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Drug Safety Surveillance Process Overview: ® MedDRA Application and Challenges From Clinical Trials to Post-Authorisation Amarilys Vega, M.D, M.P.H., Sonja Brajovic, M.D., Jung Lee, R.Ph, Mark Vieder, R.Ph., Bane Bradic, M.D. PSI International, Inc., USA Objective: To describe the application of and challenges encountered in the use of the Medical Dictionary for Regulatory Activities terminology (MedDRA® ) in the drug safety surveillance process including the FDA and EMEA perspectives. Data Collection, Entry, and Storage Collect, enter, and store in database all safety data • Data collection must be complete and detailed to facilitate clinical interpretation, MedDRA® coding, and data retrieval and analysis • Information technology tools are necessary throughout the different phases of the Drug Safety Surveillance process Data Coding and Coding Quality Control Develop and implement coding and quality control guidelines MedDRA® Coding Guidelines and coding practices have great impact on: Data accuracy, consistency, and uniformity Data reconciliation, retrieval, and analysis Post-authorisation pharmacovigilance efforts Example of an Adverse Event Narrative 2-3 weeks after starting Suspect drug, patient is fatigued, with no appetite, blood pressure 95/65 mmHg. Diagnosed with ARF and hyperkalemia, due to pre-renal azotemia. Physician suspects known drug interaction with patient’s on-going therapy. Patient’s medical history: hypertension, no prior renal insufficiency. Organisation’s Specific Coding Guidelines Based on the ICH endorsed MedDRA® Term Selection: Points to Consider document and the organisation’s specific objectives 1. 2. 3. Coding by Organisation B MedDRA 8.1 Coding by Organisation A MedDRA 8.1 LLT Azotemia prerenal 1. PT Acute prerenal failure SOC Renal LLT Known drug-drug 2. interaction medication error PT Labelled drug-drug interaction medication error 3. SOC Injury LLT Blood pressure decreased PT Blood pressure decreased SOC Investigation Coding by Organisation C before MedDRA 8.0 LLT PT SOC LLT PT SOC LLT Acute renal failure Renal failure acute Renal Hyperkalemia Hyperkalaemia Metabolism Known drug-drug interaction medication error PT Labelled drug-drug interaction medication error SOC: Injury 1. 2. 3. LLT PT SOC LLT PT SOC LLT PT SOC Acute renal failure Renal failure acute Renal Blood pressure low Hypotension Vascular Drug interaction Drug interaction General Compare all available safety data for potential safety signals (i.e., data mining) Clinical Trials Data MedDRA® Conversion Coded in other Terminologies or in Different versions of MedDRA® MedDRA® Coded + Clinical Trials Data + Organization’s Postmarketing Safety Data USA Food and Drug Administration Adverse Event Reporting System (AERS) FDA AERS is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. AERS replaced the Spontaneous Reporting System in November 1997, with all legacy data converted to MedDRA®. FDA AERS is a passive surveillance system which collects spontaneous adverse event data submitted by manufacturers, consumers and health professionals. FDA Coding guidelines are developed based on ICH endorsed MedDRA® Term Selection: Points to Consider document and FDA’s coding principles. The goal is to capture medical concepts described in the narrative and classify them into accurate MedDRA® terms. Coding guidelines and practices are regularly reevaluated and modified according to FDA’s needs and requirements, and according to ICH-endorsed guidance. MedDRA® coding accuracy is monitored by a continuous quality assurance process. The use of MedDRA® is discretionary under FDA’s jurisdiction with exception to electronic data submission. European Medicines Agency (EMEA) EudraVigilance System Eudravigilance, the European data processing network and management system, launched in December 2001 and developed according to internationally agreed standards, enables the electronic data exchange and supports the EMEA’s drug safety surveillance program. The EudraVigilance system supports the electronic transmission of Individual Case Safety Reports (ICSRs)/Suspected Unexpected Serious Adverse Reactions (SUSARs) between the EMEA and national Competent Authorities, marketing authorisation holders (MAH), applicants and sponsors of clinical trials. EudraVigilance supports the Pharmacovigilance activities in the pre- and post- authorisation phase and contains two reporting modules: • The EudraVigilance PostAuthorisation module (EVPM) designed for post-authorisation ICSRs • The EudraVigilance Clinical Trial module (EVCTM) designed for preauthorisation SUSARs The use of MedDRA® is mandatory under EMEA’s jurisdiction for both clinical trials SUSARs and postauthorisation ICSRs. • Safety data collected during clinical trials is incorporated into the product’s approved label. • Regulatory reviewers monitor products’ safety profiles. They search for safety signals by reviewing reported data, case reports found in medical literature, and data from other passive and active surveillance systems. Most of this data is coded in MedDRA®. • One of the tools employed by the reviewers to identify safety signals is data mining. In-depth knowledge of MedDRA® is required for effective data mining. • Safety data collected along with drug class safety data will characterize the initial safety profile of the product in development. • Product label will reflect safety concerns identified thus far • The terminology used in product label is not standardized (level of MedDRA® hierarchy varies) Safety Signal Generation Clinical Trials Data Regulatory authorities monitor medicinal product safety, provide the best available tools for storing and analyzing safety reports and take action necessary to improve public health. Other Sources of Safety Data Compare data from these sources and determine which combination of MedDRA® terms suggest a potential safety signal for a particular product Safety Signal Evaluation Drug Safety review: • Create a case definition using MedDRA® terms which describe the clinical Descriptive Epidemiology Describe and summarize all available information pertaining to the adverse event of interest and the suspect product and product definitions. Add literature cases to case series. • Evaluate raw data from individual case reports and extract all relevant case Other Sources of Safety Data Data Retrieval suspect product. • Create a case series by retrieving from reported data all cases fulfilling case Create a “Case Definition” Using MedDRA® Terms Organisation’s Safety Data process of interest and create a search group containing all names for the data stratifying information as necessary. (i.e., medical literature, WHO) • Provide a clinical assessment of the findings based on the nature of the disease under treatment and adverse event characteristics. Case 1 Case 2 Case 3 Case 4 Case n • Address safety concerns identified during clinical trials by further data collection through experimental studies. Clinical assessment Summarize all case information Enhance dataset by abstracting additional information Obtain disease Natural history data Obtain adverse event’s typical characteristics data • Scientists from within the regulatory and other organisations conduct experimental and observational studies (large population-based databases). • Use of MedDRA® depends on the characteristics of the study database and When possible, code in MedDRA® the existence of terminology bridges between MedDRA® and study Analytic Epidemiology Verify identified safety signals by means of observational and/or experimental epidemiological studies Identify cases of interest in large external databases (other standard terminologies are bridged to MedDRA® ) database’s particular terminology (ICD, SNOMED, etc.). • Residual safety concerns addressed by further data collection through Phase IV commitments: Experimental studies, post-marketing epidemiologic Observational Studies Experimental Studies Descriptive Epidemiology Studies Verify Safety Signal studies, and other risk management strategies. In-depth analysis Actions Assess clinical relevance of safety signal and take the necessary steps to improve drug safety Regulatory actions: • Develop product-specific Risk Management Strategy • Assess safety issue’s impact on patient support and disease management programs • Assess impact on product marketing Regulatory authorities provide: • Continuous assessment of new safety data and its impact on patient safety. • Drug safety surveillance process guidelines. • MedDRA® terminology improvement recommendations. PSI INTERNATIONAL, Inc., 10306 Eaton Place, Suite 400, Fairfax, VA 22030 USA Phone: 1-703-352-9013; Fax: 1-703-352-8236; WWW.PSIINT.COM; WWW.MEDDRAHELP.COM