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Tutorial: “Hands-on the
Regulations for Clinical Trials
in Latin America”
Hands-on the Argentina Regulations
Carolina Dias Rato (INC research)
The views and opinions expressed in the following PowerPoint slides are
those of the individual presenter and should not be attributed to Drug
Information Association, Inc. (“DIA”), its directors, officers, employees,
volunteers, members, chapters, councils, Special Interest Area
Communities or affiliates, or any organization with which the presenter is
employed or affiliated.
These PowerPoint slides are the intellectual property of the individual
presenter and are protected under the copyright laws of the United States of
America and other countries. Used by permission. All rights reserved. Drug
Information Association, DIA and DIA logo are registered trademarks or
trademarks of Drug Information Association Inc. All other trademarks are
the property of their respective owners.
2www.diahome.orgDrug Information Association
• Overview of the complete process
– MOH revision steps
– Documents
– Electronic submission: process for initial and further applications
• Regulatory Framework
• Ethic evaluation
• Provincial evaluation processes:
– Buenos Aires City
– Buenos Aires Province
– Cordoba
– Mendoza
– Santa Fe
• Insurance
• Contracts
• Labels
• Inspections
• Controlled drug
• Challenges
Summary: Argentina
Drug Information Association www.diahome.org 3
Argentina: overview of the complete
process
Drug Information Association www.diahome.org 4
Protocol translated, ICF local
Spanish, IB (IB in English may
be accepted), LoA, labels.
Applicant submits ICF
to Ministry of Justice
(Data protection
Analysis)Local EC
approves
ANMAT issues approval
document covering
protocol and site + IL
Maximum legal period: 90 business days
Current situation: 4 to 6 months
Investigator
Applicant submits to ANMAT (EC approval letter + Director approval +
other site information (e.g. CVs) + import and export information +
EFCA2 form [electronic submission]
4 weeks
For every single shipment ANMAT
has to approve ”15 Points” document
permitting importation
Best scenario: 5 - 8
months
Phase I and II: extra step
INAME (1 month)
MOH revision steps
Drug Information Association www.diahome.org 5
Phase III
& IVFront desk
DEM
Legal department
“Dirección
Técnica”
Despacho
Front desk
Phase I & II
INAME
Total Time: within 90
business days per
regulation
Important: phases I and
II may take 1 extra
month due to INAME
revision
– For initial submission: general docuemnts
• EFCA1 Form
• Data Safety Monitoring Board Membership composition
• Certified Legal recognition (“Acreditación de personería o Poder”) – from
• Sponsor/CRO
• Apostilled Letter of authorization /POA from Sponsor to CRO or from Headquarter
• to Local affiliate (translated into Spanish by certified translator)
• Original Sworn declaration from Sponsor regarding GMP compliance for IP. In
• case not all manufacture process are in compliance with GMP, this should be
• notified
• Study documents: protocol (Spanish - electronic) +ICF (Spanish - electronic) +IB
(English - electronic)
• Note listing all materials or samples to be imported and samples to be exported.
• Investigational Product Label in Spanish
Documents
Drug Information Association www.diahome.org 6
– For initial submission: site specific documents
• EFCA2 Form
• Investigator’s documents:Certified copies of professional degree, professional
registration and proof of training and/or experience in clinical research
• Certified copies of the title of specialist or completed residence certificate or post-
graduate certificate in the specialty that corresponds to the disease under study, for
Phase II and III studies.
• Commitment note of the investigator and his team to respect the protocol, the
Declaration of Helsinki and the GCP-CPS Scheme of ANMAT
• Certified copy of approval of the study by the REB (one per center)
• Dated list of members of the REB, including name, date of birth, sex, profession or
occupation, position on the board and relationship with the institution
• Certified copy of authorization letter of the center authority
• Certified copy of authorization letter of the center authority for the review of the study
by an external REB, if applicable
• Site authorization for medical practice (“Habilitación”)
• Others:
– Placebo rational,
– Justification vulnerable population
– Conflict of interest
Documents
Drug Information Association www.diahome.org 7
Electronic submissions
Electronic Signature: provision Nº 2577/2011 • ANMAT and applicants started using electronic signature in 2012
• Gradual plan until covering all submissions
Electronic submissions: provision 3586/ 21June2012:
• Clinical Trials submited via ANMAT web page (electronic system´+ electronic signature)
• Not applicable to Bioequivalence and Biodisponibilidad
• Only EFCA 1 and EFCA2 (within initial application)
• Phase I and II are still evaluated at: Instituto Nacional de Medicamentos (INAME) - Departamento de Farmacología and Dirección del INAME
• Requirements and correspondence with evaluators via e-mail
A- PROCESS FOR INITIAL APPLICATION
Steps:
1- Perform electronic payment
2- Request of electronic signature/ registration
3- Documents prepared in PDF format
4- Electronic signature
5- Upload of documents at: www.anmat.gov.ar or http://portal.anmat.gov.ar
Important:
- First submission may lack site specific documents (PART A)
- 30 days after initial application we must attach at least 1 site (PART B)
- After this 30 calendar days, if no site is attached, the application is cancelled
• Access
ELECTRONIC SUBMISSIONS
Drug Information Association www.diahome.org 10
• Electronic signature:
ELECTRONIC SUBMISSIONS
Drug Information Association www.diahome.org 11
• EFCA1 or EFCA 2:
ELECTRONIC SUBMISSIONS
Drug Information Association www.diahome.org 12
• Filling in information that will generate the study authorization letter:
ELECTRONIC SUBMISSIONS
Drug Information Association www.diahome.org 13
• Uploading the documents:
ELECTRONIC SUBMISSIONS
Drug Information Association www.diahome.org 14
• The electronic dossier was generated succesfully:
ELECTRONIC SUBMISSIONS
Drug Information Association www.diahome.org 15
Submission Considerations
Progress and Final
reports
At least annually
Controlled medication: every 6 months
Form EFCA5 (section F): 1 report per local investigator
The periodic report must contain at least the number of
participants included, in monitoring and withdrawn, coded list
of participants, serious adverse events and their supposed
relationship to the investigational product and protocol
deviations relevant to the safety of the participants observed
during the period.
Administrative Amendments
To include DSMB (Data Safety Monitoring Board) reports
Others: administrative changes, change composition EC
Global final report within 1 year after all sites’ closure
B- Other applications
Drug Information Association www.diahome.org 16
Submission Considerations
Deviations 8.4. The sponsor must report to ANMAT the following
deviations from the protocol within 10 business days from the
time it has become aware of them:
(a) major deviations that have affected the rights or safety of
the participants;
(b) repeated minor deviations despite the fact that the
investigator was warned of their occurrence.
Safety reports 7.1. The sponsor must report to ANMAT all serious and
unexpected adverse drug reactions (ADRs) related to the
investigational product within 10 administrative business
days from the time it becomes aware thereof. The ADRs
caused by a comparator product already registered with
ANMAT for marketing in the country or those related to placebo
must be reported only to the ANMAT Pharmacovigilance
System.
Six monthly Safety reports
B- Process for other applications
Drug Information Association www.diahome.org 17
Regulatory Framework
Local MOH:
ANMAT - Administración Nacional de Alimentos, Medicamentos y Tecnología
Médica
Main Regulation: ANMAT Provision 6677/10
dated 01-Nov-2010 available at: http://www.anmat.gov.ar/principal.asp under
“news”
ANMAT regulations available at: www.anmat.gov.ar
Other Regulatory bodies involved:
INAME: Instituto Nacional de Alimentos de Medicamentos
- First step evaluation for Phase I & II
Ministry of Justice: Dirección Nacional de Protección de Datos Personales
- Data Protection evaluation of Informed Consent
- http://www.jus.gob.ar/datos-personales.aspx
Ethic Evaluation:
Drug Information Association www.diahome.org 19
Site has Institutional Ethic
Committee (IEC)
YES
NO
IEC ICH GCP compliant?
Registered and certified (if applicable)?
The institutional
director must
approve and
provide delegation
letter (“subrogate”)
for protocol review
to ICH GCP/ 6677
compliant
Institutional EC
(“similar inst.”)No actions needed
Very important: to verify in which provinces there is a local registration/
certification process
YES
NO
• Law 3301: Protection of subjects participating in
clinical research
• Resolution N.°485-MSGC/11: Agreement/
Convenio
• Decree Nº 1163/2009- City Government Hospitals
(payments to “investigators’ career”)
• Web page MOH CABA: www.buenosaires.gov.ar
• Web page CEC:
http://www.buenosaires.gob.ar/areas/salud/dircap/i
nvestigacion/ccei.php?menu_id=29732
Buenos Ares City
Drug Information Association www.diahome.org 20
Buenos Aires City (CABA): Process
Principal investigator performs Initial submission
The hospital’s
CODEI
The hospital’s
EC
Intervention of the DGDOIN
(MoH Buenos Aires city)
Execution of the Agreement by
the Minister of Health and the
Investigator and/or the sponsor
ANMAT
Execution of the
Agreement
between the
Investigator and
the sponsor.
Becomes informed and files
the approval
The Hospital’s Director
If approves
CECEC Teaching and Research Committee
30 days10 days
10 days
• ECs have to be certified and registered by CEC
• Agreement/ “Convenio”: Public Hospitals only
– After EC approval Site Director approves the trial he/ she performs the
liaison with Ministry of Health in order to get fully executed Agreement
– This agreement is signed between CRO/ Pharmaceutical lab + Ministry
of Health.
– This is a separate contract (we still sign contract between CRO/
Pharmaceutical lab + Investigator)
– Hospital director estimates costs that reseach project may generate to
site
• Depending on site (Public only), we may receive documents for MOH
(ANMAT) submissions before Agreement execution.
• Nowadays there is electronic submission process under development
• ANMAT + MOH CABA: Agreement
Buenos Aires City (CABA):
Important aspects
Drug Information Association www.diahome.org 22
Buenos Aires City (CABA): Ethic
Committees
When Law 3301 was enforced, there was a “grace – period” for Certification/Registration, nowadays all of them must comply the regulation
• Public ECs registered in CABA
http://estatico.buenosaires.gov.ar/areas/salud/dircap/mat/investigacion/ceipublico.pdf
• Private ECs registered in CABA http://www.buenosaires.gov.ar/areas/salud/dircap/mat/investigacion/ceiprivado.pdf
Study registration: is performed by ECs:
• http://www.buenosaires.gob.ar/areas/salud/dircap/investigacion/ccei.php?menu_id=29732
• Law 11044 and Decree 3385/2008
• Resolution: 4106/2009;
• Resolution 4107/2009;
• Resolution 116/2010;
• Resolution 709/2010,
• Web page: www.ms.gba.gov.ar
• Web page: CCIS
http://www.ms.gba.gov.ar/sitios/ccis/instancias-
aprobatorias/
Buenos Ares Province
Drug Information Association www.diahome.org 24
Buenos Aires Province: ProcessInitial submission
CCIS
Ministry of Health
Buenos Aires
CEC *
Final report
ANMAT
approval
Resolution
ANMAT
Approval
signed by
Ministry
signature
Technical report
Front desk*For pediatric,
phase 2 and
oncology studies
must be approved
first by the
Province Central
EC (CEC).
Insurance analysis
CRO
90 days30 days
Buenos Aires Province: Ethic
CommitteesECs are certified and registered by the Central Ethic Committee:
http://www.ms.gba.gov.ar/CEC/comitesacreditados.html)
• Certification has to be renewed every 3 years
• From August 1st 2012, ECs are organized in regions
• A site must ensure to use an EC within its region
• Timelines may increase in case of projects involving
vulnerable population, pregnant women, pediatrics, oncology
area, etc, since Central Ethic Committee will evaluate them
Buenos Aires Province:
Contract for Public Hospitals: there is a specific template (Resolution 3209/11)
Insurance (special requirements):
• The policy must be valid until one year after the end of the trial
- If the policy is provided in English, we must get a translation into Spanish (by a
certified translation in Argentina).We can take care of this locally
- The company has to be registered in the “Superintendencia de Seguros de la
Nacion” (official body where insurance companies are registered, and where
the insurance policy will be forward for revision within Provincial revision
process in Buenos Aires MOH)
The insurance must cover:
- I. Clinical research: protocol number and title must be included.
- II. Name and degree of Principal investigator have to be detailed.
- III. Name of the institution where the study will take place has to be detailed as
well
- We must submit complete insurance policy and be in force at the moment we
included in the submission dossier (expiration date not less than 15 working
days)
• Resolution N° 00022/2007
• Law 9694/2009
• Provincial resolutions:
0118/07: Creation COEIS
0739/07: Certifications CIEIS
1618/07: CIEIS certified per research area
0870/08: Registration of Research Projects
Others: 094/12, 095/12, 096/12, 097/12 y 153/12
802/12
1126/12
• Web page COEIS: http://www.cba.gov.ar/coeis/
Córdoba Province
Drug Information Association www.diahome.org 28
Cordoba Province: Process
Initial submission (Principal investigator)
COEIS
Local MOH
(if applicable)
CIEIS
local EC
ANMAT
approval
ANMAT
RePIsCRO
Approval(if available it is
included in initial
application to
ANMAT)
Registration of the
project
Approval + +
30 days30 - 45 days automatic
Córdoba Province
In some cases we must perform submission to Provincial MOH (COEIS):
• Reproduction/ Fertility trials
• Phase I and II and vaccines in any research phase
• High risk trials
• Genetic projects
• Vulnerable population
• New procedures not described, approved yet
- Local ECs (CIEIS) are certified and registered by the COEIS
- All projects must be notified and registered in the Provincial Registry of Research projects (Registro Provincial de Investigaciones en Salud - RePIS), through a specific form submitted by the CIEIS
Very important: to verify authorization of site for medical practise (habilitación):
• Investigators are registered in the COEIS
• Sites are also registered in the COEIS
http://www.cba.gov.ar/vercanal.jsp?idCanal=66086,
• Decree 423/ 2008: Creation of DICyT: Dirección de
Investigación, Ciencia y Técnica: Research,
Science and Technical Direction (belongs to
Provincial MOH).
• Resolution 2334/2010: Creation of COPEIS: Consejo
Provincial de Evaluaciones Eticas de investigación
en Salud
• Resolution 2583/09: research projects’ registration
Web page:
http://www.infosalud.mendoza.gov.ar/
http://www.salud.mendoza.gov.ar/x/dicyt/
Mendoza Province
Drug Information Association www.diahome.org 31
Mendoza Province: Process
Initial submission (Principal investigator)Must be registered in local Registry
COPEIS
(if applicable)
Local MOH
CEIS
local EC
ANMAT
approval
ANMAT
Registration
CRO
DICyT
(provincial MOH)
Approval DICyT
communicates
approval
CEIS approval
+
COPEIS approval
+
Registration
30 days
30 days
automatic
Mendoza Province
• Research project’s Registration: REPRIS
– Is performed by the investigator
– Online registration through (user name and pasword provided by the DICYT)
• Once complete, the registration form has to be submitted in paper to the DICYT.
• There is a local registry of Ecs:
• http://www.infosalud.mendoza.gov.ar/sisap/interfaz/Controlador.php?accion=consultaPredefinida&paso=2&categoria=RepComites&consulta=Tabla1Comites&formulario=RepComites&ruta=RepComites
• Ecs are not certifed locally yet.
• There is a registry for investigators
• Resolution1084/ June 1, 2011: creation Bioethic committee
• Registry of Research projects:
• http://www.santafe.gov.ar/index.php/web/content/download
/151603/741706/file/Formulario%20A2.pdf
Santa Fe Province
Drug Information Association www.diahome.org 34
Santa Fe Province: Process
Initial submission (Principal investigator)
Bioethics
Committee
(depends on
Provincial
MOH)
local EC
ANMAT
approval
ANMATRegistration
CRO
Approval(if available it is
included in initial
application to
ANMAT)
Registration of the
project
Approval + +
30 days
30 – 60 days
automatic
Santa Fé province
• Investigator has to submit to the Provincial MOH (Bioethic Committee):
- Application Form including: “pertinencia” (explanation about whether the project is appropriate/ beneficial for the local population), details of financial aspects, etc
- Site Director approval
- Local EC approval
• Initially, the Bioethic committee only registered projects
• Nowadays, they analyze the projects and also request changes to ICF
• The insurance certificate + policy must:
I. be provided in Spanish,
II. when the submission start the insurance has to be valid
III. specify duration of the insurance that must be appropriate to length of trial (in
case we have sites located in Buenos Aires Province, the policy must be valid
until one year after the end of the trial)
• The insurance must cover:
I. Clinical research: protocol number and title must be included.
II. Name and degree of Principal investigator have to be detailed.
III. Name of the institution where the study will take place has to be detailed
as well
• We must submit complete insurance policy and be in force at the moment
we included in the submission dossier (expiration date not less than 15
working days)
• The information must be included in the ICF: Policy number + Name of the
company that provides insurance, address and telephone in Argentina
Insurance
Drug Information Association www.diahome.org 37
• Contract + budget: has to be submitted to ECs (notification only)
• Fully executed contract is not needed to start submissions
• Bilingual format is strongly recommended
• CABA: specific contract process (Convenio)
• Buenos Aires Province: specific format
• Is not part of MOH (ANMAT) submission
Contract
Drug Information Association www.diahome.org 38
According to 6677: Labeling requirements for drugs under research: pre-printed or
blank spaces to be filled in handwriting
• All information detailed in Spanish
• Drug name or blind code number
• Dosage and administration route, strength or potency per unit
• Batch/lot number to identify manufacturing process and packing
• Patient code or visit number or date administration
Also in primary packaging if possible or secondary packaging:
• Name, address and phone number for contact person that can provide drug
information, study and un blinding information in case of emergency (Sponsor, CRO
or Investigator)
• Storage conditions
• Expiration date (month/ year)
• Instructions for Use
• The inscription "For clinical trials use only"
• The inscription “Keep out of reach of children” if medication is provided to the patient
Labels
Drug Information Association www.diahome.org 39
• Timing: ANMAT perfoms inspections:
– before the project starts: in case of Phase I trials: Department of Drug
Evaluation may conduct an inspection prior to the authorization of the study to a
research center
– while the projects are running
• Where:
2. SCOPE AND AUTHORITY: 2.1. The inspections of the studies are mainly aimed at
investigators and research centers. However, ANMAT may determine the need for
inspections to other entities involved in the activity, such as the sponsor and contract
research organizations (CRO).
• Selection criteria:
• 4.1. The selection criteria of the study are the following:
– (a) inclusion of vulnerable populations;
– (b) priority in early stages of the research;
– (c) studies of investigational products in high-risk research.
Inspections: 6677 regulation: Section D:
INSPECTIONS OF CLINICAL PHARMACOLOGY
STUDIES
Drug Information Association www.diahome.org 40
• 4.2. The investigator’s selection criteria are the following:
(a) high recruitment in relation to the rest of the study investigators;
(b) high or low incidence of ADRS in relation to the rest of the study investigators;
(c) history of the investigator in previous studies;
(d) participation in a significant number of studies;
(e) any relevant information received in safety and/or periodic reports to warrant an
inspection at the choice of ANMAT;
(f) complaints received on the investigator’s misconduct.
• Results:
12.2. The Inspection Results are the following:
(a) No Action Indicated (NAI): No objectionable conditions or practices were found during
the inspection;
(b) Indication of Voluntary Action (IVA): conditions or practices that require corrective action
were observed during the inspection by the investigator or sponsor, but do not require any
action by ANMAT;
(c) Indication of Official Action (IOA): actions by ANMAT.
Inspections: 6677 regulation: Section D:
INSPECTIONS OF CLINICAL PHARMACOLOGY
STUDIES
Drug Information Association www.diahome.org 41
• “Blanket authorization”: covers the whole project
• Letter about GMP compliance:
– signed by CRO or Pharmaceutical local affiliate
– Recommended to attach supporting certificates
• Minimum content: Letter requesting importation or exportation (for samples)
permit:
- For drugs: Name, Pharmaceutical dosage form, strength and amount
- For biological samples: Type of sample and destination
- Controlled medication
• Sworn declaration from technical director detailing batch numbers
• List of investigators that will receive the drug
• Other materials: Description and amount of devices and Lab kits
• Devices: for instance: ECG machines, tablets, blood pressure device, etc
– Temporary vs. Definitive
Importation:
Drug Information Association www.diahome.org 42
• To be submitted with EFCA 1 form
– Sworn declaration from Technical Director – Sponsor listing the
• drug batches to be imported and authorized investigators that
• will receive them
– Specific Sworn declaration from each investigator/ sub investigator that
will administer/ handle the controlled medication
• Progress reports every 6 months (It used to be every 3 months)
• Since our import permit covers multiple shipments, depending from which
country the medication be exported, we should provide clarification letter to
allow exportation
Controlled drug
Drug Information Association www.diahome.org 43
Challenges How to Tackle these Challenges
Mental Health area: The Law of Mental
Health (N°26.657) was regulated by Decree
No. 603/2013 on 28 May 2013.
All clinical trials which involve Mental
Health that are nowadays under revision,
have been put on hold until the
enforcement of the mentioned decree be
discussed and agreed between Ministry of
Health and Ministry of Justice and Human
Rights.
Until MOH authorities define the impact of
mentioned Decree:
- To analyze carefully those projects
where patients cannot provide consent
- CIRCULAR 1: voluntary presentation by
sponsors of the rationale and key
information involved in research
projects, prior to the initiation of the
relevant application for approval.
The sponsor/ CRO, 60 days before
submitting initial application may request
via email ([email protected]) to the Drug
Evaluation Office a presentation meeting of
rationale and content, accompanied by the
documents specified in Annex I,
paragraph 3.
Objections to placebo arm To provide placebo rational within initial
application
Challenges in Argentina
Drug Information Association www.diahome.org 44
Challenges How to Tackle these Challenges
Studies where patient cannot provide
consent
People with temporary or permanent
mental disorders, such as a coma or
Alzheimer’s disease, and who do not have
a representative court-designated (for
instance: in emergencies, hospitalized
patients, intensive care unit, etc)
- According to 1480 regulation: In
accordance with National Mental Health
Law (No. 26.657 and National Law of
Patients’ Rights No. 26.529, any
relative up to the fourth degree of
consanguinity, the spouse, or partner
of patients are those who could best
safeguard their interests and the
decision the patient would take if he
were of sound mind. As far as
possible, or when the participant
recovers, he must be informed about
the research and requested his consent
before proceeding therewith.
- However, nowadays ANMAT’s Legal
Department is discussing internally
definition of “patient’s representative”
Challenges in Argentina
Drug Information Association www.diahome.org 45
Challenges How to Tackle these Challenges
Provision of access to treatment
after study ends in some cases
- In certain provinces like Santa Fe and
Cordoba, the local ECs are requesting
commitment to provide medication after
end of trial (only in those cases where
the investigators considers it beneficial)
- MOH leaves on EC’s hands this
requirement
- Recommended to analyze posibility of
extension or other benefit
Insurance requirements are strict - To advice about all local requirements at
early stages of the project
- Ensure to receive certificate + policy
- Original or certified copy
Logistical issues - Need of broker and depot/ distribution
services
Challenges in Argentina
Drug Information Association www.diahome.org 46
Challenges How to Tackle these Challenges
Regulatory timelines longer depending
on site location (that may involve extra
regulatory step by Provincial MOH)
- To balance site selection covering
different provinces
- To balance type of sites: Private vs
Public
- To verify carefully site contract process
to forecast execution timelines
The clinical trial regulations in
Argentina are very dynamic
- To be in close contact with local
regulatory experts
Pediatric trials - To ensure previous phases of research
are completed and information available
- To verify if similar study in adults was
already performed and provide
information
- To discuss with local Key opinion Leader
if the project is considered appropriate
regarding local public health scenario
(“Pertinencia”)
Challenges in Argentina
Drug Information Association www.diahome.org 47
Questions