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GLOBAL ONCOLOGY CRO Your goal is to give people a better quality of life. We’re proud to be a part of your mission. Global Oncology Trials: Planning For Success This paper explores several of the upfront areas critical to the success of global oncology trials, including study planning, conducting feasibility and navigating regulatory submissions. A Novella Clinical White Paper Moving Potential. Forward. Oncology Clinical GlobalTrial Oncology Operations CRO Global Oncology Trials: Planning For Success Global Oncology Trials: Planning For Success Many pharmaceutical, biotechnology and medical device companies have adopted globalization as a business model for their clinical trials. This model is especially pertinent within oncology with the number of competing trials consistently rising while patient access across North America and Western Europe has plateaued. Globalization has enabled access to appropriate patient populations, which is particularly important given the pipeline for oncology far out numbers that of other priority disease areas as designated by the World Health Organization (WHO), surpassing 500 products.i While this geographic diversity of oncology trial sites has potential to open future markets, it also adds logistical hurdles ranging from import and export licenses to regulatory approval to variances in standard of care. Strategic, detailed planning between a sponsor and a clinical research organization (CRO) that maps out each study step, especially for the first ... geographic diversity of oncology trial sites has potential to open future markets, it also adds logistical hurdles ranging from import and export licenses to regulatory approval to variances in standard of care. six months or year, can turn cross-border barriers into collaborative checkpoints along a global cancer trial’s journey to completion. When a sponsor works with an experienced international oncology CRO, such as Novella Clinical, to develop a comprehensive set of study plans and step-by-step processes, regional issues are proactively addressed before the first patient is even enrolled. On-the-ground knowledge, acquired via an oncology CRO’s daily experience working with local regulatory agencies, local labs, logistic experts, study sites and investigators, is critical to a global cancer trial’s success. This paper explores several of the upfront areas critical to the success of global oncology trials, including study planning, conducting feasibility and navigating regulatory submissions. 2 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success The World is My Trial Site The clinical trial landscape has never been more vast and it’s still expanding. Nearly 28,000 principal investigators participated in clinical trials globally during 2012, according to the Tufts Center for the Study of Drug Development.ii The United States is a location for less than half of the more than 145,076 trials registered on Clinicaltrials.gov.iii Of note, clinical trials in China, India and Eastern Europe conducted by Food and Drug Administration (FDA)-regulated investigators have steadily increased in the last decade, particularly for confirmatory, later stage clinical trials, Tufts reports. When narrowed to trials focused on cancer, the scope and scale of clinical research remains striking. Clinicaltrials.gov lists 38,520 cancer trials, of which 22,723 have a U.S. location and 9,396, European locations, yet Africa (513) and Central America (456) also are active as cancer trials sites.iv This geographic diversity speaks to the robust oncology research community’s shared goal of developing new standards of care for patients with cancer, getting those treatments to patients sooner and to industry’s need to decrease costs in the face of increased competition for appropriate patient populations. Yet, the conduct of such research can be as varied as the many forms of cancer, especially when a trial spans borders. This paper explores the critical activities to be undertaken during the first six to 12 months of a trial. Such actions will result in well-run studies yielding the best possible data to determine if a candidate therapy should come to market and become a part of standard oncology care. Developing Comprehensive Operational Study Plans A clinical trial protocol and study plans are the foundations by which the research goal can be realized. The trial protocol explains the study rationale, the number and criteria of eligible participants, the procedures and medications required, and an associated schedule of assessments.v In contrast, the study plans specify how the trial’s operational aspects unfold for all involved parties, from the sponsor and CRO, to central laboratories and vendors, and in some cases to investigational sites. Having comprehensive study plans on a trial will ensure all team members, globally, understand their function and how to address unforeseen issues that may arise. A set of strategic, detailed clinical study plans that accounts and assigns responsibilities for the regulation and operationalization of each task is essential. The overarching goal of study plans, particularly for a large global trial, are to ensure every person involved consistently follows the same instructions and procedures so the resulting data are valid for analyses and regulatory submissions, regardless of whether the patients are in India or Ireland. Plans are also the basis for staff training, measurement of trial progress and quality, and a path for issue escalation when trial or site issues occur. 3 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Organizing to Prioritize Study plans often are organized by functional area such as regulatory, clinical monitoring and data management, even though many plans will overlap functional activities. For example, clinical monitoring and data management plans both include data cleaning responsibilities. The best practice is to prioritize plan completion in alignment with clinical trial process. Plans that Study Planning affect study start-up, such as regulatory plans, should be completed first — before addressing plans that impact a trial’s readout phase, such as the statistical analysis plan. Study plans clearly define the expectations sponsors and CROs share about the trial’s performance at the functional and operational levels. To that end, plans should always include: All plans should address requirements such as staffing, • Project Management & Communication training, documentation and compliance. For example, • Vendor Management does the plan describe the responsibility for and is • Clinical Monitoring adequate time allocated to create electronic data • Regulatory Document Management capture or interactive voice response systems when • Safety Management different native languages are involved? Or as an- • Data Management other example, does the plan address global varia- • Statistical Analysis tions in imaging methods and account for differences in radiologist training? This is certainly crucial to any global oncology trial that looks at target lesions, responses, and progression as part of its major endpoints, especially in light of recent trends to leverage surrogate endpoints in lieu of overall survival for registration. A comprehensive plan will drive prioritization and allocation of resources, either directly from the sponsor or via a CRO or other vendors. Ideally, a sponsor and a CRO would agree and sign off on all parts of a study plan — functions, resources, timing, sites — before a study begins. Other plans that may be very useful to have for a trial include: • Medical Monitoring • Unblinded Clinical Monitoring • Integrated Data Review • Patient Transfer • Randomization & Unblinding • Clinical Unblinding • Risk Management • Cohort Management • Patient Recruitment By documenting operational procedures, the study Project-specific work practices may also benefit from plans and include: plans act as a guide for anyone involved, providing • Filing clarity on how the study is conducted. Having com- • Site Activation prehensive study plans on a trial will ensure all team • ICF/CTA Reconciliation members, globally, understand their function and • EDC Training how to address unforeseen issues that may arise. They may even be provided to auditors seeking information on how various issues were handled. 4 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Robust Feasibility: Standards, Sites and Care Performing clinical trial feasibility is one of the initial and most important steps in conducting a global clinical trial. Feasibility can help determine the best mix of countries and sites, each of which have their own challenges that could influence the completion of a study.vi A robust feasibility ensures a realistic assessment of the capability of each region, country, and potential trial site to conduct the trial and will ultimately influence study site selection. Feasibility must also address provision of the standard of care for trial participants, where the trial stands in the overall competitive landscape, and the ability to obtain and distribute the medicines or devices involved in the study. Evaluating National Standards Because standards of care, comparator medicines access, and diagnostic testing capabilities — among other trial components — will vary from nation to nation, all late-phase protocols should be evaluated for regional- and country-specific feasibility. Depending on the trial size and indication, a CRO well versed in conducting feasibility can assist a sponsor in providing large-scale feasibility or a more targeted effort. Large-scale feasibility is appropriate for oncology studies anticipated to run in more than 10 countries and more than 100 sites in relatively common indications, such as non-small cell lung cancer or prostate cancer. This approach is typically a site survey coupled with regional key opinion leader feedback, which yields country-level input as well as global feasibility for the trial. Conversely, targeted feasibility may be appropriate for smaller scale studies in relatively rare indications, such as leiomyosarcoma or gastric cancer, or with an unusually complex investigational product. This approach favors one-on-one physician communication to gauge site-specific interest and challenges, as these issues can be magnified in a smaller trial. Regardless of the approach, the questions being asked are critical to the depth of the feasibility and to ultimately seeing a trial come to fruition in a given country. The CRO involved must have the oncology experience and global expertise to ask the right questions, for example: • Will this protocol align or compete with the typical patient treatment pathway in this country in this indication, inclusive of newly approved therapies and off-label use of others? • Is the mechanism of action of the investigational product compelling, and how will this drug be viewed locally versus other competing trial options? • Is the required diagnostic test approved and available at all sites or will the sites be able to ship tissue samples abroad for diagnostic analysis? • Will the local Competent Authority or Ethics Committee (EC) find use of additional diagnostics, such as MRI scans, acceptable? • Must the comparator drug be provided or may this be reimbursed? 5 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success The ultimate goal of feasibility conduct is to provide a report to the sponsor that outlines the likelihood of successful patient recruitment and study completion in any given country, along with potential issues for the trial as a whole as well as at a regional, country or local level. A robust feasibility will help reduce start-up time and resources as well as the enrollment period because it anticipates and addresses all of the regulatory and clinical hurdles, thus ensuring fewer approval and site issues and smoother trial progression. A sponsor, with the help of a CRO, can use the feasibility analysis to adjust the protocol or trial plans to allow for regional variances. For example, a sponsor may dictate a specific number of cycles for adjuvant oncology therapy in the protocol, but advanced feasibility may indicate this cycle number is only standard in some regions and could lead a sponsor to relax criteria for minimum and maximum numbers of cycles. As another example, feasibility results may help sponsors identify and incorporate the methods necessary to address potential differences in protocol interpretation by region. Recently, protocol deviations were tied to a 75 percent increase in the risk of treatment failure and overall mortality in an analysis of radiation oncology studies. The investigators found in their review of quality assurance data from eight clinical trials, together addressing seven cancer types, protocol deviations A robust feasibility will help reduce start-up time and resources as well as the enrollment period ... ranged from 8 to 71 percent, and were associated with significant decreases in overall survival (P < .001) and increased risk of treatment failure (P = .009).vii Obviously, an ability to identify and address areas of the protocol that can lead to substantial variation in treatment by country, and thus the ultimate outcome of the trial, points to the significant value of a thorough feasibility in the early trial planning stages. Selecting Sites Ideally, a sponsor chooses sites based on the prevalence of the type of cancer targeted by the investigational therapy and access to those patient populations combined with the on-theground feasibility results. Sponsors also consider the caliber and capabilities of the clinical research institutions and investigators that care for these patients. Sponsors may also select sites based on the potential future markets for the candidate drug should it prove safe and effective in trials and receive regulatory approval. A known benefit of large oncology global trials is that they enable investigators, regulators and patients to become familiar with the sponsor and the candidate therapy long before marketing approval submissions occur. 6 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Also, having opinion leaders in each region or country provide a review of the draft protocol aids in site selection, timely regulatory approval of the trial and, ultimately, study success. The comments from such experts on the study’s scientific design, patient population, standards of care, and familiarity with and tolerance of an investigational product or approach can help refine a protocol to ensure that sites and regulators in that region find the trial acceptable. For sponsors for whom the trial is the beginning of an investigator or institutional relationship, an experienced CRO can offer guidance in assessing the study feasibility and directing the sponsor to like-minded key opinion leaders who are effective at study implementation. After all such criteria are compiled and considered, some sponsors may anticipate that selection means a review of all eligible sites. Such a comprehensive approach in a global trial, with well more than 100 sites, is costly and is not typically necessary. Rather, Novella Clinical recommends sponsors establish minimum requirements for sites, perhaps using a scoring system, so as to efficiently eliminate low-ranking sites from consideration. Factors with representative weights can be used in the scoring such as monthly patient volume in the specific oncology ... having opinion leaders in each region or country provide a review of the draft protocol aids in site selection, timely regulatory approval of the trial and, ultimately, study success. niche pursued by the protocol, or perceived screen failure rate as dictated by the inclusion/exclusion criteria or specific biomarkers pursued. A CRO with a long working history in oncology and with cancer sites globally can add value by leveraging proprietary data on historical site performance on past trials inclusive of time to open, enrollment, and data quality. All of this can help focus the site selection effort to hone in on the sites with the potential to work best for that particular trial. Covering the Cost of Care Standards of cancer patient care differ by country and even from site to site. For example, while the patient’s stage of cancer at diagnosis is a significant factor in the selection of care, so are treatment availability and costs as well as health care professionals’ knowledge of and skill with those treatments. The consequences are apparent in the wide variety in patient survival rates.viii A 2009 study found five-year survival rates for breast cancer patients ranged from about 84 percent in the U.S. to 39 percent in Algeria.ix These same factors have implications for large global oncology trials. Novella Clinical recommends sponsors establish how standards of care will be upheld and paid for, including reimbursement, as early as possible in the trial planning period because of the potential for significant budget impact. 7 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success While sponsors provide participants the candidate medicine at no charge, the reimbursement costs and policies for comparator drugs or concomitant therapies related to a patient’s condition change with the trial site. For example, if the investigational drug is added to a standard treatment regimen, how will the cost of the standard treatment be covered — through insurance, governmental support or paid for by the sponsor? Often, a sponsor may select a comparator medicine such as a chemotherapy because it is a reimbursed standard in the U.S. However, the drug may not be available in China or is available but must be reimbursed in Eastern Europe. In fact, Novella Clinical has found some hospitals and EC request sponsors not only pay for the comparator drug for the duration of the trial, but also for as long as the patient needs it before another treatment is available. Obviously, this reimbursement component can result in a substantial cost burden on the sponsor. This financial aspect could ultimately influence the decision of whether to run a trial in a particular country, thus highlighting the importance of early identification of such local factors. Procuring Drugs Nearly 60 percent of biopharmaceutical companies conducting emerging market-based trials report shipping and logistical support are significant challenges to their trials.x Many sponsors may try to handle such negotiations directly, but a CRO can be of great assistance, especially on the scale of a global trial. For drug procurement, a CRO can have an advantage over a sponsor in that they can apply their expertise in running trials as well as their independent status to act as a broker to achieve optimal pricing and efficient supply chains for medicines needed for the trial. A CRO is particularly well suited to manage the logistics of meeting customs regulations for drug importation into each country in the trial. Getting Real about Regulations Despite the existing guidance and the common goals of conducting ethical, rigorous clinical trials, the process for authorization to conduct international clinical trials is as varied as the geographies in which they take place. For each study site under consideration in a large global trial, the approval process layers can be overwhelming for an experienced sponsor, let alone one embarking on its first international study. Each country has a national agency for clinical trial protocol authorization, each with particular processes and procedural requirements for document preparation, submission, review and approval. Moreover, despite national standards, some countries also impose everchanging regional and local requirements, in addition to individual site Institutional Review Board (IRB) and EC reviews, as well as varied requirements on the timing and status of budget negotiations and contracts. Additionally, in Europe, all investigational medical product (IMP) trials must receive an EU Drug Regulating Authorities Clinical Trials (EudraCT) number, issued by the European Medicines Agency.xi 8 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Voluntary Harmonization Procedure The EU clinical trials directive 2001/20 EC addresses good clinical practice in the conduct of clinical trials on medicinal products for human use. In April 2009, the EU Heads of Medicines Agency’s Clinical Trials Facilitation Group launched the Voluntary Harmonization Procedure (VHP) as part of this directive. VHP allows sponsors of EU multi-national clinical trials to obtain a harmonized assessment of their Clinical Trial Authorization application by all the National Competent Authorities (NCAs) of all of the EU member countries involved. Via the VHP, a sponsor submits a single set of core documents electronically to the VHP coordinator. Following fixed timelines, the NCAs simultaneously and in a coordinated manner then assess the documents. After the assessment, a sponsor receives a single, harmonized set of questions that stem from the scientific discussion between the Lead Member State and the other Member States involved in the assessment. A 2011 report documented that from March 2009 until November 2011, 97 applications were received, comprised of 86 standard and 11 accelerated, which stemmed from the pandemic influenza vaccines. Some 55 different sponsors applied for VHP, the majority of which came from the U.S., Germany, France, the United Kingdom, Belgium and Switzerland. The average number of member states selected and participating in particular VHP assessments is six, but have ranged from two to 14. Of the 22 countries participating, Germany, France and Spain were the most active. Another authorization influencer may not readily be apparent to some sponsors: the competitive environment. Because of the dynamic nature of oncology research, countries will differ on the evolution of their standard medical practices. This diversity means that across borders, regulatory authorities will possess different levels of in-house expertise with treatments that might be comparators or competitors to a sponsor’s investigational product. Having a precedent drug for specific countries as a reference point in a regulatory submission can be helpful to authorization. Additionally, sponsors should consider the role of local key opinion leaders who may be consulted by reviewing authorities. Such experts might be approached by sponsors to review a draft study protocol or help in the identification and recruitment of local investigators, affording these leaders more familiarity with the details of the trial, which then enables them to provide more informed opinions to reviewers. 9 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Considering the Clock An experienced CRO can shepherd sponsors through the myriad of approval processes because the team already knows the required steps and documentation for each trial venue, as well as current issues or likely questions for particular reviewers. Among the topics for guidance a CRO should offer sponsors is estimating the actual time it takes to achieve authorization for trials to commence, inclusive of all country / local approvals, contracts, and site activation / IP release, as well as understanding the meaning and implications of review responses. With such counsel, a sponsor can proactively prepare tailored submission documentation, which creates trial efficiencies downstream. Many country-level agencies have well documented timelines and processes for regulatory review; however, these can still vary significantly, leading to large delays in regulatory authorizations. Novella Clinical’s experience has repeatedly shown the agencies in countries such as the U.S., Belgium, the U.K. and the Netherlands have fairly quick and efficient processes, while others such as India, China or Brazil have variable timelines largely dependent on individual reviewers. In some South American countries and certainly in China, country-level approval timelines may grow to nine to twelve months; these slower review timelines can obviously impact trial activation and enrollment timing.xii Many country-level agencies have well documented timelines and processes for regulatory review; however, these can still vary significantly, leading to large delays in regulatory authorizations. A recent, first-of-its-kind analysis of a large phase III breast cancer trial with 8,300 participants conducted in 44 countries had regulatory approvals ranging significantly in median time from 236 days in South America to 26 days in North America. The authors noted country economics played a role in the approval timing, but surprisingly with upper-middle economies having longer median times to approval, 123 days, than either highor lower-middle income economies, 47 and 57 days, respectively. In contrast, no significant difference occurred for EC/IRB approval times, which had a median of 59 days across the studied regions. Similarly, the median times from EC/IRB approvals to first recruited patient did not differ, tallying 169 days. The long delay in recruiting patients may have occurred because of the time required to negotiate contracts between the sponsor and sites, delays in importing the study drug or investigators’ interest in referring patients to the study, the authors noted.xiii These hurdles are just some of the bottlenecks that affect all global trials, but ones that an experienced CRO can help mitigate for a sponsor. 10 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Local approvals must also be considered, as these often must be pursued in parallel or serially with country or regional reviews. Local approvals will be impacted by site and investigator evaluations, contracts and site initiations, as well as other factors. Sponsors must consider these local steps in a trial’s overall timeline, as they can significantly add to the time “budget” and are often the rate limiting step in the overall initiation process. Novella Clinical has a proprietary model for trial startup and enrollment timelines that begins the day a sponsor says “go,” and includes: • Feasibility-based enrollment rate assumptions by country • Full site selection activities • Approvals at regional, country and local levels, including contracting • Timed ramping of site initiations by country as many sites open over a range of months • Average time from site initiation to first patient dosing • Allowances for regional slow-downs by month due to local cultural nuances All of this enables us to assist sponsors with the “real world” planning for a trial, providing a comprehensive view from startup to last patient. Because of the variance in timelines for approvals, a CRO that understands country-, region- and site-specific requirements can help a sponsor navigate the concurrent processes necessary to obtain authorization for international trials. While no timeline is perfect, ones that account for delays, questions and changes, even holidays, permit realistic planning. Interpreting Responses The nature of the review process itself varies by country. Some agencies prefer submission and no communications, while others, Novella Clinical has found, require much more interaction to move authorization forward. A CRO with long-standing regulatory relationships can manage such discussions, answering questions in face-to-face meetings and creating significant timesaving for sponsors. Differences in the style of regulatory responses also vary with geography, which for the novice sponsor can lead to misinterpretations. Some agencies, like those based in Eastern Europe, are extremely succinct when responding. In such instances, Novella Clinical has found that while a written response may be a simple no, speaking with the staff reveals what criteria and decisions led to that conclusion, thus providing a roadmap to a sponsor for the modifications necessary for approval. Accounting for Treatment Complexities Documenting and describing all of a trial’s treatments, not just the investigational drug or device, adds complexity to requesting regulatory authorization of a study. The type, number and combination of study treatments that a patient might receive and their previous regulatory approvals or marketing authorizations must be considered. Additionally, the sourcing and classification of treatments must be carefully accounted for as part of the regulatory submissions. 11 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Authorizing organizations require information regarding the chemistry, manufacturing and controls (CMC) of the drug substance and the drug product to assure the proper identification, quality, purity and strength of the investigational drug.xiv The detail required in CMC documentation will vary, however, with the trial’s phase, size and duration as well as the quality, control and manufacturing of the treatment.xv These factors might include a drug’s dosage form, delivery, bioavailability, stability, prior usage and regulatory history, as well as other factors. The goal of CMC is to demonstrate the identity, quality, purity and strength of the investigational product to help ensure safety of patients, so documentation in earlier trials focuses on risk, while later trials also address the relationship of the investigational treatment to a potential marketed product. Drugs in trials must be made under good manufacturing practice (GMP), but may require special trial-specific modifications. If a sponsor manipulates a drug in any way for the trial, new labeling and packaging are necessary. Sponsors who do not adequately address GMP issues can receive a rejection of their trial by a regulatory authority, which can cause a scramble to replace an entire country just as a trial is getting underway.xvi In the EU, regulations require the manufacturer or importer must authorize the medicines, with a qualified person based in the EU and independent of the sponsor assuming responsibility for quality assurances. In contrast, sponsors of U.S. trials can assume this responsibility.xvii The FDA CMC requirements are similar to those found in many European countries, but other global regions can differ. For example, while Korea parallels the U.S. FDA requirements for CMC information to be submitted in an IND, China requires a significant amount of CMC information, which can be an issue for products with a complex manufacturing process or for studies with more than one investigational product. The Chinese State Food and Drug Administration also requires extremely detailed manufacturing protocols that can enter into what sponsors consider to be the realm of intellectual property.xvii GMP drug modifications are not just a country-specific concern and may also extend to the institutional pharmacies, if significant preparation or manipulation of the product has to occur at a trial site. Submissions for study protocols that use drug combinations must consider whether the treatment as a whole or any of its As oncology trial sponsors begin testing more biologics, the regulatory path becomes more complicated given the greater complexity of biologics and because many agencies differ in their review processes for biologics compared to small molecules. components are standard. For example, not all countries use the combination chemotherapy known as CHOP as the standard regimen for treating patients with Non-Hodgkin’s lymphoma. Similarly, if a protocol requires prior treatment with a specific drug as inclusion criteria, the drug should be in regular use in the market under consideration. If not, regulatory authorities are likely to decline the application. 12 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success Moreover, drug classification as a small molecule or biologic matters. As oncology trial sponsors begin testing more biologics, the regulatory path becomes more complicated given the greater complexity of biologics and because many agencies differ in their review processes for biologics compared to small molecules. Unlike many small molecule-based protocols, those using biologics, especially when examining the complexity imparted by vaccines and gene therapies, can require additional approvals as well as process and quality control steps and approvals for shipping, reconstitution, storage and administration. Ensuring Informed Consent Informed consent is the process of ethically explaining the trial to a patient so that he or she can decide whether to participate. Each site’s IRB/EC must approve the appropriate forms to be used at that site as, on occasion, do the country-level regulatory agencies. Health literacy and cultural norms play roles in the creation of informed consent forms (ICFs). These documents contain the trial intent, procedures, potential risks and benefits, as well as other technical information. Using the same descriptions for investigators, regulators and patients is not appropriate, as patients must receive the information in words they readily understand. The “translation” from trial protocol to patient documents has legal, scientific and cultural considerations, about which a sponsor can seek counsel from a CRO. The CRO can, as needed, develop the documents into collateral that can be used for patient discussions if relying on patients’ reading ability is not appropriate. The CRO also can provide language translation services for the collateral into the site-specific language, including regional dialects if necessary. For example, India has two official languages, but the national government recognizes more than a dozen. India’s states also recognize even more regional languages, while patients may communicate in dialects. The result? ICF translations into a minimum of eight to 10 languages.xix Informed consent is not just about a patient’s participation. Ethically, this process also must address the number and kind of the patient’s biological samples, the methods of collection, their immediate and long-term use, and their storage and disposal, so that patients know their personal privacy is ensured and respected. Sponsors should be transparent about such plans because regulators may ask and the wait to provide the answers can cause trial approval delays. Also, as cancer treatments have become more targeted, pre-screening patients for trial eligibility may require separate consents from those obtained for actual trial enrollment. For example, in a trial for a drug designed to counter a specific genetic mutation, a patient’s eligibility will be determined based on a tissue sample, for which informed consent is required. 13 ©2013 Novella Clinical Oncology Clinical Trial Operations Global Oncology Trials: Planning For Success On the Horizon Advances in the harmonization of international clinical research are anticipated to beneficially impact the scientific and ethical integrity, quality and efficiencies of such investigations.xx Thought leaders have called on organizations such as the WHO or the Institute of Medicine to help reach consensus to speed harmonization efforts on trial design and conduct, with contributions from academia, industry and regulatory agencies as well as from developed and developing countries.xxi American Society for Clinical Oncology’s International Affairs Committee also is assessing regulatory issues, burdens and diversities in international cancer clinical research, and its initial 2011 report documented that low- and middle-income countries consider the regulatory procedures of competent authorities a significant barrier that should be optimized.xxii While these efforts move forward, one noticeable action toward such harmonization is the 2012 establishment of TransCelerate BioPharma, a consortium of 10 international biopharmaceutical companies that aims to improve the quality and efficiency of clinical trials.xxiii TransCelerate’s initial focus is the execution of clinical trials, which includes five projects that could have major impacts on times and costs. These projects include the development of a shared user interface for investigator site portals, mutual recognition of study site qualification and training, approaches and standards for risk-based site monitoring, clinical data standards, and comparator drug supply Advances in the harmonization of international clinical research are anticipated to beneficially impact the scientific and ethical integrity, quality and efficiencies of such investigations. modeling.xxiv The FDA’s Center for Drug Evaluation and Research applauded the TransCelerate initiative, noting that in the pre-competitive arena, such collective use of experience and resources has the promise to lead to new paradigms and cost savings in drug development that in turn would strengthen the development of innovative and much-needed therapies for patients.xxv More information is available at http://transceleratebiopharmainc.com/. xxvi 14 ©2013 Novella Clinical A Novella Clinical White Paper i ii iii iv v vi vii viii ix x xi xii xiii xiv xv xvi xvii xviii xix xx xxi xxii xxiii xxiv xxv xxvi xxvii xxviii “The Global Use of Medicines: Outlook Through 2015,” Report by the IMS Institute for Healthcare Informatics “Investigative Site Landscape Remains Highly Fragmented as the Number of Active Investigators Worldwide Reaches an All-time High,” Tufts Center for the Study of Drug Development News Release. March 13, 2013. Accessed at http://csdd.tufts.edu/news/complete_story/ir_pr_mar_apr_2013. http://clinicaltrials.gov/ct2/results/map?recr=Open&cond=Cancer. Accessed April 18, 2013. http://clinicaltrials.gov/ct2/results?cond=Cancer&show_down=Y Accessed April 18, 2013. http://clinicaltrials.gov/ct2/info/understand “Conducting feasibilities in clinical trials: an investment to ensure a good study.” Rajadhyaksha V. Perspect Clin Res. 2010 Jul;1(3):106-9.PMID: 21814631. Radiotherapy Protocol Deviations and Clinical Outcomes: A Meta-analysis of Cooperative Group Clinical Trials,” Ohri, Nitin , et. al. JNCI J Natl Cancer Inst (2013) 105 (6): 387-393. doi: 10.1093/jnci/djt001 First published online: March 6, 2013 “Barriers to Clinical Research in Countries with Limited Resources,” Cufer, T. ASCO 2011 Daily News. Accessed at http://chicago2011.asco.org/ASCODailyNews/BarrierstoCare.aspx. ASCO Global Cancer Facts & Figures, page 5, cited to Coleman MP, Quaresma M, Berrino F, et al. 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About Novella Clinical Novella Clinical, a Quintiles company, is a full service clinical research organization specializing in supporting emerging oncology companies. Headquartered in Research Triangle Park, N.C., and Stevenage, UK, Novella is experienced in early, mid- and late-phase oncology trials and provides the experience and insight to bring cancer medicines to market on time and on budget. For more information, visit novellaclinical.com/oncology or contact us at 866-303-4966. You see beyond the clinical trial. Your goal is to ultimately give people a better quality of life and more time to enjoy those special little moments. Novella Clinical is proud to be a part of your mission. Moving Potential. Forward. Novella Clinical’s Global Headquarters: 1700 Perimeter Park Drive, Morrisville, NC 27560 | Phone: 919-484-1921 European Operations: Richmond House, Walkern Road, Stevenage, Hertfordshire SG1 3QP | Phone: +44 (0)1438 221122