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International Clinical Trials

Big Shot

When planning a mega-trial, it is crucial to consider how best to tailor the management and evaluation of these studies, in order to comply with regulatory and compliance rules while keeping the costs in check.

Large randomised clinical trials (RCTs), or ‘mega-trials’, have produced some of the most influential healthcare research in recent decades, particularly in cardiovascular disease indications such as myocardial infarction, stroke, hypertension and atrial fibrillation. However, the need for trials involving 10,000 or more patients in other therapeutic indications has become increasingly critical to help answer important clinical questions. With regulatory agencies pushing for more outcome-based research in the wake of recent safety issues linked to several notable therapies, the role of mega-trials in helping pharmaceutical and biotechnology companies to better identify serious and rare adverse events (AEs) associated with their drugs has never been greater.

The growing importance of mega-trials has further magnified the responsibility of sponsors and their contract research organisation (CRO) partners in effectively managing and evaluating these studies. Mega-trials are expensive to run and require the participation of many investigators from multiple sites and from many different countries. In order for these trials to be successful, they require a sophisticated, logistical setup, and study protocols need to be prepared carefully, most often by multiple authors. Equally crucial is the implementation of various operational and technological strategies that are unique to the resource-intensive demands of mega-trials. RCTs such as these typically involve a simple design and a heterogeneous patient population and, therefore, offer several key advantages over smaller-sized studies. Due to their large sample size and resulting statistical power, mega-trials can detect a small signal in a particular patient population. Also powered for statistically valid subgroup analyses, mega-trials enable evaluation of a drug’s effects by gender, age and certain baseline characteristics such as duration of pre-existing disease or by background medications. Mega-trials are only as good as the quality of the treatment protocol. With that recognition at the forefront, sponsors and CROs must approach the design and execution of their mega-trials accordingly.

Momentum Builds

Large RCTs first evolved amid the recognition that large numbers of patients are essential to detect a small signal and to minimise the influence of confounding factors. The practice of mega-trials, particularly in evaluating treatments for acute emergencies such as myocardial infarction, evolved further upon the realisation that such large trials would be impossible without simple and limited data collection and very pragmatic procedures (1). Today, an increasing number of companies are conducting mega-trials worldwide. These studies are most common in cardiovascular disease, but are gaining traction in diabetes and metabolic disorders. In oncology, large RCTs have been conducted in indications such as breast cancer, with some notably focused on breast cancer prevention (2).

A major goal of mega-trials is to improve the chances of finding a difference between two or more interventions, if such a difference exists. A recent attempt at doing just that in diabetes research generated wide attention in the medical community. Enrolment in a mega-trial designed to compare the long-term effects of popular type 2 diabetes drugs Avandia and Actos was ordered stopped by the US Food and Drug Administration (FDA) in July 2010 amid renewed safety concerns surrounding Avandia, which had previously been linked to an increased risk of heart attack and chest pain. The mega-trial planned to evaluate 16,000 patients. Avandia had recently undergone a three-year review of the drug’s heart risks after the FDA issued a safety alert in 2007 (3). Later in 2010, Avandia was pulled from the European market and restricted in the US. The drug was ultimately removed from the US market in November 2011 (4).

Amid the Avandia saga, regulators have established more stringent guidelines for evaluating cardiovascular risk for non-cardiovascular therapies. In late 2008, the FDA introduced tighter testing standards for new diabetes drugs, now requiring companies to evaluate such drug candidates for heart risks before they can be approved. For sponsors, cardiovascular outcomes studies add substantial cost and extend timelines significantly. Specifically, the FDA’s safety guidance recommends that Phase 2 and Phase 3 clinical trials demonstrate that new antidiabetic therapies do not increase cardiovascular risk. In the past, the FDA only required that drugs for diabetes prove they could lower blood sugar-control as measured by HbA1c (5). The new requirements have accelerated the momentum for megatrials by illustrating the heightened desire of regulators to require more endpoint studies, rather than merely relying on results and conclusions derived from laboratory parameters. Mega-trials often evaluate anywhere from 1,000 to 18,000 safety and efficacy endpoints requiring adjudication. In its guidance on diabetes, the FDA states that sponsors should have any cardiovascular events in their trials prospectively adjudicated by committees of outside cardiologists who are unaware of which patients received the test product and which were on placebo or an active control drug. These events should include cardiovascular mortality, myocardial infarction, and stroke, and can include hospitalisation for acute coronary syndrome, urgent revascularisation procedures, and possibly other endpoints.

Mega-trials evaluating such outcomes can provide useful findings. For example, sponsors and CROs are able to identify when certain dosage levels of a drug are not effective across all sub-populations in the trial. The drug may work better in certain ethnic groups than in others, or conversely, cause more side effects – a realisation that is not always apparent in smaller trials. Mega-trials can reveal a drug’s risk for dangerous or fatal AEs in a more real-world setting, and with increasing likelihood of drug-drug interactions, can help sponsors better identify safety signals before a product enters the market.

These findings may help companies avoid the costly legal and regulatory hassles that occurred in such cases as Avandia, and years earlier, the painkiller Vioxx, all of which were pulled from the US market due to heart risks. To that end, sponsors in the diabetes space, for example, are engaged in large, multicentre endpoint trials for investigational drugs in classes such as dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium glucose cotransporter 2 (SGLT2) inhibitors. In the metabolic space, developers of new weight-loss drugs have also learnt from the recent pitfalls of branded diet pills (several antiobesity drugs were withdrawn from the market in the last decade because of harmful side effects), with one company proposing to conduct a large postmarketing cardiovascular outcomes trial for their recently approved drug (6).

Meridia (sibutramine), a diet pill first approved in 1997, was withdrawn in the US and Canada in 2010 after a mega-trial involving 10,744 subjects showed that Meridia increased the risk of heart attack and stroke in patients with a history of heart disease. The Sibutramine Cardiovascular Outcomes Trial (SCOUT), which was part of a postmarketing requirement to look at cardiovascular safety of Meridia after its European approval, demonstrated a 16 per cent increase in the risk of serious heart events with Meridia versus a placebo (7). SCOUT was a randomised, double-blind trial that was conducted from January 2003 through March 2009 at 298 centres in 16 countries in Europe, Central America, South America, and Australia. Eligible patients included men and women, 55 years old or older, with pre-existing cardiovascular risk factors and with a body-mass index of at least 27 and no more than 45 (8).

In dyslipidaemia, the experimental drug anacetrapib is undergoing a 30,000-patient cardiovascular outcomes study to determine if it reduces heart attacks and death, rather than just affecting cholesterol levels (9). Anacetrapib belongs to the class of compounds known as cholesterylester transfer protein (CEPT) inhibitors, which are designed to boost HDL, or ‘good’ cholesterol, an unmet need in dyslipidaemia. Development of the CEPT inhibitor torcetrapib was famously abandoned in 2006 after a randomised study involving 15,067 patients identified an increased risk of cardiovascular events linked to torcetrapib and found that subjects taking the drug were 60 per cent more likely to die than those who did not receive it. Torcetrapib caused an increase in blood pressure of 5.4 mmHg with an increase in sodium and aldosterone and a decrease in potassium – all undesirable effects that probably contributed to the unfavourable outcome of this trial and the demise of the drug (10).

The Phase 3 programme for torcetrapib, which cost $800 million, was terminated by the sponsor on the basis of the recommendation of the trial’s independent steering committee, which was acting on advice from the independent data and safety monitoring board (DSMB).

All large clinical trials have a DSMB, so appropriate reviews of safety data can be conducted. There are typically multiple interim analyses that examine safety limited to a certain number of parameters of interest. The goal of these analyses is two-fold: to detect safety signals that would mandate that the study be discontinued or the protocol be changed, such as excluding certain high-risk patients; and to identify when drug response is so overwhelmingly positive or negative that the study should be completed early. Armed with such data before the entire study has been completed will guide sponsors when making decisions involving largescale manufacturing investments, expanding the drug into additional indications, and various other considerations.

Challenging Terrain

With mega-trials now required to evaluate cardiovascular risk for non-cardiovascular medicines, these studies pose some of the greatest operational challenges in drug-development history. By nature, mega-trials require a significant amount of planning and setup in the startup phase. In addition, these trials require an unprecedented level of feedback from regulatory agencies to ensure that all parties are in agreement regarding design, endpoints, sample size and statistical power to detect the desired signal and so forth. Sponsors must be willing and able to undergo often intense rounds of discussions with involved academic groups, key opinion leaders, and various global regulators. Sponsors and CROs must make sure that senior and executive oversight committees are structured accordingly and are able to oversee and control all the functional teams to address any startup issues that may arise.

A mega-trial improves the likelihood that the results can be broadly applied. These types of RCTs recruit a very large and heterogeneous population, with fewer inclusion and exclusion criterion than in a typical Phase 3 trial, thus more accurately mirroring a real-life situation. Along with that comes an increased potential for background noise to cover up key signals compared to more puristically designed studies. It is crucial, therefore, to remember that a megatrial’s success, to the same degree as smaller studies, hinges greatly on having a well-constructed treatment protocol. If one or more of the treatment arms has significant limitations in demonstrating optimal therapy for a particular product, then the clinical applicability of the results for patient care is less meaningful (11).

Management Plan

Designing a robust plan is crucial for effective management of trials of all sizes. For large RCTs such as mega-trials, however, there is added responsibility for sponsors, as well their CRO partners. It is critical that management of the project from startup through to closeout is properly planned upfront and includes details of the arrangements for developing and monitoring all aspects of the trial, including servicing the steering committee and the DSMB but, most importantly, how the day-to-day execution of the trial will be completed and managed. Establishing a thorough statistical analysis plan supported with sufficient resources and time to complete the trial efficiently is a crucial component of project management for mega-trials (12).

Safety reporting is another key facet. Clinical teams must be adept at surveying the research landscape and identifying emerging trends that could affect the trial. Issue escalation reporting must be defined very clearly to address situations where safety issues surface in a particular region initially. These items can be looked at immediately to determine if it might ultimately be a trend for future regions to be addressed and mitigated early on or specifically an issue for certain regions for handling at a smaller level.

The FDA, EMA and Medicines and Healthcare Products Authority (MHRA) all released documents in 2011 in support of the developments of risk-based monitoring (13). The guidelines recommend the use of monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities both on-site and remotely to oversee a study effectively. To help ensure success in this FDA initiative, the guidance specifically encourages greater use of a centralised monitoring model as an important strategy. This is especially true for large mega-trials. It also outlines the types of data and processes that should routinely be subjected to more intensive monitoring, including procedures for documenting appropriate accountability and administration when ensuring the integrity of randomisation at the site level (14).

A potential benefit for mega-trials emphasised in the guidance is the realisation that 100 per cent source document verification (SDV) – a very expensive endeavour for any large trial – is no longer necessary. The global regulatory agencies note that source data verification and other activities traditionally performed by on-site monitoring can now often be accomplished remotely. In addition, more objective endpoints such as death or hospitalisation may be more amenable to remote verification. Electronic data capture (EDC) systems are increasingly ushering in centralised monitoring methods that can enable decreased reliance on on-site monitoring. No matter the nature of the approach; it is critical that a mega-trial programme establishes a model for risk-based monitoring that incorporates the appropriate use of a centralised model.

With mega-trials involving numerous sites across the world – more than 1,500 locations in some cases, the need to have regional project management leaders in place is critical. Those individuals should be responsible for directing essential activities such as investigator and staff recruitment; staff management; communication with sponsors, CROs, vendors and other key players; recruitment and retention monitoring, data management; and trial advertising and outreach. It is also important that an advanced IT group is accessible to the clinical and project management teams. These groups can help staff to develop the comprehensive reports required for mega-trials, particularly requests for query and listing-type reports. Automation of the collection of data will ensure timely and quick response to critical success factors and key progress indicators throughout the study, which could potentially take more time due to the sheer size of a mega-trial if not automated. It is important to identify which items are to be collected both in the EDC (or other database) and in a clinical trial management system (CTMS) and the reports to be generated at the onset of the trial in order for the data collection to begin promptly from the start. IT support is also key when constructing reports for DSMBs and special reports that go only to sponsors or executive management. Mega-trials can uniquely benefit from access to patient recruitment and retention specialists as well – independent of internal recruitment staff.

Interface with Personalised Medicine

New considerations in the conduct of mega-trials may arise in the future as the role of RCTs becomes more clearly defined in the emerging era of personalised medicine. Personalised medicine tailors therapy to individual patients based on their genetic characteristics. Oncology has experienced the biggest gains from this approach, with recent drug launches for diseases such as breast cancer and multiple melanoma that target patients with specific genetic mutations. With healthcare providers engaged in more advanced protein profiling and deeper analytics, some predict that standardised medicine will eventually evolve into personalised medicine (15).

The direct effects of mega-trials, specifically, on efforts in personalised medicine, however, may be a long way off. It is widely viewed that while findings from large-scale RCTs may apply to the population as a whole, they do not apply to every individual. Thus, assigning overall results of RCTs and systematic reviews to decisions about individual patients is often very difficult. Many argue that the essence of clinical science is to understand a disease and its treatment at the level of the individual subject; however, the analysis of a megatrial is only based on the entire patient population studied (16). In addition, with increasing development of ‘targeted drugs’, it is thought that these trials could dramatically reduce the number of patients a sponsor would need to study; mechanisms of action are becoming more understood and accurate biomarkers for responsiveness will be available (17).

Nevertheless, there has been recent research focused on designing RCTs to evaluate personalised medicine. One published report proposes making efficient use of high-throughput data such as gene expression microarrays or protein levels in tissue specimen collected at baseline from all participants. This data, along with clinical baseline risk factors such as participant age and tumour stage, can provide new opportunities for identifying a high-risk group who may benefit most from a certain treatment (18).

Although research approaches in personalised medicine are not common in therapeutic areas such as cardiovascular disease and diabetes, there is potential for this application. It is well understood that conditions such as type 2 diabetes, heart failure, and hypertension are partly driven by genetics. Genes have been identified that can increase an individual’s risk for these diseases and also increase the risk or benefit of taking a certain therapy. Applying the DNA-profiling approach could help advance clinical research for these conditions and would likely require large and complex trials involving multiple analysis.

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  2. Study of Tamoxifen and Raloxifene (STAR) for the Prevention of Breast Cancer in Postmenopausal Women. Visit:
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  4. Glaxo’s Diabetes Drug Avandia Pulled From U.S. Pharmacies. Bloomberg. Published online 18 May, 2011. Visit: com/news/2011-05-18/glaxo-s-diabetes-drug-avandiapulled- from-u-s-pharmacies.html
  5. Visit: RegulatoryInformation/Guidances/ucm071627.pdf
  6. Obesity Pill Qsymia Gains FDA Approval. CBS News. Published online 18 July, 2012. Visit: 10391704/obesity-pill-qsymia-gains-fda-approval/
  7. Visit: SafetyAlertsforHumanMedicalProducts/ucm228830.htm
  8. James W, Caterson I, Coutinho W, Finer N, Van Gaal L, Maggioni A, Torp-Pedersen C, Sharma A, Shepherd G, Rode R and Renz C, SCOUT Investigators, Effect of Sibutramine on Cardiovascular Outcomes in Overweight and Obese Subjects. N Engl J Med 363(10): pp905-917, 2010, Visit:
  9. Merck HDL Drug Appears Safe, Very Effective-Study. Reuters. Published online 17 November, 2010. Visit: article/2010/11/17/heart-merck-hdl-idUSN172204202010111
  10. Barter P, Caulfield M, Eriksson M, Grundy S, Kastelein J, Komajda M, Lopez-Sendon J, Mosca L, Jean-Claude T, Waters D, Shear C, Revkin J, Buhr K, Fisher M, Tall A and Brewer B, ILLUMINATE Investigators, Effects of Torcetrapib in Patients at High Risk for Coronary Events, N Engl J Med 357(21): pp2,109-2,122, 2007 Visit
  11. Visit: Randomized%20Clinical%20Trials.htm
  12. Farrell B, Kenyon S and Shakur H, Managing Clinical Trials, Trials 11(7): 78, 2010. Visit:
  13. FDA: GuidanceComplianceRegulatoryInformation/Guidances/UCM269919. pdf. EMA: Scientific_guideline/2009/09/WC500002873.pdf. MHRA: http://www. con111784.pdf
  14. Visit:
  15. Personalized Medicine Will Transform Healthcare. InformationWeek Healthcare. Published online 17 July, 2012. Visit:www. will-transform-hea/240003806
  16. Charlton BG, Mega-Trials: Methodological Issues and Clinical Implications. J R Coll Physicians Lond. 29(2): pp96-100, 1995 Visit:
  17. Sacristán J, Exploratory Trials, Confirmatory Observations: A New Reasoning Model in the Era of Patient-Centered Medicine, BMC Medical Research Methodology, published online 25 April, 2011 Visit:
  18. Baker S and Sargent D, Designing a Randomized Clinical Trial to Evaluate Personalized Medicine: A New Approach Based on Risk Prediction, J Natl Cancer Inst 102(23): pp1,756-1,759, 2010. Visit:

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Hans-Peter Guler joined INC Research in 2010. He has over 20 years of experience in clinical research in industry. Prior to joining INC Research, Guler served as Chief Medical Officer/VP Clinical Development at Phenomix for six years. His work in clinical research included studies at all stages from first-in-man to large registration trials. Indications studied included diabetes mellitus, obesity, rheumatoid arthritis, hepatitis C, asthma, sepsis, cardiovascular disease, and renal failure. He is an author of over 30 peer-reviewed articles. Guler trained in Switzerland and received his MD from the University of Zurich.

Kelly Henkel is a Senior Project Manager at INC Research. She has more than 14 years’ experience in the fast-paced, pharmaceutical clinical research industry with a strong focus in managing large projects in Cardiology across many indications. She received her BSc in Biology with a minor in Chemistry from the University of North Carolina at Chapel Hill, and is a current member of the Project Management Institute. In September 2005 Kelly received her Project Management Professional Certification as set forth by the Project Management Institute.

Hans-Peter Guler
Kelly Henkel
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