Let's talk causality attribution: Current practices and path forward
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The document discusses the challenges of causality attribution in pharmacovigilance, highlighting how current practices often lead to ineffective safety signal detection due to the lack of sufficient data and subjective interpretations. It emphasizes the need for improved data collection systems and standardized protocols to enhance the reliability of causal assessments. The document advocates for the adoption of advanced methodologies and regulatory clarity to address discrepancies and optimize patient safety.
![ICH E2B(R3)– ICSR Implementation Guide
Let's talk causality attribution: Current Practices and Path Forward 7
9/27/2023
FDA - E2B(R3) Electronic Transmission of Individual Case Safety Reports (ICSRs) Implementation Guide – Data Elements and Message Specification
EMA - ICH E2B (R3) Electronic transmission of individual case safety reports (ICSRs) - data elements and message specification - implementation guide
CAUSALITY ASSESSMENT FOR EACH DRUG-EVENT PAIR – EXPECTATIONS AT
DATABASE LEVEL
Global introspection = overall impression [related / not related]
Database infrastructure is in place to accommodate requirements for Sponsor/MAH to use multiple different
algorithmic and Bayesian methods in addition to global introspection as performed by multiple sources.
So why do discrepancies persist?
Problem Statement Current Practices Path forward
Standards](https://image.slidesharecdn.com/wdseccausality2023sep27circulated-230927214853-09dc3a87/85/Let-s-talk-causality-attribution-Current-practices-and-path-forward-7-320.jpg)
Let's talk causality attribution: Current practices and path forward
- 1. Problem Statement Current Practices Path forward LET’S TALK CAUSALITY ATTRIBUTION Current Practices and Path Forward Let's talk causality attribution: Current Practices and Path Forward 1 9/27/2023 Veronika Valdova Standards Presented at WDSEC in Amsterdam on October 5, 2023
- 2. Let's talk causality attribution: Current Practices and Path Forward 2 9/27/2023 Veronika Valdova, DVM is a multi-disciplined professional in the pharma and medical device sectors, with extensive knowledge of all aspects of drug safety in post-market surveillance and clinical research. She works with global corporations, niche manufacturers, and startups as a freelance consultant or B2B. Current endeavors. Independent consultant for Navitas Life Sciences (since 2023), Oriel STAT A MATRIX (since 2023), and several medical device manufacturers (since 2016). Co-founder and Consultant at Arete-Zoe, LLC (since 2013). Experience. Pharmacovigilance officer at IVAX Pharmaceuticals in Opava, Czech Republic (2004-6); Senior Drug Safety Officer at Stiefel Laboratories, UK (2007-8); Pharmacovigilance Manager at Dr. Reddy's Laboratories, UK (2009); independent consultant (2009 onwards); Inspector for medical devices at the Czech Institute for Drug Control (2012-13); Case processor at Accenture Services (2018-2019); Chief Scientific Officer at Veracuity (2019-2022); Co-founder and Consultant at Arete-Zoe, LLC (since 2013), providing consultancy for drug safety and MDD to MDR transition for device manufacturers. Contact: veronikav@arete-zoe.com | +420-721-079-971 | +1-631-791-8129 Links: LinkedIn | Arete-Zoe, LLC | SlideShare Veronika Valdova Independent Consultant Czechia Problem Statement Current Practices Path forward Standards
- 3. PART 1: Causality attribution at case level remains a major challenge in pharmacovigilance case management, resulting in suboptimal effectiveness and reliability of safety signal detection. Let's talk causality attribution: Current Practices and Path Forward 3 9/27/2023 Information obtained from traditional reporting formats such as MedWatch or CIOMS forms is rarely sufficient to establish a causal relationship. Variability in interpretation of information on collection forms necessitate multiple follow-up requests, which are then subjectively interpreted by the collector, often far removed from the patient due to outsourcing of data processing. The result is a high share of unassessable reports compounded by inconsistencies in subjective information exchanges, resulting in low-confidence causality attribution at case level. Accurate, consistent causality attribution is the cornerstone of reliable safety signal detection. Attribution of causality is central to the sponsor’s ability to detect safety concerns since only SUSARs are reportable in most jurisdictions. Problem Statement Current Practices Path forward Standards
- 4. Part 2: No causal relationship in PV databases 9/27/2023 Let's talk causality attribution: Current Practices and Path Forward 4 Causal inference from data currently available in PV databases is not currently computable. Causal inference from FAERS reports depends on many components with complex logical relationships that are yet to be made fully computable. (Kreimeyer, 2021) • FAERS. FDA does not require a proven causal relationship. Reports often do not contain enough detail to evaluate an event. (FDA) • VAERS. The report is not documentation that a vaccine caused the event. (HHS) Data currently available in PV databases do not document causal relationship between drug/vaccine and an adverse event. Problem Statement Current Practices Path forward Standards
- 5. Let's talk causality attribution: Current Practices and Path Forward 5 9/27/2023 Accurate, consistent causality attribution is the cornerstone of reliable safety signal detection. Regulation (EU) No 520/2012 on the performance of pharmacovigilance activities EU GVP Guideline - Module IX – Signal management Problem Statement Current Practices Path forward Standards ‘Signal’ means information arising 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, which is judged to be of sufficient likelihood to justify verificatory action. (Article 19 - Identification of changed risks and new risks) ‘Signal validation’ means the process of evaluating the data supporting the detected signal in order to verify that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal. (Article 21 - Signal management process)
- 6. 9/27/2023 Let's talk causality attribution: Current Practices and Path Forward 6 EXPEDITED ICSRs: ICH E2A (Clinical) & ICH E2D (Post-market) So why the discrepancies? Remediation reduces risks and liabilities! Problem Statement Current Practices Path forward Standards Clinical studies • Single cases of serious, unexpected ADRs (SUSARs) are subject to expedited reporting • Causality assessment is required for clinical investigation cases and post-study events • All cases judged by either the reporting investigator or the sponsor as having a reasonable suspected causal relationship qualify as ADRs. ICH Guidelines ICH E2A (Clinical safety data management) Post-market surveillance • Serious, unexpected ADRs always reportable • Reportability of serious, expected ADRs depends on country • ADRs associated with marketed drugs (spontaneous reports) usually implied causality. • PASS Studies and solicited cases: at least a possible causal relationship is reportable ICH Guideline ICH E2D (Post-approval safety data management)
- 7. ICH E2B(R3)– ICSR Implementation Guide Let's talk causality attribution: Current Practices and Path Forward 7 9/27/2023 FDA - E2B(R3) Electronic Transmission of Individual Case Safety Reports (ICSRs) Implementation Guide – Data Elements and Message Specification EMA - ICH E2B (R3) Electronic transmission of individual case safety reports (ICSRs) - data elements and message specification - implementation guide CAUSALITY ASSESSMENT FOR EACH DRUG-EVENT PAIR – EXPECTATIONS AT DATABASE LEVEL Global introspection = overall impression [related / not related] Database infrastructure is in place to accommodate requirements for Sponsor/MAH to use multiple different algorithmic and Bayesian methods in addition to global introspection as performed by multiple sources. So why do discrepancies persist? Problem Statement Current Practices Path forward Standards
- 8. Let's talk causality attribution: Current Practices and Path Forward 8 9/27/2023 Good Pharmacovigilance Guidelines (EU) RELATEDNESS FOR EACH DRUG-EVENT PAIR EXPRESSED BY MULTIPLE SOURCES WITH MULTIPLE METHODS • The degree of suspected relatedness of each medicinal product to each reported adverse reaction can be presented in a structured manner in the ICSR. • It can be expressed for multiple sources (reporters, competent authorities, marketing authorization holders) while using multiple methods of causality assessment. • CURRENT SAFETY DATABASE SOLUTIONS SUPPORT COMPLEX CAUSALITY ATTRIBUTION REQUIREMENTS Systems structure and regulatory expectations are unambiguous. So why do discrepancies persist? Problem Statement Current Practices Path forward Standards
- 9. 9/27/2023 Let's talk causality attribution: Current Practices and Path Forward 9 • Accurate definition of clinical harm is often lacking. • Brighton Collaboration Case Definitions define clinical harm for syndromes following immunization. • RegiSCAR scoring system specifies criteria for severe cutaneous adverse drug reactions • Drug labels describe expected (experienced, non-hypothetical) ADRs • National Action Plan for ADE Prevention addresses ADEs that are common, clinically significant, preventable, and measurable; resulting from high-priority drug classes in high-risk populations. • REMS/RMPs exist for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. CLINICAL HARM IN POSTMARKETING USE: One size does not fit all. Some degree is a reasonable expectation and should be anticipated in the data collection scheme. Problem Statement Current Practices Path forward Standards The data collection schemes need to reflect relevant product risks.
- 10. Let's talk causality attribution: Current Practices and Path Forward 10 9/27/2023 REMS DRUG LABELS (SmPCs) OZEMPIC – semaglutide drug label (DailyMed) FDA REMS program for Zyprexa Approved REMS for Zyprexa Relprevv (olanzapine) ZYPREXA RELPREVV Patient Care Program Medication Guide Drug-specific harm is often well-defined in product labeling. However, is it well understood by clinicians, and communicated effectively to patients, so they can achieve informed consent? Problem Statement Current Practices Path forward Standards
- 11. 9/27/2023 Let's talk causality attribution: Current Practices and Path Forward 11 * Marketing Authorization Holder (MAH) – operated call-center or a generic form on company website ** Multiple follow-ups to determine causal relationship through data collector HCP or Pharmacist Patient MAH* Medical Reviewer Outsourced data processing (global)** Database location used to synchronize communication between participants. Outsourced data collection, regional by language, with translation* Uncoordinated collector enquiries often conflict with HCP’s schedule. 1) The HCP documentation on drug potential ADRs from MAH must be more comprehensive and accessible. 2) The MAH’s data collection systems must be drug-specific to account for relevant risks, including case definitions, lab thresholds, biological half- life relevant for event timing and patient differentiation. 3) Each of the blue arrows represent a variable delay between inquiry and response. Meanwhile, other patients continue to be treated absent pertinent emerging information. Regulatory Agency Problem Statement Current Practices Path forward Standards
- 12. 9/27/2023 Let's talk causality attribution: Current Practices and Path Forward 12 CIOMS I Drug label information for Lamictal: What to anticipate ≠ Steven-Johnson Syndrome / Toxic Epidermal Necrolysis (SJS/TEN) What are the patient’s risk factors? • Variant pharmacogenomic profile • HIV infection • Associated cancer Focus on early detection • Was the patient informed when to seek medical care? • When did the medical personnel recognize SJS/TEN? Problem Statement Current Practices Path forward Standards
- 13. Let's talk causality attribution: Current Practices and Path Forward 13 9/27/2023 No gold standard exists. A variety of methods* are available, typically 2 or more are used in parallel. WHO-UMC • Widely adopted • Easy to use • Accuracy depends on expert judgment • Reproducibility of results tends to be poor • Roussel-Uclaf (RUCAM) • Jones' algorithm • Naranjo algorithm • Yale algorithm • Karch algorithm • Begaud algorithm • ADRAC • Quantitative approach algorithm • MONARCSi • Bayesian Adverse Reactions Diagnostic Instrument (BARDI) • MacBARDI • Updated Logistic method EXPERT JUDGMENT ALGORITHMIC BAYESIAN (PROBABILISTIC) • Algorithms do not consider medication errors • Algorithms are less able to detect interactions, contributory causation, or secondary harms. • Missing information at ICSR level cannot be corrected by an algorithm. CAUSALITY ATTRIBUTION Problem Statement Current Practices Path forward Standards *However, no methodology can be effective without essential relevant information gained through the collection interaction.
- 14. Let's talk causality attribution: Current Practices and Path Forward 14 9/27/2023 WHO-UMC CAUSALITY CATEGORIES: The use of the WHO-UMC system for standardised case causality assessment Summary description of causality assessment Standard protocol questions • What are the suspect drug(s)? • What other drugs is the patient taking? • What are the therapy and event dates for all drugs (temporal relationship)? • What action was taken with drugs in response to the event? (Drug stopped, dose reduced, drug continued as before) • What was the patient’s response (dechallenge)? • Was/were the drug(s) reintroduced? • What was the patient’s response (rechallenge)? Causality term Assessment criteria CERTAIN • Event or laboratory test abnormality, with plausible time relationship to drug intake • Cannot be explained by disease or other drugs • Response to withdrawal plausible (pharmacologically, pathologically) • Event definitive pharmacologically or phenomenologically (i.e. an objective and specific medical disorder or a recognized pharmacological phenomenon) • Rechallenge satisfactory, if necessary PROBABLE /LIKELY • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Unlikely to be attributed to disease or other drugs • Response to withdrawal clinically reasonable • Rechallenge not required POSSIBLE • Event or laboratory test abnormality, with reasonable time relationship to drug intake • Could also be explained by disease or other drugs • Information on drug withdrawal may be lacking or unclear UNLIKELY • Event or laboratory test abnormality, with a time to drug intake that makes a relationship improbable (but not impossible) • Disease or other drugs provide plausible explanations CONDITIONAL /UNCLASSIFIED • Event or laboratory test abnormality • More data for proper assessment needed, or • Additional data under examination UNASSESSABLE /UNCLASSIFIABLE • Report suggesting an adverse reaction • Cannot be judged because information is insufficient or contradictory • Data cannot be supplemented or verified Reporter and collector should share standard protocols to orient communications Problem Statement Current Practices Path forward Standards
- 15. Let's talk causality attribution: Current Practices and Path Forward 15 9/27/2023 Questions YES NO DNK Are there previous conclusive reports on this reaction? +1 0 0 Did the adverse event appear after the suspected drug was administered? +2 -1 0 Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? +1 0 0 Did the adverse event reappear when the drug was re‐administered? +2 -1 0 Are there alternative causes (other than the drug) that could on their own have caused the reaction? -1 +2 0 Did the reaction reappear when a placebo was given? -1 +1 0 Was the drug detected in blood (or other fluids) in concentrations known to be toxic? +1 0 0 Was the reaction more severe when the dose was increased or less severe when the dose was decreased? +1 0 0 Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 Was the adverse event confirmed by any objective evidence? +1 0 0 Sponsor/MAH Knowledge HCP Reporter /Investigator Knowledge *Case definition shall define objective evidence required, i.e., specific labs or tests • Company Medical Reviewer needs to obtain this information via follow-up SCORES 9 = DEFINITE ADR 5-8 = PROBABLE ADR 1-4 = POSSIBLE ADR 0 = DOUBTFUL ADR NARANJO CAUSALITY SCALE * These questions should appear as a prompt at the MAH point of contact and should be part of the initial submission. Problem Statement Current Practices Path forward Standards
- 16. • System design is adequate for its intended purpose of controlling risk. • Regulatory requirements are clear. • A suite of causality assessment tools exists. • Database infrastructure is in place. • The only missing component is diligence prioritizing reduction of patient risk and optimal outcome. • Current practices deny potential AI advantages. 9/27/2023 Let's talk causality attribution: Current Practices and Path Forward 16 Problem Statement Current Practices Path forward Standards CONCLUSION