Federal Commission for the Protection Against Sanitary Risks (COFEPRIS)

As set forth in GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, and COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is the regulatory authority responsible for approving all clinical studies in human beings and/or their biological samples, for scientific research purposes. COFEPRIS is authorized to monitor and verify approved clinical studies to be conducted in Mexico in accordance with the provisions of the aforementioned documents.

Under the terms of Reg-COFEPRIS and GenHlthLaw, the Ministry of Health (Secretaría de Salud) supervises the regulation, control, and promotion of health through COFEPRIS. Per MOH-Org, COFEPRIS, a decentralized administrative body, is overseen by the Ministry of Health’s head of the Undersecretariat of Prevention and Health Promotion. Reg-COFEPRIS and GenHlthLaw state that COFEPRIS is headed by a Federal Commissioner appointed by the President of Mexico, upon the Ministry’s recommendation. Per GenHlthLaw, the Ministry of Health is also responsible for supervising COFEPRIS. Per Reg-COFEPRIS and GenHlthLaw, the agency has technical, administrative, and operational autonomy in regulating, evaluating, controlling, promoting, and disseminating the conditions and requirements to prevent and manage health risks in the Mexican population.

Reg-COFEPRIS specifies that COFEPRIS comprises eight (8) administrative units and four (4) government advisory bodies that manage the agency’s organizational and operational responsibilities. Included among COFEPRIS’s administrative units, and central to the research protocol authorization process, is the Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)). As delineated in Reg-COFEPRIS, GenHlthLaw, and MEX-53, CAS is responsible for issuing, extending, or revoking research protocol authorizations. According to MEX-104, CAS’s work is performed by its protocols area.

Other Considerations

Per MEX-41, Mexico is a regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). As indicated in MEX-2, COFEPRIS is in the process of implementing the ICH Guideline for Good Clinical Practice E6 (R2) (MEX-22). However, COFEPRIS-GCP complies with the Guideline for Good Clinical Practice E6 (R1) (MEX-32).

Please note: Mexico is party to the Nagoya Protocol on Access and Benefit-sharing (MEX-5), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see MEX-35.

Contact Information

As per MEX-71 and MEX-15, COFEPRIS’s contact information is as follows:

Comisión Federal para la Protección contra Riesgos Sanitarios
Oklahoma No. 14
Colonia Nápoles
Del. Benito Juárez
C.P. 03810, Ciudad de México

Note: Per MEX-37, MEX-15, and MEX-25, the preceding address should also be used to contact COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37) for technical inquiries or those inquiries requiring an official response.

COFEPRIS Call Center Phone: 01-800-033-5050 (toll free within Mexico) or 55 53 40 09 96 (international calls) (per MEX-37)
Foreign Processing Area Phone (for entry and/or tracking number of procedure): 01-800-420-4224 (toll free within Mexico) (per MEX-25)
Email: contactociudadano@cofepris.gob.mx (per MEX-71 and MEX-37)

Ministry of Health

As per the ClinDrugTrialGCP, PharmLaw-VNM, DecreeMOH, and ASTTReg, Vietnam’s Ministry of Health (MOH) is the regulatory authority responsible for clinical trial approvals, registration, oversight, and inspections. The MOH grants permission for clinical trials to be conducted in Vietnam.

As indicated in DecreeMOH, the MOH is a governmental agency whose mission is to oversee all aspects of public health care management and protection for the Vietnamese population. With regard to pharmaceuticals, the MOH’s activities include, but are not limited to, formulating and promulgating legal documents, regulations, and national standards; granting and withdrawing pharmaceutical practice certificates; and issuing certificates of eligibility, registration permits, medicine import/export permits, and certificates of good manufacturing practice (GMP).

The ClinDrugTrialGCP and ASTTReg specify that the MOH’s Administration of Science, Technology and Training (ASTT) is responsible for managing the clinical trial review process. As per the ClinTrialSup, the MOH’s ASTT is also responsible for registering contract research organizations (CROs) that support clinical studies and provide other research services. (See the ClinTrialSup for detailed information on clinical trial research support activities and the related registration forms.)

Pursuant to the DrugRgstrtn, an Advisory Council created by the MOH issues registration papers for drug and medicinal ingredient circulation. The Advisory Council consists of experts with appropriate professional qualifications and experience to ensure the ability to evaluate dossiers, critique experts' opinions and recommendations of the MOH’s Drug Administration of Vietnam (DAV), and advise the Minister of Health on issues related to pharmaceutical legislation, quality, safety, and efficacy records of drugs and medicinal ingredients. See the Scope of Assessment section for more information on the Advisory Council’s role in drug clinical trial phase exemptions.

Please note: Vietnam is party to the Nagoya Protocol on Access and Benefit-sharing (VNM-2), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see VNM-6.

Contact Information

According to VNM-11, the contact information for the ASTT is as follows:

Ministry of Health
Administration of Science, Technology and Training
No. 138B Giang Vo
Ba Dinh District
Hanoi City, Vietnam

Phone: 04.33846688
Fax: 04.32373236
Email: cuck2dt@moh.gov.vn

Overview

In accordance with GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, and COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is the regulatory authority responsible for reviewing, evaluating, and approving all requests for research protocol authorization in human beings and/or their biological samples using registered or unregistered investigational products (IPs). Per NOM-257-SSA1-2014, COFEPRIS requires biotechnological drugs used in clinical research studies to follow the same protocol authorization procedure as is required for all IPs. COFEPRIS-GCP and HlthResRegs specify that the scope of COFEPRIS’s assessment includes all clinical trials (Phases I-IV).

As indicated in HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, COFEPRIS’s review and approval of a protocol authorization request is dependent upon obtaining a favorable decision from the health institution’s Research Ethics Committee (REC) and Research Committee where the study is being conducted, and when applicable, the Biosafety Committee. Therefore, the COFEPRIS and EC reviews may not be conducted in parallel. In addition, per NOM-012-SSA3-2012, the REC’s favorable decision is only later submitted to COFEPRIS with the protocol authorization request. Refer to the Ethics Committee section for detailed information on the REC, and the Initiation, Agreements & Registration section for additional information on the Research Committee and Biosafety Committee.

Clinical Trial Review Process

As delineated in Reg-COFEPRIS and MEX-53, COFEPRIS’s Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)) is responsible for recording, evaluating, and issuing opinions on requests for human research protocol authorizations. According to MEX-104, CAS’s work is performed by its protocols area. Per MEX-15, CAS’s technical/protocols area conducts its work via COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37), a public service system established by the Mexican government to facilitate the processing of the agency’s standardized procedures and services.

As indicated in G-HumResProt and G-ResProtocolAmd, the applicant must submit an application to the CIS (MEX-37) to request protocol authorization or modification/amendment of a protocol authorization, and the application is then forwarded to CAS’s technical/protocols area for evaluation. (Note: COFEPRIS refers to applications as requests or procedures). Per G-HumResProt, the designated evaluator reviews and evaluates the information, comparing the information presented to assess whether it complies with current Mexican legislation on the matter. The information is also evaluated for completeness and accuracy and is reviewed to detect deficiencies or anomalies in the documentation or in the study process. Once the evaluator issues a resolution of authorization or a prevention letter, it is forwarded to the head of CAS for signature.

Following its review of the application documentation, per G-HumResProt and G-ResProtocolAmd, CAS’s technical/protocols area issues an official resolution of authorization or a prevention letter (in which additional or missing information is requested). If authorized, the clinical study may begin. However, if a prevention letter is received, the applicant must respond to what is stated in the letter and resubmit a request for continued processing after addressing all of the issues raised. CAS’s technical/protocols area will issue a final resolution following resubmission of the application for protocol authorization or modification/amendment. G-HumResProt also indicates that for in-person submissions, applicants can go to the CIS (MEX-37) to obtain the resolution.

G-ResProtocolAmd specifies that protocol modifications may be submitted to amend the research protocol, amend the informed consent/assent form, update the clinical and/or preclinical sections of the investigator’s brochure (also known as investigator’s manual in Mexico), remove or add research center(s)/research institution(s), or provide updated clinical and/or preclinical security/safety IP information. Refer to G-ObsrvStdies information on submitting applications to conduct risk-free research (observational studies), and G-BioequivStud for information on submitting applications to conduct bioequivalence studies.

Additionally, as indicated in G-DIGIPRiS-ResProts, once an official authorization from COFEPRIS is obtained, some of the data provided by the applicant via COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86), will be migrated to the CIS (MEX-37) and to the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). According to MEX-109, the G-RNECManual is useful for information on registering with RNEC for clinical trial applications submitted in person at the CIS (MEX-37). See also G-DIGIPRiS-DocComp for instructions on validating and comparing resolutions issued through DIGIPRiS (MEX-86) for research protocols). See Submission Process section for detailed DIGIPRiS (MEX-86) submission requirements.

Reg-HlthProd further explains that applicants must submit a request to COFEPRIS to obtain a sanitary registration for biosimilar biotechnological drug products. The specific requirements for the approval of each biosimilar biotechnological drug (e.g., in vitro studies, preclinical study reports, and comparative pharmacokinetic study reports) will be determined by the Ministry of Health, who will take into consideration the opinion of the Committee of New Molecules. When there is no relevant information in the Pharmacopoeia of the United Mexican States (Farmacopea de los Estados Unidos Mexicanos (FEUM)) and its supplements, nor in national guides or monographs, the Ministry may evaluate biosimilar tests using clinical data obtained from biosimilar biotechnological drug studies conducted in other countries. However, clinical trials are required to be conducted in Mexico when an applicant requests the renewal of an approval for a biosimilar biotechnological drug product. According to MEX-91, COFEPRIS’s acceptance of data produced abroad will accelerate the introduction of biosimilar drug products into Mexico. Additionally, per MEX-120, COFEPRIS has implemented modifications to NOM-177-SSA1-2013, the standard which establishes the tests and procedures to demonstrate that generic drugs or biosimilar biotechnological drugs comply with established interchangeability tests and delineates requirements for the authorized third parties that perform these tests. Pursuant to NOM-177-SSA1-2013-Mod, the modification expands the standard to include studies that are carried out in Mexico as well as in other countries to demonstrate interchangeability and biocomparability. MEX-120 also notes the modifications in NOM-177-SSA1-2013-Mod are designed to expedite the registration of generic and biosimilar biotechnological drugs. See NOM-177-SSA1-2013 and NOM-177-SSA1-2013-Mod for details.(Note: In Mexico, biosimilar is also referred to as biocomparable.)

UHAP Evaluations

Per HlthResRegs, prior to submitting an authorization request, applicants may also obtain a pre-assessment evaluation by an authorized third party that helps to facilitate COFEPRIS’s review. MEX-21 and MEX-10 explain that rather than submitting the application directly to the CIS, the applicant has the option of first choosing to obtain a pre-assessment (third party) evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Speciality Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) or a UHAP within the Mexican Social Security Institute (Instituto Mexicano del Seguro Social (IMSS)). MEX-9 states that the CCINSHAE oversees (12) UHAPs. According to MEX-90, the Faculty of Medicine of the Autonomous University of Nuevo León (Facultad de Medicina de Universidad Autónoma de Nuevo León (UANL)) UHAP is another third-party unit authorized by COFEPRIS to assist in the evaluation and assessment of human research protocols. Refer to MEX-19, MEX-69, and MEX-70 for detailed information on the CCINSHAE, the IMSS, and the UANL UHAP application submission requirements and evaluation process. See also HlthResRegs for information on the third party authorization process by the Secretariat, and MEX-10 and MEX-121 for additional information on authorized third parties. See Timeline of Review section for timeline information on submitting UHAP applications.

According to MEX-10, the UHAP has a maximum of 30 calendar days to respond to an evaluation request. See the Scope of Assessment and Submission Process sections for detailed UHAP information.

Overview

In accordance with the ClinDrugTrialGCP, PharmLaw-VNM, and ASTTReg, Vietnam’s Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT) manages the clinical trial review process for registered and unregistered investigational products (IPs). The ASTT is responsible for reviewing all clinical study documents, and per the ClinDrugTrialGCP, PharmLaw-VNM, the ECReg, and the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), the MOH’s national level ethics committee (EC), the National Ethics Committee in Biomedical Research (NECBR), is responsible for approving the research protocol. The ECReg further indicates that for research involving humans, institutions with ECs are responsible for overseeing an initial ethical and scientific appraisal of the research before it is reviewed by the NECBR. (Note: institutional level ECs are known as Councils of Ethics in Biomedical Research at the Grass Root Level (CEBRGLs) in Vietnam.) For institutions conducting research that do not have a CEBRGL, the review and evaluation of the research is performed by the NECBR or the CEBRGL of another institution with appropriate expertise.

According to the ClinDrugTrialGCP, the ASTT reviews a clinical trial registration dossier submitted by the sponsor, as well as a study approval dossier submitted by the institution. Evidence of institutional EC approval from a CEBRGL is a required element of the study approval dossier, so CEBRGL and ASTT approval cannot be conducted in parallel. Additionally, the NECBR’s review of the protocol is initiated by the MOH as part of the ASTT’s study approval dossier review procedures. Per the ClinDrugTrialGCP and PharmLaw-VNM, ASTT review is finalized once NECBR approval is obtained and the entire study approval dossier is sent to the Minister of Health for final approval. (Note: The ClinDrugTrialGCP and BioequivTrial also refer to the sponsor as “organizations and individuals with clinical reagents” or “donor”.)

As per the ClinDrugTrial and PharmLaw-VNM, the scope of the MOH’s assessment includes all clinical trials (Phases I-IV) for the following:

• Drugs that contain a new active ingredient, or products with a new combination of marketed ingredients
• Newly developed biologics or biologics with a new combination of marketed ingredients
• Newly developed vaccines that are manufactured and used for the first time in Vietnam
• Drugs, biologics, and vaccines which have been legally marketed for a period of less than five (5) years in the country of origin (or a country of reference if provided for under international treaties to which Vietnam is a signatory)
• Drugs, biologics, and vaccines for which a clinical trial has been conducted, but have not met the MOH’s or internationally recognized good clinical practice (GCP) requirements

In addition, per the TradMedicine, the MOH also reviews and approves traditional medicines to be used in clinical trials (Phases I-IV) unless deemed exempt by the agency. The category of traditional medicine includes drugs developed from a provincial-level scientific research project or higher, drugs that were granted a certificate, or drugs used for treatment at health establishments at a provincial level or higher for 10 years or more and for 200 or more patients. The drugs must also have been approved by a Science and Technology Council or an EC specialized in traditional medicine as effective and safe to treat traditional medical diseases. Traditional medicines also include ancient methods.

For information on bioequivalence trials and testing, see the BioequivTrial and the BioTestReq.

Clinical Trial Review Process

Registration Dossier Review

According to the ClinDrugTrialGCP, the ASTT requires the sponsor to submit a clinical trial registration dossier. Upon receipt of the appropriate files, the ASTT will check the validity of the dossier. If the dossier is incomplete, the ASTT will provide a written notice and specific instructions for the sponsor to supplement the dossier. The sponsor is responsible for coordinating with the ASTT to complete the dossier within a maximum of 60 days from the date of receipt of the written notice. Past this time limit, the submitted application is no longer valid. Following the review of a complete and valid dossier, the ASTT Director will either issue a written approval (see Form 13 in Appendix III of the ClinDrugTrialGCP) or clearly state the reason for disapproval in writing.

See the Submission Process, Submission Content, and Timeline of Review sections for more information on registration dossiers.

Approval Dossier Review

Per the ClinDrugTrialGCP, research institutions must submit dossiers requesting clinical drug trial approval to the ASTT. The ASTT checks the validity of the dossier, and if it is incomplete, the ASTT will provide a written notice and specific instructions for the institution to supplement the dossier. The institution is responsible for coordinating with the ASTT to complete the dossier within a maximum of 60 days from the date of receipt of the written notice. Past this time limit, the research approval procedure must be repeated from the beginning.

The ClinDrugTrialGCP states that following receipt of a complete and valid dossier, the MOH will organize a meeting of the NECBR. After receiving the NECBR’s evaluation report of the research protocol, the ASTT will synthesize and complete the dossier, then submit it to the Minister of Health for approval if the protocol meets the requirements. If the protocol is not approved or needs correction, the ASTT will notify the institution in writing and clearly state the reason. If the protocol needs to be modified, the institution is responsible for coordinating with the ASTT to complete the dossier in up to 90 days from the date of receipt of the written notice. Past this time limit, the protocol approval procedure must be repeated from the beginning.

Procedures for the approval of research protocol amendments follow the same procedure described above for clinical drug trial approval. For more information, see the ClinDrugTrialGCP.

See Submission Process, Submission Content, and Timeline of Review sections for more information on the approval dossier.

Inspection

The BioequivTrial indicates that the ASTT may conduct inspections to ensure the rights and health of participants in the trial, ensure the quality and integrity of the research data, ensure that the responsibilities of stakeholders in the research are implemented in accordance with applicable regulations, and promptly detect violations of the research protocol. The MOH will determine the inspection scale and frequency based on the objective, purpose, design, complexity, blinding technique, scale, and end date of the research. The MOH must send an inspection notice to the sponsor and institution at least five (5) days before the inspection, and the inspection report must be completed and sent to the sponsor and institution within 20 days of the inspection.

Clinical Trial Exemptions

The DrugRgstrtn indicates that based on the opinion of the MOH’s Advisory Council, the Minister of Health may exempt certain new drugs, vaccines, and biological products from one (1) or more phases of a clinical trial (including clinical data exemption or reduction). Registration certificates may be issued with the clinical trial phase exemption in the following cases:

• Medicines that meet urgent needs for national defense and security, epidemic prevention and control, and overcoming the consequences of natural calamities and catastrophes in which other drugs are not yet available on the market
• The drug has been licensed for circulation by at least one (1) of the reference regulatory agencies specified in Article 2 of the DrugRgstrtn
• Medicines used to treat rare and fatal diseases
• Vaccines and biological products manufactured in Vietnam in the form of technology transfer in one (1), several, or all phases of the finished product manufacturing process, which have clinical data on the products prior to the technology transfer in compliance with the DrugRgstrtn

See the DrugRgstrtn and the PharmLaw-VNM for more information on drugs that are exempted from a trial or certain phases of a trial.

Federal Commission for the Protection Against Sanitary Risks (COFEPRIS)

As indicated in G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, MEX-84, G-DIGIPRiS-ResProts, the applicant is responsible for paying a non-refundable fee (also referred to as “Proof of Payment of Rights”) to submit a request for protocol authorization to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)).

According to MEX-37 and MEX-15, applicants may obtain the fee information for a specific procedure or service using COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37). Per MEX-15, CIS is a public service system established by the Mexican government to facilitate the processing of the agency’s standardized procedures and services. MEX-15 and MEX-37 indicate that applicants may call CIS (MEX-37) or schedule an appointment for assistance with determining the COFEPRIS procedure code to obtain the correct processing instructions and fees and for help with submitting the payment. See MEX-37 and MEX-15 for information on scheduling an appointment with CIS.

G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, and MEX-11 provide requirements and corresponding costs to submit requests to COFEPRIS for protocol authorizations or amendments/modifications. The costs linked to these procedures are as follows:

• Request for authorization of research protocol in humans for medicines, biological, and biotechnological: 7,553.00 Mexican Pesos (G-HumResProt and MEX-11)
• Authorization of research protocol in humans (bioequivalence studies): 7,553 Mexican Pesos (G-BioequivStud)

• Authorization of research protocol without risk (observational) in humans: 7,553.00 Mexican Pesos (G-ObsrvStdies)
• Amendment or modification to the research protocol or inclusions to the protocol: 5,665 Mexican Pesos (G-ResProtocolAmd and MEX-11)

In addition, per G-UnregDrugImprts, the fee to request a health permit to import investigational products for research purposes is 6,727.65 Mexican Pesos.

As indicated in MEX-10, the fee for requesting a pre-assessment application evaluation through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Speciality Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) is 60,000 Mexican Pesos. The cost is the same for obtaining a review from any of the UHAPs within CCINSHAE. In addition, if the applicant selects a scientific committee within an institution that has a UHAP, the cost is 40,000 Mexican Pesos. The cost for each amendment is 3,500 Mexican Pesos, and corrections to the pre-assessment document are free.

Payment Instructions

As explained in MEX-50, G-HumResProt, G-BioequivStud, G-ObsrvStdies, and G-ResProtocolAmd, applicants should make payments for these procedures and services through an authorized credit institution using E5cinco (MEX-52). (See also MEX-52 for a link to participating financial institutions). Per MEX-50 and MEX-52, E5cinco is an electronic scheme created to enable users to submit the Payment of Rights, Products and Benefits (Derechos, Productos y Aprovechamientos (DPAs)) to a participating credit institution through its Internet portal or banking window. See also MEX-51 and MEX-6 for detailed DPA payment instructions via E5cinco (MEX-52).

In addition, G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, and MEX-84 provide a website link, Help Sheet for the Generation of the Fee Payment Format, for users to generate a payment form for fees based on their procedure in order to make a payment at the banking institution of their choice. Refer to G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, MEX-84, and G-DIGIPRiS-ResProts for additional information on this process.

No information is currently available regarding fees required to submit a clinical trial application for authorization to the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT).

Overview

As delineated in GenHlthLaw, HlthResRegs, REC-Op, REC-Op-Ref, G-RECs-Op-2018, and NOM-012-SSA3-2012, Mexico has a decentralized process for the ethics review and approval of clinical trial research. Accordingly, every health care institution which carries out research activities in human beings is required to have a Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) that is responsible for evaluating and ruling on research protocols in human beings. RECs are subject to current legislation and the criteria established by the National Bioethics Commission (Comisión Nacional de Bioética (CONBIOÉTICA)).

RECs must also comply with guidelines for the ethical evaluation of research involving human beings as delineated in GenHlthLaw, G-RECs-Op-2018, HlthResRegs and NOM-012-SSA3-2012. Pursuant to G-RECs-Op-2018, RECs must adhere to international guidelines relevant to research with human beings including the Declaration of Helsinki (MEX-76) and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MEX-22)).

In addition, per GenHlthLaw, HlthResRegs, and NOM-012-SSA3-2012, every health institution where research is conducted is required to establish a Research Committee and a Biosafety Committee. Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, REC and Research Committee approval is required for each trial site where a study is being conducted, and when applicable, Biosafety Committee approval is required as well.

GenHlthLaw further notes that in addition to establishing an REC, public, social, or private sector health care establishments of the National Health System must have a Hospital Bioethics Committee for the resolution of problems arising from medical care along with engaging in other bioethical and ethical related activities.

As per HlthResRegs, REC-Op, REC-Op-Ref, G-RECs-Op-2018, and NOM-012-SSA3-2012, Hospital Bioethics Committees also operate through CONBIOÉTICA. MEX-47 specifies that CONBIOÉTICA is responsible for registering RECs and Hospital Bioethics Committees. See the Oversight of Ethics Committees section for details on ethics committee registration.

Ethics Committee Composition

Research Ethics Committee Composition

As indicated in GenHlthLaw, RECs must be interdisciplinary gender-balanced groups composed of medical personnel from different specialties; professionals from psychology, nursing, social work, sociology, anthropology, philosophy, or law fields who have bioethics training; and community representatives affected by the health condition under study or other health services users who may or may not be attached to the health unit or institution. In addition to the previously stated criteria, G-RECs-Op-2018 indicates that these professionals should have a professional license and accredited training and experience in research ethics, good clinical practice, bioethics, and have experience related to the research area they will be evaluating. HlthResRegs further notes that the REC must consist of at least three (3) scientists including both genders and recommends that at least one (1) of them be based outside the health institution. The medical professionals should also represent the moral, cultural, and social values of the research groups. By comparison, NOM-012-SSA3-2012 states that REC health professionals should have expertise in the subjects investigated at the institution, regardless of whether the professionals have experience in the scientific methodology applied to the research. Further, the community representatives should embody the moral, cultural, and social values of the research participants.

Per REC-Op and REC-Op-Ref, the REC members must also be recognized and able to document their professional excellence in research/research bioethics, have personal records that prove ethical suitability and conduct, and advanced knowledge in qualitative and quantitative methodology. Additionally, GenHlthLaw, G-RECs-Op-2018, and NOM-012-SSA3-2012 state that REC members may or may not be based at the associated institution where the study is being conducted.

Additionally, NOM-012-SSA3-2012 specifies that the REC should be composed of a minimum of three (3) scientists, plus community representatives, as deemed necessary, with a total of at least six (6) members and a maximum of 20. G-RECs-Op-2018, REC-Op, and REC-Op-Ref note that the REC should comprise a president, at least four (4) members, one (1) of whom will serve as secretary, a representative from the affected study group or other health services users, with at least one (1) member who has expertise in bioethics and research ethics, and internal or external specialists to be included on an as needed basis. G-RECs-Op-2018 also notes that the member acting as a representative is not required to have a professional license in research or medical care and may include individuals with basic education or technical training.

Hospital Bioethics Committee Composition

Per GenHlthLaw and G-CHBs-Op, Hospital Bioethics Committees must be multidisciplinary, diverse, gender-balanced groups composed of medical personnel from different specialties and the health team; professionals from psychology, nursing, social work, sociology, anthropology, and philosophy fields; lawyers with knowledge in health matters, and community representatives affected by the health condition under study or other health services users who may or may not be attached to the health unit or institution. G-CHBs-Op notes that the members must have previous bioethics training or receive the training within the six (6) months after joining the Committee. Administrative personnel, directors of institutions, or people who occupy managerial positions in the institution should not be included, in order to promote an environment of equity.

In addition, per G-CHBs-Op, the Hospital Bioethics Committee should be composed of a president and a minimum of four (4) members with assistance from a secretary, to be appointed from among the members by the president. At least one (1) member not assigned to the health establishment must be included.

Terms of Reference, Review Procedures, and Meeting Schedule

Research Ethics Committees

Per NOM-012-SSA3-2012, the constitution and operation of the REC will be subject to the provisions of current legislation and, where appropriate, to the criteria referred to in article 41 Bis of the GenHlthLaw. REC-Op, G-RECs-Op-2018, NOM-012-SSA3-2012, and COFEPRIS-GCP specify that RECs should operate within written standard operating procedures (SOPs) to conduct their reviews. REC-Op and G-RECs-Op-2018 indicate that the health institution owner must approve the SOPs and issue a certificate of appointment to each of the REC members. HlthResRegs, G-RECs-Op-2018, and NOM-012-SSA3-2012 note that members must hold office for three (3) years and may be approved for an equal period.

Per REC-Op, G-RECs-Op-2018, NOM-012-SSA3-2012, and COFEPRIS-GCP, the following minimum requirements must be met (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• RECs must meet at least six (6) times a year, and at least once every two (2) months
• The minimum number of members required to complete a quorum must be greater than 50% of the members, and the president and/or secretary must be present to form a quorum
• In the evaluation of multicenter studies and when otherwise warranted, the REC may meet jointly with other RECs that belong to other establishments in the country, for the assessment and opinion for these protocols
• Minutes must be prepared for legal and administrative purposes in meetings
• An annual report of activities should be presented to the institutional head in the first 30 calendar days of the year
• Avoid conflicts of interest in protocol evaluations or be declared disqualified for that particular review
• Participation is required in initial training and bioethics continuing education
• Liaisons with other RECs within and outside the country to better carry out its functions
• A general policy on the confidentiality of information for protocols reviewed must be established and implemented
• A code of conduct for REC members must be established and implemented
• Members must refrain from participating in the evaluation and opinion of their own research
• Members will remain in office for the time established in each committee’s installation act and may be ratified at the end of each period, if applicable. Members may be replaced in a staggered manner, for which documentary evidence must be kept
• The committee will designate the person who will occupy the position of president and who will be responsible to the head of the institution or establishment and for the committee’s activities
• In the committee sessions, members of external committees may participate or have the support of external advisors, who will have a voice but no vote. In these cases, researchers from the institution or establishment itself may also participate as long as they work in areas related to the subject of the project or research protocol in the opinion phase
• It is the responsibility of the committee to issue the technical opinion on ethics, according to the nature of the proposed investigations

For detailed REC procedures and information on other administrative processes, see REC-Op, G-RECs-Op-2018, NOM-012-SSA3-2012, and COFEPRIS-GCP. See also MEX-72 for information on CONBIOÉTICA’s REC follow-up monitoring reports.

As per G-RECs-Op-2018, the REC should also keep documentation related to its integration, operation, and registration activities for up to three (3) years after the conclusion of the committee’s activities. The committee should also define the procedure for transferring the files and appoint the responsible person at the institution where the REC registration was granted. In addition, the REC will keep all the essential documents reviewed and related to each evaluated investigation, up to five (5) years following the end of the investigation or during the period established in the applicable provisions.

See G-RECs-Op-2018 for additional REC recordkeeping requirements.

Hospital Bioethics Committees

As indicated in G-CHBs-Op, Hospital Bioethics Committees must establish operating rules, which specify member functions as well as the internal mechanisms and procedures for operations during the sessions. In newly created Committees and during the first six (6) months, the members must be trained in bioethics on an ongoing basis. Per G-CHBs-Op and GenHlthLaw, the Committee will also promote, with the head of the hospital, the dissemination, elaboration and implementation of institutional bioethical guidelines and guides for medical care and teaching. It will also promote the ongoing the bioethical education of its members and hospital staff. GenHlthLaw also notes the Hospital Bioethics Committees must comply with current legislation and CONBIOÉTICA guidelines.

G-CHBs-Op further explains that Hospital Bioethics Committees must meet in an ordinary manner, at least six (6) times a year, and in an extraordinary way, at any time, at the President’s request, or when requested by the majority of its members. Quorum requirements to review and decide on a request must include attendance of at least half the number of committee members and the president. Minutes will also be prepared for each of the Committee sessions. The resolutions issued by the Committee are the result of the analysis and deliberation of the members present at the session and must be communicated through a letter addressed to the applicant who presented the case. The recommendations issued by the Committee must not be incorporated into the clinical file. The Committee President is responsible for safeguarding the files. For detailed Hospital Bioethics Committee procedures and information on other administrative processes, see G-CHBs-Op.

Overview

As per the ECReg, the ClinDrugTrialGCP, the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), and PharmLaw-VNM, Vietnam requires institutional and national level ethics committee (EC) approval for clinical trials. According to the ECReg and VNM-12, institutional level EC approval is provided by a Council of Ethics in Biomedical Research at the Grass Root Level (CEBRGL). PharmLaw-VNM states that national level EC approval is conducted by the Ministry of Health (MOH)’s National Ethics Committee in Biomedical Research (NECBR).

Ethics Committee Composition

The ECReg details general EC requirements applicable to both the CEBRGLs and the NECBR, as well as specific requirements for each type of EC.

Per the ECReg, EC membership should include the following:

• Members with a professional degree in the health sector related to the common research areas assessed by the EC, including at least one (1) person independent from the organization that establishes the EC
• Clinical doctors
• Members with legal expertise or knowledge of ethical principles in biomedical research, with a university degree or higher
• Members with no expertise in the health sector
• Members under 40 years of age, members from 40 years old to under 50 years old, and members aged 50 or older
• Male and female members (neither gender may be less than 20% of the total membership)

The ECReg further indicates that EC members must have the necessary experience, knowledge, skills, and ability to perform their duties in order to validate the science and protect the interests of research participants. Members with expertise in the health sector must have at least five (5) years of experience working in the field of research assessed by the EC. All members must also have time to participate in and perform the duties of the EC, and keep confidential any information related to the research, opinions discussed during the meeting, commercial secrets of individuals and organizations participating in the study, and personal information about the research participant. Members must also receive training and certification from the MOH or MOH-accredited organizations in Good Clinical Practice (GCP) and the EC’s standard operating procedures (SOPs).

Council of Ethics in Biomedical Research at the Grass Root Level

As explained in the ECReg and the CEBRGLReg, institutional ECs, known as CEBRGLs, should consist of at least five (5) members. The ECReg states that a CEBRGL consists of one (1) chair, one (1) to two (2) vice-chairs, a standing division, and specialized subcommittees (if necessary).

The CEBRGLReg further indicates that CEBRGLs may have at most 11 members. All members must be honest, objective, and have biomedical research ethics knowledge and expertise. The chair and vice-chair should be prestigious scientists.

The ECReg requires that the chair and vice-chairs have at least 15 years of experience working in the field of research evaluated by the EC, a good reputation, and the capacity to independently manage and run the EC. The chair and vice-chairs must also be fair and impartial, and not be pressured by the research institution, investigators, and other agencies, organizations, and individuals. An individual cannot be appointed as the chair of the EC for more than two (2) consecutive terms.

According to the ECReg, a CEBRGL should have no more than two (2) professional secretaries and no more than two (2) administrative secretaries. Professional and administrative secretaries must be honest, objective, and university educated. Furthermore, professional secretaries must have knowledge about scientific and technological management, scientific research, and ethics in biomedical research, while administrative secretaries must have administrative, clerical, and archival skills.

According to the CEBRGLReg, a secretariat based in the host institution’s Science Research Management Office should assist the CEBRGL with application processing and other administrative tasks.

See the ECReg and the CEBRGLReg for additional CEBRGL membership criteria.

National Ethics Committee in Biomedical Research

The ECReg requires the NECBR to have at least nine (9) official members, including one (1) chair, three (3) vice-chairs, and other official members, including professional and administrative secretaries. The NECBR also includes data monitoring and other subcommittees as needed. The Administration of Science, Technology and Training (ASTT) and the MOH act as standing members of the office of the NECBR.

The ECReg requires that the chair and vice-chairs have at least 15 years of experience working in the field of research evaluated by the EC, a good reputation, and the capacity to independently manage and run the EC. The chair and vice-chairs must also be fair and impartial, and not be pressured by the research institution, investigators, and other agencies, organizations, and individuals. An individual cannot be appointed as the chair of the EC for more than two (2) consecutive terms.

According to the ECReg, the NECBR should have no more than three (3) professional secretaries, and two (2) administrative secretaries at most.

The ECReg states that professional and administrative secretaries must be honest, objective, and university-educated. Professional secretaries must have knowledge about scientific and technological management, scientific research, and ethics in biomedical research, while administrative secretaries must have administrative, clerical, and archival skills.

See the ECReg for additional NECBR membership criteria and VNM-1 for the list of 2023-2028 NECBR term members.

Terms of Reference, Review Procedures, and Meeting Schedule

According to the ECReg, both CEBRGLs and the NECBR have five (5) year terms. However, the CEBRGLReg indicates that CEBRGLs have three (3) to five (5) year terms, as specified in the EC’s establishment decision. The ECReg also stipulates that the EC must be established or reorganized at the end of the term. The EC for the next consecutive term must include at least 25% new members.

As stated in the ECReg, EC activities are non-profit. The EC must fully apply the ethical principles prescribed in the ECReg and relevant legal documents, and comply with ethical guidelines of international organizations. The ethical guidelines used by the EC should be clearly stated and disseminated to investigators. In addition, ECs function on the principles of collectivity, democracy, and independence when evaluating research proposals and making decisions. If necessary, ECs may invite an independent consultant to provide a professional opinion to the EC. ECs should also facilitate the coordination of and/or reference the evaluation results of other domestic or foreign ECs.

According to the ECReg, the EC’s decision for a research proposal should be based on the consensus of the EC members and must be recorded in the EC’s meeting minutes. In case it is difficult to reach a consensus, the EC’s chair has the right to decide to immediately commence voting, or request that the principal investigator supplement the research dossier for the EC to consider and vote on during the next EC meeting. Research is approved only when there is no more than one (1) disapproval vote out of the total number of valid votes.

In addition, the ECReg states that ECs must conduct periodic assessments of ongoing studies within a time period that is consistent with the level of risk for study participants, but at least once a year on or before the date the EC approved the research protocol. The conclusion of the periodic assessment results should state that the EC’s previous decisions are still valid, or have been changed, suspended, or revoked.

The ECReg requires that EC members be trained prior to appointment and provided with updated and supplementary training in the ethical and scientific aspects of biomedical research. The head of the organization that establishes the EC is responsible for assigning a unit to manage scientific research activities to develop and deploy training plans for EC members. The updated and supplementary training must be conducted at least once every two (2) years. For more information on training requirements for EC members, see the ECReg.

As set forth in CEBRGLReg, the CEBRGLs should operate within written SOPs to conduct their reviews. The chair oversees the meetings, makes conclusions, and reports this information to the institutional head. Voting members must have no conflict of interest with the research. The CEBRGL members must review research documentation and prepare comments for the secretary prior to the meeting. Most CEBRGLs do not meet regularly but instead meet upon request for review and on the availability of the majority of its members. The CEBRGLs should also refer to the NECBR’s SOPs to develop their own SOPs. See CEBRGLReg for detailed CEBRGL review procedures.

Overview

According to HlthResRegs, REC-Op, and G-RECs-Op-2018, the primary scope of information assessed by the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) relates to maintaining and protecting the dignity and rights of human research participants and ensuring their safety throughout their participation in a clinical trial. Per HlthResRegs and G-RECs-Op-2018, RECs must also pay special attention to reviewing informed consent and protecting the welfare of certain classes of participants deemed vulnerable. (See Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations.)

HlthResRegs and G-RECs-Op-2018 also state that RECs must ensure an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants, and they must verify the adequacy of confidentiality and privacy safeguards. See HlthResRegs and G-RECs-Op-2018 for detailed ethical review guidelines.

Role in Clinical Trial Approval Process

Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the applicant must obtain a favorable decision from the REC and the Research Committee at the health institution where the study is being conducted, and when applicable, a favorable decision from the Biosafety Committee. As per COFEPRIS-GCP, HlthResRegs, and NOM-012-SSA3-2012, the REC must provide a favorable decision for the research protocol and informed consent form prior to the applicant submitting a request for protocol authorization to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Consequently, the REC and COFEPRIS reviews may not be conducted in parallel.

HlthResRegs, GenHlthLaw, and G-HumResProt explain that the REC provides ethics recommendations on protocols for research in human beings, including a review of the research risks and benefits, and per G-HumResProt, assesses the technical quality and scientific merit of the protocol. HlthResRegs further notes that RECs also prepare ethics guidelines for conducting research in humans.

As delineated in G-RECs-Op-2018, the REC agenda and documents corresponding to each session should be delivered at least seven (7) days prior to the meeting. It is then recommended that the REC’s decision be sent within a period not exceeding five (5) working days after the committee has met, or if applicable, not to exceed 30 calendar days from the review request date. G-RECs-Op-2018 and G-DIGIPRiS-ResProts also state that the approval of a new application is valid for one (1) year.

After obtaining a favorable opinion from the REC that validated the initial project or protocol, per NOM-012-SSA3-2012, the principal investigator (PI) must submit an amended protocol to the Ministry of Health (Secretaría de Salud) to request a new authorization for any amendments to be made to the methodological design of the initial research project. In those cases where the lives of research participants are endangered, amendments can be applied immediately, prior to approval by the REC and authorization by the Ministry of Health. However, in these situations, it will be necessary for the PI to provide documentary evidence following the event to the REC and the Ministry.

In addition, G-RECs-Op-2018 indicates that the REC should establish procedures for monitoring approved studies, from the point at which the decision was made until the completion of the investigation and reporting of results. Per NOM-012-SSA3-2012 and G-RECs-Op-2018, the REC must assess and approve the research protocol at the beginning of the project, and periodically throughout the project’s duration to ensure conformance with ethical principles and applicable regulations. NOM-012-SSA3-2012 further specifies that the REC must propose to the head of the institution or establishment where health research is carried out that the research be suspended or cancelled in the presence of any adverse effect that is an impediment from an ethical or technical point of view to continue with the study.

(See Submission Process and Timeline of Review sections for detailed REC submission process and timeline details.)

Overview

According to the ECReg, the CEBRGLReg, the ClinDrugTrialGCP, and the PharmLaw-VNM, the primary scope of information assessed by ethics committees (ECs) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. The ECs involved in clinical trial approval in Vietnam include institutional level ECs, called Councils of Ethics in Biomedical Research at the Grass Root Level (CEBRGLs), and the Ministry of Health (MOH)’s National Ethics Committee in Biomedical Research (NECBR).

As per the ECReg, the CEBRGLReg, and the PharmLaw-VNM, ECs must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable or those with limited or no legal capacity. The ECReg further indicates that when considering research related to vulnerable groups, representatives of the research participants or experts with knowledge and experience working with the groups must participate in the EC meeting. (See the Vulnerable Populations; Children/Minors; and Pregnant Women, Fetuses & Neonates sections for additional information about these populations.)

The ECReg and the CEBRGLReg also state that CEBRGLs and the NECBR are responsible for ensuring independent, timely, and competent reviews of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. See the ECReg and the CEBRGLReg for detailed ethical review guidelines.

The ECReg indicates that when ECs conduct research record evaluations, ongoing research supervision, and research results evaluations, they should evaluate the following:

• Research design and conduct
• Potential risks and benefits
• Selection of research populations and participant selection and protection
• Financial benefits and financial costs related to research participants
• Protecting the research participants’ privacy and confidentiality
• The process of providing information and obtaining participants’ written consent to participate in research
• Impact of research on the participants’ community
• Researcher capacity and research goal

Role in Clinical Trial Approval Process

As delineated in the ClinDrugTrialGCP, the MOH’s Administration of Science, Technology and Training (ASTT) is responsible for reviewing the clinical trial registration and study approval dossiers for completeness. Evidence of institutional EC approval from a CEBRGL is a required element of the study approval dossier, so CEBRGL and ASTT approval cannot be conducted in parallel. Additionally, the NECBR’s review of the protocol is initiated by the MOH as part of the ASTT’s study approval dossier review procedures. Per the ClinDrugTrialGCP and the PharmLaw-VNM, the ASTT’s review is finalized once NECBR approval is obtained and the entire study approval dossier is sent to the Minister of Health for final approval.

The ECReg indicates that for research involving humans, institutions with ECs are responsible for overseeing an initial ethical and scientific appraisal of the research before it is reviewed by the NECBR. For institutions conducting research that do not have a CEBRGL, the review and evaluation of the research is performed by the NECBR or the CEBRGL of another institution with appropriate expertise.

The ECReg indicates that ECs may assess a research dossier or application under an expedited process if:

• The research involves minimal risk
• The research documents have been previously reviewed by an EC
• The research documents have been reviewed and approved by an EC of the same level
• It is a periodic report on implementation of research that has already been approved
• It is an application for amendment and supplementation of a research protocol that has already been approved
• It is reporting adverse events occurring in research that has already been approved
• It is reporting violations of an approved research protocol

According to the ECReg, research dossiers are reviewed under the EC’s full process if they do not qualify for expedited review as stipulated above, or if the evaluator requests that the dossier be examined according to the full process. The EC’s decision under the full review process is legally valid when at least five (5) members (including at least one (1) member with appropriate expertise in the health sector, one (1) member with no expertise in the health sector, and one (1) independent member), including members of both sexes, are present at the EC’s meeting and vote in the decision. The meeting must also have been convened by the EC’s chair or vice-chair (if authorized), and record meeting minutes. The EC's expedited review process decision is legally valid when at least two (2) members of the EC have reviewed and evaluated the dossier. See the Timeline of Review section for more information on the expedited and full review processes.

According to the ECReg, the EC must send a written notification of its evaluation to the leading research institution and principal investigator (PI), and publish the evaluation results on a bulletin board or on the website of the EC or the organization that established the EC. The EC may approve, conditionally approve, or decide not to approve a research dossier, and the written notifications must be issued accordingly.

Per the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), for administrative changes to the clinical trial protocol, the research institution must report in writing to the ECs at all levels and the ASTT. Changes that do not affect the health and interests of trial participants, or the research designs, processes, and procedures, must be approved by the CEBRGL and the NECBR. The application and evaluation process are carried out in accordance with the provisions of the ECReg. Changes affecting the health and interests of trial participants, or the research designs, processes, and procedures, must be approved by competent regulatory agencies. The application for approval of changes and procedures must comply with the ClinDrugTrialGCP. See the ECReg and the ClinDrugTrialGCP for more information.

For internal NECBR forms and documents, see VNM-3.

According to the BioequivTrial, ECs may also conduct periodic or unscheduled inspections. The sponsor and EC should determine the scale and frequency of the inspections based on the objectives and design of the research. The purpose of the inspection should be to evaluate trial conduct and PI/study team compliance with the protocol, standard operating procedures (SOPs), good clinical practices (GCPs), and other applicable regulatory requirements. The sponsor or the EC must send an inspection notice to the institution and PI at least five (5) days before the inspection, and the inspection report must be completed and sent to the institution and PI within 20 days of the inspection.

The ECReg indicates that ECs must conduct periodic reviews of ongoing studies within a time period that is consistent with the level of risk for study participants, but at least once a year on or before the date the EC approved the research protocol. The conclusion of the periodic review results should state that the EC’s previous decisions are still valid, or have been changed, suspended, or revoked. Circumstances for unscheduled reviews include:

• Modification of the protocol that has the potential to affect the rights, safety, and/or interests of the research participants or investigators
• A serious adverse event related to the research or the research product
• Discovery of new facts or information that could affect a potential benefit or risk of harm related to the study
• A request to suspend all or a portion of the study by the sponsor or regulatory agency

As set forth in G-RECs-Op-2018, COFEPRIS-GCP, and REC-Op, Research Ethics Committees (RECs) (Comités de Ética en Investigación (CEIs)) do not charge sponsors/investigators for their review. Rather, the health institution must finance REC operating expenses, without this causing any conflict of interest in the committee’s functions.

G-RECs-Op-2018 further states that the institution may also receive support from external sources for evaluating protocols. However, this funding should not be given directly to any of the REC members, and the contributions should not lead to a conflict of interest between the funding source and the REC’s functions. Similarly, the committee’s evaluations should not result in financial gains as a result of these contributions.

Per G-RECs-Op-2018, REC financial support should not be used for purposes other than for its operation, and all activities should be handled with full transparency. Support is provided for the following activities:

• Time for participation in committee meetings
• Work recognition for their performance in the REC
• Support for training in bioethics and research ethics inside and outside the institution
• Physical space for the REC headquarters, both for meetings and receipt of documents, and safeguarding of documentation protocols, opinions, and minutes
• Administrative assistance for REC activities

No information is available on Hospital Bioethics Committee fees.

As stated in the ECReg, ethics committees (ECs) should indicate the fee structure (if any) required to assess a proposed study. Fee requirements should be included in the written instructions provided to investigators for submitting research dossiers for evaluation. The head of the organization that establishes the EC is responsible for allocating sufficient resources for the EC to perform its duties effectively.

According to VNM-12, the Ministry of Health (MOH)’s National Ethics Committee in Biomedical Research (NECBR) and institutional level ECs (known as Councils of Ethics in Biomedical Research at the Grass Root Level (CEBRGLs)) charge a fee to review clinical trial documentation. The current NECBR and CEBRGL fees are $1,000-$2,000 USD.

Overview

The National Bioethics Commission (Comisión Nacional de Bioética (CONBIOÉTICA)) was established as a decentralized entity of the Ministry of Health (Secretaría de Salud) in 2005, as specified in D-CONBIOETICA. According to D-CONBIOETICA and MEX-55, the agency has technical and operational autonomy in defining and establishing national bioethics policies in medical care and health research. Per D-CONBIOETICA, GenHlthLaw, G-RECs-Op-2018, and MEX-57, CONBIOÉTICA is also responsible for promoting the organization and operation of Research Ethics Committees (RECs) (Comités de Ética en Investigación (CEIs)) and Hospital Bioethics Committees in public and private health institutions, for establishing and disseminating criteria to support development of REC activities, and for providing committee member training support.

In addition, per D-CONBIOETICA, CONBIOÉTICA’s other roles include:

• Exercising the Commission’s legal authority and head Commission operations
• Presiding over the Commission’s Advisory Council
• Issuing positions on bioethical issues relevant to society
• Establishing links with federal entities to promote the creation and operation of state bioethics commissions
• Signing and implementing collaborative agreements with organizations and opportunities that favor the development and consolidation of bioethical culture
• Carrying out activities assigned by the Secretary of Health
• Providing information and technical cooperation required by the Ministry of Health’s administrative units and other dependencies/entities within the Federal Public Administration

Registration, Auditing, and Accreditation

Research Ethics Committees

As delineated in HlthResRegs, REC-Op, REC-Op-Ref, REC-Op-Amd, G-RECs-Op-2018, G-RECReg, and MEX-57, all RECs are required to register with CONBIOÉTICA in order to conduct health research in humans.

G-RECs-Op-2018, and G-RECReg further state that CONBIOÉTICA has 10 working days from the business day following application receipt to accept the application, or require the applicant to correct omissions in the application within 15 working days from the business day following the date when the applicant is notified. If the applicant fails to respond within this timeframe, the application must be deemed not filed. Once the application has been admitted for processing, the Commission has 30 working days to notify the applicant of receipt, and if appropriate, to issue the corresponding registration certificate, which will be valid for three (3) years. The registration record must also be visibly displayed in the institution where REC operations occur and on its website, if applicable. Additionally, the registration number must be included in all official committee communications.

Per REC-Op-Amd, MEX-58, and G-RECReg, the REC registration form (MEX-29) is available for completion or download via MEX-58 or G-RECReg, and should be submitted in person according to the requirements outlined in REC-Op-Amd, MEX-58, and G-RECReg. The application must include the REC’s health institution identification data, an email address in order to receive Commission notifications, and the name and signature of the responsible person heading the REC. G-RECReg specifies that the applicant may request an appointment by phone or email to deliver all the documentation in printed form to CONBIOÉTICA, or send the application documentation via certified mail.

Refer to REC-Op-Amd, G-RECs-Op-2018, MEX-58, and G-RECReg for detailed registration application instructions and documentation requirements. See also MEX-57 for a list of registered RECs.

As delineated in REC-Op-Amd, G-RECs-Op-2018, and G-RECRegRenew, a registration renewal application must be submitted by the principal or owner of the health establishment or by the legal representative to CONBIOÉTICA within 45 working days prior to the expiration of the validation period covered by the registration certificate. From this point, the timing requirements are the same as for the initial application. See REC-Op-Amd, G-RECs-Op-2018, and G-RECRegRenew for detailed registration renewal application requirements and the application form.

In addition to CONBIOÉTICA’s REC registration requirement, per GenHlthLaw, G-RECs-Op-2018, REC-Op, and REC-Op-Ref, RECs must be installed under the responsibility of the head of the health institution where the study is taking place. They are required to sign a REC Installation Certificate (MEX-27), which stipulates its characteristics and functions. Refer to G-RECs-Op-2018 for detailed certificate requirements. See also MEX-72 for information on CONBIOÉTICA’s REC follow-up monitoring reports.

According to NOM-012-SSA3-2012, the research institution owner must also register the REC with the Ministry of Health (Secretaría de Salud), and report on the modification, designation, or substitution of any of its members. Additionally, an annual report documenting the integration and activities of these committees must be submitted to the Ministry during the first 10 business days of June each year.

Hospital Bioethics Committees

G-CHBs-Op and G-CHBReg indicate that Hospital Bioethics Committees must also register with CONBIOÉTICA, who is, in turn, required to issue a registration record within a maximum of 15 business days. CONBIOÉTICA’s registration is valid for three (3) years. Per G-CHBs-Op, the Hospital Bioethics Committee registration form must be submitted electronically through CONBIOÉTICA’s website. The application for registration renewal can be submitted one (1) month prior to the registration’s expiration date. Refer to G-CHBs-Op, MEX-56, MEX-59, and G-CHBReg for additional Hospital Bioethics Committee registration information.

Overview

According to the ECReg, the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT) is responsible for registering the institutional level ethics committees (ECs), known as Councils of Ethics in Biomedical Research at the Grass Root Level (CEBRGLs) in Vietnam.

Registration, Auditing, and Accreditation

The ECReg indicates that the ASTT is responsible for maintaining a list of ECs on the ASTT website. The ASTT must update the list within 15 days from the date of receiving a notice of establishment from the EC. ECs are periodically inspected by the ASTT to ensure that they comply with the requirements specified in the ECReg. If the EC is found to be noncompliant, the ASTT will withdraw the EC’s name from the updated list on the website. The ASTT may suspend, or propose suspension to a competent authority, of an EC’s operation in case it is found that the EC violates the provisions of the ECReg, affecting the protection of rights, safety, and health of research participants.

Overview

In accordance with GenHlthLaw, Reg-COFEPRIS, HlthResRegs, and NOM-012-SSA3-2012, Mexico requires the applicant to obtain research protocol authorization from the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the applicant must also obtain a favorable decision from the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee at the health institution where the study is being conducted, and when applicable, a favorable decision from the Biosafety Committee. Because COFEPRIS’s review and approval of a protocol authorization request is dependent upon obtaining a favorable decision from the REC and Research Committee, the COFEPRIS and ethics committee (REC and Research Committee) reviews may not be conducted in parallel.

Regulatory Submission

MEX-15 states that applicants may submit research authorization requests or protocol modification/amendment requests in person or by mail to COFEPRIS at the Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37), a public service system established by the Mexican government to facilitate the processing of the agency’s standardized procedures and services. According to G-HumResProt, G-ResProtocolAmd, MEX-109, and MEX-37, however, requests should be submitted to the CIS (MEX-37) in person or electronically via COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86). (Note: COFEPRIS refers to applications as requests or procedures).

Pre-submission Registrations

As delineated in G-DIGIPRiS-Regis and G-DIGIPRiS-SystAccess, prior to submitting a request for research protocol authorization via DIGIPRiS (MEX-86), an applicant must first register in (MEX-86) using an e.signature (also known as e.firma) digital certificate. MEX-49 explains that the signature is a secure, encrypted digital file that identifies an applicant, and can be used to carry out procedures electronically with various government agencies. An e.signature can be obtained from the Tax Administration Service (Servicio de administración tributaria (SAT)) as described in MEX-105. G-DIGIPRiS-Regis and G-DIGIPRiS-SystAccess further explain that an e.signature is used to validate the natural person or legal entity registering in MEX-86. DIGIPRiS’s Terms of Use, which is accessible via MEX-86, also notes that the applicant is required to be registered with the Federal Taxpayer Registry (Registro Federal de Contribuyentes (RFC)). See G-DIGIPRiS-Regis, G-DIGIPRiS-SystAccess, and DIGIPRiS’s Terms of Use for details on registering in MEX-86. See also MEX-106 for an instructional tutorial on registering in MEX-86, and see G-DIGIPRiS-FAQs for frequently asked questions on using MEX-86.

DIGIPRiS Submissions

DIGIPRiS’s Terms of Use further explains that the application process is carried out entirely electronically via DIGIPRiS (MEX-86), unless the user is required to present printed documents with a handwritten signature or a physical inspection is required. The application request will be considered active when the documentation is signed and submitted, otherwise it will only remain in the system for 90 calendar days. When the request is active, the user receives a “Procedure Entry Receipt” through which COFEPRIS assigns a procedure number and the entry date and time is recorded. Once the procedure has begun, the user will be notified in MEX-86 of all request related administrative acts (e.g., requirements, actions, preventions or missing information, and resolutions). Authorizations issued via MEX-86 will take effect on the date and time indicated in the corresponding document. The email address the user provides during registration will be used to send notices of notification availability related to submitted applications. Refer to DIGIPRiS’s Terms of Use for detailed information on the administrative act notification process via MEX-86. See also G-DIGIPRiS-SystAccess for instructions on registering and updating emails in MEX-86.

Pursuant to G-DIGIPRiS-SystAccess and G-DIGIPRiS-ResProts, users can view the flow and status of the entire application process (application, evaluation, verification, signature and resolution) in DIGIPRiS (MEX-86), as well as view previously authorized applications. Additionally, multiple requests and procedures can be in process simultaneously in MEX-86. See also G-DIGIPRiS-DocComp for instructions on validating and comparing documents issued through MEX-86 for research protocols. Refer to MEX-96, MEX-97, and MEX-108 for additional background information on MEX-86. Per G-HumResProt, electronic submissions via MEX-86 are tracked via the applicant’s e.signature (MEX-105). See also G-DIGIPRiS-Reqs&Amdts for instructions on submitting requests for protocol amendment/modification via MEX-86.

CIS Submissions

As indicated in MEX-37 and MEX-15, applications submitted in person at the CIS (MEX-37) can be tracked via a CIS assigned reference number in the COFEPRIS Electronic Procedures Portal (MEX-103). MEX-109 specifies that the Electronic Procedures Portal (MEX-103) is only to be used for procedures submitted in person at the CIS (MEX-37) while procedures submitted via DIGIPRiS (MEX-86) should be tracked through the DIGIPRiS platform.

As per MEX-15, and MEX-71, applications as well as technical inquiries, or those inquiries requiring an official response, should be submitted to the CIS (MEX-37) at:

COFEPRIS
Centro Integral de Servicios
Oklahoma No. 14
Colonia Nápoles
Del. Benito Juárez
CP 03810, Ciudad de México

COFEPRIS Call Center Phone: 01-800-033-5050 (toll free within Mexico) or 55 53 40 09 96 (international calls) (per MEX-37)
Foreign Processing Area Phone (for entry and/or tracking number of procedure): 01-800-420-4224 (toll free within Mexico) (per MEX-25)
Email: contactociudadano@cofepris.gob.mx (per MEX-71 and MEX-37)

Per G-DIGIPRiS-ResProts, all documents uploaded to DIGIPRiS (MEX-86) must be in “.pdf” format (unrestricted text file), unless another format is specified.

Per G-HumResProt, G-ResProtocolAmd, and MEX-18, the Authorizations, Certificates and Visits form (MEX-25) should also be included in the application submission, as well as the original proof of payment of rights with two (2) copies of the receipt for protocol authorization and protocol modification/amendment requests. See the Submission Content section for detailed submission documentation requirements.

G-HumResProt and G-ResProtocolAmd state that all documentation related to submitting applications for research protocol authorization and protocol modification/amendment is required to be in Spanish. MEX-84 also specifies that the protocol, investigator’s brochure (known as the researcher’s manual in Mexico), and the informed consent forms should be in Spanish.

Enabled Pre-Assessment Support Unit (UHAP) Evaluation Submissions

Per MEX-21 and MEX-10, rather than submitting the application directly to the CIS, the applicant has the option of first choosing to obtain a pre-assessment evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Speciality Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) or a UHAP within the Mexican Social Security Institute (Instituto Mexicano del Seguro Social (IMSS)). See Scope of Assessment section for detailed information on UHAPs.

Ethics Review Submission

As earlier stated, per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, all requests for research protocol authorization in human beings and/or their biological samples in Mexico require the applicant to obtain a favorable decision from the REC and the Research Committee, and when applicable, a favorable decision from the Biosafety Committee. Because the submission process at individual institutional RECs will vary, applicants should review and follow their institution’s specific requirements.

Overview

In accordance with the ClinDrugTrialGCP, PharmLaw-VNM, and ASTTReg, Vietnam requires the applicant to obtain clinical trial authorization from the Ministry of Health (MOH). The Administration of Science, Technology and Training (ASTT) is the department within the MOH that manages the clinical trial review process. As delineated in the ClinDrugTrialGCP, the MOH’s national level ethics committee (EC), the National Ethics Committee in Biomedical Research (NECBR), must also approve the research protocol.

As per the ClinDrugTrialGCP, evidence of institutional EC approval from a Council of Ethics in Biomedical Research at the Grass Root Level (CEBRGL) is a required element of the study approval dossier submitted to the ASTT, so CEBRGL and ASTT approval cannot be conducted in parallel. Additionally, the NECBR’s review of the protocol is initiated by the MOH as part of the ASTT’s study approval dossier review procedures. Per the ClinDrugTrialGCP and the PharmLaw-VNM, ASTT review is finalized once NECBR approval is obtained and the entire study approval dossier is sent to the Minister of Health for final approval.

Regulatory Submission

According to VNM-12, the registration dossier and the study approval dossier should be submitted to the MOH’s ASTT at the address found in VNM-11:

Ministry of Health
Administration of Science, Technology and Training
No. 138B Giang Vo
Ba Dinh District
Hanoi City, Vietnam

As per the ClinDrugTrialGCP, the sponsor must submit, directly or via post, one (1) copy of the clinical trial registration dossier signed by the sponsor’s representative(s) to the ASTT. Separately, research institution(s) must submit one (1) copy of the study approval dossier, signed by the principal investigator (PI) and the head of the testing facility, directly or via post to the ASTT. See Appendix III of the ClinDrugTrialGCP for the registration form and the forms that comprise the study approval dossier. (Note: The ClinDrugTrialGCP also refers to the sponsor as “organizations and individuals with clinical reagents” or “donor” throughout the document.)

As delineated in the ClinDrugTrialGCP, the clinical trial application and accompanying material must be provided in Vietnamese or English. If the document is not available in Vietnamese or English, a notarized translation of the document must be provided in Vietnamese or English. The ClinDrugTrialGCP also indicates that the Investigator’s Brochure (IB) summary (also referred to as the research product profile in Vietnam) submitted to the MOH with the registration application should be in Vietnamese or in English with a supplementary summary in Vietnamese. See the Submission Content section for detailed information on documentation to be submitted.

Ethics Review Submission

As per VNM-12, the application for NECBR approval should also be submitted at the address found in VNM-11:

Ministry of Health
Administration of Science, Technology and Training
No. 138B Giang Vo
Ba Dinh District
Hanoi City, Vietnam

VNM-12 indicates that for NECBR review, the applicant must submit four (4) copies of the relevant documents directly or via post to the ASTT. Except for the IB, the Certificate of Analysis, and the good manufacturing practices (GMP) certificate, which may be in English, all relevant documents must be submitted in Vietnamese.

According to the ECReg, ECs issue their own guidelines for research evaluation submissions, providing information and regulatory forms for investigators. See the Submission Content section for the minimum requirements of the EC evaluation guidelines.

Regulatory Authority Requirements

As specified in GenHlthLaw, HlthResRegs, NOM-012-SSA3-2012, COFEPRIS-GCP, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the following documentation must be submitted to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) as part of the approval process (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Authorizations, Certificates and Visits form (original and two (2) copies) (MEX-25)
• Proof of payment of rights (original and two (2) copies)
• Request letter (in editable format (.docx) containing study data (title, investigator’s name, etc.), description of study risk level and duration (including estimated start and end dates (DD/MM/YYYY), and documents submitted for research protocol authorization (original)
• Response to COFEPRIS prevention letter requesting missing or additional information should be submitted in a new request letter
• Research protocol (original and one (1) copy)
• Acceptance letter from research institution head and responsible principal investigator (PI)
• Sponsor letter of acceptance of position and delegation of responsibilities (must include at least sponsor contact information, description of obligations and protocol rights, sponsor legal representative/authorized person signature, protocol number, when applicable, a certified copy of the apostilled, notarized, and translated power of attorney) (one (1) copy)
• Letter of No Conflict of Interest from the sponsor (one (1) copy)
• Document proving applicant’s legal identity (e.g., health license, operating notice or, where appropriate, the Federal Taxpayer Registry (Registro Federal de Contribuyentes (RFC)) (one (1) copy)
• Follow-up letter from sponsor providing monitoring/auditing plan
• Model letter of informed consent in Spanish
• Informed consent of the research participant or, where appropriate, the legal representative (original and one (1) copy)
• Study schedule (original and one (1) copy)
• Health warehouse license for operation of storage and distribution warehouse for biological products for human use, with handling of medications: narcotics, psychotropics, vaccines, toxoids, serums and antitoxins of animal origin and/or blood derivatives (one (1) copy)
• Letter of acceptance of responsibility from the importer (signed by legal representative of the importer)
• Importer name, license number, and address
• Sanitary license of the warehouse for storage and distribution of the research product (only narcotics, psychotropics, biologicals, radiopharmaceuticals, and vaccines)
• Letter of import supplies providing approximate total quantity and description of investigational products (IPs) requiring importation at each stage of the study; letter serves as acknowledgement of information, not authorization (original and one (1) copy)
• IP route of administration
• Insurance policy or current document from the financial fund that covers all study participants at the local level (one (1) copy)
• Current Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and Research Committee registration and Biosafety Committee registration, where applicable (one (1) copy)
• Favorable opinion of REC, Research Committee, and where appropriate, Biosafety Committee (original and one (1) copy)
• REC member list
• REC member letters recusing themselves if on research team (one (1) copy)
• REC letter describing study follow-up monitoring process (one (1) copy)
• Letter of No Conflict of Interest and Confidentiality signed by REC members (one (1) copy)
• Institution’s or establishment’s sanitary license or notice of operation (one (1) copy)
• Letter of authorization to carry out the research, signed by institutional head or health institution owner (must include protocol title/number, PI name, institution/establishment head signature and position, research center name/address) (original and one (1) copy)
• Where applicable, copy of agreement between research centers that have agreements for emergency medical care with other institutions
• Acceptance letter from the head of the institution or establishment describing resources available for emergency management (original and one (1) copy)
• Health license of the establishment to carry out medical emergency care
• Agreement or contract of the establishment for the care of medical emergencies of the research (must include at least title/protocol number; PI name; scope, clauses, and validity; signature of holders and legal representatives of both institutions; statement establishing the care of medical emergencies)
• Agreement or contract with institution or establishment to provide care for research related medical emergencies (one (1) copy)
• Letter of acceptance, confidentiality, and commitment to report suspected adverse reactions and events signed by the PI (original and one (1) copy)
• Summary of PI’s professional record/official professional documentation issued and registered by competent educational authorities (original and one (1) copy)
• Professional background of the PI (one (1) copy)
• Summary of academic preparation and experience of medical personnel, paramedics, and other experts involved in study (include updated Curriculum Vitae (CV), dated and signed, for each member; include a copy of documentation issued and registered by competent educational authorities accrediting academic preparation) (original and one (1) copy)
• Express letter of No Conflict of Interest to conduct the research, signed by the PI and research team
• PI letter describing research team’s delegation of responsibilities (must including protocol title/number, detailed description of activities, PI name/signature, team member signatures) (one (1) copy)
• Investigator’s Brochure (IB) (original and one (1) copy) (also known as investigator’s manual in Mexico)
• Letter describing the sponsoring institution’s or establishment’s resources for the study’s development (include institution/establishment name, PI name, protocol title/number, type of support required (e.g., human, material, financial, advisory information, equipment, auxiliary laboratory services, cabinets, and other resources), and how support will be provided and distributed) (original and one (1) copy)
• Document indicating drugs used in study comply with Good Manufacturing Practices (GMPs) and have the expected quality characteristics for IPs to be used in study, or letter documenting GMPs (one (1) copy)
• Status of stability studies, or letter documenting IP stability studies comply with applicable regulations (one (1) copy)
• Basic pharmacological and preclinical product information
• Additional study information (countries where research will be conducted, health conditions/problems, public consultation contact, scientific consultations contact)
• Optional pre-assessment evaluation opinion (See Scope of Assessment and Submission Process sections for details on pre-assessment evaluations)

See also Scope of Assessment and Timeline of Review sections for additional COFEPRIS review process and timeline information.

Refer to GenHlthLaw, HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, G-DIGIPRiS-ResProts, and MEX-18 for more detailed submission information. See also MEX-36 for information on obtaining a certificate of GMPs.

Ethics Committee Requirements

As indicated in MEX-84 and G-DIGIPRiS-ResProts, the following documentation should be submitted to obtain the favorable opinion of the REC, the Research Committee, and where appropriate, the Biosafety Committee:

• Full title and number of the research protocol
• Research protocol with the version and date in Spanish
• IB with the version and date in Spanish
• Full name of the IP corresponding to the research center
• Research center company name and address
• Informed consent forms with the version and date in Spanish
• Protocol summary
• Detailed description of the documents evaluated and approved in Spanish, citing version and date
• Validity of the approval opinion (not greater than one (1) year)
• Name, position, and signature of the person responsible who supports the opinion
• Confirmation of the evaluation of aspects of a scientific nature, the risk/benefit of the protocol as well as the guarantee and well-being of the participants

Additionally, a signed opinion issued on letterhead should be submitted that includes:

• Committee name and address (in accordance with its current registration)
• Date the opinion was issued
• PI name
• Company name and address of the research center
• Title of the study and protocol number
• Status/result of the evaluation of the documents (must be approved)
• Date of issue of the opinion (day, month, and year)
• Name and position of the signatory who supports the opinion (must be the President or the Secretary Member)

G-DIGIPRiS-ResProts, also notes that only the opinions with the signature of the President of the REC (or, where appropriate, the Secretary-Vocal) will be accepted with a letter attached stating “NO VOTE” or a justification for the absence of the president. See MEX-84 and G-DIGIPRiS-ResProts for additional ethics committee requirements.

Clinical Protocol

As set forth in MEX-84 and G-DIGIPRiS-ResProts, which are in compliance with the Guideline for Good Clinical Practice E6 (R2) (MEX-22), and NOM-012-SSA3-2012, the research protocol should include the following elements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Title, acronym, and protocol number (corresponds to the opinion of the committee(s) evaluators)
• Document version and date, and amendments (if applicable) (corresponds to the opinion of the committee(s) evaluators)
• Sponsor name/address and monitor, if different from sponsor
• Theoretical framework (IP name/description, preclinical findings summary, etc.)
• Definition of problem
• Participant selection and withdrawal criteria
• Statement that the clinical trial will be conducted in accordance with the protocol, good clinical practices, and local regulatory requirements
• Background
• Rationale
• Hypotheses (if applicable, includes statistical hypotheses)
• General objective (if applicable, includes specific, primary, secondary, or exploratory objectives)
• specific objectives)
• Materials and methods
• Study design (e.g., inclusion/exclusion and elimination criteria; information input, processing, analysis, and interpretation)
• Phase and type of study
• Study duration
• Sample size (global and local, as appropriate)
• Countries where the research will be carried out
• Health conditions or problems studied
• Capture, processing, analysis, and interpretation of the information obtained
• Route of administration, dose, dosing regimen, and treatment period(s) and justification
• Accountability procedure for handling the IP and placebo (if applicable)
• Mechanisms for maintaining randomization and blinding (if applicable), and codes for breaking them (e.g., criteria for premature unblinding, etc.)
• Statistical considerations
• Ethical considerations
• Efficacy and safety assessments
• Study schedule (document detailing activities to be carried out during the investigation)
• Bibliographic references and relevant trial data
• Names and signatures of PI and associate researchers (no more than five (5), classified according to their involvement in the research project)
• Other documents related to the research project or protocol
• Optional pre-assessment evaluation opinion (See Scope of Assessment and Submission Process sections for details on pre-assessment evaluations)

In addition to the protocol submission, per NOM-012-SSA3-2012, an additional letter should accompany the application. Please refer to NOM-012-SSA3-2012 for more specific letter instructions. See also MEX-84 and G-DIGIPRiS-ResProts for more detailed protocol requirements.

Regulatory Authority Requirements

As per the ClinDrugTrialGCP, the following documentation must be submitted to the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT) for clinical trial registration dossiers:

• Clinical trial registration application form signed by a representative of the sponsor (See Form No. 6 in Appendix III of the ClinDrugTrialGCP)
• Summary of the Investigator’s Brochure (IB) (also referred to as the research product profile in Vietnam) including general information about the clinical reagent (name, ingredients, indications, physical properties, chemistry, preparation, and other relevant information), pre-clinical research materials, and clinical trial study documents from previous phases

For clinical trial study approval dossiers, the ClinDrugTrialGCP indicates that the following documentation must be submitted to the MOH’s ASTT:

• Clinical trial approval application form signed by the principal investigator (PI) and the head of the research institution (See Form No. 7 in Appendix III of the ClinDrugTrialGCP)
• Full IB, including proof of compliance with Good Laboratory Practices (GLPs) for research institutions or proof of compliance with Good Manufacturing Practices (GMPs) (also referred to as good medicine production standards in Vietnam) for drug manufacturers, and proof of compliance with quality testing requirements from national inspection agencies or ex-warehousing certificates for vaccine or biological batches (Refer to the Quality Requirements section for detailed IB requirements)
• A copy of the written approval for clinical trial registration from the MOH’s ASTT
• For phase IV clinical trials, a certified or notarized copy of the written request for phase IV clinical drug testing from the respective regulatory authorities
• A certified or notarized copy of the research institution’s certificate of eligibility for pharmaceutical business
• Certification of participation by all study sites for multicenter research studies in Vietnam
• A certified or notarized copy of the approval from the People’s Provincial Committee (for community-based studies)
• Contract/agreement between the sponsor and the host institution; and contract/agreement between sponsor and the contract research organization (CRO), if applicable
• Explanation of study protocol (See Form No. 8 in Appendix III of the ClinDrugTrialGCP)
• Case report form (CRF)
• PI’s Curriculum Vitae (CV) and a copy of the Good Clinical Practice (GCP) certificate issued by the MOH or an institution recognized by the MOH
• Informed Consent Form (ICF) (See Form No. 9 in Appendix III of the ClinDrugTrialGCP) (See also the Required Elements section for additional information)
• Council of Ethics in Biomedical Research at the Grass Root Level (CEBRGL) evaluation report
• Investigational product (IP) labeling

See the ClinDrugTrialGCP for detailed requirements.

Ethics Committee Requirements

The ECReg indicates that both the institutional level ethics committees (ECs) (CEBRGLs) and the national EC (National Ethics Committee in Biomedical Research (NECBR)) issue guidelines for research evaluation submissions, providing information and regulatory forms for investigators. The guidelines include information on the following:

• Name and address of the secretary, employee, or member of the EC receiving the application file, or address of the website (if any)
• List of all written material in record
• Specifications of the documents
• Language of the document in the record
• Number of copies to be submitted
• Application deadline compared to evaluation date
• Recording and notification processes for invalid documents
• Estimated time for post-assessment decision announcement
• The timeframe that should be followed if the EC requires the applicant to provide additional information or documents
• Evaluation fee of research records (if any)
• Procedures for requesting EC approval of an amendment of the outline or related documents
• Specification of materials for selection, information, and consent to participate in the study

According to ECReg, the documents that ECs must review when evaluating a research proposal include:

• Signed and dated application, including signatures of co-applicant and representative of the relevant organization
• Research protocol (with version number and date), with documents and appendices (if any)
• A summary of the study in simple and understandable language
• Description of ethical considerations relevant to the study (may be included in the protocol); measures that will be taken to protect participant privacy and data confidentiality; protective care for participants; compensation to be provided to participants; and insurance package for participants (if applicable) (See the Required Elements and Participant Rights sections for detailed information)
• IB
• Study data collection forms (with version numbers and dates)
• Forms, documents, and advertisements used in the participant selection process
• ICF (with version number and date) for participants that are 18 years or older and have full civil capacity to give consent
• ICF (with version number and date) for participants and their parents and/or legal guardian(s), if the participant is 16 years old to under 18 years old
• ICF (with version number and date) for parents and/or legal guardian(s), if the participant is under 16 years old
• Assent form (with version number and date) for participants who do not have the capacity to give legal consent, including children from 12 years old to under 16 years old, a person with inadequate civil act capacity, or a patient in a limited cognitive condition
• Description of participant selection and ICF collection processes
• Procedures for monitoring, evaluating, and managing adverse events (AEs) (See the Safety Reporting section for additional AE/serious adverse event information)
• All previous decisions of other ECs or regulatory authorities regarding the proposed study (including decisions and reasons for objecting or proposing amendments to the previous protocol)
• Documents demonstrating that the research institution has agreed to allow the study after the regulatory authority’s approval (if the study is conducted outside the organization that established the EC)
• Investigators' commitment to agree to comply with the ethical guidelines
• The PI’s current scientific background and qualifications related to the relevant research

See the ECReg for additional information on documentation requirements for research protocol re-evaluation or amendments, as well as for evaluation applications for periodic reports, AE reports, protocol violation reports, and research result reports.

Clinical Protocol

As per the ClinDrugTrialGCP, the MOH requires the following elements to be included in a protocol submission:

• Title
• Protocol code
• Duration
• Management level (state/ministry/institution/province)
• PI/co-investigator(s) names and contact information
• Funding
• Phase requested
• Institution to conduct research
• Sponsor and contact information
• Situation of domestic and foreign research
• Objectives
• Methodology (including trial design, random selection method, and standard operating procedures (SOPs) for each research technique)
• Participant selection/withdrawal
• Participant treatment
• AE reporting requirements (See the Safety Reporting section for additional information)
• Laboratory test methods
• Ethical considerations
• Inspection and monitoring
• Post study medical care
• Study team training
• International cooperation
• Implementation progress
• Format of the expected results
• Activities of coordinating organizations

See Appendix III in the ClinDrugTrialGCP for a copy of the full form.

Overview

As delineated in HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS))’s review and approval of a protocol authorization request is dependent upon obtaining a favorable decision from the health institution’s Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee, and where applicable, the Biosafety Committee. Therefore, COFEPRIS and ethics committee (REC, Research Committee, and Biosafety Committee) reviews may not be conducted in parallel. However, per HlthResRegs, the REC, the Research Committee, and the Biosafety Committee may meet together to decide whether to authorize a protocol to conduct research on humans, as appropriate.

Regulatory Authority Approval

Pursuant to HlthResRegs, COFEPRIS must approve a request for research protocol authorization within 30 working days from the day following an application’s filing. However, according to G-HumResProt, COFEPRIS is required to complete its review of a research protocol authorization request and notify the applicant within three (3) months.

According to Reg-COFEPRIS and MEX-53, COFEPRIS’s Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)) is responsible for recording, evaluating, and issuing opinions on requests for human research protocol authorizations. Per G-HumResProt, the evaluator in CAS issues a resolution of authorization or a prevention letter, and it is forwarded to the head of the area (CAS) for signature. If a prevention letter is issued in which additional or missing information is requested, the applicant is required to address the issues within 30 calendar days. See Submission Process section for details on tracking submitted procedures via the Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37) or COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86).

Per G-ResProtocolAmd, G-ObsrvStdies, and G-BioequivStud, COFEPRIS’s review deadlines (three (3) months or 90 calendar days) to notify applicants are also applicable to requests for authorization of protocol amendments or modifications and requests for authorization to conduct risk-free research (observational studies) and bioequivalence studies. Refer to G-ResProtocolAmd, G-ObsrvStdies, and G-BioequivStud for details. See Submission Process section for detailed submission requirements.

Additionally, per Reg-HlthProd and G-UnregDrugImprts, COFEPRIS has 10 days to approve import requests for investigational drug products. If COFEPRIS does not respond within this timeframe, the request is deemed approved. G-UnregDrugImprts also notes that COFEPRIS has four (4) business days to send the applicant a prevention notification regarding missing or additional information required. The applicant, in turn, has five (5) business days to respond.

Per HlthResRegs and G-RNECManual, once the applicant obtains an official authorization from COFEPRIS, the applicant has a maximum of five (5) working days to enter this information into the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). The RNEC is in charge of the CAS’s Clinical Trials technical area and serves as the interface through which applicants are required to submit their application documentation in order to maintain an updated national inventory of clinical studies involving humans and/or their biological samples.

Enabled Pre-Assessment Support Unit (UHAP) Evaluations

Per HlthResRegs, prior to submitting an authorization request, applicants may also obtain a pre-assessment evaluation by an authorized third party that helps to facilitate COFEPRIS’s review. MEX-21 and MEX-10 explain that rather than submitting an application directly to the CIS, the applicant has the option of first choosing to obtain a pre-assessment (third party) evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Specialty Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) or a UHAP within the Mexican Social Security Institute (Instituto Mexicano del Seguro Social (IMSS)). According to MEX-10, the UHAP has a maximum of 30 calendar days to respond to an evaluation request. See MEX-10 and MEX-121 for additional information on authorized third parties. See the Scope of Assessment and Submission Process sections for detailed UHAP information.

Ethics Committee Approval

As delineated in G-RECs-Op-2018, the REC agenda and documents corresponding to each session should be delivered at least seven (7) days prior to the meeting. It is then recommended that the REC’s decision be sent within a period not exceeding five (5) working days after the committee has met, or if applicable, not to exceed 30 calendar days from the date of request for its review. G-RECs-Op-2018 and G-DIGIPRiS-ResProts also state that the approval of a new application is valid for one (1) year.

In addition, G-RECs-Op-2018 indicates that the REC should establish procedures for monitoring approved studies, from the point at which the decision was made until the completion of the investigation and reporting of results. RECs should conduct at least one (1) review a year.

Overview

As per the ClinDrugTrialGCP, evidence of institutional ethics committee (EC) approval from a Council of Ethics in Biomedical Research at the Grass Root Level (CEBRGL) is a required element of the study approval dossier submitted to the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT), so CEBRGL and ASTT approval cannot be conducted in parallel. Additionally, the National Ethics Committee in Biomedical Research (NECBR)’s review of the protocol is initiated by the MOH as part of the ASTT’s study approval dossier review procedures. Per the ClinDrugTrialGCP and the PharmLaw-VNM, ASTT review is finalized once NECBR approval is obtained and the entire study approval dossier is sent to the Minister of Health for final approval.

Regulatory Authority Approval

Registration Dossier Review

As delineated in the ClinDrugTrialGCP, the ASTT initially checks the validity of the sponsor-submitted registration dossier (which includes the registration application form and Investigator’s Brochure (IB) summary) within five (5) working days from the date of receipt of the application. If any issues are identified, the ASTT will issue a written notice to the sponsor, who must coordinate with the ASTT to complete the dossier within 60 days of receipt. Past this time limit, the submitted application is no longer valid. The ASTT Director will issue a written decision within five (5) working days of receiving a complete and valid dossier.

Approval Dossier Review

The ClinDrugTrialGCP indicates that research institutions must submit dossiers requesting clinical drug trial approval to the ASTT. The ASTT checks the validity of the study approval dossier within five (5) working days from the date of receipt of the application. If any issues are identified, the ASTT will issue a written notice to the institution, which must coordinate with the ASTT to complete the dossier within 60 days of receipt. Past this time limit, the research approval procedure must be repeated from the beginning.

The ClinDrugTrialGCP states that within 25 days of receiving a complete and valid study approval dossier, the MOH will organize a meeting of the NECBR. Within five (5) working days after receiving the NECBR’s evaluation report, the ASTT gathers all materials related to the dossier and submits it to the Minister of Health for approval.

If the research protocol is not approved or needs to be corrected, the ASTT must notify the institution and state the reason, as per the ClinDrugTrialGCP. The institution must coordinate with the ASTT to complete the dossier within 90 days from the date of the notice. Past this time limit, the protocol approval procedure must be repeated from the beginning. Within five (5) working days after receiving the completed research protocol in accordance with the written notice, the ASTT gathers all materials related to the dossier and submits it to the Minister of Health for approval.

Ethics Committee Approval

The ECReg indicates that ECs issue their own guidelines for research evaluation submissions, providing information and regulatory forms for investigators. The guidelines include information regarding the application deadline in relation to the evaluation date, the expected timeframe for notification of a decision, and the timeframe to follow if the EC requires applicants to submit additional information or documents. See the Submission Content section for detailed information on minimum requirements for the EC guidelines.

According to VNM-12, the review and approval process for CEBRGLs takes 30 days. Meetings are scheduled upon request and are based on the availability of the majority of its members.

The ECReg indicates that under both the expedited and full review processes, within 30 days from the date of receipt of a complete and valid dossier, the EC must organize an examination of the dossier and notify the applicant of the EC’s decision. While both processes may take up to 30 days, the expedited review is streamlined with fewer reviewers.

According to the ECReg, within five (5) working days from the date that the research dossier evaluation results are available, the EC must send a written notification to the leading research institution and principal investigator, and publish the evaluation results on a bulletin board or on the website of the EC or the organization that established the EC.

See Scope of Review section for details on the EC’s role in the clinical trial approval process.

Overview

In accordance with GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, COFEPRIS-GCP, G-HumResProt, and MEX-84, a clinical trial can only commence after an applicant receives authorization from Mexico’s Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Per HlthResRegs, G-HumResProt, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the applicant must also obtain a favorable decision from the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee at the health institution where the study is being conducted, and when applicable, a favorable decision from the Biosafety Committee. No waiting period is required following the applicant’s receipt of these approvals.

As per GenHlthLaw, an applicant must be a resident of Mexico and is required to obtain an import license from COFEPRIS for the shipment of an investigational product to be used in the trial. The applicant must be a resident of Mexico or have a legal representative submit the application on their behalf. (See the Manufacturing & Import section for additional information).

As set forth in NOM-220-SSA1-2016, the health record holder, principal investigator (PI), sponsor, or person responsible for a study authorized by COFEPRIS must also issue a notice of a study’s commencement (e.g., first visit of the first patient) and a notice of its completion (e.g., last visit of the last patient).

Clinical Trial Agreement

Prior to initiating the trial, as set forth in NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, if applicable, the sponsor must sign a letter of acceptance that serves as an agreement to assume the project obligations and rights stated in the letter. G-DIGIPRiS-ResProts also notes that the letter must include the sponsor’s delegation of activities to other institutions and/or companies duly authorized to accept the obligations, responsibilities, and rights imposed by the development and conduct of the study. Per G-DIGIPRiS-ResProts and NOM-012-SSA3-2012, in the case of corporate entities, this position must be accepted by an individual authorized to do so or by a corporation’s legal representative, according to its organizational structure or incorporation regime.

Additionally, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts state that the sponsor must sign a letter to ensure there are no conflicts of interest that could lead to the interruption of treatment for the research participant. NOM-012-SSA3-2012, further specifies that when the research is sponsored by a public or private organization, that it must be guaranteed that this will not generate conflicts of interest that could cause the interruption of treatment for the research participant. A detailed explanation of the resources available and the way in which they will be provided and distributed must also be attached in the research protocol.

According to COFEPRIS-GCP, COFEPRIS requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. COFEPRIS-GCP indicates that the sponsor must establish in writing each of the research team member functions and responsibilities, and the financial agreement with the PI. The sponsor or the CRO must also establish a declaration of financing, sponsorship, affiliations, contracts of agreements with other institutions involved, and procedures for handling any conflict(s) of interest, and a system for providing incentives and quantity/payments to research participants. MEX-32 specifies that the financial aspects of the trial should be documented in an agreement between the sponsor and the investigator and the institution.

Further, per MEX-32, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure and should provide sufficient time for the investigator and institution to review the protocol and the information provided.

COFEPRIS-GCP further states that in the case of delegating investigation-related activities to a CRO, the sponsor must also establish in writing each of the activities that are delegated. However, the ultimate responsibility for all CRO activities remains with the sponsor. Additionally, COFEPRIS-GCP indicates that the sponsor or the CRO must establish a declaration of financing, sponsorship, affiliations, contracts, or agreements with other institutions involved, handling of any conflict of interest, incentives, and quantity and payments to the research participants.

According to MEX-32, the sponsor or the CRO must also obtain the investigator(s)’s and the institution(s)’s agreement to:

• Conduct the trial in compliance with MEX-32 and the protocol agreed to by the sponsor and approved by the ethics committee
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor informs them that they are no longer needed

Per MEX-32, the sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

Per G-DIGIPRiS-ResProts, once an official authorization from COFEPRIS is obtained, some of the data provided by the applicant in COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86), will be migrated to COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37) and to the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). According to MEX-109, the G-RNECManual is useful for information on registering with RNEC for clinical trial applications submitted in person at the CIS (MEX-37).

Governance

Per GenHlthLaw, HlthResRegs, and NOM-012-SSA3-2012, every health institution where research is conducted is required to establish a Research Committee and a Biosafety Committee. Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, REC and Research Committee approval is also required for each trial site where a study is being conducted, and when applicable, Biosafety Committee approval is required as well.

HlthResRegs explains that the Research Committee evaluates the technical quality and scientific merit of the proposed research, and its opinion must contain the REC opinion and, where applicable, the Biosafety Committee opinion. The Biosafety Committee, in turn, is responsible for determining and regulating the use of ionizing radiation or genetic engineering techniques within the health institution as indicated in HlthResRegs, GenHlthLaw, and NOM-012-SSA3-2012. Pursuant to HlthResRegs, NOM-012-SSA3-2012, and G-HumResProt, the Biosafety Committee issues a technical opinion on the biosafety aspects of the proposed research and ensures that research study staff, research participants, the community, and the environment are protected against radiological risks.

Additionally, per MEX-47, COFEPRIS is responsible for registering Research Committees and Biosafety Committees. Refer to MEX-47, G-BiosafetyReg, and G-ResCommReg for detailed Research Committee and Biosafety Committee registration requirements. See MEX-26 for COFEPRIS’s Research Committee and Biosafety Committee registration form.

Overview

As delineated in the ClinDrugTrialGCP, the PharmLaw-VNM, and the ASTTReg, a clinical trial can only commence in Vietnam after authorization from the Ministry of Health (MOH) has been received. The MOH’s Administration of Science, Technology and Training (ASTT) manages the clinical trial review process. The ClinDrugTrialGCP indicates that the ASTT is responsible for reviewing the clinical trial registration and study approval dossiers. The MOH’s national level ethics committee (EC), the National Ethics Committee in Biomedical Research (NECBR), is responsible for approving the research protocol. Once the ASTT has completed its review and the NECBR has reviewed and approved the research protocol, the Minister of Health must give final approval to the entire study approval dossier. The ECReg further indicates that for research involving humans, institutions with ECs are responsible for overseeing an initial ethical and scientific appraisal of the research before it is reviewed by the NECBR. (Note: institutional level ECs are known as Councils of Ethics in Biomedical Research at the Grass Root Level (CEBRGLs) in Vietnam.) For institutions conducting research that do not have a CEBRGL, the review and evaluation of the research is performed by the NECBR or the CEBRGL of another institution with appropriate expertise.

As per the ExprtImprtMeds, an import license must be obtained for the shipment of an investigational product (IP) to be used in the trial from the MOH’s Drug Administration of Vietnam (DAV). See the Manufacturing & Import section for additional information.

Clinical Trial Agreement

As per the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), the sponsor is required to enter an agreement with the participating principal investigator (PI)/host institution(s) before the trial begins to demonstrate the financial agreement between the parties. The PharmLaw-VNM also states that the sponsor is required to sign a clinical trial contract with the investigator(s).

Clinical Trial Registration

According to VNM-12, the ASTT encourages the sponsor and the PI to register their study with the United States National Institutes of Health’s ClinicalTrials.gov (VNM-13).

Safety Reporting Definitions

In accordance with NOM-220-SSA1-2016, NOM-012-SSA3-2012, G-ClinResPV, and G-PharmPerSafRpt, the following definitions provide a basis for a common understanding of Mexico’s safety reporting requirements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Adverse Event/Experience (AE) – Any undesirable medical event that may occur in a research participant during the clinical investigation stage of a drug/vaccine, but does not necessarily have a causal relationship to it
• Adverse Drug Reaction or Adverse Reaction (ADR) – An unwanted response to a drug, in which the causal relationship with it is, at least, reasonably attributable
• Unexpected Adverse Drug Reaction – One whose nature or severity is inconsistent with the applicable product information, or in the documentation presented for its sanitary registration
• Suspected Adverse Drug Reaction (SRAM) – Any clinical or laboratory manifestation that occurs after administration of one (1) or more drugs

Safety Reporting Requirements

As specified in NOM-220-SSA1-2016-Mod, for clinical study related incidents involving health professionals (public and private) or institutions conducting health research, notifications to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS))’s National Pharmacovigilance Center (CNFV) must be submitted according to the following timelines:

• Serious SRAMs or serious AEs/ADRs must be reported within a maximum of seven (7) calendar days, if fatal, and within a maximum of 15 days, if not fatal (severe cases from abroad should only be included in the final study safety report, if the study has a research center in Mexico)
• Not serious SRAMs or AEs/ADRs must be reported at the end of the study
• Two (2) or more serious cases, in the same place with the same drug and the same batch, must be reported immediately, and no later than 48 hours
• When a review of scientific literature shows a safety issue, it should be reported within a maximum of 30 calendar days from first knowledge of the AE/ADR

HlthResRegs and NOM-012-SSA3-2012 state that the institution must notify and provide a report to the Ministry of Health (Secretaría de Salud) within a period of 15 days after the suspension or cancellation of the research has been agreed upon. The report should specify the effect(s) detected, all medical care steps adopted, and the consequences produced. A detailed report on the research participant(s) physical condition should also be included. NOM-012-SSA3-2012 indicates that all serious or deadly adverse reactions or effects must be immediately reported to the Ministry. Per NOM-012-SSA3-2012, the principal investigator (PI), the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), the institutional head(s), or the Ministry of Health must also suspend or cancel the research as soon as any AE representing an ethical impediment to research is identified.

Additionally, per NOM-220-SSA1-2016, institutions must notify the CNFV of a study’s suspension or cancellation within a maximum of 15 days. If the study is resumed, the CNFV must also be notified within a maximum of 15 working days following the study’s recommencement.

Per MEX-2, COFEPRIS has also implemented the following International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines:

• Guideline E2B (R3) on Electronic Transmission of Individual Case Safety Reports (ICSRs) – Data Elements and Message Specification – Implementation Guide (MEX-79)
• ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (MEX-80)
• ICH Harmonised Tripartite Guideline: Pharmacovigilance Planning (E2E) (MEX-82)

Investigator Responsibilities

As specified in HlthResRegs, NOM-012-SSA3-2012, and COFEPRIS-GCP, the PI must report to the REC all probable AEs or any AEs directly related to the research study. Per NOM-012-SSA3-2012, the investigator is also responsible for submitting safety reports to the CNFV.

Other Safety Reports

As indicated in NOM-220-SSA1-2016, a pharmacovigilance study protocol should be prepared and submitted to the Executive Director of Pharmacopeia and Pharmacovigilance through COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37).

Per NOM-220-SSA1-2016, a clinical safety report is also required to be submitted to the CNFV for all trials, sponsored or not, that have at least one (1) site or research center in Mexico. In addition, G-ClinResPV explains that a final safety report must be submitted to the CNFV in the following circumstances:

• A study is completed that has included at least one (1) research center in Mexico
• A study has been cancelled, discontinued, or definitively suspended
• A bioequivalence, bioavailability, and pharmacokinetics study is concluded

Refer to G-ClinResPV and G-PharmPerSafRpt for additional report writing instructions and criteria that align with the safety reporting requirements delineated in NOM-220-SSA1-2016 and NOM-220-SSA1-2016-Mod. See also G-PharmRptReq for detailed pharmacovigilance reporting guidelines and to extend sanitary registrations for drug products.

Form Completion & Delivery Requirements

G-ClinResPV specifies that clinical safety reports must be written in Spanish and submitted electronically (in PDF format) to the CNFV. In addition, reports should be submitted by either the health record holder or the sponsor or the legal representative to avoid sending duplicate information to the CNFV. G-PharmPerSafRpt states, in turn, that the safety report must be written in Spanish in the sections delineated in Annex 1 of G-PharmPerSafRpt and submitted electronically via CD or USB in editable PDF format. As indicated in G-ClinResPV and G-PharmPerSafRpt, the annual safety report submission date is determined by the date of the study’s first national authorization by COFEPRIS.

As per MEX-117, the E-Reporting Industry platform, which is linked to VigiFlow (MEX-43), was developed by the World Health Organization (WHO)’s Uppsala Monitoring Centre for the pharmaceutical industry to manage individual case safety reports at the national level. Reports are submitted by pharmaceutical industry professionals including health registration holders or their legal representatives and institutions/establishments where research is conducted as well as contract research organizations, distributors, and marketers. MEX-117 also specifies the CNFV is responsible for granting access to the E-Reporting Industry tool, and requests can be made via email: xmlvigiflow@cofepris.gob.mx. Refer to MEX-117 for details. Additionally, per MEX-77, state centers, institutional coordinating centers, institutional centers, and pharmacovigilance units of the National Health System should also report AE/ADRs, SRAMs, ESAVIs, and other safety issues via MEX-43.

MEX-78, in turn, provides patients, consumers, and health professionals instructions on reporting ADRs via VIGIRAM (MEX-118). See MEX-12 for instructions on using MEX-118, see MEX-30 for the form to be completed via MEX-118, and see MEX-119 for additional information on MEX-118. See also G-ADR-PatientRpt for information on how patients, consumers, and/or family members report suspected ADRs.

Refer to NOM-220-SSA1-2016 for detailed reporting requirements, and the G-AENotif, MEX-44, and MEX-117 for submitting safety reports via VigiFlow (MEX-43). See also MEX-54 for additional CNFV issued pharmacovigilance guidelines and requirements.

Safety Reporting Definitions

As delineated in the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP) and the AERprtingD62, the following definitions provide a basis for a common understanding of Vietnam’s safety reporting requirements:

• Adverse Event (or Adverse Experience) (AE) – Any untoward medical occurrence (including any signs, symptoms, illnesses, or test results) in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product
• Serious Adverse Event (SAE) – Any untoward medical occurrence that may lead to death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability or permanent incapacity, creates a congenital anomaly/birth defect, or requires appropriate medical intervention to prevent the aforementioned situations or medically important event
• Unexpected AE – AEs in which the essence, severity, specificity, or consequences are different or have not been recorded or considered in the study protocol or relevant study documents

Also, according to VNM-12, the Ministry of Health (MOH) uses the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (VNM-5) to define its safety reporting terminology.

Safety Reporting Requirements

Investigator Responsibilities

As per the BioequivTrial and the AERprtingD62, the principal investigator (PI) is responsible for detecting and settling SAEs and updating AE/SAE information to ensure the timeliness of reporting and the safety of the research participants. The PI is required to report to the sponsor, the institutional ethics committee (EC), also known as a Council of Ethics in Biomedical Research at the Grass Root Level (CEBRGL), the MOH’s National Ethics Committee in Biomedical Research (NECBR), the MOH’s Administration of Science, Technology and Training (ASTT), and the National Centre for Drug Information and Adverse Drug Reaction Monitoring (National DI and ADR Centre).

The ECReg further states that the NECBR is responsible for assessing the PI's recording, reporting, and handling of AEs occurring during the study.

The BioequivTrial indicates that depending on the type of AE/SAE, the PI must comply with the following reporting requirements:

• Fatal or life-threatening SAEs in Vietnam: A report, in accordance with Form 4 in the Appendix of the BioequivTrial, must be submitted to the NECBR, the ASTT, and the National DI and ADR Centre within seven (7) working days from the date of receiving information about the SAE. Updates on the SAE must be provided in additional reports until the participant recovers or stabilizes.
• SAEs that are not fatal or life-threatening in Vietnam: A report, in accordance with Form 4 in the Appendix of the BioequivTrial, must be submitted to the NECBR, the ASTT, and the National DI and ADR Centre within 15 working days from the date of receiving information about the SAE.
• Non-serious AEs occurring in Vietnam: The AEs must be recorded and summarized in a periodical report, and reported in the full results of the trial research results to the NECBR and the ASTT.

The BioequivTrial indicates that in the event of fatal or life-threatening AEs/SAEs, the PI and the host institution are required to suspend the trial immediately, provide care and treatment to the participant(s), overcome and resolve the consequences, and document the events. According to the AERprtingD62, the PI must also document any deaths. The BioequivTrial and the AERprtingD62 further indicate that the PI and the host institution must report these events to the CEBRGL, the NECBR, the ASTT, and the National Center of DI and ADR.

For AEs that cause harm to the participant’s health, the BioequivTrial and the AERprtingD62 indicate that the PI is responsible for treating and following up on the participant’s health until the person is stable.

According to the BioequivTrial, the PI should provide periodic updates regarding AEs/SAEs to the sponsor, the CEBRGL, the NECBR, the ASTT, and the National Center of DI and ADR. If the extent and frequency of AEs/SAEs exceeds the allowable limit, investigators may propose to the sponsor, EC, and competent regulatory authority that the clinical trial be suspended.

The BioequivTrial and the AERprtingD62 indicate that all the following must be reported:

• SAEs occurring at study sites in Vietnam
• SAEs occurring at study sites outside of Vietnam in a multicenter Vietnamese study that lead to cessation/suspension of the study or a change in the protocol
• All other AEs occurring in clinical drug trials at study sites in Vietnam

Sponsor Responsibilities

Per the BioequivTrial and the AERprtingD62, the sponsor must coordinate with the PI to report AEs/SAEs occurring at study sites in Vietnam to the CEBRGL, the NECBR, the ASTT, and the National Center of DI and ADR. The sponsor must collect AE/SAE data.

For SAEs occurring at study sites outside of Vietnam in a multicenter Vietnamese study, the BioequivTrial states that the sponsor must report to the NECBR, the ASTT, and the National Center of DI and ADR within 10 working days from the date of a decision to stop/suspend the study, withdraw participants from the study, or change the research protocol.

In addition, the AERprtingD62 requires that the sponsor report findings from clinical studies, epidemiology studies, in vitro studies, and other information that may lead to an important risk of the investigational product.

Form Completion & Delivery Requirements

Per the BioequivTrial, SAEs in Vietnam should be reported using a Reporting Form for SAEs in Clinical Trials (Appendix, Form 4).

Interim and Annual Progress Reports

Per HlthResRegs, NOM-012-SSA3-2012, and MEX-28, the principal investigator (PI) must prepare and submit a progress report (also referred to as a partial technical or technical-descriptive report) (MEX-31) to the Ministry of Health (Secretaría de Salud) at any time, but at least once a year, to communicate progress and partial research study results. In addition, per NOM-012-SSA3-2012, information related to any investigation that the PI submits to the Ministry of Health must be classified as confidential. NOM-012-SSA3-2012 further states that the PI must also provide a copy of every report to the head of the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee, and if applicable, the Biosafety Committee of the institution where the research takes place.

NOM-012-SSA3-2012 specifies that the progress reports should describe the results obtained and at a minimum should include the following elements:

• Identification data
• Materials and methods
• Results
• Conclusions
• Bibliographic references
• Any relevant exhibits

In accordance with NOM-012-SSA3-2012, a report should be submitted annually to the Ministry of Health on the integration and activities of the REC, the Research Committee, and, if applicable, the Biosafety Committee, during the first 10 business days of June.

Final Report

As set forth in HlthResRegs, NOM-012-SSA3-2012, and MEX-28, the PI is also required to submit a final report to the Ministry of Health in order to communicate the final results of a research protocol or project as well as the major findings obtained throughout the course of the study. Additionally, per NOM-012-SSA3-2012, the PI must deliver a copy of this report to the research team members, the REC, the Research Committee, and the Biosafety Committee, as applicable, where the study was conducted.

As per NOM-012-SSA3-2012, the final reports should describe the results obtained and at a minimum should include the following elements:

• Identification data
• Summary
• Introduction
• Materials and methods
• Results
• Discussion
• Conclusions
• Bibliographic references
• Any relevant exhibits/Annexes

See section 7.4 of NOM-012-SSA3-2012 for additional required report information.

HlthResRegs further states that the PI is also required to submit a final report to the Research Committee at the institution where the study was conducted. Refer to MEX-31 for the reporting form.

Interim and Annual Progress Reports

The BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP) indicates that investigators are responsible for providing periodic and unscheduled reports.

According to the ECReg, progress reports submitted to ethics committees (EC) for evaluation must contain the following:

• Summary of research protocol
• Complete research protocol, including previously approved revisions, if applicable
• Reports on research progress
• Reports on the number of participants who were selected for the study, completed the study, and withdrew from the study
• Detailed report on adverse events (AEs) and issues causing risks to participants, if applicable
• Summary of relevant information, especially safety information
• Current informed consent form (ICF)
• Independent inspection report of investigator and sponsor
• Notice of principal investigator (PI) or sponsor regarding early suspension/termination or completion of the study, if applicable

Final Report

The BioequivTrial and the ClinDrugTrialGCP indicate that the PI, the sponsor, and the host institution are responsible for submitting a final report to the Ministry of Health (MOH) when a study is completed. The final report, which must include an analysis of the data and information on AEs/serious adverse events (SAEs), must be submitted in accordance with Form No. 12 in Appendix III of the ClinDrugTrialGCP. The BioequivTrial further states that the clinical trial results must be made public within three (3) years from the date of issuance of the competent authorities' decision approving the results, and should comply with applicable copyright regulations.

As set forth in NOM-012-SSA3-2012, COFEPRIS-GCP, and MEX-84, a sponsor is defined as an individual or corporation willing to undertake responsibilities to participate and finance a research project or protocol, in full or in part.

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. Per COFEPRIS-GCP and MEX-32, a sponsor is an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. A sponsor may also hire a CRO to conduct one (1) or more of the activities related to health research that are sponsored in the country. The sponsor must specify in writing any trial-related duty and function that is transferred to and assumed by a CRO. However, the ultimate responsibility for all CRO activities remains with the sponsor. Additionally, MEX-32 notes the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, and any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. COFEPRIS-GCP also indicates that CROs of foreign origin must also have a registered address in Mexico, and an authorization to carry out clinical research activities in the country.

As per the ECReg and the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), the sponsor is defined as an individual, entity, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial. (Note: The ClinDrugTrialGCP and the BioequivTrial also refer to the sponsor as “organizations and individuals with clinical reagents” or “donor”.)

In addition, per the PharmLaw-VNM, the sponsor may select a qualified contract research organization (CRO) (also known as a research support organization in Vietnam) to run the clinical trial. The ClinTrialSup defines a CRO as an organization with the legal status to operate in the field of clinical trial research support and that is staffed with appropriately qualified personnel.

According to the ClinTrialSup, CROs may perform clinical research support activities such as implementing sponsors’ clinical research responsibilities, carrying out administrative support activities, and conducting clinical research monitoring. The ClinDrugTrialGCP indicates that a cooperative contract should exist between the sponsor and a CRO, if applicable. According to the PharmLaw-VNM, a sponsor and the CRO may be domestic or foreign.

In addition, as per the ClinTrialSup, CROs are also responsible for registering their organizations with the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT). Before implementing any activities in support of a clinical trial, a CRO must submit a registration dossier and the applicable forms for approval. The CRO is also required to report annually on its clinical research activities to the MOH’s ASTT. (See the ClinTrialSup for detailed information on clinical trial research support activities and the related registration forms.)

Overview

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. COFEPRIS-GCP states the sponsor or the CRO is responsible for selecting each research center and ensuring that COFEPRIS has authorized its operation as well as the human and material resources needed to conduct research. MEX-32 indicates the sponsor should ensure the investigator(s) have adequate resources to properly conduct the trial for which they are selected. Additionally, MEX-32, explains the investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.

Per COFEPRIS-GCP, the sponsor must establish in writing each of the research team member functions and responsibilities, and the financial agreement with the principal investigator (PI). G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts also note the sponsor or the CRO must specify in a letter the human and material resources that will be allocated for the research and the way in which they will be provided and distributed to the research sites.

As stated in the HlthResRegs and NOM-012-SSA3-2012, all investigators must possess appropriate qualifications, training, and experience. Per COFEPRIS-GCP, the PI is also responsible for selecting a research team with knowledge, education, and training in MEX-32, and in the process of the investigation in which the investigator is involved. Per MEX-32, the sponsor must ensure each investigator is qualified by education, training, and experience to assume responsibility for the proper conduct of the trial; meets all the qualifications specified by the applicable regulatory requirement(s); and provides evidence of such qualifications through updated curriculum vitae (CV) and/or other relevant documentation requested by the sponsor, the ethics committee (EC), and/or COFEPRIS. G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts also indicate the PI should provide legally issued and registered documentation delineating appropriate academic training and experience appropriate to the research to be conducted, which includes academic preparation, representative scientific production, and clinical practice.

G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts also indicate that institutions in charge of providing medical care for study related medical emergencies are required to sign an agreement or contract to provide these services, and a provide letter stating the institution’s acceptance, authorization, and description of the available resources.

Foreign Sponsor Responsibilities

COFEPRIS-GCP indicates that foreign CROs must have a registered address in Mexico, and an authorization or notice specifying the activities to be carried out in the country.

Data Safety Monitoring Board

According to COFEPRIS-GCP, the sponsor or the CRO is responsible for the continuous monitoring of the study which should be established based on the nature of the study, and must ensure study monitoring is carried out in compliance with MEX-32. Per MEX-32, the sponsor or the CRO may consider establishing an independent data monitoring committee to assess the progress of a clinical trial, the safety data, the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial. The committee should have written operating procedures and maintain written records of its meetings.

Multicenter Studies

As delineated in MEX-32, in the event of a multicenter clinical trial, the sponsor or the CRO must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and, if required, by COFEPRIS, and given ethics committee approval
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
• Investigator responsibilities are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
• Communication between investigators is facilitated

Overview

As set forth in the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP) and PharmLaw-VNM, the sponsor is responsible for selecting the investigator(s), the principal investigator (PI), the consultant experts, and the research institutions, taking into account the appropriateness and availability of the study site and facilities.

As stated in the BioequivTrial, all investigators must possess appropriate qualifications, training, and experience. All investigators involved in the trial must obtain completion certificates for a good clinical practice (GCP) course and a safety reporting course, each to be updated every three (3) years, from the Ministry of Health (MOH) or an authorized training facility.

See the BioequivTrial for information on PI and investigator rights and responsibilities.

Foreign Sponsor Responsibilities

No information is currently available on foreign sponsor requirements.

Data and Safety Monitoring Board

According to VNM-12, there are no requirements for establishing a Data and Safety Monitoring Board (DSMB). However, the MOH’s National Ethics Committee in Biomedical Research (NECBR) may recommend the establishment of a DSMB.

Multicenter Studies

The BioequivTrial states that for multicenter studies, in addition to analyzing general research results, it is necessary to conduct a separate analysis of key safety and efficacy variables on Asian or Vietnamese research populations using drugs for which racial factors are considered to have an effect on efficiency and safety. Furthermore, per the ClinDrugTrialGCP, the clinical trial study approval dossier must include documentation certifying the participation of research institutions in multicenter studies in Vietnam.

Insurance

As set forth in COFEPRIS-GCP, the sponsor or the contract research organization (CRO) must establish a financial fund or have insurance to cover serious adverse events that result from the medication or the research study.

Additionally, per COFEPRIS-GCP, which requires the sponsor or the CRO to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/institution against claims arising from the trial, except for those claims arising from malpractice and/or negligence. Per MEX-32, if required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator and the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

Compensation

As specified in COFEPRIS-GCP, the sponsor or the designated CRO must establish a statement of funding and describe the quantity and payments to be allocated for research participants.

Per MEX-32, the ethics committee (EC) should review both the amount and method of payment to participants to ensure that neither presents problems of coercion or undue influence on the trial participants. Payments to a participant should be prorated and not wholly contingent on the completion of the trial by the participant.

Injury or Death

Although NOM-012-SSA3-2012 does not specifically ascribe responsibility to the sponsor, it indicates that the research budget must include the availability of a financial fund as well as mechanisms to guarantee continuity of medical treatment and indemnity of the research participant, in the event of trial-related injuries. Additionally, the head of the institution or establishment, the, Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), Research Committee, or Biosafety Committee, the PI, and, where applicable, the sponsor, must be responsible, in accordance with their area of ​​competence, for the damage to health resulting from the development of the research as well as damage resulting from the interruption or early suspension of treatment for reasons not attributable to the research participant.

Per HlthResRegs and GenHlthLaw, the health care institution and the sponsor or the CRO must provide medical attention to injured participants, and where appropriate, legally required compensation, if the injuries are directly related to the study. Medical attention that is provided to such participants will not prejudice the compensation that may be legally due from the study.

In addition, per COFEPRIS-GCP, the sponsor or the CRO is also responsible for ensuring that research institutions provide urgent care resources, or where appropriate, have a written agreement with the health institution that will handle the emergencies. The agreement must comply with NOM-206-SSA1-2002, which establishes the criteria for the operation and attention in providing emergency services in health care institutions

MEX-32 explains the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s). In addition, when study participants receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).

In addition, per G-DIGIPRiS-ResProts and G-HumResProt, the sponsor should provide the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) with a copy of the financial fund or current insurance policy, which guarantees the continuity of the medical treatment and the compensation to which the participant will be legally entitled in the event of suffering damages directly related to the development of the research. MEX-84 specifies that the insurance policy or current document from the financial fund should cover all study participants at the local level. The document guarantees coverage to the participant in case of any injury or damage related to the research. The insurance policy and certificate must indicate the number of participants that will be covered, study title, protocol number, and must be on behalf of the license holder and the sponsor.

Trial Participation

Per COFEPRIS-GCP, the sponsor or the CRO must ensure that each and every treatment, clinical analysis procedure, and other study procedures are delivered in a timely manner, in good condition, and free of charge to the research participant.

Insurance

According to VNM-12, there is no specific Vietnamese guidance that addresses indemnity agreements between the sponsor and the contract research organization (CRO), investigator(s), or institution(s). However, the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP) lists an insurance contract as an essential document to be obtained by the principal investigator (PI), institution, and sponsor before conducting a clinical trial. The purpose of the insurance contract is to ensure that research participants will be compensated in the event of a trial-related injury.

Compensation

Injury or Death

As specified in the PharmLaw-VNM, the sponsor is responsible for providing compensation to research participants in the event of trial-related injuries. The BioequivTrial also states investigators are responsible for compensating participants when an adverse event that seriously impacts the participant’s health was caused by the investigator’s violation of the research protocol.

Trial Participation

According to the BioequivTrial, payment and compensation, if any, to clinical trial participants must be clearly indicated in the research protocol. Per the ECReg, ethics committees (ECs) must consider the amount and method of payment to ensure that there is no coercion or influence on the voluntariness of participants. Payments should be made according to each visit.

Quality Assurance/Quality Control

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32), and to ensure and control the quality of the research during a study. Per COFEPRIS-GCP and MEX-32, the sponsor or the CRO is also responsible for establishing written standard operating procedures (SOPs) for each stage of the investigation. In addition, the sponsor or the CRO must implement and maintain quality assurance (QA) and quality control (QC) systems to make certain the trial is conducted, and data are generated, recorded, and reported in compliance with the protocol.

MEX-32 further delineates the sponsor or the CRO is required to obtain agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. The sponsor and investigator(s) agreement should be confirmed in writing prior to the trial. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

Monitoring Requirements

According to COFEPRIS-GCP, the sponsor or the CRO must ensure and control the quality of the research through periodic monitoring visits and audits to ensure compliance with the protocol and the SOPs, and if necessary, compliance with reports derived from inspections or verifications by COFEPRIS. The principal investigator (PI) is responsible for reporting and guaranteeing the quality and validity of the data obtained during the investigation. MEX-32 indicates the sponsor should ensure that the trials are adequately monitored and determine the appropriate extent and nature of monitoring, which should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial.

Additionally, per MEX-32, the sponsor should also appoint the monitors who should be appropriately trained, and have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented. Monitors should also be thoroughly familiar with the investigational product(s), the protocol, written informed consent form, and any other written information to be provided to research participants, the sponsor’s SOPs, COFEPRIS-GCP, and the applicable regulatory requirement(s).

MEX-32 further indicates the sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits and ensure the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented. The sponsor should also ensure the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports. The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of study participants, the type and complexity of the trial, the level of risks to the study participants, and any identified problem(s). Auditor(s) observations and findings of the auditor should be documented.

Pursuant to MEX-32, noncompliance with the protocol, SOPs, good clinical practice, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance. If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution’s participation in the trial and notify promptly the regulatory authority(ies). Also, upon the request of the monitor, auditor, ethics committee (EC), or COFEPRIS, the investigator/institution should also make available for direct access all requested trial-related records. See MEX-32 for detailed monitoring and auditing requirements.

Per NOM-012-SSA3-2012, the institutional head, the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), Research Committee, or Biosafety Committees, the PI, and, where applicable, the sponsor, must be responsible, in accordance with their area of competence, for monitoring the research. NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts further require the sponsor or the CRO to provide a follow-up letter to COFEPRIS describing the monitoring and auditing plan to be carried out during the investigation. G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts specify the letter must contain the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Type of plan: audit or monitoring
• Frequency of application
• Responsibility for monitoring, and where appropriate, cite the third party to carry out the activity
• Objective and scope of monitoring
• Evaluation tools and methodology implemented
• Methodology to carry out the scientific, technical, and ethical monitoring
• Communication and notification strategies between investigator, sponsor, ECs, and COFEPRIS
• Profile of the monitor or auditor
• Classification of findings and decision-making
• Decision-making derived based on severity classification
• Notification mechanism to the PI, ECs, and COFEPRIS
• Design of the Action Plan: Corrective, Improvement, or Preventive
• Reporting results through the partial and annual technical report (See MEX-31 for the partial reporting form)

COFEPRIS-GCP also states that the PI is responsible for reporting and guaranteeing the quality and validity of the data obtained during the investigation.

Premature Study Termination/Suspension

Per HlthResRegs the PI, the REC, the institutional head or other authorized institutional officers, or the Ministry of Health (Secretaría de Salud) must order the immediate suspension or cancellation of a research study as soon as any adverse effect is identified that might become an ethical or technical impediment to continuing with the study. The health care institution will submit a report to the Secretariat within 15 business days following the day in which the suspension or cancellation of the study was agreed, specifying the effect noticed, the measures adopted, and consequences produced. NOM-012-SSA3-2012 similarly states the head of the institution or establishment, the REC, the Research Committee, the Biosafety Committee, or PI must order the immediate suspension or cancellation of research, in the presence of any severe adverse effects, which become an ethical or technical impediment to continue with the study and notify the Secretariat in detail. The institutional head must notify the Secretariat of any adverse effect resulting from the experimental research within a maximum period of 15 working days from the event occurrence, including the care measures adopted, the identified sequelae, as well as a detailed report on the physical condition of the patient, which mentions whether the patient is free of any risk at the time of notification. In such case, the resumption of the research will require a new authorization. The investigator is also responsible for suspending the investigation if there is a risk of serious injury, disability, or death of the research subject in accordance with GenHlthLaw. Additionally, per NOM-220-SSA1-2016, institutions must notify the National Pharmacovigilance Center (CNFV) of a study’s suspension or cancellation within a maximum of 15 days. If the study is resumed, the CNFV must also be notified within a maximum of 15 working days following the study’s recommencement. The investigator is responsible for submitting safety reports to the CNFV.

MEX-32 delineates if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s). The EC should also be provided with a detailed written explanation of the termination or suspension.

MEX-32 further indicates that if the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial participants, ensure appropriate therapy and follow-up for the participants, and, where required by the applicable regulatory requirement(s), inform the regulatory authority(ies). If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the EC and provide the sponsor and the EC with a detailed written explanation of the termination or suspension. If the EC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution where applicable, and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

Quality Assurance/Quality Control

As stated in the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), the sponsor is responsible for assigning a monitor to assist in maintaining a quality assurance (QA) system with written standard operating procedures (SOPs) that ensure trials are conducted and data are generated, recorded, and reported in compliance with the protocol. In addition, the quality management system applied in clinical trials must meet International Organization for Standardization (ISO) 9001-equivalent standards or higher.

Per the BioequivTrial, the principal investigator (PI) is responsible for ensuring the accuracy, truthfulness, confidentiality, integrity, and verifiability of the research data. Correction of data must be in accordance with applicable regulations: without deleting the original data, the assigned researcher must name, sign for confirmation, and specify the date of correction. The lead investigator must submit an encrypted list of trial participants to the regulatory agency after the clinical trial ends. The retention and submission of the list of participants after decryption must be kept secret.

The trials should be conducted in compliance with good clinical practice (GCP) principles and standards outlined in the ClinDrugTrialGCP and the BioequivTrial Appendix, which are based on the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (VNM-5) and the World Health Organization’s (WHO) Guidelines for Good Clinical Practice for Trials on Pharmaceutical Products (Please refer to Annex 3 of The Use of Essential Drugs: Sixth Report of the WHO Expert Committee for these guidelines (VNM-10)).

Monitoring Requirements

As part of its QA system, the BioequivTrial states that the sponsor should assign a monitor to inspect the trial. The sponsor should appoint individuals who are independent from the trial and are qualified by training and experience to conduct inspections, in accordance with the ClinTrialSup. The ClinDrugTrialGCP further indicates that SOPs, the monitoring/inspection plan, and procedures must also be submitted to the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT).

For information on ASTT and ethics committee (EC) monitoring responsibilities, see the Scope of Assessment and Scope of Review sections.

Premature Study Termination/Suspension

According to the BioequivTrial, the sponsor may terminate a trial early if the sponsor learns of any serious protocol violations that seriously affect the health of trial participants, or, the accuracy and truthfulness of the data during an inspection. The sponsor should send notices to the Council of Ethics in Biomedical Research at the Grass Root Level (CEBRGL), the MOH’s National Ethics Committee in Biomedical Research (NECBR), and the relevant authority, in addition to notifying the institution and PI.

Electronic Data Processing System

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. Per MEX-32, the sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

In addition, per MEX-32, when using electronic trial data processing or handling systems or remote electronic trial data systems, the sponsor should:

• Ensure and document that the electronic data processing system(s) conform(s) to the sponsor's established requirements for completeness, accuracy, reliability, and consistent intended performance
• Maintain standard operating procedures (SOPs) for using these systems
• Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data
• Maintain a security system that prevents unauthorized access to the data
• Maintain a list of the individuals who are authorized to make data changes
• Maintain adequate backup of the data
• Safeguard the blinding, if any

See MEX-32 for additional data processing requirements.

Records Management

As indicated in MEX-32, the sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see section 8 of MEX-32). The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the investigational product (IP) is approved, and/or where the sponsor intends to apply for approval(s). If the sponsor discontinues the clinical development of an IP (i.e., for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least two (2) years after formal discontinuation or in conformance with the applicable regulatory requirement(s).

MEX-32 also states the essential documents should be retained until at least two (2) years after the last marketing approval or at least two (2) years have elapsed since the formal discontinuation of clinical development of the IP. These documents should be retained for a longer period, however, if required by the applicable regulatory requirement(s) or if needed by the sponsor. The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) when trial-related records are no longer needed.

In addition, as delineated in COFEPRIS-GCP, the principal investigator (PI) is responsible for preparing, integrating, using, filing, and ensuring the safekeeping of the research participant’s clinical file for a minimum of five (5) years in accordance with NOM-004-SSA3-2012, MEX-32, and Good Documentation Practices per NOM-164-SSA1-2015.

Per NOM-004-SSA3-2012, clinical records are the property of the institution or the medical services provider that generates them. However, the patient/participant has ultimate ownership rights over this information to protect their health and the confidentiality of their data. Consequently, because the documents are prepared in the interest and benefit of the patient/participant, they must be kept for a minimum period of five (5) years, which is calculated from the date of the last medical procedure/visit.

Electronic Data Processing System

According to the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), when using electronic trial data processing systems, the sponsor should use appropriate data handling programs and have adequate standard operating procedures (SOPs) for these systems. In addition, per the ClinDrugTrialGCP, the research institution’s general documentation must include a brief description of any electronic document system in its technical and professional standards, if applicable.

Records Management

As per the BioequivTrial, all information on clinical trials must be recorded, handled, managed, and kept in accordance with applicable regulations in order to accurately report, interpret, monitor, and check the accuracy and reliability of clinical trial information and data. Research institution facilities for storing clinical trial records and documents must ensure confidentiality; restricted access; fire and explosion prevention and control; and avoidance of adverse effects of light, temperature, humidity, and penetration of insects and other animals. In addition, research dossiers and documents should be archived and preserved according to the contract between the sponsor and the institution. For research and development of new products, documentation needs to be kept for at least 10 years.

Responsible Parties

According to the PDP-PrivateLaw, the PDP-Reg, the PDP-Public, and MEX-4, a private entity that processes personal data is called the “responsible person or entity” or “controller.” Federal, state, or local authorities are referred to as “obliged subjects” and make decisions about the processing of personal data. The private and public entities must protect personal data in accordance with the above laws and regulations.

Data Protection

PDP-PrivateLaw, PDP-Reg, and PDP-Public provide the requirements, responsibilities, and restrictions for handling personal data in the public and private sectors. The PDP-Public regulates the processing of personal information in the public sector by “obliged subjects”. The PDP-PrivateLaw and the PDP-Reg regulate the processing of personal information in the private sector by an individual or legal entity of a private nature.

Per the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public, the sponsor or the sponsor’s representative(s) must comply with the principles of data protection: legality, purpose, loyalty, consent, quality, proportionality, information, and responsibility in the processing of personal data.

According to the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public, the sponsor is also required to protect the confidentiality of the owner of the personal data and their background. The PDP-PrivateLaw further notes that this obligation will remain in place even after the data processing activities have been completed and the relationship between the sponsor or the sponsor’s representative(s) and the data owner has concluded.

Additionally, the PDP-PrivateLaw and the PDP-Public provide definitions to address health related data. Sensitive personal data refers to the most intimate sphere of its owner, whose improper use may result in discrimination, or carries a serious risk of resulting in discriminatory activities. More specifically, data considered to be sensitive may reveal personal information such as racial or ethnic origin, present or future health status, genetic information, religious, philosophical, and moral beliefs, political opinions, and sexual preferences.

Per the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public, data owners have the right to be informed about the collection and use of their personal data. Per the PDP-Reg, the person responsible must also inform the information owner regarding the existence and main characteristics of the treatment to which their personal data will be subjected through the consent document, known as the “privacy notice,” in accordance with the provisions of the PDP-PrivateLaw and the PDP-Reg.

Please refer to the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public for detailed information on the principles guiding the protection and handling of personal data. See also MEX-3 and MEX-4 for additional information on data protection requirements.

Consent for Processing Personal Data

As explained in the PDP-PrivateLaw and the PDP-Public, the consent document or “privacy notice” is a physical document, electronic, or any format generated by the sponsor, that is made available to the data owner prior to processing the owner’s personal data. The PDP-Reg further explains that the privacy notice must be characterized as simple, with necessary information expressed in clear and understandable language, and with a structure and design that facilitates the owner’s understanding.

The PDP-PrivateLaw states that in the case of sensitive data, the sponsor is required to obtain the express and written consent of the data owner for the sponsor’s use, through a written or electronic signature, or any authentication mechanism established for that purpose. In cases where sensitive personal data is being processed, the sponsor must make reasonable efforts to limit processing to the minimum period necessary to complete the goal as delineated in the privacy notice. Moreover, databases containing sensitive personal data may not be created without justifying their creation for legitimate, concrete purposes, and if they are not in accordance with the specified activities delineated and pursued by the sponsor. The PDP-Reg also notes that sponsors may only create databases containing sensitive personal data when they obey a legal mandate; are justified pursuant to the territorial scope of the regulation; or are required by the sponsor for legitimate, concrete purposes, and in accordance with the activities or explicit purposes indicated in the privacy notice.

The PDP-Reg, whose focus is on regulating the process of personal data held in physical or electronic media, further indicates that the sponsor must obtain prior consent to process the data when acquired personally or directly from its owner. Whether tacit or express, the consent process must be:

• Free: without error, bad faith, violence, or intent, which may affect the manifestation of the owner’s will
• Specific: referring to one (1) or more specific purposes that justify the treatment, and
• Informed: the owner has knowledge of the privacy notice prior to granting consent to the processing of their data

The sponsor must obtain the owner’s express consent when their data is deemed sensitive. The express consent must also be unequivocal; that is, there are elements that indisputably demonstrate its granting.

As delineated in the PDP-Public, the sponsor will not be required to obtain consent when processing sensitive data in the following cases:

• When an applicable law authorizes such processing, and is consistent with and does not contravene the bases, principles, and provisions set forth in the PDP-Public
• When sensitive personal data transfers are made between those responsible, the transfers are compatible with the original purpose that motivated the processing of personal data
• When there is a judicial order, resolution, or well-founded and motivated mandate of the competent authority
• For the recognition or defense of the owner's rights before the competent authority
• When personal data is required to exercise a right or fulfill obligations derived from a legal relationship between the owner and the person in charge
• When there is an emergency that could potentially harm an individual or the individual’s property
• When personal data is necessary to carry out a treatment for the prevention, diagnosis, or provision of health care
• When the personal data appear in publicly accessible sources
• When personal data is subject to a prior dissociation procedure
• When the owner of the personal data is a person reported missing under the terms of the law on the matter

Please refer to the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public for detailed consent and privacy notice requirements.

Consent for Processing Personal Data of Minors

Per the PDP-Public, in processing the personal data of minors, the best interest of the children and adolescents must be prioritized in accordance with the applicable legal provisions. MEX-4 further states legal guardians must always give consent when processing children’s personal data. This applies to any individual younger than 18 years of age.

(See the Children/Minors section for additional information on consent requirements for children/minors.)

Responsible Parties

Per Decree13, the personal data controller is an organization or individual that decides the purposes and means of processing personal data. The personal data processor is an organization or individual that performs data processing on behalf of the data controller, through a contract or agreement with the data controller. An organization or individual that both decides the purposes and means for, and directly processes, personal data is referred to as a personal data controller and processor.

Decree13 states that the personal data controller must:

• Implement organizational and technical measures, as well as appropriate safety and security measures, to prove that data processing activities have been carried out in accordance with Decree13, reviewing and updating these measures as necessary
• Record and store a system log of personal data processing
• Notify the Ministry of Public Security (MPS) of violations of regulations on protection of personal data as prescribed in Decree13
• Select a personal data processor in accordance with a clear mandate and work only with a personal data processor that has appropriate safeguards in place
• Ensure the rights of data subjects as prescribed in Decree13

Additionally, Decree13 indicates that the personal data processor must:

• Only receive personal data after having a contract or agreement on data processing with the personal data controller, and process personal data in accordance with the contract or agreement
• Fully implement measures to protect personal data specified in Decree13 and other relevant legal documents
• Delete and/or return all personal data to the personal data controller after finishing data processing

According to Decree13, both the personal data controller and processor are also responsible to the data subject for damages caused by the processing of personal data. In addition, they must cooperate with the MPS and competent state agencies in protecting personal data by providing information for investigation and handling of violations of Decree13.

Per VNM-8, the MPS is responsible for protecting the rights of data subjects against violations of Decree13, and for maintaining the National Information Portal on Personal Data Protection (VNM-7). See VNM-7 for additional personal data protection resources.

Data Protection

Per Decree13, organizations and individuals involved in personal data processing must apply personal data protection measures to prevent unauthorized collection of personal data from translation systems and equipment. It is illegal to set up software systems, enact technical measures, or organize activities of collecting, transferring, buying, and selling personal data without the consent of data subjects.

According to Decree13, personal data protection measures must be applied from the beginning and throughout the processing of personal data, including management, technical, investigational, and procedural measures. Network security for the data processing system, as well as the means and equipment, must be checked before processing data, irrecoverably deleting data, or destroying devices containing personal data.

Decree13 states that in the case of sensitive personal data, a department with the function of protecting personal data must be designated, personnel in charge of personal data protection must be appointed, and information about the department and individual in charge of personal data protection must be exchanged with the agency specializing in personal data protection (e.g., MPS). Additionally, data subjects must be notified that their sensitive personal data is being processed.

Decree13 states that if a violation of Decree13 has been detected, the personal data controller/personal data controller and processor must notify the MPS’s Department of Cybersecurity and Prevention within 72 hours after the violation occurs using Form No. 03 (see Appendix of Decree13 or VNM-9). If the notification is submitted after 72 hours, the reason for the late notice must be attached. Additionally, the personal data processor must notify the personal data controller of the violation as quickly as possible. See Decree13 and VNM-9 for more information on notification requirements for violations of personal data protection regulations.

Consent for Processing Personal Data

Decree13 delineates that a data subject’s consent is only valid when the data subject voluntarily and clearly knows the type of personal data to be processed; the purpose of processing personal data; that organizations and individuals are allowed to process the personal data; and the rights and obligations of data subjects. The data subject’s consent must be expressed clearly, specifically in writing, by voice, by ticking the consent box, in the syntax of consent via text message, by selecting consent technical settings, or through another action that demonstrates consent. When there are multiple purposes for the data collection, the personal data controller/personal data controller and processor must list the purposes for the data subject to agree to one (1) or more of the stated purposes, and consent must be given for each purpose. The data subject’s consent must be expressed in a format that can be printed or reproduced in writing, including in electronic or verifiable formats. Silence or non-response of the data subject is not considered as consent, and the data subject may give partial or conditional consent. The data subject’s consent is valid until the data subject decides otherwise or when the competent state agency requests in writing.

Per Decree13, data subjects also have a right to: be aware of data processing activities; access their data; delete data; restrict data processing; provision of data; object to data processing; complain, denounce, and initiate lawsuits; claim damages; and self-defense. For the processing of sensitive personal data, the data subject must be informed that the data to be processed is sensitive personal data.

Decree13 states that in certain cases, the data subject’s consent is not required for the processing of personal data. This includes urgent cases where it is necessary to immediately process relevant personal data to protect the life and health of the data subject or others, and in the event of a state of emergency on national defense, security, social order and safety, major disasters, or dangerous epidemics.

See Decree13 for more details on obtaining consent from data subjects; the rights of data subjects; and situations where consent is not required for the processing of personal data.

Withdrawal of Consent

According to Decree13, withdrawal of consent must be in a format that can be printed or reproduced in writing, including in electronic or verifiable format. Upon receiving a request from a data subject to withdraw consent, the personal data controller/personal data controller and processor must notify the data subject of possible consequences and damages that may occur when consent is withdrawn. The personal data controller, personal data processor, personal data controller and processor, and any third parties must stop, and request any relevant organizations and individuals to stop, processing the data of the data subject that has withdrawn consent. Withdrawal of consent does not affect the legality of the data processing that was agreed to prior to the withdrawal.

Children

Per Decree13, children’s personal data must be processed in accordance with the principle of protecting the rights and ensuring the best interests of the children. The processing of children’s personal data must have the consent of the child if the child is seven (7) years of age or older, as well as the consent of the parent(s) or legal guardian(s). The personal data controller, personal data processor, personal data controller and processor, and any third parties must verify the age of the children before processing the children's personal data. The relevant parties must stop processing the children’s personal data and/or irreversibly delete or destroy the children’s personal data in the following cases:

• The data was processed for improper purposes, or the purpose of processing personal data with the consent of the data subject has been fulfilled, unless otherwise provided for by law
• The child’s parent(s) or legal guardian(s) withdraws consent for the processing of the child’s personal data, unless otherwise provided for by law
• At the request of a competent authority when there are sufficient grounds to prove that the processing of personal data affects the children’s legitimate rights and interests, unless otherwise provided for by law

Obtaining Consent

In all Mexican clinical trials, a freely given informed consent is required from each participant in accordance with the requirements set forth in HlthResRegs, GenHlthLaw, NOM-004-SSA3-2012, and COFEPRIS-GCP. Per COFEPRIS-GCP, the principal investigator (PI) is required to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) in obtaining and documenting informed consent, and per G-RECs-Op-2018, the PI must also comply with consent requirements as delineated in the Declaration of Helsinki (MEX-76). (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MEX-22)).

As per HlthResRegs and G-RECs-Op-2018, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by a Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and provided to COEFPRIS with the request for research protocol authorization. (See the Required Elements section for details on what should be included in the form.)

HlthResRegs, COFEPRIS-GCP, and NOM-012-SSA3-2012 state that the PI must provide detailed research study information to the participant or legal representative/guardian. As delineated in HlthResRegs, G-RECs-Op-2018, NOM-012-SSA3-2012, MEX-32, and MEX-84, the ICF content should be presented with a clear explanation and provided in a format that facilitates understanding. Per NOM-012-SSA3-2012 and MEX-32, the participant or legal representative/guardian should also be given adequate time to consider whether to participate. GenHlthLaw and MEX-84 further note the ICF should be expressed in writing in an accessible, timely manner and in understandable language, using accurate and complete information, including the possible benefits and expected risks, and the treatment alternatives, to ensure that services are provided on the basis of free and informed consent. Once comprehension of the information is guaranteed through the necessary means and supports, individuals have the right to accept or reject consent. G-DIGIPRiS-ResProts, MEX-84, and G-HumResProt indicate the ICF and/or assent form, as applicable, is a document through which the research participant agrees to voluntarily participate in a research study and to undergo experimental procedures when the information is presented in a sufficient, timely, clear and truthful manner regarding the expected risk and benefits.

As per HlthResRegs, G-RECs-Op-2018, and MEX-32, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

Re-Consent

According to G-RECs-Op-2018 and MEX-32, any change in the ICF that is relevant to the participant’s consent should be approved by the REC prior to implementing any changes. Per G-RECs-Op-2018 and MEX-32, the participant or legal representative/guardian should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participating in the trial. MEX-32 further states the communication of this information should be documented.

Language Requirements

G-HumResProt states that the applicant must submit the request for protocol authorization application and all associated documentation (including the protocol and the ICF) in Spanish.

Documenting Consent

As delineated in HlthResRegs, G-RECs-Op-2018, and MEX-32, the participant or legal representative/guardian, as well as two (2) witnesses, must sign the ICF. MEX-32 specifies that the ICF should be dated, and any updates must also be signed, and a copy of the amendments provided to the participant or legal representative/guardian. If the participant does not know how to sign, the participant will provide a fingerprint and will also need to designate someone to sign the participant’s name on their behalf. A copy of the signed ICF will be provided to the participant or legal representative/guardian. Per G-DIGIPRiS-ResProts, which complies with MEX-22, the ICF version and date must coincide with what is recorded as approved in the opinions of the ethics committees (ECs). G-HumResProt further specifies the ICF should be signed by the PI, the participant and the participant’s family, or a legal representative and two (2) witnesses. The names of the witnesses, the addresses, and the relationships the witnesses have with the research participant must be indicated. MEX-84 also notes a section in the ICF should be provided for the participant or the legal representative to sign the document to indicate express acceptance. The section must include general data (full name, address, relationship with the participant) and signatures of two (2) witnesses.

Waiver of Consent

No information is currently available regarding waiver requirements.

Obtaining Consent

In all Vietnamese clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the ClinDrugTrialGCP, the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), and the PharmLaw-VNM. As per the ClinDrugTrialGCP, the BioequivTrial, and the ECReg, the informed consent form (ICF) is viewed as an essential document that must be sent to the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT) as part of the clinical trial study approval dossier, for which the Minister must issue final approval.

The ECReg indicates that a research proposal involving humans, including the ICF, must undergo ethical and scientific review by the MOH’s National Ethics Committee in Biomedical Research (NECBR) and an institutional level ethics committee (EC) (known as a Council of Ethics in Biomedical Research at the Grass Root Level (CEBRGLs)).

The BioequivTrial states that the principal investigator (PI) or the clinical testing facility is responsible for obtaining written consent from trial participants before carrying out any study procedures.

As per the ECReg, the ICF should be provided in easy-to-understand language, suitable for potential research participants to support their ability to give fully informed consent. For participants with limited education, the ICF should be provided and explained verbally. According to the BioequivTrial and the ECReg, the information should also be presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The ClinDrugTrialGCP further states that the participant or legal representative/guardian should also be given the opportunity to ask questions about the research, and given adequate time to consider whether to participate.

Re-Consent

No information is currently available on re-consent.

Language Requirements

As delineated in the ClinDrugTrialGCP, the clinical trial application and accompanying material must be provided in Vietnamese or English. If the document is not available in Vietnamese or English, a notarized translation of the document must be provided in Vietnamese or English.

VNM-12 indicates that the ICF content should be presented in Vietnamese and English for global clinical studies, but for studies with domestic sponsors, only Vietnamese is required. The English copy serves as a reference to the NECBR. The study information sheet should be in Vietnamese.

Documenting Consent

As per the ClinDrugTrialGCP, the BioequivTrial, the ECReg, and the PharmLaw-VNM, the participant or the legal representative/guardian must sign and date the ICF. No information is provided in these sources concerning copies to be issued to the participant or legal representative/guardian.

Waiver of Consent

The ECReg indicates an EC may waive the requirement for written voluntary consent from research participants if the study requires absolute confidentiality. The EC’s decision to waive the voluntary written consent requirement must consider the benefits and risks of the study to the participants, as well as measures to protect the rights and safety of the participants.

As delineated in G-RECs-Op-2018 and MEX-84, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Identification data (Title, protocol number, version, version date, research institution data, principal investigator (PI) name, medical emergency establishment data, and Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), and this data must coincide with the opinions of the ethics committees)
• The study rationale and objectives
• Purpose and procedures, including all invasive procedures
• Identification of experimental aspects of the study
• Trial duration
• Participant’s responsibilities
• Investigator responsibilities
• Approximate number of participants
• Circumstances that may terminate the study
• Duration of study
• Any expected risks or discomforts to the participant
• Any expected benefits to the participant; if no benefit is expected, the participant should be informed of this point (physical examination, laboratory tests and imaging should not be considered as benefits to the participant)
• Alternative treatments that may be beneficial to the participant
• Trial treatment(s) and the probability for random assignment to each treatment
• Explains the blinding of the study (if applicable) and what it consists of
• Allocation method
• Compensation and/or treatment available for the participant by the health care institution in the case of trial-related injury
• All drugs, products, and procedures are free
• That participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
• Assurance that the participant will not be identified and that their confidential information relating to their privacy will be maintained
• Confidentiality of records identifying the participant will be maintained (including sensitive personal data and data derived from the study), and permission given to monitors, auditors, the REC, and the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) to access the participant’s medical records to verify the procedures or trial data, without violating the participant’s confidentiality, insofar as the applicable laws and regulations permit
• Contact information for the sponsor and PI in the event of participant problems or trial-related injuries
• Communication channels and data to request clarification and to guarantee a response to questions and clarification of concerns about procedures, risks, benefits, and other matters related to the investigation and treatment of the participant
• Foreseeable circumstances under which the PI(s) may remove the participant without their consent
• Commitment to provide updated information throughout the study although this may affect the participant’s willingness to continue
• Notification that any additional research study expenses will be absorbed by the research budget

The Guideline for Good Clinical Practice E6 (R1) (MEX-32) also mentions the following required elements:

• Any expected risks or discomforts, when applicable, to the embryo, fetus, or nursing infant
• Any anticipated prorated payment to the participant for participating in the trial
• Any expenses the participant needs to pay to participate in the trial

Additionally, per NOM-012-SSA3-2012, the investigator must ensure that the ICF explicitly states the compensation to which the research participant is entitled in the event of suffering damage to their health directly attributable to the research, and the availability of free medical treatment, even in the event the participant decides to withdraw from the study before it is concluded.

See HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, and MEX-32 for additional details related to ICF requirements. (Note: Per MEX-2, COFEPRIS is in the process of implementing the International Council for Harmonisation's Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

Also, see the Vulnerable Populations and Consent for Specimen sections for further information.

Based on the ClinDrugTrialGCP, the informed consent form (ICF) should include the following statements or descriptions, as applicable:

• Description of research with an explanation of its purpose and objectives
• Expected duration of study
• Research methods to be followed
• Inclusion and exclusion criteria for research participants
• Identification of investigator(s) who will be responsible for assessing confidential medical information to select study participants
• Number of participants involved in the study
• Description of any foreseeable risks to the participant
• Any expected benefits to the participant and/or the community, and any study-related payment to the participant
• Alternative procedures or treatment that may be available to the participant
• The extent to which confidentiality of records identifying the participant will be maintained
• Selection of those parties who will be able to access, inspect, supervise and monitor the participant’s records
• Compensation and/or medical treatment available in the event of a trial-related injury
• Person(s) to contact for further information regarding the trial and the rights of trial participants and whom to contact in the event of trial-related injury
• Statement that participation is voluntary and the participant may withdraw at any time for any reason

See Form No. 9 in Appendix III of the ClinDrugTrialGCP for a copy of the ICF.

Compensation Disclosure

Per the ECReg, ethics committees (ECs) must ensure that information relating to payment for study participants, including the method, amount, and payment schedule, is included in the ICF and other documents given to participants.

Overview

In accordance with HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, and the Guideline for Good Clinical Practice E6 (R1) (MEX-32), Mexico’s ethical standards promote respect for all human beings and safeguard the rights of research participants. (COFEPRIS-GCP requires the principal investigator (PI) to comply with MEX-32). HlthResRegs and MEX-32 state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation's Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

The Right to Participate, Abstain, or Withdraw

As stated in HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, MEX-32, and MEX-84, the participant or legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As per HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, MEX-32, and MEX-84, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

According to G-RECs-Op-2018, MEX-32, and MEX-84, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. In addition, per NOM-004-SSA3-2012, although clinical records are the property of the institution or the medical services provider that generates them, the participant has ultimate ownership rights over this information to protect their health and the confidentiality of their data.

The Right of Inquiry/Appeal

MEX-32 states that the research participant or legal representative/guardian should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or their rights. G-RECs-Op-2018 further specifies that the names and contact information of the PI and the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI))’s president, including a 24-hour telephone number in case of emergency, should be provided.

The Right to Safety and Welfare

HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, COFEPRIS-GCP, and MEX-32 that upholds the Declaration of Helsinki (MEX-76), clearly state that a research participant’s right to safety and the protection of their health and welfare must take precedence over the interests of science and society.

See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

Overview

In accordance with the ClinDrugTrialGCP, Vietnam’s ethical standards promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As stated in the ClinDrugTrialGCP and the PharmLaw-VNM, the participant or the legal representative/guardian should be informed that participation is voluntary and that the participant may withdraw from the research study at any time for any reason without being held liable.

Additionally, the PharmLaw-VNM states that participants have the responsibility to comply with investigators’ instructions according to approved clinical trial documents.

The Right to Information

As per the ClinDrugTrialGCP and the PharmLaw-VNM, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, and any compensation or treatment in the case of injury.

The Right to Privacy and Confidentiality

According to the ClinDrugTrialGCP and the PharmLaw-VNM, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

The Right of Inquiry/Appeal

The ClinDrugTrialGCP states that the research participant or legal representative/guardian should be provided with contact information for a person to contact regarding trial-related inquiries.

Furthermore, the PharmLaw-VNM states that the participant has the right to file a complaint or lawsuit against any illegal acts committed by the sponsor or investigator.

The Right to Safety and Welfare

As set forth in the ECReg, the risks to the research participant must take precedence over any anticipated benefits to the participant and the interests of society.

See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

The HlthResRegs and the Guideline for Good Clinical Practice E6 (R1) (MEX-32) make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies (COFEPRIS-GCP requires the principal investigator (PI) to comply with MEX-32). (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation’s Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

According to HlthResRegs, in an emergency, when it is deemed necessary to use an investigational drug, or a known drug with indications, doses, or routes of administration other than the established uses, the treating physician must obtain the favorable opinion of the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee, and an informed consent form (ICF) signed by the research participant or legal representative/guardian. The terms under which this documentation is obtained must meet the following requirements:

• The REC and Research Committee will be informed of the use of the investigational drug in advance if the researcher can anticipate the need for use in emergency situations. If this is not possible, an opinion must be obtained after the situation occurs. In both cases, the committees will issue an opinion in favor or against approving the planned or recurring unintended use of the drug.
• A signed ICF must be obtained from the participant or legal representative/guardian unless the participant’s condition prevents them from signing the form, the legal representative/guardian are not available to sign the form, or stopping use of the drug constitutes an almost absolute risk of death to the participant.

Per MEX-32, in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant or legal representative/guardian cannot be obtained, the ethics committee must provide documented approval in order to protect the participant’s rights, safety, and well-being, pursuant to the applicable regulations. The participant or legal representative/guardian should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

In addition, per GenHlthLaw, in cases of medical emergency, and when the terminally ill patient is unable to express their consent, and in the absence of family members, a legal representative, guardian or trusted person, the specialist doctor and/or the institution’s Bioethics Committee will make the decision to apply a necessary surgical medical procedure or treatment.

The ECReg indicates an ethics committee (EC) may waive the requirement for written voluntary consent from research participants for research in emergency situations where the participant or the legal representative/guardian cannot voluntarily agree to participate in the study. The EC’s decision to waive the voluntary written consent requirement must consider the benefits and risks of the study to the participants, as well as measures to protect the rights and safety of the participants.

Overview

As delineated in G-RECs-Op-2018, in all Mexican clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. G-RECs-Op-2018 characterizes vulnerable populations as individuals or groups experiencing diminished autonomy due to imposing social, political, and/or economic situations that prevent them from having control over their quality of life. Populations traditionally viewed as vulnerable include minors, women, persons with disabilities, the elderly, those suffering from mental illness, immigrants, those who are illiterate, those belonging to ethnic or racial minorities, the unemployed, the homeless, and reclusive individuals.

As per COFEPRIS-GCP, the principal investigator (PI) is required to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32), which similarly characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from not participating. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; employees of the pharmaceutical industry; members of the armed forces; and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent. (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation’s Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

G-RECs-Op-2018 specifies that Research Ethics Committees (RECs) (Comités de Ética en Investigación (CEIs)) should ensure that additional security mechanisms are implemented to minimize the specific risks for each group. MEX-32 similarly states that ethics committees must pay special attention to protecting participants who are from vulnerable populations.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations. Information on the other vulnerable populations specified in HlthResRegs is provided below.

Persons in Dependent Groups

As indicated in HlthResRegs, for clinical trials involving participants who are involved in subordinate or dependent relationships, the REC must ensure the following:

• Participation or refusal of individuals to participate or withdrawal of consent during the study, will not affect their school, work, military status, or that which is related to the judicial process and any conditions of compliance with a sentence, if applicable
• Research results are not used to the detriment of the individuals involved
• The health institution and sponsors take responsibility for dangers associated with medical treatment, and where appropriate, provide legally required compensation for the harmful consequences of the investigation

Per G-RECs-Op-2018, the following criteria must also be met to conduct a study with a subordinate population:

• The PI must clearly define the reasons for planning to recruit a subordinate population
• Protocol approval must also be obtained in which a written statement from the immediate boss or corresponding authority of the subordinate participant(s) verifying that no coercion has existed
• If resident doctors or partners are recruited for the study, the program director must provide the REC with a letter of support issued by a person without ties to the study
• Confidentiality of research data for the group of subordinate and student participants is important to consider to avoid negatively impacting the participants’ employment possibilities, professional development, study plans, or social relationships. The REC will also need to pay special attention to the PI’s plans to safeguard data security

The HlthResRegs and G-RECs-Op-2018 further specify that these relationships include participants who are in junior or subordinate positions in hierarchically structured groups, such as students, employees, workers in laboratories and hospitals, members of the armed forces, prisoners, social rehabilitation centers, and other members of special population groups in which informed consent can be influenced by some authority.

Persons in Local Communities

As per HlthResRegs, clinical trials involving participants in local communities must meet the following requirements:

• Research will be permitted when the expected benefit is reasonably assured, and when previous studies carried out on a small scale have not produced conclusive results
• The PI must obtain the approval of the health authorities and other civil authorities of the community to be studied, in addition to obtaining informed consent from individuals who are included in the trial
• In the case of vulnerable communities due to their economic or social conditions, such as indigenous communities, the REC is also required to issue a favorable opinion
• Experimental investigations in communities may only be carried out by establishments that have the Ministry of Health (Secretaría de Salud)’s prior authorization
• The experimental design should offer practical measures of protection for research participants, and ensure that valid results will be obtained, involving the minimum number of participants
• The most pertinent ethical considerations applicable to research on participants must be extrapolated to the communal context

Terminally Ill Persons

As stated in GenHlthLaw, if a terminally ill patient is a minor, or is incapable of expressing their consent, consent should be provided by the patient’s parent(s) or guardian(s), and in their absence, by their legal representative(s).

Overview

As per the ECReg and VNM-4, in all Vietnamese clinical trials, research participants selected from vulnerable populations must be provided additional protections by the ethics committee and the investigator(s) to safeguard their health and welfare during the informed consent process. VNM-4 characterizes vulnerable populations as those incapable of giving consent, which may include children, pregnant women, people with mental disabilities, people living with HIV/AIDS, people who are illiterate, prisoners, detainees, sex workers, and other special populations.

See the Children/Minors and Pregnant Women, Fetuses & Neonates sections for additional information about these vulnerable populations.

Per ChildRts, a child is defined as under 12 years of age, and adolescents are those between 12 and 18 years of age. When there is doubt as to whether the person is over 18 years of age, it should be presumed that the person is an adolescent. When there is doubt as to whether the person is over or under 12 years of age, it should be presumed that the person is a child.

Additionally, per HlthResRegs, in all cases, a written informed consent must be obtained from those exercising parental authority, or the legal guardian(s) of the minor, except in the case of emancipated minors over 16 years of age. Moreover, when the mental capacity or psychological state of the minor or incapacitated person permits, their acceptance must also be obtained after the investigator(s) have explained what they intend to do in the study. However, the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) may waive compliance with these requirements for justified reasons.

As set forth in G-RECs-Op-2018 and HlthResRegs, a research study involving minors must ensure that similar studies have been previously done in older people and in immature animals, except when it comes to studying conditions that are specific to the neonatal stage or specific conditions associated with certain ages.

Per G-RECs-Op-2018, research studies classified as risky and likely to benefit the minor directly, will be admissible when the following requirements are met:

• The risk is justified by the importance of the benefit that the minor will receive
• The benefit is equal to or greater than other alternatives already established for its diagnosis and treatment
• When the mental capacity and psychological state of the minor allow, the informed assent must also be obtained, after explaining what is intended to be done. The REC may waive compliance with these requirements for justified reasons
• The informed consent information provided is appropriate for the understanding of minors

Per G-RECs-Op-2018 and HlthResRegs, when two (2) persons exercise the parental authority of a minor, only the consent of one (1) of them must be permitted if there is irrefutable or manifest proof that the other is unable to provide it, proof of the parental authority’s negligence, or imminent risk to the minor’s health or life.

HlthResRegs indicates that investigations classified as risky, and with a probability of direct benefit for the minor, will be permitted in the following circumstances:

• The risk is justified by the importance of the benefit that the minor will receive, and
• The benefit is equal to or greater than other alternatives already established for diagnosis and treatment

Per HlthResRegs, investigations classified as risky and without direct benefit to the minor, will be allowed in the following circumstances:

• When the risk is minimal: The intervention or procedure must represent a reasonable experience for minors, and comparable with those characteristics of their current or expected medical, psychological, social, or educational situation. Also, the intervention or procedure should have high probability of obtaining generalizable knowledge about the condition or illness of the minor to benefit others with this disorder as well
• When the risk is greater than the minimum: The research should offer a good chance of understanding, preventing, or alleviating a serious problem affecting the health and well-being of children. Also, the head of the health institution should establish strict supervision to evaluate the magnitude of the risks anticipated or others that may arise, and immediately suspend the investigation when the risk could affect the biological, psychological, or social welfare of the minor

Assent Requirements

The applicable regulatory requirements do not specify the age of assent required for minors.

Per G-RECs-Op-2018, assent must also be obtained from a minor who is deemed capable of providing assent, and the minor must be informed about the study in a manner tailored to their emotional and intellectual maturity level, considering at all times the seriousness of the decision.

According to ChildLaw, a child is someone under 16 years of age.

As set forth in the PharmLaw-VNM, when the participant is a minor, informed consent must be obtained from the legal representative/guardian.

Per the ECReg, signed informed consent forms (ICFs) are required for:

• The parent/legal guardian, if the participant is under 16 years old
• The participant and the parent/legal guardian, if the participant is 16 years old to under 18 years old
• Participants that are 18 years or older and have full civil capacity to give consent

Assent Requirements

The ECReg further specifies that a signed assent form is required for participants who do not have the capacity to give legal consent, including children from 12 years old to under 16 years old. The assent form should contain information similar to an ICF, but be simpler, shorter, and easier to understand. For participants from seven (7) years old to under 12 years old, the assent form content should be provided and explained verbally.

As per HlthResRegs, studies involving women of childbearing age; women who are in any stage of pregnancy or are postpartum; or studies involving treatments or procedures using embryos, fetuses, or newborns, are required to obtain an informed consent form (ICF) from the woman and her spouse or partner. In addition, HlthResRegs and G-RECs-Op-2018 note that consent from the spouse or partner may only be waived in the case of their incapacity (or irrefutable or manifest inability) to provide it, or when there is imminent risk to the health or life of the woman, embryo, fetus, or newborn. All studies must also comply with the general ethics requirements that must be fulfilled prior to research involving humans as delineated in HlthResRegs.

HlthResRegs and G-RECs-Op-2018 further state that research in pregnant women will only be permitted if it is for therapeutic benefit, and represents an opportunity to understand, prevent, or alleviate any serious pathology. HlthResRegs and G-RECs-Op-2018 indicate that these studies are allowed when they are aimed at improving a pregnant woman’s health with minimal risk to the embryo or fetus, or per HlthResRegs, seek to increase the fetus’s viability, with minimal risk to a pregnant woman. G-RECs-Op-2018 adds that the ICF should mention the possible risk to the fetus.

According to HlthResRegs, investigations to be carried out on pregnant women should be preceded by studies carried out on non-pregnant woman to demonstrate the study’s safety, with the exception of studies requiring the specific condition. Those investigations classified as higher than minimum risk and will be conducted using women of childbearing age should implement the following measures:

• Certify the women are not pregnant prior to their acceptance as research participants, and
• Decrease the chances of pregnancy as much as possible during the development of the investigation

Per HlthResRegs and G-RECs-Op-2018, during studies conducted with pregnant women, the following requirements must be met:

• The investigators will not have the authority to decide on the time, method, or procedure used to terminate the pregnancy, nor will they participate in decisions regarding the viability of the fetus
• The Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI))’s authorization is required prior to any modification of the method used to terminate the pregnancy. These modifications mean that there will be minimal risk to the mother’s health and do not represent any risk to the survival of the fetus, and
• In any case, it is strictly forbidden to grant monetary or other incentives to interrupt the pregnancy, for the interest of the investigation or for other reasons

As set forth in HlthResRegs and G-RECs-Op-2018, investigators must comply with the following additional criteria when conducting studies with women who are in any stage of pregnancy or are postpartum:

• Research without therapeutic benefit in pregnant women, whose objective is to obtain general knowledge about pregnancy, should not represent a risk greater than the minimum for the woman, the embryo, or the fetus
• Investigations in pregnant women that imply an intervention or experimental procedure not related to pregnancy, but with therapeutic benefit for women (e.g., cases of toxemia gravidarum, diabetes, hypertension, and neoplasms, etc.) should not expose the embryo or the fetus to a greater than minimum risk, except when the use of the intervention or procedure is justified to save the life of the woman
• For investigations during labor, the informed consent must be obtained prior to initiating the study and must expressly state that consent may be withdrawn at any time during labor
• Investigations in women during the puerperium will be allowed when they do not interfere with the health of the mother and the newborn
• Research on women during lactation will be authorized when there is no risk for the infant, or when the mother decides not to breastfeed, she ensures her feeding by another method and provides informed consent

Per HlthResRegs, studies involving treatments or procedures using embryos, fetuses, or newborns must meet the following requirements:

• Fetuses will be permitted to be subjects of investigation only if the techniques and means used provide maximum security for them and the pregnant woman
• Newborns will not be used as subjects of investigation until it has been established with certainty whether or not they are live births, except when the research is aimed at increasing their probability of survival until the viability phase, the study procedures do not cause the cessation of their vital functions or when, without adding any risk, they seek to obtain important generalizable knowledge that cannot be obtained in any other way
• Live births may be used as subjects of investigation if the investigator(s) obtain consent from the woman and her spouse or partner

In addition, HlthResRegs indicates that investigations involving embryos, deaths, fetuses, still births, macerated fetal matter, cells, tissues and the use of biological materials extracted from them, must comply with GenHlthLaw. GenHlthLaw specifically prohibits the use, for any purpose, of embryonic or fetal tissues caused by induced abortions. G-RECs-Op-2018, by comparison, states that for investigators to use biological materials derived from abortions, the informed consent must be independent from the consent granted for an abortion, and will not include financial compensation.

The PharmLaw-VNM states that for studies involving women who are pregnant or breastfeeding, the rationale for participant selection and appropriate protection measures for these participants must be clearly stated in the study approval dossier.

No applicable requirements

No information is currently available.

The Mexican government has updated the GenHlthLaw to prioritize mental health with the development of health policies required to be in accordance with the provisions of the MexConstitution and international treaties on human rights. For the purposes of this law, mental health is understood as a state of physical, mental, emotional, and social well-being determined by the individual's interaction with society and linked to the full exercise of human rights. Refer to GenHlthLaw for details on consent requirements for the treatment of the mental health services user population.

Per HlthResRegs, when the mental capacity and psychological state of the participant permits, their acceptance must also be obtained after the investigator(s) explain what they intend to do during a clinical study. The Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) may waive compliance with these requirements for justified reasons. All studies must also comply with the general ethics requirements that must be fulfilled prior to research involving humans as delineated in HlthResRegs.

As indicated in HlthResRegs, investigations classified as risky, but with a probability of direct benefit for the mentally incompetent participant, will be allowed when:

• The risk is justified by the importance of the benefit that the incompetent participant will receive, and
• The benefit is equal to or greater than other alternatives already established for diagnosis and treatment

In addition, per HlthResRegs, investigations classified as risky and without direct benefit to the mentally incompetent, will be allowed in the following circumstances:

• When the risk is minimal: The intervention or procedure must represent a reasonable experience for the incompetent participant and be comparable with those characteristics of their current or expected medical, psychological, social, or educational situation. The intervention or procedure should also have a high probability of obtaining generalizable knowledge about the condition or illness of the mentally incompetent participant to benefit others with this disorder
• When the risk is greater than the minimum: The research should offer a good chance of understanding, preventing, or alleviating a serious problem affecting the health and well-being of the mentally incapacitated. In addition, the head of the health institution should establish strict supervision to evaluate the magnitude of the risks anticipated or others that may arise, and immediately suspend the investigation when the risk could affect the biological, psychological, or social welfare of the mentally incompetent participant.

The ECReg states that a signed assent form is required for participants who do not have the capacity to give legal consent, including people with inadequate civil act capacity or in a limited cognitive condition. The assent form should contain information similar to an informed consent form (ICF), but be simpler, shorter, and easier to understand.

As delineated in COFEPRIS-GCP and the Guideline for Good Clinical Practice E6 (R1) (MEX-32), an investigational product (IP) is defined as any pharmaceutical form containing an active ingredient or placebo, or a product of biological or biotechnological origin that is used or tested in a clinical trial, including a registered product when used or packaged in a different way with for which it was authorized, or when it is tested for indications that have not been authorized, or when it is used to obtain more information about its authorized use. COFEPRIS-GCP also notes this definition also applies to new chemical and biological entities, generics, new formulations, combination products, and biosimilars, and medical devices with or without the release of some active ingredient.

NOM-012-SSA3-2012 similarly states that investigational medicines or devices are used or applied to humans for scientific research purposes, for which there is insufficient scientific evidence to demonstrate its preventative, therapeutic, or rehabilitative effectiveness, or is intended to modify the therapeutic indications of already known products.

NOM-059-SSA1-2015 further defines an IP as a drug or biological product for which there is no previous experience in the country, has not been registered by the Ministry of Health (Secretaría de Salud), and therefore, has not been distributed commercially. This definition also encompasses medicines registered and approved for sale, when they are being investigated for an unapproved indication, dose, or route of administration, including their use in combination with other products that are different from the approved use.

(Note: In Mexico, IPs are also referred to as “drugs/products in research”).

The ClinDrugTrial defines an investigational product (IP) as a pharmaceutical product, biomedical product, vaccine, traditional medicine, or herbal medicine that contains a new active ingredient or substance, or a product with a new combination of already marketed pharmaceutical substances.

Manufacturing

According to GenHlthLaw, Reg-COFEPRIS, and Reg-HlthProd, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is responsible for authorizing the manufacture of all drug products for human use, including investigational products (IPs), in Mexico. Pursuant to GenHlthLaw, COFEPRIS, acting on behalf of the Ministry of Health (Secretaría de Salud), also issued NOM-059-SSA1-2015 and NOM-164-SSA1-2015 to provide standards delineating the minimum requirements necessary for the manufacture of drugs or active ingredients to be marketed in the country or used in clinical research. See NOM-059-SSA1-2015-Annexes to access the annexes to NOM-059-SSA1-2015.

As indicated in GenHlthLaw and Reg-HlthProd, drug manufacturers must submit a request to COFEPRIS to obtain a sanitary registration prior to initiating any drug manufacturing activities. Reg-HlthProd states that COFEPRIS must complete its review in 60 days, or the application will be deemed approved. Per GenHlthLaw, the sanitary registration is valid for five (5) years. The sanitary registration may be extended for an additional five (5) years if the extension is requested prior to the expiration of the current authorization, or the registration will be cancelled or revoked. See also GenHlthLaw and Reg-HlthProd, for detailed drug manufacturer registration submission requirements. In addition, per MEX-110, COFEPRIS is recognized as a National Regulatory Authority of Regional Reference of Medicines and Biological Products by the Pan American Health Organization (PAHO)/World Health Organization (WHO), and per MEX-111, is also a member of Pharmaceutical Inspection Co-operation Scheme (PIC/S). Per MEX-2, COFEPRIS has also implemented the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s Harmonised Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Q7) (MEX-81).

Import

As delineated in GenHlthLaw, Reg-COFEPRIS, Reg-HlthProd, and G-UnregDrugImprts, COFEPRIS is also responsible for authorizing the import of IPs. According to Reg-HlthProd, G-UnregDrugImprts, and G-UnregDrugImprts, an applicant or the legal representative may submit a request to import an IP after COFEPRIS has approved the sanitary authorization request for those drugs that are neither narcotic nor psychotropic, that do not have sanitary registrations, and that are intended to be used for human research. As per GenHlthLaw, the applicant must be a resident of Mexico or have a legal representative submit an import request on the applicant’s behalf. Additionally, per MEX-84 and G-DIGIPRiS-ResProts, the following documentation is required for submission to COFEPRIS:

• Letter of delegation of responsibility to the importer signed by the sponsor
• Letter of acceptance of responsibility from the importer signed by the importer’s legal representative

Per Reg-HlthProd, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, foreign manufacturers must submit a license, a good manufacturing practices (GMP) certificate, or a document issued by the competent authority in the country of origin that proves the company has permission to manufacture drugs. See MEX-36 for additional information on obtaining a GMP certificate.

Reg-HlthProd further states that COFEPRIS may grant permission to import raw materials or finished products without sanitary registration only in the following cases:

• When a contingency arises
• When required by health policy
• For purposes of scientific research, registration, or personal use, or
• For laboratory tests

In addition, Reg-HlthProd indicates that three (3) types of sanitary import permits may be issued:

• Definitive import – authorizes the entry of products to remain in the national territory for an unlimited time
• Temporary import – authorizes the entry of products for a limited time and with a specific purpose, with the understanding that they must return to the country of origin in a period not exceeding one (1) year
• Import in transit – authorizes the entry of products for their transfer from one (1) national office to another, for their departure to leave the country, within a period not exceeding 30 days, and for sale or temporary distribution. The sale or distribution is authorized exclusively for medicines to be used for strategic purposes

Reg-HlthProd, G-UnregDrugImprts, and G-UnregDrugImprts state that an import request may be submitted to COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37) once the agency has authorized the protocol for research to be conducted on human beings. The following documentation should be included (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Authorizations, Certificates and Visits Form (see MEX-25) (Original)
• Proof of payment of fees (original and two (2) copies)
• Health License
• Notice of Operation (original and one (1) copy)
• Approval from the research protocol office authorized by COFEPRIS and its amendments, (only in the case of research on human beings) (original and one (1) copy)
• Technical and scientific information demonstrating the identity and purity of its components in accordance with Pharmacopoeia of the United Mexican States (Farmacopea de los Estados Unidos Mexicanos (FEUM)) and its supplements; the stability of the finished product in accordance with the corresponding standards, and; therapeutic efficacy and safety according to the corresponding scientific information
• Prescribing information (broad and reduced versions)
• Sample label
• Free sale certificate issued by the health authority of the country of origin
• Certificate that the company has permission to manufacture medicines and proof of good manufacturing practices issued by the corresponding authority of the country of origin
• Letter of representation, when the laboratory that manufactures import product abroad is not a subsidiary or parent company of the laboratory requesting the registration

In addition, Reg-HlthProd requires documents originating from a foreign country to be presented in Spanish, or if in another language, with a Spanish translation made by an expert translator.

Per Reg-HlthProd and G-UnregDrugImprts, COFEPRIS has 10 days to approve the request. If COFEPRIS does not respond within this timeframe, the request is deemed approved. G-UnregDrugImprts also notes that COFEPRIS has four (4) business days to send the applicant a prevention notification regarding missing or additional information required. The applicant, in turn, has five (5) business days to respond. Reg-HlthProd and G-UnregDrugImprts further states that the maximum validity of import authorizations is 180 days, which may be extended for an equal period, provided the conditions in which they have been granted have not changed.

As set forth in Agrmnt_RegHlthSup, COFEPRIS published an agreement that recognizes the requirements, tests, and evaluation procedures carried out by an approved list of regulatory authorities specified in this agreement to be equivalent to those conducted in Mexico for the purposes of evaluating and approving allopathic drug products for sale, distribution, and use. Per Agrmnt_RegHlthSup, COFEPRIS will also permit the regulatory authorities referenced in this agreement to import raw materials or finished drug products, aimed at any disease or condition, whether the products are registered or unregistered in Mexico, and even if the products do not meet COFEPRIS’s quality, safety, efficacy, and GMP standards. The imported products or raw materials must be registered by the approved regulatory authorities, be prequalified by the WHO, or be registered with a regulatory agency that is a PIC/S member like COFEPRIS. See NOM-059-SSA1-2015-Annexes for additional information on COFEPRIS’s compliance with PIC quality risk management and master file preparation requirements that are included as annexes to NOM-059-SSA1-2015.

Per Agrmnt_RegHlthSup, the Ministry of Health may only grant permission for these unregistered drug products to be imported from regulatory authorities approved by COFEPRIS if the drugs are required by necessity in accordance with Reg-HlthProd, as described earlier in this section. Agrmnt_RegHlthSup requires the manufacturer to initiate the sanitary registration process with COFEPRIS within five (5) business days following the import of an unregistered drug product. COFEPRIS will then have a maximum of 60 business days to issue its decision.

As discussed in detail in Agrmnt_RegHlthSup, imported drugs must comply with the legal and technical provisions laid down in GenHlthLaw and Reg-HlthProd. MEX-13 further notes that COFEPRIS is allowed to purchase medicines anywhere in the world with the fundamental goal of avoiding a drug shortage in Mexico. The agreement also guarantees the quality of imported drugs through the regulatory measures COFEPRIS established mandating the analysis of all drug batches that enter the country to go through the Analytical Control and Coverage Expansion Commission, the laboratory that will then carry out a corresponding analysis. The imported drugs must also originate from countries with a regulatory standard equivalent to COFEPRIS and from those manufacturers that can provide health records from the country of origin demonstrating that the drugs have already been used in their population.

Refer to Agrmnt_RegHlthSup for detailed information and documentation requirements to register drugs and biological products. See also MEX-42 for additional background information on this agreement.

D-CargoTransprt bars exclusive cargo shipments to the Mexico City International Airport (AICM). See D-CargoTransprt and D-ModCargoTransprt for more details regarding the relocation of cargo shipments to other airports in Mexico.

Please note: Mexico is party to the Nagoya Protocol on Access and Benefit-sharing (MEX-5), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see MEX-35.

Manufacturing

As set forth in the PharmLaw-VNM, Decree54, and the ClinDrugTrialGCP, the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT) has overall responsibility for authorizing the manufacture of all drug products. According to VNM-4, once the ASTT reviews and the Minister of Health approves the study approval dossier, the Drug Administration of Vietnam (DAV) coordinates with the ASTT to review and approve the investigational product (IP) for manufacture or import.

In addition, the ClinDrugTrialGCP states that IPs which are under review for phase IV clinical trials require a certified or notarized copy of the written request for phase IV clinical drug testing from the respective regulatory authorities.

Import

As delineated in the ExprtImprtMeds, the MOH’s DAV is responsible for authorizing the import and export of drugs in Vietnam. According to ExprtImprtMeds, IPs for use in clinical trials are categorized as finished drugs without registration numbers. Once the MOH approves the study approval dossier, an import permit application must be submitted to the MOH’s DAV for approval of the IP. The import permit is valid for one (1) year.

The PharmLaw-VNM further indicates that a drug/medicinal ingredient that does not have a certificate of free sale must be licensed for import with a quantity not exceeding that which is written on the import license when it is to be used in a clinical trial, a bioequivalence study, a bioavailability assessment, or as a sample for registration, testing, scientific research, or display at a fair or exhibition.

The ExprtImprtMeds and Decree54 require the following documents to be included in an import permit dossier (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Import order form (three (3) copies)
• Copy of study protocol approved by the MOH
• A Certificate of Pharmaceutical Product (CPP) (may be substituted with a Free Sale Certificate (FSC) or Good Manufacturing Practice (GMP) certificate)
• The importer’s document bearing the importer’s seal, specifying the purposes and quantity of imported drugs and commitment to use the drugs for its intended purposes
• Quality standards and testing methods
• Drug label(s) and instruction manual(s) with importer seal (See the Labeling section for detailed labeling requirements)
• Preclinical and clinical records for drug(s) containing new pharmaceutical substances, or drug(s) with new combinations of circulating pharmaceutical substances, and an information sheet on placebo’s composition, if applicable

According to the ExprtImprtMeds, dossiers and documents attached to the order form must be prepared on size A4 paper and bound into a solid set. The records must be arranged in the order of the table of contents, with separation between the sections. The separators must be numbered for easy reference and must be affixed for certification by the importing enterprise on the first page of each section of the entire dossier and must have a cover page clearly stating: the name of the importer, order number, date of order, and type of order. The application for foreign drug import must be written in Vietnamese or English. If the application is written in English, the information in the package insert must be written in Vietnamese, except for the following information that may be written in other languages with Latin origin:

• Brand name, generic name, or international generic name of the drug
• International generic or scientific name of ingredient or ingredient quantity of the drug in case it cannot be translated into Vietnamese
• Name and address of the foreign enterprise that manufactures or franchises the drug

The MOH’s DAV will review and approve the import permit application within 15 working days from the date of receipt. According to VNM-12, however, the DAV review and approval process may take two (2) to eight (8) weeks if the DAV requires further clarification on the application. See the ExprtImprtMeds for applicable forms.

Please note: Vietnam is party to the Nagoya Protocol on Access and Benefit-sharing (VNM-2), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see VNM-6.

Investigator’s Brochure

As indicated in MEX-2, COFEPRIS is in the process of implementing the ICH Guideline for Good Clinical Practice E6 (R2) (MEX-22). G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts are in compliance with the Guideline for Good Clinical Practice E6 (R2) (MEX-22), regarding investigational product (IP) quality/manufacturing and investigator’s brochure (IB) requirements (also known as investigator’s manual in Mexico), while COFEPRIS-GCP complies with the Guideline for Good Clinical Practice E6 (R1) (MEX-32).

As set forth in GenHlthLaw, and G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, which are in compliance with (MEX-22), the applicant or sponsor is responsible for providing the investigators with an investigator’s brochure (IB). MEX-22 specifies that the sponsor is generally responsible for ensuring that an updated IB is made available to the investigator(s), and the investigators are responsible for providing the updated IB to the responsible ethics committees (ECs). The sponsor should also update the IB as relevant new information becomes available. According to MEX-84, G-DIGIPRiS-ResProts, and MEX-22, the IB should include the following elements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Title
• Confidentiality statement
• Table of Contents
• Summary
• Introduction
• Investigational product (IP) identification data (IP number, generic name of the drug or device, international nonproprietary name, trade name, if applicable)
• Collection of clinical and preclinical IP data relevant to the study of IP(s) in human participants
• Preclinical information (includes non-clinical pharmacology, pharmacokinetics and metabolism in animals, toxicology)
• Clinical information (includes pharmacokinetics and metabolism in humans, safety and efficacy, experience during commercialization)
• Data summary and guide for the investigator
• Document version and version date (coinciding with the approving opinions of the ECs)
• For drug authorization requests: (include IP physicochemical and pharmaceutical properties, formulation, presentation, manufacturing, labeling, storage, packaging and stability, when applicable, etc.)
• For COFEPRIS-04-010-D modality (risk-free research (observational studies)) authorization requests: include prescribing information

MEX-84 further notes the purpose of the IB is to provide researchers and others involved in the trial with information to facilitate their understanding of the rationale for and compliance with key protocol features such as: dose, dose frequency/interval, administration methods, and safety monitoring. The IB also provides information to support the design of the clinical phase of the study subjects over the course of the clinical trial. The information in this document must be presented in a concise, objective, and balanced manner which allows the principal investigator, as well as the other parties involved in the trial, to assess the suitability of the proposed trial, emphasizing the relevant and updated scientific information on the IP to monitor participant safety.

See MEX-84, G-DIGIPRiS-ResProts, and MEX-22 for detailed IB guidelines.

Quality Management

As specified in COFEPRIS-GCP, GenHlthLaw, Reg-HlthProd, NOM-059-SSA1-2015, NOM-164-SSA1-2015, NOM-176-SSA1-1998, NOM-073-SSA1-2015, G-HumResProt, MEX-84, G-DIGIPRiS-ResProts, and MEX-22, the sponsor must verify that the products are manufactured in accordance with the current codes of Good Manufacturing Practices (GMPs). See NOM-059-SSA1-2015-Annexes to access the annexes to NOM-059-SSA1-2015.

In accordance with the GenHlthLaw, Reg-HlthProd, NOM-059-SSA1-2015, NOM-164-SSA1-2015, NOM-176-SSA1-1998, G-HumResProt, G-DIGIPRiS-ResProts, and MEX-22, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires that drug manufacturers ensure IPs meet the required safety, efficacy, and quality characteristics and are manufactured, handled, and stored in accordance with applicable GMPs and provide the following additional information (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Issue the corresponding certificate of analysis signed by the health officer to verify the drugs comply with the quality specifications indicated in the current edition of the Pharmacopoeia of the United Mexican States (Farmacopea de los Estados Unidos Mexicanos (FEUM)) and its supplements, or those specified in the pharmacopeias from other countries, if applicable (per NOM-176-SSA1-1998)
• In case of foreign manufacture, the manufacturer must have a GMP certification, license, or document proving that the manufacturer has permission to manufacture medicines, issued by the competent authority in the country of origin (per Reg-HlthProd)

MEX-84 further specifies that the following IP documentation is required to demonstrate compliance with GMPs:

• Letter under oath, declaring that the IP and placebo are manufactured under standards that ensure a product is safe for use and that it has the ingredients and potency it claims to have in accordance with established quality requirements, or
• Certificate of good practices for the IP, or
• Certificate of pharmaceutical product

Additionally, per GenHlthLaw, verification of GMP compliance must be conducted by the Ministry of Health (Secretaría de Salud) or the Ministry’s authorized third parties, or if necessary, recognition of the respective certificate issued by the competent authority of the country of origin, provided there are recognition agreements in place between the competent authorities from both countries. See MEX-36 for additional information on obtaining a GMP certificate.

NOM-059-SSA1-2015 also notes that the manufacture of IPs for use in clinical studies presents greater complexity than marketed drug products due to the lack of systematic procedures resulting from the variety of clinical trial designs. In addition to applying basic GMP principles, drugs for research use in Mexico must also be released in accordance with good clinical practices, and the personnel involved in IP production and control must be experienced in handling drugs in the clinical research phase and be familiar with GMPs.

In addition, per MEX-110, COFEPRIS is recognized as a National Regulatory Authority of Regional Reference of Medicines and Biological Products by the Pan American Health Organization (PAHO)/World Health Organization (WHO), and per MEX-111, is also a member of the Pharmaceutical Inspection Co-operation Scheme (PIC/S).

Investigator's Brochure

According to the BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP), the Investigator’s Brochure (IB) is considered an essential document to submit before a clinical trial may be conducted. Vietnam requires the sponsor to submit a summary of the IB to the Ministry of Health (MOH)’s Administration of Science, Technology and Training (ASTT) in the clinical trial registration dossier. Research institutions are required to submit the full IB to the ASTT in the study approval dossier. (Note: The ClinDrugTrialGCP and the BioequivTrial also refer to the sponsor as “organizations and individuals with clinical reagents” or “donor”.)

As per the ClinDrugTrialGCP and the BioequivTrial, the IB contains information and data about preclinical research and clinical trials on the investigational product(s) (IPs). The IB also demonstrates that clinical information related to the IP has been provided to the principal investigator (PI).

As specified in the ClinDrugTrialGCP, the IB must provide coverage of the following areas:

• Information about the IP, including the ingredients, production processes, and quality standards
• For pharmaco-chemical drugs, pharmaceutical drugs, traditional medicines: proof of compliance with Good Laboratory Practices (GLPs) for research institutions or proof of compliance with Good Manufacturing Practices (GMPs) (also referred to as good medicine production standards in Vietnam) for drug manufacturers
• For vaccines: proof of compliance with quality testing requirements from national inspection agencies or ex-warehousing certificates for vaccine or biological batches
• Preclinical research documents for the IP: research reports on pharmacological effects, toxicity, safety, recommendations on dosage, route of administration, and usage
• Clinical research papers from the previous phases (if clinical trials are recommended in the next phase and the IP is not subject to exemption from previous phases)

Quality Management

The ClinDrugTrialGCP specifies that the IPs must be manufactured in a GMP-certified facility. The research institutions must also include a copy of the GMP certificate in the study approval dossier that is submitted to the ASTT.

(See the Product Management section for additional information on IP supply, storage, and handling requirements).

Investigational product (IP) labeling in Mexico must comply with the requirements set forth in COFEPRIS-GCP, NOM-164-SSA1-2015, NOM-059-SSA1-2015, and the Guideline for Good Clinical Practice E6 (R1) (MEX-32).

As delineated in COFEPRIS-GCP and NOM-059-SSA1-2015, the IP label must be written in Spanish and contain, at a minimum, the following information (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Name, address, and telephone number of the sponsor or main contact
• Protocol identification number
• Pharmaceutical form and route of administration
• Manufacturer name and address
• Lot number, identification code, and dosage form
• Statements: “For clinical studies only” or "Permitted use only investigation ", "Forbidden marketing", and "Keep away from the reach of children"
• Symbol or pictograms warning, if applicable
• Expiration date
• Storage conditions

NOM-164-SSA1-2015 also states that the IP label must indicate it is material under investigation.

In addition, MEX-22 indicates the sponsor should verify the IPs are coded and labeled in a manner that protects the blinding, if appropriate. In blinded trials, the IP coding system should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding. A sample of the attached IP container label(s) should also be provided to document compliance with applicable labelling regulations and appropriateness of instructions provided to the study participants.

Per NOM-164-SSA1-2015 and NOM-059-SSA1-2015, IPs for use in clinical trials should be packaged in a way that protects the products from alteration, contamination, and damage during storage and shipment. Additionally, procedures or instructions for the control of packaging, labeling, and distribution operations should be prepared.

Per NOM-059-SSA1-2015, in the case of products packaged for blinded clinical studies, manufacturers must ensure that the unused products and supplies are completely (100%) retrieved.

Investigational product (IP) labeling in Vietnam must comply with the requirements set forth in PharmLaw-VNM. Per VNM-12, the requirements in Articles 7 and 8 of the MedLabel should also be applied to IP labeling.

According to the MedLabel, the outer packaging label of the drug must show the following:

• Drug name
• Dosage form
• Ingredients, content, and volume or concentration of pharmaceutical ingredients and medicinal materials in the drug formula
• Packaging specifications
• Indications, usage, and contraindications of the drug
• Circulation registration number or import license number (if any)
• Production batch number, date of manufacture, expiry date of the drug, quality standards, and drug storage conditions
• Signs to note and recommendations when using the drug
• Name and address of the drug manufacturing facility
• Name and address of the import facility (for imported drugs)
• Origin of the drug

Additionally, as stated in the MedLabel, the intermediate packaging label of the drug must contain at least the following information:

• Drug name
• Production batch number
• Expiry date

As set forth in PharmLaw-VNM, the IP must also be clearly labeled with the wording: “Products used for clinical trials. Use for other purposes is prohibited.” While there is no specified language requirement for IP labeling in the regulatory resources, according to VNM-12, this wording should be in Vietnamese. A sample IP with the label in the smallest packed unit must also be included in the study approval dossier.

(See the Product Management section for additional information on IP supply, storage, and handling requirements).

Supply, Storage, and Handling Requirements

COFEPRIS-GCP and the Guideline for Good Clinical Practice E6 (R2) (MEX-22) state the sponsor is responsible for supplying investigators with the investigational products (IP(s)) while ensuring that only the quantity of products necessary to carry out the study is provided, and that none of the products will be marketed or used for purposes unrelated to the investigation.

MEX-22 further specifies that the sponsor is responsible for supplying the investigator(s)/institution(s) with the IP(s) and for ensuring the timely delivery of the IPs. However, the sponsor should not supply an investigator/institution with the IP(s)) until all the required documentation is obtained, such as the favorable opinion of the ethics committee (EC) and approval from the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)).

The sponsor should ensure written procedures include instructions that the investigator/institution should follow for the handling and storage of IP(s), adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).

Additionally, MEX-22 indicates the IP should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). The sponsor should determine acceptable storage temperatures, storage conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any, for the IPs, and inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations. Additionally, the sponsor should:

• Take steps to ensure that the IP(s) are stable over the period of use
• Maintain sufficient quantities of the IP(s) used in the trials to reconfirm specifications, should this become necessary, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period

Refer to MEX-22 for detailed sponsor-related IP requirements and MEX-36 for additional information on obtaining a GMP certificate.

COFEPRIS-GCP also delineates the sponsor is responsible for ensuring that IP manufacturing complies with NOM-073-SSA1-2015, which states that during the clinical trial, the manufacturer must validate the stability of the IP until the date of the last administration. The sponsor and the contract research organization (CRO) are responsible for ensuring that the research institution has a restricted storage area to protect the IPs and other products required for the investigation, including adequate temperature controls, humidity, and other conditions according to the manufacturer’s provisions. Additionally, the principal investigator is required to keep track of the receipt, storage, distribution, administration, destruction, or retrieval of the IP and other products required for the clinical study, in accordance with the research protocol provisions.

In addition, NOM-164-SSA1-2015 and NOM-059-SSA1-2015 indicate that there must be a procedure for the retrieval of IPs for clinical use that describes the responsibilities of all the members of the supply chain using the drug to include the manufacturer, the sponsor, the investigator, the clinical monitor, and the head of the research unit. NOM-164-SSA1-2015 further states that a system must be in place for the release of each lot of manufactured IPs and that a qualified person must approve the release. See NOM-059-SSA1-2015-Annexes to access the annexes to NOM-059-SSA1-2015.

According to MEX-84, the following IP documentation is also required to be submitted to COFEPRIS:

• Letter under oath guaranteeing the shelf life (stability) of the IP from the date of manufacture to the date of the last administration that will be carried out as part of the investigational protocol, or a protocol and report of results of the accelerated and long-term stability study of the IP and placebo, guaranteeing its stability from the date of manufacture to the date of the last administration in the research protocol
• Letter under oath, declaring that the IP and placebo are manufactured under standards that ensure a product is safe for use and that it has the ingredients and potency it claims to have in accordance with established quality requirements; a certificate of good practices for the IP; or a certificate of pharmaceutical product
• Letter of description of import inputs that expresses the approximate quantity of the IP

MEX-84 further notes that compliance with GMP and product stability are not equivalent. In the case of a letter under oath, it is valid to declare together compliance with GMP and that the shelf life of the IP is guaranteed at least until the date of the last administration of the IP and/or placebo.

In addition, per G-DIGIPRiS-ResProts, a letter of import supplies should be provided to COFEPRIS that clearly establishes the quantity and description of supplies that will be imported during each stage of the study. The letter should include the IP or placebo (when applicable), pharmaceutical form, presentation, concentration, and number of participants to be enrolled in Mexico. A letter of the stability studies should also be provided to support the IP and the placebo comply with the physical, chemical, and biological parameters which must be complied with throughout its useful life, and to maintain established quality specifications during storage and use.

Record Requirements

As indicated in the MEX-22, the sponsor should:

• Maintain records that document shipment, receipt, disposition, return, and destruction of the IP(s)
• Maintain a system for retrieving IPs and documenting this retrieval (e.g., for deficient product recall, reclaim after trial completion, expired product reclaim)
• Maintain a system for the disposition of unused IP(s) and for the documentation of this disposition

MEX-22 further states the investigator/institution and/or a pharmacist, or other appropriate individual who is designated by the investigator/institution, should maintain records of the IP's delivery to the trial site, the inventory at the site, the use by each participant, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the IP(s) and trial participants. Investigators should maintain records that document adequately that the participants were provided the doses specified by the protocol and reconcile all IP(s) received from the sponsor.

Per NOM-059-SSA1-2015, the sponsor is also responsible for storing files related to the manufacture and control of the IP for at least five (5) years after product registration has been granted. Additionally, the sponsor must ensure that this documentation is safeguarded, and that the files are stored at the sponsor’s facilities or in specific facilities contracted for this purpose.

Supply, Storage, and Handling Requirements

The BioequivTrial (which amends Appendix I of the ClinDrugTrialGCP) indicates that at the end of a clinical trial, the principal investigator (PI) must inventory the investigational product (IP). The sponsor is responsible for storing the IP and for working with the host institution to withdraw and destroy the unused or remaining products, in accordance with applicable regulations.

Record Requirements