Monitoring and Signal Detection

• Signal detection at PharmaLex is performed by qualitative (review of ICSR, aggregate reports, literature) and quantitative methods (statistical analyses) or a combination of both. We review various sources of information including but not limited to ICSRs, literatures, Health authority websites (e.g., PRAC minutes & recommendations), EVDAS, FAERS, etc (This is primarily defined in conjunction with the client)

  We ensure Signal detection methods applied are appropriate for the data set under analyses as qualitative analyses alone may not suffice for large data sets and complex statistical tools may not be appropriate for smaller data sets.

  Focus areas:

  • Information from all the available sources is reviewed and considered.
  • Systems and SOPs in place to ensure consistent quality.
  • Data is reviewed by a qualified person periodically.
  • Audit trail with adequate documentation is maintained for the processes, procedures, and the systems for signal detection.

  Identification of a signal does not mean that a drug has caused the adverse event. Evaluation of the signals is required to establish causality between the drug and the adverse event. Signal evaluation is a mandatory requirement to ensure that the benefit-risk balance of a drug is maintained, and it is a part of routine pharmacovigilance. Identification of a signal should prompt for further evaluation to classify the association.

Signal validation at PharmaLex is performed by:

• The supporting data of the detected signal is evaluated with an aim to verify that the available evidence contains sufficient evidence indicating a potentially new causal association or a new aspect of a known association justifying a further analysis of the signal.
• As a principle, only newly identified signals or known associations with new information on increased frequency, severity or occurrence in special populations are validated.

Factors considered while validating a signal:

a.    Clinical relevance

• Strength of evidence supporting the causal association which depends on the number of reports, biological plausible mechanism, temporal relation, de-challenge, re-challenge, and exposure
• Severity, seriousness and outcome of the reaction
• Drug-drug interaction, drug-food interactions
• Novelty of the reaction-newly observed serious reactions
• Reactions observed in the special populations such as elderly, paediatric, pregnant and lactating mothers, hepatic or renal impaired patients, or populations not studied in the clinical trials

b.    Previous awareness

• The available information in the product labels or patient leaflets
• Whether the signal was subject to regulatory request, discussed and accepted or refuted by scientific committees or if the association was assessed in PSUR or the RMP

c.    Other Relevant Sources of Information

• Literatures with similar cases
• Pre-clinical or clinical studies on biological mechanisms
• Review of larger databases such as EudraVigilance, Vigibase, and FDA AERS for similar cases

In the event of insufficient information to validate a signal, cases with the event of interest are followed up for further information or conduct descriptive or analytical studies to reinforce the information to have a further understanding on the magnitude and clinical significance.

Prioritisation

The validated signals are comprehensively evaluated by PharmaLexperts to identify if any additional data can be collected to support the causal association and for any regulatory actions (e.g., CCDS, SmPC, RMP update etc).

Consistency of information among the various sources of information increases the likelihood of the causality for the association between the drug and the event. Information gathering to confirm, validate and recommend any action may take time. However, every effort is made to ensure the risks are prevented or minimised at the earliest.

Additional sources that PharmaLexperts look at:

• Pharmacokinetics and pharmacodynamics of the drug
• Pre-clinical study data on toxicology
• Clinical data
• Application dossier
• Expert consultation
• Epidemiological data
• Literature
• ICSR database
• Class effect analysis
• Search at MedDRA broad/narrow SMQ level
• Clinical complications of the events of interest
• External databases of the regulatory agencies (FDA AERS, WHO Vigibase, EU EudraVigilance)

Once the signals are identified as risks, further characterization is made by acquiring additional information through:

• Post-authorisation safety studies (PASS)
• Clinical trials
• Analytical/observational epidemiological studies
• Setting up active registries

Based on the signal evaluation/assessment and considering the impact of the safety issue on the benefit-risk of the product, PharmaLex proposes an appropriate action in consultation with the client.

In close coordination with our Regulatory team of experts, PharmaLex even supports the communication and dissemination of necessary regulatory actions to the Health authorities, patients, healthcare professionals and other stake holders, as required. (e.g. Submission of Variations, DHPC, etc)