1. PMS Forum 1 MedDRAの基礎知識 出典： MSSO-DI-6225-7.1.0 2004 Northrop Grumman Corporation. PMS担当者研修テキスト （7） PMS フォーラム作 成 スライドは英語のままですが、ノート部に訳がついて います。 保存後確認ください。

2. PMS Forum Data Quality, Coding and MedDRA ® MedDRA ® is a registered trademark of the International Federation of Pharmaceutical Manufacturers Associations (IFPMA)

3. PMS Forum 3 Course Overview To provide an understanding of: Importance of good quality data How clinical data are coded MedDRA background Coding examples Benefits of good quality data

4. PMS Forum 4 Data Quality and Clinical Trials Highly regulated environment with increasing emphasis on safety surveillance and data quality EU Clinical Trials Directive effective May 1, 2004 –Key provisions include conduct of clinical trials & pharmacovigilance –Notification of suspected unexpected serious adverse reactions (SUSARs) Similar FDA regulations governing pre- & postmarketing safety reporting Objective is global harmonization

5. PMS Forum 5 What is meant by good quality data? Complete Accurate Diagnosis supported by appropriate investigations Causality assessment for adverse events

6. PMS Forum 6 Quality of Input = Quality of Output IN OUT

7. PMS Forum 7 Coding of Clinical Trial Data Most data entered on Case Report Forms are “coded” in some form Facilitates storage, retrieval, analysis and presentation of data Some coding is performed by investigators at point of data entry –e.g. numeric codes for severity of adverse event: 1= mild, 2= moderate etc. Other coding of text data is performed by the sponsor company after data collection Accuracy of initial coding determines accuracy of analysis

8. PMS Forum 8 MedDRA Background

9. PMS Forum 9 What is MedDRA? Med = Medical D = Dictionary for R = Regulatory A = Activities

10. PMS Forum 10 MedDRA Definition MedDRA is a clinically-validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry. The terminology is used through the entire regulatory process, from pre- marketing to post-marketing, and for data entry, retrieval, evaluation, and presentation.

11. PMS Forum 11 Key Features of MedDRA Standardized terminology International scope - translated into several languages, including Spanish, French and Japanese Managed by Maintenance and Support Services Organization (MSSO) and updated bi-annually with input from User Groups (company subscribers)

12. PMS Forum 12 Key Features of MedDRA (cont) Structure facilitates data analysis and reporting and electronic communication Large terminology with > 60,000 terms at lowest level - allows greater specificity Approx. 16,000 Preferred Terms, each representing a unique medical concept Typically used for coding adverse events, signs and symptoms, procedures, investigations, indications and medical and social histories MedDRA is not a drug dictionary

13. PMS Forum 13 Regulatory Status of Mandate US FDA –MedDRA used in FDA’s internal adverse event database –Proposed Rule for Safety Reporting Requirements (2003): FDA proposes to use MedDRA for postmarketing safety reports European Union –All reports (electronic) – January 2003 –EudraCT (European Clinical Trials Database) requires MedDRA –SUSARs (Suspected Unexpected Serious Adverse Reactions) require MedDRA Japanese Ministry of Health, Labour and Welfare –Electronic reports mandatory from October 2003 –MedDRA to be used in Periodic Infection & Safety Reports from April 2004

14. PMS Forum 14 Regulatory Status of Mandate (cont) Common Technical Document –A standard format for new drug and biologic product applications to regulatory authorities –Includes summary documents and reports from individual clinical trials –MedDRA is the recommended terminology for describing adverse events, both serious and non- serious –CTD format is mandatory in EU and Japan and is highly recommended in the US from July 2003

15. PMS Forum 15 Diseases Diagnoses Signs Symptoms Therapeutic indications Investigation names & qualitative results Medical & surgical procedures Medical, social, family history Drug product terms Equipment, device, diagnostic product terms Device failure terms Clinical trial study design terms Patient demographic terms Population-level qualifiers Numerical values for results Severity descriptors OUT Terms from: COSTART © WHO-ART © HARTS © IN Scope of MedDRA

16. PMS Forum 16 Making the Most of MedDRA To take advantage of MedDRA’s richness and specificity, the source data should be –clear –concise –complete –accurate General principles apply to all clinical data

17. PMS Forum 17 Problems with coding data Appropriate coding requires clear initial data A meaning that is clear to the investigator at the point of data entry may be unclear to the sponsor at the point of data coding Example: Ambiguous information –Congestion (nasal, liver, sinus, pulmonary?) –Cramp (muscle, menstrual, abdominal?) –Pain (pain where?)

18. PMS Forum 18 Problems with coding data (cont) Example: Ambiguous abbreviations –MI (myocardial infarction or mitral incompetence?) –GU pain (gastric ulcer pain or genito-urinary pain?) –Decreased BS (breath sounds, bowel sounds or blood sugar?) –COLD (feeling cold, common cold or chronic obstructive lung disease?) Exercise caution with abbreviations that could be misinterpreted ECG, URI, HIV are examples of standard abbreviations

19. PMS Forum 19 Problems with coding data (cont) Example: Vague information –Patient felt “fuzzy”, “weird”, “experienced every adverse event” Try to use accepted medical terminology Example: Non-specific information –“Left wrist edema” (coded as Peripheral edema) –More specific - “Injection site edema left wrist” (coded as Injection site edema)

20. PMS Forum 20 Problems with coding data (cont) Death is an outcome and is not usually considered to be an adverse event Provide details of cause of death if known Example: –“Death due to myocardial infarction” – Myocardial infarction is coded and death is captured as the outcome

21. PMS Forum 21 Problems with coding data (cont) Example: Ambiguous laboratory data –“Glucose of 40” –(Source of specimen - blood, urine, CSF? What units?) –Would have to code as “glucose abnormal” if additional clarification is not obtained Example: Conflicting laboratory data –“Hyperkalemia with serum potassium of 1.6 mEq/L” –Would have to code as “serum potassium abnormal” If using numeric values, provide units and reference range. Be specific about specimen source and diagnostic result/clinical diagnosis

22. PMS Forum 22 Problems with coding data (cont) Example: Combination terms –Diarrhea, nausea and vomiting Try to avoid combination terms - these will have to be split into 3 individual terms Diarrhea Nausea Vomiting

23. PMS Forum 23 Reporting a specific diagnosis Where possible, report the most important medical event or specific diagnosis rather than individual signs and symptoms Can provide provisional diagnosis e.g. “possible”, “presumed”, “rule out” Accuracy is important in preventing dilution of safety signals or generating false signals SIGNS & SYMPTOMSDIAGNOSIS Chest pain, dyspnea, diaphoresis, ECG changes Myocardial infarction

24. PMS Forum 24 Safety signals Accuracy in diagnosis is important for detection and evaluation of safety signals Events of importance in drug safety surveillance include: –QTc prolongation –Hepatotoxicity –Stevens Johnson syndrome –Convulsions –Rhabdomyolysis

25. PMS Forum 25 Generating Quality Data Clear Concise Complete Accurate Be specific if necessary - MedDRA can handle multiple specific medical concepts: –Headache - more than 50 types, including cluster, sinus, migraine, lumbar puncture headache –Organisms - down to species level e.g. Staphylococcus aureus

26. PMS Forum 26 Miscellaneous Verbatims: Coding Challenges Recurrent fatal stroke LK RTCTL UNSP XTRNDL ORG Hears New Age music when furnace turns on Funk exacerbated Normally normal after drinking coffee Went to hell Patient is intermittently tiresome Infection in first finger of the right foot Fireballs in uterus Blast (menopause) Flintstone feet Barely visible posterior

27. Company-specific conventions Insert slides as required to cover company’s specific data collection and recording conventions Could include instructions on how to complete data fields for adverse events, medical history etc. on paper or electronic CRFs Could include general principles of how to record text-based information as well as specific instructions for particular therapeutic areas

28. PMS Forum 28 Benefits of Quality Data Fewer queries for investigator and sponsor

29. PMS Forum 29 Benefits of Quality Data (cont) Accurate and timely information on issues that affect conduct of clinical trial and affect patient safety Improved communication among sponsors, investigators and regulatory agencies about medicinal products –Aids in safety signal detection and evaluation –Ensures accuracy of information about the product including investigators’ brochures and prescribing information –Benefits medical professionals –Benefits patients

30. PMS Forum 30 Quality Data INOUT

31. PMS Forum 31 Course Evaluation Thank you for taking this course Please take the time to fill out the evaluation form Thank you for your feedback

32. PMS Forum 32 MSSO Contacts Mail MSSO VAR1/MSSO 12011 Sunset Hills Road Reston, VA 20190-3285 USA Telephone –Toll-free Worldwide 877.258.8280 (AT&T) Web page –www.meddramsso.com

33. PMS Forum 33 Acknowledgements MedDRA ® is a registered trademark of the International Federation of Pharmaceutical Manufacturers Associations (IFPMA) COSTART Thesaurus Fifth Edition Copyright  1995 US Food and Drug Administration (FDA) Hoechst Adverse Reaction Terminology System (HARTS) © 1992 Aventis Pharma WHO Adverse Reaction Terminology (WHO-ART), Copyright  World Health Organization Collaborating Centre for International Drug Monitoring