Signal Management in Pharmacovigilance

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Signal management is one of the key steps in pharmacovigilance and it is defined in several guidelines. [1]  The European Medicines Agency (EMA), together with the

regulatory authorities in the Member States and marketing authorisation holders are responsible for detecting and managing safety signals.The EU Guideline on good pharmacovigilance practices (GVP) Module IX - Signal Management defines signal management as the set of activities performed to determine whether, based on an examination of individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, literature information or other data sources, there are new risks associated with an active substance or a medicinal product or whether risks have changed. [2]

The signal management process involves detection, validation, confirmation, analysis and prioritization, assessment and recommendation for actions [3] to determine whether a signal represents a risk which may warrant further assessment, communication or other risk minimization actions in accordance with the medical importance of the issues.” [4]


A safety signal is information on a new or known adverse event that may be caused by a medicine and requires further investigation. The European Medicines Agency (EMA), together with the regulatory authorities in the Member States and marketing authorisation holders are responsible for detecting and managing safety signals. [5]


Safety signal

Pharmacovigilance principally involves the identification and evaluation of safety signals. Signals generally indicate the need for further investigation, which may or may not lead to the conclusion that the product caused the event. After a signal is identified, it should be further assessed to determine whether it represents a potential safety risk and whether other action should be taken. The FDA defines safety signal as a concern about an excess of adverse events compared to what would be expected to be associated with a product's use. [6]


A safety signal is information on a new or known adverse event that may be caused by a medicine and requires further investigation. The European Medicines Agency (EMA), together with the regulatory authorities in the Member States and marketing authorisation holders are responsible for detecting and managing safety signals. [7] A safety signal is information on a new or known adverse event that may be caused by a medicine and requires further investigation. The European Medicines Agency (EMA), together with the regulatory authorities in the Member States and marketing authorisation holders are responsible for detecting and managing safety signals. [8]
The EU Guideline on good pharmacovigilance practices (GVP) Module IX - Signal Management defines safety signal as information that arises from one or more sources which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, as it is judged to be of sufficient likelihood to justify verification. [9] The WHO has defined safety signal as Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented. [10]
“Information that arises from one or multiple sources (including observations and experiments), which suggest a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action” Report of Council for International Organisations of Medical Sciences WG VIII Practical Aspects of Signal Detection in Pharmacovigilance (CIOMS, Geneva 2010). [11], safety signals Information on a new or known adverse event that is potentially caused by a medicine and that warrants further investigation. Signals are generated from several sources such as spontaneous reports, clinical studies and the scientific literature.

The European Medicines Agency (EMA), together with the regulatory authorities in the Member States and marketing authorisation holders are responsible for detecting and managing safety signals. For more information, see Signal management.

Safety signals can be detected from a wide range of sources, such as spontaneous reports, clinical studies and scientific literature. The EudraVigilance database is an important source of information on suspected adverse reactions and signal. [12]

The essential definitional features of a safety signal are:

  • That it is based on one or more reports of an association between an intervention or interventions and an event or set of related events (e.g. a syndrome), including any type of evidence (clinical or experimental);
  • It represents an association that is new and important and has not been previously investigated and refuted;
  • It incites to action (verification and remedial action);
  • and it does not encompass intervention-event associations that are not related to causality or risk with a specified degree of likelihood and scientific plausibility. [13]


A signal may include any medicinal product with a valid marketing authorisation in the EU, irrespective of the authorisation procedure i.e. national (including mutual recognition and decentralized or centralized. A signal generally involves an active substance regardless of its indication, strength or route of administration and applies to all brand names / medicinal products containing the active substance, including fixed combinations. However, in some instances, a signal may be relevant only to a particular indication, strength or route of administration and on the other hand, it may encompass all active substances of a therapeutic class. [14]


Early identification of the hazards associated with drugs is the main goal of those involved in pharmacovigilance ‘Signal detection’, ‘signal generation’ or ‘signalling’ refers to a process that aims to find, as soon as possible, any indication of an unexpected drug safety problem which may be either new ADRs or a change of the frequency of ADRs that are already known to be associated with the drugs involved. [15]

There are various subcategories of signals:

  • Regulatory Signal: A signal which includes one or more of the following: unexpected AEs/SAEs, changes in severity, characteristics or frequency of expected ADRs, changes in outcomes of known ADRs.
  • Indeterminate Signal: A signal that has been or is being worked up for which there is no conclusion in regard to whether it is verified (validated) or refuted (closed).
  • Verified or Validated Signal: A signal which has been worked up and found indeed to be real, a true risk.
  • Refuted Signal: A signal after a signal work-up which has been found not to be a risk or potential risk. That is, the signal was “false”.
  • New Signal: A recently discovered signal.
  • Ongoing Signal: A signal that has been known for some time and which is being worked-up, tracked, undergoing evaluation etc.
  • Closed Signal: A signal for which an evaluation was completed.
  • Potential Signal and Validated Signal who have no formal definition. [16]

Potential Sources of Data for Signal Management

Individual Case Reports * Regulatory Authority reports (e.g. Anonymised Single Patient Reports [ASPRs])
* Clinical Trials SAEs
* Post-marketing reports (to MAH)
* Serious adverse reaction reports from organized data collection systems (if applicable) e.g. clinical trials, post-authorisation studies, registries, post-authorisation named-patient use programs, other patient support and disease management programes, surveys of patients or healthcare providers
* Medical and scientific literature
Information (including reports) from sources including Non-interventional studies e.g. marketing projects
* Post-authorisation safety studies
* Medical and scientific literature
* In vitro and in vivo laboratory experiments
* The Media – the internet (including company-sponsored websites, internet forums, social media), journals and newspapers (as appropriate)
Other Department Data * Regulatory data requests, e.g. regulatory agency requests for information, product referrals, reference safety information (e.g. SmPC) updates
* Product quality complaints associated with adverse events
Medical inquiries
Aggregate Data * Aggregate clinical trial data (include periodic reports e.g. Development Safety Update Reports [DSURs] / Adverse Events [AEs], laboratory data, pre-clinical data)
* Periodic Safety Update Reports (PSURs)
* Milestone data specified in the Risk Management Plan (RMP)
Other Data Sources Regulatory databases (e.g FDA AERS, MHRA drug analysis prints [DAPs] / product

analysis prints [PAPs])

* Other databases (e.g WHO Vigibase)
* New Drug Application (NDA),safety database
* Epidemiological data (e.g. General Practice Research Database [GPRD] / registries)
* Competitor product SmPCs (e.g. from the eMedicines Compendium [eMC])
* Competitor intelligence.
* Data mining [17][18]

Some of these sources can be useful for identification of signals, some of them are used primarily for validation of signals, while some would be used for both. [19]

Signal management process

Signal management covers all steps from signal detection, through their validation and confirmation, analysis, prioritization and assessment to recommending action, as well as the tracking of the steps taken and of any recommendations made. [20] The evaluation of safety signals is a part of routine pharmacovigilance and is essential to ensuring that regulatory authorities have the most up-to-date information on a medicine’s benefits and risks. [21]

Signal Detection

Signal detection is defined as the act of looking for and/or identifying signals using data from any source. [22]

Main article: (Signal Detection in Pharmacovigilance)

Whichever methods are employed for the detection of signals, the same principles should apply namely

  • The method used should be appropriate for the data set; for example, the use of complex statistical tools may not be appropriate for smaller data sets.
  • Data from all appropriate sources should be considered.
  • Systems should be in place to ensure the quality of the signal detection activity.
  • Any outputs from a review of cumulative data should be assessed by an appropriately qualified person in a timely manner
  • The process should be adequately documented, including the rationale for the method and periodicity of the signal detection activity.

[23]

Signal Validation

Signal validation is defined according to the EMA's GVP Module IX, as the process of evaluating the data supporting a detected signal, which takes into account the strength of the evidence, the clinical relevance and the previous awareness of the association, in order to verify that the available documentation contains sufficient evidence to justify further analysis of the signal. [24]

Signal Confirmation

Signal confirmation is defined as the process of communication via EPITT (a database developed by the EMA to promote the communication of pharmacovigilance and risk management issues between the EMA and Member States), within 30 days of its receipt by the Rapporteur (the lead Member State or a national competent authority) that the validated signal is confirmed or not. The process of signal confirmation does not represent a full assessment of the signal. The fact that a signal is confirmed does not indicate that a causal relationship exists, and that signal should be discussed at EU level and further investigated by PRAC. [25][26]

Signal Analysis and Prioritization

Signal analysis and prioritization are performed by taking into account the potential impact of the signal on the benefit-risk profile of the involved medicine(s). The prioritization dictates the time frame for the subsequent steps of the evaluation of the signal. It is affected by several factors including any potential impact on the benefit-risk profile of the product, the strength of evidence supporting a causal association, the severity and seriousness of the reaction, its estimated frequency of occurrence, its preventability, the consequences of discontinuing treatment and the availability of alternative therapeutic options, the extent of utilisation of the medicinal product in the general population or in particular patient groups, the complexity of the issue and the expected volume of data. These elements dictate the timelines for the subsequent steps of the signal evaluation. These timelines usually include 2 months for submission of responses by the MAHs (Marketing Authorization Holders) and 60 days for assessment by the PRAC (Pharmacovigilance Risk Assessment Committee), but when appropriate, shorter or longer timelines may apply. [27][28]

Signal Assessment

Signal Recommendation for action

The Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for prioritising and assessing signals and issuing subsequent recommendations on medicines authorised in the European Union, including nationally and centrally authorised medicines.

The PRAC recommendation may include one or a combination of conclusions, including:

  • No need for further evaluation or action at present;
  • Need for additional information, including:
    • monitoring any relevant emerging information as it becomes available,;
    • additional analysis in EudraVigilance or other data sources;
    • additional data from the marketing authorisation holder in the next periodic safety update report (PSUR) or submit an ad-hoc PSUR;
    • a post-authorisation safety study conducted by the marketing authorisation holder;
  • Need for regulatory action, such as:
    •  updating of the product information (summary of product characteristics and package leaflet) and/or risk management plan through a variation;
    • a referral procedure;
    • urgent safety restrictions.

Exchange of information and implementation

It should be noted that the terminology used in the EU signal management process is different from the terminology used commonly in scientific literature. [29]

The legal basis for signal management in different regions

European Union (EU)

Signal management is defined in article 107h of Directive 2001/83/EC, article 28a of Regulation (EC) No 726/2004 and chapter III of Commission Implementing Regulation (EU) No 520/2012. [30][31] In 2012, EMA published Module IX of the guideline on good pharmacovigilance practices (GVP) - Signal management, which is entirely dedicated to the lifecycle of safety signals. This module provides general guidance and requirements on structures and processes involved in signal management and describes how these structures and processes are applied in the setting of the EU Pharmacovigilance and regulatory network. This guidance is the principal guidance supporting the implementation of and compliance with above mentioned legal requirements. [32][33]

Implemented recommendation in EudraVigilance In the EV signal detection system (eRMR) the following information are separately visualised and highlighted for each DEC when new reports are submitted:

  • Abuse, misuse, overdose, medication error or occupational exposure*;
  • Positive re-challenge;
  • Literature cases.[34]

Module IX comprises three following sections:

  • Introduction including the definitions of signal and signal management.
  • General requirements on structures and main processes. This section includes information and guidance with regard to the data sources and different methods of signal detection, a description of the six steps of a signal management process and overall quality aspects.
  • Description of the function of the EU PV network with clear definitions of the responsibilities and tasks of all parties involved (MAHs, NCAs, EMA and PRAC). [35]

The Pharmacovigilance Risk Assessment Committee (PRAC) is responsible for prioritising and assessing signals and issuing subsequent recommendations on medicines authorised in the European Union, including nationally and centrally authorised medicines. [36]

The PRAC recommendation may include one or a combination of conclusions, including [37]:

  • No need for further evaluation or action at present;
  • Need for additional information, including:
 monitoring any relevant emerging information as it becomes available;
 additional analysis in EudraVigilance or other data sources;
 additional data from the marketing authorisation holder in the next periodic safety update report (PSUR) or submit an ad-hoc PSUR;
 a post-authorisation safety study conducted by the marketing authorisation holder;
  • Need for regulatory action, such as:
 updating of the product information (summary of product characteristics and package leaflet) and/or risk management plan through a variation;
 a referral procedure;
 urgent safety restrictions. 

United States (US)

In the US there is no guidance document quite alike the European GVP-Module IX, which is only dedicated to the management of safety signals and describes all process steps for every stakeholder involved. Instead, there are several guidance documents that describe the handling of safety signals and provide advice to the different parties involved. The most relevant guidance documents are:

  • The “Guidance Drug Safety Information - FDA’s Communication to the Public” from 2007, which outlines how the FDA makes important safety information regarding medicinal products, including emerging drug safety information. A revision is currently under development; a draft of the updated version was first published in March 2012.
  • The “Guidance for Industry and FDA Staff - Dear Health Care Provider (DHPC) Letters: Improving Communication of Important Safety Information” from 2014, which describes the communication of safety updates on Medicinal products healthcare professionals via Dear Health Care Provider (DHCP) letters.
  • MAPP (Manual Of Policies and Procedures) 6700.9 “FDA Posting of Potential Signals of Serious Risks Identified by the Adverse Event Reporting System” and SOPP 8420 “ FDAAA (the Food and Drug Administration Amendments Act) Section 921: Posting of Potential Signals of Serious Risk” from 2011, who describe the policy and general procedures for the development and publication of quarterly lists of potential signals of serious risks identified by the Adverse Event Reporting System (AERS) in response to the FDAAA.
  • MAPP 4121.2 4 “Tracking of Significant Safety issues in Marketed Drugs - Use of the DARRTS Tracked Safety Issues”, which explains how FDA staff works with the Document Archiving, Reporting, and Regulatory Tracking System (DAARTS).
  • Draft guidance “Classifying Significant Postmarketing Drug Safety Issues” from 2012, which describes the process that the FDA intends to use for prioritization of significant safety signals and to classify adverse drug events as the priority, standard, or emergency. [38]

Japan

The Japanese pharmaceutical regulation provides two important ordinances for signal management in Japan: the Japanese Ministry of Health, Labour and Welfare (MHLW) Ministerial Ordinance No.135 of 2004, called ‘Ordinance on Good Vigilance Practices’ (GVP Ordinance) and the MHLW Ordinance No. 171 of 2004, called ‘Good Post-marketing Study Practice’ (GPSP). The GVP Ordinance comprises the main principles of safety management in the postauthorization pharmacovigilance, as defined in the Pharmaceutical and Medical Devices Law. In March 2013, the document has been amended by the PFSB Notification No. 0311/7 to enforce MHLW Ordinance No. 26 and include enhanced guidance on risk management plans. Articles 7-9 of the GVP Ordinance are of particular significance with regard to signal management activities. According to article 7, it is mandatory for MAHs to collect safety information from various sources, including e.g. HCPs, scientific meetings, literature screenings or national and international governmental institutions/ organizations. [39]

Signal management challenges

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References

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