Published in Pharmaceutical Manufacturing and Packing Sourcer, Aug 2014
Latin America looks set to become a favourite of international companies hoping to extend the reach of their clinical trials. However, the varied — and often time-consuming — regulatory procedures can prove frustrating without a good understanding of each market
With worldwide attention placed on Brazil as hosts of this year’s World Cup, and with the 2016 Olympics in Rio de Janeiro approaching, Latin America has taken centre stage in the sporting world. But this is not the only area in which the region has come to prominence. Clinical trials have also experienced a boom throughout Latin America, with a greater number of trials occurring in more locations than ever before.
Global pharmaceutical companies have set up more than 5,800 trials in the region. More than 2,100 have occurred in Mexico alone. There are clear reasons why pharma manufacturers have shifted their focus and funds towards R&D in this market:
Large Total Population
More than 570 million people call Latin America home, with the majority living in Brazil (192 million) and Mexico (103 million). Add in Argentina (41 million), and the total population surpasses that of the US. Working through only three federal regulatory bodies to reach such a vast population – and at a substantially reduced cost for operations — presents a significant advantage when setting up clinical trials.
Dense urban areas provide another avenue to gain cost efficiencies for manufacturers that seek to reach a large volume of trial subjects without having to spread their operations too thinly. With over 22 million residents, Mexico City is one of the largest metropolitan areas in the world. São Paolo is not far behind, with 20 million, and Buenos Aires and Rio de Janeiro both top 10 million each.
Variety of Data
With so many people in the region, and such a variety of healthcare systems and economic conditions, manufacturers conducting trials in Latin America are bound to gather a wide spectrum of data sets — vital to successful studies.
However, despite the numerous opportunities available for clinical research in Latin America, challenges still abound for manufacturers working in this market.
The social divide in the region is often extreme, with a wealthy middle class suffering from typically Western conditions like diabetes and heart disease, while poorer populations suffer from diseases of poverty, including parasitic infection and malnutrition. For manufacturers looking for study candidates, the breadth of patient types can be both a blessing and a curse.
Vaccines are being trialled for diseases including rotavirus, which is prevalent with millions of cases occurring every year — leading to tens of thousands of deaths, particularly of young children. The local regulatory authorities have not been slow to realise the potential here, and many countries have set up regulatory agencies to speed up the process of approving clinical trials.
That said, it is important to remember that Latin America includes 20 individual countries, each with its own regulatory requirements intended to serve its own, vastly diverse populations. Even something as fundamental as language becomes more complex as one digs deeper. Most people in the region speak either Spanish (around 340 million) or Portuguese (approximately 192 million), but there are also large pockets of native French and Creole speakers. In Patagonia, the Welsh-speaking population is thought to be larger than the number of native speakers in Wales itself.
Conducting trials in the region, then, becomes an exercise in seeing the vast opportunities offered by the region as a whole — while also accepting and understanding the nuances of individual markets. For example, in some countries — such as Argentina — all materials have to be provided at the beginning of the initial regulatory submission, while in others, this may not be needed until the protocol is approved and the import licence is requested. As a result, it can become extremely difficult to estimate timing and costs in the early stages of planning a project.
Mexico: Trials and Logistics
The Mexican Ministry of Health, Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS), has experienced delays recently due to the increased volume of clinical trial applications. Previously, the agency had regularly met its processing target of three months; this can now take up to four or five months. The good news is that the old system, called ‘negative dicta’ — which meant that companies should assume their trial application had been unsuccessful if COFEPRIS had not confirmed approval within the three-month timeline — is no longer applied, due to the longer approval process.
Importing requires care and a host of documents. Products with a high value and originating from a country with international trade agreements with Mexico — including the US and Canada — will pay less duty, providing a certificate of origin is available, together with the import permit.
Due to complicated rules, an import permit is not always necessary. For clinical supplies and medical kits, customs rule 3.1.28 (formerly rule 3.1.11 and rule 4.3) allows the import of drugs, kits and clinical supplies for trials without a permit, if the protocol is approved by COFEPRIS. In all cases, it remains prudent to verify any shipment strategy with a qualified logistics provider.
In most cases, companies will need to transport products with an import permit, which should be obtained from COFEPRIS by the importer of record, takes 30-60 days to be processed, and expires after 180 days. The permit is valid for a specific quantity of product, and requires the importer of record to also apply for sanitary registration, which takes 20-40 days. Every shipment must be accompanied by a commercial invoice which must show unit value and quantity, as well as total value. All details have to match the import permit, and shippers should take particular care over the details, as even a small issue will result in significant delays.
If the value of any shipment exceeds $1,000 and/or it requires a special licence — which is advised when the protocol approval is issued — then it must be cleared as a formal entry, needing a broker. All brokers pre-inspect shipments before declaring them to customs, as the customs authorities have the right to open all shipments to ensure that products match with every document (invoice, import permit and certificate of origin, if applicable). If customs authorities find that the product does not match the documents, then all stakeholders – including the importer of record and the broker – can be fined, and an embargo applied.
Brazil: Import Licences
As one of the vaunted BRIC markets (Brazil, Russia, India and China), Brazil has spearheaded the drive to bring clinical trials to South America. The country’s regulatory agency, Agência Nacional de Vigilância Sanitária (ANVISA), is aiming for a trial approval time of 45 days but, to date, they have failed to achieve this demanding timeline. Instead, it often takes months for approval to be granted. When it comes to logistics, every single shipment requires an import licence — applied for by the importer of record — and typically takes around a week. ANVISA demands that consignees are registered within the agency’s electronic control, which is arranged by the importer of record. All shipments need the full litany of customs paperwork, invoices and permits, as well as an electronic paper, or general valuation statement (GVS), which is unique to Brazil. The GVS process requires fees to be paid on a sliding scale — free for public institutions; $15-30 for private corporations — before shipments can be cleared through customs. Consignees can give powers to apply for the GVS to their transport company, which will also be more likely to expedite the process.
￼Temperature control during shipment clearance delays: case study
Among the problems associated with clearance process delays at customs, maintaining a suitable environment for temperature-sensitive medical products is one which companies have to be aware of. Each shipment must be kept at the correct temperature for the duration of its journey. Each airport has differing facilities, and it is vital to understand what is available.
The following case study demonstrates the fluctuations within the temperature control area at Argentina Cargo Terminal, which is in charge of logistics and storage at Ministro Pistarini International Airport, Argentina.
Total surface area: 1,030m2
Refrigerated area: 2°C to 8°C
Controlled ambient: stated range of 15°C to 17°C. Because this storage is located next to the refrigerated area and is only separated by a curtain, our experience is that the actual temperature is much closer to 6°C
Total surface area: 4,310m2
Refrigerated area: 2°C to 8°C
Controlled ambient: 15°C to 17°C
Argentina: Electronic Management Systems
Argentina has proved an increasingly popular location, and the country has invested heavily in clinical trials. Its regulatory agency, La Administración Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT), was created in 1992. It aims to work to a three-month approval timetable and introduced an electronic management system to work towards this. However, as with Mexico and Brazil, this stated goal is not always followed. Even when an approval is granted, it can still take two months for ANMAT to issue the import permit to allow any supplies to be brought in.
Aside from this permit — which is issued for the whole study — another is required for every shipment in the protocol, and this takes a full working day to obtain. ANMAT charges a fee for each permit related to pharmaceutical shipments — at the time of writing, this is $239 for an import permit and $105 for an export permit.
February 2012 marked the introduction of a new import regulation, 3252/12 — applicable to formal import clearance via cargo section. It requires the importer of record to declare details on Argentina’s customs website before a purchase order or similar document is issued. This process is known as an ‘affidavit of anticipated importation’. Finally, the customs invoice must be submitted with another form to customs for each individual import. This form must also include the departure and arrival date of the shipment. Customs entries can only be made after proper and timely registration of all documents.
These complicated procedures, which are mirrored in many other Latin American countries, mean that many companies use an external broker to clear their shipments, making the process extremely slow.
While the delays in issuing approvals and permits can be frustrating, the longer approval procedures give companies the chance to thoroughly plan for shipping — avoiding the anxiety and costs of having shipments held at customs for any longer than necessary. Local knowledge is vital for success, and finding partners who understand the intricacies of specific geographies and cultures is an often overlooked component of a successful clinical trial.