This document discusses signal detection and management in pharmacovigilance. It provides a history of pharmacovigilance programs internationally and in India. It defines pharmacovigilance and outlines the objectives, processes, and steps involved in signal detection, validation, prioritization, assessment, and recommendation for action. These include ongoing monitoring of adverse event reports, identifying potential safety signals, validating signals based on factors like strength of association and biological plausibility, prioritizing signals based on impact and evidence, assessing signals, and recommending actions to address validated safety issues.

1. SIGNAL DETECTION AND
MANAGEMENT
DR SEKHAR BABU BANDAR
post graduate 2nd year
Department of pharmacology
Moderator : Prof.k.Sankar MD;DTCD
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2. • Dying due to disease is sometimes unavoidable
but Dying due to medicine is unacceptable.
Lepakhin V. Geneva 2005
• Primum non nocere
meaning FIRST DO NO HARM.
• HIPPOCRATES formulated first reason -
To do our utmost to minimise harm due to
pharmacotherapy.
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3. HISTORY
• 1968-WHO program for International Drug monitoring was started .
• 1978- later moved to Uppsala after agreement between Sweden &
WHO.
• 1986-ADR monitoring system for INDIA proposed 12 regional centers.
• 1997-INDIA joined WHO-ADR reporting program based in Uppsala
,Sweden .
• 2004- National pharmacovigilance program officially inaugurated by
Central Health Minister at New Delhi.
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4. • 2005- Ministry of Heath And Family Welfare in India initiated the NPP
,coordinated by the Central Drug Standard Control Organization (CDSCO).
• July2010-PVPI initiated - AIIMS ,New Delhi as National Co-ordination center
for monitoring ADRs .
• 15 April 2011,the NCC shifted from AIIMS ,Delhi to Indian pharmacopeia
commission ,Ghaziabad.
• July 8,2009- MCI made mandatory - EVERY MEDICAL COLLEGE IN INDIA
SHOULD HAVE PHARMACOVIGILANCE COMMITTEE
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5. DEFNITION
• Pharmacovigilance (PV) is defined as the science and activities
relating to the
• Detection,
• Assessment,
• Understanding and
• Prevention of adverse effects or any other drug-related problem
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6. OBJECTIVES
• Identify and analyse new signal from reported cases
• Benefit-risk ratio of marketed medications
• Evidence based information on safety of medicines
• Communicate the safety information on use of medicines
• Exchange of information and data management with other centres
• Provide training and consultancy support
• Rational use of medicines
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7. MONITORING OF ADVERSE EVENTS
• Ongoing monitoring of adverse event reports comprises the retrieval
of data from the global safety database at monthly intervals for all
monitored products, and review of the data with the purpose of
timely identification of (potential) new safety signals requiring further
investigation. The monitoring also comprises data retrieval from the
clinical databases for the analysis of non-serious adverse events.
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8. SIGNAL MANAGEMENT PROCESS
• Based on the examination of individual case safety reports (ICSR),
aggregate data from active surveillance systems or studies, and
literature information or other data sources.
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9. SIGNAL MANAGEMENT PROCESS INCLUDES
• Signal detection
• Signal validation
• Signal prioritization
• Signal assessment
• Recommendation for action
• Exchange of information
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10. SIGNAL DETECTION: INPUT, PERIODICITY,
MATERIALS
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11. • Tabulation of AEs / ADRs for the monitoring period including,
but not limited to,
1. Designated medical events (DME)
2. Targeted medical events (TME),
3. Relating to new cases over the time period under study.
• Cumulative summary tabulation listing all AEs / ADRs on the
database for the product.
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12. • Aggregate reports (monthly requests) of adverse events including serious,
non-serious, and any other events of interest, obtained from:
1. Clinical studies
2. Regulatory reports
3. Commercial complaints
4. Preclinical in vitro and in vivo studies
5. Epidemiologic data
6. Media. Internal and external websites, and social media
7. Medical literature
8. Data from off-label use
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13. ONGOING MONITORING ACTIVITIES FOR
SIGNAL DETECTION
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14. • Retrieve tables and listings as defined in the Product Safety
Monitoring Plan
• Review the retrieved data set within 1 week
• accepted standards for identifying safety signals do not exist. Expert
knowledge and medical judgment are always required
• Consider the following elements during ongoing monitoring of case
reports for signal identification:
• Document the ongoing monitoring activities and any findings via the
Product Safety Signal Monitoring Tracking Sheet
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15. FOLLOWING ELEMENTS ARE CONSIDERED
DURING SIGNAL IDENTIFICATION:
• Information from summary tabulations, for the monitoring period
and for cumulative data.
• Line listing information, as demographics (age, gender), dose of
suspect product, temporal relationship, information on de-challenge
and re-challenge.
• Causality assessment.
• Specific topics / medical concepts to be monitored, if applicable.
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16. SIGNAL DETECTION
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17. IDENTIFY POTENTIAL SAFETY SIGNALS THROUGH
VARIOUS PHARMACOVIGILANCE ACTIVITIES,
• Ongoing monitoring of AEs / ADRs.
• Individual medical review of ICSRs and customer product quality
complaints.
• Preparation of aggregate reports (as for example the Periodic Benefit
Risk Evaluation Report, PBRER)
• Review of scientific and medical literature.
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18. • Data obtained from company-sponsored clinical and non-clinical
studies, including surveillance systems.
• Information obtained from a health authority.
• Other, such as data on quality, systematic reviews, meta-analyses,
internet and digital media under the management.
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19. COMBINATION OF STATISTICAL AND CLINICAL
METHODS FOR THE EVALUATION OF A SIGNAL
• Careful review of individual case details.
• Comparing rates to an historical period of reporting rates.
• Using more reliable data sources such as incidence rates from
previous clinical studies.
• Preclinical studies from biologic effects, or pharmacokinetics or
pharmacodynamics effects.
• Search for additional cases that meet similar criteria (similar events)
of the signal.
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20. DETERMINE IF A NEW OR POTENTIAL SAFETY
SIGNAL EXISTS THAT WARRANTS FURTHER
INVESTIGATION INCLUDING
• New AEs, not currently documented. Specially if they are serious and have
occurred in rare sub-populations.
• An apparent increase in the severity of an AE
• Occurrence of serious adverse events (SAE) known to be extremely rare in
the general population
• Previously unrecognized interactions with other products, supplements or
food.
• Identification of a previously unrecognized at-risk patient population or
subgroup of patients, such as patients with specific medical conditions,
comorbidities, or with specific racial or genetic predispositions.
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21. • Adverse events arising from the way a product is being used either on
or off-label (e.g. adverse events seen at doses higher than those
normally prescribed or in sub-populations not recommended in the
label.
• Adverse events arising from user errors, or from medication errors.
• Other concerns that may be identified by PV department or a
regulatory agency.
• PV SCIENTIST ADDS THE DETECTED -POTENTIAL- SAFETY SIGNAL TO
THE PRODUCT SAFETY SIGNAL MONITORING TRACKING SHEET.
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22. SIGNAL VALIDATION
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23. SIGNAL VALIDATION : CLINICAL RELEVANCE
• Strength of the association with the product
• Evidence of dose-response effect
• Frequency, that is, for example the number of spontaneous reports in
comparison to earlier periods and/or in relation to estimated patient
exposure; same type of information in the context of clinical trial
data.
• Quality of the reports. Completeness of data, plausibility of the
information, availability of data to substantiate reported diagnosis.
• Reporter and company causality assessment of individual cases.
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24. • Temporal relationship of the product use and event, including information
on de-challenge and re-challenge.
• Consistency of data patterns indicating potential risk groups.
• Consistency of findings across available data sources.
• Specificity of a case series (for example, same histopathology or subtype of
a disorder is reported in all cases of a series of reports.
• Alternative medical or technical explanations.
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25. • Seriousness and severity of the reaction and its outcome, relative to
the disease being treated.
• Drug-drug interactions.
• Potential to mitigate the risk in the population.
• Feasibility of a further study using controlled or observational
designs.
• Degree of benefit the product provides, including availability of other
therapies.
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26. SIGNAL VALIDATION:PREVIOUS AWARENESS
• Biological plausibility of the event in light of the known or assumed
pharmacological properties of the suspect drug or the drug class.
• Extent to which information is already included
• Association has already been addressed in an aggregate report, or has
been subject to a regulatory procedure
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27. • Richer set of data on the same AE /ADR:
1.Literature findings
2.Experimental findings or biological mechanisms
3.Screening of databases with larger datasets
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28. After the investigation of the safety signal, the
conclusion can be:
• Validated and accepted: a causal association between the product and the
event is assumed
• Not validated and rejected: no causal association between the product
and the event is assumed, or
• Pending, not confirmed signal: no clear conclusions regarding causality can
be drawn. The signal is further monitored and re-evaluated at a defined
time point
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29. SIGNAL PRIORITIZATION
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30. FOR PRIORITIZATION OF A SIGNAL, CONSIDER
THE FOLLOWING ASPECTS
• Impact on patients depending on the severity, reversibility, potential
for prevention and clinical outcome
• Consequences on treatment discontinuation on the disease and the
availability of other therapeutic options
• Strength and consistency of the evidence supporting the association
• Clinical context
• Public health impact
• Enter the outcome of the signal prioritization process in the product
safety signal monitoring tracking sheet
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31. SIGNAL ASSESSMENT
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32. STEPS TO BE PERFORMED FOR SIGNAL
ASSESSMENT:
• Review appropriate internal and external sources to obtain further
information
• Document the risk assessment of the signal per product safety signal
investigation report, and recommend no further action, or further
action to prevent or minimize patient risk as described in the next
section, Recommendation for Action.
• Assess the significance of a signal to obtain a potential link to a
complex disease, to a prior stage or a reaction or to clinical
complications of the adverse reaction of interest.
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33. RECOMMENDATION FOR ACTION
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34. • Initiation of a Health Hazard Assessment (HHA) for potential field action
(field alert reporting evaluation)
• Request quality complaint investigation for further product evaluation
• Expedited reporting to regulatory agencies
• Direct healthcare professional communication / Dear Doctor Letters
• Updating safety related labeling or prescribing information
• Clinical expert statements
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35. • Reporting to investigators, Institutional Review Boards (IRB), Ethics
Committees, updating study documents, or holding or stopping
ongoing studies early
• Continued assessment of the product benefit-risk balance
• Further investigation of the safety risk through additional studies
• Development of a pharmacovigilance plan focused on evaluating the
identified risk
• Reporting via periodic report submission
• Risk management document updates
• Additional educational materials or training
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36. For all validated signals, and in accordance with
final recommendations from the committee:
• Modification of the ongoing monitoring strategy of the product
• Initiation of label change and/or other external communication
activities
• Initiation of recall/correction procedure
• Information to concerned health authorities
• Issuing or updating a Risk Management Plan
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37. • Introduction of enhanced pharmacovigilance activities
• Introduction of additional risk minimization activities
• Conducting a post-authorization safety study
• Periodic review of the signal
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38. EXCHANGE OF INFORMATION
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39. • Communicate immediately to regulatory affairs as an Emerging Safety Issue
all validated signals pointing towards an implication for public health or the
benefit-risk profile of the specific product.
• Depending on the severity of the signal, communicate validated signals
representing a new potential signal or a new aspect of a known risk and
not having implications for the benefit-risk profile to applicable regulatory
authorities.
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40. • Communicate the outcome of signal assessment involving new or
changed risks to the public including health care professionals and
patients as well as to the concerned marketing authorization holders.
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