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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)

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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


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


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


– 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


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

http://www.anmat.gov.ar/

http://portal.anmat.gov.ar/

• Access

ELECTRONIC SUBMISSIONS


• Electronic signature:



• EFCA1 or EFCA 2:



• Filling in information that will generate the study authorization letter:



• Uploading the documents:



• The electronic dossier was generated succesfully:



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


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


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

http://www.anmat.gov.ar/principal.asp

http://www.anmat.gov.ar/

http://www.jus.gob.ar/datos-personales.aspx

Ethic Evaluation:


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


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


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

http://estatico.buenosaires.gov.ar/areas/salud/dircap/mat/investigacion/ceipublico.pdf

http://www.buenosaires.gov.ar/areas/salud/dircap/mat/investigacion/ceiprivado.pdf

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


http://www.ms.gba.gov.ar/

http://www.ms.gba.gov.ar/sitios/ccis/instancias-aprobatorias/

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

http://www.ms.gba.gov.ar/CEC/comitesacreditados.html

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


http://www.cba.gov.ar/wp-content/4p96humuzp/2012/07/sal_coeis_resol1807.pdf




http://www.cba.gov.ar/wp-content/4p96humuzp/2012/07/sal_coeis_resol94.doc



http://www.cba.gov.ar/coeis/

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,

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


http://www.infosalud.mendoza.gov.ar/

http://www.salud.mendoza.gov.ar/x/dicyt/

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

http://www.infosalud.mendoza.gov.ar/sisap/interfaz/Controlador.php?accion=consultaPredefinida&paso=2&categoria=RepComites&consulta=Tabla1Comites&formulario=RepComites&ruta=RepComites

• 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


http://www.santafe.gov.ar/index.php/web/content/download/151603/741706/file/Formulario A2.pdf

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


• 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


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


• 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


• 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


• “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:


• 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


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


mailto:[email protected]


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”




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




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”)



Questions

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