FURTHER GUIDANCE ON A DATA AND SAFETY MONITORING FOR PHASE I AND PHASE II TRIALS

Release Date:  June 5, 2000

NOTICE:  OD-00-038

National Institutes of Health

Policy: Beginning with the October 2000 receipt date, investigators 
must submit a monitoring plan for phase I and II clinical trials to the 
funding Institute and Center (IC) before the trial begins.

Background  

In June 1998, the National Institutes of Health (NIH) issued a policy 
on data and safety monitoring 
(http://grants.nih.gov/grants/guide/notice-files/not98-084.html) that 
requires oversight and monitoring of all intervention studies to ensure 
the safety of participants and the validity and integrity of the data.  
The policy further elaborates that monitoring should be commensurate 
with risks and with the size and complexity of the trials.  The NIH 
already requires data and safety monitoring, generally, in the form of 
Data and Safety Monitoring Boards (DSMBs) for phase III clinical 
trials.  For earlier trials (phase I and II), a DSMB may be appropriate 
if the studies have multiple clinical sites, are blinded (masked), or 
employ particularly high-risk interventions or vulnerable populations.  

This document provides further guidance for monitoring of phase I and 
II trials.  This guidance does not take the place of Institutional 
Review Board (IRB) guidelines, Food and Drug Administration (FDA) 
requirements, or special NIH guidelines e.g., NIH Guidelines for 
Research Involving Recombinant DNA Molecules.  Specifically, phase I 
and II gene transfer trials must comply with additional requirements 
imposed by the latter NIH Guidelines, e.g., reporting of adverse events 
to the Office of Biotechnology Activities.    

Monitoring plan

For phase I and II clinical trials, investigators must submit a general 
description of the data and safety monitoring plan as part of the 
research application.  This plan will be reviewed by the scientific 
review group and any comments and concerns will be included in an 
administrative note in the summary statement.   A detailed monitoring 
plan, however, must be included as part of the protocol and submitted 
to the local IRB and reviewed and approved by the funding Institute and 
Center (IC) before the trial begins.  We strongly encourage the IRB to 
review the plan.  Each IC should have a system for appropriate 
oversight and monitoring of the conduct of clinical trials to ensure 
the safety of participants and the validity and integrity of the data.  
IC oversight of the monitoring activities is distinct from the 
monitoring itself.  Oversight of monitoring must be done to ensure that 
monitoring plans are in place for all phase I or II trials and that the 
IC is informed of recommendations and any necessary actions that 
emanate from the monitoring activities. 

At a minimum, all monitoring plans must include a description of the 
reporting mechanisms of adverse events to the IRB, the FDA and the NIH.  
Investigators must ensure that the NIH is informed of actions, if any, 
taken by the IRB as a result of its continuing review.  ICs have the 
flexibility to determine the reporting requirements of adverse events.  
The reporting requirement to the NIH may range from individual adverse 
event reports to summary reports from the monitoring group. In specific 
cases where the funding IC is the sponsor of the test agent, i.e., 
holder of the Investigational New Drug (IND) application, investigators 
must submit individual adverse event reports to the IC (as sponsor) in 
accordance with FDA regulations.  Occasionally, there are phase I or II 
trials that have established safety monitoring committees.  In these 
cases, summary reports of the committees’ discussions of adverse events 
must be submitted to the IC and IRB.  The reporting requirements for 
adverse events, as approved by the ICs, are in addition to the annual 
progress reports to the NIH for type 5 awards (non-competing awards).   

The overall elements of the monitoring plan may vary depending on the 
potential risks, complexity, and nature of the trial.  In phase I and 
II trials, a number of factors influence risk. A phase I trial of a new 
drug or agent may involve increasing risk, to a small number of 
participants, as the drug is escalated in dosage.  For phase II trials, 
there is sometimes information about risks in normal subjects, but risk 
may be increased as more participants are involved and the toxicity and 
outcomes may be confounded by the disease process. In situations 
involving potentially high risks or special populations, investigators 
must consider additional monitoring safeguards. 

For many phase I and phase II trials, independent DSMBs may not be 
necessary or appropriate when the intervention is low risk.  
Continuous, close monitoring by the study investigator may be an 
adequate and appropriate format for monitoring, with prompt reporting 
of toxicity to the IRB, FDA and/or NIH.  In some instances, the study 
investigator or the IRB may determine that an independent individual 
may be needed for monitoring.  In studies of small numbers of subjects, 
toxicity may more readily become apparent through close monitoring of 
individual patients, while in larger studies risk may better be 
assessed through statistical comparisons of treatment groups.  

For multisite phase I and II trials, study investigators should 
organize a central reporting entity that will be responsible for 
preparing timely summary reports of adverse events for distribution 
among sites and the IRBs.  The frequency of the summary reports will 
depend on the nature of the trials.   Additional NIH guidance for 
reporting adverse events for multisite clinical trials with a DSMB has 
been published in 1999.  (See 
http://grants.nih.gov/grants/guide/notice-files/not99-107.html)

Grantee institutions with a large number of clinical trials may develop 
standard monitoring plans for phase I and II trials.  Thus, individual 
study investigators will be able to include the IRB-approved monitoring 
plan in their submission to the NIH.   However, such plans should 
always be evaluated for appropriateness to the particular 
investigation.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.