REGULATORY SCENARIO
The frst time that biologics were ofcially recognised in the applicable legislation, the General Health Law, was in June 2009, with the inclusion of article 222-bis defning a 'biologic/biotechnological product' as any substance that has been manufactured by molecular biotechnology; has therapeutic, preventive or rehabilitative effects; is provided in a dosage form; and is identifed as such by its pharmacological activity and physical, chemical and biological properties.
In October 2011, the Health Law Regulations were amended to establish the requirement to approve biologics and biocomparables (also known as biosimilars) – an area that was previously poorly regulated.
In 2012, a Mexican Ofcial Standard Rule (NOM) was enacted to provide further clarity and certainty on the related regulatory process: Mexican Ofcial Emergency Standard Rule NOM-EM-001-SSA1-2012.
After several amendments and other versions of the NOM, the main legislation for this type of product, besides the General Health Law and its regulations, is currently NOM-257-SSA1-2014 concerning biologics (NOM 257), which was published by the Federal Commission for Protection against Sanitary Risk (COFEPRIS) in the Ofcial Gazette. NOM 257 essentially outlines key points to ensure that the safety, efcacy and quality of biologics are already regulated in other NOMs, such as those concerning clinical trials and pharmacovigilance.
Prior to the entry into force of the amendments to the General Health Law that gave recognition to biotechnological drugs, and during the subsequent period in which the legal framework was not yet defned or completed for the regulation of those medicines, COFEPRIS granted some marketing authorisations for non-innovative biotechnological medicines that were not properly classifed as biosimilars according to the relevant criteria to guarantee their quality, safety and efcacy when compared to the reference medicine requirements and international health standards. Hence, non-innovative biotechnological drugs that were processed or granted prior to the formation of the corresponding legal framework and pending classifcation as biosimilars were known colloquially as biolimbos.
Owing to the above, one of the main objectives of NOM 257 was that all the non-innovative biotechnological drugs identifed as biolimbos would be submitted to a new review process that would prove that those drugs have the required quality, safety and efcacy characteristics.
However, this regularisation procedure was not duly observed, so today there are some biocomparables that have never met the quality, safety and efcacy requirements established by current health legislation, in the terms indicated by NOM 257, and that consequently fail to comply with the new specifcations for biocomparability studies and tests and the pharmacovigilance processes necessary to protect and guarantee the health of patients.
On 31 May 2021, the Ministry of Health issued a decree in the Ofcial Gazette amending several articles of the Health Law Regulations. Among other things, the most relevant points of this decree for biologics were the following:
- regarding the approval of biocomparable medicines, the participation of the Subcommittee for the Evaluation of Biotechnological Products was eliminated and an opinion of the New Molecules Committee is now sufcient; and
- clinical studies in the country of origin of biocomparable medicines can be submitted as evidence for the marketing authorisation application. When applying for a renewal of the marketing authorisation, clinical studies in Mexico must be submitted.
In general, these amendments to the Health Law Regulation are focused on improving the analysis and resolution of various processes.
The Health Law Regulations defne 'biocomparables' as products that must be comparable to reference products regarding safety, quality and efcacy. Innovative biological products are considered as the reference products for the approval of non-innovative products.
The Health Law Regulations and NOM 257 provide that an approved biocomparable may be a reference product for another follow-on if there is no longer an approved innovative product.
COFEPRIS divides marketing authorisation applications for biocomparables in accordance with the manufacturing of the product (national manufacturing or foreign manufacturing). Legally speaking, the review process and timeline for approval is the same for national manufacturing and foreign manufacturing.
COFEPRIS makes this classifcation to identify the requirements that applicants must meet. For example, for foreign manufacturing, applicants must submit ofcial documents, such as good manufacturing practice certifcates, which must be apostilled or legalised and translated into Spanish by an authorised translator.
In general terms, the standard dossier submission requirements for marketing authorisation applications for all medicines usually comprise: legal and administrative information; summaries; chemical, pharmaceutical and biological information; non-clinical reports; and trial reports.
The additional dossier requirements for biological products include describing the manufacturing process, providing information concerning the starting and biological origin materials and describing the manufacturing facilities and equipment.
The essential dossier submission requirements for biocomparables are almost the same as those for innovative biological products, except for additional requirements to prove safety, efcacy and quality comparable to the reference biological product.
To prove safety, efcacy and quality, biocomparable applicants must submit:
- in vitro studies or comparative non-clinical studies;
- comparative pharmacokinetic test reports, if requested by the Ministry of Health, to show pharmacokinetic comparability on key parameters between both the biocomparable and the reference biological product;
- pharmacodynamics test reports; and
- comparative efcacy and safety clinical tests to show comparability between both the biocomparable and the reference biological product.
Once approved, close pharmacovigilance should be followed.
The average time to obtain approval is one to three years; however, this depends on each case.
In this context, the legal framework applicable in Mexico for biological medicines provides the basic requirements and allows certain directionality to the sanitary authority to act based on a case-by-case regulatory scheme of criteria, tests and requirements applicable to a given biosimilar product, which are determined by the specifc molecule with which comparability is intended.
In addition to the above, the case-by-case scheme indicates that once a biosimilar has demonstrated its biosimilarity, the indications that the reference biological medicine has approved will be authorised as long as the biosimilar medicine is presented in the same pharmaceutical form and dose as the reference biologic and these indications share the same mechanism of action or the biosimilar drug has the same pharmacodynamic effect. In other words, extrapolation of clinical data to other indications of the reference product could be acceptable but must be scientifcally justifed.
If it is unclear whether the safety and efcacy confrmed in one indication would be relevant for another indication or whether additional data will be required. Extrapolation should involve inclusion of the totality of the data (ie, the quality of non-clinical and clinical data). It is expected that safety and efcacy can be extrapolated when biocomparable biotechnological product comparability has been demonstrated by thorough physico-chemical and structural analyses as well as by in vitro functional tests complemented with clinical data in one therapeutic indication.
This procedure is carried out between the applicant and the health authority so that the owner of the innovative drug does not have the recognised right or legal standing to assert before the authority technical and scientifc elements of safety and efcacy related to the biologic medicine.
The lack of transparency in the process of evaluation and the granting of marketing authorisations for biosimilars by the health authorities means that it is unclear whether the authorities are observing the correct fulflment of the applicable regulatory requirements and mechanisms and, consequently, whether they are observing the industrial property rights related to those products.
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Originally published by IAM
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