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Planning and preparation, along with imaginative innovations, can put an investigative site on the road to best research practices.
The mission of an investigative site is to conduct ethically sound clinical studies while protecting and caring for the subjects. Ethical and scientific criteria for clinical research standards have been laid down by the Declaration of Helsinki, in FDA regulations and guidelines, and in the ICH Guideline for Good Clinical Practice. Some innovative organizational practices at investigative sites can enhance and facilitate adherence to regulations and guidelines. This article rests on the premise that investigative sites have an ethical and scientific mindset, trained and motivated personnel, progressive management, and an adequate infrastructure.
Investigative sites are part of a wider environment, which consists of a large number of partners involved in the clinical trials process. The partners can include sponsors, contract research organizations (CROs), central laboratories, couriers, providers of interactive voice response systems (IVRS), and others. In these times of regulatory and economic constraints, each brings to the partnershipalong with its responsibilities for conducting a clinical trialits own demands and expectations. All involved parties need to be finely coordinated from within investigative sites to ensure that trials run smoothly.
Sponsors generally conduct themselves in the manner of other commercial enterprises that work with subcontractors. That means they grade investigative sites on such factors as data quality, speed and reliability of subject recruitment, number of protocol violations, on-site facilities (personnel and infrastructure), respect for data deadlines, number of data clarifications, audit reports, and more. Sponsors that need to choose investigative sites for early pivotal or registration studies therefore tend to collaborate with efficient sites that are capable of the highest quality.
FDA regulations and the ICH Guideline for Good Clinical Practice must be respected. New European Union Directives will become law by 2004, and also must be considered when addressing matters of informed consent, ethics committees, and EMEA (European Medicinal Evaluation Agency) inspections of investigative sites. Investigators who conduct investigator-initiated studies must assume the responsibilities of sponsors in their dealings with other investigative sites.
Investigative site trial teams must be made fully aware of differences between European and FDA regulationsand trained to adhere to appropriate regulations and guidelines in their clinical investigative practices.
Sites are conducting more and more complex studies designed to address regulatory needs, safety and efficacy, health economics, quality of lifeall in one protocol. These are high stakes studies for sponsors, and that puts investigative sites under pressure to provide high quality data that must stand up to the most stringent audits and inspections.
In addition, physician-investigators are aware of the debate on the therapeutic orientation to clinical trialsand they must guard against obscuring ethically significant differences between clinical research and medical care.1 Clinical trial subjects today are more informed about their rights, have greater access to information and new drugs, and therefore have higher expectations than ever before. In parallel with the many regulations to protect them, however, have come more complex demands upon the subjects.
Not only the studies but also the concepts being studiedgenetic testing of biological samples, for exampleare complex. Long, comprehensive patient information documents require effort to understand before making informed consent to participate in a study. In addition, subjects are required to complete more and more questionnaires and diaries at and between study visits so that investigators can collect data on medication adherence and quality-of-life evaluations. For investigative site personnel, this means allocating a great deal of time to coaching and encouraging subjects during their participation.
Innovation in practice
In the setting described, pressure on clinical investigative sites comes from the outside environment and, of course, the desire to perform high-quality studies should also come from within the sites. Investigative sites therefore must be highly organizedyet allow a little space for creativity.
Here are a number of practices that can be said to have been finely distilled from those trials we call experience. The source document templates described below, for example, were refined and redefined upon the advice of an excellent auditor who generously offered her ideasduring an audit visit, of course.
Over time, we developed our practices in a bid to optimize staff time management and to keep faith in the concept that quality of life for an investigative site team is indeed compatible with an evolving clinical trials environment.
Standard operating procedures (SOPs). It is surprising that in todays clinical research practicewhich is of such ethical, medical, and scientific importanceinvestigative sites are not obligated to document the way in which study procedures are carried out. Other safety-conscious and highly regulated fields that collect safety and efficacy data (aeronautics and engineering, for example) require rigorous documentation.
SOPs are simple, clear descriptions of the methods of practice for an investigative site. In the not too distant past, in clinical research, those documents were the exclusive domain of pharmaceutical companies, CROs, and site management organizations (SMOs). Now, however, sites also need to develop written SOPs to document and standardize their practices for site personnel. It is, for example, preferable to avoid a situation in which staff members weigh subjects differentlyone with subjects in their undergarments, another with the subject fully dressed (possibly in winter attire with pockets full of change and keys). Over successive visits, a subject haphazardly weighed could show significant weight gain (or loss). This could potentially create a serious situation for a subject or a study of heart failure or metabolic disorders.
At our center, we find that documenting everyday activities leads our teams to reflect on the way things are done. Large investigative teams (more than 10 persons) may wish to nominate an SOP Group to draw up the SOPs, organize discussions, and supervise revisions, reviews, and archiving. A list of topics for site SOPs, though not exhaustive, includes study medication handling, biological sample processing, serious adverse events management, subject recruitment methods, the informed consent process, preparing for monitoring visits and audits, subject visits to the site, and filing systems and other administrative procedures. The SOPs checklist box provides a list of minimal standards to strive for with SOPs.
Documentation of procedures and detailed job descriptions can be of tremendous help when used as teaching aids (in-house training) for new site personnel and for ongoing training of more seasoned members of the team.
It seems inevitable that in the near future regulatory authorities and sponsors will require rigorous documentation of all procedures being performed in clinical trials at investigative sites.
Efficiency and qualitySubject site visits. Many sites conduct a number of trials simultaneously. Consequently, physician-investigators and research nurses see subjects who are involved in different studies during the same clinic session.
Subject follow-up visits are most often managed in a busy hospital or clinic environment. The inherent challenge, therefore, is finding a successful compromise between time limitations and the quest for quality. Subjects are in a hurry to get back to their work or college. Mothers are rushing to pick up children from school or nursery. Site personnel are equally hurried to complete the procedures necessary for the studies while maintaining the quality of care for their subjects, and producing reliable data for sponsorsand reasonable job satisfaction for themselves. The Follow-up Visits checklist provides a guide that can make the process easier for subjects and investigators.
Paper documents. Case report formsthe classic paper versionscan weigh up to several kilos. Every site professional knows how cumbersome and inconvenient they can be in a clinic. In parallel to this, documentation of source data at study visits is of the highest importance for the study and the subjects medical file. Our center developed a system of support source data collection documents (see below) to ensure that all procedures are performed and that complete data is collected at each follow-up visit.
For studies in which study medication is dispensed and returned at follow-up visits, it is useful to incorporate into the documents a template for precalculating the medication expected to be returned by subjects at each follow-up visit. This can easily be adjusted if the subject comes before or after the planned appointment date. In this way, poor adherence or nonadherence to the study regimen is apparent from the pill count and can be addressed immediately with the subject.
Subject management could include providing them with prospective visit schedules at the start of the study. The schedule could include information about all of the expected clinic follow-up visits for the whole study follow-up period. This can help subjects plan other activitiesvacations and holidays, for example. This also helps investigative site personnel to order additional study drug and materials as needed.
Important study documents (such as drug accountability and consent forms) can easily be misplaced in the busy environment of hospitals and clinics. Print these documents on paper of distinctive colors so that they are easily recognized by everyone, and therefore treated with extra care and less easily lost.
To conform to the ICH guideline for GCP, we found it useful to develop support systems in source data documentation for the convenience of clinical research personnel. During any one follow-up visit as many as 20 items of data may have to be noted. Documenting clinical trial follow-up data by hand is laborious, time consuming, and sometimes incompletebecause busy people may forget to perform some procedures. Easy-to-use standard document templates, which can be tailored to each study and each follow-up visit, help prevent these data collection oversights (see Preparing Source Documents checklist). At the beginning of each study, the research nurses and research assistants responsible for the management of the study assemble all the data required for the study from the protocol and case report forms (CRFs) and draw up study-specific data collection forms. We use the same text as the CRF to avoid any risk of ambiguity in language (the mother tongues of our clinical research team are French and Dutch).
Phase 2, 3, and 4 studies generally require three types of forms: screening, baseline, and follow-up. Data for screening and baseline visits are study-specific. The form for follow-up visits includes spaces for the same data required for all study visits, but has not applicable options for information that is not required at a specific follow-up visit.
Very important datasuch as The design and side effects of the study have been explained to the subject, and A copy of information for subjects and the consent documents have been given to the subjectis preprinted on the document with a space for the investigator to sign and date at the screening visit. Those who perform each procedure and write the results (the physicians or research nurses) identify themselves with their initials or signature, and they date the documents, making the process completely traceable. The completed documents are placed in each subjects medical file at each visit because they serve as both the medical record of the patients visit and the source data for the study. Templates cover source documentation on clinical data, drug accountability, concomitant medication and other documents you may wish to include.
The advantage of the above support system is that the clinical research team simply needs to complete the appropriate parts of the data collection forms. That allows them to concentrate on the care and concerns of their subjects, who benefit from a subject-oriented rather than a data-oriented approach to their follow-up visits. There is complete and rapid documentation of all data required for the study, and monitors and auditors have a reliable and easy system of clear source documentation.
Details. Radio-controlled digital clocks are a good investment in accuracy, especially when study procedures are carried out by personnel who move from one consulting room to another. The time on a conventional round-faced clock can be interpreted differently depending on the angle from which it is viewed. With digital clocks all set at the same time, an auditor is unlikely to find documentation indicating that the same research nurse was in two places, performing two different procedures, at the same time. When an auditor made that discovery at our site, subsequent investigation revealed that the problem was the minute hand setting on the clocks in two neighboring consulting rooms.
Investigators generally have no opportunity to reflect on a studys design or discuss it with the sponsor before they receive a protocol. When the investigator and his team find themselves uncomfortable with a protocols ethical, scientific, or feasibility issues, the investigator should write to the sponsorand be satisfied with the sponsors responsebefore agreeing to participate in the study. Before accepting a study, a site must also consider finance, staffing, compatibility with practice guidelines and SOPs, the amount of time and space required, and other practical matters. Once the investigative site team accepts a study, and it is approved by the ethics committee or IRB, the most critical and challenging time of the studyeven when things go wellbegins: the study start-up.
Unless thorough testing and verification is carried outbefore study start-upon every procedure, apparatus, and system that a sponsor provides to a site, problems are likely to occur. That is a cruel, but certain, fact of life for the research professional. Even with conscientious preventive measures, trouble may still follow. Sponsors, through their monitors, should ensure that everything provided to the site is functional. Those at the site level should have trust (without naivet), but verify everything prestudy.
Try out the interactive voice response system (IVRS). Test new equipment, especially any with novelty features, such as telephone transmission of electrocardiograph signals to a central reading facility with a 12-hour time difference.
Do not be anaesthetized into complacency by video demos of new equipment or systems. The wise know that real-life technical problems are never shown in those demos, so try it out in the comfort of a prestudy setting without a live subject in a study situation.
If your center is the very first to recruit subjects in a large multinational, multicenter trial with central laboratories, IVRSs, and multiple external service partners chosen by the sponsor, enroll slowly at first. Despite following all the testing and verification advice above, the first center to screen subjects (thus activating the study) is the pioneer that discovers the unforeseen, time-consuming early start-up problems. Planning for this probability can avoid stress and heartbreakand, after all, the solutions will benefit all the other centers participating in the study.
Be aware of hidden timelines. In keeping with the concept of rapid flow data, investigative sites must fax data to some sponsors within a very short time after the subjects follow-up visit and prior to on-site data monitoring. This is often announced at the initiation visit just before study startup. It requires specific management at the site and may justify an amendment to the financial agreement.
Prior to their enrollment as subjects in clinical trials, patients biological follow-ups are part of their records in the hospital and clinic computer systems. Investigative sites can request that sponsors periodically forward biological results from central laboratories on diskette or by email in addition to those results forwarded by fax and on hard copy. This procedure can prevent any blanks in subjects hospital or clinic biological files during their participation in a clinical trial. Be aware of the timelines and of any particularities (for example, insurance requirements or transport expense refunds to subjects) required by the institutional review board (IRB) so that any problems can be resolved with the sponsors before the submission of the protocol and study documents.
Monitors are often the only representatives of sponsors in contact with an investigative site during a study. They have important responsibilities regarding study data and are the pivotal persons for contact between the site, the sponsor, and other partners (such as central laboratories) in the study process. Investigative sites can improve the quality of life for these precious collaborators.
It is helpful at study start to have the names and contact information for the organizational and medical supervisors. It is also useful to have SOPs in place for site personnels management of monitor visits. Monitors often find it helpful at study start to have a letter from the site that includes clear guidelines on the sites practices (the SOPs). This could include names of site personnel and their functions (who will do what for the study, with first- and second-line responsibilities), the availability of center staff, schedule of ethics committee meetings, requirements of the investigative site from central laboratories. This can help to ensure smooth collaboration during the study.
When sponsors and CROs are actively involved in the study, make sure to document clear definitions of the role of each during the study preferably with only one contact person. That can avoid the awkward situation in which site personnel have to deal with two organizationsboth applying pressure on the investigative site at the same time. When problems arise with a central laboratory, an IVRS, a courier, or others, we prefer that a study monitor contact them, if a first contact by the center personnel is unsuccessful. This keeps sponsors aware of poor service to investigative sites by their partners. It also has frequently been our experience that a sponsor can elicit a much more rapid resolution to problems than an investigative site team can. He who pays the fiddler, calls the tune.
Planning simplifies complex problems
The processes involved in conducting GCP-compliant studies are, paradoxically, both complex and simple. Planning and preparationwhen practiced with some imaginative innovationcan result in best practices at investigative sites. The desire to perform these high-quality studies with innovative organizational systems must, however, come from within the investigative sites themselves.
Sites that respond to pressure from sponsors, subjects, and regulators by developing the capacity to perform scientifically relevant, high-quality, ethical studies will be in a position to offer high-quality care to their subjects, high-quality data to sponsors, and high-quality scientific papers to the scientific community. This is the complete win-win-win scenario.
1. Franklin G. Miller and Donald L. Rosenstein, The Therapeutic Orientation to Clinical Trials, New England Journal of Medicine, 348 (14) 13831386 (2003).