Clinical Trial: The Rites of Passage

Every medical device has to pass a series of tests before it can be made available for general use on human patients. This is a long, arduous process with many unknowns and potential roadblocks along the way. Making it work requires close cooperation between the manufacturer and clinical teams at a variety of institutions who have an interest in testing the device for the good of their patients and the good of a great many patients in the general population. For good reason, the FDA imposes rigorous guidelines on all clinical trials to ensure that the therapy is tested on appropriate patients, that all relevant data are collected, and that patients are adequately protected at all stages of the trial. In addition, each institution must seek approval from their individual Institutional Review Board (IRB) whenever research of any kind is conducted that involves human subjects, even if the research consists only of asking questions. In the case of the very first ablation catheter seeking approval for an elusive target such as atrial flutter, the clinical trial was especially interesting and especially demanding. Between October 1999 and July 2001, sixteen research centers tested the Biosense Webster Dual Sensor 8 mm Tip Ablation Catheter for safety and efficacy in providing a bi-directional anatomical block to treat atrial flutter. David Wilber, MD, was the Principal Investigator at Loyola University Medical Center and the University of Chicago. Sonia Maccioni in the Clinical Research Department at Biosense Webster was his primary contact at the company. Dr. Wilber enrolled the largest cohort of patients in the trial: there were 40 patients out of a total of 190 patients. Let s look at the experience of the research center as they conducted this major trial of a potentially breakthrough product. Before patients were enrolled in the trial, a team of experts from the Clinical Research Department at Biosense Webster conducted a comprehensive initiation and in-service for the staff at the center. This is a critical step in the ultimate success of a clinical trial. It is absolutely essential that investigators, sub-investigators, and staff at all research centers understand the study design and have a clear concept of what the trial is intended to prove or disprove. Only strict adherence to all the protocols both of the FDA and of the specific study will ensure that the proper data are collected and that they are collected in a manner that protects their validity. The clinical trial process was greatly facilitated by the research nurse, Millie Cary, RN, who played a key role in coordinating the study and maintaining the protocol. Patients are often referred to an electrophysiologist because they ve been treated unsuccessfully with conventional therapy. In some cases, the electrophysiologist may think that a new technology under study may be beneficial for that patient and will recommend that the patient participate in a clinical trial. Before a patient is admitted into the clinical trial, however, the center must conduct a rigorous screening process to make absolutely certain that the specific therapy under study is appropriate for that specific patient. Study protocol typically includes both criteria for inclusion and criteria for exclusion. In this case, among other things the patient had to have documentation of symptomatic episodes and clinical proof that the condition was, in fact, atrial flutter and not a similar but different arrhythmia. Beyond the clinical documentation, a great deal of time was spent with each potential enrollee to ensure that the patient had a clear understanding of his/her role and responsibilities in the trial. It was important for every patient to recognize the significance of the research, not only for themselves, but also for the benefit of others. Patients needed to understand why the conventional therapy did not work for them, why they were eligible for this study, and why the therapy under study might provide better results. In addition, each patient should feel a sense of involvement and enthusiasm so that they would participate willingly and cooperate with all of the crucial follow-up elements of the study. A great deal of time was also spent addressing patient fears and concerns. With any new procedure, there is typically a concern about the potential risks of the procedure balanced against potential benefits. Patients wanted to know how many others had already been treated, how many would be in the trial, and what the procedure would be in the event of an unsuccessful outcome. It was important to address all the concerns of the patient, and also of the patient s family. At this research facility, Millie Cary, RN, played a key role in coordinating the study. Although the principal investigator, David Wilber, MD, was ultimately responsible for every aspect of the clinical trial, Millie Cary carried a lot of the day-to-day responsibility for getting things done. For example, she was directly involved in collecting the data from the lab and making sure all the lab data forms were filled out correctly. She transferred the data to the appropriate reporting data forms. She also conducted inservice training for the lab from time to time to make sure the lab understood the study design, the endpoints, the kind of data that needed to be collected, and what the study was intended to demonstrate. The research nurse also interacted directly with patients during the initial qualifying phase and coordinated their involvement during the study. She also consulted with the investigator and sub-investigators on a continuing basis to make sure that everyone at the institution shared the same understanding of the study design, the protocols, and the ultimate purpose of the study. During the clinical trial, Biosense Webster s role as the manufacturer of the product under study and sponsor of the clinical trial was to help ensure that the staff at all research centers had the information and training they needed to conduct rigorous research and that they provided the appropriate data to accurately document the performance of the product under study. The company s primary contact with the clinical trial was through the principal investigator and the research nurse, and to a lesser extent with the staff. There was no direct contact with patients during this trial. After the initial in-service, representatives of the Biosense Webster Clinical Research Department visited the center regularly to monitor the study. The Clinical Research staff checked for data integrity, checked the data against the clinic records to ensure that appropriate patients were entered into the trial, and verified that all procedures were being followed. They also verified that the center was meeting the appropriate endpoints according to the study protocol, was mediating appropriately, and was using the investigational catheter only within the trial with patients who had been properly screened and enrolled. If irregularities in any of the study procedures or protocols were discovered at a particular center, the Clinical Research staff worked with the center s staff to identify the specific areas where the system was breaking down and fix the problem through corrective action or additional training. Since this was the first catheter that had ever been submitted for this indication, the FDA was very cautious in approving research with patients. They approved small patient cohorts at various phases during the study. Biosense Webster collected the data from the research centers, performed the statistical analysis, and prepared incremental submissions for the FDA for each cohort. When the clinical trial was finally complete, Biosense Webster compiled all the data, performed a comprehensive statistical analysis, and included it as a summary within the final submission for new product approval. The FDA has up to 180 days to complete the initial review of an application. During that time, additional data may be required, additional testing may be requested, or other information may be needed. The Dual Sensor 8 mm Tip Ablation Catheter we tested in this clinical trial and is under FDA review for marketing approval. Introducing a new interventional device for use in human beings is a tremendous responsibility. The right product has the potential to provide enormous benefits for patients who would otherwise suffer without hope. The wrong product, however, has the potential to increase the suffering of those patients. Only rigorous, careful research can determine which is which. The two primary keys to valid research though a clinical trial are 1) seamless communication and cooperation between the sponsor and the research centers conducting the trial, and 2) scrupulous adherence to the approved protocols.