Depending on the trial, the DSMB may request a report explaining why potential study participants were disqualified from participation. For individuals enrolled in the study, the DSMB should review their eligibility criteria, any protocol deviations and/or violations, and the demographic distribution of the study population.

Protocol Compliance

The DSMB must assess compliance with the protocol, including compliance with safety and administrative procedures. Examples of participation rules include discontinuing participation or withholding treatment due to elevations in liver function tests, severe neuropsychiatric disturbances, or changes in vital signs. The DSMB should also monitor the quality and completeness of the study data being collected. For data collected at specified times, the DSMB should monitor the frequency of missing or erroneous data, as well as the presence and frequency of outliers.

Safety Data

Monitoring of safety data should include review of adverse events, serious adverse events, and any data that allows for comparisons of safety among treatment (active and control) groups, e.g. clinical laboratory data, treatment retention, and reasons for subject drop out.  Safety information for all studies should be reported to the Board in an un-masked manner.  Formal statistical analyses of the safety data may be requested by the Board.

For adverse events, data should be summarized by treatment groups, with individual subject data being available for DSMB review as needed.  Serious adverse events should include all patient outcomes that meet the FDA definition of a serious adverse events. In the assessment of serious adverse events, the DSMB should review each individual case, including treatment group assignment.

Efficacy Data

Efficacy data as determined by the protocol is based on the primary and secondary outcome variables. DSMB monitoring of efficacy data will depend on: 1) study design (e.g., sample size, length of treatment, nature of treatment, and the nature of the primary outcome variable); 2) the nature of the blinding employed in the study; and 3) procedures for interim analyses in the data and safety monitoring plan.

In the event that a safety concern requires an interim analysis of efficacy data, an analysis may be made on a for-cause basis.  Any for-cause interim analysis requested by the DSMB should specify the efficacy outcome of interest, the number of comparisons to be made for purposes of the analysis, the statistical method to be employed in the analysis, the significance required to reach a decision, and the new p value necessary to reject the null hypothesis should the study run to completion (such that the probability of a Type I error is maintained at <0.05 for all primary analyses that would be conducted).

Unblinded Clinical Trial Data

All DSMBs of NIAAA-funded clinical trials can request to review unblinded clinical trial data. The data may be presented for all treatment groups, either combined, by treatment group, or at the participant level.  The presentation of data relating to outcome measures should be presented to the DSMB in the manner and per the timing described in the data and safety monitoring plan for that study.  Clinical trials that include interim analyses of efficacy data should provide the proposed number of analyses to be made, the specific comparisons to be made at each analysis, the termination rules on the basis of efficacy findings (including both standards for the determination of “overwhelming efficacy” and an “inevitable failed trial”), and the methods of statistical correction to be used to control the final overall Type I error. This interim review should be addressed in the study protocol, including steps for facilitating preparation of the data and review by the DSMB in a timely manner so that any resulting DSMB decision can impact the study.   

Contact

For questions or comments about these guidelines, please contact:

Megan Ryan, M.B.A., C.C.R.P.
Clinical Program Director
SBIR/STTR Program Coordinator
NIAAA
6700B Rockledge Drive
Room 1324
Bethesda, MD  20892 - 6902
Tel: (301) 443-4225
E-mail: mryan1@mail.nih.gov

Notes

[1] NIH Clinical Trial Definition - A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. See more at: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-015.html

[2] Site IRBs are responsible for ensuring adequate and appropriate operation of locally (site)-appointed DSMBs.

[3] Serious Adverse Events include adverse events that result in death, require either inpatient hospitalization or the prolongation of hospitalization, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based upon appropriate medical judgment, may also be considered Serious Adverse Events if a trial participant's health is at risk and intervention is required to prevent an outcome mentioned.

[4] Unfavorable changes in health, including abnormal laboratory findings, that occur in trial participants during the clinical trial or within a specified period following the trial.  Two types of adverse event data are to be reported: “Serious” and “Other (Not Including Serious)” adverse events.

Click Here to Submit Serious Adverse Event Report Form to NIAAA.
 

Introduction

Clinical trial investigators are responsible for reporting Serious Adverse Events (SAE), Unanticipated Problems (UPs), and other significant research-related events to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for all NIAAA-funded research. Reporting such events is necessary for NIAAA's oversight and protection of the rights and welfare of participants in NIAAA-funded research. The following describes expectations and steps for reporting SAEs, including SAEs that are considered UPs, to NIAAA. Investigators are also responsible for reporting SAEs and UPs to other regulatory and administration groups (e.g., OHRP, FDA, local IRB, etc.) in addition to NIAAA. Unless otherwise stated in the Notice of Grant Award, summary non-serious adverse events should be reported during each reporting cycle.

Background

In June of 1998, NIH issued a policy stating that each NIH Institute or Center (IC) "should have a system for the appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of the data for all NIH-supported or conducted clinical trials." According to this policy, data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (Phase I); efficacy studies including human laboratory studies (Phase II); efficacy, effectiveness, and comparative trials (Phase III); etc. It includes all types of intervention studies, whether medication or non-medication (e.g., behavioral, prevention, diagnostic) trials. To this end, all clinical trials are required to track and report adverse events (AEs), SAEs, and UPs.

Definitions

Adverse Event (AE): Any untoward or unfavorable medical occurrence in a human study participant, including an abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participants' involvement in the research whether or not considered related to participation in the research.

Serious Adverse Event (SAE): Defined by OHRP guidance as any adverse event temporally associated with the subject's participation in research that meets any of the following criteria:

• Results in death;
• Is life-threatening;
• Requires inpatient hospitalization or prolongation of existing hospitalization;
• Results in a persistent or significant disability/incapacity
• Results in a congenital anomaly/birth defect;
• Any other adverse event that may jeopardize the subject's health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Relatedness:  The event's relationship to the study intervention and/or participation as assessed by the site manager.

Unanticipated Problem (UP):  Defined by 45 CFR part 46 as any incident, experience, or outcome that meets all of the following criteria:

1. Unexpected (in terms or nature, severity, or frequency) given the research procedures described in protocol-related documents and the characteristics of the participant population being studies; AND
2. Related or possibly related to participation in the clinical research; AND
3. Suggests the research places participants or others at a greater risk of harm than was previously known or recognized. 
   **The vast majority of adverse events are not unanticipated problems. Only a small proportion of adverse events are unanticipated problems. Unanticipated events can include other incidents experiences, and outcomes that are not adverse events.

Policy

Consistent with NIH policy, the Clinical Investigator is responsible for the accurate documentation, investigation, and follow-up of adverse events occurring during a clinical trial.  

Procedures for identifying, monitoring, and reporting SAEs including UPs must be described in the study's Institutional Review Board (IRB) and NIAAA approved Data and Safety Monitoring Plan (DSMP) and the study protocol submitted to the NIAAA.  At a minimum, the procedures must include:

• Reporting all SAEs including UPs during the treatment and follow-up phases to NIAAA within 48 hours using the NIAAA SAE Reporting tool.
• For multi-center studies, procedures for notifying all participating study clinical investigators of events and resulting consequences in study procedures. 
• For all UPs, a corrective action plan and measures to prevent reoccurrence must be submitted to NIAAA subsequent or in parallel with the initial UP report. For UPs that are also SAEs, use the NIAAA SAE Reporting tool for reporting the event. 

Clinical Investigator Responsibilities

Investigators are responsible for completing initial SAE documentation as well as completing any follow-up or final SAE forms (if applicable). Reporting SAEs to NIAAA does not supplant reporting these events to other regulatory bodies such as local IRBs, FDA, OHRP, etc. in a timely manner. NIAAA requires Investigators to report SAEs to NIAAA using the NIAAA Serious Adverse Event Reporting tool.  

Determining if an Adverse Event is a Serious Adverse Event

All adverse events should be noted and considered important, but the SAE Reporting tool should only be used for prompt reporting of SAEs. Adverse events not considered an SAE, except for a non-serious UP, should be documented and reported to NIAAA during the appropriate reporting period (e.g., annual, quarterly, etc.). To assist in determining if an adverse event is an SAE, see the Adverse Event Decision Tree for Principal Investigators [PDF - 393 KB]. If further clarification is needed, investigators should consult their IRB of record and the NIAAA SAE Coordinator for additional guidance.  

Contact

For questions or comments please contact: NIAAASAEreports@mail.nih.gov.

Before transitioning into the R00 phase the K99 recipient must secure a tenure-tenure track, full time assistant professor (or equivalent) at an institution eligible to receive NIH funds.

In the final year of the K99, the institution where the R00 phase will be activated, shall alert the NIAAA OEA that an R00 application will be submitted by sending an email addressed to the NIAAA Office of Extramural Activities (NIAAAOEA@mail.nih.gov). OEA will reply through NIH Secure Mail.  The PDF file should be attached by the AOR in response to OEA/NIAAA's email. NIAAA must receive the application package not later than 90 days before the termination of the K99 phase.

In preparing the application follow the instructions (includes, face page with institutional signature, abstract, relevance, performance sites, key personnel, budget pages and justification, biosketches, new resources & environment, final progress report of the K99, R00 specific aims, research strategy section, new checklist).

The application package must include the following:

A copy of the official offer letter (with signed acceptance by the applicant PI) for a faculty position and any additional correspondence from the Chairperson or Dean of the institution where the K99 awardee has been recruited that addresses the following issues:

• Independent position: Describe the employment status as a tenure-track, full-time Assistant Professor (or equivalent). The appointment must NOT be contingent on the transition (or continuation) of the R00 award to the sponsoring institution. 
• Institutional Commitment: Describe the institution's plans for providing start-up funding, technical personnel, research resources and facilities, and/or paying the salary. The start-up package and other institutional support must be similar to that which is typically offered to new faculty members at that institution, and the institutional letter should state whether this is the case. 
• Research and Office Space: Describe the laboratory and office space (size and whether you will share equipment with others, be charged for use of equipment, etc.) that will be provided for conducting the proposed research. 
• Clinical Space: For patient-oriented research projects, describe the clinical space that will be accessible to you for conducting the proposed research. Include details of other research support services (e.g. core facilities, research coordinators, statistical support, nurse coordinators, etc.). For clinical projects performed within an institutional General Clinical Research Center (GCRC) or Clinical and Translational Science Award (CTSA), submit a letter from the GCRC or CTSA Director indicating support of your R00 research project.
• Plan to Independence: If the applicant intends to stay at the mentored phase institution during the independent phase, this letter should describe the plan by which the applicant will separate from the postdoctoral mentor and advance to independence. 
• K99 Mentor's Final Evaluation Statement 
• Timeline to Submit R01: Include a plan and timeline for submitting an independent research grant application in a research area relevant to the mission of an NIH awarding component. 
• Level of effort: R00 awardee must devote a minimum of 9 person-months/year (75% full-time professional effort) devoted to research as required by the R00 award for its entire duration, and a description of the level of effort spent on teaching, clinical and/or administrative duties. Teaching, clinical and/or administrative duties should be minimal during the R00 phase. Please specify the number of hours per week in preparation and contact time for teaching , administrative and other duties outside the scope of the R00 phase. 

JIT information for R00 Phase: The following is not required at the time of review, but will be required before any funding can be released.

• Updated other support 
• IRB approvals 
• IACUC approval

NIAAA requires enhanced monitoring and reporting for NIAAA-supported clinical trials that are rated as greater than minimal risk (as defined in federal regulations at 45 CFR 46.102(i) and 21 CFR 50.3(k)). The purpose of this guidance document is to clarify risk level definitions and NIAAA's monitoring and reporting expectations for all NIAAA-funded clinical trials.

The NIAAA Program Officer (PO) will assess the risk level, proposed level of monitoring, and reporting frequency and requirements for each clinical trial assigned. The level of monitoring and reporting should be commensurate with the level of risk.

In all cases, the Principal Investigator (PI) and the Institutional Review Board (IRB) retain their monitoring and oversight responsibilities for the study regardless of any additional monitoring requirements that may be added (e.g., a Data and Safety Monitoring Board). All requirements specified here are in "addition to" and not "in lieu of" the PI and IRB monitoring and oversight responsibilities.

Risk Levels

LOW RISK means no greater than minimal risk to clinical trial participants. This means that the probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical and psychological examinations or tests and that confidentiality is adequately protected. This category includes protocols that pose "no greater than minimal risk" according to federal regulations.

LOW RISK: Requires ongoing monitoring by the PI and IRB - reporting frequency at least annually to NIAAA.

MEDIUM RISK means greater, but not significantly greater than minimal risk to clinical trial participants. This means that the probability and magnitude of harm or discomfort anticipated in the research risks are more than minimal risk, but not significantly greater. Studies that fall under this category will range in their probability of a moderate-severity event occurring as a result of study participation (and the level of safety monitoring will depend on that probability) but there are adequate surveillance and protections in place to identify adverse events promptly and to minimize harm.

MEDIUM RISK: Requires ongoing monitoring by the PI and IRB and may also require monitoring by an Independent Safety Monitor or an independent Data and Safety Monitoring Board (DSMB) - reporting frequency at least every 6 months (unless otherwise noted in Notice of Award) to NIAAA.

HIGH RISK means significantly greater than minimal risk to clinical trial participants. This means that the probability of an event that is serious, prolonged and/or permanent occurring as a result of study participation or there is significant uncertainty about the nature or likelihood of adverse events. Trials with Significantly Greater than Minimal Risk require adequate protections for foreseeable adverse events.

HIGH RISK: Requires ongoing monitoring by the Principal Investigator, IRB, and a DSMB (or equivalent) - reporting frequency at least every 3 months (unless otherwise noted in Notice of Award) to NIAAA.

Monitoring Recommendations Based on Level of Risk

Safety monitoring for a protocol must be appropriate for the level of risk identified (e.g., Low, Medium, or High). A combination of factors used in assessing the level of risk drives the intensity of monitoring required for a protocol. The requirements outlined below represent the minimal necessary to ensure subject safety. In some cases, the NIAAA PO may require more frequent and/or enhanced monitoring. Additionally, changes to the research project during the course of a study may necessitate an increased level of monitoring (see NIH Guidance NOT-OD-12-129).

Regardless of the level of risk, the PI (or approved co-investigator) will monitor the study with prompt reporting of serious adverse events (SAE) or unanticipated problems and other study related information to the IRB, NIAAA, and other agencies as required. For all clinical trials, it is expected that team meetings between the PI and his/her staff will be conducted on a routine basis to discuss any new adverse events or changes in the protocol. A Data and Safety Monitoring Plan (DSMP) that addresses the potential risks, reporting requirements of adverse events, and elements set-forth by NIAAA will be reviewed and approved by the NIAAA Program Officer. Please refer to the NIAAA DSMP requirements for NIAAA expectations and DSMP elements. This plan will be revised and updated in concurrence with protocol changes that affect risk.

Standard reporting of unanticipated problems and serious adverse events to the IRB is required regardless of the level of monitoring.

Low Risk Studies - Standard monitoring requirements and reporting frequencies.

Medium Risk Studies - Non-serious adverse events and unrelated serious adverse events will be reported in the progress report at the frequency determined by the Program Officer's risk assessment but at least annually. In addition, for clinical trials falling into this risk category, the IRB-approved clinical protocols will be reviewed by the NIAAA Program Officer for completeness and consistency with the grant application. For all Medium Risk (greater than minimal risk) studies, sufficient surveillance and protections must be in place to adequately identify adverse events promptly. An Independent Safety Monitor should monitor the clinical trials when the Principal Investigator is blinded to treatment arms. An Independent Safety Monitor or independent DSMB may also be utilized for the studies/trials that have a higher probability of a moderate-severity event occurring, to review adverse events as they occur and make recommendations as they deem necessary to the study team.

High Risk Studies - Non-serious adverse events and unrelated serious adverse events will be reported in the progress report at the frequency determined by the Program Officer's risk assessment but at least annually. In addition, for clinical trials falling into this risk category, the IRB-approved clinical protocols will be reviewed by the NIAAA Program Officer for completeness and consistency with the grant application. For all High Risk (significantly greater than minimal risk) studies, sufficient surveillance and protections must be in place to adequately identify adverse events promptly. An Independent Safety Monitor should monitor the clinical trials when the Principal Investigator is blinded to treatment arms. An independent DSMB is required and must be utilized for all studies rated as High Risk.

Contact

For questions or comments, please contact:

Megan Ryan
Clinical Trial Operations and Technology Innovation Officer
Office of the Director/NIAAA
mryan1@mail.nih.gov

Purpose

To support a two-phased award without a break in funding in which transition to the second phase depends on several factors, including the achievement of negotiated milestones.

Currently this applies to the following activity codes:

• R21/R33
• R61/R33
• UH2/UH3
• UG3/UH3

A phased award includes: 1) Phase I for milestone-driven exploratory or feasibility studies with a possible transition to 2) Phase II for expanded development.

Transition to Phase II depends on the awardee's completing milestones evaluated in peer review and negotiated with NIAAA program staff before Phase I was awarded, as well as program priorities and the availability of funds.

Submission of Phase II (R33, UH3) Due date, 90 days before the termination date of phase I.
Electronic submission of the phase II through eRA, Grants.Gov and/or ASSIST is not yet available. The recipient institution shall submit the application package in PDF format by initially sending an "email of intent to submit" niaaaoea@mail.nih.gov. OEA/GMB will respond by providing instructions to the AOR on how to submit through NIH Secure mail. Grant applications must not be sent by regular emails to NIH Staff.

GMB/OEA processes the submitted phase II and arranges with CSR to create a record in eRA.

The phase II application (PDF forma) must include the following

• Completed face page using page 1 from Non-Competing Continuation Progress Report (PHS 2590) PDF
• The packet must include:
  • Abstract and Public Health narrative of the Phase Summary of the Phase I/II
  • Detailed budget/justification pages for each year of Phase II
  • Biosketches
  • Specific Aims and importance of the work accomplished
  • A section called "Milestones," describing in detail the milestones and progress achieved in Phase I
  • If applicable, summary of the amendments to address reviewers' comments from the initial peer review as justification that would provide additional information about Phase II and/or amendments related to alternate plans as originally described in the original application approved for funding (1 page)
  • Research Plan section describing the phase II of the original funded phase I/II application (not to exceed the phase II section in the original funded grant).

Administrative Review by Program Staff and Grants Management Specialist

• Program Officer assigned to the application shall conduct the scientific merit review of phase II as described in the review criteria in the NOFO.
• Grants Management Specialist conducts administrative and financial review and may request updated JIT and other pertinent information and/or documents.
   

Contact

Dr. Philippe R Marmillot, Acting Director OEA
marmillotp@nih.gov

Judy S. Fox, GMO
judy.fox@nih.gov