Irina Petrova

Proper study budget is vital for a successful trial for both parties, contract research organizations (CRO) and pharma companies. Therefore, it is essential to take the time and prepare your financial plan by thoroughly thinking of all expenses.

So, what does a typical clinical trial budget consist of? First of all, the study budget can be broken into two main big parts: the cost of CRO services, and pass-through costs (PTC).

PTC, for their part, are all the expenses that are passed directly to the Sponsor at actual cost:

—grant fees paid to principal investigators and sites for the recruitment of patients; these costs often comprise the most significant part of the study budget;

—Central Labs, IDMC, depots, ePRO, and any other vendors, if they are subcontracted by the CRO;

—depending on the study design, purchase, and logistics of these might add up to quite a significant sum that should be planned for in advance.

—complexity of study procedures may require specific equipment not usually used at site in routine practice, so there might be a need to purchase it for the study. Sometimes it can be expensive to procure, deliver, and then at the end of the study, collect it from the site.

—keep in mind that travel costs may also form a substantial part of the budget, depending on the study design and needs (for example, frequency of on-site monitoring visits and site geography). Another important factor to be taken into consideration, especially when planning a multinational clinical study, are currency fluctuations that may influence the cost of travel, which is very hard to predict or plan for.

Logistics and courier costs, depot services

—these costs do not only depend on the study geography, but on the number of subjects (and, as a consequence—sites) as well. The larger the sample size is, the more medication and biosamples shipments, thus the more expensive the study is. And again, do not forget about currency fluctuations. So, it is imperative that logistics managers help plan the budget as precisely as possible.

Regulatory authorities’ fees and patients’ insurance

—make sure to include all local RA (as well as LECs—where applicable) fees and patients’ insurance that directly depends on the sample size and on the study phase and local country requirements.

—don’t forget about the licensing fees that can be both paid and free of charge. In certain cases, they can be accompanied by considerable costs.

—local specific requirements for taxes and bank commissions vary among countries. So, your partner CRO should be responsible for double-checking that.

Taking a deeper dive into the structure of the CRO service costs we will see the following:

—one of the highest in the overall structure of service fees, and it may account for the largest part of the clinical study budget. Amount of monitoring (including site initiation visits, interim monitoring visits, and closeout visits) will depend on both the sample size and Sponsor’s requirements towards SDV (Source Data Verification) percentage.

—in general, data management costs strongly depend on the number of patients and sites. Another powerful cost driver for the cost of these services, is the complexity of CRF (which, in turn, depends on the amount of study procedures) as well as the duration of the study.

—the cost of project management (PM) depends on study duration and complexity (including number of sites, countries and specific vendors involved). And even though there is no direct connection between the number of subjects and cost of PM, if the increased number of subjects requires involvement of additional sites or even countries—this of course will add to the project management cost.

—geography definitely has an impact on the cost of regulatory support services, as the duration of clinical trial approval and the CTA process itself varies (sometimes significantly) from country to country. Different countries and regions may have their own requirements for submission packages and sometimes it can be a challenge to put everything together. For instance, in Russia, the package is relatively easy to collect as it is similar to what EMA and FDA require, but all documents should be translated into Russian language, which takes time and some additional costs. In Ukraine, the package is also simple, as they EU CTA for initial submission and EU requirements (for example, submission of complete IMPD for IMP), but the Ministry of Health requires a lot of documents from investigators, not only principal investigators. Accreditation and certification of each medical institution involved in the trial have to be collected and reviewed for validity. Of course, collection of such packages takes more time and costs are higher with respect to the services. Meanwhile, there is no need in full translation of study core documents into Ukrainian.

—even though the cost of services connected with medical writing, and CTA package preparation are normally lower than other project costs, it is hard to overestimate the importance of biostatisticians’ and medical writers’ work - both experts’ decisions regarding study approval and the efficiency of the clinical trial depend directly on properly and expertly prepared study design.

—when we say “logistics” here, we are talking about CRO support in coordinating the import and shipments of investigational drugs, study supplies, concomitant or comparator medications, biosamples (while the cost of those shipments are pass-through costs, described above).

—quality assurance costs spent on maintenance of QA and QC systems, training and audit expenses, as well as PVG, even though highly important, usually comprise a smaller part of the overall study budget.

However, contingencies are hard to avoid in real life, therefore it is necessary to be ready to face the out-of-scope. So, how to find ways to effectively manage it? Indeed, with large-scale international studies, especially in the long term, it is almost impossible to map out study budgets with 100% precision. The majority of companies have all the responsibilities of project managers or those of other project-related specialists listed in their SOPs and project management plans. What is more, take a tip from insiders—if a project manager not only presents an issue of out-of-scope to Sponsor, but also comes up with a possible solution within the current study budget, it will be clear evidence of his professional competence and individual approach to clients. There might be some internal monetary resources if you look into the budget carefully. For example, depending on how the enrollment goes at each site, you can adjust monitoring frequency and extend the break between visits but make them longer. This is an opportunity to cut back on travel costs which, in case of big countries like Russia, might be quite significant. Besides, the CRO service cost for a two-day monitoring visit will be lower than two one-day visits, as the CRA will not have to spend additional time travelling to site. One more thing which can help avoid out-of-scope situations is an accurate and detailed budget grid. For example, the budget template of OCT Clinical CRO consists of over 400 items and covers all the tasks that will be done for a particular project, which provides maximum transparency and reduces the risks of hidden costs. Planning for the unexpected, such as costs associated with slow enrollment, protocol amendments, additional IMP imports and other contingencies—is, indeed, of paramount importance.

, MD, is the Director of Clinical Operations, 

Articles

It's almost impossible to map out study budgets with absolute precision. Planning for the unexpected costs, such as those associated with slow enrollment, protocol amendments, and other contingencies—is vital.

Key Cost Drivers in Clinical Research: Guide to Successful Budgeting

	The number of clinical studies conducted across the world has been demonstrating a steady growth. With an estimated value of $44 billion in 2019, the global clinical trials market is 

 to show a CAGR of 5.7% by the end of the year. For Russia specifically, which joined the World Health Organization (

) international drug control program in 1998, the nation has been actively involved in international clinical trials for about 20 years. While relatively young, the region has been demonstrating a lot of potential and increased significance over the past decade for sponsors looking for new clinical trial options.

Russian Ministry of Health Registry of the Approved Clinical Trials

of new clinical trials approved in Russia, more than 50% (385 trials) were initiated by non-local multinational pharmaceutical companies, with the share of multinational, multicenter trials having increased by 2.1% compared to the previous year. The list of companies with the highest number of trial approvals in 2018 is topped by Novartis and Roche (Switzerland). Pfizer (USA) made a leap from 15th place to 3rd/4th, sharing it with Janssen Pharmaceutica (Belgium). Next on the list are AbbVie Inc. (USA), AstraZeneca (UK), and Merck & Co. (USA).

	U.S. sponsors took the lead among the non-Russian companies, having secured approval for 108 trials in Russia in 2018. Meanwhile, European sponsors initiated 223 trials in the country last year, 73 of which were sponsored by the Swiss 

. While Phase III studies traditionally prevail in the overall list, most studies approved in 2018 will run in oncology (114 studies), rheumatology (10%), and neurology (less than 10%).

	“The ongoing trend has been taking shape over the past several years, showcasing the growing attractiveness of the area for international sponsors,” says Dmitry Sharov, president, OCT Clinical Trials, a CRO operating in Eastern Europe (the company started more than 30 new studies in 2018, including projects in oncology, gastroenterology, neurology, and ophthalmology). “Considering the obvious advantages of the Eastern European, Russian, and CIS regions, including a solid scientific platform, it is no surprise on how quickly this area has developed the necessary infrastructure and local expertise for running high-quality clinical trials. While the emergence of new firms is inevitable for any developing market, for the past several years we have been witnessing a consistent and necessary trend of tightening the regulatory requirements initiated by local lawmakers. These measures gradually even out the market landscape, form a solid quality platform and the proper code of clinical trials, which results in creating conditions where sponsors are willing to pay for quality.”

	Evaluating the structure of the Russian market, it is worth noting that Phase III studies prevail among the foreign-sponsored trials in 2018. Historically, these are not only the largest studies in terms of the number of patients recruited, but also the most costly and time-consuming. At the same time, Russian pharmaceutical companies led the way in number of bioequivalence projects initiated in 2018. Irina Petrova, OCT clinical operations director, attributed this to an import substitution trend, lowered drug prices for taxpayers, and an increase in the number of generics worldwide.

	The next step in Russia could be the development of innovative products for the global market, including stem cell therapies, opportunities made possible by the 2018 amendments to Russian legislation in this area. Last year, the government of the Russian Federation approved an action plan for the creation of new high-tech production sites and collective-use centers. According to the decree (No. 337-r), the number of medical organizations accredited to conduct clinical trials of biomedical cell products will increase from five in 2018 to 50 in 2020.

	Local opportunities to enhance global trials strategy

	There are several factors driving the attractiveness of Russia as a region for conducting clinical research. It is one of the leading countries in terms of population size and diversity (Russia is the world's ninth-largest country by population, with more than 146 million people). This points to an advantage of fast patient recruitment. According to 

analytical reports, Russia entered the top 10 and ranked second after the U.S. in terms of the number of patients included in clinical trials.

	Russia has a developed network of more than 1,600 R&D and specialized medical centers covering virtually all therapeutic areas. The territorial distribution of these centers covers most of the regions in the country, which also increases the accessibility and proximity to patients. Moreover, as a rule, doctor-patient relationships tend to be quite strong, thus securing good patient retention within sites.

	The scientific qualifications of researchers and experience of doctors in Russia allows them to conduct projects of any complexity. According to the UNESCO, Russian medical universities are among the best medical schools in the world. Moreover, inclusion of Russian specialists into the global context and international scientific dialogue and a good command of English by medical specialist are important prerequisites for successful sponsor-CRO-site communication.

	As for the technological infrastructure, the local clinical research industry fully corresponds to the advanced global levels. Both CROs and research centers in Russia have been successfully working with eClinical solutions (EDC, ePRO, etc.), including products and services to automate development processes, take advantage of cloud solutions, and access information on a project 24/7.

	Despite the high growth rate of the Russian pharmaceutical market in general and the development of state drug supply programs, modern/innovative drug therapy in areas such as cell therapy and orphan diseases remain unavailable for the majority of patients. Inclusion of the latest developments in international clinical research is sometimes the only way to get access to necessary and often expensive treatment. This reality spurs additional motivation for patients to participate in trials, as well as the ability to register participants in large regional hospitals due to the centralized Russian healthcare system.

	Another key factor that will determine the future of the Russian market is the establishment of a unified regulatory and economic environment for the circulation of medicines on the territory of the Eurasian Economic Union (

). The decision to create such a market was announced on May 6, 2017. The synergy effect from combining the potential of all the member states, as well as the lowering of non-tariff barriers in mutual trade, can stimulate a steadfast development of the industry. A key breakthrough opportunity for pharmaceutical companies and CROs is the option of unified electronic drug registration within the Union. This results in a full-fledged mechanism, when it is possible to run clinical trials in one of the member states and then apply for marketing authorization in any of the remaining participating countries through a simplified procedure.

Irina Petrova, Director of Clinical Operations for OCT Clinical Trials, explores why U.S. companies are turning to Russa after having secured approval for 108 trials there in 2018.

Irina Petrova

Articles

Key Cost Drivers in Clinical Research: Guide to Successful Budgeting

Why do U.S. Sponsors Come to Russia for Clinical Trials?