Pharmaceutical products are subject to the following provisions.
Essentially, applicants for marketing authorisations must prove the safety and efficacy of their products through standard clinical trials, according to the rules set out by the General Health Law, its regulations and NOMs of good manufacturing of medicines and active ingredients. Concurrently, they also have to request approval of their products as new molecules from the New Molecules Committee of COFEPRIS. According to the Health Law Regulations article 2 section XV, a new molecule is:
- an active ingredient or drug not approved worldwide (a new molecular entity);
- an active ingredient or drug already available in other countries but with limited clinical experience or disputed information, that has not been approved in Mexico;
- a drug which is a non-marketed combination of two or more active ingredients; or
- an active ingredient or drug already available on the market, but to be marketed for a new therapeutic indication.
R&D companies benefit from a special procedure for drugs that have been previously approved by a regulatory authority abroad to be approved for the first time in Mexico.
Applicants for marketing authorisations have to prove that their products are bioequivalent to the innovator product. They have to provide information concerning dissolution profiles or bioavailability studies regarding the reference product. COFEPRIS periodically issues a reference list of medicinal products. Recently, the NOM setting the test to prove that a generic drug is interchangeable with a reference drug was updated (NOM-177-SSA1-2013). Legally, COFEPRIS should not grant marketing authorisation for generics breaching exclusivity rights.
There is a linkage system between COFEPRIS and IMPI, which aims to prevent the granting of marketing authorisations in violation of patent rights. According to the Intellectual Properties Regulations, every six months IMPI must publish a gazette that includes patents covering allopathic medicines (the Linkage Gazette). The initial IMPI position was that only patents relating to a compound were relevant to linkage review (excluding formulation and use patents). On 31 July 2012, for the first time the IMPI included formulation patents in the Linkage Gazette, in accordance with a 2010 ruling of the Mexican Supreme Court (Jurisprudence No. 2a/J7/2010, Federal Judicial Gazette, No. XXXI, page 135).
Use patents are included in the Linkage Gazette by a court order, since IMPI considers that they should not be included in the linkage system.
Under the linkage regulations, at the filing of the application, the applicant must prove that he or she is the owner or licensee of the patent of the active ingredient of the product (recorded before IMPI), or state under oath that their application does not violate the list of products published in the Linkage Gazette and observes patent law.
Amendments to the legal framework to regulate the approval of biologics are recent and being tested. Under the General Health Law, applicants have to prove the quality, safety and efficacy of their products, and that they meet their regulations and applicable NOMs, particularly those for good manufacturing practices for medicinal products (NOM-059-SSA1-2015) and for active ingredients (NOM-164-SSA1-2015).
In accordance with NOM-257-SS1-2014, all biological drugs that were authorised before the legal reform and that are still on the market must enter a regularisation process in order to comply with the latest standards for biologics. NOM 257 emphasises that key points to ensure the safety, efficacy and quality of biologics are already regulated in other NOMs currently in effect, such as those for clinical trials and pharmacovigilance. NOM 257 empowers the Assessment Subcommittee on Biotech Products (SEPB) to assess technical and scientific data in connection with clinical trials, approval or renewal of innovator biologics or follow-on biologics (biocomparables), and to issue opinions to characterise biologics as innovators, reference products or biocomparables.
NOM 257 provides transitional provisions for the renewal of marketing authorisations of biologics granted before the amendments to the Health Law Regulations for Biologics issued in 2011 came into force. These provisions establish that:
- COFEPRIS will assess whether biologics refer to innovators or biocomparables;
- renewal applications for innovators will not require assessment by the SEPB; and
- renewal applications for biocomparables will require prior assessment by SEPB to identify the product of reference in order for applicants to submit the corresponding tests.
These provisions will be applicable only for those renewal applications submitted before 31 December 2015. COFEPRIS, however, missed an opportunity to address the current uncertainty in respect of Regulatory Data Protection for Biologics, as NOM 257 does not provide for guidelines in this regard.
Applicants must submit clinical tests, and when appropriate in vitro tests, to prove the safety, efficacy and quality of this product comparable (similar) to those of the reference biologic. The pre-clinical and clinical test used by an applicant for a biocomparable must use the corresponding reference biologic to perform comparative and physico-chemical studies. For this, the applicant must submit:
- in vitro studies;
- the report of a comparative pharmacokinetic test, if determined by the Ministry of Health, to show pharmacokinetic comparability on key parameters between both the follow-on and the reference biologic;
- pharmacodynamics test reports; and
- comparative efficacy and safety clinical test to show the similarity between both the follow-on and the reference biologic.
Although industry participants have welcomed amendments to the approval of biologics, specific rules to approve follow-ons have caused debate. There is currently no indication of a data protection period for biologics. Currently, recognition of data package exclusivity rights for biologics can only be achieved through litigation. Accordingly, there are also concerns regarding the accurate application by COFEPRIS of linkage provisions.
Orphan drugs were recently introduced into the General Health Law and the Mexican Pharmacopeia. In practice, they are approved by a particular procedure, following rules for new molecules when applicable and appropriate. Specific rules are still pending. The draft of an NOM compiling requirements for granting marketing authorisations includes orphan drugs.
The primary legislation for medical devices and diagnostics are the General Health Law, its regulations and the NOM for good manufacturing practices regarding medical devices (NOM-241-SSA1-2012). In general, it would be fair to say that regulation regarding medical devices is lighter than that for drugs and other substances. According to their use, the General Health Law classifies medical devices into:
- medical equipment;
- prosthetics, orthotics and functional supports;
- diagnostic agents;
- dental supplies;
- surgical and healing materials; and
- hygiene products.
Marketing authorisation requirements for these devices depends on the level of risk involved in their use, according to a threefold classification:
- Class I: products that are well known in medical practice and for which safety and efficacy have been proven. They are not usually introduced into a patient’s body;
- Class II: products that are well known in medical practice, but may have material or strength modifications. If introduced, they remain in a patient’s body for less than 30 days; and
- Class III: products either recently accepted in medical practice or that remain in a patient’s body for more than 30 days.
COFEPRIS analyses both medical devices and, if applicable, software that enables them to work. Conversely, mobile medical applications are a new area that COFEPRIS may address in future with particular regulations, especially if they represent health risks. As an incentive, applicants can benefit from a special procedure for certain devices that have been previously approved by the US Drug and Food Administration and Health Canada to be approved in Mexico. This procedure is essentially based on a dossier filed with the foreign regulatory agency, to reduce approval time frames by up to 30 working days. Industry participants have welcomed these new rules, but they are still being tested.
Powers to monitor compliance
COFEPRIS can request reports from marketing authorisation holders, and make on-site inspection visits in the manufacturing, distribution or storage facilities, essentially to verify that their products meet the approved specifications and do not represent a risk for the public health and to ensure that good manufacturing practices, stability, pharmacovigilance and labelling standards are complied with. COFEPRIS can initiate ex officio legal proceedings to sanction non-compliance. Ultimately, these legal proceedings can result in the revocation of the marketing authorisation.
COFEPRIS is also entitled to implement measures on behalf of public health, such as the seizure of products and ordering partial or total suspension of activities, services or adverts.
Under certain conditions, COFEPRIS has statutory authority to revoke any manufacturing approval or impose sanctions, ranging from a fine of up to 16,000 times the minimum wage to closure of the establishment. The imposition of administrative sanctions does not exclude civil and criminal liability. Administrative infringements can incur penalties ranging from a fine of up to 20,000 times the minimum wage to final closure of the establishment. Repeated infringement is also considered a criminal offence.
COFEPRIS has broad jurisdiction to seize counterfeit or illegal medicines. The General Health Law classifies the manufacturing and sale of counterfeit or falsified medicine as a crime. In addition, COFEPRIS commonly enters into collaboration agreements with the PGR and the Customs Office in order to investigate and prevent counterfeit and illegal medicines.
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