Release Date:  June 11, 1999

National Institutes of Health

Effective July 1, all multi-site trials with data safety monitoring 
boards are expected to forward summary reports of adverse events to 
each IRB involved in the study.  This action in no way reduces the 
responsibilities of individual IRBs to address such reports coming to 
them from the site over which they have responsibility.  NIH program 
staff will ensure that this language appears in new solicitations for 
clinical trials and is broadly disseminated to current principal 
investigators with appropriate follow-up.  

This National Institutes of Health (NIH) document provides guidance to 
investigators engaged in NIH-supported multi-center clinical trials to 
promote effective reporting of adverse events to the appropriate IRBs.  
The mechanism for reporting should be optimized to protect study 
participants from research risks, while at the same time reducing the 
regulatory burden on these committees.  It is recognized that multiple 
parties, e.g., NIH, Food and Drug Administration (FDA), or industrial 
sponsors, must be notified of adverse events.  However, this document 
provides guidance specifically for IRB notification.  The NIH is 
directing principal investigators to report adverse events by 
identifying the DSMB to the IRB and ensuring reports of assessments of 
adverse events are transmitted from the DSMB to each IRB. 


In response to a congressional request to streamline and reduce 
unnecessary Federal regulations that govern the conduct of extramural 
scientific research, the NIH recently published a report �NIH 
Initiative to Reduce Regulatory Burden� following extensive interviews 
and focus group meetings with the research community 
(  Among 
the five major areas of focus, the report identified the reporting of 
adverse events to the IRB for multicenter clinical trials as burdensome 
and confusing.  Some of the confusion stems from the different 
regulations governing the NIH and the FDA in this area.    

Federal regulations (45 CFR Part 46, Subpart A), shared by 17 
Departments and Agencies as the Common Rule, require written procedures 
and policies for ensuring reporting of �unanticipated problems� 
involving risks to participants to the IRB, appropriate institutional 
officials, and the Department or Agency Head.  Under a different set of 
regulations, 21 CFR 312, the FDA requires the sponsor to notify the FDA 
and participating investigators of any adverse event associated with 
the use of a test article that is �both serious and unexpected.�  The 
reporting of adverse events is in addition to, and does not supplant, 
periodic reports to the IRB at intervals appropriate to the degree of 
risk in the study, generally, an annual report.


The definitions and reporting requirements for adverse events differ 
between the two Federal regulations.  The notification requirements 
described in the Common Rule define adverse events as �unanticipated 
problems� involving risks to study participants or others.  Generally, 
the funding Institutes and Centers establish operational definitions of 
adverse events that apply to the particular trial.  The National Cancer 
Institute (NCI), for example, defines adverse drug reactions in its 
clinical trials involving antineoplastic agents, as: (1) previously 
unknown toxicities; and (2) life-threatening or fatal toxicities 
regardless of whether or not previously unknown.  Toxicity criteria are 
generally included in the protocols.  

The FDA, in Federal regulations 21 CFR Part 312, defines adverse events 
as any untoward medical occurrence that may present itself during 
treatment or administration with a pharmaceutical product, and which 
may or may not have a causal relationship with the treatment.  In the 
guideline entitled �Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting�, the Agency further clarifies and 
defines serious adverse events stemming from a drug study as any 
untoward medical occurrence that at any dose results in  death; is 
life-threatening; requires inpatient hospitalization or prolongation of 
existing hospitalization; creates persistent or significant 
disability/incapacity, or a congenital anomaly/birth defects 


For multicenter clinical trials, an IRB may receive individual adverse 
event reports from sites other than its own.  Such off-site reports may 
not be presented in a useful format and duplicate reports are received, 
sometimes, months apart. The receipt of reports that are not aggregated 
(no numerators or denominators are included) and that come from 
disparate sources contributes to confusion and added workload of the 
IRB.  More importantly, the format of the reports jeopardizes the IRB�s 
ability to make an informed judgement on the appropriate action, if 
any, to be taken.

Investigator Responsibility

An investigator is responsible for knowing the policies of the local 
IRB, adhering to these policies, and maintaining a copy of the policies 
in the study file.  An investigator is also responsible for the 
accurate documentation, investigation and follow-up of all possible 
study-related adverse events.  For NIH-supported multicenter clinical 
trials, investigators do not necessarily report these events to off-
site IRBs as long as the local IRB has been notified.  In lieu of 
receiving individual adverse event reports from each of the clinical 
sites, the IRBs should receive from the investigator a written summary 
report whenever a data safety monitoring board (DSMB) review has taken 
place (see below).  It should be noted that these summary reports do 
not replace other reporting requirements to the local IRBs, e.g., 
annual reports.  

Any protocol submitted for IRB approval should both identify the DSMB 
(not members� names), if any, that will be reviewing interim results, 
and include a brief description of the monitoring plan as well as 
procedures for transmitting the DSMB�s summary reports to the IRB.
Communication between Data Safety Monitoring Board and IRB

DSMBs play an essential role in protecting the safety of participants, 
and assuring integrity of the study.  They accomplish the former by 
being familiar with the protocol, proposing appropriate analyses, and 
periodically reviewing the developing outcome and safety data.  They 
accomplish the latter by reviewing data on such aspects as participant 
enrollment, site visits, study procedures, forms completion, data 
quality, losses to follow-up, and other measures of adherence to 
protocol.  The Board makes recommendations based on those data, 
regarding appropriate protocol and operational changes.  DSMBs (and the 
investigators) monitor toxicity and discuss any concern in this regard. 
The DSMB monitoring function is above and beyond the oversight 
traditionally provided by IRBs and as such is particularly important 
for multicenter trials. 

Typically, the study statisticians and the investigators, along with 
the DSMB, develop monitoring guidelines.  However, for some trials, the 
study statisticians and the investigators develop interim monitoring 
guidelines that are reviewed as part of the protocol review process by 
the Institutes and Centers. 

In the recent re-issuance of the policy for data and safety monitoring 
(NIH Guide for Grants and Contracts, June 12, 1998), the NIH clearly 
addressed the need for communication between the DSMB and IRB.  Once a 
DSMB is established, each IRB should be informed of the operating 
procedures with regard to data and safety monitoring (e.g., who, what, 
when, and how monitoring will take place).  This information will serve 
to assure the IRB that the safety of the research participants is 
appropriately monitored.  If the IRB is not satisfied with the 
monitoring procedures, it should request modifications.  While it is 
recognized that it may not be possible to satisfy every IRB completely, 
IRB comments should be considered seriously.  

The DSMB�s summary report should provide feedback at regular and 
defined intervals to the IRBs. The Institutes and Centers should assure 
that there is a mechanism in place to distribute the report to all 
participating investigators for submission to their local IRB.  For 
example, after each meeting of the DSMB, the executive secretary should 
send a brief summary report to each investigator.  The report should 
document that a review of data and outcomes across all centers took 
place on a given date.  It should summarize the Board�s review of the 
cumulative toxicities reported from all participating sites without 
specific disclosure by treatment arm.  It should also inform 
investigators of the study the Board�s conclusion with respect to 
progress or need for modification of the protocol.  The investigator is 
required to transmit the report to the local IRB. 

IRB Responsibilities

An IRB has the authority to suspend or terminate approval of research 
at its site that has been associated with unexpected serious harm to 
participants.  When an IRB takes such action, it is required to provide 
a statement of reasons for the action and to promptly report this 
action to the investigator, appropriate institutional officials, the 
Department or Agency head, Office for Protection from Research Risks 
(OPRR), and the FDA if an investigational new drug or device is 
involved.  For studies that have a DSMB, the investigator should 
forward summary reports to the IRB as soon as they are received; it is 
within the purview of the IRB to request this information.  IRBs could 
make reporting contingent on IRB approval for specific studies that are 
deemed appropriate.  An IRB should communicate concerns to the DSMB 
and/or the Institute sponsoring the study if it believes that the 
safety of study participants is in jeopardy. 


The NIH program staff will review multicenter clinical trials with the 
following expectations:

A. Investigators submitting a protocol for IRB review must identify the 
DSMB involved, if any.  They must describe plans for monitoring 
adverse events.

B. Investigators must submit a written summary of DSMB periodic review 
to their IRB.

C.	When a study is conducted in multiple sites, the funding Institutes 
and Centers must assure that there is a mechanism in place to 
distribute the report to all participating investigators for 
submission to their local IRBs.

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