Best Corporate Practices in Meeting the FDA’s Safety Reporting Requirements FDA Regulatory and Compliance Symposium Presenter: Saundra Beacham, Director, Drug Safety Operations Actelion Pharmaceuticals US, Inc.

Presentation Objectives Addressing the corporate practices for meeting FDAs Safety Reporting Requirements in the following areas: Standard Operating Procedures (SOPs) & Guidelines Training Program Assessment / Triage of Adverse Events Evaluation of Labeling Post-marketing Commitments Lessons from Regulatory Inspections 26 Jul 2005

Standard Operating Procedures (SOPs) & Guidelines Development of SOPs & Guidelines or Working Instructions SOPs – broader in scope Guidelines & Working Instructions – step by step details Ensure that SOPs are consistent with the regulations Set realistic expectations Train colleagues Ensure SOPs / Guidelines reflect work practices 26 Jul 2005

Standard Operating Procedures (SOPs) & Guidelines, cont. Periodically review SOPs, update as needed Revise SOP before implementing changes Have a system in place for revising SOPs Remove reference for inactive documents When more frequent review is not needed, SOPs and guidelines should be reviewed on an annual basis. 26 Jul 2005

Training Program Develop a Training Program Training of Colleagues in Department Permanent and Contract colleagues CFR, ICH Guidelines Standard Operating Procedures Guidelines / Working Instructions 26 Jul 2005

Training Program Training of Colleagues in Other Departments New company employees Overview of Drug Safety Department and AE reporting Sales and Marketing colleagues Procedures designed for Sales colleagues for reporting AE information AE Collection Form available on company intranet Distributors Interface with distributors, provide instructions & form(s) for reporting adverse experience information to company 26 Jul 2005

Assessment of Adverse Events Individual case assessment by Medical Reviewer Case review of all adverse events upon receipt of information in department. Evaluation of information from the reporter and company perspectives: Seriousness criteria Labeling Causality / Relationship Comments and recommendations for follow-up 26 Jul 2005

Assessment of Adverse Events Group assessment by Global Drug Safety (GDS) representatives GDS representatives meet weekly for case review (physician input required). Each Drug Safety unit identifies: Potential expedited cases Other cases of interest GDS representatives discuss cases in meeting and make final decisions regarding reporting to which countries and regulatory agencies. 26 Jul 2005

Evaluation of Labeling Determine whether the adverse event is labeled or listed in the labeling documents An event is unlabeled when the event term is more specific or more severe than what’s indicated in the label. When an event is associated with a patient death, then the event is unlabeled unless the labeling document indicates fatalities are associated with the event. An event is unlabeled when its only reference is in class labeling. 26 Jul 2005

Evaluation of Labeling Create Labeling Conventions to assist in determination of labeling. Here are a few examples, document: Interpretations in labeling, e.g. Anemia is labeled, yet anemia w/blood transfusion is not labeled. Weight gain is labeled, but weight gain greater than 20% is not labeled. How Lack of Efficacy will be handled How labeling will be handled when drug use is off-label. 26 Jul 2005

Evaluation of Labeling Those terms that are included in association with indication for drug. Any labeling issues that are part of the post-marketing commitment. 26 Jul 2005

Post-marketing Commitments Meeting additional regulatory obligations associated with drug approval may include: Expediting abnormal liver function events Expediting all pregnancies Holding periodic meetings with medical experts 26 Jul 2005

Lessons from Regulatory Inspections Document correspondence from meetings regarding adverse events. Have a system of tracking all incoming events and source information from receipt at company to submission. Track expedited reports. When reports are late, provide a reason for late submissions. Have a procedure in place for determining when a case should be closed Be prepared to produce safety training records for all company employees who are likely to hear of AEs (e.g. Supply Chain Mgmt) 26 Jul 2005

Lessons from Regulatory Inspections Have written procedures for handling adverse events / product complaints. Have contractual agreements with distributors and/or 3rd parties for collecting and reporting adverse events. Be able to readily tabulate different types of event categories by time period, e.g. non-serious events, unlabeled, by quarter. Be aware that the regulatory clock starts when an adverse event is confirmed. The generic ‘adverse event’ or ‘SAE’ does not meet the basic element of an AE. 26 Jul 2005

Summary To accomplish the objectives of meeting the FDA’s Reporting Requirements is a collaborative effort for the entire company, involving not only all of the Drug Safety units, but also Regulatory Affairs, Clinical, Sales, and Marketing Departments. bml@zanderins.com 26 Jul 2005