1. Field Investigators: ADE Detectives

2. Section One Introduction to the Team and Their Roles

3. FDA’s Postmarketing Adverse Drug Experience Inspectional Program

4. …”promote and protect public health by assuring that safe and effective drugs are available to Americans.”

5. …”provide pharmacovigilance resources to the Center for Drug Evaluation and Research to ensure the safety of marketed drugs.”

6. Field Investigations Office of Drug Safety Office of Compliance Regulatory Policy Staff Office of Chief Counsel

7. …”serve as industry watchdog, performing inspections or investigations that help protect the safety of all our citizens.”

8. After approval, drugs are used in many types of patients -- including older, sicker or those taking medications --- that were not studied during the pre-approval period. Rare, serious adverse reactions are often not discovered until many thousands of patients have taken the drug.

9. Labeling changes related to prescribing information are complete and up-to-date. Drug risks are quickly and appropriately managed.

10. Regulations Guidance Information on how to conduct an inspection Helpful tips and information

11. Section Two The Regulations

12. Safety reporting requirements cover all persons who market over-the-counter drugs with approved applications and prescriptions drugs Applicants Manufacturers Packers Distributors

13. Title 21 of the Code of Federal Regulations

14. Section 314.80 - Postmarketing Safety Reporting Regulations for Human Drugs with Approved New Drug Applications

15. Section 314.98 - Postmarketing Safety Reporting Regulations for Human Drugs with Approved Abbreviated New Drug Applications

16. Section 211.198 - Requires Industry to Establish Written Procedures for Handling Complaints, Including ADEs

17. An adverse event occurring in the course of the use of a drug product in professional practice; from a drug overdose, whether accidental or intentional; from drug abuse; from drug withdrawal; and from any failure of expected pharmacological action

18. Death A life-threatening ADE Inpatient hospitalization or prolongation of existing hospitalization A persistent or significant disability or incapacity A congenital anomaly or birth defect Other important medical events

19. What must be reported? Any spontaneous adverse event occurring within the U. S. Any foreign reports, literature and study reports that involve serious and unexpected events.

20. 3 Types of Required Reports? Expedited or 15-day alert reports Periodic reports Follow-up reports

21. Four Basic Elements : identifiable patient Identifiable reporter Suspect drug An adverse experience or fatal outcome

22. Form 3500A or CIOMS 1 Form - From the council for International Organizations of Medical Sciences

23. Surveillance Receipt Evaluation Reporting

24. Firms should collect quality information Identify and confirm drug safety issues as soon as possible Communicate drug safety information to FDA and to the public efficiently and effectively Maintain all ADE records, including all raw data, for 10 years

25. http://www.fda.gov/medwatch/how.htm

26. By Mail: Use the postage-paid MedWatch form By Phone: 1-800-FDA-1088 By FAX: 1-800-FDA-0178 And by Internet

28. Section Three Compliance Program Guidance

29. Your job as an investigator will depend more on computers and telecommunications.

30. Types of Inspections : For-cause or directed inspections Routine surveillance inspections

31. Selection Criteria: A review of the Adverse Event Reporting System database Firms that have a history of violations, are on the Application Integrity Policy List, or that have a history of recalls Routine surveillance The drug is a new molecular entity or Is on the TOP 200 List

32. Selection Criteria: Safety issues Bioequivalence issues and Special situations

33. Timeliness reports Direct reports vs. Mandatory reports Completeness reports

34. Getting Ready for an Inspection Review previous establishment inspection reports Review information provided with the assignment, which may include 3500A forms, current approved labeling and AERS-generated ADE lists Review applicable CFR sections, Compliance Program Information, and FDA guidelines Contact the staff member who initiated your assignment

35. All of the firm’s written procedures that describe receipt, evaluation, and submissions of ADEs during the time period under investigation. Organizational charts showing which persons were or are responsible for all compliant handling during the time period under investigation. All written procedures describing who is responsible for changing complaint handling procedures during the time period under investigation.

36. All correspondence, meeting minutes, and documents relating to all ADEs. List of all the company’s drug products and approval dates. Package inserts for products covered under the inspection.

37. A listing of all ADE complaints received over a specific timeframe, such as 2 years, including foreign and domestic events. Periodic reports, specific 3500A forms, and associated raw data. Lists of collection sites, processing centers, and reporting units. Copies of all contractual agreements related to collection, evaluation and reporting ADEs.

38. Section Four How to Conduct an Inspection

39. Is there a difference between a GMP inspection and a post-marketing ADE inspection?

40. What is the main objective of these ADE inspections?

41. What are some the questions you typically ask while interviewing representatives of the company?

42. How do they do their job when each type of ADE comes into the company? Are there meetings on ADEs? Who presides; how often; what topics are discussed? Which persons in the company are responsible for labeling and making sure the labeling reflects the ADEs coming into the company?

43. How does the process work for assuring labeling reflects ADEs? Who first receives the incoming mail or calls relating to ADEs? Where are and how are ADEs logged in? Who performs the medical evaluations? Who performs follow-up?

44. Who assesses seriousness? Who determines if the ADE is a labeled or an unlabeled event? Who determines if the ADE is a 15-day or a periodic report? Who transmits or sends the 3500A Form to FDA?

45. How is information shared among departments? Be aware that the legal department might be receiving and maintaining ADEs too. Who determines if the ADE is a labeled or an unlabeled event? How are ADEs tracked? How are control numbers assigned?

46. Does the firm use a computerized database for tracking Is this database national or global? What information is kept in the database? Is there an audit trail? How does the firm track ADE receipt and submission?

47. What about a firm’s written procedures?

48. What kind of procedures do you mean?

49. What are some common deficiencies found in these inspections?

50. Inspectional deficiencies : A firm’s failure to submit or the untimely submission of the 15-day report. Failure to submit or the untimely submission of periodic reports. Submission of inaccurate or incomplete ADEs.

51. Inspectional deficiencies : Failure to conduct follow-up investigations into the outcome of serious and unexpected ADEs. No written SOPs; inadequate SOPs; or failure to follow SOPs. Failure to validate computer systems used to generate ADE report.

52. 301-827-9057

53. Section Five Tips

54. www.fda.gov/cder/aers/index.htm www.fda.gov/medwatch/report/mfg.htm