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Drug Safety & Pharmacovigilance - Introduction - Katalyst HLS
The document outlines the history and evolution of drug safety and pharmacovigilance, highlighting significant events from the 19th century to the present, including important legislation and drug withdrawals due to safety issues. It emphasizes the ongoing need for pharmacovigilance to ensure drug safety post-marketing, as adverse drug reactions can occur even after thorough pre-approval trials. Key concepts such as adverse events, reporting processes, and the responsibilities of industry and regulatory agencies in monitoring drug safety are also discussed.
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Introduction to drug safety and pharmacovigilance as crucial aspects of healthcare.
Chronological overview of significant events in drug safety history from 1848 to 1938.
Continuation of historical drug safety developments from 1961 to 1990, highlighting key regulations.
Insights on drug safety, showing 121 safety-related withdrawals from 1960 to 1999.
Details of specific drugs withdrawn for safety issues, highlighting risks like rhabdomyolysis and cardiac issues.
Discussion on the inherent risks of all medicines and ongoing safety monitoring by manufacturers and regulators.
Definition and scope of pharmacovigilance in both investigational and marketed products.
Definition of pharmacovigilance, focusing on adverse effects, drug-related problems, and safety monitoring.
Clarification of key terms including adverse events, side effects, and adverse drug reactions.
Comparison between Adverse Events (AEs) and Adverse Drug Reactions (ADRs) in drug safety.
Definitions for Serious Adverse Events (SAE) and other critical safety terminologies.
Distinction between the terms 'serious' and 'severe' in the context of adverse reactions.
Explanation of safety signals in pharmacovigilance and criteria for their detection.
Overview of the main sources of information for drug safety during pre-marketing and post-marketing phases.
Discussion on limitations of pre-approval clinical trials regarding sample size and population diversity.
Table showing the number of patients required for a certain statistical confidence in detecting adverse reactions.
Reasons why continued pharmacovigilance is necessary for capturing drug safety issues post-marketing.
Statistics highlighting the prevalence and financial costs of adverse drug reactions.
Types of adverse drug reactions categorized as Type A, B, C, and D.
Description and examples of Type A adverse drug reactions, which are predictable and common.
Discussion of Type B adverse reactions, which are unpredictable and rare.
Details on Type C reactions that can be rationalized based on chemical structures of drugs.
Explanation of Type D reactions focusing on delayed effects.
Aims of pharmacovigilance include early detection of safety problems and risk prevention.
Key responsibilities for drug safety within pharmacovigilance systems.
Factors to consider when assessing adverse reactions including causality and severity.
Importance and timelines regarding the reporting of adverse events to regulatory authorities.
Specific information required for ADR reports including patient and drug details.
The essential data points required for a reportable adverse reaction.
Key regulatory bodies and their distinct regulations guiding pharmacovigilance.
Overview of European pharmacovigilance regulations and reporting requirements.
Overview of the US pharmacovigilance guidelines and reporting timelines.
Outlined procedures for monitoring safety during clinical trials to ensure patient safety.
Summary slide emphasizing post-marketing drug safety awareness.
Different types of safety reports and documents required in pharmacovigilance.
Essential qualifications, systems, and workflows necessary for drug safety professionals.
Conclusion of the presentation, inviting questions and providing contact information for further inquiries.
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Drug Safety & Pharmacovigilance - Introduction - Katalyst HLS
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- 2. History of DrugSafety - I 1848 – 15 year old Hannah Greener died in course of routine anaesthesia with chloroform (problem: ingrown nail of toe; fibrillation of ventricles?). 1893 - Lancet initiated foundation of a commission and starting collection of notifications about side effects 1906 - US Federal Food and Drug Act - required, that the pharmaceuticals should be “pure” and “free of any contamination” (nothing about the efficacy) 1936 - USA-s 107 lethal cases after sulphanilamides (diethylene glycol was used to solubilize); 1938 - Food, Drug, and Cosmetic Act, 1938. Firms had to prove to FDA that any new drug was safe before it could be marketed: the birth of the new drug application. 12/10.16Katalyst Healthcares & Life Sciences 2
- 3. History of DrugSafety - II 1961 - Dr William McBride (Australia) reported 20% increase in foetal abnormalities and phocomelia in relation with thalidomide use, later numerous reports from other countries (more than 4000 cases) 1962 - USA Kefauver-Harris amendment to the law (requirement to prove safety and efficacy before issuing MA) 1963 - resolution WHA 16.36 reaffirmed the need for early action in regard to adverse drug reactions 1964 - UK started “yellow cards” system 1965 - European Union issued EC Directive 65/65 - first European pharmaceutical directive. The directive was a reaction to the Thalidomide tragedy in the early 1960s, and aimed to establish and maintain a high level of protection for public health in Europe. 1968 - start of WHO Programme for International Drug Monitoring 1990 - ICH - elaboration of intra-regional requirements for safety starts. ICH Safety Guidelines 12/10.16Katalyst Healthcares & Life Sciences 3
- 4. Are Drugs SaferToday? During 1960-1999 there were 121 safety related withdrawals Worldwide Market life less than 2 years 31% Market life less than 5 years 50% Fung et al. Drug Information Journal, 2001; 35:293-317 During 1972-1994 in 583 new active substances were approved Of these 59 were withdrawn later 12/10.16Katalyst Healthcares & Life Sciences 4
- 5. Recent Drug Withdrawals Drugswithdrawn from market due to Safety Issues Cerivastatin (Baycol, Lipobay) 2001 Withdrawn due to risk of rhabdomyolysis Rofecoxib (Vioxx) 2004 Withdrawn due to risk of myocardial infarction 12/10.16Katalyst Healthcares & Life Sciences 5 Terfenadine (Seldane) 1998 Withdrawn due to risk of cardiac arrhythmias; Mibefradil (Posicor) 1998 Withdrawn due to dangerous interactions with other drugs Trovafloxacin (Trovan) 1998-1999 Withdrawn due to risk of liver failure Troglitazone (Rezulin) 2000 Withdrawn due to risk of hepatotoxicity; superseded by pioglitazone and rosiglitazone Cisapride (Propulsid) 2000s Withdrawn in many countries due to risk of cardiac arrhythmias
- 6. Drug Safety Nomedicine is absolutely safe and all pose some magnitude of safety and health risks Making sure that medicines are safe for their intended use is an on-going process that starts in the developmental stage & continues long after medicine is in the market. The process is closely monitored by manufactures and the Regulatory Agencies. 12/10.16Katalyst Healthcares & Life Sciences 6
- 7. Pharmacovigilance Marketed ProductsInvestigational Products Vigilance:Watching carefully in order to avoid danger Development phase Post-marketing 12/10.16Katalyst Healthcares & Life Sciences 7
- 8. Drug Development 12/10.16Katalyst Healthcares& Life Sciences 8
- 9. What is Pharmacovigilance? Pharmacovigilanceis a science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems (e.g. interactions, misuse, medication errors, abuse, overdose, addiction potential). 12/10.16Katalyst Healthcares & Life Sciences 9
- 10. Drug Safety –some definitions Adverse event/adverse experience (AE)- Any untoward medical occurrence that may occur during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment undesirable signs & symptoms disease or accidents abnormal lab finding ( leading to dose reduction / discontinuation / intervention ) Side effect - Any unintended effect of a pharmaceutical product occurring at doses normally used in man, which is related to the pharmacological proprieties of the drug Adverse drug reaction (ADR) - A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for modification of physiological function – causal role is suspected 12/10.16Katalyst Healthcares & Life Sciences 10
- 11. AEs versus ADRs AE ADR 12/10.16Katalyst Healthcares & Life Sciences 11 AEs Versus ADRs
- 12. Drug Safety –some definitions SAE (Serious Adverse Event) - an AE or ADR that is associated with Death Life threatening Results in hospitalization /Prolongs existing hospitalization Persistent or significant disability or incapacity Congenital anomaly or birth defect Medically significant SUSAR (Serious, unexpected, suspected adverse reaction) Serious Not included in Product Core Safety Data Sheet Suspected link to the drug 12/10.16Katalyst Healthcares & Life Sciences 12
- 13. Serious vs Severe Theterm "severe" is often used to describe the intensity (severity) of a specific event (as in mild, moderate, or severe pain); the event itself, however, may be of relatively minor medical significance (such as severe headache). This is not the same as "serious" which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning. 12/10.16Katalyst Healthcares & Life Sciences 13
- 14. Safety Signal SafetySignal - information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Detected / generated during pharmacovigilance Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information 12/10.16Katalyst Healthcares & Life Sciences 14
- 15. Drug Safety – Mainsources of information Pre-marketing (During Development) Pre-clinical (animal / in-vitro) studies Clinical studies – Phase I – III Post-marketing Spontaneous adverse reaction reporting national and international Regulatory authorities Contractual partners Published medical literature Clinical trials - PMS & Phase IV studies, epidemiological studies Data collected for other purposes routine statistics special purpose registries databases of prescription and outcomes 12/10.16Katalyst Healthcares & Life Sciences 15
- 16. Limitations of pre-approvalclinical trials Size (maximum 3,000-5,000 subjects) Sometimes larger for vaccines Narrow Population Often does not include special groups (e.g., children, elderly) Narrow indications not covering actual evolving uses in practice Short Duration (1-3 years) Latent effects not directly measured 12/10.16Katalyst Healthcares & Life Sciences 16
- 17. No. of patientsrequired to be 95% certain of detecting 1, 2 or 3 ADRs Incidence of ADR No. of patients required One Case Two Cases Three Cases 1 in 100 300 480 650 1 in 1,000 3,000 4,800 6,500 1 in 2,000 6,000 9,600 13,000 1 in 10,000 30,000 48,000 65,000 12/10.16 Katalyst Healthcares & Life Sciences 17
- 18. Rationale for continued Pharmacovigilance Informationobtained prior to first marketing is inadequate to cover all aspects of drug safety: Tests in animals are insufficiently predictive of human safety, In clinical trials patients are selected and limited in number, Conditions of use in trials differ from those in clinical practice, Duration of trials is limited Information about rare but serious adverse reactions, chronic toxicity, use in special groups (such as children, the elderly or pregnant women) or drug interactions is often not available. 12/10.16Katalyst Healthcares & Life Sciences 18
- 19. Why Pharmacovigilance Impact ofADRs 4-6th leading cause of death (Lazarou et al, JAMA; 1998) Upto 19 % of in-patients will have an ADR (Davies et al, J Clin Pharm & Ther; 2006); up to 70 % ADRs are preventable (Pirmohamed et al, BMJ; 2006. The cost factor 588 million $ / year in Germany (1997), > $ 177.4 billion in the US in 2000, $847m / year in the UK (2006, BMJ) 12/10.16Katalyst Healthcares & Life Sciences 19
- 20. Classification of ADRs Type A Type B Type C Type D 12/10.16Katalyst Healthcares & Life Sciences 20
- 21. Type A Augmented reactions- pharmacologically predictable from the known activity of the drug, and are usually discovered during early research. They are common, dose related, but are usually benign with a low mortality and morbidity. 12/10.16Katalyst Healthcares & Life Sciences 21
- 22. Type B Bizarre reactionswhich are unpredictable and are rare, often at rates of less than 1:1000 patients per annum. are usually dose-independent have a high morbidity or mortality. Eg Agranulocytosis with Clozapine, Anaphylaxis with Penicillins 12/10.16Katalyst Healthcares & Life Sciences 22
- 23. Type C Type Cor chemical reactions are those reactions whose biological characteristics can be either rationalized or even predicted based on the chemical structure of the parent drug, or of reactive intermediates and metabolites. Example: hepatotoxicity caused by high doses of acetaminophen 12/10.16Katalyst Healthcares & Life Sciences 23
- 24. Type D Delayed effects E.g.the development of vaginal cancer of the offspring where the mothers had received the drug Diethylstilbestrol during pregnancy between 1938 & 1971 12/10.16Katalyst Healthcares & Life Sciences 24
- 25. Pharmacovigilance Aims Earlydetection of unknown safety problems Detection of increases in frequency Identification of risk factors Quantifying risks Preventing patients from being affected unnecessarily Rational and Safe use of Medicines Combined responsibility of Industry & Regulators 12/10.16Katalyst Healthcares & Life Sciences 25
- 26. Pharmacovigilance MAH*Responsibilities Timely collectionof data, recording and notification (reporting) – PV systems & processes, safety database Appropriate assessments (data completeness, seriousness, relatedness, expectedness, medical significance, reporting requirements & timelines) Expedited and periodic reporting to RA Signal detection & proactive risk management * Marketing Authorization Holder 12/10.16Katalyst Healthcares & Life Sciences 26
- 27. Assessing Adverse Reactions Nature, organ/system involved, severity, duration Serious / not serious Causality – relationship to the drug (definite, probable, possible, unlikely) Expected / unexpected (as per known safety profile of the drug) Medical significance (significant / not significant) 12/10.16Katalyst Healthcares & Life Sciences 27
- 28. Regulatory Reporting ofAdverse Reactions Why Report? Ethical requirement Regulatory requirement Legal requirement Who Reports? Company (post marketing), Company & investigator joint responsibility (clinical trials) When to Report? Expedited – 7 to 15 days Periodic – depending on when launched / region 12/10.16Katalyst Healthcares & Life Sciences 28
- 29. Reporting Adverse Reactions Whatto report? - Patient details: Pt. identifier, initials, sex, age etc - Suspected drug: generic name, indication, dates of admin., dose, starting & stopping date and time - Other treatments - Details of suspected ADR – nature, severity, duration, relationship to drug, action taken - Outcome - Details about the reporter/ investigator Formats for reporting Expedited reports – ICSR, MedWatch 3500A, CIOMS I & II Periodic reports – annual safety reports, PSUR, NDA PADER 12/10.16Katalyst Healthcares & Life Sciences 29
- 30. Minimum Data fora Reportable ADR Identifiable patient AE/ADR Suspected Medicinal Product Reporter (HCP) 12/10.16Katalyst Healthcares & Life Sciences 30
- 31. PV Regulations Main Players– EMEA (EU), US FDA, MHRA (UK), TGA (Australia), Japan Slightly different regulations, based on ICH guidelines 12/10.16Katalyst Healthcares & Life Sciences 31
- 32. EU Requirements ApplicableRegulations / Guidelines: Pre-authorization - Clinical Trials Directive 2001/20/EC Post-marketing - Volume 9A Eudralax ICH guidelines - E2A (pre-approval safety data management); E2D (post-approval safety data); ICH E2B (electronic reporting); ICH E2C (PSURs) Expedited Reporting to RA Timelines - 7 days for Fatal or Life threatening events; 15 days for other SUSARs Mandatory e-reporting of Individual Case Safety Reports (ICSR) in pre & post-authorization phase Regulatory-compliant ADR database QPPV Main contact for the RA on pharmacovigilance issues Residing in the EU region with access to medically qualified safety expert PSURs Pre- authorization : EU Annual Safety Reports (ASR) 6 monthly for 1st two years after authorization ; Yearly for next 2 years ; 3 yearly thereafter Signal generation & ongoing communication with RA Risk Management Plan 12/10.16Katalyst Healthcares & Life Sciences 32
- 33. US Requirements ApplicableRegulations / Guidelines 21 CFR parts 310, 312, 314, 320, 600, 601, 606 FDA Guidance for Industry on Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment – March 2005 ICH guidelines - E2A (pre-approval safety data management); E2D (post-approval safety data); ICH E2B (electronic reporting); ICH E2C (PSURs) Expedited Reporting to RA Timelines – 7 days for Fatal or Life threatening events; 15 days for other SUSARs Electronic reporting possible but not mandatory 21 CFR Part 11 compliant safety database Safety Reports - NDA PADERs (post approval), ASRs (pre-approval) Quarterly for first 3 years after approval, yearly thereafter in NDA PR format PSURs in ICH format accepted on agreement with FDA Annual Safety Reports (pre-approval) - yearly Signal generation, ongoing communication with RA RiskMAPs – Risk Minimization Action Plans (REMS) 12/10.16Katalyst Healthcares & Life Sciences 33
- 34. Clinical Trial SafetyMonitoring Adverse Event experienced by Patient Medical evaluation and patient safety decisions (Investigator) AE noted in CRF / SAE reported to Company / CRO within protocol-specified timelines Data Capture & Entry (Receive SAE & assign Unique ID No / Data entry in ADR Database) (Company / CRO) Medical Evaluation & Reporting Assessment Preparing reports in CIOMS / MedWatch / SAE narrative format (Com / CRO) Reporting to Reg Authority within prescribed timelines, if reportable (Com / CRO) Reporting to IRB & DSMB Reporting to other investigators Data Mining, Safety Signal & Report Writing - Annual Safety Reports (Com / CRO) 12/10.16Katalyst Healthcares & Life Sciences 34
- 35. 12/10.16Katalyst Healthcares &Life Sciences 35
- 36. Drug Safety PostMarketing 12/10.16Katalyst Healthcares & Life Sciences 36
- 37. Safety Reports &Documents Individual Case Safety Reports (ICSR) Paper or electronic MedWatch 3500 / CIOMS forms Patient safety narratives (individual reporting / incl in CSR) Periodic / Aggregate Safety Reports Annual safety reports, DSURs (EU) – pre-marketing IND Annual Safety Reports (US) – per-marketing Periodic Safety Update Reports - PSUR (EU) – post-marketing NDA PADER (US) – post-marketing Canadian Annual Report (CAR) Integrated safety summary (US) – for NDA Safety overview (EU) – for NDA Risk Management Plan (EU) RiskMAP or REMS (US) 12/10.16 Katalyst Healthcares & Life Sciences 37
- 38. Drug Safety Requirements Understanding of global requirements & regulations Workflow management SOPs for collection of ADRs, collation, assessment, reporting , risk management Validated database e.g. Arisg, Argus, Oracle AERS Data / documents management systems, storage, security Data back-up & disaster management People Drug Safety Associates - Medical (allopathic or integrated alternative system BAMS, BHMS) or Life Sciences graduates Drug Safety Physicians – Medical graduates / post-graduates with experience in safety assessment Medical / Safety Writers Drug safety expert –experienced drug safety physician 12/10.16Katalyst Healthcares & Life Sciences 38
- 39. Thank You & Questions 12/10/2016 Contact: Katalyst Healthcare’s& Life Sciences South Plainfield, NJ, USA 07080. E-Mail: [email protected] 39