Clinical Trials in Argentina 10 years of experience

1
Clinical Trials in Argentina10 years of
experience

• Analia Perez
• Biologist
• Director Drug Evaluation
• ANMAT- Drug Regulatory Authority

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ARGENTINA Demographic Data
2,791,810 km2. Total population 38226051 Crude
birth rate ( 1000) 19.3 Crude death rate ( 1000)
7.7 Annual birth average ( thousand) 727 Annual
deaths average (thousand) 297. Annual pop growth
rate 1.2 Urban population 88.5 Maternal
mortality rate (1000.000 lb) 4.0 52 under social
security
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Legal framework for clinical trials

• Law 16463 of Drugs and ANMAT Provisions
• Good Clinical Practices
• Pharmacology 5330/97
• Medical Devices 969/07
• 690/05 Investigator's Inspection
• 2124/05 Safety reports
• Good Manufacture Practices
• - 2189/05 (based on WHO 2003)

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Parties involved

• Ethical Committees
• Ad-hoc organized for Biomedicines with SOP
• Institutional Review
• External Independent Committees
• Hospital Ethical committees regular ethical
  evaluation
• Ethics Committee Review/Institutional Review
  Board review and authorization required prior to
  initiating a clinical trial/amendments

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Regulatory Drug authority A N M AT objective
To control and guarantee the quality and safety
of products for human consumption, both imported
and locally produced, aimed at protecting and
contributing to human health
Decree 1490/92
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ANMAT Clinical Trial

• Primary Objective
• Assure the safety rights of subjects
• ANMAT involved areas are
• Institute of Drug Good Manufacture Practices
  and Evaluate Preclinical Data evaluation
• Direction of Drug Evaluation Participate in
  previous authorization, follow up and
  investigators inspections

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CLINICAL TRIAL PROTOCOLS ASSESSED AND APPROVED
BETWEEN 1994 - 2006
1894 TRIALS (until Dec.31)
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SPONSORSPROFILE (1994-2006) N1894
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CLINICAL TRIALS ACCORDING RESEARCH PHASE
(1994-2006)
1894 TRIALS
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CLINICAL TRIALS ACCORDING PROTOCOL DESIGN
(1994-2006)
1894 TRIALS (Dec.31th)
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CLINICAL TRIAL APPLICATION PACKAGE

• ECLIN, form 1.0.1 for Sponsors submition
• Protocol
• Inform Consent
• Investigator's Brochure
• Facilities and staff related documents (ie CV)
• Ethical Committee approval
• Other Institutional Board/Committee approvals
• Letter of authorization enabling the applicant
  to act on behalf of sponsor

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PROTOCOL EVALUATION PROCESS

• Deep analysis according therapeutic group
• Preclinical and no clinical according to Phase
  are evaluate by Institute of drug
• Analysis of local Country impact
• Investigators and sites are case by case
  evaluated
• Phase I sites studies are pre-inspected

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FLOWCHART

• SUBMITION. ECLIN FEE (US 1300)
• 
  DEPARTMENT OF ADMINISTRATIVE CONTROL
• DRUG EVALUATION DIRECTION (
  INAME ONLY EARLY PHASES)
• Clinical Trial area
• NO OBJECTIONS OBJECTIONS WRITTEN
• CLOCK STOP
• APPROVAL
• 
  
• ANMAT PROVITION ANSWER ANALYSIS
• (legal time 90 days)
• REJECTION....legal Department

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APROVAL PROVISION INCLUDES

• Authorization to run the trial accordingly to
  protocol
• Facilities and investigators
• Version of Informed consent
• Enrollment advertising (if applicable)
• Drug, devices and documents to import
• Samples or other issues to export
• Special ANMAT exigencies if required

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AFTER APPROVAL ACTIONS

• Fast track authorizations ( provision from
  director is not required)
• New Facilities/sites (or change)
• New investigators (or change)
• Protocol technical Amendments ( includes new
  Inform consent)
• Justified Increase or modification of quantities
  to be imported/exported

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IMPORT/EXPORT

• Customs form must be signed by an ANMAT official
  with certified signature
• Presentation to ANMAT requires a fee of 30 us
• Signature takes less than 2 hours at ANMAT
• In 2006 there were more than 6000 authorizations

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FRECUENT REASONS OF DELAY

• Eclin forms are incomplete
• Documents from institutional Ethical committees
  are missed or not completed
• Selection of private sites /investigators with
  poorly documented history
• Requests of exemption of fee in public
  institutions
• Sponsors representative not complete

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FRECUENT REASONS OF DELAY

• ANMAT special requirements
• Inclusion/Exclusion criteria are not fully in
  agreement with local standards
• Additional safety issues are locally necessary
• Placebo uses are not scientifically and ethically
  justified.
• Informed consents are uncompleted or legal local
  statements are omitted

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INSPECTIONS SCOPE

• Guidelines for Clinical Investigators
  Inspection 690/05 Describes procedure and
  conduction of the inspections carries out by
  ANMAT to control GCP- 5330/97 provision.
• Ongoing inspections applied to investigators
  to control GCP adherence to standards to ensure
  integrity and protection of voluntaries
• Provides the actions to be implemented during
  and after the GCP inspection

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CRITERIA for Selection

• BY TYPE OF PROTOCOLO
• Vulnerable population
• Phase of investigation
• High risk studies
• BY SITE
• High enrollment
• - Low/high safety reports
• Investigator history
• High number of studies/site
• - Any relevant information due to safety
  reports and/or included in advanced reports
• Complaints

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INVESTIGATORS MEDICAL SITE INSPECTIONS
(1997-2006)
374 INTEGRAL INSPECTIONS
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RESULTS OF INSPECTION

• NON ACTION INDICATED (NAI) No special issues or
  practices to object.
• INDICATION OF VOLUNTARY ACTION(IAV)
• Objections observed during the inspection
  demands corrections that investigator and
  sponsors may solved without ANMAT new intervention

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RESULTS OF INSPECTION

• Official action indicated (OAI)
• 1) to implement additional controls
• To include restrictions to the investigator
• To restrict the investigator in future studies
• To change the investigator
• To ask sponsor to increase monitoring at that
  site
• 2) to initiate legal actions
• To inform justice of misconduct
• To inform other health authorities of
  professional misconduct
• 3) ANMAT has the right to stop the study at any
  time

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INSPECTIONS RESULTS TO CLINICAL
INVESTIGATORS(1997-2006)
-374 INSPECTIONS
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FOR

• 10 years of continued experience
• Ongoing Inspections have provided self-confidence
  to ANMAT and investigators
• Sites are increasing in number and quality
• There are new and trained investigators
• Trainings activities are increased ( almost 15 p/
  year)

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.. AGAINST

• GCP 5330/97, including Inspection Guideline and
  Safety expedited reports must be up dated.
• Ethical Committees activities must be regulated
• Sponsor responsibilities as well as legal status
  must be clarified (ie conflict of Interest, rol
  of Contract research organizations)

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TRENDS IN NEAR FUTURE

• An strengthen of federal regulation will be added
  to ANMAT regulatory responsibilities.
• Ethical committees will be more actively
  participating
• Institutions will provide new transparency
  criteria concerning sponsors commitments
• Clinical Trials Law is under discussion for 2008
  as well of a new Drug Law

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FINAL RECOMENDATION TO SPONSOR

• To strength investigator and site selection
  process in terms of transparency and sound
  background in GCP
• To analyze current practices and standards of the
  country before submission to ANMAT
• To privilege expedited safety or deviation
  communication and reduce unnecessary
  administrative information to ANMAT

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• THANK YOU
• Lic Analia Pérez
• aperez_at_anmat.gov.ar
• ANMAT Avda de Mayo 969 Buenos Aires
• Argentina 0054114340 0800