Outline. Post-Submission and Post-Approval Requirements. PDUFA/MDUFA-What are they? What I have tried to provide

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1 Outline Post-Submission and Post-Approval Requirements Monica S. Krieger, Ph.D, M.B.A. Vice President, Regulatory Affairs OncoGenex Technologies, Inc. Introduction to PDUFA/MDUFA Amendments to Unapproved Applications Approved Applications Scheduled Annual Reports Distribution Reports Safety Reports User Fees Unscheduled Changes to Approved Applications CMC Supplements Efficacy Supplements Reports of Problems and Errors Promotional Literature Individual Safety Reports 1 2 What I have tried to provide PDUFA/MDUFA-What are they? Reference in the CFR and/or FDC Act Available guidance documents on FDA website Brief summary of requirements Impact on the sponsor/company and various departments What is PDUFA? Prescription Drug User Fee Act What are PDUFA I, II, III? 5-year phases Approved by Congress What is MDUFA Medical Device User Fee and Modernization Act 3 4

2 PDUFA PDUFA Goals Goal PDUFA I PDUFA II PDUFA III Congress passed PDUFA in 1992 Goal was to decrease time to approval FDA and the drug industry struck a deal Industry would provide funding for the drug review program FDA would agree to meet drug-review time performance goals. Authorized the agency to collect fees from companies that produce certain human drug and biological products Application Fee Manufacturing Facility Fee Product Fee Complete review of priority original new drug and biologic applications and efficacy supplements Complete review of standard original new drug and biologic applications and efficacy supplements Complete review of manufacturing supplements Complete review of resubmitted new drug and biologic applications Complete review of resubmitted efficacy supplements Discipline review letters for pre-submitted Reviewable Units of new drug and biologic applications 90% in 6 months 90% in 12 months 90% in 6 months 90% in 6 months No Goal No Goal 90% in 10 months 90% in 4 months if prior approval needed, 6 months otherwise 90% of class 1 in 2 months and 90% of class 2 in 6 months 90% in 6 months 90% of class 1 in 2 months and 90% of class 2 in 6 months * 90% in 6 months * 5 6 PDUFA Goals-Drugs and Biologics Where can I find the PDUFA Goals? Goal Report of substantive deficiencies (or lack thereof) PDUFA I No Goal PDUFA II PDUFA III 90% within 14 days of filing date * Current PDUFA performance goals can be found at Respond to industry requests for meetings No Goal 90% within 14 days Meet with industry within set times No Goal 90% within 30, 60, or 75 days, depending on type of meeting Provide industry with meeting minutes No Goal 90% within 30 days Communicate results of review of complete industry responses to FDA clinical holds No Goal 90% within 30 days Resolve major disputes appealed by industry No Goal 90% within 30 days Complete review of special protocols No Goal 90% within 45 days Electronic application receipt 7and review No Goal In place by the end of FY 2002 Enhanced by the end of FY

3 MDUFA MDUFA MDUFA is the Medical Device User Fee and Modernization Act Success with drug/biologic user fees prompted MUDFA Passed by Congress in October 2002 Goal was to provide three significant benefits: Safe and effective medical treatments will reach patients more rapidly Assure timely, high-quality reviews Maintain high standards for safety and effectiveness Current MDUFMA performance goals can be found at USER FEES-2006 User Fees-Exceptions and Waivers Application fees-drugs /Biologics $767,400 for an application requiring clinical data $383,700 for an application not requiring clinical data $383,700 for a supplement requiring clinical data Annual Fees $264,200 for establishment fees $42,130 for product fees Designated Orphan Drug or Indication An application for product designated as an Orphan Drug A supplement for a new indication for an Orphan Drug Small business or its affiliate (< 500 employees) Agency will waive the application fee for the first human drug application 11 12

4 MDUFA User Fees-Device-2005 Reviews Subject to User Fees Effective October 1, 2002, a user fee is assessed for FDA review of a 510(k) Premarket application PMA, PDP, Premarket Report (reprocessed device), or BLA. Panel-track supplement 180-day supplement Real-time supplement BLA efficacy supplement 510(K) Panel-track Supplement 180-day Supplement Application Premarket Application (PMA, PDP, BLA) Premarket Report (premarket approval application for a reprocessed device) First premarket application by a small business Efficacy Supplement (for BLA) Standard Fee $3,502 $239,237 $239,237 NA $239,237 $239,237 $51,436 Small Business Fee $2,802 $90,910 $90,910 Fee is waived $90,910 $90,910 $19, Real-time 14 Supplement $17,225 $6,546 MDUFA-User Fee Reductions MDUFA- User Fee Exceptions A small business is one with gross receipts or sales < $30 million Small business status must be evidenced by submission of Federal Income Tax returns Small business fees are 38% of standard fee, except 510(k) is 80% of standard fee Humanitarian Device Exemption First premarket application (PMA, PDP, BLA, or premarket report) from a small business Premarket report by holder of PMA for same reprocessed device Third-party 510(k) Application from a State or Federal Government entity Any application intended solely for pediatric use 15 16

5 Post Submission Requirements Amendments to Unapproved Applications 21CFR Amendments 21 CFR PMA Amendments Amendments to Unapproved Applications Guidances/SOPPs CBER/CDER Good Review Management Principles and Practices for PDUFA Products (CBER/CDER) Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act Classifying Resubmissions in Response to Action Letters SOPP : Issuance and Review of Responses to Information Requests and Discipline Review Letters to Pending Applications Guidances-CDRH FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Performance Assessment Premarket Approval Application Filing Review Amendments to Unapproved Applications FDA Review of Unapproved Applications The BLA, NDA or PMA is rarely the last submission prior to an Approval Letter FDA will formally and informally communicate during the review process Responses need to be submitted to the application Designate whether priority or standard application (6-month vs. 12-month review clock) Check if fees paid Document presence of all of the required filing elements Form the review committee and meet Make a refusal-to-file decision by the 45-day meeting Make Information Requests Complete review - issue an action letter (complete response or approval) Other actions - withdrawal or denial 19 20

6 Types of FDA Letters for Drugs/Biologics Effect of Letters on Review Clock Information request letters Requests for additional information Discipline review letters Not a complete review Early thoughts from members of review team Identify deficiencies that need to be corrected May describe actions that need to be taken Action letter Issued after complete review of the filed application Preliminary comments on draft labeling The IR/DR letters will not affect the user fee review clock Your response affects the review clock Review team will review responses at their discretion They may or may not consider a response to a DR a major amendment Major amendments extend the review time (3 months) Only one extension allowed The Agency is not obligated to review the response before the issuance of an action letter The action letter will include all deficiencies that must be answered to place the application in condition for approval Resubmissions in Response to Action Letters Types of Amendments Class 1 Resubmission (2-month review) Final labeling Safety updates Commitments of phase 4 studies Assay validation Lot release of last 1-2 lots used to support approval Class 2 Resubmission (6-month review) Everything else Answers to questions Additional information (i.e.) Adverse events Manufacturing tests New analyses Updated ISS and ISE Data from studies in progress Protocols for Post-approval Commitments 23 24

7 # Amendments to Unapproved Applications Types of Responses for Devices Drug Bextra Year 2001 Company GD Searle Number of Amendments (K) Additional information letter Fuzeon (HIV) 2003 Roche 57 PMA First action major deficiency letter Iressa (Cancer) 2003 AstraZeneca 46 All other first actions (approval, approvable, approvable pending GMP inspection, not approvable, or denial) Baraclude (HbSAg) 2005 BMS What Does this Mean for the Company? Don t think your work is done if you get past the Refusal to File (RTF) deadline Pressure is still on Personnel still tied to project Clinical Regulatory (including any e-sub personnel) Data management Post-Approval Reports Scheduled Reports Annual Reports Distribution Reports Safety Reports 27 28

8 Annual Reports-Regulation Annual Reports-Guidance CDER b (2) CBER 21 CFR Changes in Application 21 CFR Post-marketing Commitments 21 CFR Adverse Events 21 CFR Distribution Report CDRH 21 CFR Draft Guidance for Industry: Providing Regulatory Submissions in Electronic Format--Annual Reports for New Drug Applications and Abbreviated New Drug Applications - 8/27/ Annual Report-Drugs and Biologics Annual Report-What is included (314.81) When is it due? within 60 days of the anniversary date of U.S. approval of the application What time frame should it cover? must include all the information obtained during the interval that ends on the U.S. anniversary date Summary New information that might affect the safety, effectiveness, or labeling Actions the applicant has taken or planned based on this information Distribution data Information about the quantity of the drug product distributed Total number of dosage units of each strength or potency Disclosure of financial or pricing data is not required. Labeling Currently used professional labeling, patient brochures or package inserts (if any), and a representative sample of the package labels A summary of any changes in labeling since the last report 31 32

9 Annual Report-What is included (314.81) Annual Report-What is included (314.81) Chemistry, manufacturing, and controls changes Reports of experiences, investigations, studies, or tests that may affect FDA`s previous conclusions about the safety or effectiveness of the drug product. A full description of the manufacturing and controls changes not requiring a supplemental application Nonclinical laboratory studies Copies of unpublished reports and summaries of published reports of new toxicological findings Clinical data Published clinical trials of the drug (or abstracts ) including clinical trials on new uses; Review articles, papers describing the use in medical practice, Summaries of completed unpublished clinical trials or prepublication manuscripts Status reports of post-marketing study commitments A status report of each post-marketing study concerning clinical safety, clinical efficacy, clinical pharmacology, and nonclinical toxicology that is required by FDA Must be reported annually until FDA agrees the commitment has been fulfilled or the study is no longer feasible or would no longer provide useful information Status of other post-marketing studies Chemistry, manufacturing, and controls studies that the applicant has agreed to perform Product stability studies Log of outstanding regulatory business To facilitate communications between FDA and the applicant Post-Marketing Commitments Post-Marketing Commitments Regulation FDA Modernization Act of 1997 added a new provision (section 506B) on post-marketing studies to the Federal Food, Drug, and Cosmetic Applicable to drugs and biologics NOT devices Guidance Reports on the Status of Post-marketing Studies - Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 Clinical Studies Called phase 4 commitments Studies required of or agreed to by a sponsor conducted after FDA has approved a product FDA may require commitment prior to approval May even require study to have started Commitments are published on FDA website with yearly progress results 35 36

10 Post-Marketing Commitments- When likely? Post-Marketing Commitments Commitment Required Under: Accelerated Approval Approved based on surrogate endpoints that reasonably predict clinical benefit Clinical benefit must be confirmed through additional human studies Commitment Required Under: Animal Efficacy Rule New drug or biological used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances Approved for marketing based on evidence of effectiveness in animals Sponsor must verify clinical benefit when such studies are feasible and ethical CMC Related May request additional validations Stability data Commitments are NOT published on FDA website Considered confidential Commitment Required Under: Pediatric Research Equity Act Pediatric Research Equity Act of 2003 Designed to improve the quality of pediatric information in drug labeling FDA has explicit authority to require applications to include pediatric studies Studies to gather additional information about a product's safety, efficacy, or optimal use Post-Marketing Commitments-Examples Post-Marketing Commitments-Examples DESCRIPTION OF STUDY Bexxar vs Rituximab* Bexxar vs Zevalin Retreatment with Bexxar Use of Prophylactic Vaccines 1,090 NDAs were approved These NDAs plus supplemental applications generated a total of 2,328 postmarketing commitments 1,737 reporting under FDAMA 130 Long-term effects of HAMA-effect on patients Long-term effects of HAMA-effect on IVD tests Occurrence of MDS *Accelerated Approval Commitment 39 40

11 Post-Marketing Commitments Failure of PMC Clinical Trial FDA can pull approval Considered with Astrazeneca s IRESSA after PMC trial failed To date has not happened Concern with companies not meeting the commitments Post-Marketing Commitments- Impact on Company Initial approval may not be the last clinical trial Accelerated approval=confirmatory Trial Complicated products =follow-up trials $$$$ Resources may be required Recent drug problems mean this is only going to increase Annual Report-Devices (PMA) Annual Report-PMAs Due annually at intervals of 1 year from the date of approval of the original PMA Post-approval reports for supplements approved under the original PMA are included in the next and subsequent annual reports for the original PMA Identification of changes described in 21CFR814.39(a) and changes required to be reported to FDA under 21CFR814.39(b) Bibliography and summary of the following information: Unpublished reports of data from any clinical investigations or nonclinical laboratory studies involving the device or related devices Reports in the scientific literature concerning the device 43 44

12 Scheduled Reports Distribution Reports-Biologics Annual Reports Distribution Reports Safety Reports 21 CFR Distribution reports. Must be submitted every 6 months FDA can require other time frames Must contain: bulk lot number fill lot numbers label lot number (if different from fill lot number) labeled date of expiration number of doses in fill lot/label lot date of release of fill lot/label lot for distribution Distribution Reports-Devices Medical Device Tracking Form 3417-Medical Device Reporting -Baseline Report (for first report) Annual update required Includes a line for # devices distributed 21 CFR Part 821 Section 519(e) of the FDC Act Guidance for Industry and FDA Staff: Medical Device Tracking May 5,

13 Medical Device Tracking Examples of Products that must be Tracked Devices that are life sustaining or life supporting and used; are permanently implanted; serious consequences if they fail Company must ensure that devices can be traced from the manufacturing facility to the patient Requires effective tracking of through the distributor network to the patient Must be capable of patient notification or device recall Can use a contractor but manufacturer is responsible Mandibular condyle prosthesis Temporomandibular Joint (TMJ) prosthesis Abdominal Aortic Aneurysm Stent Grafts Automatic implantable cardioverter/defibrillator Cardiovascular permanent implantable pacemaker electrode Implantable pacemaker pulse generator Replacement heart valve (mechanical only) Implanted cerebellar stimulator Implanted diaphragmatic/phrenic nerve stimulator Implantable infusion pumps Dura mater Breathing frequency monitors Continuous Ventilators DC-defibrillators and paddles Ventricular Bypass (assist) Device Scheduled Reports Safety Reports - Annual Reports Distribution Reports Safety Reports 21 CFR Periodic adverse experience reports are due at quarterly intervals, for 3 years from the date of licensing annual intervals from then on within 30 days of the close of the quarter Annual report within 60 days of the anniversary date of the license 51 52

14 Contents of Annual Safety Report (example) Device-Annual Report -Safety Introduction Initial Reports List of Serious Listed Initial Reports List of Non-Serious Unlisted Initial Reports List of Non-Serious Listed Initial Reports List of Serious Listed Follow-up Reports List of Non-Serious Unlisted Follow-up Reports List of Non-Serious Listed Follow-up Reports List of 15-Day Reports by Body System Submitted During Reporting Period Tabulation by Body System of AII Events Reported Analysis and Discussion of Serious Listed Initial Reports Analysis and Discussion of Non-Serious Unlisted Initial Reports Analysis and Discussion of Non-Serious Listed Initial Reports Summary and Analysis of the 15-Day Reports Submitted During Reporting Period Summary of Actions Taken During Reporting Period Appendix A: Current United States Prescribing Information for the Product 21 CFR 803 If you are a manufacturer or importer, you must report deaths and serious injuries that your device has or may have caused or contributed to, certain device malfunctions, and specified follow-up and baseline reports. MDR regulation requires submission of a baseline report on a device model the first time it is the subject of a device report (Form 3417) Annual updates required Summary report of all reportable adverse events submitted to manufacturers or the FDA Scheduled Reports Unscheduled Reports Annual Reports Distribution Reports Safety Reports Changes to Approved Applications CMC Supplements Efficacy Supplements Reports of Problems and Errors Promotional Literature Individual Safety Reports 55 56

15 Changes in Applications- Regulation and Guidance Regulation 21 CFR Drugs 21 CFR Biologics 21 CFR (k) 21 CFR PMA Changes in Applications- Regulation and Guidance Guidance Changes to an Approved NDA or ANDA Guidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products Guidance for Industry: Changes to an Approved Application: Biological Products 30-Day Notices and 135-Day PMA Supplements for Manufacturing Method or Process Changes in Applications-CBER/CDER Changes to Applications- Summary of Requirement CBER and CDER system are similar A change to a product, production process, quality controls, equipment, facilities, or responsible personnel must be reported in one of the following: 1) supplement requiring approval prior to distribution, 2) supplement submitted 30 days prior to distribution 3) an annual report Which one depends on its potential to have an adverse effect on the identity, strength, quality, purity, or potency of the biological product as they may relate to the safety or effectiveness of the product. Type of Submission Prior Approval 30-Day Prior Annual Report Risk of an Adverse Effect on the Identity, Strength, Quality, Purity, or Potency Substantial potential Moderate potential Minimal potential 59 60

16 Changes to Applications- Specific Examples with Substantial Potential (Biologics/Drugs) Changes in labeling, except those that increase safety Changes in indication Changes in route of administration Change in drug formulation/quantity Change in test methods Deletion of a specification or an analytical method Elimination of a test Change in acceptance criteria Scale-up requiring larger equipment Extension of the expiration dating period / change in storage temperature w/o stability protocol CMC Changes-Examples of Changes with Moderate Potential (Biologics/Drugs) Addition or reduction in number of pieces of equipment to achieve a change in purification scale Change in the fill volume (per vial) Changes in responsible individuals specified in the approved application, Modification of an approved manufacturing facility or room(s) that is not likely to have an adverse effect Change in the site of testing from one facility to another Change in the structure of a legal entity that would require issuance of new license(s), CMC Changes-Examples of Changes with Minimal Potential (Biologics/Drugs) Changes to existing PMA Addition of equipment identical to the primary system Upgrade or minor corrective change to production air handling, water, or steam supply systems Relocation of testing laboratories in areas in the license Room upgrades, (i.e. improved finishes on floors/walls) Installation of non-process equipment (ie.refrigerators) freezers Modifications in analytical procedures with no change in the basic test methodology or existing release specifications Change in harvesting and/or pooling procedures which does not affect the method of manufacture, recovery, storage conditions, etc. Replacement of an in-house reference standard or reference panel according to SOPs and specifications in approved license application. Must submit a supplement if the change affects the safety or effectiveness of the device New indications Labeling changes Different facility to manufacture, process, or package the device Changes in sterilization procedures Changes in the performance or design specifications, circuits, components, ingredients, principle of operation, or physical layout of the device Extension of the expiration date w/o approved protocol 63 64

17 Changes to existing PMA Changes to existing PMA Changes that may be made without submitting a supplement Labeling changes that add or strengthen a contraindication, warning, precaution, or information about an adverse reaction. add or strengthen an instruction that is intended to enhance the safe use of the device delete misleading, false, or unsupported indications Changes in QC or manufacturing process that add a new specification or test method, or provide added assurance of purity, identity, strength, or reliability These changes are reported in periodic reports Exception to PMA supplements Section 515(d) (6) of the act added by the FDA Modernization Act of 1998 requires a 30-day Notice for changes that that involve modifications to manufacturing procedures or method of manufacture If the notice is inadequate, a 135-day PMA supplement will be required Changes to an Existing 510(k) Efficacy Supplements New intended use for a device Requires a premarket notification submission for major changes in intended use. Most, if not all changes in intended use will require a 510(k) Change or modification of a device New submission required if that change could significantly affect safety or effectiveness The burden is on the company to decide Justification should be reflected in your device master record and change control records Required to submit for change in label Usually requires clinical data User fee must be paid prior to submission if clinical data included If not Orphan Drug Consider meeting with FDA to present outline of submission and results of clinical data prior to submission 67 68

18 CMC or Label Changes- Impact on Company Everyone needs to understand the requirements Need document control system Record of product changes made during year Procedure to evaluate importance of change Regulatory should review changes for importance Make determination whether submission is required prior to implementation Documentation of decisions Personnel to test and validate changes Unscheduled Reports Changes to Approved Applications CMC Supplements Efficacy Supplements Reports of Problems and Errors Promotional Literature Individual Safety Reports Product Problems-Regulations-FD&C Act Reporting Product Problems Sec. 301 Prohibited Acts Items that are adulterated/misbranded Counterfeit drugs Sec. 501 Definition of Adulterated Filthy, putrid or decomposed Difference (reduced) in strength/purity Sec. 502 Definition of Misbranded Labeling is false or misleading Adequate directions for use or warnings Biologics Product Deviations Drugs Field Alerts Devices Product Malfunctions 71 72

19 Biologics-Product Deviation- Guidances Product Deviations-Biologics or Blood Biologics Regulation-Biologic Products 21 CFR Guidance for Industry-Biological Product Deviation Reporting for Licensed Manufacturers of Biological Products -Other than Blood and Blood Components Regulation-Blood Products 21 CFR Guidance for Industry-Biological Product Deviation Reporting for Blood and Plasma Establishments What is reported? Any event, associated with the manufacturing, if that event meets any of the following criteria: (i) Represents a deviation that affects the safety, purity, or potency of that product; or (ii) Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; and Occurs in your facility or another facility under contract with you; and Involves a distributed biological product or blood Product Deviations- When is a Report Required? If problem is discovered AFTER PRODUCT DISTRIBUTION Product Deviations-When is NO Report Required When is a Report NOT REQUIRED: When no affected products are distributed, When it is determined prior to distribution that the safety, purity, or potency of a product is not affected. When a product is appropriately reprocessed or reworked by an FDA approved method, prior to distribution. When there is a minor record keeping omission, that has no potential to affect the safety, purity, or potency of the product

20 Product Deviations-Examples Drugs-Field Alerts Examples: Raw material contaminated or does not meet spec Manufacturing/processing performed using incorrect parameters Bulk or intermediate product stored improperly Required testing was not performed, was performed incorrectly Package insert is incorrect, not the current approved version, or not included with product Blood establishment performed compatibility testing using a patient sample from the wrong patient Regulations 21 CFR Other postmarketing reports Guidance NDA Field Alert Form and Instructions Product Recalls, Including Removals and Corrections SOPP Standing Operating Procedures for Handling NDA/ANDA Field Alert Reports Field Alerts -Drugs Field Alert-FDA Response NDA Field alert report Must submit information of the following kinds of incidents Labeling error Bacteriological contamination Significant change or deterioration Failure of to meet the specification in the application Report to the FDA district office that is responsible for the facility involved within 3 working days of receipt by the applicant. The information may be provided by telephone with prompt written followup. District Offices Post-market Surveillance Team (PST) Coordinator evaluates the Field Alert Report and conducts follow-up, if necessary The District Recall and Emergency Coordinator reviews May follow up with company Office of Compliance Postmarket Surveillance Team will evaluate the initial report and the district's follow-up information If HFD-336 determines there is a potentially significant problem, they contact the Office of Compliance Drug Recall Staff (and the Division of Manufacturing and Product Quality 79 80

21 Malfunctions Devices Regulations and Guidance 21 CFR 803-Medical Device Reporting 21 CFR 806-Reports of Corrections and Removals Medical Device Reporting -Devices Malfunction [ 803.3(m)] Failure of the device to meet its performance specifications Reportable if: chance of a death or serious injury is not remote; device is considered life-supporting/life-sustaining manufacturer takes/would be required to take action reported even if it can be corrected in routine service Who must report Manufacturer Distributor User facility Deviation Reports/Field Alerts/Malfunctions- Impact on Company Need systems to collect incoming data with SOP on documenting problems and decisions Need written procedure for reporting product deviations, field alerts or malfunctions Also need a Recall Procedure Need a tracking system for lot release Need a good lawyer Promotional Literature Guidances FDA Form Transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human Use Accelerated Approval Products: Submission of Promotional Materials (Posted 3/26/1999) 83 84

22 Promotional Literature Promotional Literature Code of Federal Regulations 21 CFR 99 - Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices 21 CFR 200 General 21 CFR 201- Labeling 21 CFR 202- Prescription Drug Advertising 21 CFR 312- Investigational New Drug Applications 21 CFR 314- Applications to Market New Drug or Antibiotic Labeling reviewed during approval process Package insert Package labels Other (based on BEXXAR experience) Training Manual Software Manual Reviewers are the individuals who reviewed the application Promotional Literature Safety Reports- Relevant Regulations Review of all promotional material Must submit w/ Form 2253 at the time of use DDMAC/APLS Failure to submit can result in a Warning Letter Except new product approved under Accelerated Approval Regulations All promotional material pre-reviewed DRUGS 21 CFR Post-marketing reporting of adverse drug experiences BIOLOGICS 21 CFR Post-marketing reporting of adverse experiences DEVICES 21 CFR 803 Medical Device Reporting 87 88

23 Safety Reports-Guidance Documents Safety Reports-ICH Documents Post-marketing Reporting of AEs Drugs (March 1992) Clarification of what to Report for Human Drug and Licensed Biological Products (August 1997) Drugs and Biologics (draft guidance - March 2001) Devices Medical Device Reporting for Manufacturers (March 1997) International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) MedDRA Term Selection: Points to Consider - Release 3.4, based on MedDRA version 7.1, an ICH-Endorsed Guide for MedDRA Users M1 MedDRA (Medical Dictionary for Regulatory Activities) M2 ESTRI (Electronic Standards for the Transfer of Regulatory Information) E2A (Clinical Safety Data Management) E2B (Guidance On Data Elements For Transmission of Individual Case Safety Reports) E2BM (Guidance on Data Elements for Transmission of Individual Case Safety Reports) E2C PSUR (Periodic Safety Update Report) Safety Reports-Requirements Safety Reports Definitions-Drugs/Biologics Obligated to Review Adverse Drug Experiences From foreign or domestic sources including Commercial marketing experience Post-marketing clinical investigations, Post-marketing epidemiological/surveillance studies Reports in the scientific literature, and Unpublished scientific papers Must Develop Written Procedures for Surveillance Receipt and evaluation, as well as Reporting of post-marketing AEs to FDA Serious adverse drug experience Death Life-threatening adverse drug experience Inpatient hospitalization or prolongation of existing hospitalization Persistent or significant disability/incapacity Congenital anomaly/birth defect Important medical events that may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition

24 Safety Reports Definitions-Drugs/Biologics Safety Reports-Drugs and Biologics Unexpected adverse drug experience Any adverse drug experience that is not listed in the current labeling for the drug product. Basically Anything Not Previously Observed Drugs and Biologics Reporting requirements Submit two copies of each report Form 3500A Postmarketing 15-day Alert reports Must report each adverse drug experience that is both serious and unexpected No later than 15 calendar days of initial receipt of the information 15-day Alert reports follow-up Must investigate all adverse drug experiences that are reported Submit followup reports within 15 calendar days of receipt of new information or as requested by FDA Safety Reports-Devices Safety Reports-Devices Reportable events What to Report Form When Serious injury/(serious illness) [ 803.3(aa)(1)] life threatening, even if temporary results in permanent impairment of a body function requires medical or surgical intervention to preclude permanent impairment Death, serious injury, malfunctions Baseline report-basic data on device Annual Certification FDA 3500A FDA 3417 FDA 3381 Within 30 days of becoming aware When device or family reported 1 st time Coincide with registration 95 96

25 Safety Reports-Impact on Company Usually Requires Development of a Group Experienced health-care professionals Nurses and Pharm.D. typical members of team Can be resource intensive Requires written procedures May require specialized software May require submissions to IND for Regulatory May require European Submissions 97