1. Pharmacovigilance and Risk Management Chapter 17

2. OBJECTIVES Understand the reporting requirements for Investigational New Drug (IND) safety data Understand the postmarketing requirements for safety data for drugs and biologics Understand the postmarketing requirements for safety data for medical devices Understand the requirements for Risk Evaluation and Mitigation Strategies (REMS) Understand the requirements for proprietary name review of drugs and biologics

3. During Clinical Trials Adverse Event - An adverse event is any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related Life-threatening Adverse Event or Life-threatening Suspected Adverse Reaction - Places the patient or subject at immediate risk of death Serious Adverse Event or Serious Suspected Adverse Reaction - Results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect, or medical judgement

4. More definitions Suspected Adverse Reaction - A reasonable possibility that the drug caused the adverse event Unexpected Adverse Event or Unexpected Suspected Adverse Reaction - Not listed in the Investigator Brochure, or is not listed at the specificity or severity, is not consistent with the risk information described in the general investigational plan or elsewhere

5. Reporting Requirements for Clinical Trials Investigator is required to promptly report to the sponsor all adverse events encountered with the drug Sponsor reports to FDA and all participating investigators in a written IND safety report of: 1.any adverse experience associated with the use of the drug that is both serious and unexpected 2.any finding from tests in laboratory animals that suggests a significant risk for human subjects, including reports of mutagenicity, teratogenicity or carcinogenicity

6. New information Must be reported to the agency within 15 days of the sponsor becoming aware of an occurrence: Findings from clinical or epidemiological studies that suggest a significant risk to study participants Serious suspected adverse reactions that occur at a rate higher than expected Serious adverse events from bioavailability studies and bioequivalence studies conducted without an IND Submitted either on a Form FDA 3500A or on a Council for International Organizations of Medical Sciences (CIOMS) I form Submit reportable event information no later than 15 calendar days after the event has been made clear

7. Generics For bioavailability (BA) and bioequivalence (BE) studies conducted without an IND, the person conducting the study, including any contract research organization (CRO), is required to notify FDA of any serious adverse event within 15 days of its occurrence, and of any fatal or life-threatening adverse event from the study within seven days of its occurrence. Must be submitted to the director, Office of Generic Drugs in CDER Relevant follow-up information to a BA/BE safety report must be submitted as soon as the information is available Upon request from FDA, the person conducting the study, including any CRO, must submit to FDA any additional data or information that the agency deems necessary within 15 days after receiving the request

8. Post Marketing Safety Reporting Adverse Drug Experience - An adverse drug experience is any adverse event associated with the use of a drug, whether or not considered drug related, including the following: in the course of the use of a drug product in professional practice from drug overdose whether accidental or intentional from drug abuse from drug withdrawal any failure of expected pharmacological action

9. Post Marketing Safety Reporting Associated With the Use of the Drug - There is a reasonable possibility that the experience may have been caused by the drug Disability - An adverse event that results in a substantial disruption of a person’s ability to conduct normal life functions Life-threatening Adverse Drug Experience - Any adverse drug experience that places the patient, in the view of the initial reporter, at immediate risk of death Serious Adverse Drug Experience - Same as clinical Unexpected Adverse Drug Experience – Not in current labeling

10. Authorities CDER’s Office of Surveillance and Epidemiology Divisions consists of three divisions: Division of Drug Risk Evaluation (DDRE) - detect and assess safety signals for all marketed drug products Division of Medication Errors and Technical Support (DMETS) – premarketing reviews of all proprietary names, labels and labeling and analysis of medication errors Division of Surveillance, Research, and Communication Support (SRCS) – oversees MedWatch, risk communication research and activities such as Medication Guides, Patient Package Inserts and pharmacy information surveys, and international regulatory liaison activities for all drug and biologic postmarketing safety issues.

11. Postmarketing Drug/Biologic Surveillance: Individual Case Safety Reports (ICSRs) Individual case safety report (ICSR), applicants should, at a minimum, have knowledge of the four data elements: an identifiable patient an identifiable reporter a suspect drug or biological product an adverse experience or fatal outcome believed to be due to the suspect drug or biological product

12. Sponsors of approved products Review ADE information obtained from all potential sources (foreign and domestic), including: marketing experience scientific literature (peer-reviewed and non-peer-reviewed) unpublished reports postmarketing clinical investigations postmarketing epidemiological or surveillance studies

13. Timelines and Forms Keep ADE files for 10 years per SOP All adverse events (domestic and foreign) that are both serious and unexpected must be submitted within 15 calendar days of initial receipt by anyone in the employ of the applicant Use form FDA 3500A or a CIOMS I form (Foreign Sponsor) Electronic or Paper is acceptable Causality is not a concern, unless during an investigational study Follow up reports required as in an IND

14. And More Reports…. The Dietary Supplement and Nonprescription Drug Consumer Protection Act (DSNDCA) (PL 109-462) amended the Federal Food, Drug, and Cosmetic Act (FD&C Act) to add safety reporting requirements for nonprescription drug products that are marketed without an approved application Post Marketing Periodic Safety Reports – Quarterly for the first 3 years, then annually

15. Reports… The regulations require a postmarketing periodic report to contain: a narrative summary and analysis of the information in the report and an analysis of the 15-day Alert Reports submitted during the reporting interval a Form FDA 3500A for each spontaneously reported adverse experience occurring in the US that was not reported in a 15-day Alert Report a history of actions taken since the last report because of adverse experiences

16. Report sections Section 1: Narrative summary and analysis—A narrative summary and analysis of the information in the postmarketing period report and an analysis of the 15-Day Reports (i.e., serious, unexpected adverse experiences) submitted during the reporting period must be provided Section 2: Narrative discussion of actions taken—A narrative discussion of actions taken must be provided, including any labeling changes and studies initiated since the last periodic report Section 3: Index line listing—An index line listing of Form FDA 3500As or Vaccine Adverse Event Reporting System (VAERS) forms included in Section 4: Form FDA 3500As or VAERS forms— Form FDA 3500As or VAERS forms must be provided for the adverse events that have not already been submitted as 15-Day Alerts for experiences that occurred in the US during the reporting period. Or, Prepare an PSUR as described in ICH

17. Safety Monitoring by FDA FDA tracks adverse drug reaction reports by entering all safety reports for approved drugs and therapeutic biologic products into the computerized FDA Adverse Event Reporting System (FAERS) database May lead to a Dear Health Care Professional Letter Also posted quarterly on FDA Website

18. REMS FDAAA created Section 505-1 of the FD&C Act, which authorizes FDA to require sponsors of certain applications to submit and implement a REMS assessing a product’s benefit-risk balance developing and implementing tools to minimize a product’s risks while preserving its benefits evaluating tool effectiveness and reassessing the benefit:risk balance making adjustments, as appropriate, to the risk minimization tools to further improve the benefit:risk balance Need to ensure the REMS is effective

19. Device PostMarketing Surveillance 21 CFR 803: Medical device reporting: Device user facilities must report deaths and serious injuries that a device has or may have caused or contributed to, establish and maintain adverse event files and submit summary annual reports Manufacturers or importers must report deaths and serious injuries their device has or may have caused or contributed to. In addition, they must report certain device malfunctions. They also must establish and maintain adverse event files. In addition, manufacturers must submit specified follow-up information Medical device distributors must maintain records of incidents but are not required to file these incidents. 21 CFR 806: Medical devices; reports of corrections and removals 21 CFR 822: Postmarket surveillance

20. MEDSUN Medical Product Safety Network (MedSun)— MedSun is an enhanced surveillance network comprised of approximately 280 hospitals nationwide that work interactively with FDA to better understand and report on device use and adverse outcomes in the real-world clinical environment Specialty networks within MedSun focus on device-specific areas such as cardiovascular devices (HeartNet) and pediatric intensive care unit devices (KidNet).

21. Postapproval Studies—FDA may order a postapproval study as a condition of approval for a device approved under a Premarket Approval (PMA) application Postmarket Surveillance Studies—FDA may order a manufacturer of certain Class II or Class III devices to conduct postmarket surveillance studies (often referred to as “522 studies”) FDA Discretionary Studies—FDA also conducts its own research to monitor device performance, investigate adverse event signals and characterize device-associated benefits and risks to patient sub- populations

22. Sentinel Initiative FDAAA required a long-term effort to create a national electronic system for monitoring FDA-regulated medical product safety It uses pre-existing electronic healthcare data from multiple sources exploring a variety of approaches for improving the agency’s ability to quickly identify and assess safety issues Pilot program is mini-sentinel