1. 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) Drug Safety Surveillance Process Overview: MedDRA ® Application and Challenges From Clinical Trials to Post-Authorisation PSI International, Inc., USA 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 Data Collection, Entry, and Storage  Collect, enter, and store in database all safety data Data Coding and Coding Quality Control  Develop and implement coding and quality control guidelines Safety Signal Generation  Compare all available safety data for potential safety signals (i.e., data mining) Safety Signal Evaluation Actions  Assess clinical relevance of safety signal and take the necessary steps to improve drug safety Descriptive Epidemiology  Describe and summarize all available information pertaining to the adverse event of interest and the suspect product Analytic Epidemiology  Verify identified safety signals by means of observational and/or experimental epidemiological studies 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 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. Coding by Organisation A MedDRA 8.1 1.LLT Azotemia prerenal PT Acute prerenal failure SOCRenal 2.LLT Known drug-drug interaction medication error PT Labelled drug-drug interaction medication error SOC Injury 3.LLT Blood pressure decreased PTBlood pressure decreased SOCInvestigation 1.LLTAcute renal failure PTRenal failure acute SOCRenal 2. LLTHyperkalemia PTHyperkalaemia SOCMetabolism 3.LLT Known drug-drug interaction medication error PTLabelled drug-drug interaction medication error SOC: Injury 1.LLTAcute renal failure PT Renal failure acute SOC Renal 2.LLT Blood pressure low PT Hypotension SOC Vascular 3.LLT Drug interaction PT Drug interaction SOC General Organisation’s Specific Coding Guidelines  Based on the ICH endorsed MedDRA ® Term Selection: Points to Consider document and the organisation’s specific objectives Coding by Organisation B MedDRA 8.1 Coding by Organisation C before MedDRA 8.0 + Compare data from these sources and determine which combination of MedDRA ® terms suggest a potential safety signal for a particular product 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 Post- Authorisation module (EVPM) designed for post-authorisation ICSRs The EudraVigilance Clinical Trial module (EVCTM) designed for pre- authorisation SUSARs  The use of MedDRA ® is mandatory under EMEA’s jurisdiction for both clinical trials SUSARs and post- authorisation ICSRs. Drug Safety review: Create a case definition using MedDRA ® terms which describe the clinical process of interest and create a search group containing all names for the suspect product. Create a case series by retrieving from reported data all cases fulfilling case and product definitions. Add literature cases to case series. Evaluate raw data from individual case reports and extract all relevant case data stratifying information as necessary. Provide a clinical assessment of the findings based on the nature of the disease under treatment and adverse event characteristics. Address safety concerns identified during clinical trials by further data collection through experimental studies. 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 the existence of terminology bridges between MedDRA ® and study database’s particular terminology (ICD, SNOMED, etc.). Residual safety concerns addressed by further data collection through Phase IV commitments: Experimental studies, post-marketing epidemiologic studies, and other risk management strategies. 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 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 Clinical Trials Data Coded in other Terminologies or in Different versions of MedDRA ® MedDRA ® Conversion Create a “Case Definition” Using MedDRA ® Terms Data Retrieval Clinical assessment When possible, code in MedDRA ® Summarize all case information Identify cases of interest in large external databases (other standard terminologies are bridged to MedDRA ® ) Observational Studies Verify Safety Signal Case 1Case 2Case 3Case 4Case n 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. Clinical Trials Data MedDRA ® Coded Clinical Trials Data Other Sources of Safety Data Organization’s Postmarketing Safety Data + Organisation’s Safety Data Other Sources of Safety Data (i.e., medical literature, WHO) Enhance dataset by abstracting additional information Obtain disease Natural history data Obtain adverse event’s typical characteristics data Experimental Studies Descriptive Epidemiology Studies In-depth analysis 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.