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, reports directly to the head of the Ministry of Health. 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 Health Authorization Commission (Comisión de Autorización Sanitaria (CAS)). As delineated in Reg-COFEPRIS, GenHlthLaw, and MEX-88, CAS is responsible for issuing, extending, or revoking research protocol authorizations. According to MEX-88, CAS’s work is performed by the Executive Directorate for Product and Establishment Authorization which oversees the Coordination of Clinical Trials Area, that in turn, is responsible for research protocol authorizations. See MEX-88 for an organizational flowchart.

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). Additionally, see MEX-85 for 16 ICH efficacy guidelines adopted by COFEPRIS.

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, COFEPRIS’s contact information is as follows:

Comisión Federal para la Protección contra Riesgos Sanitarios
Oklahoma 14
Col. Nápoles
Demarcación Territorial Benito Juárez
C.P. 03810, Ciudad de México

For general inquiries:

Phone: 55 5080 5200
Email: contactociudadano@cofepris.gob.mx

For technical inquiries:

Call Center (CAT) Phone: 800 033 5050 (toll free within Mexico) or 55 53 40 09 96 (international calls) (per MEX-37)

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). (Note: COFEPRIS refers to applications as requests or procedures and refers to official procedure codes as homoclaves).

As indicated in HlthResRegs, NOM-012-SSA3-2012, Agrmnt_ResProtProcs, 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 GenHlthLaw, Reg-COFEPRIS, Agrmnt_ResProtProcs, G-DIGIPRiS-Prots&Amdts, and MEX-88, COFEPRIS’s Health Authorization Commission (Comisión de Autorización Sanitaria (CAS)) is responsible for issuing, extending, or revoking requests for human research protocol authorizations. According to Agrmnt_ResProtProcs, G-DIGIPRiS-Prots&Amdts, G-HumResProt, MEX-88 and MEX-104, CAS’s technical review and approval of research protocol submissions and amendments are managed through COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86). See MEX-104 for a flowchart of CAS’s review and approval process via MEX-86.

Per Agrmnt_ResProtProcs, which simplifies COFEPRIS’s administrative review process, requests for human research protocol authorization have been merged into a single procedure, the Application for Authorization of a Research Protocol on Human Beings (Homoclave COFEPRIS-04-010). The merged requests include those for medicines, biologicals, and biotechnologicals; medications (bioequivalence studies); new non-pharmacological medical methods or materials; and risk-free research (observational studies).

Agrmnt_ResProtProcs and G-DIGIPRiS-Prots&Amdts specify that protocol modification applications (Homoclave COFEPRIS-09-012) must be submitted to CAS to amend the underlying documents including the research protocol, the investigator’s brochure (also known as researcher’s manual in Mexico), and the informed consent/assent form. Other types of amendments include: the inclusion of research centers, research center address and/or name changes, principal investigator (PI) changes, research team changes, emergency center address and/or name changes, evaluation committee changes (REC, Research Committee, or Biosafety Committee), security amendment(s), authorization holder (or owner) address and/or name changes, sponsor address and/or name changes, importer change or addition, and other modifications. See Agrmnt_ResProtProcs and MEX-87 for additional information.

As indicated in G-DIGIPRiS-Prots&Amdts, CAS will begin its evaluation process once the applicant submits an application via DIGIPRiS (MEX-86) to request protocol authorization or to modify/amend a protocol authorization. The stages involved in this process are as follows:

• Request (user submits an authorization application request under Homoclave COFEPRIS-04-010 or COFEPRIS-09-012)
• Evaluation (CAS reviews and processes the application)
• Verification (CAS verifies the draft resolution to confirm whether to approve, deny, or request additional information)
• Signature (CAS signs the resolution)
• Resolution (Signed resolution is released to the user)

G-DIGIPRiS-ResProts and G-DIGIPRiS-Prots&Amdts further note that once COFEPRIS issues an official authorization, some of the data provided by an applicant via DIGIPRiS (MEX-86) is automatically migrated to its National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC v2.0)) database (MEX-68). Per MEX-88, MEX-68 was integrated into MEX-86 as RNEC v2.0. See Submission Process section for detailed DIGIPRiS (MEX-86) submission requirements.

(Note: COFEPRIS has not yet updated MEX-84, G-ResProtocolAmd, and G-DIGIPRiS-ResProts to align with the Agrmnt_ResProtProcs requirements. However, the ClinRegs team is regularly monitoring the COFEPRIS website for new developments and will post the most current sources when they become available.)

In addition, per Reg-HlthProd, applicants must submit a request to COFEPRIS to obtain a health 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.

Additionally, per NOM-177-SSA1-2013 and NOM-177-SSA1-2013-Mod, COFEPRIS requires interchangeability and biocomparability studies for generic and biosimilar (biocomparable) drugs; these studies maybe conducted in Mexico or in other countries and must be performed by authorized third parties in accordance with applicable testing and procedural requirements. See NOM-177-SSA1-2013, NOM-177-SSA1-2013-Mod, and MEX-120 for details.

Reliance Reviews

Under Agrmnt_FRAAuth, COFEPRIS issued an agreement establishing the list of Foreign Regulatory Authorities (FRAs) and the criteria for recognizing prior FRA authorizations of research protocols involving human beings using the regulatory “reliance” model. In evaluating applications, COFEPRIS will use reliance to consider the regulatory decisions submitted and approved by one (1) of the following FRAs:

• European Medicines Agency (EMA)
• US Food and Drug Administration (FDA)
• Medicines and Healthcare products Regulatory Agency (MHRA), United Kingdom
• Health Canada

Agrmnt_FRAAuth also notes that human research protocol applications must only include:

• Phase III research protocol submissions
• Trials authorized through regulatory processes under an ordinary evaluation scheme (i.e., this does not include trials approved by reliance, accelerated, or expedited methods)
• Trials with non-adaptive trial designs or designs that do not allow planned changes or that do not correspond to master protocols
• Trials that correspond to the following areas: oncology, endocrinology, cardiology, rheumatology, allergology, neurology, dermatology, pulmonology, gastroenterology, hematology, ophthalmology and nephrology, and/or those that address pathologies of high epidemiological impact in Mexico (e.g., diabetes mellitus, hypertension, lung cancer, melanoma, colon cancer, B cell lymphoma)
• Active trials (i.e., trials that are not suspended or cancelled)
• Investigational product (IP) trials that do not have special alerts or warnings from other regulatory authorities or the World Health Organization (WHO)
• Trials of drugs that have not been withdrawn from the market in any country for reasons of safety, efficacy, and quality

See Agrmnt_FRAAuth the additional details. See also the Submission Process and Timeline of Review sections for information on application submission procedures and review timelines.

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 COFEPRIS, 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)). 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-98 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.

Inspections

As outlined in MEX-88, COFEPRIS carries out health surveillance inspections (known as health verification visits) of all the parties responsible for conducting, developing, and monitoring authorized research protocols (e.g., sponsors, owners/authorization holders, RECs, Research Committees, Biosafety Committees, the PI, research centers, emergency care centers, and contract research organizations). The inspections are intended to:

• Confirm compliance with applicable legislative requirements
• Obtain information and identify health anomalies in the establishment’s physical and sanitary conditions
• Verify the clinical research studies are carried out in accordance with the provisions of authorized research protocols, as well as national and international regulations
• Ensure compliance with standards regarding ethics in clinical research, good clinical practice (GCP) and good manufacturing practice (GMP)

Refer to MEX-93 for the verification report health inspectors use to ensure compliance in clinical trial sites. See also MEX-92 for a complete list of verification reports related to medicines and other health supplies.

Federal Commission for the Protection Against Sanitary Risks (COFEPRIS)

As indicated in G-HumResProt, G-ResProtocolAmd, MEX-84, G-DIGIPRiS-ResProts, the applicant is responsible for paying a non-refundable fee to submit a request for research protocol authorization to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)).

G-HumResProt, G-ResProtocolAmd, and MEX-11 delineate the following fees (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Research protocol authorization (medicines, biological, and biotechnological in humans): 7,896 Mexican Pesos
• Research protocol amendment, modification, or addition of new research centers: 5,922 Mexican Pesos

For health permit authorization, the fees are as follows:

• Health permit to import investigational products for research purposes: 7,033.09 Mexican Pesos (G-UnregDrugImprts)
• Health permit to import cells and tissues including blood, its components, and derivatives: 866.45 Mexican Pesos (G-ImprtPermit)
• Health permit modification to import cells and tissues including blood, its components, and derivatives: 649.84 Mexican Pesos (G-ImprtPermitMod)
• Health permit to export cells and tissues including blood, its components, and derivatives: 866.45 Mexican Pesos (G-ExprtPermit)

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 Specialty 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 G-HumResProt, G-ResProtocolAmd, G-UnregDrugImprts, G-ImprtPermit, G-ImprtPermitMod, and G-ExprtPermit, fees must be paid to the applicant’s preferred bank. See G-ResProtocolAmd, G-UnregDrugImprts, G-ImprtPermitMod, and MEX-84 for access to a procedure-based form to pay fees at a chosen banking institution.

Refer to G-ResProtocolAmd, MEX-84, and G-DIGIPRiS-ResProts for additional information on this process.

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)). (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 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, 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 a 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 six (6) months after joining the Committee. See G-CHBs-Op for additional information.

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 REC member. 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 activities report should be presented to the institutional head in the first 30 calendar days of the year
• Conflicts of interest in protocol evaluations should be avoided 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 conducted to better carry out its functions
• A general policy on the confidentiality of information for reviewed protocols 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 project or research protocol subject 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. Per G-CHBs-Op and GenHlthLaw, the Committee promotes, with the head of the hospital, the dissemination, elaboration, and implementation of institutional bioethical guidelines and guides for medical care and teaching. GenHlthLaw notes the Hospital Bioethics Committees must comply with current legislation and CONBIOÉTICA guidelines. For detailed Hospital Bioethics Committee procedures and information on other administrative processes, see G-CHBs-Op.

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, Agrmnt_ResProtProcs, 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 and GenHlthLaw, explain that the REC provides ethics recommendations on protocols for research in human beings, including a review of the research risks and benefits. 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.)

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.

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. See MEX-100 for REC registration renewal instructions.

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 indicates 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. However, G-CHBReg states that CONBIOÉTICA is required to issue a registration within 25 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

In accordance with GenHlthLaw, Reg-COFEPRIS, HlthResRegs, and NOM-012-SSA3-2012, Mexico requires the applicant to submit a request 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, Agrmnt_ResProtProcs, 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

Pre-submission Registrations

As delineated in G-DIGIPRiS-Regis, prior to submitting a protocol authorization request to COFEPRIS, an applicant must first register in COFEPRIS’S digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86), using an e.signature (also known as e.firma) digital certificate. An e.signature can be obtained from the Tax Administration Service (Servicio de Administración Tributaria (SAT)) as described in MEX-83. See G-DIGIPRiS-Regis, G-DIGIPRiS-SystAccess, and MEX-89, for additional 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

As per Agrmnt_ResProtProcs, G-DIGIPRiS-Prots&Amdts, G-HumResProt, and MEX-89, research protocol authorization and amendment/modification requests must be submitted electronically via DIGIPRiS (MEX-86). MEX-89 specifies that an exception to this requirement is if the user is required to present printed documents with a handwritten signature, or a physical inspection is required. Per G-DIGIPRiS-Prots&Amdts and MEX-89, 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. According to G-DIGIPRiS-SystAccess, G-DIGIPRiS-Prots&Amdts, and MEX-89, once the procedure has begun, the user will be notified in MEX-86 of all request-related administrative acts (known as resolutions) (e.g., approvals, denials, and requests for additional information). Additionally, per G-DIGIPRiS-SystAccess, multiple requests and procedures can be in process simultaneously in MEX-86. Refer to G-DIGIPRiS-DocComp for instructions on validating and comparing research protocol documents issued through MEX-86. See also MEX-106 for additional DIGIPRiS user guides. (Note: COFEPRIS refers to applications as requests or procedures).

Agrmnt_ResProtProcs and MEX-87 further indicate that COFEPRIS will not request documentation in its physical or electronic files if the information was previously obtained in paper or electronic form. Per Agrmnt_ResProtProcs, once the research protocol has been authorized, applicants must submit the required documentation within 15 business days (See the Submission Content section for details.) Applications that do not include all required and accurate information outlined in Agrmnt_ResProtProcs may be revoked. If this occurs, applicants must resubmit their application to prevent delays in processing.

Per Agrmnt_ResProtProcs, for protocol authorization and protocol modification/amendment requests, the application must also include the original proof of payment along with two (2) copies of the receipt, as well as one (1) copy of a simple power of attorney for natural persons (i.e., a third-party signature, validation, certification, authorization, or approval), or, a public instrument which accredits legal representation must be presented for legal entities, if applicable. The G-HumResProt also indicates the same requirements for protocol authorization.

Per G-DIGIPRiS-ResProts, all documents uploaded to DIGIPRiS (MEX-86) must be in “.pdf” format (unrestricted text file), unless another format is specified. In addition, G-HumResProt and G-ResProtocolAmd indicate that all documentation related to submitting applications for research protocol authorization and protocol modification/amendment must 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.

(Note: COFEPRIS has not yet updated MEX-84, G-ResProtocolAmd, and G-DIGIPRiS-ResProts to align with the Agrmnt_ResProtProcs requirements. However, the ClinRegs team is regularly monitoring the COFEPRIS website for new developments and will post the most current sources when they become available.)

In addition, as specified in Agrmnt_FRAAuth, research protocol applications relying on prior authorizations from Foreign Regulatory Authorities (FRAs) under the regulatory “reliance” model must be submitted exclusively via DIGIPRiS (MEX-86). A certified, legalized, or apostilled copy (with Spanish translation) of the FRA’s authorization to conduct the clinical protocol must be attached under “Other documents.” The authorization must be issued within one (1) year to ensure document traceability. Copies of the protocol and the investigator’s brochure (IB) in English with Spanish translations must also be provided; only the Spanish versions require approval by the respective committees in Mexico. See the Scope of Assessment section for additional requirements governing the FRA reliance model.

As per MEX-71, for technical inquiries related to submitted procedures, applicants may contact the Comprehensive Service Center (Centro Integral de Servicios (CIS):

Call Center (CAT) Phone: 800 033 5050 (toll free within Mexico) or 55 53 40 09 96 (international calls) (per MEX-37)
Email: contactociudadano@cofepris.gob.mx

See also MEX-37, G-CIS, and G-CISMod for additional information on the CIS.

Enabled Pre-Assessment Support Unit (UHAP) Evaluation Submissions

Per MEX-21 and MEX-10, rather than submitting an application directly to COFEPRIS, an applicant may choose to have their application pre-assessed through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69). A UHAP may be selected from 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 from 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, Agrmnt_ResProtProcs, 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.

Regulatory Authority Requirements

As delineated in Agrmnt_ResProtProcs, G-HumResProt, and G-DIGIPRiS-Prots&Amdts, 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):

• Online application form (Authorization, Certificates and Visits form) (MEX-25) (see MEX-18 for instructions on completing MEX-25)
• Simple power of attorney, for natural persons (i.e., a third-party signature, validation, certification, authorization, or approval), or a public instrument which accredits legal representation for legal entities, if applicable
• Payment receipt and request letter
• Duly completed single form by institutional/establishment head where research will be conducted (one (1) copy) (See form in Single Annex in Agrmnt_ResProtProcs)
• Duly completed single form by principal investigator (PI)/research team (including certificates of studies accrediting technical competence, good clinical practice (GCP), and specialized experience by PI/research team (one (1) copy)) (See form in Single Annex in Agrmnt_ResProtProcs)
• Duly completed single form by sponsor (See form in Single Annex in Agrmnt_ResProtProcs)
• Single Committee form which consolidates approvals from applicable committees, duly required (one (1) copy) (See form in Single Annex in Agrmnt_ResProtProcs)
• Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) Registry (one (1) copy)
• Research protocol (one (1) copy)
• Study schedule (one (1) copy)
• Investigator’s Brochure (IB) (also known as Researcher’s Manual in Mexico) or equivalent document (one (1) copy)
• Informed consent form
• Research site(s)
• Emergency care center (See form in Single Annex in Agrmnt_ResProtProcs)
• Certificate of compliance with Good Manufacturing Practice (GMP) for investigational products (IPs) or equivalent document, stability report, and IP/placebo results, except for risk-free research (observational studies) (one (1) copy)

(Note: COFEPRIS has not yet updated MEX-84, G-ResProtocolAmd, and G-DIGIPRiS-ResProts to align with the Agrmnt_ResProtProcs requirements. However, the ClinRegs team is regularly monitoring the COFEPRIS website for new developments and will post the most current sources when they become available.)

In addition, Agrmnt_ResProtProcs states that once the research protocol has been authorized, applicants must submit within 15 business days, the following:

• Consent and/or informed assent, previously approved by the Research Ethics Committee
• Study insurance (Policy/Certificate) or current financial fund that certifies coverage for research participants, and
• Standard form for medical emergencies and the agreement or contract for the care of medical emergencies, if applicable

Risk-free research (observational studies) only requires the REC-approved consent and/or informed assent form to be submitted per Agrmnt_ResProtProcs.

Refer to Agrmnt_ResProtProcs, G-HumResProt, and G-DIGIPRiS-Prots&Amdts for more detailed submission information. See also MEX-36 for information on obtaining a certificate of GMP.

As outlined in Agrmnt_ResProtProcs, for any protocol authorization amendment or modification (COFEPRIS-09-012), applicants must submit a Single Amendment or Modification Request Form (See form in Single Annex in Agrmnt_ResProtProcs) and proof of payment. If applicable, a simple power of attorney for natural persons (i.e., a third-party signature, validation, certification, authorization, or approval), or a public instrument which accredits legal representation for legal entities, if applicable, must also be provided. In addition, per Agrmnt_ResProtProcs and G-DIGIPRiS-Prots&Amdts, specific documentation are required depending on which of the following amendment/modification categories is being updated:

• Protocol, informed consent/assent, or IB
• Center inclusion
• Research center change
• PI change
• Research team changes
• Emergency care center changes
• Evaluation committee changes
• Security amendment
• Establishment owner change
• Sponsor change
• Change/addition of importer
• Other modifications

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

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.

However, per Agrmnt_ResProtProcs, COFEPRIS has published a Single Committee form, which merges the REC, Research Committee, and where applicable, Biosafety Committee documentation requirements into a single form. The form includes a section for the appropriate committee to provide information concerning its review and approval of the research protocol based on the following elements:

• PI and research center names
• Committee session data (including folio, protocol number, session data, approval date, session type (ordinary/extraordinary), and minutes number)
• Research protocol data (including protocol number, study phase, title, short title, study risk level, research sponsor)
• List of approved documents (including document names, versions, and dates)
• List of committee members (including names, professions/disciplines, and positions)
• Committee registration data (including establishment name or business name, address, registration number, start of validity or issue date, validity, expiration date)
• Declaration of no conflict of interest and confidentiality
• Research monitoring (periodic and continuous monitoring)
• Express declaration of no vote for each member who is part of the research team

See Agrmnt_ResProtProcs for detailed requirements.

G-HumResProt also indicates that the Single Committee form should provide information related to the tests performed on the IP for a specific period of time under the influence of temperature, humidity, or light in the container that contains it, to ensure its shelf life from the date of manufacture to the date of the last administration.

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)
• 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. (Note: Per MEX-2, COFEPRIS is in the process of implementing MEX-22).

Overview

As delineated in HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, Agrmnt_ResProtProcs, 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 business days from the day following an application’s filing. However, according to Agrmnt_ResProtProcs and G-HumResProt, COFEPRIS is required to complete its review of research protocol authorization requests within 30 calendar days. Agrmnt_ResProtProcs further specifies that this timeline applies to the review of human research protocols that have already been authorized by a foreign regulatory authority, as well as to research protocol modifications or amendments.

In addition, per G-HumResProt, during the prevention period, COFEPRIS has 10 calendar days to notify an applicant of any deficiencies or request additional information, and an applicant must respond within five (5) business days. If COFEPRIS does not respond within the 30-day timeline, the application will be deemed denied.

See the Scope of Assessment section for additional information on COFEPRIS’s evaluation process, and see Submission Process section for details on tracking submitted procedures via COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86).

Also, as specified in Agrmnt_FRAAuth, COFEPRIS must issue a decision within 45 calendar days for research protocol applications involving human beings submitted under the regulatory “reliance” model, which are based on prior authorization from a Foreign Regulatory Authority (FRA). See the Scope of Assessment and Submission Process sections for additional requirements governing the FRA reliance model and submission procedures.

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 eight (8) 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.

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. Per MEX-21 and MEX-10, third parties are also known as Enabled Pre-Assessment Support Units (Unidad Habilitada de Apoyo al Predictamens (UHAPs)) (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 UHAPs 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-98 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

In accordance with GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, COFEPRIS-GCP, Agrmnt_ResProtProcs, G-HumResProt, G-DIGIPRiS-Prots&Amdts, 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, NOM-012-SSA3-2012, Agrmnt_ResProtProcs, 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

While NOM-012-SSA3-2012, MEX-84, and G-DIGIPRiS-ResProts state that prior to initiating the trial, 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, Agrmnt_ResProtProcs, has eliminated this requirement as of June 2025.

Additionally, as of June 2025, Agrmnt_ResProtProcs has eliminated the requirement stated in MEX-84, G-DIGIPRiS-ResProts, and NOM-012-SSA3-2012 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.

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 conflicts 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 and G-DIGIPRiS-Prots&Amdts, once COFEPRIS approves an authorization request, some of the data provided by the applicant in COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86), is automatically migrated to COFEPRIS’s National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). Per MEX-88, RNEC was integrated into MEX-86 as RNEC v2.0.

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 and NOM-012-SSA3-2012, 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, G-ResCommReg, and MEX-102 for detailed Research Committee and Biosafety Committee registration requirements. See MEX-26 for COFEPRIS’s Research Committee and Biosafety Committee registration form.

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 health 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)
• E2B(R3) Individual Case Safety Report (ICSR) Specification and Related Files (MEX-101)
• 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 permanently 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 health 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, adverse events following immunization (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 and see MEX-30 for the form to be completed via 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.

Interim and Annual Progress Reports

Per HlthResRegs and NOM-012-SSA3-2012, 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. 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 and MEX-31 specify that the progress reports should describe the results obtained and at a minimum should include the following elements (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Study data
• Participating research centers
• Amendments and modifications authorized during study development
• Partial technical-descriptive reports (include official responses to the partial/annual technical-descriptive reports carried out) (see Annex I of MEX-31)
• Materials and methods
• Summary of adverse event (AE) reports identified during study development (include a simple copy of the response letters (or a simple copy of the CIS entry form for the AE reports) issued by Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS))’s National Pharmacovigilance Center (CNFV), which corresponds with the reports submitted) (Annex I)
• Results
• Conclusions
• Bibliographic references (include only those references that served as the basis for the planning and execution of the research)
• Any relevant exhibits

MEX-31 also indicates the following annexes must be submitted:

• Annex I – A simple copy of the COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) entry form for the Free Letter of Notification of AE(s) (submitted to the CNFV); and a simple copy of the official authorization letter of the respective Security Amendment (Homoclave COFEPRIS-09-012), when applicable
• Annex II – A simple copy of the Technical Sheet of the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)), duly completed and in its entirety (except for the section referring to results, which must be presented in the Final Technical Report submission)
• Annex III – A simple copy of the PI’s signed Delegation of Responsibilities Letter, which was submitted with the initial authorization process for the research protocol and/or inclusion of the research center (including a simple copy of the amendment/modification letter, if applicable)
• Annex IV – Patient materials (documents that do not require COFEPRIS authorization, but which are acknowledged and are the same as those approved by the evaluation committees) generated from the authorization of the protocol’s implementation until the clinical study’s conclusion
• Annex V – A simple copy of the signed letters from the REC (CEI), the Research Committee, and the Biosafety Committee (as applicable) of each center where the study is carried out; the letters should notify or acknowledge receipt of each research center’s annual activities report
• Other Annexes – The researcher may include any annexes deemed necessary to support the partial technical-descriptive report, or those documents required by the institution or establishment where the research is carried out. This section must also indicate which and how many annexes are attached to the form.

Additionally, 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 and NOM-012-SSA3-2012, the PI is 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. Per NOM-012-SSA3-2012, the PI must also deliver a copy of this report to the research team members, the REC (CEI), the Research Committee, and the Biosafety Committee, as applicable, where the study was conducted.

However, per MEX-94 and MEX-28, the sponsor/the sponsor’s contract research organization (CRO) and the PI share responsibility for submitting the final report to the CIS (MEX-37). Once the final report is submitted, MEX-94 specifies that the CIS assigns an entry number to the submitted application along with the procedural code, “ES45”. The CIS’s acknowledgement of the receipt of information submitted should not be interpreted as an official authorization.

As per NOM-012-SSA3-2012 and MEX-94, the final reports should include the same basic requirements as those indicated in the Interim and Annual Progress Reports, with the following differences: they must also contain a clinical study synopsis with the main research results (including the corresponding analysis and interpretation), conclusions, and bibliographic references (including only those sources that served as a basis for planning and executing the research, as well as for analyzing the results).

Additionally, per MEX-94, the following annexes must also be submitted:

• Annex I – A simple copy of the CIS Entry Slip of the Final Safety Report Entry Form submitted to the CNFV
• Annex II – A simple copy of the RNEC Technical Data Sheet, duly completed and in its entirety
• Annex III – A simple copy of the PI’s signed Letter of Delegation of Responsibilities, which was submitted with the initial authorization process for the research protocol and/or inclusion of the research center (including a copy of the amendment/modification letter, if applicable)
• Annex IV – Patient materials (documents that do not require COFEPRIS authorization, but which are acknowledged and are the same as those approved by the evaluation committees) generated from the authorization of the protocol’s implementation until the clinical study’s conclusion
• Annex V – A simple copy of the signed letters from the REC (CEI), the Research Committee, and the Biosafety Committee (as applicable) of each center where the study was carried out, specifying that they are aware of the study’s completion
• Annex VI – Letters signed by each PI, notifying them of the study’s completion, the closure of the center's activities, and the conclusion and follow-up of the research participants enrolled at their respective research center
• Other Annexes – The researcher may include any annexes deemed necessary to support the technical-descriptive report or those required by the institution or establishment where the research is carried out. This section must also indicate which and how many annexes are attached to the form.

See section 7.4 of NOM-012-SSA3-2012 and MEX-94 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-94 for the reporting form.

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.

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. Agrmnt_ResProtProcs, G-HumResProt, and MEX-84 also specify the PI should provide legally issued and registered documentation (e.g., certificates of studies and professional licenses) delineating appropriate academic training and experience appropriate to the research to be conducted, which includes academic preparation, representative scientific production, and good clinical practice (GCP).

Additionally, Agrmnt_ResProtProcs, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts 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 provide a letter stating the institution’s acceptance, authorization, and description of the available resources. The agreement must comply with NOM-027-SSA3-2013, which establishes the criteria for the operation and care in providing emergency services in health care institutions.

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

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, COFEPRIS-GCP requires the sponsor or the CRO to comply with the Guideline for Good Clinical Practice E6(R1) (MEX-32), which states that 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

Per Agrmnt_ResProtProcs, once the research protocol has been authorized, applicants must provide the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) with a policy or certificate of study insurance or a copy of the current financial fund that certifies coverage for research participants. G-DIGIPRiS-ResProts also indicates the sponsor should provide 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, which must be on behalf of the license holder and the sponsor, must indicate the number of participants that will be covered, the study title, and the protocol number.

(Note: COFEPRIS has not yet updated MEX-84, G-ResProtocolAmd, and G-DIGIPRiS-ResProts to align with the Agrmnt_ResProtProcs requirements. However, the ClinRegs team is regularly monitoring the COFEPRIS website for new developments and will post the most current sources when they become available.)

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, will 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. HlthResRegs and GenHlthLaw also specify that 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.

MEX-32 explains the sponsor's policies and procedures should address the costs of treatment of trial participants 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).

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.

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 verify 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 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, 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 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 (GCP), 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)), the Research Committee, or the Biosafety Committee (where applicable), the PI, and the sponsor, must be responsible, in accordance with their area of competence, for monitoring the research. Agrmnt_ResProtProcs specifies that the sponsor is required to submit a monitoring and audit plan to ensure that clinical trial oversight mechanisms are in place to verify that all trial-related activities are subject to quality and other controls to reduce errors, increase objectivity, and ensure consistent processes. However, NOM-012-SSA3-2012, MEX-84, and G-DIGIPRiS-ResProts require the sponsor or the CRO to provide a letter to COFEPRIS describing the monitoring and auditing plan to be carried out during the investigation. 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 both 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 scientific, technical, and ethical monitoring
• Communication and notification strategies between the 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)

Note: COFEPRIS has not yet updated MEX-84, G-ResProtocolAmd, and G-DIGIPRiS-ResProts to align with the Agrmnt_ResProtProcs requirements. However, the ClinRegs team is regularly monitoring the COFEPRIS website for new developments and will post the most current sources when they become available.

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 (CEI), 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 to, 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 (CEI), the Research Committee, the Biosafety Committee (where applicable), or the 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 participant 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 the sponsor’s prior agreement, 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.

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.

Responsible Parties

For the purposes of data protection in Mexico, PDP-PrivateLaw and PDP-Public delineate responsibilities of the “data controller.” In PDP-PrivateLaw, which regulates the right of private individuals and legal entities to protect their personal data, the data controller who carries out the processing of personal data is the “responsible” party (or “regulated subject”). The “person in charge” is a natural or legal person who, alone or jointly with others, processes personal data on behalf of the controller.

In comparison, in PDP-Public, which regulates personal data held by public entities, the data controller who decides on the processing of the data is the “responsible” party (or “obligated subject”). The “person in charge” is a natural or legal person, public or private, outside the organization of the responsible person, who alone or jointly with others, processes personal data on behalf of and for the account of the responsible person. Public entities that process personal data include government authorities at all levels (federal, state, municipal, and Mexico City), the three (3) branches of government (executive, legislative, judicial), autonomous bodies, political parties, and public trusts and funds.

In addition, PDP-Trnspcy, which guarantees access to public information and promotes transparency and accountability, also addresses personal data protection. It requires public entities to manage and safeguard personal data as part of their broader mandate to ensure access to publicly available information. Oversight is carried out by “guarantor authorities,” which are the federal and local authorities that oversee compliance across the executive, legislative, and judicial branches, and independent constitutional bodies.

Data Protection

PDP-PrivateLaw and PDP-Public provide the requirements, responsibilities, and restrictions for handling personal data in the private and public sectors respectively. Under both laws, the data controller or responsible party must comply with the principles of data protection: legality, purpose, loyalty, consent, quality, proportionality, information, and responsibility in the processing of personal data. The data controller or responsible party must also ensure that the personal data contained in the databases are accurate, complete, correct, and updated for the purposes for which they were collected.

According to both PDP-PrivateLaw and PDP-Public, the data controller or responsible party must also establish and maintain administrative, physical, and technical security measures to protect personal data against damage, loss, alteration, destruction, or unauthorized use, access, or processing. Under PDP-Public, the controller must also guarantee the confidentiality, integrity, and availability of the data. PDP-PrivateLaw requires the data controller or responsible party to report immediately any security breaches occurring at any stage of personal data processing that significantly affect the property or moral rights of the data owners, so that they can take appropriate measures to defend their rights. Additionally, the data controller or responsible party must establish controls or mechanisms to ensure that all persons involved in processing maintain confidentiality. This obligation must continue even after their relationship with the data controller ends.

PDP-Public further provides that the data controller or the responsible party must analyze the causes of the breach and implement preventive and corrective actions in its work plan to adapt security measures and the processing of personal data, if applicable, to prevent the breach from recurring. The data controller or responsible party must promptly inform the data owner, and as appropriate, the Secretariat and the guarantor authorities (i.e., government bodies that oversee compliance with data protection obligations), of any violations that significantly affect property or moral rights. Notification must be made as soon as the violation is confirmed and once the responsible party has begun to take steps to initiate a comprehensive review of its impact, so that the affected data owners can take the appropriate measures to defend their rights.

PDP-PrivateLaw and PDP-Public also both delineate that any time, a data owner, or where applicable, their legal representative, may exercise their rights of access, rectification, cancellation, and opposition, known as ARCO rights. The exercise of any of the ARCO rights is not a prerequisite, nor does it prevent the exercise of any other rights. The data owner must have the right to:

• Access their personal data, as well as to know information related to the conditions and generalities of their processing
• Request the rectification or correction of their personal data when they are found to be inaccurate, incomplete, or outdated
• Request the erasure of their personal data from the files, records, files, and systems, so that they are no longer in the data controller’s or responsible party’s possession
• Object to the processing of their personal data or demand its cessation when: even if the processing is lawful, to prevent it from causing harm or damage; or, the personal data is subject to automated processing, which produces undesired legal effects or significantly affects the data owner’s interests, rights, or freedoms, and is intended to evaluate, without human intervention, certain personal aspects of their data, or to analyze or predict, in particular, their professional performance, economic situation, health status, sexual preferences, reliability, or behavior

Per PDP-PrivateLaw, the data owner’s right to object will not be exercised in cases where processing is necessary for compliance with a legal obligation imposed on the data controller. Additionally, the data controller should not be obliged to erase personal data when:

• The data relate to the parties of a private, social, or administrative contract and are necessary for its development and fulfillment
• The data must be processed by a legal provision
• The erasure hinders judicial or administrative proceedings related to tax obligations, the investigation and prosecution of crimes, or the updating of administrative sanctions
• The data are necessary to protect the data owner’s legally protected interests
• The data are necessary to carry out an action based on the public interest
• The data are necessary to comply with a legal obligation acquired by the data owner
• The data are processed for prevention or for medical diagnosis, or for the management of health services, provided that such treatment is carried out by a health professional subject to a duty of secrecy

Please refer to PDP-PrivateLaw and PDP-Public for detailed information on the principles guiding the protection and handling of personal data. See also MEX-95 for additional information on the protection of personal data held by private parties.

Additionally, per PDP-Trnspcy, obligated subjects and individuals must be responsible for the personal data in their possession, and may not disseminate, distribute, or commercialize the personal data contained in the information systems, developed in the exercise of their functions, unless there has been the express consent, in writing or by a similar means of authentication, of the persons to whom the information refers. See PDP-Trnspcy for detailed requirements.

Consent for Processing Personal Data

As explained in PDP-PrivateLaw and PDP-Public, the consent document or “privacy notice” is a physical, electronic, or any format document generated by the data controller or responsible party, that is made available to the data owner prior to processing that informs them of the purpose of collecting their data. Processing must be limited to the fulfillment of purposes delineated in the privacy notice. If the data controller or responsible party intends to process the data for another purpose, the data owner’s consent must be obtained again. PDP-Public specifies that the data controller or responsible party may process personal data for purposes other than those established in the privacy notice, provided that it has the authority granted by applicable law and the data owner has given their consent, unless the data owner has been reported missing, in accordance with the terms set forth in this law and other applicable provisions.

PDP-PrivateLaw and PDP-Public further explain that the consent may be given expressly or tacitly. Consent is understood to be expressed when the data owner’s will is expressed verbally, in writing, by electronic means, optically, with unequivocal signs, or by any other technology. Consent is tacit when the privacy notice has been made available to the owner, but the owner does not express their will to the contrary. As a general rule, tacit consent will be valid, unless the applicable legal provisions require that the data owner’s consent will be expressly stated. Per PDP-PrivateLaw, consent may be revoked at any time without retroactive effects being attributed to it. To revoke consent, the data controller must specify the mechanisms and procedures to be followed in the privacy notice.

PDP-PrivateLaw and PDP-Public state that in the case of sensitive data, the data owner or responsible party is required to obtain the data owner’s express written consent. PDP-PrivateLaw further indicates that the consent should be obtained through a written or electronic signature, or any authentication mechanism established for that purpose. Databases containing sensitive personal data may not be created without justifying their creation for legitimate, concrete purposes, and in accordance with the specified activities delineated and pursued by the data controller or responsible party. The data controller or the responsible party must also make reasonable efforts to limit the processing to the minimum time necessary.

As delineated in PDP-PrivateLaw and PDP-Public, the data controller or the responsible party will not be required to obtain consent when processing sensitive data in the following cases (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• When an applicable law authorizes such processing
• There is a court order, resolution, or well-founded and reasoned mandate from a competent authority
• 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 is contained 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

Also, as outlined in PDP-PrivateLaw, when a data controller or responsible party intends to transfer personal data to national or foreign third parties, the privacy notice and the purposes to which the data owner subjected the processing must be communicated. National or international data transfers carried out with the data owner’s consent may be necessary when it is:

• Provided for in a law or treaty to which Mexico is a party
• Necessary for medical prevention or diagnosis, the provision of health care, medical treatment, or the management of health services
• Made to holding companies, subsidiaries, or affiliates under the data controller’s common control, or to a parent company, or to any company of the same group that operates under the same internal processes and policies
• Necessary by virtue of a contract entered into, or to be entered into, in the data owner’s interest, by the data controller and a third party
• Necessary or legally required to safeguard a public interest, or to procure or administer justice
• Necessary for the recognition, exercise, or defense of a right in a judicial proceeding
• Necessary for the maintenance or fulfilment of a legal relationship between the data controller and the data owner

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

Consent for Processing Personal Data of Minors

Per 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.)

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 an 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 (CEI) 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.

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 (CEI), 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.

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, which 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.

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 (CEI) 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 of 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.

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 (CEI) 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 existed
• If resident doctors or partners are recruited for the study, the program director must provide the REC (CEI) 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 (CEI) 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 (CEI) 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 person is a minor, or is incapable of expressing their consent, consent should be provided by the parent(s)/guardian(s), and in their absence, by their legal representative(s).

Per GenChldRtsLaw, a child is defined as under 12 years of age, and adolescents are those between 12 and 18 years of age. For the purposes of the age of majority, children are those under 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 (CEI) 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.

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.

No applicable requirements

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.

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 way different from 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”).

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 health 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 health registration is valid for five (5) years. The health 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 and G-UnregDrugImprts, an applicant or the legal representative may submit a request to import an IP after COFEPRIS has approved the health authorization request for those drugs that are neither narcotic nor psychotropic, that do not have health 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.

Per Reg-HlthProd, Agrmnt_ResProtProcs, 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.

Additionally, as provided in Agrmnt_GMPCert, COFEPRIS has issued an agreement establishing the use of a regulatory “reliance” model for GMP certification. Under this agreement, COFEPRIS will recognize the GMP certificates or equivalent documents for drugs and medicines issued by Recognized Regulatory Authorities (RRA). RRAs include:

• National Regulatory Authorities that are PIC/S members
• National Regulatory Authorities included in the WHO List of Authorities (WLAs)
• Regional Reference National Regulatory Authorities (RRNs)
• National Regulatory Authorities of the country of origin, exclusively for foreign-manufactured drugs

Per Agrmnt_GMPCert, COFEPRIS will also consider Certificates of Pharmaceutical Product (CPP) that demonstrate GMP compliance when the issuing authority does not provide a GMP certificate. See Agrmnt_GMPCert for detailed requirements governing the reliance model for GMP certificates.

Per NOM-059-SSA1-2015-Mod, COFEPRIS uses the reliance model to recognize GMP certificates from National Regulatory Authorities (e.g., PIC/S members, WLAs, or those with equivalence agreements) to ensure access to new, safe, effective, and high-quality therapeutic options for the treatment of diseases requiring advanced therapies (mainly biotechnological drugs), such as cancer, diabetes and mellitus. See NOM-059-SSA1-2015-Mod for additional information.

Reg-HlthProd further states that COFEPRIS may grant permission to import raw materials or finished products without health 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, MEX-84, G-DIGIPRiS-ResProts, and G-UnregDrugImprts state that an import request may be submitted to COFEPRIS 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)
• Power of attorney
• 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 GMP issued by the corresponding authority of the country of origin
• Letter of representation, when the laboratory that manufactures the import product abroad is not a subsidiary or parent company of the laboratory requesting the registration
• 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

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 eight (8) business days to send the applicant a prevention notification requesting 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.

In addition, as set forth in Agrmnt_RegHlthSup, COFEPRIS issued an agreement adopting the WHO’s Good Reliance Practices for evaluating health registration applications. Under this framework, COFEPRIS may consider and rely upon the decisions of other RRAs to determine whether their requirements, tests, and evaluation procedures are equivalent to those conducted in Mexico for ensuring the quality, safety, efficacy, and performance of health supplies. In reviewing these applications, COFEPRIS will also consider the regulatory decisions of other RRAs, as well as the evaluations carried out by the WHO’s Prequalification Programme.

Per Agrmnt_RegHlthSup, for the treatment of emerging diseases, neglected tropical diseases, or in cases of national emergency, the Ministry must determine the medicines, vaccines, and medical devices that may be acquired through the Pan American Health Organization (PAHO)’s Strategic Fund or Revolving Fund (regional pooled procurement mechanisms), or through other procurement mechanisms, which will be imported for the prevention and control of diseases and health emergencies. Vaccines, medicines, and medical devices that have been acquired by the Ministry through these procurement mechanisms are exempt from health registration in Mexico. When the products are of biological origin, they are also exempt from obtaining a distribution or sale authorization. In the case of vaccines, medicines, and medical devices that have been acquired at the Ministry’s request, more than one (1) import permit may be requested under this Agreement, in accordance with the request made in an official letter submitted to COFEPRIS. See Agrmnt_RegHlthSup for additional information on COFEPRIS’s reliance model for health registration and on the import mechanisms for public health emergencies.

Mexico also has rules that govern how pharmaceutical products are transported and imported. 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.

Investigator’s Brochure

As indicated in MEX-2, Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the ICH Guideline for Good Clinical Practice E6(R2) (MEX-22). Agrmnt_ResProtProcs, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts are in compliance with MEX-22 regarding investigational product (IP) quality/manufacturing and investigator’s brochure (IB) requirements (also known as researcher’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, Agrmnt_ResProtProcs, 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 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
• 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 participants 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 Practice (GMP). 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, Agrmnt_ResProtProcs, G-HumResProt, G-DIGIPRiS-ResProts, and MEX-22, 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 GMP 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 GMP:

• 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 GMP.

Per NOM-059-SSA1-2015-Mod, COFEPRIS also uses the reliance model to recognize a GMP certificate and quality control laboratory analyses from National Regulatory Authorities (e.g., Pharmaceutical Inspection Co-operation Scheme (PIC/S) members, World Health Organization (WHO) List of Authorities (WLAs), or those with equivalence agreements) to ensure access to new, safe, effective, and high-quality therapeutic options for the treatment of diseases requiring advanced therapies (mainly biotechnological drugs), such as cancer, diabetes and mellitus. See NOM-059-SSA1-2015-Mod for additional information.

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)/WHO, and per MEX-111, is also a PIC/S member.

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). (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 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.

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. (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 MEX-22).

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 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.

In Mexico, a specimen is referred to as a “product of human beings.” According to GenHlthLaw and Reg-HumSpecDisp, products of human beings include any tissues or substances, excreted or expelled by the human body as a result of normal physiological processes.

GenHlthLaw and Reg-HumSpecDisp also provide more specific definitions for specimens including germ cells, stem cells, blood and derivatives, plasma, tissue, cellular concentrates, and organs. Please refer to these sources for more detailed information.

Additionally, G-RECs-Op-2018 states that human biological material includes organs, tissues, tissue components, cells, and products and cadavers of human beings.

Import

As delineated in GenHlthLaw, Reg-COFEPRIS, and Reg-HumSpecDisp, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is responsible for authorizing the import of specimens (referred to as “products of human beings” in Mexico).

According to G-ImprtPermit, institutions that import products of human beings including tissues, cells, blood and its components or derivatives intended for research, diagnosis, teaching, or treatment for therapeutic purposes, must comply with specific COFEPRIS documentation submission requirements to apply for an import permit. The documentation required to obtain an import permit specifically for research purposes is as follows:

• Import or Export of Products of Human Beings form (original) (see MEX-24)
• Proof of payment of fees (one (1) original; G-ImprtPermit also specifies that in terms of the Federal Rights Law, proof of payment of fees is applicable only to the application for a permit for the hospitalization of blood units, their components, and hematopoietic progenitor cells)
• Document certifying the operation of the foreign establishment issued by the health authority of the country of origin (original)
• Health license for the corresponding line of business (original)
• Notice of operation for the corresponding line of business (original)
• Authorization document issued by COFEPRIS for the protocol when it is intended for humans, or a summary of the study when in vitro is being carried out, where appropriate (original)
• Letter of acceptance in which the establishment that will receive the samples, justifying the reason and use of the samples (original)
• Letter of transmission justifying the use and purpose of sending the samples (original)
• Report on the date and procedure of destruction, if applicable (original)
• Document certifying the operation of the establishment that supplies human blood, its components and derivatives, issued by the health authority of the country of origin (original)
• Health license with the corresponding line of business (related to blood, its components or derivatives) (original)
• Power of attorney (accreditation of the legal representative)

G-ImprtPermit further notes that COFEPRIS has 45 business days to respond to the import request, and 15 business day to notify the applicant of missing or additional information required in a prevention letter. The applicant, in turn, has five (5) business days to respond to COFEPRIS’s prevention letter. The import permit approval is valid for 180 business days. Refer to G-ImprtPermit for detailed information necessary to obtain import permits for teaching, diagnosis, and therapeutic purposes including the use of human blood (i.e., umbilical cord blood or hematopoietic progenitor cells) and corneas.

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.

Export

According to G-ExprtPermit, institutions that dispose of or export products of human beings including tissues, cells, blood and its components or derivatives that are intended for diagnosis, treatment, research, or teaching purposes must also submit documentation to COFEPRIS to apply for an export permit.

G-ExprtPermit indicates the following general documentation must be provided to export cells, tissues, and products of human beings and their components:

• Import or Export of Products of Human Beings form (see MEX-24)
• Proof of payment of fees (original and two (2) legible copies) (applicable only to requests for an export permit for units of blood, its components, and hematopoietic progenitor cells)
• Document issued by the health authority of the destination country that certifies the operation of the establishment (original)
• Letter of acceptance of the establishment abroad (original)
• Authorization letter issued by COFEPRIS for the protocol when it is intended for humans, or a summary of the study when in vitro is being carried out, if applicable (original)
• Notice of operation of health establishment (original)
• Health license (original) (for cells, tissues, human products, and their components)
• Power of attorney (original)

G-ExprtPermit further notes that COFEPRIS has 45 business days to respond to the export request, and 15 business days to notify the applicant of missing or additional information required in a prevention letter. The applicant, in turn, has five (5) business days to respond to COFEPRIS’s prevention letter. The permit approval is valid for 180 business days.

In addition, G-ExprtPermit outlines the following required documentation to be submitted to COFEPRIS to export umbilical cord blood or hematopoietic progenitor cells, for cryopreservation, research, or therapeutic purposes:

• Import or Export of Products of Human Beings form (original) (see MEX-24)
• Proof of payment of fees (one (1) original and two (2) legible copies; G-ExprtPermit also specifies that in terms of the Federal Rights Law, proof of payment of fees is applicable only to the application for a permit for the hospitalization of blood units, their components and hematopoietic progenitor cells)
• Letter of acceptance of the establishment abroad (original)
• Health license (original)
• Document issued by the health authority of the destination country that certifies the operation of the establishment (original)
• Power of attorney (original)

Import/Export Permit Submission Procedures

MEX-24 indicates that an applicant may submit a request to obtain a permit to import or export specimens in print, in person via COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37), or electronically via the Mexican Digital Window for Foreign Trade (Ventanilla Única de Comercio Exterior Mexicano (VUCEM)) (MEX-114). Per G-ImprtPermit and G-ExprtPermit, the application should be submitted electronically via MEX-114 (Refer to MEX-114 for submission instructions). G-ImprtPermit and G-ExprtPermit state that to submit an application online, it is necessary to obtain an e.signature (also known as e.firma). An e.signature can be obtained from the Tax Administration Service (Servicio de Administración Tributaria (SAT)) as described in MEX-83.

See MEX-116 for instructions on completing MEX-24. See also G-ImprtPermitMod for the required documentation and submission procedures to modify an import/export permit for products of human beings including tissues, cells, and blood and its components or derivatives.

In accordance with GenHlthLaw, Reg-HumSpecDisp, and G-RECs-Op-2018, prior to collecting, storing, or using a research participant’s human biological material, consent must be obtained from the participant or the legal representative. GenHlthLaw specifically states that the consent must be obtained in writing.

From an ethical perspective, G-RECs-Op-2018 indicates it is important to consider including the following aspects in the informed consent for human biological materials use and storage:

• The document should clarify that samples may not be used for any purpose other than the one initially requested, and in accordance with the protocol approved by the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI))
• The collection, use, and storage of biological material must guarantee the confidentiality and privacy of the donor
• The commercialization of biological material is prohibited
• The investigator may not exercise undue influence by offering financial compensation to the donors of biological material
• The collection and transfer of biological material should not, under any circumstances, put at risk the medical care and safety of the research participant
• When the informed consent is revoked, the biological material collected for such purposes must no longer be used, unless the materials are irreversibly dissociated from the person. Data and biological material that are not irreversibly dissociated should be treated according to the wishes of the owner or donor in accordance with the International Declaration on Human Genetic Data (MEX-34)
• The REC (CEI) should demand to establish time limits for the use of biological material and prohibit the unrestricted use of the material

GenHlthLaw and Reg-HumSpecDisp provide additional consent requirements for the donor and the legal representatives (referred to as secondary donors in Mexico).

According to GenHlthLaw, persons may choose to donate their organs, tissues, cells, and body by tacit or expressed consent. Expressed consent may be in writing and broadly cover the donation of a person’s body, or it may be limited to certain body parts. The consent may also note that the donation is being made to a specific institution(s)/person(s) as well as the manner, place, time, and any other conditions. Further, the donor’s legal representative may also grant the earlier described consent in writing on the donor’s behalf when the donor cannot do so.

While third parties may not revoke the donor’s expressed consent, per GenHlthLaw, the donor may revoke consent at any time, without any liability. Written consent is specifically required when the donor is living for the following:

• The donation of organs and tissues
• The donation of blood, blood components, and stem cells

Reg-HumSpecDisp also notes that the donor may, at any time, revoke consent, without liability. Furthermore, if the original donor has not revoked consent during life, the donor’s legal representative revocation of consent will not be valid. Refer to Reg-HumSpecDisp for additional information on preferences for selecting the donor’s legal representatives.

In addition, per GenHlthLaw, the following restrictions apply with regard to consent by the individuals indicated below:

• Tacit or consent granted by minors or by persons unable to express their consent freely for any reason will not be valid
• All pregnant women are systematically asked for their consent to donate placental blood obtained from stem/progenitor cells for therapeutic or research purposes. However, expressed consent by a pregnant woman will only be admissible if the recipient is in danger of dying, provided that it does not endanger the woman or the fetus

(See the Required Elements and Participant Rights sections for additional information on informed consent).

GenHlthLaw also provides requirements to safeguard the confidentiality of a participant’s genetic data. A participant or their legal representative must provide their expressed consent and be informed of the results of their genetic exam and tests. Moreover, any scientific research, innovation, technological development and applications should be oriented to protect human health and respect the freedom and dignity of the participant(s).