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International Clinical Trials

Developing Locations

As more biotechnology companies look to CEE for clinical trials, Natalie G Harris and Anthony Southers of Ockham explore risk-mitigation strategies and the benefits of local knowledge

Recent pharmaceutical and biotechnology industry reports indicate that R&D spending in Canada, Europe, Australia and the US increased by two per cent to $22.8bn, after tumbling by 21 per cent during the downturn in 2009 (1,2). This finding, coupled with the rising cost of drug development, has led many biotech companies to look towards central and eastern Europe (CEE), Russia and Ukraine as a solution to their clinical trial needs and the increased competition for investigational sites in the established European Union (EU) member states.

However, given the fact that many of these biotech companies can be ‘virtual’ in nature, geographically removed from the region and may have relatively little or no experience of running trials within these regions, there may be a number of pitfalls to avoid during clinical trial execution. This article reviews some of the practical steps available to ensure an effective and successful clinical trial, defined as meeting trial timelines, quality metrics and budget.

During the development lifecycle of any product, a critical decision concerns the sponsor’s need to involve additional countries to meet their clinical development goals. More often than not the reason for requiring additional countries is to meet patient recruitment goals for larger clinical trials or challenging populations, or to ensure that partnering or out-licensing is initiated when required in the business pipeline. The question as to which countries to involve for the best return on clinical trial investment is difficult to answer.

Virtual biotech companies often have few employees with hands-on clinical research experience in a particular locality, and without global affiliate offices biotech companies often have to rely on their chosen partners in assessing the benefits and risks of each country. They also often lack a contingency budget if problems occur in the trial, placing more pressure on sponsors to get the site distribution strategy right first time.

Over the last 15 years, sponsors have increasingly turned to the emerging markets in Brazil, Russia, India and China (BRIC) to fulfi l patient recruitment accrual ahead of time and, more recently, significant growth in clinical trial activity has also been seen in CEE (3).

The benefi ts of these countries has long been cited: large patient populations; established healthcare infrastructures; and experienced research professionals motivated to work on scientifically-advanced therapies for their patients. Yet, for many sponsors considering these countries, achieving patient enrolment goals at critical points in the product development cycle would involve geographically distant sites that are unfamiliar, unlike the US or western Europe. It is important to understand these factors and how the risks may be mitigated by knowledge, planning and sound clinical project management practice.

INVESTIGATOR EXPERIENCE

Of the factors that determine site and country selection the most critical is patient recruitment, followed by the availability of sites that have the experience and technical infrastructure to perform the trial. Access to sites that can perform reliable assessment of trial feasibility and patient recruitment for the study is key to deciding if a country will contribute significantly to the trial and whether the sites will be able to manage the protocol-required assessments.

Exercising due diligence with a full feasibility study in which potential investigators are provided with all details regarding the trial under a confi dentiality agreement (CDA) is the gold standard. Therefore, however this is time consuming and labour intensive, and may still result in uncertainty about the estimated metrics. How can dependable data be obtained from sites without requiring a full feasibility assessment, especially for complex protocols such as oncology?

One option for biotechnology companies is to partner CROs or individuals with experience in the target countries and in the therapeutic area of the protocol. CROs with an established therapeutic-area focus, such as oncology, rely on a network of investigators in the proposed countries to provide quick feedback on oncology protocols. The information can be sent out ‘blinded to the protocol specifics and sponsor name’ and so bypass the CDA process. This method is efficient, quick, inexpensive and enables investigators to provide feedback on the sponsor’s concerns rather than reviewing full and detailed documents. A quick snapshot emerges, which can be reinforced by in-house experience and knowledge gained from sites of proven reliability.

This process can be taken one step further. Again, CROs with therapeutic experience (in oncology, for example) can facilitate introductions to biotechnology companies with selected key opinion leaders in oncology, facilitating ongoing relationships for future trials, future products and protocol concepts. These activities can provide the sponsor with an early indication of whether the protocol will be acceptable in each country, and the availability of sites and investigators. It allows assessment of the standard of care for the disease in question, reliable estimates for patient recruitment numbers, assessment of the technical infrastructure at sites and assessment of the experience of the proposed investigators before full-disclosure feasibility and on-site assessment. Consequently, sponsors can focus selection on countries garnering the most promising feedback without investing a of a significant proportion of the trial budget early on.

REGULATORY, ETHICS & DRUG IMPORT TIMELINES

Once country selection no longer involves the European Economic Area (EEA) where compliance with regulatory timelines is based on established guidelines supplementing a harmonised EU Directive (2001/20/EEC), the actual time needed to start a trial in a particular country is hard to estimate. Many of the CEE countries not part of the EEA have sought membership, and in a number of cases regulating authorities have started adapting in-country systems to mirror the current process in the EEA. For example, Ukraine has a well-developed regulating system for clinical trials which closely follows the European Union Drug Regulating Authorities Clinical Trials (EudraCT). Timelines, however, can still be viewed as a ‘best case’ (usually quoted as 60 days) and ‘worst case’ scenarios (as long as 180 days). Obtaining approval in 60 rather than 180 days for sites in countries where a high recruitment rate is assured will have a positive impact on patient accrual numbers. However, how long it will take to obtain approval cannot be determined and introduces uncertainty into study management plans. Figure 2, for example, illustrates timeline variability for the approval of clinical trials by the Russian Regulatory Authorities from2005 to 2009, as monitored and published by the Association of Clinical Trial Organisations in Russia (4).

Sponsors are anxious to know how a CRO can reduce risk during the approval process. The fi rst and probably most important step is attaining local knowledge: finding a regulatory representative who not only knows the local system but is also willing to maintain a close working relationship with the sponsor, ensuring good communication between all parties at all stages of the process. This allows the regulatory professional to assist the committees in their review of the protocol and other accompanying submission documents (such as the investigator brochure and the investigational medicinal product dossier) while keeping the sponsor informed on the approval progress. Failure to meet with a particular committee or scientific advisor appointed by the authority may delay approval, so it is critical that the appointed regulatory representative monitors each step of the process and provides the submission dossier in a timely manner, thereby minimising delays for both regulatory and ethics approvals.

The second step is to ensure the quality of documents accompanying the submission and maintaining central regulatory oversight of the clinical trial application (CTA) filings. It is important to ensure that the local regulatory representative has a thorough understanding of the respective regulatory authorities requirements for an efficient and timely approval of a submission. The regulatory representative must be able to review and appraise core regulatory and ethics documents prior to submission and provide early feedback on areas requiring further detail, translation or additional supporting documents. Examples include the need for compliance with GMP, labelling regulations for the clinical trial packaging, and any country-specific technicalities such as registration of the proposed investigational site with the ethics committee. All of these will affect timelines if they are not addressed sooner rather than later.

The local representative should be able to coordinate with the overall regulatory professional appointed by the sponsor or CRO to ensure consistency of submissions between other countries involved in the trial. Most importantly any communication from the regulatory or ethics authorities should fi rstly be discussed and approved by the sponsor before the local representative responds to the authorities. This is critical where requests for further information involve novel biologics, oncology products or products with an atypical risk/benefit.

Similar risk mitigation strategies can be used for drug importation to countries outside the EU. In Russia and Ukraine, a separate drug import license is required and this can be applied for shortly after regulatory approval. By partnering with an experienced drug distribution vendor in these countries, different options for drug importation can be discussed early on in the project planning phase. The drug distribution vendor will work with customs clearance brokers who are experienced and familiar with the requirements for importation of trial supplies and who can provide sound advice on avoiding potential problems with shipments, such as wastage through customs confi scation or searches at the point of entry.

ENSURING QUALITY

Once sites are initiated and start enrolling patients, data quality becomes an important issue. In recent years countries such as Russia have revised their regulatory procedures to bring timelines more in line with EU member states and also to enshrine quality safeguards in legislation, such as a minimum requirement for principal investigator experience (5). However, during the trial, quality concerns can primarily arise from indications that trial conduct is not being properly managed. Any such concerns will require investigation and intervention to ensure that issues do not become significant or lead to concerns about quality, such as unverifiable eligibility of patients enrolled, enrolment of ineligible patients and a backlog of data entry into the case report form.

In the planning phases of a trial, utilisation of electronic data capture systems (EDCs), interactive web/voice response systems (IVRS/IWRS) and clinical trial management systems (CTMS) can provide sponsors with real-time access to trial data. The systems can provide key metrics regarding conduct during the trial as well as information on trial management status both at site and monitoring level, which are invaluable tools for remote management (6).

In the conduct of the trial, other key assets to site management and quality are clinical research associates (CRAs) who will perform site monitoring. Selection of a partner CRO that can provide professional CRAs can make a significant improvement in quality and reassure the sponsor that a capable team is managing remote sites. Ideally, CRAs should be highly experienced in the trial therapeutic area, have a thorough working knowledge of the healthcare system in which their sites operate, be able to work collaboratively and take ownership of data quality. However, locating CRAs of this caliber can often be a challenge. Partnership with a niche CRO often gives virtual sponsors a better opportunity to approve prospective team members in advance and engage in direct communication with members of the CRA team. This can be hugely beneficial to a sponsor for inculcating a team approach between sponsor and CRO.

CONCLUSION

When a company sponsors a trial in a region such as CEE without a presence in the region, there is little that the sponsor can do to manage concerns or to mitigate risks on a day-to-day basis. Geographical distance, language and time zone differences provide little opportunity to be ‘hands-on’ either at a country level with regulatory submissions or at site level when the trial is underway. The idea of relinquishing control to a partner CRO and so losing the ability to manage reactively and practically can leave sponsors feeling anxious about the nature and cost effectiveness of the work ‘on the ground’. Fortunately there are many risk-mitigation strategies for the planning phases of the trial, for dealing with issues as they arise and for delivering oversight, but the most effective is alignment with a partner having experience and capability in the territory, functioning as an extension of the trial sponsor’s team.

References

  1. Ernst & Young, Global Biotechnology Report, June 2011
  2. Evaluate Pharma, World Preview 2016, 2011
  3. PriceWaterhouseCoopers, Clinical Trials in Poland – Key Challenges, 2010
  4. Association of Clinical Trial Organisations – Timelines Monitoring 2005-2009
  5. Russian Federation Law: No 61: Chapter 7, Clinical Trials of Medicinal Products for Medical use, Clinical Trial Contract, Rights of Patients Involved in Trials (articles 38-44)
  6. Levaux and Janovitz, Late Phase Studies Benefi t from EDC, Applied Clinical Trials, 2008

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Natalie G Harris is European Clinical Operations and Global Project Director at Ockham. She is responsible for Ockham’s European clinical operations and oversees Ockham’s European project management activities. After gaining a degree in Biomedical Science, she undertook drug development and clinical research training at PDD. Natalie then moved to ICON where she progressed into the position of Global Project Director and has an extensive knowledge of setting up and running global trials within Europe, the US, Latin America and Asia Pacific. Email: nharris@ockham.com

Anthony Southers is European Managing Director at Ockham. He is currently responsible for Ockham’s European contract clinical and functional service provider operations with full profi t and loss responsibility. Following his degree in Biochemistry, Anthony took initial positions at SmithKline French and Glaxo Group Research where he undertook his drug development training, before moving into the newly emerging CRO industry where he has remained over the past 19 years. Holding executive operational and business development positions at Innovex, Covance and most recently ICON, Anthony has worked extensively within Europe, but has also spent time in both the US and Asia. Email: tsouthers@ockham.com

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