TRAC Services Individual Challenges and Harmonisation: The CMC Post approval Landscape in Argentina, Mexico and Colombia

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1 TRAC Services Individual Challenges and Harmonisation: The CMC Post approval Landscape in Argentina, Mexico and Colombia

2 Introduction Latin America is a fast growing region both in terms of populations and economies with a total population reaching almost 600 million people in 2011 (WHO 2012). Although there are 26 markets in the Latin American region; Brazil, Argentina, Mexico, and Colombia contain more than two-thirds of the total population of the region. As a result these markets are considered the top four pharmaceutical powers of the region. Table 1: Populations in the Top Four Latin American Markets of Concern (2012) i The growing prosperity of the key Latin America populations is in turn creating increased demand for drug access. Regional pharmaceutical sales in 2011 were at USD 62.9 billion, a significant share of the global market value of USD 995 billion dollars that year (WHO 2012). If we consider the healthcare issues faced by Mexico as an example, 74.76% of deaths in 2009 were due to non-communicable diseases. The table below examines further the causes of death, the majority being from cardiovascular diseases.

3 Table 2: Deaths Due to Non-Communicable Diseases in Mexico Cause of Death Cardiovascular Diseases Diabetes Mellitus Malignant Neoplasms Digestive Diseases Respiratory Diseases 7.34 Other Non-Communicable diseases % of deaths from Non-Communicable diseases The time and cost associated with registering a pharmaceutical product in Latin America, both NCEs and generics, is in general, significantly lower than in Europe. In Colombia, new drugs take approximately six months to register, with similar and generic drugs taking only three months, while Argentina take around eight months to approve new medicines. With such timelines the region is very attractive for companies seeking growth. As a result, the individual governments are taking measures to develop a more robust market and regulatory framework for the pharmaceutical industry. However, although these countries have come a long way in their own rights respectively, the region has a lot of diversity in the levels of regulatory complexity and requirements. As with the EU, post-approval changes are now much more heavily regulated in the region than was previously the case. It is therefore more important than ever for a company to understand the timelines and requirements involved in post-approval activities in each market for effective lifecycle management. A single regulatory strategy for markets across the Latina region is not possible currently and makes local intelligence vital. Whilst these countries share some common regional characteristics, it is very important to be sensitive to the differences that exist amongst them. There has already been significant regulatory focus on Brazil therefore this article looks to address the individual challenges faced in Argentina, Mexico, and Colombia from a post-approval CMC aspect, and also the steps being taken to achieve regulatory harmonisation in the region. The Pan American Health Organisation (PAHO), founded in 1902, is the world s oldest international public health agency. It provides technical cooperation and mobilises partnerships to improve health and quality of life in the countries of the Americas. As stated by the PAHO, the objective and scope of a regional reference authority is as follows:

4 Participate in the quality assurance, safety, and efficacy processes for the products purchased by the PAHO on behalf of the countries. Collaborate as referents in the implementation and follow-up of recommendations approved by the Pan American Network for Drug Regulatory Harmonization (PANDRH) network. Support the PAHO in strengthening activities for other national regulatory authorities in the region, so that they can be designated as regional reference regulatory authorities. Exchange public information through its websites and in the framework of the current national legislation on the products approved by the regional reference regulatory authorities. This will enable authorities with more limited capacities to have elements available for decision-making about their own products, considering that the products registered and sold in the countries with regional reference regulatory authorities will fulfil the quality standards recommended by WHO. Establish mechanisms in agreement with the PAHO that can favour the mutual recognition processes for the functions of the pharmaceutical regulatory bodies.

5 Table 3: Members of the PAHO Member States Date of Admission Antigua and Barbuda September 1982 Argentina September 1937 Bahamas October 1974 Barbados October 1967 Belize September 1982 Bolivia March 1929 Brazil October 1929 Canada September 1971 Chile October 1929 Colombia June 1933 Costa Rica December 1926 Cuba June 1925 Dominica September 1981 Dominican Republic November 1929 Ecuador September 1930 El Salvador May 1926 Grenada September 1977 Guatemala May 1933 Guyana October 1967 Haiti June 1926 Honduras January 1957 Jamaica August 1962 Mexico March 1929 Nicaragua December 1925 Panama March 1929 Paraguay June 1939 Peru November 1926 Saint Lucia September 1980 St. Vincent and the Grenadines September 1981 St. Kitts and Nevis September 1984 Suriname September 1976 Trinidad and Tobago September 1963 United States of America March 1925 Uruguay December 1928 Venezuela March 1933

6 Argentina In 2009 the Argentinean regulatory authority ANMAT (National Administration of Drugs, Foods and Medical Devices) was the first to be recognised by the PAHO as a National Regulatory Authority of Regional Reference of Medicines and Biological products. The audit by the PAHO looked at a wide range of areas within ANMAT, including its organisation and structure, institutional development and quality management. Argentina has a fast-growing pharmaceuticals market. This is forecast to almost triple in value from around US$5.6 billion in 2012 to $15 billion by This growth in part will be driven by the strong presence of high-quality production capabilities of domestic manufacturers. However, these facilities may not be able to compete with the production capacity and lower costs offered by other manufacturing countries such as China. In Argentina, the assessment timelines for post-approval changes are not as long as some of its neighbours. A minor variation approval, e.g. change in an analytical method, may take around six months whereas a major variation approval, e.g. a shelf-life change or line extension, may take around six to eight months. However, these approval times pale into insignificance if the authorities require a site inspection. The ANMAT regulation divides the countries where the proposed manufacturing site is located into Annex I and Annex II. For Annex I countries, pharmaceutical products are required to be manufactured in facilities approved by the relevant governmental bodies of these countries or by the Argentinean Department of Health and meet the National Health Authority's manufacturing and quality control requirements. For Annex II countries, manufacturing facilities are required to be inspected and approved by the Argentinian Department of Health before export of these pharmaceutical products into Argentina. Where such a site GMP inspection is required, this should be requested as early as possible as, due to resource constraints, the site inspection may take up to two years to occur.

7 Table 4: Argentina Annex I and Annex II Country List Annex I Austria Belgium Canada Denmark France Germany Israel Italy Japan Netherlands Spain Sweden Switzerland United Kingdom USA Annex II Australia Brazil China Chile Cuba Finland Hungary Ireland Luxembourg Mexico New Zealand Norway There is a consultation tool available on the ANMAT website, which provides access to information related to the last inspection carried out by each organisation authorised by ANMAT. This verifies compliance with GMP for the manufacturing and/or import of medicinal products. This information covers all inspections carried out from 1st May It is available by clicking on the Portal del Inspector section and then entering the Áreas de inspecciones/medicamento section [Have your Spanish dictionary handy for this part of the website]. (for the English version of the ANMAT website) In February 2014 Agentina s ANMAT and Columbia s INVIMA met to sign a bilateral cooperation agreement between the 2 agencies.the memorandum of understanding stated the following objectives: To promote the exchange of information and development of collaboration activities between the agencies, in order to strengthen their regulatory capacities. To facilitate the exchange related to the drug traceability program and its Good Traceability Practices protocols.

8 Mexico In June 2012 the Mexican Regulatory Authority, Cofepris (The Federal Commission for the Protection against Sanitary Risk) was also recognised by the PAHO, which facilitated the signing of agreements with regulatory authorities in Argentina, Brazil, Colombia, and Cuba (with the latter three markets being recognised in 2010). Following on from this recognition in September 2012 Mexico and Chile signed a cooperation agreement. This mutual recognition is intended to harmonise the two markets for requirements and regulatory aspects including the sharing of health records, inspection visits and Good Manufacturing Practice. Mexico drug registration approvals were also recognised by El Salvador and Ecuador which was a major step towards harmonisation in the region. Long approval times for CMC variations in Mexico are an important factor in understanding life-cycle management in the market. Experience shows that approval timelines that are estimated in the region of 6 to 12 months can often take 24 to 36 months. To address this Cofepris have introduced a fast track process. The applications are initially reviewed by a third party, for a significant fee paid for by the applicant, which grants a preapproval letter prior to submission to Cofepris for review. The third party review should expedite the subsequent review by Cofepris and bring the approval back in-line with the original timeline of 6 to 12 months. This is not an easy route though. To date experience of the fast track procedure has shown it to be burdensome with a large amount of extra documentation requested. Multiple rounds of additional documentation requests may be received with a delay dependent on the ability of the applicant to expediently provide the documentation or data requested. Should these requests be received in several different rounds instead of all at once this could cause further delays due to the practicalities involved in the applicant s internal review and publishing processes.

9 Significant questions or document requests can also be expected in regards to registered product technical information from previous submissions which have already been assessed and approved even if they are unaffected by the scope of the proposed variations included in the application. Only further time and experience will show whether the fast track system lives up to its promise or whether the large amount of documentation requested, increased fees and delays associated negates the intended benefits. Colombia The memorandum of understanding (MOU) co-operation agreement signed by Mexico and Chile in September 2012 is currently being extended to Colombia s Ministry of Health, INVIMA (Instituto Nacional de Vigilancia de Medicamentos y Alimentos). In respect to size alone, Colombia does not hold the same importance as Mexico. However with an economic growth rate of 4% and a population of 46 million, it is considered as one of the top four pharmaceutical powers in the region. Colombia has a healthy pharmaceutical manufacturing industry with many other countries in the region importing from them, particularly Venezuela. The country has had particular challenges in the past with under-the-counter sales, and counterfeit products still make up about 2-3% of the pharmaceutical market value. However, with the adoption of good manufacturing practices, the issue of counterfeit pharmaceuticals is decreasing and it is becoming an attractive prospect for pharma companies seeking expansion into new markets. Post-approval CMC variations have equally short approval times of around six months for a source transfer, vastly different to that currently experienced in Mexico, and documentation requirements are also less burdensome. Significantly, there is flexibility on the Certificate of Pharmaceutical Products (CPP) with nonsource CPP s being accepted by INVIMA from a number of reference countries outside of

10 Latin America, such as the UK, Denmark and the USA, allowing greater supply chain possibilities for pharmaceutical companies. Mexico and other markets in the region are known to be less flexible on this requirement, often mandating a source CPP. A difference of particular note in Colombia, is that there are also instances where INVIMA doesn t require further stability data when a new proposed manufacturer is located in the same climatic zone as those studies previously presented. Although it is not guaranteed that they will not ask for site-specific data, there is the opportunity to provide a technical justification related to result extrapolation in some cases. This flexibility could accelerate site gaining approval of a CMC variation for supply to Colombia by months, when stability is often the time-limiting step for submission. Table 5: Latina Markets with Regional Reference Authority Country Argentina Brazil Cuba Colombia Mexico National Regulatory Authority ANMAT. ANVISA. CECMED INVIMA COFEPRIS Date Regional Reference Authority Status Obtained December 2009 May 2010 July 2010 July 2010 June 2012 Conclusion The Latina pharmaceutical market continues to grow fuelled by relatively short timeframe for new product registrations, however, this will lead to a requirement for more Post Marketing activity in the region. Experience has shown Post Marketing license variations applications to be challenging in Latina markets. With increasing co-operation between Latina markets it may be anticipated that the requirements for regulatory documentation will become more aligned across the region. This does not necessarily mean a lessening of the document burden for the applicant. It is unlikely those markets designated as a reference national regulatory authority and recognised as being competent and efficient in performance of the health regulation functions by the PAHO/WHO will relax the supporting document and data requirements. However, increased co-operation between markets should facilitate a more expedient approval if it has already been granted in a recognised partner market.

11 While a system and process as coherent as that implemented in the EU is a long way off, small steps appear to be being made towards a system of co-operation and recognition across the Latina region I america- and caribbean

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