Biotechnological Product Roadblocks in Mexico

On 1 July 2012 the Mexican people elected a new government. On 3 December the minister of health was replaced by Mercedes Juan López. The result of this change in leadership has yet to be understood. However, it is reasonable to assume that it may have legislative and operational implications for pharmaceutical companies with interests in Mexico. Recent announcements from the Ministry of Health have indicated a drive toward more timely approval of generic and innovative drugs and an alignment of approval processes with international best practices¹.

Despite the recent electoral changes, the Mexican pharmaceutical market remains a highly attractive target for companies investing in Latin America. Pharmaceutical sales in Mexico are forecast to grow by 8.5% from 2012 to 2016, compared with anticipated growth rates of between 0.5% and 2.5% in the traditional markets of the EU, US and Japan.² However, this market is difficult to penetrate, especially by foreign companies with little or no experience with Mexican regulations. This article outlines some of the regulatory challenges faced by manufacturers of biological products that hope to market them in Mexico. These challenges can be easily overlooked, leading to lengthy product approval delays as a consequence.

Overview of Mexican Biotechnological Legislation Development

In an unofficial translation of the Mexican standard for biotechnological and biopharmaceutical products³,Article 3.59 defines "biotechnological medications" (medicamentos biotechnolόgico)as "…all substances that have been produced by molecular biotechnology, that have therapeutic, preventive or rehabilitation effects, that are present in any pharmaceutical form, that is identified as such by its pharmaceutical activity and physical, chemical and biological properties." Furthermore Article 3.60 of the same Mexican standard goes on to define "biocomparable biotechnological medications" (medicamento biotechnolόgico biocomparable) as "…biocomparable in terms of safety, quality and efficacy to the reference biotechnological medication…." Because a separate definition for "innovative biotechnological medication" is provided in Article 3.61 and for "reference biotechnological medication" in Article 3.62, there is an implication that reference products can be different from innovators.

Until fairly recently, Mexico did not have any specific regulations for biotechnological and biocomparable biotechnological products. On 11 June 2009, the Mexican General Health Law (Ley General de Salud)⁴ was amended by decree, adding Article 222 Bis⁵ on Biotechnological Medications. This decree was designed to address the issue of biotechnological medications and biocomparable biotechnological medications, and the responsibility of the Committee of New Molecules. Subsequently the Regulation of Health Sector Products (Reglamento de Insumos para la Salud) was amended by a decree on 19 October 2011, relating to biotechnological medications (DOF-19-10-2011)⁶ and by a decree on 16 June 2012 related to biocomparable biotechnological medications (DOF-19-06-2012)⁷. Table 1 details the regulatory instruments related to biotechnological products in Mexico. The Federal Commission for the Protection against Sanitary Risks (Cofepris) is the regulatory agency responsible for approval of biopharmaceutical products in Mexico. In an encouraging development for sponsors investing in the Mexican market, the director of Cofepris, Mikel Arriola, has vowed to streamline and accelerate the application approval process. Cofepris-approved outside reviewers now have a mandate to be involved in the submission review process as defined in the operational guidelines for authorized third-party verification of units of drugs and medical devices (Lineamientos Operativos para las Unidades de Verificación Terceros Autorizados auxiliares en el control Sanitario de Medicamentos y Dispositivos Médicos 14-05-2012)⁸. At the current time, however, it is unclear whether the involvement of these authorized verification units extends to biological products.

With the implementation of these new biological regulations the importance of a Cofepris committee, El Comite de Moleculas Nuevas (Committee of New Molecules (CNM)), and its Subcommittee on Evaluation of Biotechnological Products to the regulatory process of approval has been underscored. DOF-23-02-2012 provides the regulatory instruments necessary for the operation of CNM and its subcommittees⁹. Article 222 Bis of the Mexican General Health Law and the decree of 19-10-2011 grant this committee extensive powers. Article 222 Bis also outlines the composition of the Subcommittee for Evaluation of Biotechnological Products to include members from a range of independent Mexican national institutions (National Institute of Genetic Medicine, National Autonomous University of Mexico and National Polytechnic Institute).

CNM includes a preapproval validation process as part of presubmission activities in Mexico. This formal meeting follows a different format than the scientific advice procedures provided by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Sponsors are encouraged to provide actual data from pivotal clinical trials and details of the pharmaceutical development in advance, and to present that data during CNM meetings of to up to 30 members. Subsequently, review of this data by CNM results in a preapproval decision. The results of this meeting and the preapproval decision from CNM are mandatory for a sponsor's marketing authorization application (MAA) submission and thus are critical elements of the product approval process.

Table 1: Mexican Biotechnological Regulatory Documents

 

Although not explicitly stated in the regulations for the broad category of biotechnological medications, Article 177 Bis 4 of DOF-19-10-2011 states that clinical studies for biocomparable products must be conducted locally in Mexico unless the CNM approves the use of foreign studies. Based on the author's recent experience, CNM is likely to request Mexican clinical data. As an important part of global regulatory planning, companies wishing to market biological products in Mexico should strategically consider the inclusion of Mexican patients in pivotal clinical trials. As the Mexican pharmaceutical market increases in importance, pharmaceutical companies with global aspirations may well be advised to include Mexican patients in global study packages at the outset, avoiding the expense and costly delays resulting from late initiation of Mexican clinical trials. This particular approach has been accepted anecdotally by CNM without further need for a sub-analysis of the Mexican patient data; inclusion of Mexican patients within studies is enough to satisfy the committee.

Manufacturing Regulations and Licensing

In 2008, market authorization holders in Mexico were legally required to have manufacturing capacity locally in Mexico. An amendment to the Regulation of Health Sector Products (Articles 168 and 170) on 5 August 2008 removed this rule and therefore opened the Mexican pharmaceutical market to foreign importers. Since this major change, foreign importers have been required to hold a Mexican sanitary license for their specific manufacturing or laboratory facilities in relation to both pharmaceuticals and biological products. The applicable regulations to consider for this sanitary license are the General Health Law (articles 204 & 376), Health Supply Regulation (Articles 167 and 190) and the Mexican Official Standard NOM-059-SSA1-2006.

Two types of sanitary licenses are authorised by Cofepris. The "operations" license, issued by Cofepris, is required for entities that manufacture, market, distribute and work with general pharmaceuticals. This license is relatively simple to obtain and requires the submission of minimal information to Cofepris. The second license, referred to as a "sanitary" license, is required for entities that produce, distribute or work with biological medicinal products. As one might expect, this particular license is much more difficult to obtain. On the basis of the author's experience, timelines involved in the application process for this license are lengthy (up to an average of six months) and the requirements are complex and stringent.

A sanitary license issued by Cofepris and a responsible person (i.e., a representative whom Cofepris can contact with regard to the sanitary license) is required at the time of dossier submission. A foreign company setting up operations in Mexico can obtain this license in a number of ways.

• The foreign company can set up a Mexican affiliate for local operations. This operation cannot be a paper office and must include a minimum of infrastructure (warehousing, etc). This option ensures that the marketing authorization holder is, in fact, the Mexican affiliate of the foreign company.
• Alternatively, the foreign company can contract with a third-party local pharmaceutical distributor and use its operations/sanitary license and responsible person. The third-party local pharmaceutical distributor will be the Mexican marketing authorization holder.
• Finally, the foreign importing company can organize a partnership with a Mexican pharmaceutical company and similarly utilize its licenses and responsible person. Again the foreign importing company cannot be officially recognized in Mexico as the marketing authorization holder.

In order to obtain the mandatory local sanitary and operational licenses, foreign pharmaceutical companies may need to establish complex local partnerships. The potential for long license application timelines also should be considered as part of the Mexican drug registration plans.

Post-submission Regulatory Commitments

The Mexican Standard for Biotechnological and Biopharmaceutical Products outlines the criteria to be applied to the establishment of pharmaceutical products. In addition to the criteria outlined in this standard, following approval of a biological product in Mexico, confirmation of any shelf life claim must to be confirmed using Mexican-specific batches. This requirement is included as a commitment request in marketing authorizations granted by Cofepris. Practically speaking, these long-term stability studies often are conducted in Mexico. However, anecdotally and from the author's experience, in some cases, foreign importers of pharmaceuticals have been asked to conduct long-term stability studies outside Mexico. Nevertheless, the applicant should be prepared to conduct them in Mexico.

Despite the existence of biotechnological medication regulations and guidance in Mexico, a great deal of uncertainty surrounds the interpretation and implementation of these requirements. Further, anecdotal evidence indicates the practical requirements of Mexican regulators are not always set forth in the regulations, making strategic planning a challenge. A major source of uncertainty stems from the issue of conducting Mexican clinical trials. Regulatory professionals are advised, at a minimum, to consider the inclusion of Mexican patients in global clinical trials.

References

1. SecretarÍa de Salud. "Por una regulación sanitaria eficiente de bienes y servicios" Comunicade de Presnsa No. 154. 25-03-2013.
2. IMS Market Prognosis. IMS Institute for Healthcare Informatics. May 2012.
3. Biotechnological and Biopharmaceutical Medicines. Adequate Protection Practices. Technical and Scientific Characteristics That Must Be Carried Out Regarding Safety, Efficacy and Quality. Labeling. Requirements to Perform Biocomparability and Pharmacovigilance Studies. NOM-EM-001-SSA1-2012.
4. General Law of Health (Ley General de Salud), 26-12-1983. Most recently amended by Decree Amending Article 61 of the General Law of Health, 20-12-2012 (Diario Oficial de la Federación, Primera Sección, Viernes 25 de Enero de 2013);
5. Article 222 Bis on Biotechnological Products of the General Health Law (Decreto por el que se adiciona un articluo 222 Bis a la Ley General de Salud).
6. DOF 19-10-2011.
7. Guidelines for Biocomparable Biotechnological Products DOF 19-06-2012.
8. Operational guidelines for Authorized Third-party Verification of Units of Drugs and Medical Devices. Lineamientos Operativos para las Unidades de Verificación Terceros Autorizados auxiliares en el control Sanitario de Medicamentos y Dispositivos Médicos 14-05-2012
9. Procedure of the Committee of New Molecules. DOF-23-02-2012.