PURPOSE
The purpose of this SOP is to identify and analyse new signal from reported cases whilst developing a robust risk management ratio of the marketed product. Further to that, XXX industries shall communicate the safety information on use of medicines manufactured to the relevant Health Authorities, Health Care Practitioners and the general public.
RESPONSIBILITY
The Qualified Person for Pharmacovigilance/Deputy QPPV shall be responsible for the identification of suspected and or detected safety signals and the update to the risk-benefit profile for XXX Industries products. Management team shall be responsible for the review and approval of recommendation for action in all safety signals.
No change in this SOP may be made without authority.
Introduction
What Is A Safety Signal?
The definition of a signal as provided by the council for international organizations of medical sciences (CIOMS) Working Group 8is: “Information that arises from one or multiple sources (including observations and experiments), 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, that is judged to be of sufficient likelihood to justify verificatory action”.
In essence, a signal is a hypothesis of a risk associated with medicine along with supporting data. The evidence in a signal is an early indication and not definitive as it substantially changes as the data accumulates over time. The evaluation of safety signals should be a continuous process in pharmacovigilance as it is imperative for XXX Industries to have a well-defined process to capture, evaluate and take immediate action on potential PV risks as needed. A signal may be generated either by statistical analysis or by qualitative analysis of spontaneous reports.
Signal Management
The process of signal management in pharmacovigilance consists of a set of activities that aim to determine if there are new risks associated with an active substance or a medicinal product or whether known risks have changed based on a thorough analysis of individual case safety reports (ICSRs), aggregate data from active surveillance systems or scientific literature. The set of activities includes the following steps:
- Signal Detection.
- Signal Validation.
- Signal Prioritization.
- Signal Assessment.
- Recommendation for action.
- Exchange of information.
PROCEDURE
- Monthly Operation: On 15th and the preceding five days of every month the QPPV/Deputy QPPV shall conduct all the signal management activities. These shall include-;
- Signal Detection: The QPPV/Deputy QPPV shall review form under review that shows monthly product adverse event (ADR)/product quality complaint reconciliation, form under review that shows Monthly literature review reconciliation under review, available aggregate reports and data collected as per the regulatory intelligence SOP. The result identified sources of PV data in the aforementioned period for any potential signal shall be logged in the safety signal investigation report on annexure 1.
- The QPPV/Deputy QPPV shall determine if a new or potential safety signal that exist warrants further investigation including-;
- New AEs, that has not been recorded especially if they are serious and have occurred in rare sub-population.
- Apparent increase in the severity of an AE.
- Occurrence of a Serious Adverse Event known to be extremely rare in the general population.
- Previously unrecognized interactions with other products, supplements or foods.
- Identification of a previously unrecognized at risk-patient population or sub group of patients, such as patients with specific medical condition, comorbidities or with specific racial or genetic predisposition.
- Adverse event arising from the way the product is being used either on or off label (e.g. adverse event seen at doses higher than those normally prescribed or in sub population not recommended in the label.
- Adverse Event arising from user error, or from medication error.
- Other concerns that may be identified by XXX Industries PV department or the regulatory agencies.
Signal Validation
- 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 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.
- Temporal relationship of 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 case series (for example histopathology or subtype of a disorder is reported in all cases of a series of events)
- Alternative medical or technical explanations.
- Seriousness and severity of the reaction and its outcomes, relative to disease being treated.
- Drug-drug interaction
- Potential to mitigate the risk in the population.
- Degree the benefit the product provides, including the availability of other therapies
- Extent to which information is included.
- After investigation of the safety signal, the conclusion can be-;
- Validated and accepted: A causal relationship 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 conclusion regarding causality can be drawn. The signal is further monitored and re-evaluated at a defined point.
Signal Prioritization
- The QPPV/Deputy QPPV shall assess-;
- Impact on the patient depending on severity and reversibility, and potential for prevention and clinical outcome.
- Consequences on treatment discontinuation and on the disease and the availability of other therapeutic options.
- Strength and consistency of the evidence supporting the association.
- Clinical context
- Public health impact.
- The QPPV/Deputy QPPV shall enter the outcome of signal prioritization on the remarks section of the safety signal investigation report.
Signal Assessment
- The QPPV/Deputy QPPV shall-;
- Review 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 recommendation for action.
Recommendation for Action
- The QPPV/Deputy QPPV shall submit to the management team to make a decision that shall authorize-;
- Initiation of Health Hazard Assessment for potential field action.
- Request of quality complaint for further product evaluation.
- Expedited reporting to regulatory authorities
- Direct healthcare professional communication (DHCP communication)/Dear Doctor letters.
- Continued assessment of the product benefit-risk balance.
- Further investigation of the safety risk through additional studies.
- Development of a pharmacovigilance plan focused on identifying the available risks.
- Reporting via periodic report submission.
- Risk management document updates.
- Additional educational material or training.
- Modification of the ongoing monitoring strategy of the product
- Initiation of the 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
- Introduction of enhanced pharmacovigilance activities
- Introduction of additional Risk Minimization Activities
- Conducting a post authorization safety studies.
- Periodic review of a signal.
Exchange of information
- The QPPV/Deputy QPPV shall-;
- Communicate immediately to the management team an Emerging Safety Signal with all validated signal pointing towards an implication for public health or the benefit risk profile of a 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 implication for the benefit risk profile to applicable regulatory authority.
- Communicate the outcome of signal assessment involving new or changed risk to the public including the healthcare professionals and patients as well as Local Technical Representatives in the respective countries.
ANNEXURE
Annexure I: Safety Signal Investigation Report
ABBREVIATIONS
QPPV: Qualified Person for Pharmacovigilance
PV: Pharmacovigilance
ICSR: Individual Case Safety Report
AEPQC: Adverse Events Product Quality Complaints
DHCP: Dear Healthcare Practitioners
REVISION HISTORY
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