Investigator Inspections in Latin America with focus in Argentina and Brazil

1. www.blanchardyasociados.com.ar
September 2011

2. Country # open # open # open Trend
studies1 studies 2 studies
3
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

3. Country # open # open # open Trend
studies 1 studies 2 studies 3
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

4. 0
100
200
300
400
500
700
800
600
01-ago-10
01-sep-10
01-oct-10
01-nov-10
01-dic-10
01-ene-11
01-feb-11
01-mar-11
01-abr-11
01-may-11
01-jun-11
Peru
Chile
Brazil
Mexico
Colombia
Argentina

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

6. 1997-2008 =8323 inspections analyzed in total
within and outside of USA.

7. 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

9. 40
35
30
25
20 OAI
15
VAI
10
5 NAI
0

10. Mate

11. 20
4
15
OAI
8
10 VAI
14 NAI
5
7
2 1
1
1
0
1995-1998 1999-2002 2003-2006 2007-2010
http://www.accessdata.fda.gov/scripts/cder/cliil/

12. 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 02/39 5,12%
reactions
02- Failure to obtain and/or document 01/39 2,56%
subject consent
http://www.accessdata.fda.gov/scripts/cder/cliil/

13. 14
12
10 Failure in reporting Adverse Drug
Reactions
8 Failure to Obtain and Document
Informed Consent
6
Inadequate Drug Accountability
4
Inadequate Informed Consent
2
0 Inadequate and Inprecise records
Failure in following Investigational
Plan

14. 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.
Other requirements also follow previous 690/2006 Provision by ANMAT

15. Inspection Communication (D7)
 Inspections will be previously informed to Sponsor and/or
Principal Investigator with at least 15 calendar days previous to
the designated date, in order to guarantee availability of
research staff at the time of inspection.
 If the inspection is prompted by safety reports, periodic
progress reports or a report due to inappropriate conduct by
Investigator, previous announcement of inspector visit may not
apply.
Other requirements also follow previous 690/2006 Provision by ANMAT

16. Initial Interview (D 8.2)
 Inspections will show official identification, explain scope and
audit procedures.
 During the Initial Interview Investigator study Staff and sponsor
representatives are allowed to be present.
 Inspectors will request information who, what, when, where and
how about the delegation of functions to Investigator staff
related to several items including potential study participant
evaluation and selecting and randomizing study participants.
 Inspectors may conduct interviews during the initiation to
Investigator study staff and if relevant to study participants.
Other requirements also follow previous 690/2006 Provision by ANMAT

17. Inspection Progress (D 8.3)
 Inspectors may interview study participants and such interviews will be
documented in separate records from those of the Inspection
procedure. 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 process
To 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 to
interrupt study continuity.
Other requirements also follow previous 690/2006 Provision by ANMAT

18. Documentation Review (D 9)
 Inspectors will review essential documents of investigator as per section C
of 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 consent
has been obtained in the presence of an independent witness who has also signed and
such process is documented in detail.
Other requirements also follow previous 690/2006 Provision by ANMAT

19. Documentation Review Continued (D 9)
 If Inspectors identify major deviation in any study procedure,
such study procedure will be reviewed in a bigger sample of
subjects than the one originally planned.
 Inspectors will verify gratuity of products and study
procedures and any protocol related payments to subjects by
proof of purchase or documented receipt or invoicing to
Investigator or sponsor in the case of study related tests or
exams.
Other requirements also follow previous 690/2006 Provision by ANMAT

20. Inspection on Site Records (D 10)
 If Inspectors will write an inspection on site report detailing the
type of revision and scope of review done during the
inspection, as well as observations, findings and problems
identified.
 If observations or issues remain to be answered or clarified, the
inspected party will have 10 working days to provide such
answers and clarifications.
 Inspection on site records will be signed in three original parts
by investigator/sub-investigator, Inspectors and sponsor
representative; such originals will be distributed one for each
party accordingly.
Other requirements also follow previous 690/2006 Provision by ANMAT

21. 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.
Other requirements also follow previous 690/2006 Provision by ANMAT

22. Agua du coco

23. 20
15 4
OAI
10 VAI
NAI
5 4 12
2 4 3
0
1995-1998 1999-2002 2003-2006 2007-2010
http://www.accessdata.fda.gov/scripts/cder/cliil/

24. 12
10
8
Failure to report to IRB
6
Inadequate Drug Accountability
4
Inadequate and Inprecise records
2
Failure in following Investigational
0 Plan

25. Deficiency Code Inspections % of total
05- Failure to follow investigational plan 9/28 32,14%
06-Inadequate and inaccurate records 05/28 17,85%
16-Failure to report adverse drug 03/28 10,71%
reactions
04- Inadequate drug accountability 01/28 3,57%
15- Failure to notify IRB of changes, 01/28 3,57%
failure to submit progress reports
http://www.accessdata.fda.gov/scripts/cder/cliil/

26.  ANVISA may also, during the conduct of a clinical
investigation:
◦ request more information to those responsible for its execution
or monitoring, or
◦ conduct inspections to sites to verify the level of compliance to
Brazilian legislation and Good Clinical Practices (Americas
Document on Good Clinical Practices)
Agência Nacional de Vigilância Sanitária
www.anvisa.gov.br
RDC 39/08, Artigo 8º § 2°

27.  Rutine Inspections -> notification in the
previous 15 days
 For Cause Inspections -> no previous notification
 Notification via fax or e-mail to Sponsor/CRO and
investigator.
INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09

28. •With presence •With presence
of PI + of PI + Sponsor
Sponsor/CRO
Inspection Inspection
Close Opening
Interview with
study staff + Inspection
Visit to the Opening
facilities
Max. 5 working days
INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09

29.  After the inspection the Inspection preliminary report will be
sent to Sponsor/CRO and PI with finding classifications:
◦ Critical
◦ Major
◦ Minor
◦ Information
 Sponsor/CRO will have 30 days to answer and an extension
request 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 is
being conducted according to Good Clinical Practices.
INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09

30. 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
INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09

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

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

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

34.  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

35. Pisco Sour

36. 7
6
5 4
OAI
4
VAI
3
NAI
2 3
1 1
1
0
1995-1998 1999-2002 2003-2006 2007-2010
http://www.accessdata.fda.gov/scripts/cder/cliil/

37. Deficiency Code Inspections % of total
05- Failure to follow investigational plan 04/09 44,44%
06-Inadequate and inaccurate records 03/09 33,33%
04- Inadequate drug accountability 01/09 11,11%
15- Failure to notify IRB of changes, 01/09 11,11%
failure to submit progress reports
http://www.accessdata.fda.gov/scripts/cder/cliil/