Federal Commission for the Protection Against Sanitary Risks (COFEPRIS)

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

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

Reg-COFEPRIS specifies that COFEPRIS comprises eight (8) administrative units and four (4) government advisory bodies that manage the agency’s organizational and operational responsibilities. Included among COFEPRIS’s administrative units, and central to the research protocol authorization process, is the Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)).

As delineated in Reg-COFEPRIS, GenHlthLaw, and MEX-53, CAS is responsible for issuing, extending, or revoking clinical research authorizations. According to G-ApplicReqs, G-ObsrvStdies, G-ApplicAmd, and G-SecAmdt, CAS’s work is performed by its Technical Area for the Evaluation of Human Research Protocols, also known as the Clinical Trials technical area.

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, MEX-15, and MEX-75, COFEPRIS’s contact information is as follows:

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

Note: Per MEX-37, MEX-15, and MEX-75, the preceding address should also be used to contact COFEPRIS’s Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37) for technical inquiries or those inquiries requiring an official response.

Phone: Domestic General Inquiries and CIS Technical Inquiries: 01-800-033-5050 and (55) 5080-5200
Phone: International General Inquiries: 01-800-033-5050

Phone: International CIS Technical Inquiries: (55) 5340-0996
Email: contactociudadano@cofepris.gob.mx

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. As discussed in the Regulatory Authority section, COFEPRIS acts on behalf of the Ministry of Health (Secretaría de Salud). COFEPRIS-GCP and HlthResRegs specify that the scope of COFEPRIS’s assessment includes all clinical trials (Phases I-IV).

As stated in HlthResRegs, NOM-012-SSA3-2012, MEX-7, and MEX-75, 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, Research Committee, and Biosafety Committee.

Clinical Trial Review Process

As delineated in Reg-COFEPRIS, NOM-012-SSA3-2012, and MEX-53, COFEPRIS’s Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)) is responsible for recording, evaluating, and issuing opinions on authorization requests for human research protocols. According to G-ApplicReqs, G-ObsrvStdies, G-ApplicAmd, and G-SecAmdt, CAS’s work is performed by its Technical Area for the Evaluation of Human Research Protocols, also known as the Clinical Trials technical area. Per MEX-15, CAS’s Clinical Trials technical area conducts its work via COFEPRIS’s Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37), a public service system established to facilitate the processing of agency procedures and services.

As indicated in G-ApplicReqs and G-ApplicAmd, the applicant must submit an application to the CIS to request protocol authorization or modification. Protocol modifications may be submitted to amend research procedures, to remove or add research center(s)/research institution(s), or to provide updated clinical and/or preclinical security/safety IP information. See also G-ObsrvStdies, G-AppAmdDocs, G-SecAmdt, MEX-7, MEX-16, MEX-8, and MEX-75 for additional information on submitting these applications as well as submitting other types of applications (e.g., observation studies and biological/biotechnological studies).

As per G-ApplicReqs, G-ObsrvStdies, G-ApplicAmd, G-AppAmdDocs, G-SecAmdt, and MEX-20, when the applicant submits the application requesting protocol authorization to COFEPRIS, the CIS assigns a reference number to the application and sends it to the Clinical Trials technical area in CAS for technical evaluation. If CAS’s Clinical Trials technical area responds favorably to the initial request, the authorization is approved, and the clinical study may begin. However, if the request is rejected, an objection is issued and the applicant must resubmit a request for continued processing after addressing all of the issues raised. In either case, the applicant must use the CIS reference number to track the official resolution of either an authorization or an objection of the request.

Per HlthResRegs and G-RNECManual, once an official authorization from COFEPRIS is obtained, the applicant is required to enter this information into the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). See the Timeline of Review and Initiation, Agreements & Registration sections for additional information on the RNEC.

In addition, per Reg-HlthProdAmd, applicants must submit a request to COFEPRIS to obtain a sanitary registration for biosimilar biotechnological drug products. The specific requirements for the approval of each biosimilar biotechnological drug (e.g., in vitro studies, preclinical study reports, and comparative pharmacokinetic study reports) will be determined by the Ministry of Health, who will take into consideration the opinion of the Committee of New Molecules. When there is no relevant information in the Pharmacopoeia of the United Mexican States (Farmacopea de los Estados Unidos Mexicanos (FEUM)) and its supplements, nor in national guides or monographs, the Ministry may evaluate biosimilar tests using clinical data obtained from biosimilar biotechnological drug studies conducted in other countries. However, clinical trials are required to be conducted in Mexico when an applicant requests the renewal of an approval for a biosimilar biotechnological drug product. According to MEX-91, COFEPRIS’s acceptance of data produced abroad will accelerate the introduction of biosimilar drug products into Mexico. (Note: In Mexico, biosimilar is also referred to as biocomparable.)

UHAP Evaluations

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

HlthResRegs, G-ApplicReqs, G-ObsrvStdies, G-ApplicAmd, G-AppAmdDocs, and G-SecAmdt explain that receipt of a favorable pre-assessment evaluation requires CAS’s Clinical Trials technical area to issue a response within a maximum of 30 business days as long as the applicant notifies CAS that their application was submitted with the pre-assessment evaluation. A UHAP pre-assessment may result in a favorable or unfavorable review. If the review is unfavorable, the applicant is required to respond to all the issues raised, or the submission will be designated “rejected,” and the review will be concluded and returned to the applicant.

Federal Commission for the Protection Against Sanitary Risks (COFEPRIS)

As indicated in G-ApplicReqs, G-ObsrvStdies, G-AppAmdDocs, G-ApplicAmd, and G-SecAmdt, the applicant is responsible for paying a non-refundable fee (referred to as “Proof of Payment of Rights”) to submit a clinical research application to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)).

According to MEX-15 and MEX-75, applicants may obtain the fee information for a specific procedure or service using COFEPRIS’s Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37). CIS is a public service system established by the Mexican government to facilitate the processing of agency procedures and services.

In order to navigate the CIS system, applicants need to determine the correct COFEPRIS procedure code to obtain the associated processing instructions and fees. Per MEX-15, MEX-75, and MEX-37, applicants may schedule an appointment with CIS for assistance with this process. See MEX-37 for detailed instructions on scheduling an appointment with CIS.

MEX-75, MEX-73, and MEX-11 provide requirements and corresponding costs to submit requests to COFEPRIS for protocol authorizations or amendments/modifications. The costs linked to these procedures are as follows:

• Request for authorization of research protocol in humans for medicines, biological, and biotechnological: 7,240.60 Mexican Pesos (MEX-75 and MEX-11)
• Authorization of research protocol without risk (observational) in humans: 6,717.32 Mexican Pesos (MEX-73)
• Amendment or modification to the research protocol or inclusions to the protocol: 5,430.45 Mexican Pesos (MEX-11)

(Note: MEX-74 also provides requirements to submit amendments/modification requests. However, the webpage has not yet been updated to reflect the most current fees to request amendments/modifications. Please refer to MEX-11 for this information.)

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

Payment Instructions

As explained in MEX-75 and MEX-50, applicants should make payments for these procedures and services through an authorized credit institution using E5cinco (See MEX-52 for a link to participating financial institutions). E5cinco is an electronic scheme created to enable users to submit the Payment of Rights, Products, and Uses (Derechos, Productos y Aprovechamientos (DPAs)) to a participating credit institution through its Internet portal or banking window. See also MEX-51 and MEX-6 for detailed DPA payment instructions via E5cinco. Refer to MEX-14 for COFEPRIS’s electronic procedures portal user manual.

Overview

As set forth in HlthResRegs, REC-Op, REC-Op-Ref, G-RECs-Op-2018, and NOM-012-SSA3-2012, Mexico has a decentralized registration process for Research Ethics Committees (RECs) operating through the National Bioethics Commission (Comisión Nacional de Bioética (CONBIOÉTICA)). In addition, per HlthResRegs, NOM-012-SSA3-2012, MEX-65, MEX-64, and MEX-47, Research Committees and Biosafety Committees within each health institution must also register with the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). See also MEX-57 for a list of registered RECs.

Refer to MEX-65, MEX-64, MEX-47, MEX-29, MEX-58, and MEX-26 for detailed Research Committee and Biosafety Committee registration requirements and the application forms. Additionally, see MEX-40 for a tutorial on submitting REC registration requests.

Per HlthResRegs, GenHlthLaw, NOM-012-SSA3-2012, MEX-7, and MEX-75, 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. In addition, 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, and prepares ethics guidelines for conducting research in humans. Per HlthResRegs and NOM-012-SSA3-2012, the REC must also approve the informed consent document. HlthResRegs states 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.

See also the Oversight of Ethics Committees section for additional CONBIOÉTICA REC registration requirements.

According to NOM-012-SSA3-2012, the research institution owner must also register the REC, Research Committee, and Biosafety Committee, as appropriate, following their establishment and provide committee information as required by the Ministry of Health (Secretaría de Salud). Additionally, per NOM-012-SSA3-2012, a report should be submitted annually on the integration and activities of these committees during the first 10 business days of June.

Ethics Committee Composition

Research Ethics Committee Composition

As indicated in GenHlthLaw, RECs must be autonomous and interdisciplinary gender-balanced groups composed of medical personnel from different specialties; professionals from nursing, social work, sociology, anthropology, psychology, philosophy, or law fields who have bioethics training; and community representatives affected by the health condition under study or other health services users. 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.

NOM-012-SSA3-2012 also 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.

Research Committee and Biosafety Committee Composition

As described in NOM-012-SSA3-2012, Research Committees and Biosafety Committees should be multidisciplinary, consisting of health professionals from different specialties related to the health institution’s investigational research areas. The committees should also include professionals from other disciplines, and laypersons from the community who represent the moral, cultural, and social values of the research participants. The professionals may be based at the institution where the study is being conducted or from other medical institutions. In addition, per HlthResRegs, the Research Committee and Biosafety Committee should be comprised of at least three (3) scientists each with research expertise. The Research Committee should include health institution members with scientific methodology knowledge and expertise preferably. The Biosafety Committee should include scientists with broad expertise and knowledge to ensure that research activities are performed under the best biosafety measures. Biosafety Committee scientists do not have to be on the health institution staff.

Terms of Reference, Review Procedures, and Meeting Schedule

NOM-012-SSA3-2012 details general terms of reference requirements applicable to the REC, the Research Committee, and the Biosafety Committee, as well as specific requirements for each type of committee.

As stated in NOM-012-SSA3-2012, the constitution and operation of the REC, the Research Committee, and the Biosafety Committee will be subject to the provisions of current legislation and, where appropriate, to the criteria referred to in article 41 Bis of the GenHlthLaw.

Per NOM-012-SSA3-2012, committee terms of reference, review procedures, and meeting requirements should address the following:

• 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 operation and activities of the committees must be described in each committee’s standard operating procedures (SOPs).
• Members of these committees must refrain from participating in the evaluation and opinion of their own research.
• Each 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, for the activities carried out by said committee.
• The secretary of each committee must also carry out the necessary steps for the development of the activities of the committee in question, for which reason they must be endowed with the powers of administrative management for the exercise of their functions.
• In the sessions of each committee, members of external committees may participate or have the support of external advisors, who will have a voice but no vote. In these cases, researchers from the institution or establishment itself may also participate as long as they work in areas related to the subject of the project or research protocol in the opinion phase.
• It is the responsibility of the committees to issue the technical opinion on research, ethics, and biosafety in their field of competence, according to the nature of the proposed investigations.

Research Ethics Committees

As set forth in REC-Op, G-RECs-Op-2018, NOM-012-SSA3-2012, and COFEPRIS-GCP, RECs should operate within written SOPs to conduct their reviews. REC-Op and G-RECs-Op-2018 state that the health institution owner must approve the SOPs and issue a certificate of appointment to each of the REC members. HlthResRegs, G-RECs-Op-2018, and NOM-012-SSA3-2012 note that members must hold office for three (3) years and may be approved for an equal period.

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

• RECs must meet at least six (6) times a year, and at least once every two (2) months
• The minimum number of members required to complete a quorum must be greater than 50% of the members, and the president and/or secretary must be present to form a quorum
• In the evaluation of multicenter studies and when otherwise warranted, the REC may meet jointly with other RECs that belong to other establishments in the country, for the assessment and opinion for these protocols
• Minutes must be prepared for legal and administrative purposes in meetings
• An annual report of activities should be presented to the institutional head in the first 30 calendar days of the year
• Avoid conflicts of interest in protocol evaluations or be declared disqualified for that particular review
• Participation is required in initial training and bioethics continuing education
• Liaisons with other RECs within and outside the country to better carry out its functions
• A general policy on the confidentiality of information for protocols reviewed must be established and implemented
• A code of conduct for REC members must be established and implemented

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

As per G-RECs-Op-2018, the REC should 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.

Research Committees and Biosafety Committees

Per NOM-012-SSA3-2012, the Research and Biosafety Committees will have at least four (4) members representing each of the areas related to the subject matter of the research project or protocol in the opinion phase, which may include medical, nursing, administrative staff of the institution or establishment itself, as well as of other sectors that make up said committee.

NOM-012-SSA3-2012 further specifies that the Biosafety Committee will monitor any adverse effects for each study, as the case may be, with toxic, infectious, or radiological risks. The committee must comply with the requirements for its performance, including ensuring that there is a person in charge of radiological safety, who must be registered with the National Commission for Nuclear Safety and Safeguards.

Overview

According to HlthResRegs, REC-Op, and G-RECs-Op-2018, the primary scope of information assessed by the Research Ethics Committee (REC) 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, MEX-7, and MEX-75, 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)). 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. The REC’s favorable decision is later submitted to COFEPRIS as part of the application to obtain protocol authorization. Consequently, the REC and COFEPRIS reviews may not be conducted in parallel.

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 also states 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. 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) 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

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, CONBIOETICA is also responsible for promoting the organization and operation of Research Ethics Committees (RECs) 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, CONBIOETICA’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

As delineated in HlthResRegs, REC-Op, REC-Op-Ref, and G-RECs-Op-2018, and according to MEX-57, all RECs are required to register with CONBIOETICA in order to conduct health research in humans. See MEX-29 for CONBIOETICA’S REC Registration Application form. Additionally, see MEX-40 for a tutorial on submitting REC registration requests.

REC-Op-Ref and G-RECs-Op-2018 further state that CONBIOETICA has ten (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.

G-RECs-Op-2018 further notes that the application must be submitted to CONBIOETICA according to the form and requirements delineated in Annex 1 of REC-Op-Ref. Per REC-Op-Ref and MEX-57, the REC registration form may be mailed or submitted electronically through CONBIOETICA’s website. As explained in REC-Op-Ref and MEX-57, 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. Refer to G-RECs-Op-2018 and MEX-57 for detailed registration application instructions and requirements. See also for a list of registered RECs.

As delineated in REC-Op-Ref and G-RECs-Op-2018, a registration renewal application must be submitted by the institutional head to CONBIOETICA 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-Ref and G-RECs-Op-2018 for detailed registration and renewal application requirements.

In addition to CONBIOETICA’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 CONBIOETICA’s REC follow-up monitoring reports.

G-CHBs-Op and MEX-59 indicate that Hospital Bioethics Committees must also register with CONBIOETICA, who is, in turn, required to issue a registration record within a maximum of 15 business days. CONBIOETICA’s registration is valid for three (3) years. Refer to G-CHBs-Op, MEX-56, and MEX-59 for detailed hospital bioethics committee registration information.

Overview

In accordance with GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, and COFEPRIS-GCP, Mexico requires the applicant to obtain research protocol authorization from the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Per HlthResRegs, NOM-012-SSA3-2012, G-ResProtocols, MEX-7, and MEX-75, the applicant must also obtain a favorable decision from the Research Ethics Committee (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. 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

As per MEX-37, MEX-75, MEX-15, and MEX-71, applications as well as technical inquiries, or those inquiries requiring an official response should be submitted to COFEPRIS’s Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37):

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

Phone: Domestic General Inquiries and CIS Technical Inquiries: 01-800-033-5050 and (55) 5080-5200
Phone: International General Inquiries: 01-800-033-5050
Phone: International CIS Technical Inquiries: (55) 5340-0996

Email: contactociudadano@cofepris.gob.mx

As indicated in G-ApplicReqs, G-ObsrvStdies, and MEX-7, to request research protocol authorization, applicants must submit one (1) hard copy of the application and one (1) electronic copy on CD-ROM or USB. MEX-7 further states that electronic format (Rich Text Format (RTF)) is preferable.

Application documentation should be presented as follows:

• Each page of the application submission must be printed legibly and paginated in the upper left-hand corner (per G-Bioequiv), or the upper right-hand corner (per G-ApplicReqs), with the page number (001) starting on the last page going forward
• Only the proof of payment should not be paginated (per G-ApplicReqs and G-ObsrvStdies)
• Each section should be separated by a colored sheet (per G-ObsrvStdies)
• Information must be presented with a side clasp (right side per G-Bioequiv or left side per G-ApplicReqs) without binding or folders
• Information must be identified with a colored cover or sheet on the front side, and the type of application should be indicated with a label (see G-Bioequiv for detailed instructions)
• Information can be highlighted using a highlighter pen (per G-Bioequiv)

Per G-ApplicReqs, MEX-7, MEX-75, and MEX-18, the Authorizations, Certificates and Visits form (MEX-25) should also be included in the application submission, as well as the original proof of payment of rights with two (2) copies of the receipt.

Please refer to G-Bioequiv, G-ApplicReqs, G-ObsrvStdies, and MEX-7 for detailed protocol authorization application formatting requirements.

G-Bioequiv, G-ApplicReqs, and G-ObsrvStdies state that all documentation related to submitting applications for research protocol authorization is required to be in Spanish; no documentation (e.g., protocol and researcher’s manual) should be submitted in English. Per G-Bioequiv, legal documents issued in another language must be accompanied by a translation prepared by an expert translator.

Enabled Pre-Assessment Support Unit (UHAP) Evaluation Submissions

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

HlthResRegs, G-ApplicReqs, G-ObsrvStdies, G-ApplicAmd, G-AppAmdDocs, and G-SecAmdt explain that a UHAP pre-assessment may result in a favorable or unfavorable review. If the review is unfavorable, the applicant is required to respond to all the issues raised, or the submission will be designated “rejected,” and the review will be concluded and returned to the applicant.

Ethics Review Submission

As earlier stated, per HlthResRegs, NOM-012-SSA3-2012, MEX-7, and MEX-75, 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 specified in GenHlthLaw, HlthResRegs, G-ApplicReqs, G-ResProtocols, NOM-012-SSA3-2012, COFEPRIS-GCP, and MEX-75, 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: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

• Authorizations, Certificates and Visits form (original) (MEX-25)
• Proof of payment of rights (Original and two (2) copies)
• Research protocol (original and one (1) copy)
• Acceptance letter from research institution head and responsible principal investigator (PI)
• Sponsor letter of acceptance
• Follow-up letter from sponsor providing monitoring/auditing plan
• Model letter of informed consent in Spanish
• Informed consent document (original)
• Study schedule (original and one (1) copy)
• Letter describing approximate total quantity of investigational products (IPs) requiring importation at each stage of the study; letter serves as acknowledgement of information, not authorization (original and one (1) copy)
• Copy of study’s current financial or insurance budget
• Copy of current Research Ethics Committee (REC) and Research Committee registration and Biosafety Committee registration, where applicable
• Favorable opinion of REC, Research Committee, and where appropriate, Biosafety Committee (original and one (1) copy)
• REC member list
• REC member letters recusing themselves if on research team
• REC letter describing study follow-up process
• Letter of No Conflict of Interest and Confidentiality signed by REC members
• Copy of sanitary license or notice of operation
• Letter of authorization to carry out the research, signed by health institution owner (original and one (1) copy)
• Where applicable, copy of agreement between research centers that have agreements for emergency medical care with other institutions
• Letter describing resources available for emergency management (original and one (1) copy)
• Adverse event report confidentiality letter from the PI (original and one (1) copy)
• Summary of PI’s professional record/official professional documentation issued and registered by competent educational authorities (original and one (1) copy)
• Summary of academic preparation and experience of medical personnel, paramedics, and other experts involved in study (original and one (1) copy)
• Letter describing research team’s delegation of responsibilities
• Investigator’s manual (original and one (1) copy)
• Letter describing the sponsoring institution’s resources for the study’s development (include institution/establishment name, type of support required (e.g., human, material, financial, advisory information, and other resources), and how support will be provided and distributed) (original and one (1) copy)
• Copy of document indicating drugs used in study comply with Good Manufacturing Practices (GMPs) and have the expected quality characteristics for IPs to be used in study, or letter documenting GMPs
• Status of stability studies, or letter documenting IP stability studies comply with applicable regulations
• Basic pharmacological and preclinical product information
• Optional pre-assessment evaluation opinion (See Scope of Assessment and Submission Process sections for details on pre-assessment evaluations)

Refer to GenHlthLaw, HlthResRegs, NOM-012-SSA3-2012, G-ApplicReqs, G-ObsrvStdies, COFEPRIS-GCP, MEX-7, MEX-75, and MEX-18 for more detailed submission information. See also MEX-36 for information on obtaining a certificate of GMPs.

Additionally, per G-ApplicReqs, the following must be completed to submit an application to COFEPRIS with a pre-assessment evaluation opinion issued by an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69):

• Send the submission to uhap@cofepris.gob.mx indicating the entry number to COFEPRIS, the Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37) with a pre-opinion for identification and follow-up
• Include a cover sheet indicating that it is “PROCEEDING WITH PRE-OPINION BY UHAP”
• All documents must be numbered with original UHAP stamps (no procedures are accepted with a copy of the file evaluated by the UHAP, or, if applicable, information order is different from that established by the UHAP)
• The order of the documents reviewed by the UHAP should not be changed

Ethics Committee Requirements

As indicated in COFEPRIS-GCP, the National Bioethics Commission (Comisión Nacional de Bioética (CONBIOÉTICA)) requires the PIs to submit the following documentation for REC approval:

• Research protocol
• Protocol summary
• Summary of previous studies
• Summary of therapeutic product research
• Documentation stating research participant, researcher, institution, and if applicable, sponsor commitments
• Report describing maintenance measures and life support for research participants and insurance policy agreements
• Report on procedures and people responsible for keeping participants informed of study developments
• Investigator resume
• Statement specifying external funding source information, if applicable
• Statement providing study costs and expenses, if no external funding source
• Sponsor data report
• Report on supporting material to be used for participant recruitment
• System/mechanism to protect participant privacy and maintain confidentiality during study
• Methodology to obtain informed consent
• System and procedure to communicate results to participants
• For previously rejected protocols, information on modifications made to address earlier issues
• Informed consent letter
• Investigator’s manual
• Amendments to previously approved documentation
• Targeted advertising for recruitment
• Required documentation for participants

See COFEPRIS-GCP for additional ethics committee requirements.

Clinical Protocol

As set forth in NOM-012-SSA3-2012, the research protocol should include the following elements:

• Title
• Theoretical framework
• Definition of problem
• Background
• Rationale
• Hypothesis (if applicable)
• General objective (if applicable, specific objectives)
• Materials and methods
• Design (e.g., inclusion/exclusion criteria; information input, processing, analysis, and interpretation)
• Bibliographic references
• 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.

Overview

As delineated in HlthResRegs, NOM-012-SSA3-2012, G-ResProtocols, MEX-7, and MEX-75, 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) and the Research Committee, and where applicable, the Biosafety Committee. Therefore, COFEPRIS and ethics committee (REC, Research Committee, and Biosafety Committee) reviews may not be conducted in parallel. However, per HlthResRegs, the REC, the Research Committee, and the Biosafety Committee may meet together to decide whether to authorize a protocol to conduct research on humans, as appropriate.

Regulatory Authority Approval

Pursuant to HlthResRegs, COFEPRIS must approve a request for research protocol authorization within 30 working days from the day following an application’s filing.

According to G-ApplicReqs, G-ObsrvStdies, G-ApplicAmd, and MEX-20, when the applicant sends the application requesting protocol authorization directly to COFEPRIS, the Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37) will assign a reference number to the application and send it to the Clinical Trials technical area in COFEPRIS’s Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)) for technical evaluation. If the CAS’s Clinical Trials technical area responds favorably to the initial request, then the authorization is approved and the clinical study may begin. However, if the request is rejected, an objection is issued and the applicant must resubmit a request for continued processing after addressing all of the issues raised. In either case, the applicant must use the CIS reference number to track the official resolution of either an authorization or an objection of the request.

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

Enabled Pre-Assessment Support Unit (UHAP) Evaluations

Mexico also offers a pre-assessment evaluation that helps to facilitate COFEPRIS’s review. Per MEX-21 and MEX-10, rather than submitting the application directly to the CIS, the applicant has the option of first choosing to obtain a pre-assessment evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High 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)). HlthResRegs, G-ApplicReqs, G-ObsrvStdies, G-ApplicAmd, G-AppAmdDocs, and G-SecAmdt explain that receipt of a favorable pre-assessment evaluation requires CAS’s Clinical Trials technical area to issue a response within a maximum of 30 business days as long as the applicant notifies CAS that their application was submitted with the pre-assessment evaluation. A UHAP pre-assessment may result in a favorable or unfavorable review. If the review is unfavorable, the applicant is required to respond within 30 calendar days to all the issues raised, or the submission will be designated “rejected,” and the review will be concluded and returned to the applicant. 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 also states 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, and COFEPRIS-GCP, a clinical trial can only commence after an applicant receives authorization from Mexico’s Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Per HlthResRegs, G-ResProtocols, NOM-012-SSA3-2012, MEX-7, and MEX-75, the applicant must also obtain a favorable decision from the Research Ethics Committee (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. No waiting period is required following the applicant’s receipt of these approvals.

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

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

Clinical Trial Agreement

Prior to initiating the trial, as set forth in NOM-012-SSA3-2012, G-ResProtocols, G-ApplicReqs, and G-ObsrvStdies, 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. Per NOM-012-SSA3-2012, G-ApplicReqs, and G-ObsrvStdies, in the case of corporate entities, this position must be accepted by an individual authorized to do so or by a corporation’s legal representative, according to its organizational structure or incorporation regime. The sponsor must guarantee this will not generate any conflicts of interest that could cause the interruption of treatment for the research participant. G-ApplicReqs specifies that the sponsor must also ensure there are no conflicts of interest to the PI related to protection of research participant rights, preserving the truth of study results, and allocating resources. Therefore, per NOM-012-SSA3-2012 and G-ResProtocols, the sponsor must attach to the protocol a detailed explanation of the available resources and how they will be provided and distributed.

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 contract research organization (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. Further, per the Guideline for Good Clinical Practice E6(R1) (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 ensure that they agree to comply with good clinical practices.

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

Further, per MEX-32, the sponsor or the CRO must 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

Clinical Trial Registration

Per HlthResRegs and G-RNECManual, once an official authorization is obtained from COFEPRIS, the applicant has a maximum of five (5) working days to enter this information into the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68).

See also G-RNECManual for detailed RNEC registration instructions.

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: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

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

Safety Reporting Requirements

As specified in NOM-220-SSA1-2016, 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 (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
• Reports must be submitted when a drug shows a lack of effectiveness (therapeutic failure or therapeutic ineffectiveness) within a maximum of 15 calendar days of first knowledge of the AE/ADR, with as much clinical data as possible
• 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), 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. The investigator is responsible for submitting safety reports to the CNFV.

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.

Other Safety Reports

NOM-220-SSA1-2016 indicates that a pharmacovigilance study protocol should also be prepared and submitted to the Executive Director of Pharmacopeia and Pharmacovigilance through COFEPRIS’s Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37). Once COFEPRIS has authorized the protocol, a digital copy must be submitted in PDF format to the CNFV by the same individual responsible for registering the study with the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). Refer to NOM-220-SSA1-2016 for detailed pharmacovigilance study protocol requirements, MEX-23 for further information on National Pharmacovigilance Center guidelines and requirements, and MEX-54 for additional pharmacovigilance guidelines and requirements. See MEX-38 for information on how various notifiers report suspected ADRs.

Per NOM-220-SSA1-2016, notifiers are also required to submit a periodic safety report and a clinical safety report to the CNFV. NOM-220-SSA1-2016 indicates that a periodic safety report should be developed for all authorized medicines and vaccines, and a clinical safety report is required for all trials, sponsored or not, that have at least one (1) site or research center in Mexico. G-ClinResPV further specifies that safety report information must be written in Spanish and submitted electronically (in PDF format). 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 periodic annual safety report submission date is determined by the date of the study’s first national authorization by COFEPRIS. In addition, G-ClinResPV explains that a final safety report must be submitted to the CNFV in the following circumstances:

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

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

Form Completion & Delivery Requirements

As per NOM-220-SSA1-2016, G-AENotif, MEX-45, and MEX-77, notifiers must electronically submit all AEs/ADRs, SRAMs, and any other safety issues related to the use of medicines and vaccines to the CNFV using VigiFlow (MEX-43). MEX-45 provides specific VigiFlow reporting instructions for pharmaceutical industry professionals (e.g., health registration holders or legal representatives, contract research organizations, distributors, and marketers). MEX-77 provides specific VigiFlow reporting instructions for state centers, institutional coordinating centers, institutional centers and pharmacovigilance units of the National Health System. MEX-78, in turn, provides patients, consumers, and health professionals instructions on reporting adverse drug reactions using the e-Reporting form (MEX-23). See MEX-12 for instructions on how to complete the form. See also MEX-78 for patient and consumer instructions on reporting adverse vaccine reactions.

Refer to NOM-220-SSA1-2016 for detailed reporting requirements and the G-AENotif and MEX-44 for submitting safety reports via MEX-43. See also MEX-66 and MEX-30 for the SRAM website and the corresponding reporting form.

Interim and Annual Progress Reports

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

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

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

In accordance with NOM-012-SSA3-2012, a report should be submitted annually on the integration and activities of these committees during the first 10 business days of June.

Final Report

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

The specified elements for progress reports discussed in NOM-012-SSA3-2012 are also required for final reports. The results should include, at a minimum, the following elements:

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

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

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

As set forth in NOM-012-SSA3-2012 and COFEPRIS-GCP, 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.

Per COFEPRIS-GCP, a sponsor may also hire a contract research organization (CRO) to conduct one (1) or more of the activities related to health research that are sponsored in the country. However, the ultimate responsibility for all CRO activities remains with the sponsor. 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.

As set forth in COFEPRIS-GCP, 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.

As stated in the HlthResRegs, G-ApplicReqs, G-ObsrvStdies, and NOM-012-SSA3-2012, all investigators must possess appropriate qualifications, training, and experience.

Per COFEPRIS-GCP, the sponsor and the CRO must also ensure that research institutions uphold the following additional requirements:

• Ensure urgent care resources are available, or where appropriate, a written agreement with the health institution that will attend to the emergency. The agreement must comply with NOM-206-SSA1-2002, which establishes the criteria for the operation and attention in providing emergency services in health care institutions.
• Provide a restricted and sheltered storage area for the investigational product (IP) and other supplies required for research, with adequate controls of temperature, humidity, and other conditions as established by the manufacturer

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. As stated in COFEPRIS-GCP, the sponsor may transfer any or all of the study related duties and functions to a CRO. However, the sponsor is ultimately responsible for the execution of the research protocol and results of the clinical trial and must establish the delegated responsibilities in writing.

Data Safety Monitoring Board

According to COFEPRIS-GCP and 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.

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

G-ApplicReqs further states that a copy of the current Global Insurance Policy certificate delineating the financial or insurance funding for the study should be included with the protocol submitted in the application package.

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.

Injury or Death

Although NOM-012-SSA3-2012 does not specifically ascribe responsibility to the sponsor, it indicates that the research budget must include the availability of a financial fund as well as mechanisms to guarantee continuity of medical treatment and indemnity of the research participant, in the event of trial-related injuries.

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

Post-Trial Access

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.

As indicated in MEX-32, the sponsor or the CRO is also 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 and MEX-32, the sponsor or the CRO must ensure and control the quality of the research through periodic monitoring visits and audits. 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.

G-ObsrvStdies further requires the sponsor or the CRO to provide a follow-up letter to COFEPRIS describing the monitoring and auditing plan to be used during the investigation. The letter should include at least the following information:

• 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 tool
• Methodology to carry out the scientific, technical, and ethical monitoring
• Communication strategies between researcher, sponsor, and committees
• Profile of the monitor or auditor
• Classification of findings
• Decision-making derived from findings according to their severity
• Notification mechanism to the principal investigator (PI), committees, and COFEPRIS
• Design of Corrective, Improvement or Preventive Action Plan
• Format for reporting results through the partial and annual technical report (See MEX-31 for the partial reporting form)

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

Premature Study Termination/Suspension

Per HlthResRegs, the PI, the Research Ethics Committee (REC), the institutional head or other authorized institutional officers, or the Ministry of Health (Secretaría de Salud) must order the immediate suspension or cancellation of a research study as soon as any adverse effect is identified that might become an ethical or technical impediment to continuing with the study. NOM-012-SSA3-2012 similarly states that the investigator is responsible for suspending the investigation if there is a risk of serious injury, disability, or death of the research subject in accordance with GenHlthLaw.

Additionally, per NOM-220-SSA1-2016, institutions must notify the National Pharmacovigilance Center (CNFV) of a study’s suspension or cancellation within a maximum of 15 days. If the study is resumed, the CNFV must also be notified within a maximum of 15 working days following the study’s recommencement. The investigator is responsible for submitting safety reports to the CNFV.

Electronic Data Processing System

As per MEX-32, when using electronic trial data processing systems, the sponsor or the contract research organization (CRO) must ensure that they conform to established requirements for completeness, accuracy, reliability, and consistency of intended performance, and standard operating procedures (SOPs) are maintained for using these systems.

Records Management

As indicated in MEX-32, all sponsor-specific essential documents used in the trial should be retained for at least two (2) years after formal discontinuation of the trial or the last approval of a marketing application. The sponsor should inform the investigator(s) and the institution(s) in writing 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

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

Data Protection

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

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

According to the PDP-PrivateLaw, the PDP-Reg, the PDP-Public, and MEX-4, the sponsor is also required to protect the confidentiality of the owner of the personal data and their background. The PDP-PrivateLaw further notes that this obligation will remain in place even after the data processing activities have been completed and the relationship between the sponsor or the sponsor’s representative(s) and the data owner has concluded.

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

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

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

Consent for Processing Personal Data

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

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

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

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

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

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

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

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

Consent for Processing Personal Data of Minors

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

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

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, G-RECs-Op-2018, and G-ApplicReqs, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by a Research Ethics Committee (REC) and provided to COEFPRIS with the request for research protocol authorization. G-ApplicReqs further specifies that the consent document must be sent to each participating research center, and should be personalized for each location, indicating the name and address, consistent with the authorization of each center, as well as the corporate name and management of the committees involved, and the version and date. (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 and/or the legal representative(s) or guardian(s). As delineated in HlthResRegs, G-RECs-Op-2018, NOM-012-SSA3-2012, and MEX-32, 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 and/or the legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate. GenHlthLaw further notes the ICF should be expressed in writing in an accessible, timely manner and in understandable language, using accurate and complete information, including the possible benefits and expected risks, and the treatment alternatives, to ensure that services are provided on the basis of free and informed consent. Once comprehension of the information is guaranteed through the necessary means and supports, individuals have the right to accept or reject consent. 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 and/or the legal representative(s) or guardian(s) to waive or appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

Re-Consent

According to G-RECs-Op-2018 and MEX-32, any change in the ICF that is relevant to the participant’s consent should be approved by the REC prior to implementing any changes. Per G-RECs-Op-2018 and MEX-32, the participant and/or the legal representative(s) or guardian(s) 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-ApplicReqs 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 and/or the legal representative(s) or guardian(s), 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 and/or the legal representative or 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 and/or the legal representative or guardian. G-ApplicReqs states that the ICF must contain the document version and date.

Waiver of Consent

No information is currently available regarding waiver requirements.

Based on G-RECs-Op-2018 and the G-ApplicReqs the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

• 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
• Alternative treatments that may be beneficial to the participant
• Trial treatment(s) and the probability for random assignment to each treatment
• 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, and permission given to monitors, auditors, the Research Ethics Committee (REC), and the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) to access the participant’s medical records to verify the procedures or trial data, without violating the participant’s confidentiality, insofar as the applicable laws and regulations permit
• Contact information for the sponsor and principal investigator (PI) in the event of participant problems or trial-related injuries
• The guarantee of receiving 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

See HlthResRegs, NOM-012-SSA3-2012, G-ApplicReqs, 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, G-ApplicReqs, and MEX-32, the participant and/or the legal representative(s) or guardian(s) 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, G-ApplicReqs, and MEX-32, a potential research participant and the legal representative(s) or guardian(s) 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-ApplicReqs, G-RECs-Op-2018, and MEX-32, 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 and/or the legal representative(s) or guardian(s) 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)’s president, including a 24-hour telephone number in case of emergency, should be provided.

The Right to Safety and Welfare

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

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

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. (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) and the Research Committee, and an informed consent form (ICF) signed by the research participant or the legal representative(s) or guardian(s). The terms under which this documentation is obtained must meet the following requirements:

• The REC and Research Committee will be informed of the use of the investigational drug in advance if the researcher can anticipate the need for use in emergency situations. If this is not possible, an opinion must be obtained after the situation occurs. In both cases, the committees will issue an opinion in favor or against approving the planned or recurring unintended use of the drug.
• A signed ICF must be obtained from the participant and/or the legal representative(s) or guardian(s) unless the participant’s condition prevents them from signing the form, the legal representative(s) or guardian(s) 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(s) or guardian(s), if present, should be requested. When prior consent of the participant or the legal representative(s) or guardian(s) 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 the legal representative(s) or guardian(s) 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) should ensure that additional security mechanisms are implemented to minimize the specific risks for each group. MEX-32 similarly states that ethics committees must pay special attention to protecting participants who are from vulnerable populations.

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

Persons in Dependent Groups

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

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

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

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

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

Persons in Local Communities

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

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

Terminally Ill Persons

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

As delineated in G-ApplicReqs, a minor is defined as eight (8) years to 17 years of age.

Additionally, per HlthResRegs, in all cases, a written informed consent must be obtained from those exercising parental authority, or the legal representative(s) or 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) may waive compliance with these requirements for justified reasons.

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

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

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

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

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

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

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

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

Assent Requirements

As delineated in G-ApplicReqs, assent is required when the minor is older than seven (7) years but less than 18 years of age.

Per G-RECs-Op-2018 and G-ApplicReqs, 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. G-ApplicReqs further states the assent should be personalized in Spanish for each participating research center including the version and date, center name and address, corporate name, and management of the involved committees.

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)’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 relevant provisions

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) 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, an investigational product (IP) is defined as any pharmaceutical form containing an active ingredient or placebo, or a product of biological or biotechnological origin that is used or tested in a clinical trial, including a registered product when used or packaged in a different way with for which it was authorized, or when it is tested for indications that have not been authorized, or when it is used to obtain more information about its authorized use. 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 sanitary registration prior to initiating any drug manufacturing activities. Reg-HlthProd states that COFEPRIS must complete its review in 60 days, or the application will be deemed approved. Per GenHlthLaw, the sanitary registration is valid for five (5) years. The sanitary registration may be extended for an additional five (5) years if the extension is requested prior to the expiration of the current authorization, or the registration will be cancelled or revoked. See also GenHlthLaw, Reg-HlthProd, MEX-46, and MEX-63 for detailed drug manufacturer registration submission requirements.

In addition, per MEX-67, 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-48, is also a member of Pharmaceutical Inspection Co-operation Scheme (PIC/S).

Import

As delineated in GenHlthLaw, Reg-COFEPRIS, and Reg-HlthProd, COFEPRIS is also responsible for authorizing the import of IPs. According to Reg-HlthProd, G-UnregDrugImprts, and MEX-63, an applicant or the legal representative may submit a request to import an IP after COFEPRIS has approved the sanitary authorization request for those drugs that are neither narcotic nor psychotropic, that do not have sanitary registrations, and that are intended to be used for human research. As per GenHlthLaw, the applicant must be a resident of Mexico or have a legal representative submit an import request on the applicant’s behalf.

Per Reg-HlthProd, 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, G-ApplicReqs indicates that a request for research protocol authorization must include a document stating that the IPs to be used in the clinical study comply with GMPs, and have the expected quality characteristics for the IP under investigation, or provide a letter declaring that the GMPs are valid.

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

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

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

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

Reg-HlthProd, G-UnregDrugImprts, and MEX-63 state that an import request may be submitted to COFEPRIS’s Integral Services Center (Centro Integral de Servicios (CIS)) (MEX-37) once the agency has authorized the protocol for research to be conducted on human beings. The following documentation should be included:

• Authorizations, Certificates and Visits Form (see MEX-25) (Original)
• Proof of payment of fees (Original and two (2) copies)
• Health License or 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)

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, COFEPRIS has 10 days to approve the request. If COFEPRIS does not respond within this timeframe, the request is deemed approved. Reg-HlthProd 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.

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.

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

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

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

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

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

In accordance with COFEPRIS-GCP, the sponsor or the contract research organization (CRO) is responsible for complying with the principles of good clinical practice (GCP) as specified in the Guideline for Good Clinical Practice E6(R1) (MEX-32) and for providing investigators with an Investigator’s Brochure (IB). Per MEX-32, the IB must contain all of the relevant information on the investigational product(s) (IPs) obtained through the earlier research phases, including pharmacological, toxicological, pharmacokinetic, safety, efficacy, and adverse events data. The sponsor must also update the IB as significant new information becomes available.

As specified in MEX-32, the IB must provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties and formulation parameters
• Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; and regulatory and postmarketing experiences)
• Summary of data and guidance for the investigator(s)
• Bibliography

See Section 7 of MEX-32 for detailed content guidelines.

Quality Management

As specified in COFEPRIS-GCP, GenHlthLaw, Reg-HlthProd, G-ApplicReqs, NOM-059-SSA1-2015, NOM-164-SSA1-2015, NOM-176-SSA1-1998, NOM-073-SSA1-2015, and MEX-32, the sponsor must verify that the products are manufactured in accordance with the current codes of Good Manufacturing Practices (GMPs). See NOM-059-SSA1-2015-Annexes to access the annexes to NOM-059-SSA1-2015.

In accordance with the GenHlthLaw, Reg-HlthProd, NOM-059-SSA1-2015, NOM-164-SSA1-2015, NOM-176-SSA1-1998, and MEX-32, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires that drug manufacturers ensure IPs are manufactured, handled, and stored in accordance with applicable GMPs and provide the following additional information:

• 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)

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

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

In addition, per MEX-67, 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-48, is also a member of the Pharmaceutical Inspection Co-operation Scheme (PIC/S).

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

As delineated in NOM-059-SSA1-2015, the IP label must contain, at a minimum, the following information:

• Name, address, and telephone number of the sponsor or main contact
• Pharmaceutical form and route of administration
• Lot number
• Statement: “For clinical studies only”
• Expiration date

NOM-164-SSA1-2015 also states that the IP label must indicate it is material under investigation. In addition, MEX-32 states the sponsor should verify the IPs are coded and labeled in a manner that protects the blinding, if appropriate.

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 MEX-32 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.

As indicated in the Guideline for Good Clinical Practice E6(R1) (MEX-32), the sponsor should not supply the investigator(s)/institution(s) with the IP(s) until approval is obtained from the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) and the institutional ethics committee. MEX-32 also specifies that the sponsor must ensure the following:

• Timely delivery of the IP(s)
• IP records document shipment, receipt, disposition, return, and destruction
• Written procedures including instructions for IP handling and storage, 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
• IP product quality and stability over the period of use
• IP manufactured according to any application of Good Manufacturing Practices (GMPs)
• Proper coding, packaging, and labeling of the IP(s)
• Acceptable IP handling and storage conditions and shelf-life

Refer to MEX-32 for detailed sponsor-related IP requirements and MEX-36 for additional information on obtaining a GMP certificate.

Per NOM-073-SSA1-2015, during the clinical trial, the manufacturer must validate the stability of the IP until the date of the last administration. COFEPRIS-GCP further states that 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, per COFEPRIS-GCP, 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.

NOM-164-SSA1-2015 and NOM-059-SSA1-2015 also 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.

Record Requirements

As set forth in MEX-32, the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and when the trial-related pharmacy records are no longer needed. All sponsor-specific essential documents should also be retained for at least two (2) years after the last approval of a marketing application in an International Council for Harmonisation (ICH) region, and until there are no pending or contemplated marketing applications in an ICH region, or at least two (2) years have elapsed since the formal discontinuation of clinical development of the IP. In addition, if the sponsor discontinues the clinical development of the IP, all sponsor-specific essential documents should be maintained for at least two (2) years after formal discontinuation or in conformance with applicable regulatory requirement(s).

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 and MEX-61, 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:

• Entry or Exit of Products of Human Beings form (see MEX-24)
• Proof of payment of rights (one (1) original and two (2) legible copies (per G-ImprtPermit)); MEX-61 requires one (1) original and one (1) copy. MEX-61 also specifies that in terms of the Federal Rights Law, proof of payment of rights is applicable only to the application for a permit for the hospitalization of blood units, their components, and hematopoietic progenitor cells
• Document accrediting the operation of the institution issued by the health authority of the country of origin
• Copy of the health license or operating notice for the appropriate line of business
• Copy of the 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

Refer to G-ImprtPermit and MEX-61 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 and MEX-62, 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:

• Entry or Exit of Products of Human Beings form (see MEX-24)
• Proof of payment of rights in original and two (2) legible copies
• Letter of acceptance of the establishment abroad
• Legible copy of the 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
• Copy of the operating notice or sanitary license

In addition, G-ExprtPermit and MEX-62 outline the following required documentation to be submitted to COFEPRIS to export umbilical cord blood or hematopoietic progenitor cells, for cryopreservation, research, or therapeutic purposes:

• Entry or Exit of Products of Human Beings form (see MEX-24)
• Proof of payment of rights (one (1) original and two (2) legible copies (per G-ExprtPermit); MEX-62 requires one original (1) and one (1) copy. MEX-62 also specifies that in terms of the Federal Rights Law, proof of payment of rights 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
• Health license with the corresponding line of business
• Document issued by the health authority of the destination country that accredits the operation of the establishment

See also MEX-62 for detailed documentation to be submitted to export cells, tissues, and products of human beings and their components intended for scientific research.

Import/Export Permit Submission Procedures

MEX-61, MEX-24, and MEX-62 indicate that an applicant may submit a request to obtain a permit to import or export specimens in print or electronically. Per MEX-61 and MEX-62, to submit an application online, it is necessary to obtain an electronic signature (known as e.firma). MEX-49 explains that the signature is a secure, encrypted digital file that identifies an applicant, and can be used to carry out procedures electronically with various government agencies. Refer to MEX-49 for instructions on how to obtain an electronic signature through the Tax Administration Service (Servicio de Administración Tributaria (SAT)).

See also MEX-60 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)
• 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 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).