IND Safety Reporting Patrick Archdeacon, MD Office of Medical Policy/CDER/FDA

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IND Safety Reporting Patrick Archdeacon, MD Office of Medical Policy/CDER/FDA
Patrick Archdeacon, MD
Office of Medical Policy/CDER/FDA
May 13, 2015
IND Safety Reporting
• Background – Rationale for and overview of the
2010 revisions to the IND safety reporting rule
• Challenges to implementation of the final IND
safety reporting rule
• Efforts to facilitate implementation
• Looking forward
Overview of IND Safety
Reporting Rule (21 CFR 312.32)
• The final rule, published September 2010,
– Codifies FDA’s expectations for timely review,
evaluation, and submission of important and useful
safety information
– Defines responsibilities of investigators
– Defines responsibilities of sponsors (specifically routine
review of safety information and criteria for expedited
safety reporting)
• Improves the utility of premarket safety reports
and reduces the number of uninformative
individual reports, thereby enhancing the ability of
FDA, investigators, and IRBs to focus on safety
issues that affect human subjects
Problem: Uninformative individual
IND safety reports
• Sponsors often report serious adverse events as
individual cases that are uninterpretable as single
events (i.e., require evaluation in the aggregate to
interpret) and/or
– Are likely to have been manifestations of the underlying
disease (e.g., mortality or major morbidity)
– Commonly occur in the study population independent of
drug exposure (e.g., strokes or acute myocardial infarctions
in an elderly population)
– Are study endpoints (i.e., the study was evaluating
whether the drug reduced the rate of these events)
Internal FDA Retrospective
Review of Sample of IND Safety Reports
• Purpose:
– To understand distribution of types and volume of reports
that are uninformative as individual cases
• Method:
– Retrospectively reviewed a sample of 94 initial IND safety
reports for 3 INDs submitted prior to the IND safety
reporting final rule (i.e., prior to September 2010)
• One IND – large outcome trial (reviewed 50 reports)
• Two INDs – smaller trials (reviewed 44 reports)
Highlights of Findings
• Very few of the reports were judged interpretable as single events
– Approximately 4-6% for each of 3 INDs
• Most of the events (over 90% for outcome trial) were either study
endpoints, events listed as expected in the investigator brochure, or
events anticipated in the study population and/or listed in the protocol
• Over same time period in large outcome trial, ~ 500 follow-up reports
were submitted
• Differences in attribution (i.e., reasonable possibility that the event is
related to the drug)
– Investigators rated ~90% of cases as at least “possibly related”
– Sponsors rated ~19% of cases as at least “possibly related”
– FDA rated ~5% of cases possibly related
• Overall quality of reports low – incomplete; unclear if they were
unblinded; lacked analysis with respect to similar, previous reports
But why are such uninformative
reports a significant problem?
• Drain on limited FDA, investigator, and IRB
– May discourage potential investigators from
participating in clinical trials enterprise
(contributes to investigator turnover)
– Ability of investigators and regulators and IRBs to
detect valid safety signals negatively impacted
How does 2010 IND Safety Rule improve
utility of expedited safety reports?
• Clarifies reporting requirement: Report any
suspected adverse reaction that is both serious and
unexpected – must meet all three definitions
– Suspected adverse reaction means any adverse event
for which there is a reasonable possibility that the drug
caused the event
– Unexpected means not listed in the investigator
– Serious means results in death, is life-threatening,
• Report only if there is evidence to suggest a causal
relationship between the drug and the adverse
event (sponsor judgment)
Examples of Evidence that
Suggest a Causal Relationship
• Single occurrence of an event that is uncommon and known to be
strongly associated with drug exposure (e.g., angioedema, hepatic
injury, Stevens-Johnson Syndrome)
• One or more occurrences of an event that is not commonly
associated with drug exposure but is otherwise uncommon in the
population exposed to the drug (e.g., tendon rupture)
• An aggregate analysis of specific events observed in a clinical trial
that indicates those events occur more frequently in the drug
treatment group than in a concurrent or historical control group
(e.g., known consequences of underlying disease, events common
in study population)
Determination of causality is critical to patient safety and only the sponsor has
both the sufficient data and resources to make this determination for events
requiring aggregate analyses
Implementation Challenges
Comments on draft guidance (published September
2010) and concerns expressed by sponsors
– New requirement for aggregate reports
• Requested more detail on FDA’s expectations (Thresholds)
• Concern about unblinding (Unblinding)
– Causality assessment is made by sponsors for US reports
and by either the sponsor or investigator per ICH E2A
• Required changes in structure and processes for some
sponsors of international trials (Harmonization)
Efforts to Facilitate Implementation
of the IND Safety Reporting Rule
• Final guidance – “Safety Reporting
Requirements for INDs and BA/BE Studies”
published December 2012
• Clinical Trials Transformation Initiative (CTTI)
projects on IND Safety Reporting
Final Guidance Overview
• Provides advice on other safety reporting issues that
have generated questions
– Investigator brochure
– Aggegrate analyses
– Unblinding
2012 Guidance: Investigator Brochure
• Investigator brochure is basis for determining
whether a suspected adverse reaction is
– IB should specifically list ARs for which a causal
relationship is suspected or confirmed
– Sponsors should update the IB with new safety
information, exercising judgment in determining
– Until IB is updated, subsequent occurrences of SARs
must be submitted in IND safety reports
– IBs can be updated with addendums, rather than
reissuing entire brochures
2012 Guidance: Aggregate Analysis
• Protocol-specified serious adverse events
– Identify events and monitoring plan in the protocol
– Limit to events that are common in study population
– Safety team or independent group monitors the rates at appropriate
– Report if an aggregate analysis indicates that events are occurring
more frequently in the drug treatment group
• Non-protocol-specified serious adverse events
– Serious adverse event that is not protocol-specified still may not meet
criteria for expedited reporting
– Sponsors should use judgment to determine if there is a “reasonable
possibility” that the drug caused the event
– Final guidance describes sponsor’s flexibility to report these events
• “FDA will accept expedited reports for individual cases of unexpected serious
adverse events that are not study endpoints and are not specified in the protocol as
“anticipated” (e.g., they are known consequences of the disease being treated or
common in the study population) to address concerns expressed by sponsors about
not expeditiously reporting such cases.”
• Note: This “flexibility” is an option. The preferred approach is to NOT report unless
the event meets the criteria for reporting
2012 Guidance: Unblinding
• Blinds should ordinarily be broken for IND safety
reports submitted to FDA and participating
• Unblinding single or small numbers of serious and
unexpected SARs should not compromise the integrity
of the study, as such unblinding should be rare
• Aggregate reports should include the event rates in the
treatment and comparator groups and also the
unblinded individual reports. However, if sponsor has
concern that such unblinding will compromise the
integrity of the trial, this should be discussed with
review division
International Harmonization
• ICH E2A states: “All cases judged by either the reporting HCP
or the sponsors as having reasonable suspected causal
relationship to the medicinal product qualify as ADRs…”
• However, ICH E2A also states “It may be appropriate to reach
agreement with regulatory authorities in advance concerning
serious events that would be treated as disease-related and
not subject to routine expedited reporting.”
• European Directive 2001/20/EC and the relevant guidance
(‘CT-3’) also discuss provisions for not routinely reporting prespecified categories of serious adverse events
• Ultimately, sponsors have the option of developing a single
approach that meets the requirements of various regulatory
agencies or developing parallel reporting systems.
• FDA and Duke University - founding members of a publicprivate partnership
• Members include stakeholders from government, industry,
academia, patient and consumer representatives, clinical
investigators, professional societies, and clinical research
• Mission is to identify and promote practices that will increase
the quality and efficiency of clinical trials
• Scope is to generate evidence about how to improve the
design and execution of clinical trials and to foster widespread
change based on evidence
CTTI Project:
IND Safety Assessment and
• Purpose: To promote responsible oversight of safety
for premarket drugs consistent with the intent of the
IND safety reporting final rule
• Project plan
– Collect sponsors’ current practices for premarket safety
assessment (November-December 2011)
– Convened an expert meeting in February 2012
– Convened a workgroup of biostatisticians
– Summarized current practices, concerns, and issued
recommendations (November 2013)
Survey and Expert Meeting
• 54 question survey completed by 12 of the 14 sponsors
who were solicited for input
• Survey results describe the methods and structures used
in premarket safety surveillance and reporting
• Expert meeting held to discuss gaps between current
practice and an optimal system for early detection of
valid safety signals across a drug development program
– Organization of personnel and data
– Methods and processes developed to conduct aggregate
product safety assessments
– Confirmation and escalation of potential safety signals
– Analysis of blinded studies
CTTI Recommendations on
IND Safety Assessment and Communication*
• Upfront safety planning for a development
• Implementation of safety assessment in clinical
• Threshold for expedited reporting of anticipated
• Adverse events not pre-specified in the protocol
* Full recommendations at http://www.ctti-clinicaltrials.org/files/IND_Safety/INDsafety20
CTTI recommendations:
Upfront safety planning for development program
• Prospectively identify SAEs anticipated to
commonly occur in the study population
independent of drug exposure (e.g, AMI in
• Specify in trial protocols that such anticipated
SAEs will not be reported as individual IND
safety reports
CTTI recommendations:
Implementation of safety assessment in clinical
• Sponsors should periodically evaluate totality
of safety information
• As comparisons of event rates to a historical
control are less sensitive than comparisons
across treatment arms, unblinding of SAEs
may be required.
• Unblinded analyses should be conducted by
firewalled safety committees
CTTI recommendations:
Threshold for expedited reporting
• Sponsors should not submit serious adverse
events that are prospectively identified as
anticipated to occur in the study population as
individual IND safety reports. Instead,
sponsors should report such events in
aggregate at the point in time when the
totality of the data may suggest a causal
CTTI recommendations:
SAEs not specified as anticipated
• As with anticipated events, more than one
occurrence may be necessary before the
sponsor can judge that there is reasonable
possibility of causality
• If there is uncertainty or weak evidence of
causality, sponsors could consider reporting
these as individual events
Impact of 2010 Rule, 2012
Guidance, and CTTI project
• Internal audits of FDA Document Archiving Reporting
and Regulatory Tracking System indicate that numbers
of expedited reports received have not decreased
• In CTTI follow on project focused on IND safety reports
in oncology, 92% of 191 survey respondents reported
no change (82%) or only slight change (10%) in quality
of reports
• In contrast, in same survey, majority of industry
sponsors reported that they had adopted new
practices that decreased reports by greater than 50%
Follow-up CTTI Project:
IND Safety Advancement
• Project objectives
– Understand sponsor challenges to implementation of the
IND safety reporting rule in oncology trials
– Understand sponsor motivation to change practice of IND
safety reporting in oncology trials to comply with the IND
safety reporting rule
– Understand challenges to investigator receipt and
management of IND safety reports
– Facilitate adoption of best practices for communicating and
managing IND safety reports consistent with FDA guidance,
the IND safety rule, and CTTI recommendations
Looking Forward
• Final rule has been in effect since March 28, 2011
• To date, little to no evidence that sponsors have
significantly changed practices (most of the evidence that
has been gathered relates to oncology trials)
• Strongly encourage sponsors to develop protocols that
identify adverse events that will not be submitted
• CTTI recommendations for ongoing IND Safety
Advancement follow-up project
• FDA considering the need for additional guidance and/or
other measures to decrease number of uninformative
Internet Locations
• Final rule, final guidance, and small entity
compliance guide:
• CTTI IND Safety Assessment and Communication
Project: http://www.ctti-clinicaltrials.org/whatwe-do/study-conduct/ind-safety
• CTTI IND Safety Advancement Follow-up Project:
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