In addition to speed and cost savings, Russia offers quality clinical data that is high enough to withstand FDA and EMA inspections, with both agencies approving drugs using data collected from Russian sites. [© Radu Razvan_Fotolia.com]
More than two years after Vladimir Putin promised to transform his nation into a biotech heavyweight by 2020, Russia is achieving a measure of success by one important barometer, namely a steadily growing volume of clinical trial activity.
That was supposed to be the effect of a 2010 law that requires companies looking to market their drugs in Russia to conduct at least some of their clinical trials there. That measure (“On Circulation of Medicines”), however, has drawn criticism from the industry group Association of Clinical Trial Organizations (ACTO) for slowing down clinical trial activity through what it calls overly strict requirements for patient insurance, investigators, and redundant accreditation requirements for conductors of trials. The law is under review by Russia’s health commissioner, Veronika Skvortsova, appointed to the post in May.
Instead, executives familiar with the market say the uptick in clinical trials reflects more a combination of lower costs, lower regulatory hurdles, and increased public and private investment in drug companies that carry out development work in Russia.
On October 10, U.S.-based Cleveland BioLabs and Incuron, a joint venture that is 75.8% owned by the publicly traded company, announced the dosing of the first patient in a Phase I study of the oral formulation of CBL0137 in subjects with advanced solid tumors that resist standard-of-care treatment. The trial is being conducted at five leading oncology centers across the Russian Federation. Incuron is also conducting Phase I trials for the orally administered small cancer drug CBL0102, which is being developed for orphan indications in developing markets.
The percentage of Incuron not owned by Cleveland BioLabs is held by the $120 million Russian closed mutual venture fund Bioprocess Capital Ventures, which focuses investment on what it deems innovative pharmaceutical, biotechnology, and fine chemistry projects across the Russian Federation.
“You need to define when you start—and my definition is, you start with formal preclinical. And in the United States, if you start with this and you’re pretty lucky, you’re talking about 10 years, maybe more to develop a drug. In Russia, it looks like you can ramp it up in five,” Michael Fonstein, Ph.D., president of Cleveland BioLabs, told GEN.
Ease of Recruiting
One reason for the shorter timeframe, according to Dr. Fonstein, is quicker clinical trials resulting from the ease of recruiting patients beyond Phase I, the tendency of patients once enrolled to stay on the trials, and the design of trials, which can require smaller Phase III trials of products shown to be effective earlier in clinical practice.
“If, after clinical practice, you already know the optimal conditions for your drug, and clinical practice is supposed to tell you this, then basically you can do a Phase III trial on a very small number of patients, if you can show strong effect,” Dr. Fonstein said. “What we’re trying to do is to go to a full drug development cycle in Russia, not just do a fast Phase I trial and license it to somebody and forget, but go from science to clinical practice, and we believe it can be done substantially faster, and substantially cheaper than in the United States.”
How much cheaper? Less than $100 million, compared with the oft-quoted estimate of $1 billion or more in the U.S., for getting drugs into clinical practice under Russian auspices.
According to ACTO, the average period to issue approval to conduct a clinical trial during the first half of 2012 was 118 days —12 days better than a year earlier, but still about two months longer than the period set by law of 41 business days or 57 calendar days.
In the first half of this year, according to the quarterly Clinical Trials in Russia “Orange Paper” issued by Synergy Research Group (SynRG), Russia’s Ministry of Health approved 477 new clinical trials, compared with 571 in all of last year and 492 in 2010.
During the second quarter, according to SynRG, 257 trials were approved, a 44% jump from 178 in Q2 2011. Nearly half the trials approved in Q2 2012 (107 or 42%) were bioequivalence trials, while almost as many (102 or 40%) were multinational multicenter clinical trials; the remainder (48 or 19%) were local clinical trials.
Speed, Quality, and Cost
Anna Ravdel, SynRG’s director of business development, told GEN that Russia enjoys three strengths as a clinical trials venue: speed, quality, and cost.
Patients flock to trials, she said, in order to gain access to the best physicians and medication as well as due to shortcomings of the state healthcare system ranging from limited government reimbursement for medication to the fact the insurance and governmental medical systems do not cover all patients and diseases.
The quality of clinical data is high enough to withstand FDA and EMA inspections, with both agencies approving drugs using data collected from Russian sites—13 EMA approvals and an FDA approval during Q2 alone. While Russian drug companies accounted for a plurality of approved clinical trials during the second quarter (115), five global biopharma giants—Roche, Pfizer, AstraZeneca, GlaxoSmithKline, and Teva —were approved for a combined 31 studies totaling 3,916 patients, according to SynRG.
“We recommend to our clients to include Russia early into their clinical trial program if they have plans in the future to register the drug in Russia, because otherwise, without any patients from Russia, the registrators in the Ministry of Health may require the sponsor to conduct another study in Russia, even though the entire program has been completed,” Leon Dzivinsky, senior vp and general counsel for ClinStar, a provider of clinical development services in Russia and Eastern Europe, told GEN.
Dzivinsky, whose company is involved at any point in 40 to 50 clinical studies, said Russian clinical trials enjoy faster patient recruitment timeframes—in one instance, saving 17 months or $15 million for one Phase III trial of an advanced breast cancer drug. ClinStar needed just 24 months to recruit 318 patients in Russia, Estonia, Ukraine, and Belarus, vs. 41 months for 542 patients in 18 other nations (none being the U.S).
Patients recruited for clinical studies in Russia don’t turn over as often as elsewhere: “Whatever the doctor tells the patient, they tend to follow. They treat the doctor as a top authority. And if they start with a particular doctor in an indication, they tend to stick with that doctor throughout the term of their treatment,” Dzivinsky said.
“Circulation” Draws Fire
Since the early 1990s, clinical trial activity has grown most years and especially since 2005, dipping only in 2010 following the clinical trial law called “On Circulation of Medicines.” It transferred authority within the government to the Ministry of Health; set new rules qualifying sites and investigators; and added requirements for sponsors, such as providing life and health insurance for each patient. ACTO argues the law shrunk the market for active investigators by 25%−35% and favors a two-year trial experience minimum, plus a shift to liability insurance for entities organizing and conducting clinical trials.
A pair of initiatives announced in recent months aims to keep clinical trial activity humming in Russia. Last month, Maxwell Biotech Venture Fund, founded with participation from the Russian government’s Russian Venture Company (RVC) fund of venture funds, approved an undisclosed investment in privately held Osteros Biomedica. Osteros is preparing a proof-of-concept clinical trial program to test the safety and efficacy of its first drug candidate, MBC-11, against multiple myeloma.
And in March, Russia’s $10 billion state-owned Rusnano technology fund said it would join the U.S. venture capital firm Domain Associates in investing $760 million into U.S. pharmaceutical, diagnostics, and medical device companies, plus creating a manufacturing plant and increasing drug development in Russia.
One challenge Russia must overcome in coming years is growing competition for drug trials outside the U.S. or Europe, especially from Russia’s fellow-BRIC nations (Brazil, India, and, especially, China), which like Korea have sought to position themselves as lower-cost clinical venues. In addition, Russia’s regulators will have to continue progress toward faster decisions on clinical trials, especially now that FDA has signaled through PDUFA V that it will step up the pace of its reviews of trial data and drug applications.