Radiology needs to be more closely integrated into clinical trial design -- ideally from the earliest stages -- and not merely consulted after the design is finished, according to a white paper published in Academic Radiology by the German Association of Chairmen in Academic Radiology (KLR).
"Accurate trial planning and data evaluation go hand in hand between all involved disciplines," said co-author Dr. Stefan Schönberg in an interview with AuntMinnieEurope.com. "Definition of the most appropriate imaging techniques and techniques for response evaluation needs to be done by radiologists in advance and within a dialogue between all disciplines that are involved within a study."
Especially with the rise of antiangiogenetic therapies and more molecular imaging techniques, trial planning requires a more intense and sophisticated interdisciplinary discussion, said Schönberg, a professor and chairman at the department of clinical radiology and nuclear medicine at the University Medical Center Mannheim in Germany.
KLR sees radiologists' tasks and responsibilities falling into the categories of trial planning, trial implementation, and data evaluation.
Trial planning
Radiologists who wish to participate in a clinical trial must first familiarize themselves with the trial protocol. Approval must then be obtained from the ethics commission, and it must be clarified whether radiation will be used for the purpose of medical practice or medical research, the authors wrote (Acad Radiol, May 2014, Vol. 186:5, pp. 451-457).
There needs to be a closer integration of radiology into clinical trial design, said Dr. Stefan Schönberg."This decision can only be made by a qualified physician," they wrote. "In cases of doubt, review by the independent panel of experts of the German Radiological Society should be performed. In multicenter studies, the radiologist is responsible for performing these tasks at the site of the director of the clinical trial."
Also, the radiologist is responsible for adjusting the measurement parameters defined in the trial protocol to the available equipment. For CT exams, this is usually a manageable process, but MRI exams often require "significant effort and radiological expertise" -- for instance, if the sequence parameter information is incomplete, or the parameters do not correspond to the clinical standard but to the lowest common denominator of various devices. Or, the parameters were defined for a certain system or the systems of one manufacturer and cannot be transferred to the scanners of other manufacturers.
"Radiological knowledge is highly required to determine the most appropriate imaging modalities for staging and follow-up of patients, including definition of the most applicable follow-up criteria and time points," Schönberg said. "This expertise is of particular importance because response assessment is getting more complex in the era of molecular medicine and targeted therapies for which RECIST [Response Evaluation Criteria in Solid Tumors] might not be the most appropriate tool for all studies. Defining the most appropriate imaging techniques and response criteria into clinical trials is also of major impact from an ethical perspective for our patients."
Trial implementation
Because the management of imaging exams and interventions performed as part of clinical trials differs in almost every stage of processing from application, evaluation, and result documentation to the billing of corresponding services, the establishment of a radiological trial center for the coordination of complex tasks is useful, the authors wrote.
"Such centers should be staffed with specially trained personnel who can provide support for the implementation of radiological tasks in all process steps of a clinical trial and act as an interface between clinical trial centers, referring physicians, routine radiological service providers (medical technical radiology assistants, physicians), hospital administrators, and sponsors."
The KLR also advises appropriate facilities and IT equipment that allow for networking with the software of the center or coordination center for clinical trials usually present at universities. This includes use of pre-existing electronic checklists and formulas, and automatic electronic sending of pseudoanonymized image datasets to the sponsor.
Also, the ability to electronically identify trial services within the RIS and the availability of software programs for semiautomatic image evaluation are desirable.
A radiological trial center should also have one or more radiologists and one or more study nurses depending on the workload, they added.
The KLR pinpoints specific tasks radiologists should perform during a clinical trial, such as scheduling exams in accordance with the inclusion and exclusion criteria and the intervals specified by the trial protocol and possibly by the Federal Agency for Radiation Protection. They should also make decisions regarding unblinding and evaluate possible consequences during and after unblinding.
Trial evaluation
A differentiation must be made in the clinical trial evaluation between services rendered by the individual centers and consulting, coordination, and services rendered for the evaluation in terms of core labs.
"Evaluation by the individual centers must be performed for many issues on the basis of structured procedures developed specifically for trial evaluations, such as RECIST 1.1, the WHO [World Health Organization] recommendations, the guidelines of the responsible committees, or the recommendations of professional organizations," the KLR team wrote.
The evaluations differ from diagnostic reporting with respect to scope and are associated with a comparatively higher time expenditure that must be included in calculation of costs, the authors added.
"The evaluation or authorization of an evaluation prepared by a resident physician can only be performed by a radiologist with experience in this regard," they wrote. "The precise, objective, and reproducible assessment of radiological follow-ups requires comprehensive knowledge of the response criteria defined for the particular trial."
For multicenter trials, the KLR emphasizes the importance of adequate, cross-institute training of participating radiologists to guarantee a high, objective, and reproducible quality standard for the evaluation.
Compensation
"The sponsors of a clinical trial need to provide separate contracts for radiology departments to guarantee that all radiological services are remunerated sufficiently," Schönberg said. "Services like dedicated analysis for trial purposes, anonymizing and sending of data to core labs, image protocol preparation and adaption for studies, as well as verification of appropriate radiation protocols, need to be remunerated and should not indirectly be covered by other resources in the departments."
To fundamentally and permanently improve the compensation aspect, KLR recommends the following:
- Homogenization and uniform implementation of the applications required by the Federal Agency for Radiation Protection and radiation hygienic trial conditions for conducting clinical trials
- Reduction of a financing downward spiral as a result of statements regarding purportedly significantly cheaper service providers at other participating trial centers under cost-covering amounts
"A standardized radiological procedure in this area would relieve the pressure on individual trial centers because they are currently often told that the start of a clinical trial is delayed because of their procedures although they were only required to adhere to ethical and radiation hygienic standards at the time of inclusion in the trial," the authors wrote.
If there were standardized procedures, this would relieve the pressure on individual radiological centers and strengthen the position of radiology for participation in clinical trials in general.
"As a rule, a full cost approach that includes the most important aspects of radiological services, personnel, and material costs should be targeted for the calculation of the compensation for radiological services," they added. "Institutes must continue to be allowed to differentiate between industry-sponsored trials and university-based investigator initiated trials."
They also add that services and consideration in clinical trials must be appropriate. For instance, a lump sum payment or permanent loaning of devices as consideration is an unacceptable form of compensation.
Four central principles must be observed when concluding contracts between medical facilities: the principle of separability, the transparency or approval principle, the equivalence principle, and the documentation principle, the KLR said.
Quality assurance
Lastly, the KLR addressed quality assurance. It should be performed within the relevant radiology clinic and also externally via central data acquisition at the German Radiological Society.
Internal trial coordination should be performed by an employee employed explicitly for this purpose, such as a scientific assistant with previous clinical trial experience or a study nurse. Internal trial coordination can also be performed by an employee who is made available for this task at regular intervals, the KLR said.
Superordinate recording of the central data of clinical trials with the participation of radiology also is necessary, the authors wrote. The central recording is performed by the German Radiological Society in Berlin and stores information such as the trial number, list of participating centers, etc.
The goal of external quality assurance is increased transparency and simplification of the processes of trial planning, implementation, and evaluation via better coordination of the individual trial centers, the authors wrote. As a result, a direct contact person is available for questions for every trial center and every trial.
"We aim to significantly increase the awareness of clinicians and pharmaceutical companies regarding the need for a closer integration of radiology into clinical trial design in 2014," Schönberg said.
