Pain Points In Clinical Trials
Mitigating the risk

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For small- to medium-sized companies with investors and shareholders to please, there is a tendency to set very aggressive clinical trial milestones — a necessity in a competitive climate that carries with it substantial risks. When clinical trials fail or are delayed, or protocols amended repeatedly because of inadequate design, poor data quality, slow data collection, data “cleaning” or suboptimal patient recruitment and retention, everyone loses. This article briefly addresses some significant pain points in this complex business.
Murphy should have been the patron saint of clinical studies — anything that can go wrong will, at the worst possible moment. Complex logistical considerations and steadily increasing regulatory requirements are well-known issues. Unless your company is big, you will need a clinical CRO to organize and oversee your trial. Choose wisely. Big CROs may have the advantage of large rosters of investigators and access to multi-national sites (the heft factor), but your study, being one of many, may not get the attention you feel it deserves. Smaller CROs may not have the bench depth, but can supply expertise in a clinical niche (e.g. dermatology), and provide more personalized service. It is largely a commodity-based industry, so shop around.
If there is any concern that your target indication and patient population may limit your access to patients, or that patient attrition through withdrawals and dropouts will be high for any reason, ensure your CRO can track and report back to you on recruitment and retention, preferably in as close to “real time” as possible.
Further to this, study design can be problematic for even the most seasoned companies. End points and outcomes (outcome measures) should be relevant and achievable (take particular note if your indications dictate end points that will take a long time to hit in the real world). Revisit protocol drafts regularly and by all means have them vetted by others in your field. Sample-size calculations are very important and a generous buffer should be built in for patient withdrawals. A bio-
statistician with trial experience should be consulted early and often during protocol development.
Getting and keeping the right patients can depend significantly on how onerous your trial protocol Schedule of Assessments is. Generally speaking, the more you want to put patients through, the less likely they are to agree to participate, or to continue once enrolled. In addition, competition exists for some patient groups, so the more attractive you make your study, the better. If at all possible, potential patient compliance issues should be identified before the IND/CTA is submitted. Monitoring patient compliance issues on an ongoing basis can nip trouble in the bud, and prevent data loss due to protocol violations. Moreover, inclusion/exclusion criteria should be carefully crafted to avoid needlessly excluding patients, an issue that occurs regularly in trials.
Your company and your clinical CRO should ensure the investigators are the right ones: just because a physician is a content expert or a key opinion leader does not necessarily mean she/he will deliver patients and high-quality data in a timely manner. If politics and/or business goals dictate inclusion of potentially low-recruiting sites in your study, compensate in advance by padding your inventory with more sites. Further, don’t be afraid to set patient recruitment milestones for investigators. You may even consider sharing individual recruitment success, or lack thereof, with investigational sites as an incentive. One cannot underestimate the importance of communication and study promotion to keep your trial foremost in the minds of the study site personnel who are actually screening and enrolling the patients and capturing the data; everything from posters to phone calls to promotional pens are used, often quite effectively. Promote to physicians and pharmacists, as well as directly to patients. Also consider regular investigator meetings and recruitment-focused site visits. One thing’s for sure — to initiate a site and walk away assuming your project will be as important to the site as it is to you, is a recipe for problems.
Investigator recruitment/retention and training is considered a problem in Canada. Physicians who run dedicated investigation sites are increasingly seen as one answer, as they’ve made a commitment to adhere to ICH guidelines. Although academic sites bring prestige and patients, the quality of regulated clinical trial work is sometimes not up to snuff in such centres. This problem, however, is slowly diminishing as awareness of regulatory (i.e. legal) responsibility increases, and as Health Canada continues to ramp up its clinical site inspection activities. Do your homework and investigate your investigators.
The use of information technology can help achieve some of these objectives. Electronic data collection (EDC) tools have been around for almost a decade and there is evidence that such tools can reduce costs, improve the quality of data collected, and speed up the completion of studies themselves.1 Recruitment problems can be identified very early through real-time reporting. Good recruitment and retention practices can be exchanged rapidly by posting and distributing them electronically to all participants. Furthermore, many of the mechanics of query generation, tracking, and resolution can be automated.
There are some basic elements that should be available in any EDC solution you choose. Most small- and medium-sized companies do not have an elaborate IT infrastructure and do not want to make that investment. An EDC solution should therefore be provided over the web. This allows the sponsor and the sites to enter data and produce reports through a standard web browser. Another important feature is the ability to design and modify CRFs yourself. Many EDC solutions require programmers to develop and modify CRFs. These programmer modifications, however, are time consuming and can be very frustrating. With a self-design capability, CRFs can go live in hours, and modifications can be made and distributed in minutes, rather than days or months. The difference is significant.
More advanced EDC solutions support mobile data entry — for example, on pocket PCs, Palm Pilots, tablet PCs, cellphones and laptops. Mobile devices can be used to enter data while in the field and are useful when data is being collected in fields such as subjects’ homes or places of work. They are also useful if the person collecting the information needs to move around a facility while seeing patients at the same time.
At the end of the day, the most successful uses of EDC occur when the technology matches the expected study workflow, when the systems are easy to use and learn, and when technical support is readily available to troubleshoot any issues that arise.

Dr. David G. Barnes is managing partner of BioTheraGene Consultants Inc. (Ottawa, ON), CEO of Boreal Primum Inc. (Montreal, QC), product development and regulatory advisor to PharmaGap Inc. (Ottawa, ON), SMO in Canada for CSL Australia Inc. and regulatory advisor to TrialStat Corp. (Ottawa, ON). Barnes is a former clinical evaluator, Biologics and Genetic Therapies Directorate, and former head, Biotechnology Products Surveillance Unit, Marketed Health Products Directorate, Health Canada. Barnes is former director, Clinical Drug Development, CHEO Research Institute (Ottawa, ON) and former investigator, University of Ottawa (Ottawa, ON) Evidence-based Practice Center. A physician and molecular biologist, Barnes has guest lectured on product development, regulation and safety at several Canadian universities. E-mail: d.barnes@
borealprimum.com or david.barnes@
pharmagap.com

Khaled El Emam, PhD is the chief scientist at TrialStat, a company that develops electronic data management systems for clinical research. He is also an associate professor at the University of Ottawa, faculty of medicine and a Canada Research Chair in Electronic Health Information. Previously, El Emam was a senior research officer at the National Research Council of Canada (Ottawa, ON), where he was the technical lead of the Software Quality Laboratory, prior to which he was head of the Quantitative Methods Group at the Fraunhofer Institute for Experimental Software Engineering (Kaiserslautern, Germany). Currently, El Emam is a visiting professor at the Centre for Global eHealth Innovation at the University of Toronto (Toronto, ON) University Health Network and at the school of business at Korea University (Seoul, Korea). He holds a PhD from the department of electrical and electronics engineering, King's College, at the University of London (London, U.K.).

References
1.     Bart T. “Comparison of Electronic Data Capture with Paper Data Collection - Is There Really An Advantage?”
Pharmatech. 2003:1-4.