Biosimilars and Biologics
Key facts about biosimilars and biologics in Mexico. Prepared in association with Olivares, a leading global law firm, this is an extract from The Pharma Legal Handbook: Mexico, available to purchase here for GBP 99.
1. Are biosimilar medicines considered the same as generic medicines in your country?
No, biosimilars are not considered the same as generic medicines. Biosimilars are regulated by specific provisions within the sanitary legislation.
The Mexican General Health Law defines a “biologic 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 identified as such by its pharmacological activity and physical, chemical and biological properties.
Article 222 Bis of the Health Law names follow-on biotechnology products (biosimilars) as “biocomparables”, since they must be comparable to reference products with regard to safety, efficacy and quality.
For instance, applicants for marketing authorizations of generics only have to prove basically that their products are interchangeable to the innovator product. They have to provide information concerning dissolution profiles or bioavailability studies regarding the reference product. COFEPRIS periodically issues a list of reference medicinal products.
On the other hand, the essential dossier submission requirements for biocomparables follow the same line as those requirements for innovative biotech products, except for the requirements to prove safety, efficacy and quality, since applicants must submit clinical tests and, when appropriate, in-vitro tests, to prove safety, efficacy and quality of this product biocomparable (biosimilar) to those of the reference biologic.
2. Are all biologic medicines, including biosimilar medicines, patentable in your country?
Biologic medicines are patentable in Mexico. Concerning biosimilar medicines may be protected under IP rights if the specific product, somehow fulfils, among others, the patentability requirements.
3. Is there a specific regulatory framework for the marketing authorization of biosimilar medicines in your country? If yes, what is the regulatory framework for the authorization of biosimilar medicines?
The primary legislation for the authorization of biosimilar, is the General Health Law (Ley General de Salud) (HL) and its Regulations. These law and regulations are supplemented by Guidelines and Official Mexican Standards (NOMS) published by COFEPRIS.
Biologics are treated differently to non-biologic drugs for the purposes of gaining regulatory approval. The biologics-specific path is mainly provided in the Mexican official standard Rule, NOM-257-SSA1-2014 “Regarding biologic medicines”.
In addition, the Mexican official standard Rule NOM-177-SSA1-2013 regarding “Interchangeability and biocomparability tests” mainly establishes the guidelines for generating clinical protocols, quality management system, pharmacovigilance, biocomparability and establishes the reference products.
4. What kind of data package is needed to obtain approval for a biosimilar drug? Is this any different to the requirements for the original Biologics drug?
In general terms, the standard dossier submission requirements for marketing authorization applications for drugs usually comprise legal and administrative information, summaries, chemical, pharmaceutical and biological information, nonclinical reports and clinical study reports.
The additional dossier requirements for biotech products include, for example, a description of the manufacturing process, the provision of information concerning the starting and biological origin materials, and a description of the manufacturing facilities and equipment.
Innovative biotech products may be used as the reference product for the approval of non-innovative products. The Health Law calls these products ‘biocomparables’, since they must be comparable to reference products regarding to safety, quality and efficacy. The Health Law Regulations provide that a biocomparable may be a reference product for another one, where an innovative product has not been approved in Mexico yet.
Applicants must submit clinical tests and, when appropriate, in-vitro tests, to prove 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 physic-chemical studies. For this, the applicant must have to submit essentially:
- In vitro studies
- A report of comparative test of pharmacokinetics, 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 tests to show similarity between both the follow-on and the reference biologic.
5. What are the requirements for the choice of the reference comparator product?
According to the Health Law Regulations reference medicinal products, are those indicated by the Ministry of Health as such, that has the registry of said agency, that is commercially available and is selected according to the criteria established in the Standards;
In 2018 the Federal Commission for Protection against Sanitary Risks (COFEPRIS) issued the guidelines that establish the requirements for the recognition and selection of a reference medicine, which establish that the medicine that have its marketing authorization and that was presented through New Molecules Committee, may be recognized as a reference medicine by COFEPRIS, in case of having a patent in force, it can be designated as a reference medicine, only three years before of the expiration of the same and comply with the following:
- Have a current marketing authorization issued by the Federal Commi-ssion for Protection against Sanitary Risks (COFEPRIS).
- Have the information of the clinical trials that support the safety and efficacy of the product or with the official communication of the resolution issued by the New Molecules Committee.
- Submit a letter under oath stating that the drug and its different concentrations are currently marketed, which must be signed by the Legal Representative.
- Provide the information to prescribe authorized in non-editable electronic format
- Comply with the provisions of the current Official Mexican Standard NOM-2020-SSA1-2016 “Installation and operation of pharmacovigilance.”
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
Under the guidelines that establish the requirements for the recognition and selection of a reference medicine, it is possible to have the comparator product be sourced from one of the following regulatory jurisdictions, if the product of reference (comparator) is not included within the corresponding list or may be included but is not commercially available in Mexico.
- The European Medicines Agency;
- The US Drug and Food Administration;
- Health Canada;
- The Swiss Agency for Therapeutic Products (Swissmedic); and
- The Therapeutic Goods Administration in Australia.
- The National Agency of Sanitary Vigilance (ANVISA) in Brazil.
- The Pharmaceutical and Food Safety Bureau.
7. How are the prices of biosimilar medicines regulated? Is this any different from the requirements for the original Biologics drug?
Price control in the private sector is based on a scheme of self-regulated maximum retail price (MRP) only covering patented products, overseen by the Ministry of Economy. Pharmaceutical companies’ participation is voluntary. Under the price control each product’s MRP must not exceed an international reference price, estimated as the average price in six major markets, plus a market factor. There are no established sanctions for violations of the MRP.
In the private sector, most payments are made on an out-of-pocket basis. Private insurers are improving the level of pharmaceutical coverage as the private market in medicines has grown considerably.
Public acquisitions are supported by the Committee for the Negotiation of Drug Prices (CNDP).
For direct purchasing of patented products, the CNDP analyses the effectiveness of the drugs and relevant therapeutic alternatives and the feasibility and implications of an eventual substitution with equivalent medicines. The CNDP also conducts an economic evaluation of the cost-effectiveness of patented medicines compared with potential substitutes.
For the ISSSTE, a prescribed medicinal product can be dispensed in a private drug store registered with a public insurer, provided that this is not available within ISSSTE facilities and under certain conditions. The ISSSTE reimburses the cost of that product according to previous agreements.
On August 11, 2020, the Mexican Congress published the Decree amending Article 1 of the Public Sector Procurement, Leasing and Services Law, through which the Mexican Government is now empowered to acquire medicines through intergovernmental organizations, such as UNOPS, without having to observe the procedures set forth in the applicable Law and Regulation on public procurement.
According to UNOPS’ guidelines, the process is made up of different stages grouped within three phases identified as:
- Pre-Bidding Process (market research, requirements definition and identification of potential suppliers).
- Bidding Process (publication of the bases and call for bids and/or invitations for negotiation, bid management, evaluation and award).
- Post-Bidding Process (contract management and logistics). The distribution to the final destination will be in charge of INSABI.
Therefore, during these proceedings UNOPS is entitled to negotiate the prices of the supplies.
8. What is the reimbursement policy for biosimilar medicine? Is this any different from the requirements for the original Biologic drug?
The primary legislation for the reimbursement of these kind of drugs, is the General Health Law (Ley General de Salud) (HL) and its Regulations. These law and regulations are supplemented by Guidelines and Official Mexican Standards (NOMS) published by COFEPRIS.
In private sector, there is no reimbursement in Mexico. For the ISSSTE, a prescribed medicinal product can be dispensed in a private drug store registered with a public insurer, provided that this is not available within ISSSTE facilities and under certain conditions. The ISSSTE reimburses the cost of that product according to previous agreements.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
In general terms it should not have any impact as the Institution would prescribe the product that has been appointed in previous agreements. Yet, those agreements may only appoint the biosimilar as the product to be reimbursed.
10. What is the legal framework for biosimilar medicines prescribing (clinical decision maker) and dispensing (pharmacy level, hospital or retail)? Is this any different to the requirements for the original Biologics drug?
- General Health Law (Ley General de Salud).
- General Health Law Regulations for Healthcare Products (Reglamento de Insumos para la Salud).
- Official Mexicans Standards (NOMs).
No, the requirements are the same for both drugs.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
The regulations do not prevent automatic switching /substitution. Thus, pharmacists may choose to dispense any product with the same non-proprietary name (INN). Physicians may not prohibit substitution, but in the private sector, patients may prohibit substitution.
In the private sector or out-of-pocket acquisitions, patients can prevent substitution by requesting that the pharmacist not make the substitution. If the pharmacist insists on making the substitution, the patient may choose not to purchase the medicine and may search for the prescribed product in a different pharmacy.
However, under a public insurer, patients cannot prevent substitution, and a pharmacist may dispense any product with the same non-proprietary name (INN).
There was a proposal published in 2013 to amend the Health Law to prevent automatic substitution/switching from innovative biological products to biocomparables, and vice versa. However, the proposal was not further discussed in the Mexican Senate, and has since lapsed.
12. What are the post – authorisation requirements (including pharmacovigilance, risk management plans, post-approval studies) for biosimilar medicines? Is this any different to the requirements for the original Biologics drug?
Post-authorisation requirements are the following:
- Comply with the Official Mexican Standards such as:
- Pharmacovigilance, NOM-220-SSA1-2016 (NOM-220).
- Good manufacturing practices for medicinal products (NOM-059-SSA1-2015).
- Good manufacturing practices for Active ingredients (NOM-164-SSA1-2015).
- Interchangeability and biocomparability tests (NOM-177-SSA1-2013).
- Medicinal products labelling (NOM- 072- SSA1-2012).
- • Drug manufacturers must renew their marketing authorization every five years, subject to the relevant tests, including submission of a certificate of good manufacturing practices in force.
13. Are there specific policies and requirements for labelling biosimilar medicines in the event of second medical use patents? Is this any different from the requirements for the original Biologic drug?
The requirements for the labelling of medicines are established in the Official Mexican Standard NOM-072-SSA1-2012, Labelling of medicines and herbal remedies.
Between the requirements of biologics and biosimilars there are the following differences or exceptions:
- In labeling of secondary packaging the distinctive denomination is optional in the case of generic or biocomparable drugs.
- The labeling must bear the acronyms M.B. in the case of innovative biotech drugs, and M.B.B. in the case of biocomparable biotech drugs.
14. Have there been any significant legal/judicial developments in relation to biosimilars in your country? (Including but not limited to IP, procurement, competition, misleading information campaign, access to reference comparator product)
On August 19, 2020, the regulatory agency in Mexico (COFEPRIS), announced new operating rules for the approval of generic drugs in Mexico, based on the following guidelines:
- COFEPRIS will have a special procedures window for the generic pharmaceutical industry.
- These applications for approvals could be filed, the day after the granting of the patent related to the innovative medicine.
- The respective applications would be decided at any time, prior to the expiration of the patent, if the registration or approval is given, COFEPRIS will provide a provisional official communication, which would be exchanged for the definitive sanitary registration or approval, the day after the expiration or the validity of the patent.
COFEPRIS indicates that they are complying with the elimination of the temporality of 3 years (for chemically synthesized drugs) and 8 years (for biotechnological) to research and develop generics or biocomparables, according to the reforms to the so-called Bolar Exception in the new Federal Law for the Protection of Industrial Property (New IP Law) which entered in force on November 2020.
The communication also mentions that the rules for granting sanitary registrations of generic drugs, “second-use patents, which refer to the therapeutic indication, are no longer allowed,” which seems to mean that the patents of new uses will not be considered as part of the linkage system.
These rules announced by COFEPRIS, still without legal basis, since it is only a statement on its official website.
15. Are there proposals for reform or significant change to the legal, regulatory, procurement of biosimilars? If yes, when are they likely to come into force?
Proposal of decree to amend article 222 Bis of the General Health Law:
Public health institutions should establish an effective differentiation mechanism to ensure adequate pharmacovigilance and continuity of medical treatment, thus preventing an automatic substitution of biotechnology / biocompatible drugs, without due medical prescription.
Proposal of decree to amend article 26 of the Health Supplies Regulation. “The General Health Law orders that the packaging of medicines directed to the public sector and those directed to the private sector must be differentiated, therefore the Regulation of Health Supplies is harmonized with such provision.”