|
|
|
International Clinical Trials
|
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. |
Read full article from PDF >>
|
|
 |
|
| Rate this article |
You must be a member of the site to make a vote. |
|
Average rating: |
0 |
| | | | | |
|
|
 |
News and Press Releases |
 |
New laboratory and regulatory services for biotech customers
USA/Germany, September 21, 2020. Gerresheimer adds essential laboratory
and regulatory services to its broad portfolio of products, solutions
and services for biotech companies. Specialized laboratory technicians
and an experienced team of further specialists offer these services in
the two innovation and technology centers in Bünde (Germany) and
Vineland (New Jersey/USA). Gx Biological Solutions offers full service
for biotech companies regarding product development of primary packaging
and drug delivery solutions, material and functional testing as well as
comprehensive regulatory support. The partnership with Gerresheimer
shortens the time to market for pharmaceutical companies, minimizes
risks and saves resources.
More info >> |
|
 |
White Papers |
 |
|
pAVEway™ expression system for the efficient expression of therapeutic proteins
Fujifilm Diosynth Biotechnologies
One of the major bottlenecks in the production of biopharmaceuticals is
the efficient expression of therapeutic proteins in microbial or
mammalian cells. The Escherichia coli pAVEway™ expression system
described here has been developed to ensure high product titres and
efficient scale up to GMP manufacture, whilst minimising many common
issues seen in other expression systems, such as ‘leaky’ expression
(expression of recombinant protein in the absence of inducer).
More info >> |
|
 |
Industry Events |
 |
Clinical Operations in Oncology Trials West Coast
17-18 November 2020, Hilton San Francisco Airport Bayfront
Clinical Operations in Oncology Trials West Coast will be returning this April for another 2 day event full of thought-provoking presentations, discussions and roundtables. This years' conference highlights include the high-level, interactive immuno-oncology discussion panel where specialists from Shasta Bio Ventures, Abbvie and BeiGene shared their top tips on how to run successful and impactful immuno-oncology studies.
More info >> |
|
|
