Integrity and safety of pharmaceuticals used in humans must be maintained throughout the product life-cycle. Global regulatory health authorities require Market Authorization Holders (MAHs) to routinely monitor and assess all safety issues spontaneously reported and/or identified on global regulatory authorities databases related to their medicinal products. In addition to the daily and routine monitoring, cumulative assessment of all safety signals, also known as signal detection, received through adverse drug reaction (ADR) reporting is required to capture emerging safety risks.
The process comprises of cumulative review of ADRs received/identified within a defined timeframe. Once the review is complete, assessment of identified safety issues by the signal detection committee must be performed. The committee will then document the outcome of the assessment which includes: validation of the signal, further assessment, prioritization, and escalation. A safety signal might be refuted after further assessment, continue to be monitored or regulatory actions might be required such as updating the product label (ADR section, precautions, contraindications) or market withdrawal. It is important to note that even in case of small volume of ADRs, MAHs are still encouraged to perform signal detection to avoid further risks to the population.
Depending on the product category and the duration is has been on the market, MAHs should define the frequency at which they perform signal detection and management. MAHs are required to notify the local health authority as soon as they become aware of a safety signal so that appropriate actions to protect the public health can be taken.
Our guest author, Balazs Toth, MD. PhD. – Head of Corporate Drug Safety Unit & EU QPPV at Octapharma pharmazeutika produktionsges.m.b.H, provides further insights to Signal Detection best practices and considerations for MAHs to ensure their compliance to regulatory authority guidelines.
Here is a summary of our discussion with Balazs
What are the main sources of safety signals MAH should consider?
This is a very interesting question. Luckily, health authorities provide guidance to help, e.g. the European GVP requires MAHs to consider wide variety of data sources. This should include potentially all scientific information concerning the use of medicinal products and the outcome of the use, i.e. quality, non-clinical and clinical data (including pharmacovigilance and pharmacoepidemiological data). It is very important that all the relevant sources should be considered during signal management.
What is the frequency of signal detection assessment according to common practices? And does it depend on the class of medication?
The periodicity of signal monitoring cannot be predefined generally for all MAHs, there is no one size solution that fits all. It should be rather set by the organizations performing the task. The MAHs have accumulated information on their products, the period since the first authorization, the patient exposure, risks documented in the RMP, number of ICSRs received, PSUR frequency, known safety concerns in connection with the product, etc. These factors should be all considered when defining the monitoring frequency.
How does the signal detection approach change for products with previous safety signals/concerns (history of identified risk through signal detection process)?
Safety concerns identified previously might alter the frequency and the methodology of signal detection depending on the identified issue. Authorities might also require certain activities with predefined outcomes. It is highly likely that continuous monitoring is required for signals which seriously risk the public health. In general, we can conclude that previously identified issues increase the monitoring frequency.
To your knowledge, are there any emerging changes to signal detection process under the different global jurisdictions (i.e. EMA, FDA, TGA ..among others)? And how does it impact the PV inspection process?
EMA and the European Commission have agreed on transitional arrangements to streamline the monitoring of EudraVigilance by MAHs. The pilot period which started on 22 February 2018, was recently further extended until the end of 2023. Other than changes to this requirement, I do not expect major changes in the signal management requirements. However, certain updates to the requirements are expected from countries especially in the Asian, African and South American regions.
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- Module 4: Health Canada’s review and communication of safety findings, date published Dec 13th, 2019
- EMA – Guideline on good pharmacovigilance practices (GVP), Module IX – Signal management (Rev 1), date published Oct 9th, 2017