Edgar Smeets, PhD

Apart from training and certifying individual EC members, the Dutch Central Committee on Research involving Human Subjects (CCMO) recently added training of investigators to its repertoire.  

On December 3, 2012, at the Academic Medical Center Amsterdam, Prof. dr. Marcel Levi opened the eLearning website Onderzoekswijs.nl. "Clinical Research in our country is still standing strong, as compared to other EU countries. The number of trials taking place in the Netherlands this year is even a bit higher as compared to last year," Levi said. Of all trials performed in the Netherlands, more than 40% are categorized as "investigator-initiated," a number which has remained quite stable over the last few years. 

The free-to-use modules, that were designed on the basis of frequently asked questions from the field, offer no examination. However, after the instructions, a user may test his/her knowledge gained by answering a few questions, with direct feedback. Currently six themes are covered:  					

Four of the six start off with a video fragment. More modules may be added. In principle, the eLearning is intended for those interested/involved in investigator-initiated trials. However, any investigator may benefit from its contents. 

CCMO anticipates the eLearning modules will soon be used in the compulsory training by all eight Dutch University Medical Centers.  

The website's slogan is "Test and Increase Your Knowledge" with the language used in the eLearning modules being Dutch. Further information can be obtained from 

Articles

Apart from training and certifying individual EC members, the Dutch Central Committee on Research involving Human Subjects (CCMO) recently added training of investigators to its repertoire.

Free-to-Use eLearning Modules

OpenClinica (OC) was identified as a possible means to facilitate data management aspects of small(er) scale investigator-initiated/non-commercial trials. A Dutch investigator who was willing to share user requirements, was identified through the first author’s professional network. This investigator was in need of an electronic CRF (eCRF) for a multi-center trial to be led/conducted by his team, at his own and three other sites in the Netherlands.

During three rather brief face-to-face meetings and a couple of follow-up e-mail contacts, specifics of the trial and requirements for the eCRF were collected. It took the two authors a total of 45 hours to build the 12-paged eCRF in OC that comprised of 183 items. Input from the institution’s statistician was collected as well, and basic e-mail alerts were programmed to ensure that any safety-related issues will reach the principal investigator, for appropriate reporting to the Ethics Committee and the Competent Authority. 

Whereas initially OC ran on an external server, it was eventually hosted on a server hired and managed by the principal investigator’s institution. 

This effort shows that OC can be installed, set-up, hosted and maintained by a small team, and thus serve as a relatively low cost means to manage data, patient safety, and sites’ progress in the field of investigator-initiated trials. 

 
A lean, low-budget, but at the same time solid electronic Case Report Form (eCRF) could contribute a lot to non-commercial, usually investigator-initiated clinical research projects. Nowadays, activities like forwarding spreadsheets to  other participating investigators to collect the data, and putting together paper "CRFs" that actually and at best could be regarded as source documents, should be deemed unnecessary. eCRFs options have been around for quite some years now and carry the potential to cut away bureaucracy and to avoid data-sharing/data-entry processes often prone to error. The authors identified the open source application OpenClinica (see Box 1) and were offered the opportunity to put this to the test in an investigator-initiated multi-center randomized clinical trial, conducted in the Netherlands. 

OpenClinica (OC) is the world’s leading open source clinical trial software for electronic data capture and clinical data management. OC was and is brought to the community by Akaza Research LLC (

). The first version was released in 2005. OC comes in two versions, the Community version (unsupported) and the Akaza-supported Enterprise version. The former is free for download and use, the latter comes with set-up, hosting and consulting fees. 

Within OC, the following roles can be assigned: "Study Director," "Data Manager," "Site User/Clinical Research Coordinator," ‘"Monitor," and "Investigator," each having a distinct set of authorizations. The Site User or Clinical Research Coordinator adds subjects, performs the actual data-entry, answers to "notes," and solves "discrepancies." The Monitor reviews the data, issues "notes" and  "discrepancies," based on Source Data Verification. Moreover, the Monitor may program his own ad-hoc data-sets. The Investigator has the same authorizations as the Site User, with the addition of placing electronic signatures on each of the CRFs. 

 
 OC is rather easy to use, from the perspectives of the data entry person and the monitor. Such was the experience gained by the first author in a previous Phase I trial, conducted December 2009 – April 2011, to which he was appointed the monitor. Based on this experience, we asked ourselves if installing our own OC, building and maintaining an eCRF in it, would be feasible, easy-to-use for all sites involved, (more) compliant to current regulatory CA and EC requirements, and cost-effective. 

Installing OC was performed following the documentation available on the OpenClinica website. Installing plus testing and securing the system took 24 man-hours, leading to a solid test environment which was next used to make the eCRF pages (see Box 2). 

Box 2: Equipment Used and the Workload to Install OC

Making eCRF pages was straightforward as well. The CRFs were made "from scratch" and the template eCRFs, that can be found on the OC website for everyone’s use, were not used. Using MS-Excel sheets, it is easy to define the lay-out of the eCRF page, name and define the data fields and their entry specifications. Easy-to-understand error messages can be entered, and will be shown should an out-of-specifications entry be made. Also, tips or advice can be given, leading the data entry person through the eCRF, in a motivational way, resulting in cleaner data. Care was taken that the eCRF pages and fields closely matched the paper worksheets to be used by site staff. 

At each of the local sites only limited laboratory assays are required, to be run in the local laboratory, the results of which are entered into the eCRF by the local site staff. At the same time, sub-samples are forwarded to the principle investigator’s site for other (central) analysis, the results of which are entered by one person who will be assigned data entry rights for each of the local sites, but then only for these specific fields. 

OC offers an audit trail that records whom entered or modified what data field and when. 

Box 3: Unveiling Other Dutch Academic Institutions’ Interest in OC

In order for the principal investigator to be aware of the safety aspects at any time during the conduct of this trial, automatic e-mailing was programmed for each adverse event entered meeting the ICH-GCP criteria of "serious." Once alerted via e-mail of an SAE reported by a local site, the principal investigator can log into the eCRF, review the relevant information, and contact the local site, for example to advise on next steps to alleviate the event. This obviously would rely on a very timely completion of the eCRF data. The eCRF information can be matched with the paper SAE report to be forwarded to the principal investigator, and used for the step to follow; reporting the SAE or SUSAR to the Competent Authorities and the local EC via the online portal "ToetsingOnline."

The monitor’s function/role present in OC can be used to source-verify the entries, issue queries, (collectively called "Notes and Discrepancies" in OC), review and approve the answers to queries and eventually "soft-lock" the data entered. In the current trial, this monitoring function has not yet been implemented, pending the finalization of a Monitoring Plan. It is anticipated that a delegate from the principal investigator’s site will be assigned the monitor for current study. In OC, the Data Manager(s) too can issue queries. 

At any time, any selection of CRF-items can be downloaded as "reports" in various file formats for ad-hoc review (e.g., for trends), without changing the data whatsoever. Formats available are SPSS, ODM or tab-delimited text. 

In the Netherlands, each investigational study with human subjects requires prior and ongoing safety review by the Centrale Commissie Mensgebonden Onderzoek (CCMO; the central country Ethics Committee). The CCMO hereby predominantly acts as the Competent Authority, and as such keeps an extensive record of the Dutch "trials industry".

 Of all trial applications (roughly 1,700) in 2010, nearly half (47%) can be categorized as investigator-initiated. Also, 1,063 applications were for studies to be run at more than one site (i.e., multi-center). Contrary to expectations based on more administrative demands that would be imposed on the academic investigator groups by the EU Trials Directive, the number of investigator-initiated studies is up as compared to 2009 figures ( 44% of the approximate 1,900 applications). Clearly, the "market" of investigator-initiated studies in our country remains important and solid. Not only because of its supported "real time" SAE alerts, that actually can be used to fulfill the Dutch Competent Authorities’ wish to create better safety oversight in investigator-lead studies,

 OC could be a meaningful addition to an investigator’s research portfolio.

OC was piloted, reviewed and compared with other low-cost software solutions before,

 but not so much with regards to its actual set-up and use. The work in this article was not meant to compare OC with other software but rather to see if it can be an attractive option to a small non-commercial research group. 

In its view on near-term (bio-)pharmaceutical drug developments trends,

 the Center for the Study of Drug Development anticipates a rise in pre-competitive partnering between large firms, smaller R&D organizations and academic research institutions, aiming to share risks, lower costs, improve resource management, and maximize investigative site performance. Individual academic investigators and academic research groups/institutions could improve their chances of gaining such partnerships by implementing and using the full benefits of OC, at rather low installation and running costs.

This is randomized clinical trial, enrolling 400 patients in the  Netherlands. Ethics Committee approval was gained December  2010, with first patient enrolled 04 Jan 2011

2. Annual Report 2010, CCMO. Accessible at 

rzoek naar de PROPATRIA-studie. Combined report by the Dutch  Health Inspectorate, the CCMO, and the Food & Consumer Product  Safety Authority. 17 December 2009. Accessible at 

4. Fegan GW, Lang TA (2008) Could an Open-Source Clinical Trial Data-Management System be What We Have All Been Looking For? PLoS Med  5(3): e6.
  5. Franklin, Joshua D and Guidry, Alicia F and Brinkley, James F (2011), A  Partnership Approach for Electronic Data Capture in Small-Scale  Clinical Trials. In Proceedings, Clinical Research Informatics Summit of  the American Medical Informatics Association, pages 10, San  Francisco, CA.
6. Outlook 2011 Report. Tufts Center for the Study of Drug Development,  Tufts University, Boston MA, USA

 
The authors acknowledge the VUMC teams (Peter Hompes, Jeroen Beliën, Cuneyt Parlayan and Gerrit Meijer) for the opportunity to have run this pilot, and Certu BV’s (Wouter Scholten and Maurice Hidajat) assistance in installation and hosting the initial OC database. 

OpenClinica's (low cost) eCRF, an Investigator-Initiated Study's Showcase

Amsterdam was the stage for the first-ever edition of a two-day Science2Business conference entitled "Academia-Industry Collaboration for New and Better Medicines," organized by Science Alliance, on behalf of the International Federation of Associations of Pharmaceutical Physicians, on April 18 and 19. With the bright sun reflecting on the river IJ just outside the venue, setting record-breaking spring temperatures, the attendees were updated on recent developments in the fields of safety reporting in investigator-initiated trials, pitfalls in partnering between academia and industry, and collaboration models for successful research and its publication.

The closing session was a roundtable meeting that discussed the challenges encountered, or to be encountered, when striving for the standardization of GCP education. This session was attended by 24 professionals from diverse research affiliations. Research physicians from general, teaching hospitals, and from university hospitals; research coordinators and QA staff from the larger university hospitals; decision makers from mid-size pharmaceutical companies; and policy makers associated to universities, large hospitals, and from research-funding governmental organizations, were present. 

Interesting and thought-provoking questions came to the table straight after introductions.

Should investigators be trained repeatedly on GCP, by one sponsor for one of their trials, and the next month by the sponsor of yet another of their trials? Potentially, this could lead to decreased interest in the GCP topic as a whole. One of the delegates suggested any GCP training should first of all create awareness on the day-to-day conflict of interest; a physician informing a potential trial subject to participate in a trial that brings about certain risks, yet on the other hand the physician has sworn to Hippocrates’ Oath, which is to do no harm. 

Another wish was that training should aim at changing a research staff’s mind-set. What is needed from GCP or what is helpful to know to enable staff to continue delivering high-level patient care, combined with research activities. The incentives of GCP education were clear to all, namely benefits for both science and patients. But then, should there be a single training standard for all persons on a research team, regardless of individual job title or responsibilities? 

The majority of attendees then agreed to following the basic scope of "GCP training for research staff"’; GCP ideally should be educated continuously, in sessions aimed at all research staff individuals alike, with built-in and sufficient peer-to-peer discussion on common sense topics and practical examples from the "real life/the floor." Repetition of the same education session is not warranted. Instead, two levels of training would be appropriate (which is the situation in Singapore), one basic course that can be taught in two days and is compulsory by Law, followed by either refresher courses or advancement courses the following year. 
How should this education and training be built and what concepts should it cover? Here, at least one interesting concept needs mentioning. Rather than knowledge-based, training should be outcomes- and competency-based, with competency being the product of ones’ knowledge, skills, attitude, and behavior. This idea was further clarified by another attendee as the "driver license situation," which is that a person has obtained a license to drive a car in virtually any country, and may proceed to do so. The question is if this person really drives safely.

Well-placed as the closing remark of this session was that of a network collaborative group, known as PharmaTrain. The soon-to-be-rolled-out business plan is to have course providers reach common ground on the learning objectives first, next building a curriculum or syllabus, and setting out educational plans in the field of clinical research professionals, including GCP. The training or curriculum would preferably be accredited by an already established accrediting organization, preferably tapping into Continued Professional Development plans already fostered by some professional organizations. 

Good and indeed thought provoking discussion demonstrated that standardization of GCP training and education would be appreciated very much, by virtually all working in clinical research operations and management. To this end, steps ahead are defining the actual curricula and thus the set of competencies, and looking at options to have multinational training programs accredited.

Edgar Smeets, PhD

Articles

Free-to-Use eLearning Modules

OpenClinica's (low cost) eCRF, an Investigator-Initiated Study's Showcase

Global Standardization of GCP Training