The Colombian Biological Medicines Decree
Lunes, 6 de Octubre de 2014
Key words: biological medications, biotech medications, quality, safety and efficiency standards, full dossier pathway, comparable pathway and abbreviated pathway.
The Colombian Biotechnology Decree, enacted on September 18th, is part of Colombian competitiveness policy to attract investment and to exploit biodiversity in a sustainable way. The Decree addresses two main issues: the requirements and procedure for the Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA) to evaluate biological medications quality, safety and efficiency, in order to grant the sanitary approval to commercialize them within the country.
This article explains the most important provisions of this decree, such as its application, the information requirements to grant marketing authorization for biological medicines, and the standard to assess the safety and quality of biological medications. Finally, it examines the main expectations and concerns that the Decree have raised.
The Decree is only applicable for the marketing approval and pharmacovigilance of biological medications which might be produced, imported or commercialized within Colombian market. Biological medications, as defined in the Decree are:
“Medicines derived from alive organisms, cells or their parts. The sources they can be obtained from are tissues or cells, or components of human or animal blood (antitoxins and other antibodies, cytokines, growth factors, hormones and clotting factors), or form viruses, microorganisms, and products derived therefrom as toxins”. This products are obtained by using methods including, but not limited to culturing cells of human or animal origin, growing and propagation of microorganisms and viruses, processing from human biological fluids or tissues or animals, transgenesis, deoxyribonucleic acid techniques (DNA) and hybridoma techniques. The medicines resulting from the latter three method are called biotech.”
Biological medicines, apart from synthetized medicines, cannot be completely characterized nor written into a chemical formula. The fabrication process of biological medicines is complex. It starts by placing a disease, its biological mechanisms and products, such as cell receptor proteins, to then develop molecules to target the disease. These drugs are obtained from alive organisms, so their production, purification and assessment must be followed carefully because a small change in it can alter dramatically the molecule’s safety and efficiency. Human insulin, vaccine and growth hormone are a few examples of the biologic medicines available in the market.
The technologies exemplified in the Decree -cells culturing, growing and propagation of microorganism- are used to produce biotechnology medicines, which are species within the genus of biological drugs. Biotechnology medicines aim to transform cells into substances factories needed by human body to heal. According to La Federación Colombiana de Medicina, the best-selling of biotherapeutic medicines in Colombia are Mabthera, used to treat lymphocytic leukemia, Humira (adalimumab), used for rheumatoid arthritis, and Herceptin (trastuzumab) for breast cancer.
Even thought, none of the words “biosimilar” or “follow-in biologics” nor “biogenerics” appear in the Decree, its main purpose is to allow the approval of biosimilar medicines to encourage competition and to diminish prices. In fact, Paragraph 1 of article 4 of the Decree establish that “[t]he prescription information approval must always be supported in security and safety evidence regarding the medicine subject to evaluation or to the medicines with an active pharmaceutical ingredient highly similar” to the reference innovator biotherapeutic medicine. The reference medicine is “the biologic medicine which sanitary registry has been approved by INVIMA, or by any other reference sanitary agency, through a full dossier procedure and which might be used as reference” to approve biosimilars.
Biosimilars are said to be “similar but no identical” to a reference biologic medicine. In fact, according to the pharmaceutical industry , the complexity of biologics molecular structure makes impossible to copy them. However, Colombian Health Ministry states that “[t]he difference between the first ones (biological medicines) and the second ones (biosimilars) is that the new ones get first into the market place and are patented as they are technology innovations and improvements. Biogenerics can only enter into the marked when biotechnology patents have expired, as they are copies of the latter”.
Finally, the Decree excluded from these procedure allergens drugs, magistral formulas obtained from living organisms or its tissues, and products containing or consisting exclusively of human or animal cells and/or tissues which do not have pharmacological, immunological or metabolic action, as well as homeopathic preparations derived from biological fluids, microorganism and other substances of biological origin.
2. The three Pathways
Biologic medicines information might be submitted before INVIMA through three pathways: full dossier pathway for innovator biotherapeutic medicines, and comparable and abbreviated pathways for biosimilar drugs. Eventhough, there are common information requirements; each pathway requires different probes from the applicant to assess quality, safety and efficiency of biological medicines:
|Common Requirements||Full Dossier pathway||Comparable pathway||Abbreviated pathway|
||Preclinical, whether in-vivo or in-vitro, and clinical analysis of the biological medicine. This data must probe medicine’s safety and efficiency attributes, specifically: 1. Effectiveness:1.1. Indications, contraindications, interactions, precautions and warnings1.2. pharmacokinetics1.3. pharmacodynamics1.4. dosage1.5 risk-benefit 2. Security:2.1. adverse effects2.2. immunogenicity2.3. marketing conditions2.4. special restrictions2.5. Risk-benefit relation||Comparisons results between the biologic medicine subject to assessment and the reference biotherapeutic medicine. The comparison study must lead to conclude that the medicine assessed is highly similar to the reference medicine, all along the stages from the identification and characterization of both medicines to pre-clinical and clinical test. The differences must be explained and justified by the applicant; INVIMA would determine its clinical relevance.||The abbreviated pathway application is subject to characterization and safety profile of the active pharmaceutical ingredient of the drug subject of the application to be highly defined and documented.If the information gathered details the identity, biological activity, physicochemical properties and purity of the active ingredient, it would be taken as highly defined, and the abbreviated pathway may apply.The applicant has to probe that there are no relevant clinical differences among its biological medicine and the active ingredient used as reference, by submitting clinical and pre-clinical test.|
The applicant should choose the pathway depending on how characterized and known is the pharmaceutical ingredient and substances of the biological medicine assessed. For instance, if the biological medicine is new and totally unknown, its sanitary and commercial approval will require the information required in full dossier pathway. On the contrary, if the medicine is known, it will be approved through the abbreviated pathway.
If compare with the regulation on medicines derived from chemical synthesis, the Decree brings even more requirements for marketing approval. For instance, The Regime of Pharmacovigilance for medicines, issued by Decree 677 of 1995, appoints the documentation needed for the sanitary approval of chemical synthetized medicines, this documentation is also required for biological medicines, but the Decree complemented it by asking the applicant the following information:
- Fabrication procedure of the biologic drug. It is worth saying that the fabrication of biological medicines requires for the producer the adoption of the Good Manufacturing Manual, to be issued by Health Ministry.
- The certification of reference standards used for quality control of the active pharmaceutical ingredients.
- Specifications and results of quality control on raw materials (active pharmaceutical ingredients and formulation auxiliaries).
- For fluids or tissues, either animal or human, the applicant should provide transcripts to account results of quality control stages.
3. Safety Standard
Regardless of the pathway chosen by the applicant, the safety and efficiency standards for pharmacological evaluation will be the same. INVIMA will make a severe pharmacological evaluation, in which will have into account, as criteria, evidence and information arising from countries where the medicine has been commercialized, the complexity of the medicine’s molecular structure, and all the information available in standardized international documents.
The pharmacological evaluation must be objective and explained by INVIMA in such a way that applicants and the scientific community can anticipate the potential outcomes of the evaluation.
4. Main expectations and concerns
a) The legislation for sanitary and commercial approval of medications in Colombia addressed only the safety and efficiency assessment of chemically synthesized medicines. Due to the expiration of the patents that protect this medicines, and the creation of new ones based on live organisms, it was essential to protect Colombian population to update sanitary legislation to establish the requirements of biotherapeutic medicines commercialization. Sanitary legislation has to be update without creating barriers for generic produces to enter into the market
b) Biological medicines are crucial for the financial sustainability of Colombian health care system. The treatment of chronic diseases –such as diabetes and cancer- is costly and biological medicines are new treatment alternatives but are costly as well; to make them an accessible alternative for patients it is important to control their prices. Additionally, biological medicines like vaccines can prevent children from getting expensive communicable diseases. In order to control biological medicines prices, it was necessary to encourage competition in this market by allowing the entrance of both innovative biological medicines and biosimilars.
c) However, there have been serious concerns about issues which have not been addressed by the Decree as well as the actual effects of some dispositions. For example, data protection is crucial within pharmaceutical industry, as pre-clinical and clinical trials are one of the most expensive stages of a medicine development process. Colombia legislation, as well as other WTO countries, provides protection to the data gathered from those trials, by banning others –generics- to rely on those studies to get the marketing authorization. The Decree remains silence about the protection of this data for the authorization of biosimilars in relation to innovative biotherapeutic medicines.
d) The abbreviated and comparative pathways created a lot of debate among United States government, WTO members and innovators agents who participated in the consultations realized along the Decree draft and enactment. The main concern about the pathways was the evidence that INVIMA would rely on to assess biosimilars safety and efficiency, as the Decree used the words “information available globally” and information that “the applicant considers relevant”. However, the Decree embraces WHO Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs), as it demands the applicants to submit a range of studies that meet the evaluation criteria established by the Guidelines, this information is mandatory for the applicant.
e) The reference standard to use in the Abbreviated Pathway was also a matter of debate. Unlike the standard created in the United States by the Biological Price Competition and Innovation Act of 2010, which depends on a close comparison between a innovator biological medicine (reference product) and a biosimilar one, in Colombia the comparison can be made between the biosimilar and a pharmacopeia standard or to a standard established by the applicant using accepted techniques.
5. To enter into force
The Biological Medicines Decree will not enter into force until Health Ministry issues a range of guidelines. Those guides must be issued within twelve months from the date of enactment of the Decree. Those guidelines most follow documents prepared by international organizations such as:
- WHO Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)
- WHO Good manufacturing practices for biological Products
- Good Pharmacovigilance Practices for the Americas, this document was issued by Red Panamericana para la Armonización de la Reglamentación Farmacéutica (Red PARF)
- WHO Guidelines on stability evaluation of vaccines
- WHO Guidelines on stability evaluation of Biotechnological
6. The importance of the Decree for intellectual property
Intellectual property rights (IPR), especially patents, are an effective mean to protect the investments made to discover and develop both chemically synthesized and biological medicines. IPR effectiveness to recover those investments and their profits depends heavily upon medicines obtaining marketing approval and meet the demand from physicians and patients. If the owners of IPR are to be compensated for those investments, the marketing approval must be conferred and the demand from physicians and patients must be sufficient. In other words, even if a biological ingredient manages to obtain a patent, but it does not gain the sanitary and marketing authorization, both, the investment and the patent would be worthless.
Worth noting Colombia is a mega diverse country. Natural resources and living organisms are the raw material for biotherapeutic and biotechnological medicines, which certainly will be the next generation of drugs. Pharmaceutical industry is already making huge investments on R&D of biological and biosimilar medicines, and certainly would protect and secure the revenue for those investments through patents. Additionally, governments must secure and guarantee people to have access to biological medicines. The legislation that allows the entrance of biological medicines into the Colombian market must balance all those issues without wasting resources upon which remains national competiveness.
 República de Colombia. Health Ministry. Decree 1782, 2014. By which are established the requirements and procedures for Pharmaceutical and Pharmacological Evaluations for biological medicines in the registration procedure health. September 18th, 2014. https://www.minsalud.gov.co/Normatividad_Nuevo/Decreto%201782%20de%202014.pdf
República de Colombia. Departamento Nacional de Planeación. Consejo Nacional de Política Económica y Social. Documento CONPES 3697. Política para el desarrollo comercial de la biotecnología a partir del uso sostenible de la biodiversidad. June 14th, 2011.
 Cfr. Biological Medicines Decree. Article 3.
 Boletín Infac. Medicamentos anti-tnf: Apectos prácticos en atención primaria. Volumen 17 • Nº 3 • 2009.
 Federación Colombiana de Medicina. Informes Observamed Observatorio del Medicamento – Federación Médica Colombiana. Informe SISMED 2012: Cinco años del Sistema de Información de Precios SISMED. Número BisBCM # 102013. Available: http://www.med-informatica.net/BIS/BisBCM10_InformeSISMED2012_10mar13.pdf
 Cfr. Biological Medicines Decree. 3rd Article.
 International Federation of Pharmaceutical Manufacturers & Associations. Medicamentos bioterapéuticos Comprendiendo la nueva generación de tratamientos. Switzerland. The same can be read in the commentaries made by Biotechnology Industry Organization (BIO) to the Decree’s Draft October 4th, 2013. http://www.minsalud.gov.co/salud/MT/Paginas/consulta-proyecto-decreto-registro-medicamentos-origen-biologicos-biotecnologicos.aspx
 “La diferencia entre los primeros y los segundos es que los nuevos por lo general entran primero al mercado y están patentados porque representan innovaciones tecnológicas. Los biogenéricos solo pueden entrar al mercado una vez las patentes de lo biotecnológicos nuevos se han vencido porque son copias de los mismos.” Ministerio de Salud y Protección Social. Abecé sobre medicamentos biotecnológicos.
 Cfr. Biological Medicines Decree, Paragraf of Article 2.
 Cfr. Biological Medicines Decree Article 6.
Cfr. Biological Medicines Decree Articles 4 and 7.
 Cfr. Biological Medicines Decree. Article 11.
 Cfr. Biological Medicines Decree. Article 5.
 Cfr. Biological Medicines Decree. Article 10.
 Cfr. Trade Realted Aspects on Intellectual Property Rights. Article 39.3.
 WHO Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs), file:///C:/Users/SANDRA%20MILENA/Dropbox/Propiedad%20intelectual/Bolet%C3%ADn/Decreto%20de%20biotecnologicos/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf