Pharmacovigilance in clinical trials

Victoria Nambasa
Manager Pharmacovigilance
National Drug Authority
 Outline
• Importance of Pharmacovigilance
• Key definitions
• Reporting timelines
• Gaps and opportunities
 What is Pharmacovigilance?
• Pharmacovigilance is concerned with the
detection, assessment and prevention of
adverse reactions to drugs.
• The science and activities relating to the
detection, assessment, understanding and
prevention of adverse effects or any other drug
related problem (WHO, 2004)
 Why Pharmacovigilance in CT?
• Majority of safety information considered
prior to market authorization is derived from
controlled clinical trial.
• The goals of adverse event monitoring
– Protect subjects in clinical study
– Protect future patients by determining risk benefit
and risk factors once a product is marketed
– Protect future patients by allowing new drugs to be
made available
 Key Definitions
• Adverse Event
ICH E6: “An AE is any untoward medical occurrence in a patient
or clinical investigation subject administered a pharmaceutical
product and that does not necessarily have a causal
relationship with this treatment.
 An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease temporally associated with
the use of a medicinal (investigational) product, whether or not related to the
medicinal (investigational) product.”
21CFR part312.32 (a) “Adverse event means any untoward
medical occurrence associated with the use of a drug in
humans, whether or not considered drug related.”

5
 Definition-2
• An Unexpected Reaction:
An adverse reaction, the nature or severity of
which is not consistent with description on the
reference safety information(IB for CT),
market authorization, or expected from the
characteristics of the drug.
 Definition -3
• Seriousness- is based on patient/event outcome or
action criteria usually associated with events that pose
a threat to a patient's life or functioning. serves as a
guide for defining regulatory reporting obligations
 results in death,
 is life-threatening
 requires inpatient hospitalisation or results in
 prolongation of existing hospitalisation,
 results in persistent or significant disability/incapacity
 is a congenital anomaly/birth defect,
 is a medically important event or reaction
 Who is monitoring?
• The IRB/IEC
safeguard the rights, safety, and well-being of all trial
subjects. Special attention should be paid to trials that
may include vulnerable subjects
• The Investigator
 Ensure that adequate medical care is provided to a subject
for any adverse events, including clinically significant
laboratory values, related to the trial.
 should inform a subject when medical care is needed for
intercurrent illness(es) of which the investigator becomes
aware.
 Investigator-2
• All SAEs should be reported immediately to the
sponsor.
– except for those SAEs that the protocol or
other document (e.g., Investigator's
Brochure) identifies as not needing
immediate reporting
• Comply with the applicable regulatory requirement
(s) related to the reporting of unexpected serious
adverse drug reactions to the regulatory authority(ies)
and the IRB/ IEC.
 Who is monitoring-3
• The Sponsor:
– Monitoring of the site
– Expedited reporting of individual reports
(CIOMS or MedWatch etc)
Narrative Unblinding
– Ongoing Safety Evaluation
 Sponsor –site monitoring
– Verify that: “Adverse events, concomitant
medications and intercurrent illnesses are
reported in accordance with the protocol on the
CRFs.”
– Determining whether all adverse events (AEs)
are appropriately reported within the time
periods required by GCP, the protocol, the
IRB/IEC, the sponsor, and the applicable
regulatory requirement(s).
 Systematic systems for monitoring
safety(CIOMS Working Group VI, 2005)
 Planning
Prior to study.
Ensure protocol includes detailed safety outcome
measures if specific safety issues are anticipated e.g lab,
ECG.
For trails involving special groups, details of outcome measure is
important and how it will be obtained.
Establish medical monitoring plan
During the study
After completion
 Procedures(roles and responsibilities, frameworks for decision
making, implementation of risk mitigation measures?
Systematic systems for monitoring safety-2

People
Project management
Data access
Milestones
Reporting requirements for adverse
events in clinical trials
Expedited reporting.
The purpose of expedited reporting is to make
regulators, investigators, and other appropriate
people aware of new, important information on
serious reactions.
• The purpose is to ensure the safety of trial
subjects and allow rapid reaction should the
conduct of the trial need to change
 Reporting requirements-2

Most countries have a legislative basis for the

expedited reporting of potential Adverse Events/
Drug Reactions (ADRs)
• Local requirements can differ substantially, but the basic
premise and definitions are generally applicable
• Largely based upon the definitions in ICH-E2A
• Data also form the part of the body of evidence used for
benefit:risk assessment at Marketing Authorisation
Application (MAA).
 What is subject to expedited
reporting
• Individual case safety reports (ICSRs):
– Generally require the presence of four valid elements as a minimum
– Identifiable patient (usually provided through Clinical Trial IDs)
– Identifiable reporter (Investigator)
– A suspect drug or drugs
– An event
Usually only SUSARs. However, depending on the product and
any specific safety concerns or other AEs of special interest
could also be reported , at the request of HAs
 What is subject to expedited
reporting-2
Other safety information
– Safety information from other observations that could change
the benefit: risk evaluation for the product or affect the safety
or trial subjects, e.g., increased frequency of expected events,
important preclinical findings, etc
– In EU also includes events related to the protocol design and
procedure.
 Timelines
• SUSAR
– Fatal and life threatening: 7 days
– All other SUSARS: 15 days
– Follow up information: 15 days after receipt
– Ethic committees, IRBs, investigators: also to be notified
Uganda, PI reports within 48 hours to the sponsor
Sponsor to the RA within 7 days
• Other information to be reported expeditiously:
– Any change to benefit risk: e.g., Increased frequency or
severity,important pre-clinical findings
 Gaps existing
• Failure to report SAE
• Failure to honor reporting timelines
• Incomplete or insufficient narratives for
reported SAEs.
• Lack of comprehensive Pharmacovigilance
plans in protocols.
Thank you