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home > ict > winter 2015 > uncharted territory

PUBLICATIONS

International Clinical Trials Uncharted Territory
Belarus has much to offer life sciences companies as a location for clinical trials, especially as it is not generally top of mind among study planners and is not saturated with competing trials. The country, which neighbours Poland, Ukraine, Russia and the Baltic states, has a high percentage of patients who have not been exposed to state-of-the-art treatments. At the same time, it has the clinical infrastructure required to ensure patient safety, quality data and efficient operations. Its experience with clinical trials dates back to the creation of the national Center for Examinations and Tests in Health Service (CETHS) – part of the Ministry of Health (MoH) – in 1997. Currently, about 40 to 50 international Phase 2 to 4 trials are carried out in Belarus each year – far below what the population and conditions are capable of supporting. The country’s attractions for sponsor companies include: Strong patient enrolment rates, owing to a highly motivated patient population, three-quarters of which reside in urban centres (a ratio similar to that of France and Germany) A moderately large, modern-treatment-naïve population A large pool of enthusiastic, English-speaking physicians whose experience in clinical research is continually developing. There are 4.9 physicians per 1,000 patients (double the ratio of the US) Highly educated and well-trained medical staff who are versed in Good Clinical Practice (GCP) and compliant with the requirements of both the FDA and EMA An overall cost structure that is favourable compared to other regions Healthcare System Patients’ medical expenses in Belarus are covered by the government-funded National Health Service, although coverage for pharmaceuticals generally extends only to the lowest cost products – typically local generics. Patients opting for imported, branded products must pay out of pocket. This situation contributes to the high percentage of patients who have not been exposed to the latest pharmaceutical advances and are eager to have access to groundbreaking treatments. Care is provided in regional clinics and republic scientific centres in urban areas, as well as through outpatient clinics in rural areas. Rural patients are directed to urban centres for further consultation and treatment as necessary. In most cases, patients must be referred to specialists by a general practitioner following an examination and any necessary diagnostic tests. In addition, the country has a high number of private medical centres which are licensed by the MoH and provide laboratory testing and specialist consultations. These services are not covered by the government-funded healthcare programme. Clinical Infrastructure Belarus is particularly well-suited to trials in oncology, cardiology and rheumatology as the capital, Minsk, is home to large, republic scientific centres specialising in these areas. These centres are well-equipped, staffed with clinicians who are experienced in conducting trials, and maintain rich patient databases of potential study participants. Regional treatment facilities are located within a 300km radius of Minsk, so travel costs for clinical research associates (CRAs) to and from the city are not exorbitant. The country is not, however, conducive to running Phase 1 trials sponsored by multinational companies; there is little experience within the medical community, and the MoH and local ethics commitees (LECs) impose many restrictions. Physicians within Belarus are both highly educated and motivated to serve as principle investigators (PIs). They speak English at an intermediate or advanced level, are trained in GCP, and have experience in working with LECs. Cardiovascular diseases and cancer are the leading causes of mortality in Belarus. As of 2011, cardiovascular conditions accounted for 52% of the country’s mortality, and oncology made up 13.4%. Patients’ willingness to participate in clinical trials is generally very strong. They recognise that, through the process, they receive more intense medical attention than might otherwise be available. Trial participants have access to the latest treatment advances (rather than local generics) and benefit from additional examinations and tests under the constant supervision of the PI. Typically, in routine care, such experienced staff are not available to patients until after several consultations with specialists. Navigating Requirements Legislative and Regulatory Environment Within the MoH, the CETHS regulates pharmaceutical products, medical devices and medical equipment in Belarus, ensuring their safety, efficiency and quality. A division of CETHS, the Clinical and Pharmacological Laboratory (CPL), oversees clinical trials: evaluating applications and protocol amendments, supervising trials in progress, monitoring serious adverse events reporting, and approving drug import licences. The country’s trial regulations follow the principles of the Declaration of Helsinki and the ICH guidelines. Ethics Committees There is no central ethics committee in Belarus at present. Every hospital participating in clinical trials has an established LEC that is organised and operated in accordance with ICH guidelines and internal procedures. Typically, each LEC meets on an ad hoc basis and does not charge any fees for study review. All communication with the committee is done through the investigator and his study team. Submission Package The submission process for clinical trial approval in the country involves multiple handoffs between several different entities. In general, approvals are managed by the MoH through CETHS. Initial submissions are sent to CETHS and agreement for the conduct of expertise is issued on the day of submission. The fee ($2,400) must be paid before regulatory expertise starts. CETHS forwards the hard copy files of the submission package to CPL for primary expertise and, if CPL’s feedback is positive, to independent experts for specialised expertise. These parties have eight weeks to complete their review. The files examined by the experts are then discussed during meetings of the drug committee, which are held monthly. The drug committee issues an order with a list of approved studies. Based on this list, approval letters are prepared and sent to the Deputy Minister of Health for review and signature. It can take between one and three weeks for a letter to be signed. Steps to Approval Some steps can be completed in parallel – such as obtaining the MoH import/export licence and seeking European Commission (EC) approval – but, in essence, this is a sequential process, with regulatory authority approval needed before import/export licence and EC submission. When planned properly, the entire process can normally be completed in 14-18 weeks. If any questions are raised by regulators and/or the EC, this may cause a delay. In general, the set of documents needed for submission is standard and comparable to other European countries (protocol, investigator's brochure, draft of case report form, patient information leaflet and consent form). Among the specific requirements, an apostatised and notarised Letter of Delegation, TSE/BSE certifi cates where applicable, and local insurance policy are to be mentioned. The investigational medicinal product (IMP) quality documentation for application is comparable to EU-defined requirements for an IMP dossier. Most of these documents for all drugs to be used in the study must be translated into Russian. It is worth noting that when studies are also being conducted in Russia, the documents prepared for that country can simply be replicated for Belarus – avoiding the need for a fresh translation. Should a substantial amendment to protocol be needed – for example, changes to the number of trial sites or patients, study procedures or dosing – amendment submissions and approval is required. Approval of substantial protocol amendments can take between five and eight weeks. Import/Export Licences A separate import licence is required to import pharmaceutical products into Belarus; it can be sought only after the above trial approvals are secured. Import licences are only required for IMPs, and only Belarusian residential legal entities holding a special permit for the conduct of pharmaceutical or medical activities may apply for these licences. This limits the applicants for import licences to warehouse and depot companies. Applying for licences typically takes two weeks, and involves a fee of not more than $10 per licence. Lab kits and study materials may be imported without an import licence, and can be delivered via broker companies or shipping depots. Export licences are required for biosamples, are free of charge, and may be obtained by a CRO on behalf of healthcare institutions (investigative sites). These licences can be obtained in between 7 and 20 days. New guidelines released in November 2013 require that export licences are not issued prior to at least one IMP shipment being imported to the country. The Customs Union of Belarus, Kazakhstan and Russia allows registered or marketed drug products and lab kits to be transported between these three states without having to go through customs procedures. This 'open border' can be advantageous in provisioning and distributing intellectual property within the region. Contracts In Belarus, sponsors may contract solely with the medical institution, or with the hospital and PI together. Hospital administrators, of course, prefer that the contracts are made with the institution alone so that the facility can receive up to 90% of the grant. However, PIs are naturally more motivated to conduct trials in which they have a contracted stake. A best practice approach is to give sites and PIs the opportunity to select the most suitable variant for them. After review by the site accounting, legal department and clinical teams – and when agreement with the sponsor is reached – final contracts are forwarded to the regulatory authority for approval. Site contracts are not part of the regulatory submission package, but have to be approved by the regulator. The regulatory authority checks whether the study budget covers all the site’s expenses, as well as ensuring that all necessary legal provisions are reflected in the contract. Contracting with sites can be a lengthy process, usually lasting two to four weeks (depending on the site set-up), so it is advisable to begin consultation with hospitals on the trial agreement ahead of receiving MoH approval. Study Implementation Patient Recruitment Clinical trial sites in Belarus – the large, republic scientific centres – maintain rich patient databases from which potential study participants can be recruited. PIs in these facilities also have extensive referral networks with local outpatient clinics and other consulting physicians, adding to their ability to identify potential study candidates. This, combined with patients’ eagerness to receive the latest treatments, means that conditions are conducive for rapid enrolment. In fact, efforts in Belarus can often make up for shortfalls in enrolment in other countries when one general target is used for a multinational study. Data Quality The technical code governing trials, as issued by the MoH, is in accordance with GCP. All PIs and site staff are trained in GCP, as required by law, and follow FDA and EMA requirements. In addition, CETHS inspects sites annually, and the MoH requests regular reports on study progress, results and safety findings. These steps have helped ensure consistently high standards in how trials are conducted. Strategies for Success To ensure the success of a clinical trial in Belarus, an organisation should: Tap into the knowledge of local experts in guiding trial applications through the approval process. It can be very beneficial to work with resources 'on the ground' in Belarus to ensure timelines are met Seek support from local staff that have experience in working with regulators, in order to facilitate progress in gaining customs clearance for imported products Rely on highly qualified staff, with medical doctors serving as CRAs and project managers whenever possible Train sites during investigator meetings and site evaluation visits Monitor sites, minimise travel costs and increase quality via local offices Develop relationships (or work with partners that have them) with local pharmacy depots to help furnish sites with the investigational drug in the most efficient way Plan shipments of trial supplies carefully, given the absence of umbrella import licences In summary, Belarus is a very rewarding clinical trial environment for sponsors, offering three principal benefits. There are relatively expeditious trial approvals, thanks to an efficient regulatory structure that conforms to the Declaration of Helsinki and ICH guidelines. Rapid patient enrolment is aided by rich patient databases of moderntreatment- naïve patients and extensive referral networks emanating from large, scientific centres. Finally, trials produce high-quality results, owing to well-equipped facilities and sophisticated, English-speaking clinicians who are trained in GCP and FDA/EMA requirements.
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Uncharted Territory