Signal Detection in Pharmacovigilance

Signal detection is a process used in pharmacovigilance to identify potential safety issues or new safety information associated with a medicinal product. The goal of signal detection is to detect signals, or potential safety concerns, as early as possible in order to allow for timely risk management and safety interventions.

Signal detection typically involves analyzing large amounts of safety data, including adverse event reports, clinical trial data, post-marketing surveillance data, and other sources of safety information. The data is analyzed using statistical methods and algorithms to identify any patterns or trends that may suggest a potential safety concern.

Once a potential safety concern is identified, further investigation is typically required to confirm the signal and assess the magnitude of the risk. This may involve conducting additional studies, analyzing the available data in more detail, or consulting with regulatory agencies and other stakeholders.

Signal detection is an ongoing process that continues throughout the life cycle of a medicinal product. The process is critical for ensuring the ongoing safety and effectiveness of medicinal products, and is an important component of pharmacovigilance activities.

1. Welcome Signal Detection Name: Hannah Christina Qualification: M.Sc. Biotechnology Student ID: 040/022023 6/03/2023 www.clinosol.com | follow us on social media @clinosolresearch 1 6 th March, 2023

2. Index Introduction Definition of Signal Detection Importance of Signal Detection Types of Signal Detection Sources of Signals Signal Management Methods of Signal Detection Regulatory requirements for Signal Detection Challenges in Signal Detection Importance of Signal Detection in improving patient safety Future directives References Acknowledgement www.clinosol.com | follow us on social media @clinosolresearch 2 6/03/2023

3. Introduction Definition of Signal Detection “I nformation 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”. (CIOMS, 2010) Importance of Signal Detection To identify potential safety concerns To improving patient outcome Enhancing drug development Regulatory compliance To Reduce healthcare costs To increase public confidence www.clinosol.com | follow us on social media @clinosolresearch 3 6/03/2023

4. Types of Signals Clinical Signals - Indications of potential safety with a medical product (drug or device), that are observed during clinical research Indicative of adverse drug reactions (ADRs) Indicative of other safety concerns like, drug interactions, contraindications or misuse/ abuse of the products Identified through, analysis of adverse event data (AED), laboratory tests, imaging, etc. Detection and evaluation: statistical analysis, expert opinion and regulatory guidance Safety signals Indications of potential safety issues with a medical product, that can be identified during clinical research, post-marketing surveillance, etc. Its important to carefully monitor for safety signals throughout the product lifecycle, to ensure that the medical products are safe and effective for use by patients. An effective safety detection and management is a critical aspect of pharmacovigilance (PV) www.clinosol.com | follow us on social media @clinosolresearch 4 6/03/2023

5. Types of Signals……. www.clinosol.com | follow us on social media @clinosolresearch 5 Quality signals Indications of potential quality issues with a medical product, that can be identified during manufacturing , testing, etc. Indicative of problems with manufacturing process – contamination, impurities, or deviation from established procedure Indicative of problems – with product testing – inaccurate or unreliable results Detection and evaluation: inspection of manufacturing facilities, product testing, and analysis of AED Efficacy Signals Indications of the effectiveness of a medical product, in treating a particular condition or disease Identified: Clinical trials, post marketing studies, and real-world data analyses Indicative of positive treatment outcomes- improvement in symptoms, disease progression, or patient survival Depending on the nature and strength of the efficacy signal, it will be used to support regulatory approval, labeling claims, or marketing strategies 6/03/2023

6. Source of Signals Clinical Trials Spontaneous reporting Active monitoring system Pharmaco-epidemiology studies Non-clinical studies ( Eg : animal toxicology studies) Adverse Event Reporting Post marketing Surveillance Literature Review – systematic reviews and meta-analysis www.clinosol.com | follow us on social media @clinosolresearch 6 6/03/2023

7. www.clinosol.com | follow us on social media @clinosolresearch 7 Managing signals 6/03/2023 Signal Management Summary Tabulation Line listing Causality assessment (CA) Strength Evidence Frequency Quality CA Impact on patients Strength & consistency Clinical Context Public health impact Enter the outcome Review appropriate Document – risk assessment Significance of signal Modification Initiation - label change - Recall/ procedure correction Inform Issuing & updating risk

8. Methods of Signal Detection Data Mining: This is a technique used for identifying patterns and links in large datasets. Quantitative signal detection: Done through disproportionality statistics Different ways to calculate disproportionality - Reporting Odds Ratio (ROR), Proportional Reporting Ration (PRR) and Bayesian method (Empirical Bayer's Geometric Mean [EBGM] & Information Component [IC]) www.clinosol.com | follow us on social media @clinosolresearch 8 Formulae to calculate ROR ROR = (a/b)/(c/d) Where, a = no. of primary case reports on Drug X and Adverse Event Y b = no. of primary case report involving Drug X and NOT Adverse Event Y c= no. of primary case reports involving NOT Drug X and Adverse Event Y D= no. of primary case reports involving NOT Drug X and NOT Adverse Event Y. 6/03/2023

9. Methods of Signal Detection Adverse events monitoring: - During clinical trials, AEs are closely monitored to detect any potential safety concerns Signal Detection using machine learning algorithm: - These are computer programs designed to detect potential safety concerns in large datasets. Algorithms use statistical methods to identify patterns or signals that may indicate a safety concern. Signal Detection using expert view Pharmacovigilance: Is a process of monitoring the safety of drugs and devices after approval. www.clinosol.com | follow us on social media @clinosolresearch 9 Ref: PVClinical : Active Pharmacovigilance in Clinical Environments (pvclinical-project.eu) 6/03/2023

10. Regulatory requirements for Signal Detection www.clinosol.com | follow us on social media @clinosolresearch 10 ICH (International Council for Harmonization) guidelines FDA (Food and Drug Administration) post market safety surveillance requirements EMA (European Medicines Agency) pharmacovigilance requirement Challenges in Signal Detection Incomplete and inaccurate data Signal validation and interpretation Signal prioritization and management False positive signals 6/03/2023

11. Identifies previously unknown or unexpected effects of drugs or devices Detects potential safety concerns and adverse AEs early on Provides information for healthcare professionals and patients Enables researchers to design new targeted and effective clinical trials Improves overall quality of medical treatments and the outcome Ensures regulatory compliance with post-market surveillance requirements www.clinosol.com | follow us on social media @clinosolresearch 11 Importance of Signal Detection in improving patient safety Future Directives of Signal Detection Use of RWD to provide valuable insights into the safety and efficacy of drugs and devices in real world settings Incorporation of advanced analytic technique Development of multimodal approach using multiple sources of data Incorporation of a patient-centered approach – improvising the accuracy and relevance of signal detection Development of collaborative network (industries, regulatory, and academia) 6/03/2023

12. References Dasic , G., Jones, T., Frajzyngier , V., Rojo, R., Madsen, A., & Valdez, H. (2018). Safety signal detection and evaluation in clinical development programs: A case study of tofacitinib.  Pharmacology research & perspectives ,  6 (1), e00371. https://doi.org/10.1002/prp2.371 Malikova MA. Practical applications of regulatory requirements for signal detection and communications in pharmacovigilance. Therapeutic Advances in Drug Safety. 2020;11. doi:10.1177/2042098620909614 Bate, A. and Evans, S.J.W. (2009), Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidem . Drug Safe., 18: 427-436.  https://doi.org/10.1002/pds.1742 Signal Detection in Pharmacovigilance (primevigilance.com) What is a signal? | UMC (who-umc.org) Pharmacovigilance Signal Detection: The Complete Guide (adverahealth.com) www.clinosol.com | follow us on social media @clinosolresearch 12 6/03/2023

13. Acknowledgement I would like to thank team ClinoSol Research and Ms. Shifa for the constant guidance Special thanks to, Mr. Mujeebuddin Shaik, Founder and CEO, ClinoSol Research, Hyderabad, India Ms. Uma Priya, Director, ClinoSol Research, Hyderabad, India, for all the support and encouragement www.clinosol.com | follow us on social media @clinosolresearch 13 6/03/2023

14. Thank You! www.clinosol.com (India | Canada) 9121151622/623/624 [email protected] www.clinosol.com | follow us on social media @clinosolresearch 14 6/03/2023