PDUFA/MDUFA-What are they? - University of …courses.washington.edu/pharm523/documents/6523 after Kreiger... · ¾Introduction to PDUFA/MDUFA ... Complete review of special protocols

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Post-Submission and Post-Approval Requirements

Monica S. Krieger, Ph.D, M.B.A.Vice President, Regulatory Affairs

OncoGenex Technologies, Inc.

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Outline

Introduction to PDUFA/MDUFAAmendments to Unapproved ApplicationsApproved Applications

Scheduled– Annual Reports– Distribution Reports– Safety Reports– User FeesUnscheduled – Changes to Approved Applications

– CMC Supplements– Efficacy Supplements

– Reports of Problems and Errors– Promotional Literature– Individual Safety Reports

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What I have tried to provide

Reference in the CFR and/or FDC ActAvailable guidance documents on FDA websiteBrief summary of requirements Impact on the sponsor/company and various departments

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PDUFA/MDUFA-What are they?

What is PDUFA?Prescription Drug User Fee ActWhat are PDUFA I, II, III?– 5-year phases– Approved by Congress

What is MDUFAMedical Device User Fee and Modernization Act

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PDUFA

Congress passed PDUFA in 1992 Goal was to decrease time to approval

FDA and the drug industry struck a dealIndustry 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 FeeManufacturing Facility FeeProduct Fee

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PDUFA Goals

90% in 6 months * No Goal Discipline review letters for pre-submitted “Reviewable Units” of new drug and biologic applications

90% of class 1 in 2 months and 90% of class 2 in 6 months *

90% in 6 months No Goal Complete review of resubmitted efficacy supplements

90% of class 1 in 2 months and 90% of class 2 in 6 months 90% in 6 months Complete review of resubmitted new drug

and biologic applications

90% in 4 months if prior approval needed, 6 months otherwise 90% in 6 months Complete review of manufacturing

supplements

90% in 10 months 90% in 12 months Complete review of standard original new drug and biologic applications and efficacy supplements

90% in 6 monthsComplete review of priority original new drug and biologic applications and efficacy supplements

PDUFA IIIPDUFA IIPDUFA IGoal

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PDUFA IIIPDUFA IIPDUFA IGoal

Enhanced by the end of FY 2007 In place by the end of FY 2002 No Goal Electronic application receipt

and review

90% within 45 days No Goal Complete review of special protocols

90% within 30 days No Goal Resolve major disputes appealed by industry

90% within 30 days No Goal

Communicate results of review of complete industry responses to FDA clinical holds

90% within 30 days No Goal Provide industry with meeting minutes

90% within 30, 60, or 75 days, depending on type of meeting No Goal Meet with industry within set times

90% within 14 days No Goal Respond to industry requests for meetings

90% within 14 days of filing date * No Goal

Report of substantive deficiencies (or lack thereof)

PDUFA Goals-Drugs and Biologics

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Where can I find the PDUFA Goals?

Current PDUFA performance goals can be found at www.fda.gov/oc/pdufa/PDUFAIIIGoals.html

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MDUFA

MDUFA is the Medical Device User Fee and Modernization Act Success with drug/biologic user fees prompted MUDFAPassed by Congress in October 2002 Goal was to provide three significant benefits:

Safe and effective medical treatments will reach patients more rapidlyAssure timely, high-quality reviewsMaintain high standards for safety and effectiveness

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MDUFA

Current MDUFMA performance goals can be found at www.fda.gov/cdrh/mdufma/presentations/mdufma.html

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USER FEES-2006

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

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User Fees-Exceptions and Waivers

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

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MDUFA

Reviews Subject to User FeesEffective 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

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User Fees-Device-2005

Small Business FeeStandard FeeApplication

$6,546$17,225Real-time Supplement

$19,546$51,436180-day Supplement

$90,910$239,237Efficacy Supplement (for BLA)

$90,910$239,237Panel-track Supplement

Fee is waivedNAFirst premarket application by a small business

$90,910$239,237Premarket Report (premarket approval application for a reprocessed device)

$90,910$239,237Premarket Application (PMA, PDP, BLA)

$2,802$3,502510(K)

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MDUFA-User Fee Reductions

A small business is one with gross receipts or sales < $30 millionSmall business status must be evidenced by submission of Federal Income Tax returnsSmall business fees are 38% of standard fee, except 510(k) is 80% of standard fee

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MDUFA- User Fee Exceptions

Humanitarian Device ExemptionFirst premarket application (PMA, PDP, BLA, or premarketreport) from a small businessPremarket report by holder of PMA for same reprocessed deviceThird-party 510(k) Application from a State or Federal Government entityAny application intended solely for pediatric use

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Post Submission RequirementsAmendments to Unapproved Applications

21CFR 314.60 Amendments 21 CFR 814.37-PMA Amendments

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Amendments to Unapproved Applications

Guidances/SOPPs–CBER/CDERGood Review Management Principles and Practices for PDUFA Products (CBER/CDER)Information Request and Discipline Review Letters Under the Prescription Drug User Fee ActClassifying Resubmissions in Response to Action LettersSOPP 8401.1: Issuance and Review of Responses to Information Requests and Discipline Review Letters to Pending Applications

Guidances-CDRHFDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Performance AssessmentPremarket Approval Application Filing Review

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Amendments to Unapproved Applications

The BLA, NDA or PMA is rarely the last submission prior to an Approval LetterFDA will formally and informally communicate during the review processResponses need to be submitted to the application

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FDA Review of Unapproved Applications

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 elementsForm the review committee and meet Make a refusal-to-file decision by the 45-day meetingMake Information Requests Complete review - issue an action letter (complete response or approval)Other actions - withdrawal or denial

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Types of FDA Letters for Drugs/Biologics

Information request letters Requests for additional information

Discipline review letters Not a complete review Early thoughts from members of review teamIdentify deficiencies that need to be correctedMay describe actions that need to be taken

Action letterIssued after complete review of the filed application

Preliminary comments on draft labeling

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Effect of Letters on Review Clock

The IR/DR letters will not affect the user fee review clockYour response affects the review clockReview team will review responses at their discretion

They may or may not consider a response to a DR a major amendmentMajor 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 letterThe action letter will include all deficiencies that must be answered to place the application in condition for approval

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Resubmissions in Response to Action Letters

Class 1 Resubmission (2-month review)Final labelingSafety updatesCommitments of phase 4 studiesAssay validationLot release of last 1-2 lots used to support approval

Class 2 Resubmission (6-month review)Everything else

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Types of Amendments

Answers to questionsAdditional information (i.e.)

Adverse eventsManufacturing tests

New analysesUpdated ISS and ISEData from studies in progressProtocols for Post-approval Commitments

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# Amendments to Unapproved Applications

22GD Searle2001Bextra

57Roche2003Fuzeon(HIV)

37BMS2005Baraclude(HbSAg)

46AstraZeneca2003Iressa(Cancer)

Number of Amendments

CompanyYearDrug

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Types of Responses for Devices

510(K)Additional information letter

PMAFirst action – “major deficiency” letter All other first actions (approval, approvable, approvable pending GMP inspection, not approvable, or denial)

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What Does this Mean for the Company?

Don’t think your work is done if you get past the Refusal to File (RTF) deadlinePressure is still onPersonnel still tied to project

ClinicalRegulatory (including any e-sub personnel)Data management

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Post-Approval ReportsScheduled Reports

Annual ReportsDistribution ReportsSafety Reports

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Annual Reports-Regulation

CDER -314.81 b (2)CBER

21 CFR 600.12 –Changes in Application21 CFR 600.70 –Post-marketing Commitments21 CFR 600.80 –Adverse Events21 CFR 600.81 –Distribution Report

CDRH21 CFR 814.84

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Annual Reports-Guidance

Draft Guidance for Industry: Providing Regulatory Submissions in Electronic Format--Annual Reports for New Drug Applications and Abbreviated New Drug Applications - 8/27/2003

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Annual Report-Drugs and Biologics

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

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Annual Report-What is included (314.81)

SummaryNew 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.

LabelingCurrently used professional labeling, patient brochures or package inserts (if any), and a representative sample of the package labelsA summary of any changes in labeling since the last report

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Chemistry, manufacturing, and controls changesReports of experiences, investigations, studies, or tests that may affect FDA`sprevious 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 studiesCopies of unpublished reports and summaries of published reports of new toxicological findings

Clinical dataPublished 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

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Status reports of post-marketing study commitmentsA status report of each post-marketing study concerning clinical safety, clinical efficacy, clinical pharmacology, and nonclinical toxicology that is required by FDAMust 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 studiesChemistry, manufacturing, and controls studies that the applicant has agreed to perform Product stability studies

Log of outstanding regulatory businessTo facilitate communications between FDA and the applicant

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Post-Marketing Commitments

RegulationFDA Modernization Act of 1997 added a new provision (section 506B) on post-marketing studies to the Federal Food, Drug, and CosmeticApplicable to drugs and biologics –NOT devices

GuidanceReports on the Status of Post-marketing Studies -Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997

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Clinical StudiesCalled phase 4 commitmentsStudies — 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 startedCommitments are published on FDA website with yearly progress results

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Post-Marketing Commitments-When likely?

Commitment Required Under: Accelerated ApprovalApproved based on surrogate endpoints that reasonably predict clinical benefitClinical benefit must be confirmed through additional human studies

Commitment Required Under: Animal Efficacy RuleNew drug or biological used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substancesApproved for marketing based on evidence of effectiveness in animalsSponsor must verify clinical benefit when such studies are feasible and ethical

Commitment Required Under: Pediatric Research Equity ActPediatric Research Equity Act of 2003 Designed to improve the quality of pediatric information in drug labelingFDA has explicit authority to require applications to include pediatric studies

Studies to gather additional information about a product's safety, efficacy, or optimal use

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CMC RelatedMay request additional validationsStability dataCommitments are NOT published on FDA website– Considered confidential

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Post-Marketing Commitments-Examples

*Accelerated Approval CommitmentOccurrence of MDSLong-term effects of HAMA-effect on IVD tests

Long-term effects of HAMA-effect on patients

Use of Prophylactic VaccinesRetreatment with BexxarBexxar vs ZevalinBexxar vs Rituximab*

DESCRIPTION OF STUDY

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Post-Marketing Commitments-Examples

1,090 NDAs were approvedThese NDAs plus supplemental applications generated a total of 2,328 postmarketing commitments1,737 reporting under FDAMA 130

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Failure of PMC Clinical TrialFDA can pull approvalConsidered with Astrazeneca’s IRESSA after PMC trial failedTo date –has not happened

Concern with companies not meeting the commitments

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Post-Marketing Commitments-Impact on Company

Initial approval may not be the last clinical trialAccelerated approval=Confirmatory TrialComplicated products =follow-up trials$$$$Resources may be requiredRecent drug problems mean this is only going to increase

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Annual Report-Devices (PMA)

Due annually at intervals of 1 year from the date of approval of the original PMAPost-approval reports for supplements approved under the original PMA are included in the next and subsequent annual reports for the original PMA

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Annual Report-PMAs

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

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Scheduled Reports


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Distribution Reports-Biologics

21 CFR 600.81- Distribution reports. Must be submitted every 6 monthsFDA can require other time framesMust contain:

bulk lot number fill lot numbers label lot number (if different from fill lot number)labeled date of expirationnumber of doses in fill lot/label lotdate of release of fill lot/label lot for distribution

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Distribution Reports-Devices

Form 3417-Medical Device Reporting-Baseline Report (for first report)Annual update requiredIncludes a line for # devices distributed

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Medical Device Tracking

21 CFR Part 821Section 519(e) of the FDC Act Guidance for Industry and FDA Staff: Medical Device Tracking May 5, 2003

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Medical Device Tracking

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 patientRequires 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

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Examples of Products that must be Tracked

· 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

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Scheduled Reports


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Safety Reports -

21 CFR 600.80Periodic adverse experience reports are due

at quarterly intervals, for 3 years from the date of licensing annual intervals from then onwithin 30 days of the close of the quarter

Annual report within 60 days of the anniversary date of the license

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Contents of Annual Safety Report (example)

Introduction Initial Reports List of Serious Listed Initial Reports List of Non-Serious Unlisted Initial ReportsList of Non-Serious Listed Initial ReportsList of Serious Listed Follow-up Reports List of Non-Serious Unlisted Follow-up Reports List of Non-Serious Listed Follow-up ReportsList of 15-Day Reports by Body System Submitted During Reporting PeriodTabulation by Body System of AII Events Reported Analysis and Discussion of Serious Listed Initial Reports Analysis and Discussion of Non-Serious Unlisted Initial ReportsAnalysis and Discussion of Non-Serious Listed Initial ReportsSummary and Analysis of the 15-Day Reports Submitted During Reporting PeriodSummary of Actions Taken During Reporting PeriodAppendix A: Current United States Prescribing Information for the Product

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Device-Annual Report -Safety

21 CFR 803If 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

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Scheduled Reports


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Unscheduled Reports

Changes to Approved ApplicationsCMC SupplementsEfficacy Supplements

Reports of Problems and ErrorsPromotional LiteratureIndividual Safety Reports

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Changes in Applications-Regulation and Guidance

Regulation21 CFR 314.70-Drugs21 CFR 601.12-Biologics21 CFR 807.81 -510(k)21 CFR 814.39 -PMA

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Changes in Applications-Regulation and Guidance

GuidanceChanges to an Approved NDA or ANDAGuidance for Industry: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological ProductsGuidance for Industry: Changes to an Approved Application: Biological Products30-Day Notices and 135-Day PMA Supplements for Manufacturing Method or Process

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Changes in Applications-CBER/CDER

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 distribution3) 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.

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Changes to Applications-Summary of Requirement

Minimal potentialAnnual Report

Moderate potential30-Day Prior

Substantial potentialPrior Approval

Risk of an Adverse Effect on the Identity, Strength, Quality, Purity, or Potency

Type of Submission

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Changes to Applications-Specific Examples with Substantial Potential (Biologics/Drugs)

Changes in labeling, except those that increase safetyChanges in indicationChanges in route of administration

Change in drug formulation/quantity Change in test methods

Deletion of a specification or an analytical methodElimination 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

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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 scaleChange 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 effectChange 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),

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CMC Changes-Examples of Changes with Minimal Potential (Biologics/Drugs)

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 licenseRoom upgrades, (i.e. improved finishes on floors/walls)Installation of non-process equipment (ie.refrigerators) freezersModifications 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.

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Changes to existing PMA

Must submit a supplement if the change affects the safety or effectiveness of the device

New indicationsLabeling changesDifferent facility to manufacture, process, or package the deviceChanges in sterilization proceduresChanges 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

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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 indicationsChanges 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

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Exception to PMA supplementsSection 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 manufactureIf the notice is inadequate, a 135-day PMA supplement will be required

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Changes to an Existing 510(k)

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 deviceNew submission required if that change could significantly affect safety or effectivenessThe burden is on the company to decideJustification should be reflected in your device master record and change control records

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Efficacy Supplements

Required to submit for change in labelUsually requires clinical dataUser 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

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CMC or Label Changes-Impact on Company

Everyone needs to understand the requirementsNeed document control system

Record of product changes made during year Procedure to evaluate importance of change

Regulatory should review changes for importanceMake determination whether submission is required prior to implementation Documentation of decisions

Personnel to test and validate changes

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Unscheduled Reports

Changes to Approved ApplicationsCMC SupplementsEfficacy Supplements

Reports of Problems and ErrorsPromotional LiteratureIndividual Safety Reports

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Product Problems-Regulations-FD&C Act

Sec. 301 Prohibited ActsItems that are adulterated/misbrandedCounterfeit drugs

Sec. 501 Definition of AdulteratedFilthy, putrid or decomposedDifference (reduced) in strength/purity

Sec. 502 Definition of MisbrandedLabeling is false or misleadingAdequate directions for use or warnings

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Reporting Product Problems

BiologicsProduct Deviations

DrugsField Alerts

DevicesProduct Malfunctions

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Biologics-Product Deviation- Guidances

BiologicsRegulation-Biologic Products– 21 CFR 600.14– Guidance for Industry-Biological Product Deviation

Reporting for Licensed Manufacturers of Biological Products -Other than Blood and Blood Components

Regulation-Blood Products

– 21 CFR 606.171– Guidance for Industry-Biological Product Deviation Reporting for

Blood and Plasma Establishments

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Product Deviations-Biologics or Blood

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.

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Product Deviations- When is a Report Required?

If problem is discovered AFTER PRODUCT DISTRIBUTION

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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.

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Product Deviations-Examples

Examples:Raw material contaminated or does not meet spec

Manufacturing/processing performed using incorrect parametersBulk or intermediate product stored improperly Required testing was not performed, was performed incorrectlyPackage insert is incorrect, not the current approved version, or not included with productBlood establishment performed compatibility testing using a patient sample from the wrong patient

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Drugs-Field Alerts

Regulations21 CFR 314.81 Other postmarketing reports

Guidance NDA Field Alert Form and InstructionsProduct Recalls, Including Removals and Corrections

SOPP Standing Operating Procedures for Handling NDA/ANDA Field Alert Reports

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Field Alerts -Drugs

NDA—Field alert report Must submit information of the following kinds of incidentsLabeling errorBacteriological contaminationSignificant change or deteriorationFailure 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.

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Field Alert-FDA Response

District OfficesPost-market Surveillance Team (PST) Coordinator evaluates the Field Alert Report and conducts follow-up, if necessaryThe District Recall and Emergency Coordinator reviewsMay follow up with company

Office of CompliancePostmarket Surveillance Team will evaluate the initial report and the

district's follow-up informationIf 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

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Malfunctions –DevicesRegulations and Guidance

21 CFR 803-Medical Device Reporting21 CFR 806-Reports of Corrections and Removals

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Medical Device Reporting -Devices

Malfunction [§803.3(m)] Failure of the device to meet its performance specificationsReportable 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 reportManufacturerDistributorUser facility

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Deviation Reports/Field Alerts/Malfunctions-Impact on Company

Need systems to collect incoming data with SOP on documenting problems and decisionsNeed written procedure for reporting product deviations, field alerts or malfunctionsAlso need a Recall ProcedureNeed a tracking system for lot releaseNeed a good lawyer

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Promotional Literature

GuidancesFDA Form 2253 - Transmittal of Advertisements and Promotional Labeling for Drugs and Biologics for Human UseAccelerated Approval Products: Submission of Promotional Materials (Posted 3/26/1999)

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Code of Federal Regulations21 CFR 99 - Dissemination of Information on Unapproved/New Uses

for Marketed Drugs, Biologics, and Devices21 CFR 200– General21 CFR 201- Labeling21 CFR 202- Prescription Drug Advertising21 CFR 312- Investigational New Drug Applications21 CFR 314- Applications to Market New Drug or Antibiotic

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Labeling reviewed during approval processPackage insertPackage labelsOther (based on BEXXAR experience)– Training Manual– Software Manual

Reviewers are the individuals who reviewed the application

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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

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Safety Reports- Relevant Regulations

DRUGS

21 CFR 314.80 – Post-marketing reporting of adverse drug experiences

BIOLOGICS

21 CFR 600.80 – Post-marketing reporting of adverse experiences

DEVICES

• 21 CFR 803 – Medical Device Reporting

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Safety Reports-Guidance Documents

Post-marketing Reporting of AEsDrugs (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)

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Safety Reports-ICH Documents

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 UsersM1 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)

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Safety Reports-Requirements

Obligated to Review Adverse Drug ExperiencesFrom 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 SurveillanceReceipt and evaluation, as well as Reporting of post-marketing AEs to FDA

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Safety Reports –Definitions-Drugs/Biologics

Serious adverse drug experienceDeathLife-threatening adverse drug experienceInpatient hospitalization or prolongation of existing hospitalizationPersistent or significant disability/incapacityCongenital anomaly/birth defectImportant 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.

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Safety Reports –Definitions-Drugs/Biologics

Unexpected adverse drug experienceAny adverse drug experience that is not listed in the current labeling for the drug product. Basically –Anything Not Previously Observed

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Safety Reports-Drugs and Biologics

Drugs and BiologicsReporting 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

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Safety Reports-Devices

Reportable events

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

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Safety Reports-Devices

Coincide with registration

FDA 3381Annual Certification

When device or family reported 1st

time

FDA 3417Baseline report-basic data on device

Within 30 daysof becoming aware

FDA 3500ADeath, serious injury, malfunctions

WhenFormWhat to Report

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Safety Reports-Impact on Company

Usually Requires Development of a GroupExperienced health-care professionalsNurses and Pharm.D. typical members of teamCan be resource intensive

Requires written proceduresMay require specialized softwareMay require submissions to IND for RegulatoryMay require European Submissions