sepember 2011 fda and regulatory inspections argentina & brazil

September 2011

www.blanchardyasociados.com.ar

http://www.blanchardyasociados.com.ar/

Country # open studies1

# open studies 2

# open studies 3

Trend

Brazil 581 637 737

Mexico 323 338 370

Argentina 253 271 281

Chile 163 157 173

Peru 158 150 144

Colombia 134 147 155

Info captured as open studies in clinicaltrials.gov on (1) 16 August 2010 and (2) 07 February 2011 and (3) 03 August 2011

Country # open studies 1

# open studies 2

# open studies 3

Trend

Venezuela 33 28 19

Panama 28 28 30

Costa Rica 28 17 14

Ecuador 16 16 13

Uruguay 7 9 8

Bolivia 5 5 7

Paraguay 3 4 4

Info captured as open studies in clinicaltrials.gov on (1) 16 August 2010 and (2) 07 February 2011 and (3) 03 August 2011

0

100

200

300

400

500

600

700

8000

1-ago-1

0

01

-sep-1

0

01

-oct-

10

01

-nov-1

0

01

-dic

-1

0

01

-ene-1

1

01

-fe

b-1

1

01

-m

ar-

11

01

-abr-

11

01

-m

ay-1

1

01-ju

n-1

1

Brazil

Mexico

Argentina

Chile

Peru

Colombia

Anywhere in the world as long as research data is submitted to FDA.

1997-2008 =8323 inspections analyzed in total within and outside of USA.

Canada 170 Australia 10

Rusia 78 Chile 9

Argentina 39 Peru 8

Brazil 28 Tailandia 7

Mexico 25 Guatemala 3

India 22 Colombia 3

Ukrania 14 Paraguay 1

0

5

10

15

20

25

30

35

40

OAI

VAI

NAI

0

5

10

15

20

1995-1998 1999-2002 2003-2006 2007-2010

1

7

14

21

8

4

1

OAI

VAI

NAI

http://www.accessdata.fda.gov/scripts/cder/cliil/


Deficiency Code Inspections % of total

05- Failure to follow investigational plan 11/39 28.20%

06-Inadequate and inaccurate records 06/39 15,4%

03- Inadequate informed consent form 05/39 12,82%

04- Inadequate drug accountability 04/39 10,25%

16-Failure to report adverse drug reactions

02/39 5,12%

02- Failure to obtain and/or document subject consent

01/39 2,56%



0

2

4

6

8

10

12

14

Failure in reporting Adverse Drug Reactions

Failure to Obtain and Document Informed Consent

Inadequate Drug Accountability

Inadequate Informed Consent

Inadequate and Inprecise records

Failure in following Investigational Plan

Other requirements also follow previous 690/2006 Provision by ANMAT

Selection of Study and Investigator (D4)

Studies that include vulnerable population.

Studies of Phase I-II Clinical Research.

Studies on investigational products of associated high risk.

Investigators that show a high recruitment rate in relation to other investigators in the same study.

High or low SUSAR events in relation to other Investigators in the same study

Investigator is participating in a significant number of studies

Any relevant information received in safety reports or periodic reports that justifies an Investigator Inspection according to ANMAT criteria.

Reports received by ANMAT related to inappropriate conduct by Investigator.

Inspection Communication (D7)

Inspections will be previously informed to Sponsor and/orPrincipal Investigator with at least 15 calendar days previous tothe designated date, in order to guarantee availability ofresearch staff at the time of inspection.

If the inspection is prompted by safety reports, periodicprogress reports or a report due to inappropriate conduct byInvestigator, previous announcement of inspector visit may notapply.


Initial Interview (D 8.2)

Inspections will show official identification, explain scope andaudit procedures.

During the Initial Interview Investigator study Staff and sponsorrepresentatives are allowed to be present.

Inspectors will request information who, what, when, where andhow about the delegation of functions to Investigator staffrelated to several items including potential study participantevaluation and selecting and randomizing study participants.

Inspectors may conduct interviews during the initiation toInvestigator study staff and if relevant to study participants.


Inspection Progress (D 8.3)

Inspectors may interview study participants and such interviews will bedocumented in separate records from those of the Inspectionprocedure. Such records will contain:◦ Participant ID◦ Interview objective or purpose◦ Questions that are expected to be answered◦ Answers received from study participants in the interview processTo be filed with ANMAT and will only be accessed by Investigator if the

request is justified and ANMAT expressly authorizes to do so. If during the Inspection serious deviations to the regulation or serious

risk to study participants are identified, inspectors may decide tointerrupt study continuity.


Documentation Review (D 9)

Inspectors will review essential documents of investigator as per section Cof this regulation.

Review of Informed consent documentation will include◦ If informed consent has been obtained from a legal representative of the study

participant, such power of representation will be documented with the clinical records.◦ The informed consent process is documented in the clinical records of the participant

including: date and time of process initiation, clarification whether ample time was given to potential subject to reflect and ask questions, which where the questions the potential subject asked, that understanding of the information given was verified and that two originals were signed and one given to the study participant.

◦ In the case of cultural, educational or economically vulnerable subject, informed consenthas been obtained in the presence of an independent witness who has also signed andsuch process is documented in detail.


Documentation Review Continued (D 9)

If Inspectors identify major deviation in any study procedure,such study procedure will be reviewed in a bigger sample ofsubjects than the one originally planned.

Inspectors will verify gratuity of products and studyprocedures and any protocol related payments to subjects byproof of purchase or documented receipt or invoicing toInvestigator or sponsor in the case of study related tests orexams.


Inspection on Site Records (D 10)

If Inspectors will write an inspection on site report detailing thetype of revision and scope of review done during theinspection, as well as observations, findings and problemsidentified.

If observations or issues remain to be answered or clarified, theinspected party will have 10 working days to provide suchanswers and clarifications.

Inspection on site records will be signed in three original partsby investigator/sub-investigator, Inspectors and sponsorrepresentative; such originals will be distributed one for eachparty accordingly.


Result Inspection Result (D10)

NAI No Action Indicated

No objections identified.

IAV Voluntary Action Indicated

Corrective actions on behalf of Investigator and/or sponsor are required, but no action if further needed on behalf of ANMAT

OAI Official Action Indicated

Further action is needed on behalf of ANMAT

Preventive actions may include: temporary suspension of recruitment, temporary suspension of study at inspected site,

restriction to investigator from conducting new studies.

Definite measures may include: definite suspension of recruitment of subjects, definite suspension of inspected study ,

definite suspension of all studies at inspected site, suspension of inspected study at all sites involved in the country, request

to sponsor to intensify study monitoring, request to sponsor to change investigator at site, request to sponsor to discard

study data generated at the site, notification to medical school where Investigator is affiliated, administrative or legal action

towards investigator and / or CRO and/ or sponsor.


Agua du coco

0

5

10

15

20

1995-1998 1999-2002 2003-2006 2007-2010

3

12

2 4

4

4

OAI

VAI

NAI



0

2

4

6

8

10

12

Failure to report to IRB

Inadequate Drug Accountability

Inadequate and Inprecise records

Failure in following Investigational Plan


05- Failure to follow investigational plan 9/28 32,14%


16-Failure to report adverse drug reactions

03/28 10,71%


15- Failure to notify IRB of changes, failure to submit progress reports

01/28 3,57%



ANVISA may also, during the conduct of a clinicalinvestigation:

◦ request more information to those responsible for its executionor monitoring, or

◦ conduct inspections to sites to verify the level of compliance toBrazilian legislation and Good Clinical Practices (AmericasDocument on Good Clinical Practices)

Agência Nacional de Vigilância Sanitáriawww.anvisa.gov.br

RDC 39/08, Artigo 8º § 2°

Rutine Inspections -> notification in theprevious 15 days

For Cause Inspections -> no previous notification

Notification via fax or e-mail to Sponsor/CRO andinvestigator.

INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09

•With presence

of PI + Sponsor

•With presence

of PI +

Sponsor/CRO

Inspection

Close

Inspection

Opening

Inspection

Opening

Interview with

study staff +

Visit to the

facilities

Max. 5 working days


After the inspection the Inspection preliminary report will besent to Sponsor/CRO and PI with finding classifications:◦ Critical◦ Major◦ Minor◦ Information

Sponsor/CRO will have 30 days to answer and an extensionrequest of 30 more days may be requested.

After considering Sponsor´s answers or past the due date,ANVISA will send a final report stating whether or not study isbeing conducted according to Good Clinical Practices.


Observations

Critical Observations directly related to the subjects safety that may result in death, risk of death or unsafe conditions. In relation to study data the van compromise the validity (unauthorized studies, lack of data, falsification, forgery, etc. )

Major Observations that may put in risk the research subjects health or affect validity of data.

Minor Observations not considered critical or major but that can reflect a deficiency or deviation. They must be addressed for the implementation of improvements in the conduct of clinical studies.

Informative Descriptive or complementary observations


Examples from INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09

Training and Changes in Study Team Recruitment and selection of research subjects Procedure for obtaining Informed Consent CRF Completion and correction of entered data CRF and Source Data Verification Utilization and calibration of equipments and Instruments Administration, preparation and Transportation of IP Receiving controlling and accounting of IP Destruction and Return of Investigational Product (IP) Power Failure contingency and IP Storage Collection, transportation, preparation, Identification and analysis of lab

samples Biologic and Non Biologic Materials Unblinding of codes AE and SAE notification Organization and Maintenance of Files

Pisco Sour

0

1

2

3

4

5

6

7

1995-1998 1999-2002 2003-2006 2007-2010

1

3

1

4

OAI

VAI

NAI




05- Failure to follow investigational plan 04/09 44,44%



15- Failure to notify IRB of changes, failure to submit progress reports

01/09 11,11%



sepember 2011 fda and regulatory inspections argentina & brazil

Documents