Pharmacovigilance and

Risk Management
Chapter 17
OBJECTIVES
Understand the reporting requirements for Investigational
New Drug (IND) safety data
Understand the postmarketing requirements for safety
data for drugs and biologics
Understand the postmarketing requirements for safety
data for medical devices
Understand the requirements for Risk Evaluation and
Mitigation Strategies (REMS)
Understand the requirements for proprietary name review
of drugs and biologics
During Clinical Trials
Adverse Event - An adverse event is any untoward medical
occurrence associated with the use of a drug in humans whether or
not considered drug-related
Life-threatening Adverse Event or Life-threatening Suspected
Adverse Reaction - Places the patient or subject at immediate risk
of death
Serious Adverse Event or Serious Suspected Adverse Reaction
- Results in any of the following outcomes:
death, a life-threatening adverse event, inpatient hospitalization or
prolongation of existing hospitalization, a persistent or significant
incapacity or substantial disruption of the ability to conduct normal life
functions, or a congenital anomaly/birth defect, or medical judgement
More definitions
Suspected Adverse Reaction - A reasonable
possibility that the drug caused the adverse event
Unexpected Adverse Event or Unexpected
Suspected Adverse Reaction - Not listed in the
Investigator Brochure, or is not listed at the specificity
or severity, is not consistent with the risk information
described in the general investigational plan or
elsewhere
Reporting Requirements for Clinical
Trials
Investigator is required to promptly report to the sponsor
all adverse events encountered with the drug
Sponsor reports to FDA and all participating investigators
in a written IND safety report of:
1. any adverse experience associated with the use of the
drug that is both serious and unexpected
2. any finding from tests in laboratory animals that
suggests a significant risk for human subjects, including
reports of mutagenicity, teratogenicity or carcinogenicity
New information
Must be reported to the agency within 15 days of the sponsor
becoming aware of an occurrence:
Findings from clinical or epidemiological studies that suggest a
significant risk to study participants
Serious suspected adverse reactions that occur at a rate higher than
expected
Serious adverse events from bioavailability studies and
bioequivalence studies conducted without an IND
Submitted either on a Form FDA 3500A or on a Council for
International Organizations of Medical Sciences (CIOMS) I form
Submit reportable event information no later than 15 calendar days
after the event has been made clear
Generics
For bioavailability (BA) and bioequivalence (BE) studies conducted
without an IND, the person conducting the study, including any
contract research organization (CRO), is required to notify FDA of any
serious adverse event within 15 days of its occurrence, and of any fatal
or life-threatening adverse event from the study within seven days of
its occurrence.
Must be submitted to the director, Office of Generic Drugs in CDER
Relevant follow-up information to a BA/BE safety report must be
submitted as soon as the information is available
Upon request from FDA, the person conducting the study, including any
CRO, must submit to FDA any additional data or information that the
agency deems necessary within 15 days after receiving the request
Post Marketing Safety Reporting
Adverse Drug Experience - An adverse drug experience
is any adverse event associated with the use of a drug,
whether or not considered drug related, including the
following:
in the course of the use of a drug product in professional
practice
from drug overdose whether accidental or intentional
from drug abuse
from drug withdrawal
any failure of expected pharmacological action
Post Marketing Safety Reporting
Associated With the Use of the Drug - There is a
reasonable possibility that the experience may have
been caused by the drug
Disability - An adverse event that results in a
substantial disruption of a persons ability to conduct
normal life functions
Life-threatening Adverse Drug Experience - Any
adverse drug experience that places the patient, in the
view of the initial reporter, at immediate risk of death
Serious Adverse Drug Experience - Same as clinical
Unexpected Adverse Drug Experience Not in
Authorities
CDERs Office of Surveillance and Epidemiology Divisions consists
of three divisions:
Division of Drug Risk Evaluation (DDRE) - detect and assess safety
signals for all marketed drug products
Division of Medication Errors and Technical Support (DMETS)
premarketing reviews of all proprietary names, labels and labeling
and analysis of medication errors
Division of Surveillance, Research, and Communication Support
(SRCS) oversees MedWatch, risk communication research and
activities such as Medication Guides, Patient Package Inserts and
pharmacy information surveys, and international regulatory liaison
activities for all drug and biologic postmarketing safety issues.
Postmarketing Drug/Biologic
Surveillance:
Individual Case Safety Reports
(ICSRs)
Individual case safety report (ICSR), applicants should,
at a minimum, have knowledge of the four data
elements:
an identifiable patient
an identifiable reporter
a suspect drug or biological product
an adverse experience or fatal outcome believed to
be due to the suspect drug or biological product
Sponsors of approved products
Review ADE information obtained from all potential
sources (foreign and domestic), including:
marketing experience
scientific literature (peer-reviewed and non-peer-
reviewed)
unpublished reports
postmarketing clinical investigations
postmarketing epidemiological or surveillance studies
Timelines and Forms
Keep ADE files for 10 years per SOP
All adverse events (domestic and foreign) that are both
serious and unexpected must be submitted within 15
calendar days of initial receipt by anyone in the employ
of the applicant
Use form FDA 3500A or a CIOMS I form (Foreign
Sponsor)
Electronic or Paper is acceptable
Causality is not a concern, unless during an
investigational study
Follow up reports required as in an IND
And More Reports.
The Dietary Supplement and Nonprescription Drug
Consumer Protection Act (DSNDCA) (PL 109-462)
amended the Federal Food, Drug, and Cosmetic Act
(FD&C Act) to add safety reporting requirements for
nonprescription drug products that are marketed
without an approved application
Post Marketing Periodic Safety Reports Quarterly for
the first 3 years, then annually
Reports
The regulations require a postmarketing periodic report
to contain:
a narrative summary and analysis of the information in
the report and an analysis of the 15-day Alert Reports
submitted during the reporting interval
a Form FDA 3500A for each spontaneously reported
adverse experience occurring in the US that was not
reported in a 15-day Alert Report
a history of actions taken since the last report because
of adverse experiences
Report sections
Section 1: Narrative summary and analysisA narrative summary and analysis
of the information in the postmarketing period report and an analysis of the 15-
Day Reports (i.e., serious, unexpected adverse experiences) submitted during
the reporting period must be provided
Section 2: Narrative discussion of actions takenA narrative discussion of
actions taken must be provided, including any labeling changes and studies
initiated since the last periodic report
Section 3: Index line listingAn index line listing of Form FDA 3500As or
Vaccine Adverse Event Reporting System (VAERS) forms included in
Section 4: Form FDA 3500As or VAERS forms Form FDA 3500As or VAERS
forms must be provided for the adverse events that have not already been
submitted as 15-Day Alerts for experiences that occurred in the US during the
reporting period.
Or, Prepare an PSUR as described in ICH
Safety Monitoring by FDA
FDA tracks adverse drug reaction reports by entering all
safety reports for approved drugs and therapeutic
biologic products into the computerized FDA Adverse
Event Reporting System (FAERS) database
May lead to a Dear Health Care Professional Letter
Also posted quarterly on FDA Website
REMS
FDAAA created Section 505-1 of the FD&C Act, which authorizes
FDA to require sponsors of certain applications to submit and
implement a REMS
assessing a products benefit-risk balance
developing and implementing tools to minimize a products risks
while preserving its benefits
evaluating tool effectiveness and reassessing the benefit:risk
balance
making adjustments, as appropriate, to the risk minimization
tools to further improve the benefit:risk balance
Need to ensure the REMS is effective
Device PostMarketing Surveillance
21 CFR 803: Medical device reporting:
Device user facilities must report deaths and serious injuries that a device
has or may have caused or contributed to, establish and maintain adverse
event files and submit summary annual reports
Manufacturers or importers must report deaths and serious injuries their
device has or may have caused or contributed to. In addition, they must
report certain device malfunctions. They also must establish and maintain
adverse event files. In addition, manufacturers must submit specified
follow-up information
Medical device distributors must maintain records of incidents but are not
required to file these incidents.
21 CFR 806: Medical devices; reports of corrections and removals
21 CFR 822: Postmarket surveillance
MEDSUN
Medical Product Safety Network (MedSun) MedSun is
an enhanced surveillance network comprised of
approximately 280 hospitals nationwide that work
interactively with FDA to better understand and report
on device use and adverse outcomes in the real-world
clinical environment
Specialty networks within MedSun focus on device-
specific areas such as cardiovascular devices (HeartNet)
and pediatric intensive care unit devices (KidNet).
 Postapproval StudiesFDA may order a postapproval study
as a condition of approval for a device approved under a
Premarket Approval (PMA) application
Postmarket Surveillance StudiesFDA may order a
manufacturer of certain Class II or Class III devices to
conduct postmarket surveillance studies (often referred to
as 522 studies)
FDA Discretionary StudiesFDA also conducts its own
research to monitor device performance, investigate
adverse event signals and characterize device-associated
benefits and risks to patient sub-populations
Sentinel Initiative
FDAAA required
a long-term effort to create a national electronic system
for monitoring FDA-regulated medical product safety
It uses pre-existing electronic healthcare data from
multiple sources
exploring a variety of approaches for improving the
agencys ability to quickly identify and assess safety
issues
Pilot program is mini-sentinel