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www.blanchardyasociados.com.ar                                 September 2011
Country           # open          # open    # open Trend                                              studies1        stud...
Country                  # open               # open              # open             Trend                                ...
0                 100                 200                 300                 400                 500                 700 ...
   Anywhere in the world as long as research    data is submitted to FDA.
1997-2008 =8323 inspections analyzed in totalwithin and outside of USA.
Canada      170   Australia   10Rusia       78    Chile       9Argentina   39    Peru        8Brazil      28    Tailandia ...
4035302520   OAI15     VAI10 5   NAI 0
Mate
20                                              415                                                                   OAI ...
Deficiency Code                              Inspections       % of total05- Failure to follow investigational plan   11/3...
141210   Failure in reporting Adverse Drug     Reactions8    Failure to Obtain and Document     Informed Consent6     Inad...
Selection of Study and Investigator (D4)Studies that include vulnerable population.Studies of Phase I-II Clinical Research...
Inspection Communication (D7)   Inspections will be previously informed to Sponsor and/or    Principal Investigator with ...
Initial Interview (D 8.2)   Inspections will show official identification, explain scope and    audit procedures.   Duri...
Inspection Progress (D 8.3)   Inspectors may interview study participants and such interviews will be    documented in se...
Documentation Review (D 9)   Inspectors will review essential documents of investigator as per section C    of this regul...
Documentation Review Continued (D 9)   If Inspectors identify major deviation in any study procedure,    such study proce...
Inspection on Site Records (D 10)   If Inspectors will write an inspection on site report detailing the    type of revisi...
Result              Inspection Result (D10)NAI                 No Action IndicatedNo objections identified.IAV            ...
Agua du coco
2015                                            4                                                                   OAI10 ...
12108     Failure to report to IRB6     Inadequate Drug Accountability4     Inadequate and Inprecise records2     Failure ...
Deficiency Code                              Inspections       % of total05- Failure to follow investigational plan   9/28...
   ANVISA may also, during the conduct of a clinical    investigation:    ◦ request more information to those responsible...
   Rutine Inspections -> notification in the                          previous 15 days   For Cause Inspections -> no pre...
•With presence                                 •With presence of PI +                                        of PI + Spons...
   After the inspection the Inspection preliminary report will be    sent to Sponsor/CRO and PI with finding classificati...
ObservationsCritical       Observations directly related to the subjects safety that may               result in death, ri...
Examples from INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09
Examples from INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09
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 Inform...
Pisco Sour
765                                4                                                                  OAI4                ...
Deficiency Code                              Inspections       % of total05- Failure to follow investigational plan   04/0...
Sepember 2011 FDA and Regulatory Inspections  Argentina & Brazil
Sepember 2011 FDA and Regulatory Inspections  Argentina & Brazil
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Sepember 2011 FDA and Regulatory Inspections Argentina & Brazil

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Investigator Inspections in Latin America with focus in Argentina and Brazil

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Sepember 2011 FDA and Regulatory Inspections Argentina & Brazil

  1. 1. www.blanchardyasociados.com.ar September 2011
  2. 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 155Info captured as open studies in clinicaltrials.gov on (1) 16 August 2010 and (2) 07 February 2011 and (3) 03 August 2011
  3. 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 4Info captured as open studies in clinicaltrials.gov on (1) 16 August 2010 and (2) 07 February 2011 and (3) 03 August 2011
  4. 4. 0 100 200 300 400 500 700 800 60001-ago-1001-sep-1001-oct-1001-nov-1001-dic-1001-ene-1101-feb-1101-mar-1101-abr-1101-may-1101-jun-11 Peru Chile Brazil Mexico Colombia Argentina
  5. 5.  Anywhere in the world as long as research data is submitted to FDA.
  6. 6. 1997-2008 =8323 inspections analyzed in totalwithin and outside of USA.
  7. 7. Canada 170 Australia 10Rusia 78 Chile 9Argentina 39 Peru 8Brazil 28 Tailandia 7Mexico 25 Guatemala 3India 22 Colombia 3Ukrania 14 Paraguay 1
  8. 8. 4035302520 OAI15 VAI10 5 NAI 0
  9. 9. Mate
  10. 10. 20 415 OAI 810 VAI 14 NAI5 7 2 1 1 10 1995-1998 1999-2002 2003-2006 2007-2010 http://www.accessdata.fda.gov/scripts/cder/cliil/
  11. 11. Deficiency Code Inspections % of total05- 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%reactions02- Failure to obtain and/or document 01/39 2,56%subject consent http://www.accessdata.fda.gov/scripts/cder/cliil/
  12. 12. 141210 Failure in reporting Adverse Drug Reactions8 Failure to Obtain and Document Informed Consent6 Inadequate Drug Accountability4 Inadequate Informed Consent20 Inadequate and Inprecise records Failure in following Investigational Plan
  13. 13. 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 investigatorsin the same study.High or low SUSAR events in relation to other Investigators in the same studyInvestigator is participating in a significant number of studiesAny relevant information received in safety reports or periodic reports thatjustifies 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. Result Inspection Result (D10)NAI No Action IndicatedNo objections identified.IAV Voluntary Action IndicatedCorrective actions on behalf of Investigator and/or sponsor are required, but no action if further needed on behalf of ANMATOAI Official Action IndicatedFurther action is needed on behalf of ANMATPreventive 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, requestto sponsor to intensify study monitoring, request to sponsor to change investigator at site, request to sponsor to discardstudy data generated at the site, notification to medical school where Investigator is affiliated, administrative or legal actiontowards investigator and / or CRO and/ or sponsor. Other requirements also follow previous 690/2006 Provision by ANMAT
  21. 21. Agua du coco
  22. 22. 2015 4 OAI10 VAI NAI5 4 12 2 4 30 1995-1998 1999-2002 2003-2006 2007-2010 http://www.accessdata.fda.gov/scripts/cder/cliil/
  23. 23. 12108 Failure to report to IRB6 Inadequate Drug Accountability4 Inadequate and Inprecise records2 Failure in following Investigational0 Plan
  24. 24. Deficiency Code Inspections % of total05- 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%reactions04- 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/
  25. 25.  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°
  26. 26.  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
  27. 27. •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
  28. 28.  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
  29. 29. ObservationsCritical 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
  30. 30. Examples from INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09
  31. 31. Examples from INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09
  32. 32. Examples from INSTRUÇÃO NORMATIVA Nº 4, DE 11/05/09
  33. 33.  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
  34. 34. Pisco Sour
  35. 35. 765 4 OAI4 VAI3 NAI2 31 1 10 1995-1998 1999-2002 2003-2006 2007-2010 http://www.accessdata.fda.gov/scripts/cder/cliil/
  36. 36. Deficiency Code Inspections % of total05- 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/

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