Clinical Trials in RussiaGrowing Experience and Revision of Regulations

Dmitry Reihart1 and Pyotr Platonov2

1 Department of Pharmaceutical Activities, Provision of Human Welfare, Science and Education, Ministry of Healthcare and Social Development, Moscow, Russian Federation

2 Department of Cardiology, Lund University Hospital, Lund, Sweden

Abstract Clinical trials of pharmaceuticals have been running in Russia for more than ten years and while it is anattractive location for research, it remains a largely untapped resource as researchers look to expand patientrecruitment outside the Western world.

While academic sites like Moscow, St Petersburg and Novosibirsk have all gained experience in clinicaltrials, smaller hospitals in peripheral sites have also participated. During 2004, more than 40 000 patients wererecruited and more than 500 clinical trials were initiated in Russia. Nine of 14 US Food and Drug Administrationinspections performed in the country since 1994 went without findings and no inspection required officialfollow-up action from the agency, indicating that high-quality data can be obtained from Russia.

While the recruitment and quality in clinical trials meet very high standards in Eastern European countries,the lack of information on local rules and regulations is still a factor which limits this under-used region.Executive power reforms launched in Russia in 2004 have affected clinical trial performance and brought thelegislation into accord with international guidelines. State regulation and supervision of clinical trials is underthe jurisdiction of the Federal Service for Control in Healthcare and Social Development, which itself is a partof the Ministry of Health. Two levels of ethical review are present in Russia, the National Ethics Committee(NEC) and the local ethics committees that exist at the majority of investigative sites. Approval at all levels isrequired before launching a clinical trial.

Among other developments, revised regulations have introduced a 30-day period within which the NEC hasto give its opinion on a trial, putting a limit to the time allowed for clinical trial approval. Recent changes inlegislation have made the process of clinical trial approval better defined and more transparent, thus, contributingto a decrease in the administrative burden. Economic development in Russia, while not fast enough, has leadto improvements in living standards and has helped eliminate some of the ethical concerns. We now await thefuture to see to what degree the potential of Russia to undertake clinical trials is realised.

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US investigational new drug (IND) clinical trials have beenrunning in Russia for more than ten years, and while it is anattractive location for research, it remains largely untapped asresearchers look to expand patient recruitment outside the West-ern world. Several recent publications have highlighted the highquality of data collected in Eastern Europe.[1-3] A recent analysisof factors that could affect data quality showed high recruitmentrates in these countries were associated with a lower query gen-eration rate.[4] It was a correlation that confirms the saying ‘prac-tice makes perfect’. Having established clinical trial routines anda continuous patient flow at an investigative site helps to keep theerror rate to a minimum.

While the recruitment and quality in clinical trials meet very

high standards in Eastern European countries, the lack of infor-mation on local rules and regulations is still a factor which limitsthis under-used region. Russia has been an active player in Eu-ropean clinical trials since the early 1990s. It is a large countrywith a population of over 140 million. Russia remains outside theEuropean Union (EU) and therefore is unaffected by the recentlyimplemented EU Clinical Trial Directive. This simplifies the per-formance of clinical trials in Russia while keeping the processwithin the International Conference on Harmonisation (ICH)Good Clinical Practice (GCP) framework. The aim of this paperis to give an overview of the Russian experience in clinical trialsand the regulatory environment. Russian regulations and impor-tation/exportation requirements have been addressed in several

publications in recent years.[5,6] In March 2004, executive powerreforms initiated by the Russian president Vladimir Putin, alongwith further developments in Russian legislation, have affectedclinical trial performance and prompted us to review them here.

1. Legal Framework

Clinical trials in Russia are regulated by the Drug Law of1998 (Russian Federal Law on Pharmaceutical Products, no. 86-FZ, 22 June 1998) along with several revisions to the act that wereaimed at bringing the legislation into accord with internationalguidelines (i.e. the ICH GCP guidelines). The law provides alegal framework within which detailed regulations have been is-sued. Among those, the Rules of Clinical Practice, which havethe status of a state standard, came into operation in June 2003.The rules incorporate ICH GCP guidelines into Russian legisla-tion and introduce several stricter requirements including an un-conditional ban on clinical research performed on orphans, pris-oners and servicemen who are undertaking their obligatorymilitary service.

The approval and supervision of clinical trials is under thejurisdiction of the Federal Service for Control in Healthcare andSocial Development, which itself is a part of the Russian Ministryof Health. The Federal Service maintains free Web-access to allprovisions and regulations related to clinical trials (these areavailable at http://www.regmed.ru); however, currently the reg-ulations are only available in the Russian language and no officialtranslation exists. The authors have recently published a detailedreview of the regulatory environment in Russia;[7] however, thisreview focuses on the most important regulatory issues concern-ing clinical trials.

2. Ethical Expertise

Two levels of ethical review exist in Russia, the NationalEthics Committee (NEC) and local ethical committees at in-vestigative sites.

Like the recently introduced concept of ‘single opinion’ inethics review in the EU, Russia has been working with a central(‘national’) ethical committee since the mid-1990s. Submissionsto the NEC and centralised ethical expertise have always beenparts of clinical trial application in Russia. Details of the compo-sition, functions and responsibilities of the NEC have recentlybeen laid down in new provisions on membership and operatingprocedures.[8] According to the current legislation, the essentialdocuments required for NEC review are the Investigational DrugBrochure, Patient Information Sheet and Informed ConsentForm, along with evidence of the professional experience of in-vestigators and the investigative sites, and health insurance of

study subjects. The new regulations lay down a 30-day periodwithin which the NEC has to express its opinion on the submittedclinical trial documentation.

Local ethical committees (LEC) operate on the site-level andreview documentation on trials in their respective medical insti-tutions. It is not a regulatory requirement to have a LEC on sitebut rather a legal opportunity to have an additional institutionalsafeguard for patients participating in the clinical trials. If a LECexists at the investigative site, the researchers may not undertakea clinical trial without the approval of the LEC even if approvalhas already been obtained on the federal level. However, not allinvestigative sites have a LEC on site; sites without LEC workdirectly under the NEC on the federal level.

3. Clinical Trial Approval Scheme

Clinical trial approval in Russia has always required approv-als from both the Drug Agency and the NEC. Submission of theclinical trial application to both agencies should be done in par-allel. Clinical trial approval is explicit, which means that a trialcan not be started without written authorisation from the DrugAgency. The favourable opinion of the NEC and a positive expertopinion regarding the preclinical studies are the obligatory con-ditions for approval of clinical trial.

According to the recently introduced regulations, the NECis obliged to give its opinion within 30 days of the submission ofa trial application. No such deadline exists for regulatory reviewbut the internal regulations of the Drug Agency state that a deci-sion should be made within 15 days of receiving a favourableopinion from the NEC. This brings the total evaluation time to 6weeks from submission of documents to the receipt of the clinicaltrial approval. The timeframe for a LEC decision on an applica-tion package varies dramatically depending on the size of themedical institution and number of ongoing/planned clinical tri-als; however, a decision from an on-site LEC takes, on average,2–4 weeks.

In general, submission packages include a number of docu-ments that need to be translated into the Russian language beforesubmission. One has to keep in mind the time required for thetranslation of study protocols, informed consent forms, patientinformation sheets and certain chapters of investigational drugbrochures where preclinical experience and earlier human studiesare described.

4. Russian Investigators in Clinical Trials

Nowadays, it is uncommon to find a large multinational clin-ical drug trial performed without the participation of Russianinvestigators. Russian scientists and investigators are considered

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© 2005 Adis Data Information BV. All rights reserved. Int J Pharm Med 2005; 19 (2)

an important resource both at the preclinical and clinical stage ofdrug development because they have access to the academic in-frastructure preserved from the Soviet times. A number of hospi-tals spread across Russia participate in research programmessponsored by the US National Institutes of Health.

This explains the growing attention of the US Food and DrugAdministration (FDA) to the investigative sites overseas. FDAinspections in Eastern Europe have so far shown high-qualitydata and not revealed any major violation of GCP.[1] Accordingto the Clinical Investigator Inspection List maintained by theFDA,[9] 14 FDA inspections were performed in the country be-tween 1994 and 2004. Not only the large cities of Moscow andSt Petersburg were subject to inspection, but also Arkhangelsk inNorth-West Russia and Tomsk in Siberia. Cardiologists, oncolo-gists, endocrinologists and neurologists are on the list of in-spected investigators. Half of all inspections were performed dur-ing the period 2003–2004, which indicates a clear trend towardsan exponential increase in the FDA’s activities in the region. Nineof the 14 inspections (64%) went without findings, i.e. coded byFDA as ‘no action indicated’. None of inspections performedrequired official follow-up actions by the FDA (i.e. no ‘officialaction indicated’ code was assigned).[9] These inspections go along way to dispel the myths about the poor quality of data fromthe region.

While academic sites in Moscow, St Petersburg andNovosibirsk have all gained experience in clinical trials, smallerhospitals in peripheral cities have also participated.[10] Accordingto a Russian Ministry of Health report,[11] 252 approvals formulticentred clinical trials involving the participation of Russianinvestigators were issued during the year 2004 (figure 1). Under-standably, the majority of all trials were phase III trials (66% for2004). At the same time, 23% were phase II trials and 2% were

‘first in humans’ phase I trials (figure 2); the remaining 9% werephase IV trials. The complete list of approved clinical trials ispublicly available at the Russian Ministry of Health website.[12]

Altogether 40 900 patients were enrolled in drug trials in Russiain 2004, of which the vast majority (28 900) were included in themultinational trials (figure 3).

5. Areas of Uncertainty

While the high level of study recruitment and good qualityof data collected in Russia are well established, it is necessary tolook behind these. Scientists and physicians have not only beendriven by academic interest but also national pride. Financialcompensation for participation in clinical trials is also dis-proportionately large in comparison to the regular salary of Russianphysicians, and this is an important motivating factor. Thoughthis is not the only incentive, the financial inducement may posea certain risk for conflict of interest that can not be underesti-mated.

Another issue of ethical concern common to clinical trialsconducted in countries with poorly developed health insuranceprogrammes is the continuation of ‘standard’ background therapyafter the discontinuation of the clinical trial. Some drugs consid-ered standard therapy may be unavailable to patients due to pro-hibitive costs. In this regard, there has been a substantial improve-ment in Russia over the past ten years as a number of commonlyused medications have come off patent, thus, leading to a drasticreduction in treatment costs for patients taking those drugs.

300

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252

Bioequivalencetrials

104

Clinical trials inRussia only (domestic

and internationalmanufacturers)

167

Fig. 1. Number of regulatory clinical trial approvals during 2004 in Russia(from a total of 523).

Phase I(2%)

Phase IV(9%)

Phase II(23%)

Phase III(66%)

Fig. 2. Multinational trials with participation of Russian investigators by thephase of clinical drug development in 2004. This is from a total of 252approved multinational trials that recruited 28 900 participants.

Clinical Trials in Russia 75

© 2005 Adis Data Information BV. All rights reserved. Int J Pharm Med 2005; 19 (2)

However, many new and expensive medications are still beyondreach for the majority of Russians.

6. Future Developments

Recent changes in the Russian legislation relating to the reg-ulation of clinical trials have clearly make the whole process ofclinical trial approval better defined and more transparent. Allthese changes contribute to a decrease in the administrative bur-den and can, potentially, lead to a further increase in the numberof clinical trials taking place in Russia and number of patientsrecruited into these trials. Economic development in Russia,while not fast enough, has lead to improvements in living stand-ards and has helped to eliminate some of the ethical concerns.

Russia still holds a great deal of untapped potential for under-taking clinical trials because of its history of scientific traditions,educated and experienced investigators capable of producinghigh-quality data and large patient population allowing fast re-

cruitment for a broad spectrum of indications. The future willshow to what degree this potential is realised.

Acknowledgements

No funding was used to assist in the preparation of this article.Potential conflict of interests: Pyotr Platonov does scientific consulting

for Evidence Clinical & Pharmaceutical Research.

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ropean perspective. Appl Clin Trials 2004; 13: 60-62. Motteram PAS, Richardson A. Clinical trials in CEE: harnessing the potential.

Appl Clin Trials 2004; 13: 44-593. Senakevich N, Tassignon J-P. Speeding the critical path. Appl Clin Trials 2004;

13: 42-84. Platonov PG, Escandon R, Varshavsky S. Recruitment rates and data quality: are

they linked to each other? Appl Clin Trials 2003; 12: 32-45. Varchavsky S, Ravdel A, Platonov P, et al. Handling clinical trial materials in

Russia. Pharm Manufacturing Packing Sourcer 2003 Autumn: 82-66. Varshavsky S. Clinical trials in Russia and Eastern Europe. World Pharm Dev

2001; 2: 797. Reikhart D, Platonov P. Clinical trial approval in Russia. Regul Affairs J Pharma

2004 Dec: 871-28. Russian Ministry of Health Order #57, 2004 Aug 29. US Food and Drug Administration. Investigational human drugs: clinical investi-

gator inspection list (CLIIL) [online]. Available at URL: http://www.fda.gov/cder/regulatory/investigators/ [Accessed 2004 Dec 16]

10. Platonov P. Clinical trials in Russia and Eastern Europe: recruitment and quality.Int J Clin Pharmacol Ther 2003; 41 (7): 277-80

11. Federal Service for Control in Healthcare and Social Development [in Russian].Letter #02I-66/05 [online]. Available at URL: http://www.regmed.ru/Downloads.asp?.idDownload = 2765 [Accessed 2005 Jun 15]

12. Federal Service for Control in Healthcare and Social Development. On clinicaltrials of pharmaceuticals [in Russian]. Letter #01I-79/05 [online].Available atURL: http://www.regmed.ru/Downloads.asp?.idDownload = 2769 [Accessed2005 Jun 15]

Correspondence and offprints: Dr Pyotr Platonov, Department of Cardiology,Lund University Hospital, 85 Lund, SE-221, Sweden.E-mail: pyotr.platonov@med.lu.se

30 000

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25 000

20 000

15 000

10 000

5 000

Num

ber

of p

atie

nts

Multinational trialswith participationof Russian sites

28 900

Bioequivalencetrials

1800

Clinical trials inRussia only (domestic

and internationalmanufacturers)

10 200

Fig. 3. Number of patients recruited in clinical trials in Russia during 2004.

76 Reihart & Platonov

© 2005 Adis Data Information BV. All rights reserved. Int J Pharm Med 2005; 19 (2)