The regulatory regime
Medicines and medical devices, among other health-related products, are regulated and controlled by COFEPRIS. It also creates policy and regulation, and is in charge of most of health authorisations, including pre-market clearance, health licences, good manufacturing practices certificates, and surveillance with regard to and compliance with the health regulations. The GHL and the RHS are the two main legal instruments for the health law regulatory regime.
Mexico's legal framework has a legal definition for almost every product related to human health. However, if there is a product that does not fit clearly into a category, the classification of the product can be ruled by COFEPRIS filing a Ruling Request providing the following necessary information: formula, ingredients, pharmacological properties, therapeutic claims, labelling, literature for health professionals and advertisement of the product.i Classification
The Mexican regulatory regimen classifies and regulates health products by risk analysis criteria, organised as follows.Medical products
Medicines (new drugs, generic drugs, biologics, biotechnologics, orphan drugs and vitamins) are the most regulated products within the wider regulatory framework, requiring mandatory pre-market clearance, the strictest assessment by COFEPRIS and the longest time frames. It is relevant to mention that medicines have a 0 per cent value added tax rate in Mexico.
Medical devices (medical equipment, prosthesis, osthesis, diagnostics agents, dental supplies, healing supplies, surgical materials and hygiene products), also need a mandatory pre-market clearance, however, since 2014 COFEPRIS has been working on simplifying the process, requirements and implementing a fast-track approval for approximately 100 products considered low risk. Also in 2014, COFEPRIS deregulated about 2,224 products that are no longer consider medical devices because of the minimal risk they represent.Consumer goods
Food, beverages, dietary supplements, cosmetics and cleaning products do not need pre-market clearance from the authority, but it is important to note that these products need to comply with several Rules and Mexican Official Standards regarding labelling and best manufacturing practices (no certification is needed, just compliance with the standards).
Two particular situations are worth pointing out:
- The tax and importation implications of classifying a product as food or as a dietary supplement. While food has a 0 per cent value added tax rate, dietary supplements have a 16 per cent value added tax rate. This can cause complications because tax and customs authorities may have different criteria to the importer or manufacturer for classifying the product, and this can be avoided or solved by a Ruling Request by COFEPRIS.
- COFEPRIS takes special care with dietary supplements, publishing a list of content limits for certain substances and a list of prohibited ingredients. This makes dietary supplements in the Mexican market a much more complex issue than in other jurisdictions.
Alcohol and tobacco, as products considered to present a high risk to public health, are treated differently, with a more extensive regulatory framework, and very strict controls and surveillance to avoid counterfeiting and smuggling, as well as to guarantee compliance with labelling and advertisement regulations.Controlled substances
Facilities requires a licence to produce, manage, store and distribute controlled substances, which include active substances for medicines and diagnostic agents, and toxic substances for industrial use.Chemicals
Pesticides and fertilisers do need pre-market clearance by COFEPRIS, however, favourable opinion of the Ministries of Agriculture, Livestock and Fishery, and the Ministry of the Environment and Natural Resources is required, which usually takes longer than the terms set by the law.ii Non-clinical studies
Non-clinical studies are regulated by the RCR Chapter VII and the Mexican Official Standard NOM-062-ZOO (governed by the Minister of Agriculture, Livestock and Fishery) that regulates the technical specification for the production, care and use of laboratory animals. These studies are required to comply with good laboratory practices and secure procurement of animals, storage specifications, feeding, care and conditions to minimise the suffering of animals.
Non-clinical trial should be coherent with the study model, performed in a comparative way either with placebos or the gold standards. In vitro and in vivo models must allow the characterisation of the safety of the product, with toxicity, teratogenicity and mutability tests to determine the safety and pharmacology of the product.iii Clinical trials
Clinical trials are regulated by the GHL, the RCR, Mexican Official Standards NOM-012-SSA3 for technical aspects to conduct health research in humans, NOM-220-SSA1 regarding the implementation of the pharmacovigilance, NOM-059-SSA1 regarding good manufacturing practice for medicines, the Guidelines for the integration and operation of ethics committees for research and the Ethics Code of the Pharmaceutical Industry.
According to international standards, the process and authorisation of clinical trials in Mexico should:
- be conducted in a licensed health institution;
- be led by a head investigator;
- be provided with non-clinical data backup;
- have the approval and installation of ethics, research and biosecurity committees;
- guarantee consent and legal and personal security for the subjects of study;
- inform reports of adverse reactions;
- organise follow-up meetings with the authority to inform relevant information; and
- import permits of the medicines used in the trial.
Clinical trials must evidence the full pharmacokinetic and pharmacodynamic profile of the product to prove its safety and efficiency.
COFEPRIS accepts non-clinical and clinical trials performed abroad if they comply with Mexican regulation, which is harmonised with international best practices, and in very rare cases the New Molecules Committee will request studies to be performed on members of the Mexican population.
COFEPRIS has certified academic and health institutions to function as third authorised parties to conduct clinical trials and help expedite the process of authorisation when the trials are performed in Mexico.iv Named-patient and compassionate use procedures
The regulatory framework demands a pre-market clearance for manufacturing, import, distribution and marketing of medicines and medical devices. However, if a patient has been prescribed a product that does not have pre-market clearance in Mexico, COFEPRIS can authorise the import of it in two cases: for personal medical use; and for diseases of low prevalence, judged on a case-by-case basis.v Pre-market clearance
Medicines and medical devices both need pre-market clearance granted by filing a dossier containing the legal and technical information of the product to COFEPRIS. Even though the processes for both are similar, medicines have a more complex pathway. In both cases, to apply for a pre-market clearance a Mexican legal entity should appear as legally responsible before COFEPRIS to track and respond to any kind of liability.MedicinesNew drugs
New drugs and vaccines should submit:
- administrative and legal information;
- quality and good manufacturing practices information;
- preclinical trials; and
- clinical trials.
Manufacturers of new drugs should attend the New Molecules Committee to present their case. Here it will be determined whether the product requires specific regulatory treatment, or the agency should ask for particular tests or scientific literature; for example, it may be the case that the committee asks that the trials be performed in Mexico – an exception to the rule. In the case of biotechnologics, the applicant also needs to present its case before the biotechnologics subcommittee to analyse the particularities of the product.Generic drugs
Generic drugs should submit:
- administrative and legal information;
- quality or good manufacturing practices information; and
- bioequivalence information.
Orphan drugs have a different kind of authorisation process and they do not obtain a pre-market clearance, but recognition as an orphan drug. For an orphan drug dossier the following should be submitted:
- administrative and legal information;
- quality or good manufacturing practices information;
- preclinical trials and clinical trials that are reviewed case by case, as complications may appear with low prevalence diseases; and
- recognition as an orphan drug from a recognised foreign entity.
Medicines dossiers can be filed by:
- the conventional application at COFEPRIS – submitting the dossier directly to COFEPRIS;
- a third authorised party application – a private entity certified by COFEPRIS that reviews and assesses the dossier before the submission to COFEPRIS and issues a report; when the dossier complies with the regulatory requirements it is submitted for a fast-track authorisation process; or
- the equivalence application – the applicant submits a pre-market clearance from a recognised foreign entity as part of the dossier to fulfil the compatible requirements, and this has a fast-track authorisation process.
A medical devices dossier should contain administrative and legal information, and quality or good manufacturing practices information. Filing an application follows the same pathway options mentioned for medicines.vi Regulatory incentives
From 2011 to 2018, COFEPRIS made a significant effort to simplify the regulation process, accelerating the implementation of updates to regulations and the creation of new ones by:
- eliminating the prior local manufacturing plant requirement to apply for a pre-market clearance for medicines;
- the implementation of a fast-track authorisation process as the equivalent application for medical devices and the third authorised party applications;
- the deregulation of more than 2,000 medical devices;
- the issue of the Biotechnologics Mexican Official Standard NOM-257-SSA1; and
- the issue of the Pharmacovigilance and Technovigilance Mexican Official Standard NOM-220-SSA1.
Article 47 bis of the Industrial Property Law Rules and Article 167 bis of the RHS regulates the linkage provisions in Mexico. A generic drug pre-market clearance application must include evidence that the application does not violate a patent. When the dossier does not prove this, COFEPRIS must consult the Mexican Institute for Industrial Property about a patent ownership or licence before granting a pre-market clearance for a generic drug, to protect industrial property rights. Linkage is applicable for substances and active ingredients, but not for manufacturing process or formulation.
Articles 82 and 86 bis of the Industrial Property Law and Article 167 bis of the RHS regulate the data exclusivity provisions in Mexico, referring the time frame of its protection to the commitments of international treaties Mexico has signed.
Linkage and data exclusivity grant a reasonable degree of legal certainty, however, there are some grey areas about when and how this protection applies, as Mexican legislation does not provides a fixed number of years for data exclusivity protection. There are a lot of opportunities to improve the regulatory framework.
Mexican regulation does not have market exclusivity or patent extension.vii Post-approval controls
Pre-market clearances for medicines and medical devices are valid for five years, with the possibility of filing a renewal application every five years indefinitely, as long as the regulatory requirements are fulfilled. At any time during which a pre-market clearance is valid, COFEPRIS retains the legal power to vary or revoke this authorisation.
Article 380 of the GHL establishes that a pre-market clearance can be revoked if the product represents a risk to human health, any of the product characteristics has changed from the ones authorised, or the holder failed to comply with any of the applicable regulations or obligations set forth in the relevant authorisation.
While a pre-market clearance is valid, the holder may apply for the revocation or a variation of his or her authorisation. It can be a variation of the legal and administrative information (e.g., corporate name) or a technical variation (e.g., process or formula). Technical variations are much more complicated to review as they may mean changes in the active ingredients or the manufacturing site, which would extend the time frame for approval several months longer than established in the RHS.
NOM-220-SSA1 on pharmacovigilance and technovigilance systems obliges the holder of an authorisation, the health institutions and the health professionals that use the product to report any adverse events to COFEPRIS. If the potential risk of the product is proved, the Risk Analysis Department of COFEPRIS may issue a health alert and the Surveillance Department may initiate a recall process.
The pharmacovigilance and technovigilance systems are also a requirement for the application of a pre-market clearance, so the systems and responsible officer exists and is appointed by the holder of the authorisation from day one.
In some cases, if the New Molecules Committee determines during the assessment of the pre-market clearance application, a product may obliged to perform a Phase IV clinical trial, also known as pharmacovigilance studies. This obligation is included in writing when the authorisation is issued.viii Manufacturing controls
Both medicines and medical devices need a sanitary officer to be responsible for the facility and products before COFEPRIS. This officer must be a health professional with a licence to practise (e.g., a chemist).
Medicines manufacturers are obliged to have a health licence issued by COFEPRIS to manufacture medicines in Mexico. To obtain this licence it is mandatory to have previously obtained a good manufacturing practices (GMP) certificate. The manufacturing plants should have a quality management plan that satisfies the standards for the facilities and manufacturing process set in Mexican Official NOM-059-SSA1 of good manufacturing practices of medicines, then the plant must ask for an inspection visit by COFEPRIS, and if it fulfils the regulatory requirements, the agency issues the GMP certificate. After the issuance of the GMP certificate the plant can continue with the application for the licence.
Medical devices require a notice of operation instead of a licence, where the plant should appoint its sanitary officer. But having a GMP certificate is mandatory in compliance with the Mexican Official NOM-241-SSA1 on good manufacturing practices of medical devices, following the same procedure mentioned for medicines.ix Advertising and promotion
The advertising of medicines and medical devices is regulated by the RHA. The main requirements for advertising medicines and medical devices are: (1) the information should not be misleading; (2) the information provided should be substantiated; and (3) the information should be consistent with the terms authorised in the pre-market clearance.
The pre-market clearance for each medicine indicates whether the product has authorisation to be advertised to the general public or if its advertisement is limited to health professionals. This advertisement authorisation is based on the classification made by the risk analysis of the product in the GHL. While over-the-counter medicines (OTCs) can be advertised to the general public, prescription medicines are limited to advertisements targeted only at health professionals.
Medical devices pre-market clearance also indicates whether the product has authorisation to be advertised to the general public or if its advertisement is limited to health professionals. In this case, the general rule is that the authority indicates that medical devices advertisement is limited to health professionals, except if at the moment of filing the pre-market clearance application the applicant requests to be authorised to advertise the product to the general public and includes evidence that proves the advertisement does not present a risk to public health.
Promotional activities are regulated by the RHA and by internal industry regulations, the Code of Ethics of the Pharmaceutical Industry and the Code of Good Promotional Practices of the Pharmaceutical Industry.
Advertisement to the general public requires a permit granted by COFEPRIS, while for advertisement to health professionals, only notice needs to be filed before COFEPRIS. Promotional activities also only require a notice.x Distributors and wholesalers
The distribution and wholesale of medicines and medical devices requires the filing of an operation notice and the appointment of a sanitary officer to be responsible before COFEPRIS, with the qualifications mentioned above. Only in the case of controlled substances and biologics is a health licence required. This notice of operation has indefinite validity and can be subject to variations as requested by the holder.xi Classification of products
Article 226 of the GHL classifies medicines as follows:
- prescription medicines that require barcoded medical prescription or a special permit from the Health Ministry (e.g., controlled substances);
- prescription medicines that require leaving the prescription at the pharmacy and recording the transaction in the pharmacy control books;
- prescription medicines where the prescription can be refilled three times, and is then left at the pharmacy. The prescription needs to be sealed and recorded in the control book for each refill;
- prescription medicines that can be refilled as many times as the doctor indicates in the prescription;
- medicines that do not require prescription, but their marketing is limited to pharmacies only; and
- medicines that do not require prescription and can be sold in commercial establishments other than pharmacies (e.g., OTCs).
Article 83 of the RHS classifies medical devices as follows:
- products generally known in medical practice, whose security and efficiency is proved and that generally do not enter the body;
- products generally known in medical practice that may have some variations and stay up to 30 days inside the human body; and
- innovative or recently designed products in medical practices or products that stay inside the human body for more than 30 days.
The Ministry of Economy and the Ministry of Health issued a joint resolution indicating the classification and tariff code of merchandise and products whose import or export is subject to health regulation. This resolution specifies the legal requirements for each product: (1) no importation permit, only pre-market clearance; (2) only importation permit, no pre-market clearance; and (3) both importation permit and pre-market clearance.
There are five types of import permits:
- for commercial purposes;
- for personal use and low prevalence diseases;
- for research or academic purposes;
- temporary maquila importation; and
- temporary importation for conventions.
The importer of a medical product must be expressed in the pre-market clearance and recorded in the National Importers Registry.
Generally exports do not required a permit, except for some biologics such as tissues and blood, and controlled substances. To promote exports, COFEPRIS also issues certificates of free sale and special GMP for exportation purposes.xiii Controlled substances
As risk level is the main criterion of health regulation in Mexico, controlled substances are highly regulated with regard to the traceability of the substances.
Manufacturing facilities require a health licence and mandatory visit from COFEPRIS to guarantee the safety and traceability of the substances. Transportation, storage and retail is required to be recorded in auditable books, and acquisition, imports and exports require special permits from the authority.xiv Enforcement
The COFEPRIS Surveillance Department is in charge of the regulatory enforcement, which it carries out through inspection visits. There are two kind of visits: ordinary visits, which are scheduled surveillance visits on facilities selected by lottery to keep a watch on the industry; and extraordinary visits, which are actioned by a health alert from a pharmacovigilance or technovigilance report or a complaint from a consumer or competitor.
These procedures comprise four stages: (1) the inspection visit to collect information and evidence of potential regulatory violations, stated in inspection minutes, which may include the imposition of safety measure from COFEPRIS such as product seize; (2) the assessment of the inspection minute and first resolution, confirmation of safety measures if applicable and ordering corrective actions; (3) response by the subject of the inspection with the corrective actions; and (4) final assessment of the authority where it considers the violations and corrective actions to apply a sanction if considered necessary.