Topics for today. Issues: Regulatory Obligations Post-marketing Adverse Event Reporting; MDRs and Safety Reports. Post-marketing Submissions

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1 Issues: Regulatory Obligations Post-marketing Adverse Event Reporting; MDRs and Safety Reports Martha A. Feldman, RAC Drug & Device Development Co., Inc. Topics for today Post-approval requirements for drugs (including biotechnology-derived therapeutics), devices and biologics Regulatory Submissions Adverse Events: drugs, devices, biologics Other Post-Marketing Reports Medical Device Reports Safety Reports March 28, March 28, Post-marketing Submissions Supplements , Change in Ownership Adverse Drug Experiences Other Changes and Reports Supplements 21 CFR and Prior approval needed Changes to drug substance or drug product (e.g., relax or delete specs, new analytical methods, new manufacturing methods, &/or facility, components, closure system) Major labeling changes March 28, March 28,

2 Supplements Notification Specifications, methods, facility changes providing tighter controls Labeling that strengthens safety New facility if processes are same and new facility has passed GMP inspection within last 2 years Other Changes/Reports Annual report minor changes Patent information Exception for DNA derived/monoclonal antibodies regulated by FD & C Act: - major changes require a supplement and approval prior to distribution - some other changes require supplement 30 prior to distribution of the changed product March 28, March 28, Change In Ownership Ownership of application may be transferred New and former owners must submit letters Indicate (regulatory) conditions and commitment Adverse Drug Experiences (ADEs) March 28, March 28,

3 FDA Definition of an AE (21 CFR ) Any adverse event associated with the use of a drug in humans, whether or not considered drug-related, related, including the following: an AE occurring in professional practice, an AE occurring from a drug overdose whether or not intentional, an AE occurring from drug abuse, an AE occurring from drug withdrawal, and any failure of expected pharmacological action. ICH Definition of ADR Response to a marketed drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiological function. Recommends the old term side effects no longer be used March 28, March 28, Post-Marketing Study Commitments Conducted after FDA approves a product Especially after an accelerated approval Required of or agreed to by a sponsor Agreement between sponsor and FDA may be reached before or after FDA granted approval Sponsor must file annual reports March 28, Adverse Event Reporting - Drugs Adverse Drug Experiences (21 CFR ) ADEs may be expected (i.e., listed in the labeling) or unexpected; unexpected means AE may be the same as in the labeling but is unusually severe in degree or frequency; includes overdose Review of ADEs: prompt review of ADE reported to sponsor from any source (e.g., commercial marketing experience, post-marketing clinical studies, foreign/domestic, scientific literature, unpublished papers) SOPs required: surveillance, receipt, evaluation, reporting to FDA March 28,

4 Life-Threatening ADE Any ADE that places the patient, in the view of the initial reporter, at immediate risk of death from the ADE as it occurred, i.e., does not include an ADE that, had it occurred in a more severe form might have caused death. Serious Adverse Drug Experience (SADE) Any ADE occurring at any dose that results in one of the following outcomes: death, a life-threatening ADE inpatient hospitalization or prolongation of existing hospitalization, a persistent/significant disability/incapacity, a congenital anomaly/birth/defect March 28, March 28, Unexpected Adverse Drug Reaction (UADE) Any ADE that is not listed in the current labeling for the drug product Includes events that may be related to listed events, but differ because of severity or specificity Review of ADEs Review all ADEs obtained or otherwise received from any source, foreign or domestic, including information derived from: - commercial marketing experience - post-marketing clinical investigations - post-marketing epidemiological/surveillance studies - reports in the scientific literature, and unpublished scientific papers. March 28, March 28,

5 Adverse Drug Experience Reports NOTE: This reporting mechanism does not apply to an ADE occurring g during a post-marketing study; other methods of reporting are done. 15 Day Alert Reports within 15 calendar days of hearing about ADE Alert Reports Follow-up within 15 days of receiving new information Note: retain records for 10 years Periodic Reports Periodic reports quarterly for the 1 st three years, then annually thereafter ADE Information Required date information received and date reported date of occurrence source of report narrative description of event, (include type, severity, frequency) intervention (if required: medical, surgical, etc.) resolution, (or state if ADE is ongoing) causal relationship to drug DO NOT submit patient s s identity March 28, March 28, Safety Reports for Drugs and Biologically-Derived Therapeutics Safety Reports 21 CFR Report on - life threatening ADE - SADE - UADE (ASAP, but no later than 7 calendar days by telephone or FAX) March 28, March 28,

6 Safety Reports (cont.) 21 CFR Finding from tests in lab animals that suggests a significant risk for humans Review safety info IND safety reports - include prior info * Not required of marketed drugs use Med- Watch Medical Product Safety Information FDA Database - Safety Alerts for Drugs, Biologics, Devices and Dietary Supplements Searchable FDA Safety Databases - Vaccine Adverse Event Reporting System (VAERS) - Special Nutritional AE Monitoring System - Manufacturer and User Facility Device Experience Database (MAUDE) March 28, March 28, Medical Product Safety Information (cont. slide 2) Guidance Documents - E2C: E2C: Clinical Safety Data Management, Periodic Safety Update Reports for Marketed Drugs - Addendum IDH E2C: : Draft guideline Medical Product Safety Information (cont. slide 3) Adverse Event Reporting Systems Regulations - 21 CFR Part 7 Recalls - 21 CFR Returned Drug Products - 21 CFR Drug Product Salvaging March 28, March 28,

7 Adverse Experiences - Biologics Adverse Events - Biologics 21 CFR Definition: Any adverse event associated with the use of a biologic in humans, whether or not considered biologic-related, including the following: an AE occurring in professional practice, an AE occurring from an overdose whether or not intentional, an AE occurring from abuse of the biologic material, an AE occurring from withdrawal of the biologic, and any failure of expected biological action. Definition: March 28, March 28, Adverse Experiences: Biologics AEs may be expected (i.e., listed in the labeling) or unexpected; unexpected means AE may be the same as in the labeling but is unusually severe in degree or frequency; includes overdose Review of AEs: prompt review of AE reported to sponsor from any source (e.g., commercial marketing experience, post-marketing clinical studies, foreign/domestic, scientific literature, unpublished papers) SOPs required: surveillance, receipt, evaluation, reporting to FDA AE Reports - Biological Materials NOTE: This reporting mechanism does not apply to an ADE occurring during a post-marketing study; other methods of reporting are done. Timing of reports: within 15 calendar days of hearing about ADE send in a 15-Day Alert Report retain records for 10 years periodic reports quarterly for the first three years, then annually thereafter March 28, March 28,

8 AE Reports - Biological Materials Information required date information received and date reported date of occurrence source of report narrative description of event, (include type, severity, frequency) intervention (if required: medical, surgical, etc.) resolution, (or state if AE is ongoing) name and address of manufacturer DO NOT submit patient s s identity Biological Product Deviation Report (BPDR) Manufacturers report biological deviation that may affect - Safety - Purity - Potency 21 CFT , March 28, March 28, Other Post-marketing Reports for Drugs (314.81) NDA Field Alerts: : within 3 working days to District Office, if drug product is mistaken for another article or contaminated/ deterioration batch failure Annual Reports: : new info on S, E, labeling; distribution data, labeling (summary of changes), CMC changes, update lab, animal & clinical data, status of PM studies Other Post-marketing Reports for Drugs [314.81] (cont) Advertisement & Promotional labeling: - Submit specimens at time of initial distribution/publication March 28, March 28,

9 User Reports Adverse Device Effects Users (healthcare professionals, consumers, etc.) may also file reports (MedWatch) If sponsor is notified by FDA and sent a copy of the User Report, the sponsor does not file a separate report (to avoid duplication at the FDA), but does report on follow-up research and activities. March 28, March 28, Adverse Device Effects Medical Device Effects 21 CFR 803 medical device has/may have caused/contributed to a death or serious injury device has malfunctioned/failed and that malfunction/failure has or may have caused or contributed to a death or serious injury other causes of MDE may be improper or inadequate design, problems in manufacturing, labeling or user error source of reports may be manufacturer, distributor, importer, user, healthcare professional or other semi- professionals Problems Unique to Medical Device Reporting Lack of standard nomenclature for devices These events represent numerators, usually with no clear denominator available Operator involvement and human factors issues inherent in virtually every event Complex multi-device situations are common, leading to complex evaluation March 28, March 28,

10 Device problems - continued Information in reports is often limited MDR may not be be to detect increases in rates of known events Specific disincentives to reporting, e.g., user error MDR not a good method for certain types of products, e.g., IVDs New technology and the learning curve; adequacy of training March 28, Medical Device Reports MedWatch March 28, FDA s s MedWatch Program Mandatory Reporting Manufacturers (bylaw) report deaths and serious injuries or malfunctions (near incidents) if a medical device may have caused or contributed to the event All user facilities (hospitals, nursing homes, etc.) must report deaths to FDA and serious injuries to manufacturers Voluntary reports encouraged from health professionals March 28, March 28,

11 Medical Device Reports Complete a MedWatch form (Form 3500A) Timing of reports User facility: within 10 days of becoming aware of the event Importers : within 30 days Manufacturers within 30 days for an individual event within 5 days if remedial action is needed to prevent unreasonable risk of substantial harm to the public Contents of Form 3500A March 28, March 28, Complaint Regulations Complaints 21 CFR NOTE: MDRs are a subset of complaints Need SOPs: receiving, reviewing, evaluating complaints by a formally designated unit Complaints must be: presented in a uniform and timely manner documented upon receipt (oral or written) evaluated to see if it meets criteria for an MDR (21CFR 803) March 28, March 28,

12 Complaint regulations - cont d Complaints must be evaluated to see if an investigation is needed; if not, document reason Review, evaluate, investigate involving the failure of a device, labeling or packaging to meet any of its specifications If it is reportable as an MDR, the report must be maintained separately, or clearly identified Complaint Regulations - cont d Definition: any expression (written, oral or implied) of dissatisfaction regarding a failure of a product to meet performance specifications or customer expectations Complaints must be reviewed, investigated and documented March 28, March 28, Dietary Supplements Warnings and Safety Info warn.html Veterinary Products Illnesses and Injuries associated with the use of selected dietary supplements March 28, March 28,

13 Remember... For all AE reports, the time begins when any team member* becomes aware of the information * regulatory, clinical, sales, marketing, etc. Questions? Mfeldman@druganddevice.com March 28, March 28,