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Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

35th BRAZILIAN CONGRESS OF

35th BRAZILIAN CONGRESS OF

PHARMACEUTICAL MEDICINE

PHARMACEUTICAL MEDICINE

GCP

GCP

inspections

inspections

in Brazil

in

Brazil

:

:

ANVISA

ANVISA´

´

s perspective

s perspective

RICARDO ECCARD DA SILVA Coordination of Researches, Clinical Trials and New Drugs – COPEM General Office of Drugs – GGMED

1

1 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

National

National

Health

Health

Surveillance

Surveillance

Agency

Agency

Anvisa's

Anvisa's

Mandate

Mandate

"To protect and promote the

"To protect and promote the

population`s

population`s

health, ensuring the

health, ensuring the

sanitary safety of products and

sanitary safety of products and

services and taking part in developing

services and taking part in developing

access to it."

access to it."

2

2

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Organization

Organization

Chart

Chart

General Office of Drugs

3

3 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

What

What

we

we

do

do

at

at

COPEM

COPEM

AssessmentAssessmentofofclinicalclinicaltrialtrialprojectsprojects;;

ControlControlofofproductsproductsimportationimportationfor for researchresearch involving

involvinghumanhumanbeingbeing;;

ExpandedExpandedaccessaccessandandcompassionatecompassionateuse;use;

Inspection

Inspection

of

of

clinical

clinical

research

research

sites.

sites.

4

4

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

LAW 6360/76

LAW 6360/76 --SANITARY SURVEILLANCESANITARY SURVEILLANCE

REGULATION FOR BIOMEDICAL

REGULATION FOR BIOMEDICAL

RESEARCH IN HUMAN SUBJECTS

RESEARCH IN HUMAN SUBJECTS

RDC 39/08 Clinical Trial CNS 196/1996 Biomedical Research in Human CNS 292/99 International Cooperation CNS 301/00 Placebo RDC 26/99 Expanded access RDC 305/02 BSE RDC 68/03 BSE R CNS 346/05 CEP-CONEP CNS 251/1997 New Medicines CNS 340/04 Human Genetics RDC 81/08 Importation IN. 04/2009 5 5 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS

RDC 39/2008 RDC 39/2008

Approves the RULES FOR THE CONDUCT OF Approves the RULES FOR THE CONDUCT OF

CLINICAL RESEARCH among other provisions.

CLINICAL RESEARCH among other provisions. 

Article 5: This rule applies to all clinical research Article 5: This rule applies to all clinical research

with drugs and medical devices (research

with drugs and medical devices (research

involving therapeutic interventions or diagnostic

involving therapeutic interventions or diagnostic

not registered in Brazil) phases I, II and III and it

not registered in Brazil) phases I, II and III and it

may support, in ANVISA, the record or any

may support, in ANVISA, the record or any

change post

change post--marketing, considering the current marketing, considering the current

sanitary standards and for which it requires the

sanitary standards and for which it requires the

assessment of ANVISA and subsequent

assessment of ANVISA and subsequent

issuance of CE (Approval Document).

issuance of CE (Approval Document).

6

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Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS

RDC 39/2008 RDC 39/2008

ArticleArticle66°°. : . :

This rule does not apply to

This rule does not apply to

studies of Bioavailability and

studies of Bioavailability and

Bioequivalence.

Bioequivalence.

7

7 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS

RDC 39/2008 RDC 39/2008

Article Article88ºº§§22°°

The ANVISA may, during the conduction of

The ANVISA may, during the conduction of

a clinical research, request more

a clinical research, request more

information to those responsible for its

information to those responsible for its

implementation or monitoring, and conduct

implementation or monitoring, and conduct

inspections at the sites, checking the

inspections at the sites, checking the

degree of adherence to current Brazilian

degree of adherence to current Brazilian

legislation and the Good Clinical Practices

legislation and the Good Clinical Practices

(Document of Americas

(Document of Americas

-

-

Good Clinical

Good Clinical

Practices).

Practices).

8

8

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

REGULATORY FRAMEWORK FOR CLINICAL TRIALS REGULATORY FRAMEWORK FOR CLINICAL TRIALS

RDC 39/2008 RDC 39/2008

Article 14

Article 14

°

°

Penalties: Failure to comply

Penalties: Failure to comply

with the provisions of this resolution leads

with the provisions of this resolution leads

to sanitary violation, the violator shall be

to sanitary violation, the violator shall be

subject to penalties stipulated in Law

subject to penalties stipulated in Law

6.437/77.

6.437/77.

9

9 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br Normative

NormativeStatementStatementNNºº4, 4, MayMay1111th, 2009, 2009

GUIDELINE FOR INSPECTION IN GOOD

GUIDELINE FOR INSPECTION IN GOOD

CLINICAL PRACTICES

CLINICAL PRACTICES

To harmonize

To harmonize andandguideguidethetheproceduresproceduresfor for inspectioninspection

of

ofgoodgoodclinicalclinicalpracticespractices, in , in orderorderto to promotepromote

regulatory

regulatoryactionactionononsanitarysanitarysurveillancesurveillance, to , to ensureensure

a

a unifiedunifiedstandard standard andandsecuritysecurityofofallallpartiesparties involved

involved..

10

10

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br Normative

NormativeStatementStatementNNºº4, 4, MayMay1111th, 2009, 2009

Stages

Stages

of

of

the

the

inspection

inspection

:

:

Communication Communication fromfromthetheinspectioninspectionto to thethe

sponsor

sponsor/ CRO / CRO andandPI PI

OpeningOpeninginterview interview

Interview Interview withwiththethestudystudyteamteamStudy Records Review

Other records and site facilitiesConcluding the inspection

11

11 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Normative

Normative

Statement

Statement

N

N

º

º

4,

4,

May

May

11

11

th

, 2009

, 2009

In In routineroutineinspectioninspectionits its notificationnotificationwillwillbebesentsent 15

15 daysdaysin in advanceadvance. . 

In In thethecase case ofofcomplaintcomplaintororsuspectedsuspected

irregularities

irregularitiesthetheinspectioninspectionwillwilloccuroccurwithoutwithout

notice

notice..

TheTheinspectionsinspectionswillwillbebedirecteddirectedto to researchresearchandand clinical

clinicaltrialstrials, , therethereis no site is no site certificationcertification..

12

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Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Normative

Normative

Statement

Statement

N

N

º

º

4,

4,

May

May

11

11

th

, 2009

, 2009

Inspection

Inspection

in

in

up

up

to

to

five

five

workdays

workdays

;

;

Inspection

Inspection

Report

Report

;

;

Sponsor

Sponsor

must

must

provide

provide

relevant

relevant

documention

documention

requested

requested

by

by

Anvisa

Anvisa

up

up

to 30

to 30

days

days

;

;

Final

Final

Report

Report

of

of

the

the

inspection

inspection

( ANVISA ).

( ANVISA ).

13

13 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br Normative

NormativeStatementStatementNNºº4, 4, MayMay1111th, 2009, 2009

Anvisa'sAnvisa'senforcement in cases of inappropriate enforcement in cases of inappropriate

conduct of Clinical Trials

conduct of Clinical Trials:: 

temporarytemporaryinterruptioninterruptionofofthetheClinicalClinicalTrial;Trial;

suspensionsuspensionofofInvestigator'sInvestigator'sactivitiesactivities; ;

thethedefinitivedefinitivecancellationcancellationofofclinicalclinicalresearchresearchatat

the

thesite site andand/ / oror 

thethedefinitivedefinitivecancellationcancellationofofclinicalclinicalresearchresearchin in all

allsites in sites in BrazilBrazil. .

14

14

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Studies

Studies

/Sites

/Sites

Selection

Selection

Studies

Studies

/Sites

/Sites

haven

haven

´

´

t

t

inspected

inspected

by

by

others

others

agencies.

agencies.

Number

Number

of

of

subjects

subjects

included

included

.

.

number

number

of

of

serious

serious

adverse

adverse

events

events

notified

notified

.

.

complexity

complexity

of

of

the

the

study

study

.

.

Requests

Requests

of

of

others

others

Anvisa

Anvisa

´

´

s

s

area

area

, CEP

, CEP

or

or

CONEP.

CONEP.

other

other

criteria

criteria

.

.

15

15 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

INSPECTION GUIDELINE

INSPECTION GUIDELINE

A.

A.

Facilities

Facilities

A.1 A.1 ––ReceptionReception

A.2 A.2 --OfficesOffices

A.3 A.3 ––WardWardroomroom

A.4 A.4 ––PharmacyPharmacy

A.5 A.5 ––TechnicalTechnicalFacilitiesFacilities

A.6 A.6 --WasteWasteManagementManagement

A.7 A.7 --ArchiveArchive 

B.

B.

Quality

Quality

assurance

assurance

System

System

16

16

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

INSPECTION GUIDELINE

INSPECTION GUIDELINE

DOCUMENTS

DOCUMENTS

C.1

C.1. . Before the Clinical Phase of the Trial

Commences

C.1.1 General C.1.1 General DocumentsDocuments

 InformedInformedConsentConsentFormFormsignedsigned;; 

 Case Case ReportReportFormForm(CRF)(CRF) 

 EthicalEthicalandandregulatoryregulatoryapprovalsapprovals;; 

 ListListofofsignatures signatures andandrespectiverespectiveteamteamidentificationidentification

C.1.2 Standard C.1.2 Standard OperatingOperatingProceduresProcedures(SOP) (SOP)

C.1.3 C.1.3 TechnicalTechnicalFacilitiesFacilities

C.1.4 C.1.4 InvestigationalInvestigationalProductProduct(IP)(IP)

17

17 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

INSPECTION GUIDELINE

INSPECTION GUIDELINE

DOCUMENTS

DOCUMENTS

C.2.

C.2.

During the Clinical Conduct of the Trial

C.2.1 General

C.2.1 General DocumentsDocuments+ C.1+ C.1

 Source Source documentsdocuments;; 

 Case Case ReportReportFormForm(CRF)(CRF) 

 RecruitmentRecruitmentRowRowofofsubjectssubjects; ;

 SubjectsSubjectsRowRowincludedincluded

 AmendmentsAmendments 

 ProtocolProtocolViolationsViolations

18

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Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

INSPECTION GUIDELINE

INSPECTION GUIDELINE

DOCUMENTS

DOCUMENTS

C.3.

C.3. After completion or Termination of

the Trial

C.1 + C.2 C.1 + C.2

C.3.1 General C.3.1 General DocumentsDocuments

StudyStudyFinal Final ReportReport;;

InvestigationalInvestigationalProductProductfinal final destinationdestination;;

MonitoringMonitoringReportReport;; 

ProductsProductsaccountabilityaccountability..

19

19 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Classification of inspection

findings

Critical

Critical

"C":

"C":

(critical): Observations classified as

critical may affect the rights, safety or well

being of the subjects, lead to death, life

threatening and/or the quality and integrity

of data (including studies started without

authorization, fraud...)

20

20

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Examples

Examples

Is

Is

There

There

regulatory

regulatory

approval

approval

for

for

the

the

study

study

?

?

Was

Was

there

there

a

a

team

team

training

training

on

on

the

the

protocol

protocol

of

of

the

the

study

study

?

?

Were

Were

changes

changes

/

/

corrections

corrections

in

in

the

the

CRF

CRF

performed

performed

according

according

to

to

Good

Good

Clinical

Clinical

Practice

Practice

? (

? (

dated

dated

,

,

initialed

initialed

and

and

without

without

masking

masking

the

the

original

original

records

records

)?

)?

21

21 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Classification of inspection

findings

Major "M"

Major "M"

Observations

Observations

that

that

may

may

affect

affect

sujects

sujects

health

health

or quality and integrity of data.

or

22

22

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Examples

Examples

Is there evidence that the sponsor monitors the study?

Was the monitoring plan followed? Were adverse events and serious adverse events reported in accordance with regulatory requirements?

Was the monitoring visit dated and recorded?

23

23 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Classification of inspection

findings

Minor

Minor

"Me":

"Me":

Observations

Observations

that

that

aren

aren

´

´

t

t

critical

critical

or

or

major,

major,

but

but

show

show

violations

violations

and

and

/

/

or

or

deficiencies

deficiencies

.

.

24

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Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Examples

Examples

Are the cleanliness and comfort of the area adequate to attend the research subjects?

Is access to reception appropriate for the type of study population (infants, wheelchair)?

Is there a receptionist trained to have the first contact with potential research subjects?

25

25 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Classification of inspection

findings

Informative

Informative

"INF":

"INF":

Descriptive

Descriptive

Observations

Observations

and

and

/

/

or

or

additional

additional

.

.

26

26

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Examples

Examples

Is

Is

the

the

receptionist

receptionist

who

who

feeds

feeds

the

the

database

database

with

with

basic

basic

information

information

about

about

the

the

research

research

subject

subject

?

?

Is

Is

the

the

technical

technical

facilities

facilities

located

located

in

in

the

the

research

research

site?

site?

27

27 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

ThreeThreeinspectionsinspectionshavehavedonedoneuntiluntiloctoberoctober..

CONEP CONEP membermembertogethertogetherwithwithAnvisaAnvisa..

FollowFollow--upupFDA/EMEA FDA/EMEA inspectionsinspections..

TECHNICAL COOPERATION WITH CECMED TECHNICAL COOPERATION WITH CECMED

(CUBA) ON THE GCP INSPECTION

(CUBA) ON THE GCP INSPECTION

PROGRAM.

PROGRAM.

28

28

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

SOME FINDINGSSOME FINDINGS

 TheTheofficesofficesroomsroomsdondon´´t t alowalowthetheprivacyprivacyofofthethesujectssujects

to

to getgetthetheinformedinformedconsentconsent..

 TheTheresearchresearchsujectssujectsdidndidn´´t t receivereceivea a copycopyofofthethe

informed informedconsentconsent..

 TheThedocumentsdocumentsofofcertificationcertification, , calibrationcalibration, , validationvalidation

and

andqualityquality, , guideguideandandSOPSOP’’ssequipmentsequipments//instrumentsinstruments weren

weren´´t t availableavailable..

29

29 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

SOME FINDINGSSOME FINDINGS

 TheTheinvestigationalinvestigationalproductproductwerenweren´´t t storedstoredatatthethe

pharmacy

pharmacy..

 ArchiveArchiveroomroomwithoutwithoutmanagement, management, organizationorganization, ,

control

controlandandsafetysafetyofofdocumentsdocuments..

 LackLackofofmonitoringmonitoringplanplan..

30

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Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

SOME FINDINGSSOME FINDINGS

 Some time Some time membersmemberswerenweren´´t t trainedtrainedfor for thethe

protocol

protocol.. 

 LackLackofofSOPSOP’’ssandandits training its training rowsrows..

 LackLackofofqualityqualitymanagement system.management system.

 LackLackofofinteractioninteractionwithinwithinthetheteamteam..

31

31 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS

 ImplementationImplementationofofqualityqualitymanagement system management system withwith

flowcharts, SOP,

flowcharts, SOP, indicatorsindicators, , qualityqualitymanualsmanuals. . TheTheactivitiesactivities and

andresponsabilitiesresponsabilitiesofofthethequalityqualitymanagement management teamteam members

membersmustmustbebewellwelldefineddefined. .

“The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s)” ((Document of Americas Document of Americas --Good Good Clinical Practices)

Clinical Practices)

32

32

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

MAIN RECOMMENDATIONS

MAIN RECOMMENDATIONS

““The investigational product(s) should be stored

as specified by the sponsor and in accordance with applicable regulatory requirement(s)..””

(

(Document of Americas Document of Americas --Good Clinical Practices)Good Clinical Practices)

““The investigator should ensure that the investigational product(s) are used only in accordance with the approved protocol..””((Document of Americas Document of Americas --Good Clinical Good Clinical Practices)

Practices)

33

33 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS

““When allowed/required, the investigator/institution may/should assign some or all of the

investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an appropriate pharmacist or another appropriate individual who is under the

supervision of the investigator/institution”” ((Document of Document of Americas

Americas --Good Clinical Practices)Good Clinical Practices)

 TheThedocumentsdocumentsofofcertificationcertification, , periodicperiodiccalibrationcalibration, ,

validation

validationandandqualityquality, , guideguideandandSOPSOP’’ss equipments

equipments//instrumentsinstrumentsmustmustbebeavailableavailable..

34

34

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS

“Before participating in the study, the subject or his legally authorized representative should receive a copy of the signed and dated informed consent form and any other written information furnished during the process.”

(

(Document of Americas Document of Americas --Good Clinical Practices)Good Clinical Practices)

“Recording, handling, and storage of all clinical trial information should be appropriate to allow accurate trial reporting, interpretation and verification” ((Document of Document of Americas

Americas --Good Clinical Practices)Good Clinical Practices)

35

35 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

MAIN RECOMMENDATIONS MAIN RECOMMENDATIONS

“A written monitoring plan should be available”

(Document of Americas Document of Americas --Good Clinical Good Clinical

Practices)

Practices)

“Ensuring that the investigator and the

investigator's trial staff are adequately informed about the trial”(Document of Americas Document of Americas -

-Good Clinical Practices)

Good Clinical Practices)

36

(7)

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

MAIN RECOMMENDATIONSMAIN RECOMMENDATIONS

“Make provision for the maintenance of confidentiality, not only by Inspectors but also by any other person who gain access to confidential information as a result of GCP Compliance Monitoring activities”(Document of Americas Document of Americas

--Good Clinical Practices)Good Clinical Practices)

“The investigator can only delegate duties/activities but not responsibilities; and occasionally, when initiate or conduct the study with no other sponsor, the investigator can also be responsible as sponsor” (Document of Americas -Document of Americas -Good Clinical Practices)

Good Clinical Practices)

37

37 Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Inspections

Inspections

in 2009

in 2009

MAIN RECOMMENDATIONS MAIN RECOMMENDATIONS

“The investigator should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions”(Document of Americas Document of Americas --Good Clinical Good Clinical Practices)

Practices)

“Training of the study participants should be documented including: the name of the staff persons trained, procedures and dates”(Document of Americas -Document of Americas -Good Good Clinical Practices)

Clinical Practices)

38

38

Agência Nacional

de Vigilância Sanitária www.anvisa.gov.br

Central de atendimento

Central de atendimento

ANVISA

ANVISA

0800 642 9782

0800 642 9782

www.anvisa.gov.br

www.anvisa.gov.br

Thank you for your attention!

39

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