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International Clinical Trials

Right Place, Right Time



When considering the best way to import clinical trial materials to South America, making allowances for regional variations in the regulatory approval process, plus having local knowledge and expertise on hand, is critical.

As South American countries are increasingly targeted for product launches, pharmaceutical and biopharmaceutical companies have come to recognise that the effective management of clinical trials within these countries is vital to controlling cost and maximising efficiency, leading to a successful trial outcome. The variable regulatory requirements among countries and the complexity of each regulatory system can lead to considerable variability in the timelines associated with importation of materials, and thus can have a considerable impact on the effective delivery of clinical trial material and ultimately the trial’s success. An appreciation of these variables is clearly important if a trial is to help deliver a product to market quickly and efficiently. This article will focus on key countries that are regularly targeted for clinical trials in the region and will consider the challenges of effective trial management in Argentina, Brazil, Chile, Colombia, Mexico and Peru.

Regulatory Approval Path

There are various challenges in the South American region, and chief among them are the various country-specific regulations, including material importation requirements. For any organisation managing the clinical trial process, it is paramount to understand and continuously monitor changes to each country’s regulations in order to effectively manage shipments in the region. Having a qualified and experienced local depot presence in each country will help to ensure that the impact of any regulatory change is managed correctly and the risks to reliable clinical trial supply are mitigated.

Making allowance for regulatory approval is a key part of clinical supply chain planning and the potential time taken for approval can directly impact the ability to ship an investigational medicinal product (IMP). The approval process is generally broken into various stages and there is potential for the whole process to be lengthy and difficult to plan.

Without approval of an investigational product, the trial cannot be conducted, and South American countries recognise that this may ultimately hinder their population from having access to new treatments. In Argentina, Brazil, Chile and Mexico the respective regulatory bodies are continuously working to simplify their regulatory processes, make approval times shorter and, perhaps more importantly, more predictable.

In Brazil, the application to Agencia Nacional de Vigilancia Sanitaria (ANVISA) takes approximately 192 working days until approval. Within this overall timeline, sub-tasks can be broken down as follows:

  •  7 days to translate required trial documents
  •  45 days for local ethics committee to review
  •  90 days for national ethics committee to review
  •  30 days for regulatory authority review
  •  20 days for import licence to be granted

In Chile the application is made to Instituto de Salud Publica de Chile (ISP) and typical regulatory approval is approximately 127 working days and can be broken down as follows:

  •  7 days to translate required trial documents
  •  45 days for local ethics committee to review
  •  60 days for regulatory authority review and import licence approval
  •  15 days for UCIREN (ISP) use and disposal for site shipments

When considering South America as a whole, the approvals process typically varies (see Table 1).




For the import of clinical trial materials, an overall protocol licence and permits must be obtained, and an import licence is required for every clinical trial shipment into any country in South America. Although a direct-to-site shipment can be made from outside the country, in many cases it is not practical as the time taken to reach the country may be prohibitively lengthy. Individual country requirements and complex customs regulations are a major contributor to delays and, for an IMP, this may result in temperature excursions and the compromise of time sensitive shipments. The time taken for IMPs to reach the trial population may be exasperated further in regions where there are few medical centres, and the author has experience of medication release taking more than 24 hours. Inadequate or unsuitable storage and/or temperature control systems at medical sites may also compromise the importation process, with IMPs arriving in an unusable condition or having breached temperature control guidelines.

Understanding Country Procedures

As previously described, it is not adequate to generalise on the rules governing importation to South America, and a detailed knowledge of procedures governing importation for each country is important. This is illustrated below by comparing Chile and Mexico.

Chile

First, a request for an overall import protocol licence is submitted by the CRO or the importer of record (IOR). Typically the time to obtain this licence varies from two to three months and the licence is valid for the entirety of the clinical trial. However, it is worth noting that if the trial goes on for longer than indicated and the material quantities approved for import with the license are exceeded, the CRO/ IOR can apply for an extension.

In addition to the import license, Chile also requires an import permit. Also known as the Certifica de Destinacion Aduanera (CDA), it is required for each shipment and must be submitted to the Ministry of Health (MOH) by the IOR. This permit is based on information taken from the commercial invoice, which must be pre-approved in order to apply for the import permit. It is submitted using information from both the commercial invoice and master airway bill, and there are two ways to apply, with manual entry taking between one to two weeks and web entry taking only 30 minutes to two hours. It is imperative that documentation is completely accurate, otherwise the individual timelines discussed in this example may be multiplied for any inconsistency.

Mexico

The process starts with the generation of a certificate of origin (COO), which may be obtained where products are of a high value and originate from a country that has pre-existing international trade agreements with Mexico. For example, materials originating in the US or Canada will attract less duty, providing that a COO is available together with the import permit. Importation of clinical supplies under the customs rule 3.1.33 (formerly rule 4.3) allows the import of drugs, kits and clinical supplies for clinical trials without a permit if the protocol is approved by the MOH (SALUD – Secretaría de Salud). For kits that are imported under this rule, customs require the complete protocol dossier to be available. Another aspect of utilising this rule means clinical trial materials do not require an Advance Sanitary Import Permit for Products (Sanitary Permit). Where the IOR is not applying rule 3.1.33 and importing with an import permit, this permit needs to be obtained from the MOH by the IOR. Timelines to obtain are 30 to 60 days and the permit expires after only 180 days. Furthermore, the permit is valid only for a specific quantity of material and the IOR must apply for a Sanitary Permit, which takes a further 20 to 40 days. It is important to note that the commercial invoice must show the unit value, quantity and total value of the shipment, and those details must match precisely the import permit and the shipment itself. The shipper’s tax identification number or equivalent must also be shown on the invoice. As customs authorities have the right to open all shipments to ensure that products match with all documents required, it is worth noting that all brokers pre-inspect shipments before declaring to customs and this cannot be avoided in Mexico. This is understandable as the customs authority may impose fines on all parties involved and seize the shipment if the physical product does not match the description, quantity and so on upon the documents presented. So again we can see from this example that it is imperative that documentation is accurate when applying, so as not to extend study timelines.

‘In Country’ Approach

These two examples illustrate that IMP import regulations vary greatly from country to country and managing this variation requires excellent local knowledge and expertise, ideally from within the individual countries themselves. It is strongly advised, therefore, to choose a service provider with depot facilities ‘in country’ and a proven track record of successfully delivering clinical trial materials into that country, utilising couriers with a strong local presence to ensure smooth passage of the clinical trial material.

It should also be apparent from the above that planning, preparation and consistently good communication are keys to successful importation and distribution within South America. Before submissions are made and materials ordered, it is essential to clearly define a project plan and be willing to adapt that plan as required. Project management and local knowledge of the country specific regulations are essential. The close integration of the roles and responsibilities of key players within the courier organisation and at the depot is crucial as these two entities combined must have the extensive knowledge of the regulations, timelines and infrastructure necessary to ensure effective delivery. Table 2 illustrates the transit times (subject to customs clearance), the documents required from the shipper and average clearance times at customs. Arrival times should be planned to the day because in South America customs may be closed during the weekend and avoiding weekend arrivals may avert potential delays.




Metrics

Look for a service provider that can illustrate their track record with metrics on the logistical elements of prior, similar trials. If you cannot measure it, you almost certainly cannot manage it, and the industry’s standard approach to measuring and managing the performance of a supply chain solution is through the adoption of metrics and key performance indicators (KPIs). Increasingly, service level agreements (SLAs) are placed on the clinical supplies groups by clinical teams and sponsors. In order to provide meaningful measures, the service provider and sponsor should establish agreeable KPIs for important elements of their own trial management procedures and upon critical vendors such as couriers and depot facilities. Ensuring that SLAs are in place with vendors such as couriers and third-party depots is also paramount to success. The simplest way to cover this is by measuring and managing these service providers in the supply chain to the same KPIs an organisation imposes upon its own people and processes. Ontime delivery of IMP and minimising temperature excursions are key; however, right first time documentation and other quality related measures such as non-conformance, complaints, and corrective and preventative action (CAPA) ‘close outs’ are excellent indicators of the quality and efficiency of the individual players and the supply chain process itself. These KPIs highlight, to all those involved, how individual elements of the supply chain affect the study objectives.

Conclusion

Many elements of the planning and delivery of clinical trials materials to the right place, at the right time and to the right quality sound like simple common sense when also factoring in the complexities and variations in customs and procedures within South America, careful planning and good local knowledge must be coupled with a demonstrated ability to reliably supply into these increasingly important markets.

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Angus Macleod is Senior Manager for Catalent Pharma Solutions’ Clinical Trials Services business. He is responsible for the management of Catalent’s global depot network, which provides comprehensive clinical trial storage and distribution. Angus has more than 25 years of experience in supply chain management within large multi-national companies, and he has extensive international experience spanning Europe, North America and Asia-Pacific. Prior to joining Catalent, he held senior positions within Ciba, Cable and Wireless and GEC. Educated at Thames Valley University, he holds diplomas in Material Science and Management Studies.
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Angus Macleod
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