fda perspective - high prority topics & future directions

7/31/2019 FDA Perspective - High Prority Topics & Future Directions

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FDA Perspective:FDA Perspective:High Priority Topics &High Priority Topics &

Future DirectionsFuture Directions

GPhA 2007 Fall Technical ConferenceGPhA 2007 Fall Technical Conference

October 10, 2007October 10, 2007

Deborah M. Autor, Esq.Deborah M. Autor, Esq.DirectorDirector

CDER Office of ComplianceCDER Office of Compliance


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OverviewOverview CDER OC Mission and VisionCDER OC Mission and Vision

FDA Modernization: Drug Quality for the 21FDA Modernization: Drug Quality for the 21stst CenturyCentury

Trends: Recalls, Manufacturing Sites and InspectionsTrends: Recalls, Manufacturing Sites and Inspections

Foreign InspectionsForeign Inspections

Raw Material ControlRaw Material Control FDAFDAs Pharmaceutical Ingredients Pharmaceutical Ingredient

Safety Task ForceSafety Task Force

Bioequivalence InspectionsBioequivalence Inspections Postmarketing Adverse Drug Experience (ADE)Postmarketing Adverse Drug Experience (ADE)

ReportingReporting

Marketed Unapproved Drugs InitiativeMarketed Unapproved Drugs Initiative


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MissionMission

Mission (purpose) of t he CDER Off iceMission (purpose) of t he CDER Off ice

of Complianceof Compliance::

To promote and protect public healthTo promote and protect public health

through strategies and actions thatthrough strategies and actions that

minimize consumer exposure to unsafe,minimize consumer exposure to unsafe,ineffective, and poor quality drugs.ineffective, and poor quality drugs.


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VisionVision

Vision (ambit ion) of t he CDER Off ice ofVision (ambit ion) of t he CDER Off ice ofComplianceCompliance::

Through excellence in riskThrough excellence in risk-- and scienceand science--based policy, surveillance, andbased policy, surveillance, andenforcement, we prevent consumerenforcement, we prevent consumer

exposure to unnecessary risk from drugsexposure to unnecessary risk from drugsthroughout their lifecycle.throughout their lifecycle.


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FDA Modernization:Drug Quality

for the 21st Century

FDA Modernization:FDA Modernization:

Drug QualityDrug Quality

for the 21for the 21stst CenturyCentury


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FDAFDAs Quality System Guidances Quality System Guidance

Result of the CGMP for the 21st CenturyResult of the CGMP for the 21st CenturyInitiativeInitiativefinalized August 2006finalized August 2006

Encourages the use of modern qualityEncourages the use of modern quality

management system for science basedmanagement system for science basedmanufacturingmanufacturing

Emphasizes self management of changeEmphasizes self management of change

Consistent with overall efforts to reduceConsistent with overall efforts to reducemanufacturing supplementsmanufacturing supplements -- 314.70 revisions314.70 revisions


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Pharmaceut ical Quali t yPharmaceut ical Quali t ySystems I CH Q10Systems I CH Q10

Three new letters to learn as we approach theThree new letters to learn as we approach theDesired State for pharmaceutical manufacturingDesired State for pharmaceutical manufacturing

in the 21in the 21stst Century:Century:

PQSPQSHow did we get here? Are there challenges ahead?How did we get here? Are there challenges ahead?


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I CH Qualit y VisionI CH Qualit y Vision -- 20032003 A new vision for ensuring product qualityA new vision for ensuring product quality

(Brussels, July 2003(Brussels, July 2003))

A harmonized pharmaceutical qualityA harmonized pharmaceutical quality systemsystemapplicable across theapplicable across the li fe cycleli fe cycleof the productof the productemphasizing anemphasizing an integratedintegratedapproach toapproach to qualityqualityr isk management and sciencer isk management and science

New ICH guidelines (high level guidelines,New ICH guidelines (high level guidelines,more visionary, less prescriptive, flexiblemore visionary, less prescriptive, flexibleregulatory approaches)regulatory approaches)

Pharmaceutical Development (Q8)Pharmaceutical Development (Q8) Quality Risk Management (Q9)Quality Risk Management (Q9)

Pharmaceutical Quality Systems (PQS) (Q10)Pharmaceutical Quality Systems (PQS) (Q10)


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I CH Qualit y VisionI CH Qualit y Vision PrePre--2003: quantitative guidance2003: quantitative guidance

PostPost--2003: strategic guidance2003: strategic guidance

Q8/Q9/Q10Q8/Q9/Q10

ExistingExisting GMPGMPss

Quality by Design

(PharmaceuticalDevelopment)

Quality Risk

Management

The Regulatory

Quality System

Quality

Systems

Quality

Systems

(Q10)

For companies with :1. Good design and

control strategies

2. Good Risk

Management strategies

3. Good Quality Systems

Quality Risk

Management

(Q9)

Quality

by Design

(Q8)

Reduced regulatory

burden:

Reduction of

submissions onchanges/variations

Inspection of quality

systems


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Pharmaceutical

Development

Technology

TransferManufacturing Discontinuation

GMP

Management Responsibilities

Process Performance & Product Quality monitoring

CAPA

Change Management

Management reviewPQS elements

Quality risk Management

Knowledge ManagementEnablers

ICH Q10 PQSICH Q10 PQSICH Q10 PQS


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Elements of a Robust Qualit y SystemElements of a Robust Qualit y System

1.1. ScienceScience--basedbasedapproachesapproaches

2. Decisions based on2. Decisions based on understanding productunderstanding products intended uses intended use

3. Proper identification and control of areas of3. Proper identification and control of areas ofpotentialpotential

process weaknessprocess weakness(including raw materials)(including raw materials)

4.4. Responsive deviation and investigation systemsResponsive deviation and investigation systemsthat lead tothat lead to

timely remediationtimely remediation

5. Sound methods for5. Sound methods for assessing riskassessing risk

6.6. WellWell--defined and designed processes and products,defined and designed processes and products, fromfrom

development through entire product life cycle.development through entire product life cycle.

7.7. Systems for careful analysesSystems for careful analysesof product qualityof product quality

8. Supportive management (philosophically and financially)8. Supportive management (philosophically and financially)


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Integration: CDER and ORAIntegration: CDER and ORA How do we more formally transfer our knowledge from

Qbd and Qbr from CDER (Review, Compliance) toORA? Create a knowledge transfer from Center toORA. Similar to technology transfer from R&D to

commercial

Final critical aspect of implementing desired state will berealized by new continuity between CDER and ORA

Inspectional role:

Follow-up on key areas suggested by Center Verify process implementation and state of control Assess lifecycle improvements Ensure adequate change control


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TrendsTrends


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Drug RecallsDrug Recalls

977 Recalls in FY 2007 (through 9/21)977 Recalls in FY 2007 (through 9/21)

Drug Recalls

178 162 145 187 168 130 169 128 103

100246

179236

154138

316

188

860

4

1615

15

2016

17

45

14

0

250

500

750

1000

1997 1999 2001 2002 2003 2004 2005 2006 2007

Fiscal Year

Numb

er

Class III Class II Class I


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Drug RecallsDrug RecallsAdjusted to account for multipleAdjusted to account for multiple--recall incidentsrecall incidents

Drug Recalls

178 162 145 187 168 130 169 128 103

100246

179236

154138

217188 189

4

1615

15

2016

922 14

0

250

500

750

1000

1997 1999 2001 2002 2003 2004 2005 2006 2007

Fiscal Year

Num

ber

Class III Class II Class I


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Establishment Evaluation RequestsEstablishment Evaluation Requests(EERs)(EERs)

The FD&C Act provides that FDA may notapprove an NDA or an ANDA if the facilities andcontrols used for the manufacture of the drugare inadequate.

The Office of Compliance serves a role forforeign establishments, similar to a district office

The site must be evaluated by Office ofThe site must be evaluated by Office of

Compliance with field input prior to approval viaCompliance with field input prior to approval viaproductproduct--specific PAI or based upon recent CGMPspecific PAI or based upon recent CGMPhistoryhistory


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Establishment Evaluation RequestsEstablishment Evaluation Requests(EERs)(EERs)

A recent look on a given day this summer in ourdata base found 231 generic foreignfacilities pending an inspection.

How will this challenge be met? Will the abilityto complete timely inspections become a limitingfactor in an already challenging generic drugapproval queue?

Up-to-date CGMP surveillance inspection resultscan help.


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EERs Submitted for NDAs and ANDAsEERs Submitted for NDAs and ANDAs

(Originals and Supplements)(Originals and Supplements)October 1, 2002October 1, 2002September 31, 2006September 31, 2006

34473569

27462622

3606

25852552

1928

1488

1856

0

500

1000

1500

2000

2500

3000

3500

4000

FY 02 FY 03 FY 04 FY 05 FY 06

Domestic Foreign


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Foreign InspectionsForeign Inspections


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Foreign Inspections by CountryForeign Inspections by Countryin FY 2007in FY 2007**

Switzerland

5%

Spain

5%

Japan

4%

China

4%

Others

31%

India22%

France

9%

Germany

7%

Canada

7%Italy

6%

*FY 2007 data current as of 9/25/07


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Foreign Inspection in FY 2007Foreign Inspection in FY 2007** bybyFirm TypeFirm Type

API

51%

Dosage

31%

Both

API/Dosage

7%Control Lab

10%

Others

1%



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FY 2007FY 2007** Inspections byInspections byType of InspectionType of Inspection

185

70

15

6 4

020

406080100

120140

160180200

P

reapproval/

Surveillance

P

reapproval

S

urveillance

F

orCause

T

herapeutic

Drug

*FY 2007 data ,

current as of 9/25/07


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Foreign InspectionsForeign InspectionsFiscal YearFiscal Yearss 20042004 -- 20072007**

33

27

32

31

87

57

61

70

20

24

25

25

104

137

135

140

0 50 100 150

FY 07

FY 06

FY 05

FY 04

API

DosageAPI/Dosage

Others


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Inspections in China and IndiaInspections in China and IndiaFY 2004FY 2004 FY2007*FY2007*

18

36

13

33

16

34

11

82

010

20

30

40

50

60

70

80

90

FY04

FY05

FY06

FY07

CHINA

INDIA



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Inspections in ChinaInspections in ChinaFY 2004FY 2004 -- 20072007**

18

13

16

11

0 5 10 15 20

FY 04

FY 05

FY 06

FY 07



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Inspections in China by Firm TypeInspections in China by Firm TypeFiscal YearFiscal Yearss 200420042007*2007*

1616

11

00

1515

FY 06FY 06

111113131818TotalTotal

000000Dosage ManufacturerDosage Manufacturer

110011API/Dosage ManufacturerAPI/Dosage Manufacturer

101013131717API ManufacturerAPI Manufacturer

FY 07*FY 07*FY 05FY 05FY 04FY 04FIRM TYPEFIRM TYPE



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Type of Manufacturing Facilities inType of Manufacturing Facilities inChinaChina

Intermediate

1%

Control Testing

Lab

2%

Dosage

1%

API/Dosage

4%

API

92%


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Common GMP Deficiencies inCommon GMP Deficiencies inChina FY 2006China FY 2006

Others

22%

Lab Controls

9%

Analytical

Methods

Validation

13%

Lab

Records/Reports

17%

Lack/Inadequate

SOPs

17%

Production

Records/Reports

22%


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Top Five Deficiencies in ChinaTop Five Deficiencies in ChinaFY 2007FY 2007**

3

2

2

2

2

0 1 2 3 4

Laboratory Controls

Analytical Method

ValidationProduction

Records/Reports

QA Systems

Equipment

Design/Qualification



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Inspections in IndiaInspections in IndiaFY 2004FY 2004 -- 20072007**

62

32

30

36

0 10 20 30 40 50 60 70

FY 07

FY06

FY 05

FY04



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Inspections in IndiaInspections in IndiaFiscal Year 2004Fiscal Year 2004 -- 20072007**

3434

11

1111

66

1616

FY 06FY 06

626233333636TotalsTotals

663333Contract LabContract Lab

14147766Dosage ManufacturerDosage Manufacturer

882222API/DosageAPI/Dosage

ManufacturerManufacturer

414121212525API ManufacturerAPI Manufacturer

FY 07FY 07FY 05FY 05FY 04FY 04FIRM TYPEFIRM TYPE



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Type of Manufacturing Facilities inType of Manufacturing Facilities inIndiaIndia

API

66%

Intermediate

1%

Control Testing

Lab9%

Dosage

19%

API/Dosage5%


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Common GMP Deficiencies inCommon GMP Deficiencies inIndia FY 2006India FY 2006

Others31%

QA Systems

4%

Equipment Design/

Qualification

4%

Stability Program

4%

Lab Records/Reports

6%

Failure/OOS

Investigations

4%

Equipment

Cleaning/Maintenanc

e, Cleaning

Validation

7%Lack/Inadequate

SOPs

9%

Process Validation

Study/Protocol

9%

Lab Controls

9%

Production

Records/Reports

13%


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Top Five GMP Deficiencies in IndiaTop Five GMP Deficiencies in IndiaFY 2007FY 2007**

14

11

10

9

8

0 5 10 15

Equipment

Cleaning/Maintenance,

Cleaning Validation

Lack of/Inadequated

SOPs

Equipment Design/

Qualification

Laboratory

Records/Reports

Laboratory Controls



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Raw Material ControlRaw Material ControlRaw Material Control


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DEG ContaminationDEG ContaminationDEG Contamination Scope of the Problem: Recurrent DEG poisoningScope of the Problem: Recurrent DEG poisoning

worldwide (resulting in hundreds of deaths)worldwide (resulting in hundreds of deaths)

20062006PanamaPanama

19951995--19961996HaitiHaiti

19901990--19981998Argentina, Bangladesh, India, andArgentina, Bangladesh, India, and

NigeriaNigeria 19371937United States (Elixir Sulfanilamide)United States (Elixir Sulfanilamide)

FDA issued guidance in May 2007FDA issued guidance in May 2007

to recommendto recommend

testing and other controls to avoid DEG contamination:testing and other controls to avoid DEG contamination:

Guidance for Industry: Testing of Glycerin forGuidance for Industry: Testing of Glycerin forDiethylene GlycolDiethylene Glycol


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Guidance on Testing Glycerinfor DEG

Guidance on Testing GlycerinGuidance on Testing Glycerinfor DEGfor DEG

Drug product manufacturers should:Drug product manufacturers should: Perform a specific identity test and a limit of detection testPerform a specific identity test and a limit of detection test

for DEG (the USP limit for DEG is 0.1%)for DEG (the USP limit for DEG is 0.1%)

Test all containers of all lotsTest all containers of all lots Use the identity tests described in the USP GlycerinUse the identity tests described in the USP Glycerin

Monograph, including the limit test for DEG, orMonograph, including the limit test for DEG, or

Use an equivalent test, such as the thinUse an equivalent test, such as the thin--layerlayerchromatography method published in the Journal ofchromatography method published in the Journal ofAOAC International Vol. 81, No. 1, 1998AOAC International Vol. 81, No. 1, 1998

Guidance on Testing GlycerinGuidance on Testing GlycerinGuidance on Testing Glycerin


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Guidance on Testing Glycerin

for DEG

Guidance on Testing GlycerinGuidance on Testing Glycerin

for DEGfor DEGHow you can prevent use of DEG-contaminated glycerin: Drug product manufacturers should know the supply chain for

glycerin including the component manufacturer and any

distributors. Identify reliable suppliers & know the actual source.

Manufacturers should ensure proper testing of glycerin forDEG and should make personnel aware of the importance of

testing and the potential hazards if testing is not done. Repackers, and others who distribute and prepare glycerin for use

in drug products, should test glycerin used, sold for use, orintended for use in drug products.

Pharmacies that use glycerin in compounding drug productsshould either test the glycerin for DEG content or ensure that suchtesting was properly done by a reliable supplier.


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FDAs Pharmaceut icalIngredient

Safety Task Force

FDAFDAs Pharmaceut icals Pharmaceut icalIngredientIngredient



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Pharmaceutical Ingredient SafetyPharmaceutical Ingredient SafetyTask ForceTask Force

DEG/glycerin incidents point out potential risksDEG/glycerin incidents point out potential riskswithin global supply chain for ingredientswithin global supply chain for ingredients

should take measures to anticipate and preventshould take measures to anticipate and prevent

similar occurrences with other imported ingredientssimilar occurrences with other imported ingredients

FDA formed task force in midFDA formed task force in mid--20072007

developed recommended action itemsdeveloped recommended action items

recommendations seem to be aligned withrecommendations seem to be aligned with PresidentPresidentss

Interagency Task ForceInteragency Task Force initial recommendationsinitial recommendations

regarding import safety publicized this monthregarding import safety publicized this month


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FDAFDAs Pharmaceutical Ingredients Pharmaceutical Ingredient


Task Force convened by CDERTask Force convened by CDERs Office ofs Office of

Compliance in May 2007 to: (cont.)Compliance in May 2007 to: (cont.)

define proactive steps to address risks posed bydefine proactive steps to address risks posed bysourcing poor quality, adulterated andsourcing poor quality, adulterated andmisbranded pharmaceutical raw materialsmisbranded pharmaceutical raw materials

and propose other specific ways to enhanceand propose other specific ways to enhance

FDAFDAs oversight of pharmaceutical ingredients oversight of pharmaceutical ingredientsafetysafety

f


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What can drug manufacturers do toWhat can drug manufacturers do to

prevent similar occurrence with anyprevent similar occurrence with anypharmaceutical ingredient?pharmaceutical ingredient?

Apply quality systems approach to monitor ingredient supplyApply quality systems approach to monitor ingredient supplychain integritychain integrity

Establish a robust supplier qualification program (e.g. audits,Establish a robust supplier qualification program (e.g. audits, qualityquality

agreements, appropriate ongoing QC of incoming lots)agreements, appropriate ongoing QC of incoming lots)

Only do business with trustworthy sourcesOnly do business with trustworthy sources

Verify each ingredient shipment comes from approvedVerify each ingredient shipment comes from approved

suppliers/manufacturerssuppliers/manufacturers

Verify shipments came through expected routes and were notVerify shipments came through expected routes and were notdiverted or tampered withdiverted or tampered with

Isolate ingredients that are suspected of being nonIsolate ingredients that are suspected of being non--genuine orgenuine or

mishandled or perhaps adulteratedmishandled or perhaps adulterated


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Bioequivalence (BE)

Inspections

Bioequivalence (BE)Bioequivalence (BE)

InspectionsInspections


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Bioequivalence (BE) InspectionsBioequivalence (BE) Inspections

Verify the quality and integrity ofVerify the quality and integrity ofin vivoin vivoandand in vitroin vitrobiopharmaceutics databiopharmaceutics data in vivoin vivostudiesstudies

pharmacokinetic BE studiespharmacokinetic BE studies

focus on 3 components: clinical, analytical, and statisticalfocus on 3 components: clinical, analytical, and statistical

clinical endpoint BE studiesclinical endpoint BE studies multimulti--site studies involving numerous clinicalsite studies involving numerous clinical

investigatorsinvestigators

in vitroin vitrostudiesstudies e.g., study nasal spray drug products for locale.g., study nasal spray drug products for local

actionaction


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BE Program FocusBE Program Focus

Audit studies pivotal to approval decisionsAudit studies pivotal to approval decisions generic and innovator drug productsgeneric and innovator drug products

PEPFAR applicationsPEPFAR applications

expedited review processexpedited review process many studies conducted outside U.S.many studies conducted outside U.S.

Address CDER reviewer concerns aboutAddress CDER reviewer concerns about

data integrity and study conductdata integrity and study conduct Investigate complaintsInvestigate complaints

allegations of improper study conduct, fraudallegations of improper study conduct, fraud


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Inspectional OversightInspectional Oversight

BE program monitors studies from multipleBE program monitors studies from multiplesourcessources

contract research organizations (CROs)contract research organizations (CROs)

sponsor facilitiessponsor facilities

clinical investigatorsclinical investigators

academic laboratoriesacademic laboratories

sites within and outside the U.S.sites within and outside the U.S.

inspections in India increasinginspections in India increasing

FY02, no BE inspections in IndiaFY02, no BE inspections in India

Since FY05, ~50 BE inspections in IndiaSince FY05, ~50 BE inspections in India


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Problem of Unreliable DataProblem of Unreliable Data

Some applications contain unreliable dataSome applications contain unreliable data failure to assure proper dosingfailure to assure proper dosing

study sample contamination not investigatedstudy sample contamination not investigated

failure to assure data accuracyfailure to assure data accuracy

failure to demonstrate accurate analytical methodsfailure to demonstrate accurate analytical methods

ConsequencesConsequences

FDA rejection of unreliable dataFDA rejection of unreliable data

unfavorable application outcomeunfavorable application outcome

can affect multiple applicationscan affect multiple applications


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For exampleFor examplerecent actionrecent action

Global CRO that conducts pharmacokineticGlobal CRO that conducts pharmacokineticstudies for many pharmaceutical companiesstudies for many pharmaceutical companies

Studies over a 4Studies over a 4--year period from 2 sites wereyear period from 2 sites werenot reliablenot reliable

These studies now must be audited or repeated,These studies now must be audited or repeated,or specimens must be reor specimens must be re--analyzedanalyzed

FDA notified affected sponsorsFDA notified affected sponsors

CDER will monitor followCDER will monitor follow--up to ensure thatup to ensure thatapprovals and pending applications reflect validapprovals and pending applications reflect validdatadata


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Inspectional FindingsInspectional Findings

Examples of deficiencies for generic BEExamples of deficiencies for generic BEstudies includestudies include

failure to follow protocols and SOPsfailure to follow protocols and SOPs

dosing and reserve sample issuesdosing and reserve sample issues method not adequately validatedmethod not adequately validated

inappropriate analytical run acceptanceinappropriate analytical run acceptance

inadequate record keepinginadequate record keeping


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Goal: Data Quality and IntegrityGoal: Data Quality and Integrity

Adherence to FDA regulations andAdherence to FDA regulations andguidance is keyguidance is key

Thoroughly planned and carefullyThoroughly planned and carefully

executed studies provide the bestexecuted studies provide the bestchance for successchance for success

DonDont ignore problemst ignore problems followfollow--up investigations are critical toup investigations are critical to

assure suitable study conclusionsassure suitable study conclusions


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Postmarketing Adverse

Drug Experience (ADE)Reporting

Postmarketing AdversePostmarketing Adverse

Drug Experience (ADE)Drug Experience (ADE)ReportingReporting

Postmarketing Adverse DrugPostmarketing Adverse Drug


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Postmarketing Adverse DrugPostmarketing Adverse Drug

Experience (ADE) ReportingExperience (ADE) Reporting FDA monitors ADE data reporting byFDA monitors ADE data reporting by

Rx & OTC firms:Rx & OTC firms: NDA/ANDA holdersNDA/ANDA holders

Manufacturers, packers, and distributors whoseManufacturers, packers, and distributors whose

names appear on drug labelsnames appear on drug labels Affiliates, marketing partners, and contractorsAffiliates, marketing partners, and contractors

Compliance assessed through riskCompliance assessed through risk--basedbased

inspections and surveillance ofinspections and surveillance ofsubmissionssubmissions

Postmarketing ADE ReportingPostmarketing ADE Reporting


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(cont.)(cont.) New FD&C Act requirements for adverseNew FD&C Act requirements for adverse

event reporting:event reporting: Unapproved OTC and Dietary SupplementsUnapproved OTC and Dietary Supplements

Manufacturers, packers, and distributors whoseManufacturers, packers, and distributors whose

names appear on drug labelsnames appear on drug labels Contact information on labelContact information on label

All serious events reported within 15 daysAll serious events reported within 15 days

Guidance soon, effective December 23, 2007Guidance soon, effective December 23, 2007

Monitoring for compliance begins inMonitoring for compliance begins in

FY2008.FY2008.



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Postmarketing ADE Reportingg p g

(cont.)(cont.) FDA reviews:FDA reviews:

SubmissionsSubmissions Complete, Accurate, TimelyComplete, Accurate, Timely Postmarketing ADE dataPostmarketing ADE data

Initial and followup individual event reportsInitial and followup individual event reports

Periodic summary reportsPeriodic summary reports

Pharmacovigilance: Surveillance,Pharmacovigilance: Surveillance,Receipt, Evaluation, & ReportingReceipt, Evaluation, & Reporting Written proceduresWritten procedures

Actual performanceActual performance

Internal QC/QA and Corrective ActionsInternal QC/QA and Corrective Actions



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5656

44

4946

49

66

57

26

33

22 2329

45

38

22

3 2

711

5 5

00

10

20

30

40

50

60

70

2001 2002 2003 2004 2005 2006 First Half

2007NAI VAI OAI


ADE FY01ADE FY01-- FY06 inspect ional f indings:FY06 inspect ional f indings:



57/70

5757

30

19

9

5 4 3

30

1816

5 4 5

42

1916

4 3 2

0

5

10

15

20

25

30

35

40

45

Late

Reporting

Written

Procedures

Non-

Reporting

No

Followup

Incomplete

Inaccurate

Other

2004 2005 2006


Cit ed Def iciencies by Category/ Year:Cit ed Def iciencies by Category/ Year:

P t k ti ADE R tiPostmarketing ADE Reporting


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(cont.)(cont.)

Generic Firms should anticipateGeneric Firms should anticipatereceiving increased postmarket ADEreceiving increased postmarket ADEdata and subsequent FDA monitoring.data and subsequent FDA monitoring.

Regulatory Actions vsRegulatory Actions vs


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Regulatory Actions vs.Regulatory Actions vs.

Corrective ActionsCorrective Actions

Regulatory Action: Legal authority toRegulatory Action: Legal authority toact to remove the risk by terminating aact to remove the risk by terminating aperformance which creates a risk, soperformance which creates a risk, sothat the harmful outcome of thethat the harmful outcome of the

process is not produced. This mayprocess is not produced. This maystop, but may not correctstop, but may not correctnoncompliance.noncompliance.

Regulatory Actions vsRegulatory Actions vs


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Regulatory Actions vs.Regulatory Actions vs.

Corrective ActionsCorrective Actions

Corrective Actions: Identification andCorrective Actions: Identification andreduction of risk by modifying thereduction of risk by modifying theperformance that may create a risk, soperformance that may create a risk, sothat the beneficial outcome of thethat the beneficial outcome of the

process can continue to be obtained.process can continue to be obtained. Improve the process to improve theImprove the process to improve the

productproduct


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Quality ImprovementQuality Improvement

Development and Implementation ofDevelopment and Implementation ofCorporate Quality Assurance andCorporate Quality Assurance andCorrective Action can prevent nonCorrective Action can prevent non--compliance.compliance.

Development and Implementation ofDevelopment and Implementation ofQuality Assurance and CorrectiveQuality Assurance and CorrectiveActions can avert subsequentActions can avert subsequentregulatory action.regulatory action.

Regulatory Meetings


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Regulatory MeetingsRegulatory Meetings

A meeting requested by FDA management toA meeting requested by FDA management to

inform responsible individuals or firms aboutinform responsible individuals or firms about

how products, practices, processes, or otherhow products, practices, processes, or other

activities violate the lawactivities violate the law

A tool to obtain prompt voluntary complianceA tool to obtain prompt voluntary compliance

As a followAs a follow--up to a Warning Letter (WL) when firmsup to a Warning Letter (WL) when firms

have not corrected all significant violationshave not corrected all significant violations

To achieve voluntary correction more quickly thanTo achieve voluntary correction more quickly than

through written communication or legal remediesthrough written communication or legal remedies In conjunction with a WL to emphasize theIn conjunction with a WL to emphasize the

significance of violationssignificance of violations


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Marketed UnapprovedMarketed Unapproved

Drugs InitiativeDrugs Initiative

Marketed Unapproved DrugsMarketed Unapproved Drugs


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InitiativeInitiative

Improve the safety and effectiveness ofImprove the safety and effectiveness of

the nationthe nations drugss drugs Encourage companies to comply with theEncourage companies to comply with the

drug approval process, while minimizingdrug approval process, while minimizing

disruption to the marketplacedisruption to the marketplace

Provide notice that any product that isProvide notice that any product that is

being marketed illegally without approvalbeing marketed illegally without approvalis subject to FDA enforcement at any timeis subject to FDA enforcement at any time



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Initiative (cont.)Initiative (cont.) June 2006June 2006Compliance Policy Guide onCompliance Policy Guide on

marketed unapproved drugs explainsmarketed unapproved drugs explainsFDAFDAs risks risk--based enforcementbased enforcement Drugs with potential safety risksDrugs with potential safety risks

Drugs that lack evidence of effectivenessDrugs that lack evidence of effectiveness

Fraudulent drugsFraudulent drugs Unapproved drugs that directly compete with anUnapproved drugs that directly compete with an

approved drugapproved drug

Drugs from firms that otherwise violate the ActDrugs from firms that otherwise violate the Act((e.g.e.g., GMP or ADE reporting violations), GMP or ADE reporting violations)

Drugs with formulation changes made as aDrugs with formulation changes made as apretext to avoid enforcementpretext to avoid enforcement



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Initiative (cont.)Initiative (cont.)ClassClass--Wide Actions:Wide Actions:

HydrocodoneHydrocodone Drug Products (SeptemberDrug Products (September2007)2007)

TimedTimed--ReleaseRelease GuaifenesinGuaifenesin Drug ProductsDrug Products(May 2007)(May 2007)

Suppository Products ContainingSuppository Products ContainingTrimethobenzamideTrimethobenzamide (April 2007)(April 2007)

ErgotamineErgotamine Drug ProductsDrug Products Warning LettersWarning Letters

(March 2007)(March 2007) Quinine SulfateQuinine Sulfate Drug ProductsDrug Products (December(December

2006)2006)

CarbinoxamineCarbinoxamine Drug ProductsDrug Products (June 2006)(June 2006)



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Initiative (cont.)Initiative (cont.)Enforcement ActionsEnforcement Actions -- Specific FirmsSpecific Firms

Syntho/ I ntermaxSyntho/ I ntermax GMP violations and unapproved drugsGMP violations and unapproved drugs

Consent decreeConsent decree

Pharmakon LabsPharmakon Labs

GMP violations and unapproved drugsGMP violations and unapproved drugs

CourtCourt--ordered injunctionordered injunction

PharmaFabPharmaFab

GMP violations and unapproved drugs (longGMP violations and unapproved drugs (longhistory of poor manufacturing practices withhistory of poor manufacturing practices withrepeated failure to institute appropriate correctiverepeated failure to institute appropriate correctiveaction)action)

Consent decreeConsent decree



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Initiative (cont.)Initiative (cont.) EducationEducation

Comprehensive information available on FDAComprehensive information available on FDAss

Unapproved Drugs web siteUnapproved Drugs web sitehttp://www.fda.gov/cder/drug/unapproved_drugs/default.htmhttp://www.fda.gov/cder/drug/unapproved_drugs/default.htm

Marketed Unapproved Drugs WorkshopMarketed Unapproved Drugs Workshop

(January 2007), Docket # 2003D(January 2007), Docket # 2003D--04780478 Educated firms (especially small firms) on how to obtainEducated firms (especially small firms) on how to obtain

approval for their unapproved productsapproval for their unapproved products

Responded to frequently asked questionsResponded to frequently asked questions Participants from more than 150 companiesParticipants from more than 150 companies

We hope that education and incentives will reduce theWe hope that education and incentives will reduce the

need for enforcementneed for enforcement


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SummarySummary Risk-Based

Strategic

Maximizing our impact on the public health


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fda perspective - high prority topics & future directions

Documents