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 person’s 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 current labeling
Authorities
• CDER’s 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 analysis—A 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 taken—A narrative discussion of actions
taken must be provided, including any labeling changes and studies initiated since
the last periodic report
• Section 3: Index line listing—An 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 product’s benefit-risk balance
• developing and implementing tools to minimize a product’s 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 Studies—FDA may order a postapproval study as a
condition of approval for a device approved under a Premarket
Approval (PMA) application
• Postmarket Surveillance Studies—FDA 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 Studies—FDA also conducts its own research to
monitor device performance, investigate adverse event signals and
characterize device-associated benefits and risks to patient subpopulations
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 agency’s ability to
quickly identify and assess safety issues
• Pilot program is mini-sentinel