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International Clinical Trials
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Belarus has much to offer life sciences companies as a location for
clinical trials, especially as it is not generally top of mind among
study planners and is not saturated with competing trials. The country,
which neighbours Poland, Ukraine, Russia and the Baltic states, has a
high percentage of patients who have not been exposed to
state-of-the-art treatments. At the same time, it has the clinical
infrastructure required to ensure patient safety, quality data and
efficient operations.
Its experience with clinical trials dates
back to the creation of the national Center for Examinations and Tests
in Health Service (CETHS) – part of the Ministry of Health (MoH) – in
1997. Currently, about 40 to 50 international Phase 2 to 4 trials are
carried out in Belarus each year – far below what the population and
conditions are capable of supporting.
The country’s attractions for sponsor companies include:
- Strong
patient enrolment rates, owing to a highly motivated patient
population, three-quarters of which reside in urban centres (a ratio
similar to that of France and Germany)
- A moderately large, modern-treatment-naďve population
- A
large pool of enthusiastic, English-speaking physicians whose
experience in clinical research is continually developing. There are 4.9
physicians per 1,000 patients (double the ratio of the US)
- Highly
educated and well-trained medical staff who are versed in Good Clinical
Practice (GCP) and compliant with the requirements of both the FDA and
EMA
- An overall cost structure that is favourable compared to other regions
Healthcare System
Patients’
medical expenses in Belarus are covered by the government-funded
National Health Service, although coverage for pharmaceuticals generally
extends only to the lowest cost products – typically local generics.
Patients opting for imported, branded products must pay out of pocket.
This situation contributes to the high percentage of patients who have
not been exposed to the latest pharmaceutical advances and are eager to
have access to groundbreaking treatments.
Care is provided in
regional clinics and republic scientific centres in urban areas, as well
as through outpatient clinics in rural areas. Rural patients are
directed to urban centres for further consultation and treatment as
necessary. In most cases, patients must be referred to specialists by a
general practitioner following an examination and any necessary
diagnostic tests.
In addition, the country has a high number of
private medical centres which are licensed by the MoH and provide
laboratory testing and specialist consultations. These services are not
covered by the government-funded healthcare programme.
Clinical Infrastructure
Belarus
is particularly well-suited to trials in oncology, cardiology and
rheumatology as the capital, Minsk, is home to large, republic
scientific centres specialising in these areas. These centres are
well-equipped, staffed with clinicians who are experienced in conducting
trials, and maintain rich patient databases of potential study
participants. Regional treatment facilities are located within a 300km
radius of Minsk, so travel costs for clinical research associates (CRAs)
to and from the city are not exorbitant.
The country is not,
however, conducive to running Phase 1 trials sponsored by multinational
companies; there is little experience within the medical community, and
the MoH and local ethics commitees (LECs) impose many restrictions.
Physicians
within Belarus are both highly educated and motivated to serve as
principle investigators (PIs). They speak English at an intermediate or
advanced level, are trained in GCP, and have experience in working with
LECs.
Cardiovascular diseases and cancer are the leading causes
of mortality in Belarus. As of 2011, cardiovascular conditions accounted
for 52% of the country’s mortality, and oncology made up 13.4%.
Patients’
willingness to participate in clinical trials is generally very strong.
They recognise that, through the process, they receive more intense
medical attention than might otherwise be available. Trial participants
have access to the latest treatment advances (rather than local
generics) and benefit from additional examinations and tests under the
constant supervision of the PI. Typically, in routine care, such
experienced staff are not available to patients until after several
consultations with specialists.
Navigating Requirements
Legislative and Regulatory Environment
Within
the MoH, the CETHS regulates pharmaceutical products, medical devices
and medical equipment in Belarus, ensuring their safety, efficiency and
quality. A division of CETHS, the Clinical and Pharmacological
Laboratory (CPL), oversees clinical trials: evaluating applications and
protocol amendments, supervising trials in progress, monitoring serious
adverse events reporting, and approving drug import licences. The
country’s trial regulations follow the principles of the Declaration of
Helsinki and the ICH guidelines.
Ethics Committees
There
is no central ethics committee in Belarus at present. Every hospital
participating in clinical trials has an established LEC that is
organised and operated in accordance with ICH guidelines and internal
procedures. Typically, each LEC meets on an ad hoc basis and does not
charge any fees for study review. All communication with the committee
is done through the investigator and his study team.
Submission Package
The
submission process for clinical trial approval in the country involves
multiple handoffs between several different entities. In general,
approvals are managed by the MoH through CETHS. Initial submissions are
sent to CETHS and agreement for the conduct of expertise is issued on
the day of submission. The fee ($2,400) must be paid before regulatory
expertise starts.
CETHS forwards the hard copy files of the
submission package to CPL for primary expertise and, if CPL’s feedback
is positive, to independent experts for specialised expertise. These
parties have eight weeks to complete their review. The files examined by
the experts are then discussed during meetings of the drug committee,
which are held monthly. The drug committee issues an order with a list
of approved studies. Based on this list, approval letters are prepared
and sent to the Deputy Minister of Health for review and signature. It
can take between one and three weeks for a letter to be signed.
Steps to Approval
Some
steps can be completed in parallel – such as obtaining the MoH
import/export licence and seeking European Commission (EC) approval –
but, in essence, this is a sequential process, with regulatory authority
approval needed before import/export licence and EC submission. When
planned properly, the entire process can normally be completed in 14-18
weeks. If any questions are raised by regulators and/or the EC, this may
cause a delay.
In general, the set of documents needed for
submission is standard and comparable to other European countries
(protocol, investigator's brochure, draft of case report form, patient
information leaflet and consent form). Among the specific requirements,
an apostatised and notarised Letter of Delegation, TSE/BSE certifi cates
where applicable, and local insurance policy are to be mentioned.
The
investigational medicinal product (IMP) quality documentation for
application is comparable to EU-defined requirements for an IMP dossier.
Most of these documents for all drugs to be used in the study must be
translated into Russian. It is worth noting that when studies are also
being conducted in Russia, the documents prepared for that country can
simply be replicated for Belarus – avoiding the need for a fresh
translation.
Should a substantial amendment to protocol be
needed – for example, changes to the number of trial sites or patients,
study procedures or dosing – amendment submissions and approval is
required. Approval of substantial protocol amendments can take between
five and eight weeks.
Import/Export Licences
A
separate import licence is required to import pharmaceutical products
into Belarus; it can be sought only after the above trial approvals are
secured. Import licences are only required for IMPs, and only Belarusian
residential legal entities holding a special permit for the conduct of
pharmaceutical or medical activities may apply for these licences. This
limits the applicants for import licences to warehouse and depot
companies.
Applying for licences typically takes two weeks, and
involves a fee of not more than $10 per licence. Lab kits and study
materials may be imported without an import licence, and can be
delivered via broker companies or shipping depots.
Export
licences are required for biosamples, are free of charge, and may be
obtained by a CRO on behalf of healthcare institutions (investigative
sites). These licences can be obtained in between 7 and 20 days. New
guidelines released in November 2013 require that export licences are
not issued prior to at least one IMP shipment being imported to the
country.
The Customs Union of Belarus, Kazakhstan and Russia
allows registered or marketed drug products and lab kits to be
transported between these three states without having to go through
customs procedures. This 'open border' can be advantageous in
provisioning and distributing intellectual property within the region.
Contracts
In
Belarus, sponsors may contract solely with the medical institution, or
with the hospital and PI together. Hospital administrators, of course,
prefer that the contracts are made with the institution alone so that
the facility can receive up to 90% of the grant. However, PIs are
naturally more motivated to conduct trials in which they have a
contracted stake. A best practice approach is to give sites and PIs the
opportunity to select the most suitable variant for them.
After
review by the site accounting, legal department and clinical teams – and
when agreement with the sponsor is reached – final contracts are
forwarded to the regulatory authority for approval. Site contracts are
not part of the regulatory submission package, but have to be approved
by the regulator.
The regulatory authority checks whether the
study budget covers all the site’s expenses, as well as ensuring that
all necessary legal provisions are reflected in the contract.
Contracting with sites can be a lengthy process, usually lasting two to
four weeks (depending on the site set-up), so it is advisable to begin
consultation with hospitals on the trial agreement ahead of receiving
MoH approval.
Study Implementation
Patient Recruitment
Clinical
trial sites in Belarus – the large, republic scientific centres –
maintain rich patient databases from which potential study participants
can be recruited. PIs in these facilities also have extensive referral
networks with local outpatient clinics and other consulting physicians,
adding to their ability to identify potential study candidates. This,
combined with patients’ eagerness to receive the latest treatments,
means that conditions are conducive for rapid enrolment. In fact,
efforts in Belarus can often make up for shortfalls in enrolment in
other countries when one general target is used for a multinational
study.
Data Quality
The technical code governing
trials, as issued by the MoH, is in accordance with GCP. All PIs and
site staff are trained in GCP, as required by law, and follow FDA and
EMA requirements. In addition, CETHS inspects sites annually, and the
MoH requests regular reports on study progress, results and safety
findings. These steps have helped ensure consistently high standards in
how trials are conducted.
Strategies for Success
To ensure the success of a clinical trial in Belarus, an organisation should:
- Tap
into the knowledge of local experts in guiding trial applications
through the approval process. It can be very beneficial to work with
resources 'on the ground' in Belarus to ensure timelines are met
- Seek
support from local staff that have experience in working with
regulators, in order to facilitate progress in gaining customs clearance
for imported products
- Rely on highly qualified staff, with medical doctors serving as CRAs and project managers whenever possible
- Train sites during investigator meetings and site evaluation visits
- Monitor sites, minimise travel costs and increase quality via local offices
- Develop
relationships (or work with partners that have them) with local
pharmacy depots to help furnish sites with the investigational drug in
the most efficient way
- Plan shipments of trial supplies carefully, given the absence of umbrella import licences
In
summary, Belarus is a very rewarding clinical trial environment for
sponsors, offering three principal benefits. There are relatively
expeditious trial approvals, thanks to an efficient regulatory structure
that conforms to the Declaration of Helsinki and ICH guidelines. Rapid
patient enrolment is aided by rich patient databases of moderntreatment-
naďve patients and extensive referral networks emanating from large,
scientific centres. Finally, trials produce high-quality results, owing
to well-equipped facilities and sophisticated, English-speaking
clinicians who are trained in GCP and FDA/EMA requirements.
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Dr Pavle Vukojevic is Vice President, Regulatory and Medical Affairs at Pharm-Olam International, and has been involved in clinical research for over 20 years. As the Regional Director of Operations, he was responsible for opening the company’s representative offices in multiple Central and Eastern European countries. Pavle is one of the founders of the Association of Clinical Research Professionals in Serbia, and was Chapter President until 2008. He has authored numerous articles about clinical trials in the region.
Dr Alexey Zarubov is the Clinical Operations Manager and Country Manager for the Belarus office of MB Quest, an affiliate of Pharm-Olam International. He has been with Pharm-Olam since 2004, and is integral to the substantial growth in the number of studies being run in the Belarus region. Alexey earned his doctorate in Paediatrics from Minsk State Medical Institute, and is extensively trained in paediatric gastroenterology, endoscopy and surgery.
Amira Al-Sendi is a Regulatory and Logistics Specialist for the Belarus office of MB Quest, an affiliate of Pharm-Olam International. She has more than seven years of experience in clinical trials, and has worked with Pharm-Olam since 2008. Amira has a degree in Economics from the Belarusian State Economic University.
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Dr Alexey Zarubov |
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Amira Al-Sendi |
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