Smooth Drug Development continues the cycle of publications devoted to bringing more transparency to the field of clinical trials in Russia and Eastern Europe and presents an overview of critical articles, which bring more confusion than help in understating the perspective of outsourcing clinical trials to Eastern Europe.

There are no more visible walls between what we still conveniently call the “East” and the “West.” The end of the twentieth century marked a new wave of globalization, which presumably had to leave no half-words between the two imagined geographical entities. However, theory rarely works well in practice. An observer can notice a tremendous asymmetry of information presented in two hemispheres, as if the heavy iron curtain was replaced with a nylon one, a light substitution, which transcends, but deflects information. Unfortunately, the topic of clinical trials is not an exception to this rule. While some Russian sources tend to interpret high interest of western companies to certain advancements of the Russian pharmaceutical market as covert operations (e.g. collection of DNA for Pentagon, non-acceptance of western money for development of national vaccines, etc.), English language publications often depict Russia as a space of profound underdevelopment, which deeply offends the Russian medical community. It is striking, but our surveys reveal that neither Russian, nor western professionals of the pharmaceutical industry share ideas of such publications, but one cannot disregard that the myth-spreading articles maintain dominance on the Internet.

Clinical Trials in Russia in Comparative Perspective

It is hardly surprising, but clinical trials in Russia are no different from the European or American ones. The Russian national standard of clinical trials is a direct translation of ICH GCP and differs only in the spheres where the international standards intersect with particular regional regulations. Russia has been one of the most popular destinations for clinical trials outsourcing in the last couple of years. Russia attracted not only hundreds of western trials, but also many FDA inspections.

This chart is composed on the basis of the results of 113 FDA inspections in Russia, 138 FDA inspections in Germany, 110 FDA inspections in France, and 129 FDA inspections in Great Britain. This data is all that is available in the FDA databases. We excluded inspection parameters that didn’t find any issues in the countries from the chart. Unfortunately, it is complicated to make a comparison with the United States because FDA conducted thousands of inspections in its homeland and a fair comparison will demand a separate methodology.

As one can observe, the FDA inspections of Russian research sites demonstrate better results than those of the leading European countries. Russia has the highest number of sites with no deficiencies. Russian research sites demonstrate high adherence to the ethical standards, providing adequate ICFs and appropriate payments to volunteers. Clinical research in Russian sites also demonstrates high accuracy of records and strict adherence to investigational plans. Why? The answer is plainly simple: Russia is still considered a newbie in the clinical trials market, so the only way to obtain success is to try to be the best. Smooth Drug Development is also a part of this and that is why we are so concerned with ISO certifications of all major activities, constant training of our staff, development of e-solutions (e-PRO, CTMS, etc), and the advancement of clinical trials in Russia to the highest international standards.

The strive to become respected equally to the western colleagues does not exclude premises of many potential problems, which are embedded in the Russian clinical trials market. For example, there is significant drug-naïve population, research infrastructure is less developed than in the United States, and it is necessary to work with proven vendors to get better results. Significant difference in local currency rate and current economic decline make trials cost-effective, but patients are becoming more vulnerable and this aspect should be monitored by Sponsors and CRO companies. Doctors and medical staff are very well educated, but low paid, which is usually a positive stimulation for hard working on clinical trials, but also rises chances of unethical behaviors to hold onto the high-paying positon. Smooth Drug Development has its own means of managing those risks, minimizing them to the default level. However, risk aversion is a topic of interest to the professionals of pharmaceutical industry and is often ignored by outside observers.

A Story of Russian Clinical Medievalism

If one googles “negative experience of clinical trials in Russia” or a similar request, the browser will offer to read a report by the Swiss NGO Bern Declaration. This non-profit organisation strives to protect rights of poor populations of the world and it paid attention to the question of clinical trials in Russia, Argentina, India, and Ukraine. The report under review accurately identifies potential risk of clinical trials conduct in Russia but disregards the institutions that were erected to prevent them. The noble intention to protect the rights of Russian citizens and provide careful analysis of potential problems of clinical trials in Russia wrecked into misunderstanding of local regulations and clinical trials in general.

The first section of the report asks the question if Russia and the European Union have the same standards. However, it does not address the issues of legislation. Instead, it attempts to prove “a well-known peculiarity of the Russian system [which] is that direct contact between patients and ethics committees is not allowed” (Russia: The Mirage of Swiss Clinical Trials, p.4). Driving from this statement, the authors propose a theory about greedy investigators, who do not allow patients to contact Ethic Committees and hold them in trials in order to keep the grants. The authors conclude this “well-known” fact from the “Analytical report – cooperation with Russia in the field of clinical trials,” a brilliant paper on specificities of clinical trials in Russia, compiled by the European Commission. However, this analytical report does not provide such a misleading information and correctly states:

"Direct contacts of an applicant with the Ethics Council or the Expert Organization are not allowed. This is different in EU where a dialogue between applicant and drug regulatory authorities and Ethics Committees is considered to be beneficial. Recommendation : In order to quickly resolve e.g. questions of the Ethics Council concerning provisions in the study protocol, direct contacts with the applicant should be possible." (Analytical report – cooperation with Russia in the field of clinical trials, p.42)

This passage illustrates that the authors of the Bern report did not understand the meaning of the term “applicant,” confused a Sponsor/CRO with a patient/subject and Ethic Committee with Ethic Council. Although clinical trials are a very complex subject for people outside of the industry, the authors should have noticed that the EU report states that “for the conduct and supervision of clinical trials in the EU and the RF equivalence of the respective regulatory/legislative framework provisions are given” (Analytical report – cooperation with Russia in the field of clinical trials, p.8). Russian regulation of clinical trials is a direct translation of ICH GCP, and the differences of the EU and Russian legislations are in minor legal acts that intertwine with other state activities. The Russian normative clinical trial environment is the same as in the EU or the USA and alleged investigators’ unethical activities, described by the authors of the report, would result in a prosecution.

As it was mentioned above, clinical trials are a complex topic for outside observers and such mistakes are common. However, this misleading information might have been abandoned if the authors would addressed clinical trial materials and noticed that all ICFs include address, name of the chairman, phone of a Local Ethical Committee (LEC): it is required by the Russian law. In the cases of mistrust to a LEC, subjects are recommended to direct their requests to various supervisory authorities such as the Federal Service for Surveillance in Healthcare, the Federal Service for Supervision of Consumer Rights Protection and Human Welfare, Federal Compulsory Medical Insurance Fund, and other institutions that intertwine with clinical trials in Russia.

The authors of the Bern report continue to criticize ethical aspects of clinical trials in Russia, arguing that LECs are powerless and all decisions are made in the higher state agencies. Unfortunately, it is yet another mistake. According to the Russian law each study must be approved by an Ethical Committee, which has control over the trial. After the 2010 reform, Central Ethic Council of the Ministry of Health functions were limited to evaluation of the trial applications and certain amendments to protocols. The other functions were transferred to LECs, which became responsible for approval of ICFs and other required documents. LECs have a right to pause or stop a trial without the sanction of the Central Ethic Council (CEC). Hence, the authors’ assessment that LECs are paralyzed due to the lack of power and rigid bureaucracy of the CEC is not willing to intervene into unethical trials is hardly convincing. The CEC bureaucracy is normally engaged only at the stage of approval and ethical control over the trial is guided by LECs.

In their picture of clinical trials in Russia, the Bern report experts portray investigators as greedy and poor doctors who have financial motives and a conflict of interest when recruiting patients. According to the report, they keep retention by misleading and frightening patients or even falsifying data. The report exemplifies these assumptions with two stories: first, a story of Novartis’s investigator in Gilenya trial from St. Petersburg, who attracted naïve (in an emotional sense) patients into trials, advertising “trial” as a “free observation programme” and a second story about an investigator from Oufa, who frightened patients that they would never be enrolled into clinical trials again if they quit, and etc.[i] However, it was indeed an observation program, conducted in accordance with legal norms. The authors were writing with a premise that all clinical studies are interventional and a term “observation program” is just demagogic attempt to conceal the nature of the project.

We are inclined to think that investigators are usually respected doctors, whose success in clinical trials heavily relies on their reputation. Why should they risk their careers and freedom (in case of serious offences) when the demand for participation in trials is higher than the number of available spots? For example, according to the articles, published in the result of Gilenya studies, and internet forums, there were lines of people who wanted to participate in the trial and get the opportunity to use the medication for free before it will be commercialized in Russia.

There are so many other things to comment. The authors suggest that investigators at sites use “urine of laboratory assistants.” They also use statements such as “some patients explained to us that they chose to participate in a Swiss drug trial because of the government policy of imposing low quality, or even ‘mortally dangerous’ medicines (known as ‘generics’ or ‘analogs bio’)” and make many more unreasonable claims about clinical trials in Russia, which show the Russian clinical trials industry in a bad light.

Those who conducted clinical trials in Russia know that doctors in the post-Soviet area are people highly devoted to their craft. This profession does not promise a lot of money and a decision to spend at least six years in medical college, experience years of de-facto volunteer internship, and in many other cases spend another several years in grad school could only be made by people loyal to the Hippocratic Oath. It is very insolent to hear that someone assumes that investigators, who are very often professors, can run around the center collecting urine of their assistants to fraud the results of the trial. Unfortunately, the report that initially aimed at illuminating a very important issue of rights and real motivations of people trapped in medical needs turned into a blundering verdict to the entire Russian clinical trial environment.

A Vexing Case of Clinical Trials in Russia or Predestined Analysis?

Smooth Drug Development hopes that the authors of the report did not try to produce “fake news,” were motivated by endeavors to protect rights of Russian citizens and decided to act vigorously because of the intention to stop alleged injustices. One should admit that if the misinterpreted statements were correct, the problem with ethics could be legitimately considered a disaster. The authors did their analysis, talked to people, collected facts, and cherry picked the cases and phrases in a way that portrays clinical trials in Russia similar to the medieval inquisition. It seems that the authors had a certain image of Russia, which they attempted to prove in their report.

Russia shares the same problems as the rest of the world and tries to overcome them. None of the addressed issues is absent in the practice of clinical trials in the western hemisphere (the SFBC Miami test center, TGN 1412, and etc.), but fortunately reasonable information overcomes attempts to tarnish the entire markets in the countries. However, Smooth Drug Development entirely supports the initiative for disclosing unpleasant facts and discussion of clinical trials failures. We will dedicate our next article to the analysis of problems associated with outsourcing clinical trials to Russia.

Instead of an Epilogue

Smooth Drug Development will be happy to help the Bern Declaration experts to revise the report, which can be useful for people looking for medical assistance, pharmaceutical industry professionals, and other readers interested in clinical trials in Russia.

[i] Unfortunately, the authors do not make references to a detailed clinical trial information. Hence, we are making an assumption about the nature of the study basing on open sources. The authors refer to a Gilenya trial by Novartis of 2012 as an example of multiple violations. They call it a “trial,” concealed as “observation programme.” According to the State Register of Medicines, Novartis registered Gilenya on 17.08.2010 and had all legal and ethical premises to start an observation program in 2011, which included provision of the drug to patients until it would be accessible in Russia. We examined various patients’ forums, which prove that Novartis conducted an observational study in 2011. Also, there is a paper published in the result of the Gilenya observational program, which continued until 2014. It seems that Novartis indeed held an observational study of Gilenya.







