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Signal detection and management
- 1. SIGNAL DETECTION AND MANAGEMENT DRSEKHAR BABU BANDAR post graduate 2nd year Department of pharmacology Moderator : Prof.k.Sankar MD;DTCD 1
- 2. • Dying dueto 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. 2
- 3. HISTORY • 1968-WHO programfor 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. 3
- 4. • 2005- Ministryof 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 4
- 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 5
- 6. OBJECTIVES • Identify andanalyse 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 6
- 7. MONITORING OF ADVERSEEVENTS • 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. 7
- 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. 8
- 9. SIGNAL MANAGEMENT PROCESSINCLUDES • Signal detection • Signal validation • Signal prioritization • Signal assessment • Recommendation for action • Exchange of information 9
- 10. SIGNAL DETECTION: INPUT,PERIODICITY, MATERIALS 10
- 11. • Tabulation ofAEs / 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. 11
- 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 12
- 13. ONGOING MONITORING ACTIVITIESFOR SIGNAL DETECTION 13
- 14. • Retrieve tablesand 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 14
- 15. FOLLOWING ELEMENTS ARECONSIDERED 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. 15
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- 17. IDENTIFY POTENTIAL SAFETYSIGNALS 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. 17
- 18. • Data obtainedfrom 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. 18
- 19. COMBINATION OF STATISTICALAND 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. 19
- 20. DETERMINE IF ANEW 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. 20
- 21. • Adverse eventsarising 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. 21
- 22.
- 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. 23
- 24. • Temporal relationshipof 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. 24
- 25. • Seriousness andseverity 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. 25
- 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 26
- 27. • Richer setof data on the same AE /ADR: 1.Literature findings 2.Experimental findings or biological mechanisms 3.Screening of databases with larger datasets 27
- 28. After the investigationof 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 28
- 29.
- 30. FOR PRIORITIZATION OFA 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 30
- 31.
- 32. STEPS TO BEPERFORMED 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. 32
- 33.
- 34. • Initiation ofa 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 34
- 35. • Reporting toinvestigators, 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 35
- 36. For all validatedsignals, 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 36
- 37. • Introduction ofenhanced pharmacovigilance activities • Introduction of additional risk minimization activities • Conducting a post-authorization safety study • Periodic review of the signal 37
- 38.
- 39. • Communicate immediatelyto 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. 39
- 40. • Communicate theoutcome 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. 40
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Editor's Notes
- #7 Signal is essentially a hypothesis of a risk with a medicine with data and argument that support it. It is not a conclusive, and is only an early indication ,it may change substantially over time as more data accumulates.
- #8 This 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. Retrieval strategies (case selection criteria, format, and periodicity of retrievals from the global safety database, for example) should be defined in advance on a per-product basis. Retrieval strategies and results of all ongoing monitoring activities must be documented.
- #10 Generally accepted procedures for signal investigation, objective thresholds for accepting safety signals, or generalizable rules for subsequent action do not exist. Expert knowledge and medical judgment are always required. Likewise, the timelines for processing a potential signal depend on the severity and potential public health impact on the population concerned. Potential safety signals that, if accepted, may pose a significant public health threat (e.g. an unexpected adverse event that is both serious and frequent) should be processed with priority until timelines are defined by the safety management team and/or regulatory authorities. The signal management process is always based on the information available at the time of the review and may change over time. Events which do not fall under the definition of a reportable (valid) ICSR but may affect the benefit-risk balance of a medicinal product and/or impact on public health shall be notified as Emerging Safety Issue, per applicable regulatory requirements.
- #12 The Pharmacovigilance Scientist defines the retrieval strategy on a per-product basis depending on the maturity of the safety profile and number of case reports for the concerned product. At a minimum, retrieves no less frequently than monthly a standard dataset comprising the following:
- #13 Aggregate safety data may include the following elements: MedDRA coded terms, by System Organ Class (SOC) and Preferred Term (PT); frequency of events; nature and type of events (serious, non-serious, events of special interest, expectedness, relatedness). Also, it will be important to: Define additional retrievals (additional datasets and/or higher monitoring frequency depending on, for example, regulatory commitments, an existent risk management plan (RMP), or known safety issues. Document the retrieval strategy on a per-product basis via a “Product Safety Signal Monitoring Plan”.
- #15 Following are the steps PV scientist will perform, regarding ongoing monitoring:
- #17 PV personnel may identify potential safety signals through various pharmacovigilance activities, including the following:
- #23 Normally, the PV scientists performs the following steps for signal validation: Evaluate the data supporting a detected signal in order to verify that the available source documentation contains sufficient evidence demonstrating the existence of a new potentially causal association or a new aspect of a known association, and therefore justifies further prioritization and assessment of the signal. Depending on the nature and context of the signal investigation, the below describes aspects that will be considered when validating a signal:
- #28 Availability of other relevant sources of information providing a richer set of data on the same AE /ADR:
- #29 Document this conclusion in the product safety monitoring tracking sheet. Set deadline or threshold for re-investigation of pending signals and document in the product safety monitoring tracking sheet. In collaboration with the PV physician, document each safety signal investigation depending on its context using the product safety signal investigation report, and sign the form. Include the documentation background, information sources and methods, results and conclusion of the investigation. Examples of additional sources of documentation include the company comments on the ICSRs, aggregate reports, or other documents submitted to health authorities.
- #30 The following steps are to be performed by the PV scientist: The PV scientist will promptly identify validated signals with important public health impact or that may significantly affect the benefit-risk profile of the medicinal product in treated patients. These signals require urgent attention and need to be prioritized, that is, evaluated without delay. For prioritization of a signal, consider the following aspects, if applicable:
- #32 The objective of signal assessment is to further evaluate the significance and potential risk of a validated signal so as to identify the need for additional data collection, risk mitigation or minimization activities in a timely manner, or for any regulatory action.
- #34 The next steps are performed by the PV physician: Based on the level of safety risk or patient impact, recommend action and review recommendations with the product safety board. Recommended actions may include, but are not limited to, any of the following with appropriate time frame for action consistent with the nature and severity of the signal:
- #38 The product safety review committee will determine appropriate timelines for initiation and completion of suitable actions for all validated signals, which will be documented in the meeting minutes and in the individual product safety signal investigation report. The PV scientist documents all detected signals including validation, prioritization, assessment, actions including timelines and reporting dates, as well as current status in the product safety signal monitoring tracking sheet.
- #39 The following steps will be performed by the PV physician: