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


Release Date:  June 5, 2000


NOTICE:  NOT-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 

  (<a href="http://grants.nih.gov/grants/guide/notice-files/not98-084.html">http://grants.nih.gov/grants/guide/notice-files/not98-084.html</a>) 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 

<a href="http://grants.nih.gov/grants/guide/notice-files/not99-107.html">http://grants.nih.gov/grants/guide/notice-files/not99-107.html</a>)


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.

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