| T H E N I H C A T A L Y S T | M A R C H - A P R I L 2000 |
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NEW STANDARDS SETFOR NIH-BASED CLINICAL RESEARCH |
About six years ago, when the Clinical Center was devising a course on the principles and practice of clinical research, CC Director John Gallin contemplated the complementary creation of standards for clinical research at NIH—a blueprint to facilitate a transition from the armchair to the frontlines of clinical research on campus.
Other institute directors wanted standards, too, and some clinical directors readily expressed frustration over gaps in the clinical research infrastructure at their institute that could be corrected by uniform standards.
But the timing wasn’t right then, Gallin recalls. Other changes to support clinical research were under way, and clinical standards, per se, were put off.
The timing was right, though, in January 1999, when a presentation before the CC Board of Governors detailed the variability among institutes in resources—appropriate staff, biostatistical expertise, protocol review mechanisms, monitoring capabilities, and data collection—to support the conduct of intramural clinical research.
The Board recognized a need for trans-NIH standards, which led the CC Medical Executive Committee (MEC) to hold a retreat last March. Standards were drafted, massaged, and reviewed by the CC Advisory Council and the scientific directors; they were revised accordingly and finally approved by the institute directors. In December 1999, the MEC issued the Standards for Clinical Research at NIH. From retreat to delivery took nine months and "no less pain" than that other nine-month event, Gallin observes.
Gallin and Michael Gottesman, deputy director for intramural research, are developing a process for the implementation of the standards and review of institute compliance, which will be the subject of a future Catalyst article. Implementation of the data management standards, in particular, will be aided by the Clinical Research Information System (CRIS), which the CC is building to replace the current Medical Information System and which will contain fully "searchable and minable" clinical care data for all patients enrolled in CC trials. It will also "interface in a seamless way" with the laboratory data kept by investigators at each institute.
"This will be a challenge, but we’ll meet it," Gallin says. The $42–50 million CRIS project will be implemented gradually over a four- to five-year period and will also be addressed in a future Catalyst article. The standards for clinical research are reprinted below.
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Clinical Research Standards Introduction Adequate training and the infrastructure to support principal investigators conducting clinical research are essential to patient safety, protocol implementation, and quality assurance, especially in interventional clinical trials. Indeed, even in natural history studies, such infrastructure can only enhance quality and access to the research by ensuring that data are collected as required by the protocol and are stored in a way that allows access to the information without dependence on any individual clinical researcher. The International Conference on Harmonisation, a consortium of regulatory bodies for the European Union, Japan, and the United States (Food and Drug Administration), has issued a series of guidelines for good clinical research that has begun to define the resources required for clinical principal investigators (PIs). A central requirement identified by the Conference is the availability of "an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely." (1) To assure patient safety and high quality NIH intramural clinical research programs, the Medical Executive Committee of the NIH Clinical Center has developed the following essential standards for performing clinical research categorized in six subject areas: 1. Clinical Informatics, Data Management, and Protocol Tracking 2. Biostatistics Support 3. Quality Assurance and Quality Control 4. Protocol Review 5. Human Resources and Physical Plant 6. Training and Education Each standard, with its rationale, is listed below: 1. Clinical Informatics, Data Management, and Protocol Tracking Rationale Collecting clinical data is a complex task that must be integrated into the medical practices of the institution. To monitor the study’s progress and patient safety, data collection is best done as data are generated. Data management organized and supported at the institute level is more efficient and reliable than that left to the individual investigator. There are often unforeseen uses for the kinds of information gathered in the conduct of a clinical trial, and a central database, with appropriate archiving, assures that this information remains the legacy of the institute. Standard Each institute sponsoring clinical research should develop a central clinical investigations database that maintains all data specified to be collected in the clinical study (either intervention or natural history). The clinical research information system being developed by the Clinical Center will interface with and support each institute’s clinical research needs. Data management infrastructure is required by institutes to maintain their central data registry, to enhance existing databases, to provide eligibility checklists, to record patient randomization and entry into their protocols, to provide report generation, data warehousing and data entry forms, and to monitor data collection. 2. Biostatistics Support Rationale The design of clinical trials should be based on sound statistical principles. Issues such as sample size, stopping rules, endpoints, and the feasibility of relating endpoints to objectives are pivotal to a successful trial. Typically, if the PI is not a skilled biostatistician, a biostatistician should be listed as an associate investigator on the protocol and should be involved in the protocol at all stages from design to analysis of results. Standard All clinical protocols must be reviewed by a qualified biostatistician prior to approval and implementation. 3. Quality Assurance and Quality Control Rationale The International Conference on Harmonisation is very clear on the responsibilities of research sponsors. The sponsor is defined as the organization that "takes responsibility for the initiation, management and financing of a clinical trial." In the context of the intramural program, the research sponsor is each institute conducting intramural clinical research. The sponsor "is responsible for implementing and maintaining quality assurance and quality control systems with written standard operating procedures to ensure that trials are conducted and data generated, documented, and reported in compliance with the protocol, good clinical practices, and the applicable regulatory requirements." To accomplish this, quality assurance programs are necessary to assure that each participating investigator is fulfilling his/her responsibilities. Quality assurance provides institutes with data about the quality of execution of their clinical research, and it provides investigators an opportunity to learn through external evaluation. Some interventional trials should be overseen by an external expert committee (data safety and monitoring board [DSMB]) to assure that adverse events are recognized and reported and that protocols are implemented in conformance to the protocol design and are closed to accrual when endpoints are met or unanticipated adverse events occur. At a minimum, all randomized or blinded studies should be reviewed at least semiannually by a DSMB. Standard Each institute must establish a quality assurance program with infrastructure that ensures that clinical trials are monitored adequately and centrally. The institute should determine the appropriate extent and nature of monitoring. This determination should be based on considerations of the study objectives, purpose, design, complexity, blinding, size, and endpoints and should include the following:
4. Protocol Review Rationale All protocols involving human subjects must undergo review of scientific content by an institute scientific review committee. These protocol review committees assess scientific quality, the importance to clinical practice, and the appropriateness of the study to the sponsoring institute. Following the scientific review, all protocols must be reviewed by an institutional review board (IRB) to establish and ensure patient safety and good ethical conduct of the study. Standard Each institute must provide or have access to:
5. Human Resources and Physical Plant Rationale A cadre of skilled personnel is required for support and oversight of clinical trials. The appropriate organization of a clinical trial team may differ depending on program objectives. PIs need to be supported by a team comprised of an appropriate mix of case managers, research nurses, physician assistants, nurse practitioners, data managers, and programmers. Standard Necessary personnel, office space proximal to patient care areas, and accompanying resources are required to support the clinical research infrastructure. 6. Training and Education Rationale Clinical protocol design requires a working knowledge of clinical trials methodology, biostatistics, and regulatory medicine. Similarly, monitoring the trial during its execution involves many distinct responsibilities, including reviewing each case record to confirm protocol eligibility, reviewing each case record to determine compliance with the protocol, reporting adverse events to the IRB, determining necessary changes in the protocol and the informed consent documents and submitting them as protocol amendments to the IRB, monitoring accrual to the study, and stopping the study when the requirements of the study design have been fulfilled or when it is clear that the rate of accrual fails to meet expectations. Training and education are first-order requirements to ensure that the PIs on clinical trials have a consistent and complete understanding of their responsibilities. Standard
–The Medical Executive Committee NIH Clinical Center December 1999 ____________________________________________________________________ 1) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Guidance for Industry: E6, Good Clinical Practice, Consolidated Guideline, April 1996, Section 4–Investigator: |
Onsite protocol monitoring during clinical trials. Statistically controlled
sampling is an acceptable method for selecting the data to be verified.
For interventional trials, the institutes should demonstrate a capacity
to review a minimum of 10 percent of patient records on selected clinical
trials to assure data accuracy, protocol compliance, and adherence to
regulatory requirements.