Clinical Study Startup Timelines in Central and Eastern Europe

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1 Vol. 11, No. 10, October 2015 Happy Trials to You Clinical Study Startup Timelines in Central and Eastern Europe By Vlad Bogin The complexity of regulatory approval pathways and time to first-site initiation play a significant role in deciding which countries to include in an international clinical trial. As these parameters change from time to time, this article gives an update on current timelines and the existing or emerging requirements that a sponsor faces in the following Central and Eastern European (CEE) countries: Belarus Czech Republic* Georgia Hungary* Lithuania* Poland* Romania* Russia Ukraine * Countries in the European Union, in which national legislation has been harmonized with EU Directive 2001/20/EC. No licenses are required for imports between EU countries. The following CEE countries are not covered in this article: Albania, Bulgaria, Croatia, Latvia, Estonia, Slovakia and Slovenia. The timelines cited in this article are typical, i.e., average, based on small sample sizes, so actual results might differ. Acronyms: CEC CTA IMP LEC MoH RA Central or national ethics committee Clinical trial agreement Investigational medicinal product Local ethics committee Ministry of Health Regulatory authority

2 Belarus: Tied for Sixth-Fastest Start-Up Timeline Belarus timelines would be faster if the RA did not have to approve CTAs, which takes about a month. While national legislation permits CTAs with sites but not investigators, CTAs can be submitted for review by the RA only after it has approved the study. There is no central or national ethics committee. LEC reviews take only two to three weeks, on average. 2

3 Czech Republic: Fifth-Fastest Start-Up Timeline The CEC reviews all aspects of the study, except for investigator s qualifications and site suitability, while LECs review only investigator qualifications and site suitability. Study approval requires a favorable opinion only from the CEC. The RA website lists multicentric ECs that can play the CEC role. RA and CEC reviews are separate and usually in parallel. The study dossier submitted to the CEC must include CTAs, but they can be drafts that can be further negotiated during the CEC and LEC reviews, so this requirement does not cause any delays. 3

4 Days Weeks Months week 1 week 2 week 3 week 4 week 5 week 6 week 7 week 8 week 9 week 10 week 11 week 12 week 13 week 14 week 15 week 16 week 17 week 18 week 19 week 20 week 21 week 22 week 23 week 24 week 25 Georgia: Fastest Start-Up Timeline INDIVIDUAL STAGES Translation of docs and submission dossier preparation Review & approval by RA Review & approval by CEC Review & approval by LECs Negotiating & signing CTAs Obtaining import/export licenses; import & distribution of IMP SUMMARY From submission until study approval From submission until first site initiation From start of work until first site initiation There is no central or national ethics committee. In contrast to many other countries, review and approval by LECs precedes submission of study-related documents to the RA. RA approval serves as the import and export licenses. 4

5 Hungary: Second-Fastest Start-Up Timeline The RA typically completes its review of studies about two weeks before expiration of the Directive-defined 60-day review period. Review by the CEC runs in parallel and normally finishes sooner than the RA review. LECs do not play a role in the study approval process, and only oversee the trials at the appropriate sites. 5

6 Lithuania: Tied for Sixth-Fastest Start-Up Timeline The duration of the RA s study dossier review often exceeds the 60 days specified by EU Directive 2001/20/EC. In addition to the RA review, the State Data Protection Inspectorate (SDPI) is tasked with ensuring a high level of personal data protection and privacy. Per legislation, SDPI approval should also be issued within 60 days after submission. However, the submission package must include copies of RA and CEC approvals, meaning that SDPI review cannot start until after RA and CEC reviews. In practice, however, the SDPI accepts a guarantee letter that RA and CEC approvals will be provided later, so SDPI approval is usually received about two weeks after RA and CEC approvals. LECs are not involved in reviewing and approving studies. The CEC approves and then forwards the approved application and all accompanying documentation to the appropriate LECs. The two other Baltic states, Estonia and Latvia, while too small to justify a full page in this article, have shorter approval timelines than that of Lithuania because there is no SDPI review. Estonia has the third-fastest startup timeline (3.7 months). Latvia has the fourth fastest (3.9 months). 6

7 Poland: Tied for Slowest Start-Up Timeline RA review of the submitted dossier officially begins only after the RA has checked the study dossier for completeness and accepted it. Total actual time from submission to approval in Poland is thus longer than in the neighboring CEE countries, despite the 60-day timeline specified by EU Directive 2001/20/EC. Dossiers must include executed CTAs with sites and investigators, so these documents must be signed before submission (i.e., not during RA review or after study approval, as in most other CEE countries). However, this requirement is less onerous than it seems because the dossier can be submitted with only the CTAs with the leading site and investigator ( National Study Coordinator ). During the review period, no additional documents can be submitted to the RA unless directly requested, but the submission can be amended with the other CTAs after the RA has approved the study. The LEC of the National Study Coordinator serves as the CEC. The CEC asks the LECs of the other sites to review the documentation and provide their opinion on appropriate investigators and sites for the study. However, since the LECs need to respond within 14 days, this process is usually just a formality, so review by the LECs does not affect the study approval timelines. 7

8 Romania: Tied for Ninth-Fastest Start-Up Timeline All site contracts (not just the National Study Coordinator agreement, as in Poland) need to be signed before submission to the EC (which is usually done in parallel with the RA submission). This is the major limiting factor, which might cause unpredictable delays. It is thus important to obtain quick CTA signatures for study start-up in Romania. Further cause for delay is the fact that contrary to the European Clinical Trials Directive 2001/20/EC of 4 April 2001 the national legislation requires the study approval to be explicit and in writing, while the 60-day legal timeframe is often not respected due to the accumulated backlog of studies to review. Taking this into account, the submission to the RA can be done before submission to the EC (for the RA to have more time for study dossier review while CTAs are yet negotiated and signed to prepare submission to the EC). However, the RA will not issue the study approval without the EC s favorable opinion in any case. On the positive side, the situation is expected to improve with some expected legislative changes next year. 8

9 Russia: Tied for Slowest Start-Up Timeline The RA forwards the submission package to the CEC for an independent review. In most cases, site LECs will not approve or even accept documents for review until the RA has approved a study. CTAs with sites generally cannot be signed without RA study approval, but they can be negotiated and readied for signature during the RA review. To receive marketing approval for a medicinal product in Russia, the product must be tested locally as part of an international registration trial. So, if local patients have not already participated in a pivotal trial, the RA requires repeating a late stage trial in Russia. 9

10 Ukraine: Eighth-Fastest Start-Up Timeline The RA consists of two entities: the Ministry of Health (MoH) and the State Expert Center (SEC), which is within the MoH. Duration of the SEC review can vary significantly, from eight to 12 weeks. The MoH then requires an additional two to three weeks for its review. LECs then require three to four weeks for their reviews. After MoH approval of the study, the study sponsor must apply for a study drug importation license. After receiving this license, an importation permit for each study drug shipment is also required. It has been reported recently that the MoH is planning to do away with these import requirements for study drugs. 10

11 Conclusions Typical study startup timelines in CEE countries vary from three to five-and-one-half months, much faster than in other emerging clinical research markets, such as China, India and countries of Latin America. In addition, timelines have become shorter in recent years, and this trend should continue, since most CEE countries recognize the economic, educational and reputational advantages of hosting clinical trials, albeit not at the cost of risking the health of their citizens. Study Startup Timelines in Selected CEE Countries (Months) Author Vlad Bogin, MD, FACP, is Founder and CEO of Cromos Pharma. Contact him at or 11