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International Clinical Trials
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Over the last decade, the number of clinical trials conducted in Russia
has grown steadily by more than 50%. The total number of trial approvals
climbed from about 500 in 2004, to 791 in 2013, with the high point
being 2012, when 915 approvals were issued (1).
Yet, for a
country with a population of around 140 million, the limit may be far
from being reached. According to Igor Kagramanyan, Deputy Minister of
Healthcare, currently only 10% to 15% of the country's potential for
conducting clinical trials is being realised (2).
The
statistical data indicate that, in terms of the sheer number of annually
issued approvals for trials, Russia is not that far behind its European
counterparts. For comparison purposes, in the EU, which has a total population of more than 508 million, some 4,400 clinical trials are applied for each year (3).
At
the same time, the country's trial market has been hit by a slowdown
since 2013, and approvals have dropped sharply, which some attribute in
part to new regulation. In addition, the total number of applications
for trials in the EU has dropped by 25% from 2007 to 2011 (4). Russia is
also having to contend with increasing competitiveness from other
emerging countries. So is further growth in Russia really achievable?
In
considering this, one has to remember that some 20 years ago, Russia's
clinical trial industry was virtually non-existent; its whole
infrastructure – including the regulatory framework – had to be
established from scratch. From the recent initiatives of the government
directed towards boosting investment for the healthcare and
pharmaceutical sectors, it is clear that Russia is committed to
improving its clinical trial climate and making conscious efforts to
become an attractive destination for innovative drug development.
The generally acknowledged advantages of conducting clinical trials in Russia are:
- The costs involved: the average cost per patient can be up to 1.5 times lower than in Western countries (5)
- An
easy to reach population which tends to reside in major urban areas,
plus the presence of large, centralised health institutions
- A relatively high number of treatment-naïve patients
- Committed relationships between patients and well-qualified physicians
These
benefits are not only directly cost-efficient; through facilitating the
enrolment process and diminishing the dropout, they offer more time
and, therefore, cost-saving benefits.
Language and Quality
When
some people consider Russia, they perceive the language barrier and the
quality of conducted trials as potential problem areas – but how
legitimate are these concerns?
While the older generation of
Russian medical doctors are less likely to speak English, the young
doctors – especially those located in major urban centres – tend to be
more proficient. This trend is only expected to increase in the years to
come. Furthermore, the growing army of local and global CROs operating
in the country appear to successfully address issues around both
language and quality.
The post-capture data correction rate is
comparable or lower than that in the Western world – this further
indicates the high level of efficiency and quality (6). Data from Good
Clinical Practice inspections does not identify any significant issues.
In fact, it demonstrates that the quality of conducted research is in no
way inferior – and is often superior – to the West (7).
In
addition, the presence of good clinical and quality standards in Russian
medical institutions helps ensure trials are conducted effectively.
Anthony N DeMaria, Editor-in-Chief of the Journal of the American College of Cardiology,
has dismissed what some see as concerns around quality. Following a
personal visit to the Moscow City Center of Interventional
Cardioangiology, he commented: “The implications of my Russian
experience were particularly impressive for clinical research. Given the
standard of care, one could be confi dent that medical practice would
not invalidate the extrapolation of the results to the rest of the
world. Patients in these centers are managed in a standard fashion
according to existing guidelines by knowledgeable and skilled physicians
using up-to-date pharmaceuticals, supplies and equipment” (8).
Federal Law
Clinical
trial regulations in Russia, however, may not stand up to scrutiny. The
federal law, 'On circulation of medicines', came into effect in April
2010 as a major regulatory step designed in part to help transform the
country into an attractive place for clinical R&D. But, while the
introduction of the new law was a tangible effort to establish improved
practices – for example, limiting the timeframe for reviewing
application documents and safeguarding the interest of patients – the
growth in trial approvals up to 2012 quickly turned into the slowdown of
2013.
Many analysts attribute this stagnation to the
shortcomings in the federal law. The Association of Clinical Trial
Organisations said: “As a result of the reforms, the Russian market for
clinical trials has significantly turned towards copy medicines” (9).
While
the intention of the regulation was to enhance the growth of
international trials, the actual number of approvals issued in Russia in
2013 fell sharply to 2006 levels – a decrease of 9.5%. The data from
the first half of 2014 does not look optimistic either, showing a drop
of nearly 15% in the number of international multi-centre trial
approvals, compared to the same period in 2013 (10).
Import Provisions
Certain
provisions of the federal law proved to be more of a hindrance than a
help, and have had to be revised. For example, there was an obvious
omission in the legislation regarding the import of already registered
medicinal products for trials. The lack of regulation here resulted in
the situation where, from October 2010, the country's Ministry of
Healthcare and Social Development refused to issue related import
permits.
Furthermore, the Ministry of Industry and Trade turned
away those sponsors that did not hold a pharmaceutical licence to the
registered study drug. It took eight months – and many unnecessary trial
delays and cancellations – before new amendments were made to the law
that finally addressed this problem, allowing the Ministry of Healthcare
and Social Development to deal with import of both unregistered and
registered medicinal products for clinical trials.
Local Registration Studies
Article
38(1) of the federal law explicitly prohibits the conduct of Phase 1
trials for establishing the safety and/or tolerance on healthy
volunteers in a situation where investigational medicinal product is
manufactured outside the Russian Federation. Another highly
controversial regulation (Articles 14, 18, 21 and 27) requires the
conduct of so-called local registration studies on the territory of the
Russian Federation prior to the registration procedure, unless Russia
has originally been included among the participating countries of the
respective international multi-centre trial.
This requirement to
repeat safety and efficacy trials is widely criticised within Russia
itself, mostly from an ethical standpoint, and subsequently for its
inconsistency with the principles of the Declaration of Helsinki, which
sets out ethical principles for medical research involving human
subjects.
The fact that the Russian population is genetically no
different from that of other European countries makes it difficult to
justify the exposure of patients to unnecessary risks during the conduct
of confirmatory trials that have already been successfully carried out
elsewhere. The same can be said for the lack or delay in drug
availability for those patients who stand to benefit from them.
In
March 2012, the Federal Antimonopoly Service of the Russian Federation
came forward with proposed amendments to the federal law, 'On
circulation of medicines'. Among others, it called for the requirement
to conduct local registration studies to be made redundant by way of
recognising the results of international clinical trials (11).
Long-Awaited Changes
Some
steps have already been taken. New amendments to the federal law,
published by the Ministry of Health, were approved in November 2014 by
the Russian Parliament. The changes introduce new terminology for
innovative and biogeneric drugs. Most importantly, the law now defines
the status of orphan drugs and allows for their accelerated registration
procedure.
The first three generic drugs of an original medicine
which has not been previously registered in the Russian Federation as
generic – with the exception of biogenerics – as well as drugs that are
intended exclusively for paediatric practice, are also eligible to
benefit from accelerated registration (12). Referring to orphan drugs,
Elena Maksimkina, the Director of the Department for the Provision of
Medical Products, commented: "These products will benefit from
significant preferential treatment, which means the requirement to
conduct local clinical trials for this category of drugs will be
dropped" (13).
There are also plans to legalise, by the end of
2015, a fast-track registration procedure for immune-biologic agents and
vaccines developed for the treatment of infectious diseases caused by
newly emerged microorganisms (14).
However, many critics remain
sceptical and frustrated in a situation where long-awaited changes like
these come too slowly. Svetlana Zavidova from the Federal Antimonopoly
Service of the Russian Federation was disappointed with the insuffi
cient response from the Ministry of Health, pointing out that even
though the recent amendments make an exception for orphan medicines, for
the rest of the drug candidates this requirement still remains in
force. “No doubt, sooner or later the regulatory authorities will revise
this requirement. The question is, how long will it take and how many
patients will have to suffer the consequences of this delay?" (15).
Policy Direction
Russia
has many natural advantages to further explore its clinical trial
potential; it is for the country's legislator to address those issues
which might impede its full utilisation. Deliberate policy directed
towards international harmonisation of trial regulations, easing the
administrative burden, introducing more transparency in study data, and
accelerating the registration process for drugs addressing conditions
with unmet medical needs are all expected to become benefi cial for
sponsors and patients alike.
Furthermore, in view of the new EU
Clinical Trial Regulation – due to come into effect in 2016 with the aim
of addressing the very issues mentioned above – it would be to Russia's
advantage to timely align its regulations with wider global trends.
This would help share the gain from introducing and promoting measures
to enhance clinical trial development.
References
1. Visit: www.grls.rosminzdrav.ru and www.roszdravnadzor.ru
2. Visit: www.rosminzdrav.ru/news/2013/12/19/1676-intervyuzamestitelya-ministra-igorya-kagramanyana-rossiyskoy-gazete
3. Visit: http://ec.europa.eu/health/files/clinicaltrials/2012_07/proposal/2012_07_proposal_en.pdf
4. Visit: http://ec.europa.eu/health/files/clinicaltrials/2012_07/proposal/2012_07_proposal_en.pdf
5. Medidata PICAS database. Visit: www.samedanltd.com/magazine/13/issue/201/article/3577
6. Medidata Insights database. Visit: www.samedanltd.com/magazine/13/issue/201/article/35777. Visit: www.fda.gov
8. Visit: http://content.onlinejacc.org/article.aspx?articleid=1478373&resultclick=1
9. Visit: http://acto-russia.org/files/ACTO_Newsletter_8.pdf
10. Visit: http://acto-russia.org/files/ACTO_Newsletter_9.pdf
11. Visit: http://fas.gov.ru/legislative-acts/legislative-acts_50891.html
12. Visit: www.rosminzdrav.ru/news/2014/12/23/2183-vneseny-izmeneniya-v-federalnyy-zakon-ob-obraschenii-lekarstvennyh-sredstv12
13.
Visit:
www.rosminzdrav.ru/news/2014/02/27/1740-rukovoditelidepartamentov-minzdrava-rossii-prinyali-uchastie-v-kruglomstole-posvyaschennom-probleme-orfannyh-zabolevaniy
14.
Visit:
www.rosminzdrav.ru/news/2014/05/16/1835-veronikaskvortsova-prinyala-uchastie-v-zasedanii-prezidiuma-soveta-priprezidente-rossiyskoy-federatsii-po-modernizatsii-ekonomiki-iinnovatsionnomu-razvitiyu-rossii
15. Visit: http://fas.gov.ru/fas-in-press/fas-in-press_38143.html
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