The Changing Face of Phase I Cancer Clinical Trials: New Challenges in Study Requirements.

Abstract

Background-Phase I studies in cancer have changed in recent years. With the advent of new less toxic targeted agents, more patients may now be candidates for new drug studies earlier in the course of their disease. It is to the advantage of the members of the oncology community to know more about the details and requirements for participation in early phase clinical trials so they can advocate for their patients and help them decide when such trials may be an appropriate choice. In order to examine the work intensity of early phase cancer clinical trials, we compared the study requirements of phase I and II protocols. Methods-As a surrogate of study complexity, we examined five parameters-number of physical exams, vital sign determinations, electrocardiograms (ECGs), non-pharmacokinetic laboratory tests, and pharmacokinetic (PK) sampling-in the first four weeks of protocol, in 90 studies (49 phase I and 41 phase II). Findings-From July 2004 through March 2007, there were 49 phase I trials in the Phase I Program, nine phase II studies conducted by physicians appointed in that program, and 32 phase II trials with accessible data in the Department of Thoracic/Head & Neck Medical Oncology. In the phase I versus phase II trials, there were significantly more (p < 0.05) physical exams (mean ± SE = 3.16 ± 0.24 vs. 2.22 ± 0.13), vital signs (5.63 ± 0.61 vs. 2.80 ± 0.26), ECGs (4.36 ± 1.16 vs. 0.80 ± 0.17), non-PK lab tests (18.08 ± 1.31 vs. 10.12 ± 0.65), and PKs (15.14 ± 1.79 vs 1.02 ± 0.53). These values were also significantly different (p<0.005 for each) when comparing medians by non-parametric tests. Interpretation-While both phase I and phase II trials have substantial study requirements, those for the phase I studies were significantly higher. Successful conduct of early phase clinical trials requires significant research infrastructure.

Compliance in Early-Phase Cancer Clinical Trials Research

“…Perhaps in part as a result of the increasing desire to reduce toxicities, as well as the historic low benefit rate of many drug interventions in oncology, adverse events are closely scrutinized and patients enrolled in clinical trials are intensively monitored. The earliest stage trials, that is, phase I trials, commonly require frequent repetition of a variety of tests or procedures, such as vital sign measurements, physical examinations, ECG monitoring (in order to evaluate QT interval and rhythms), blood draws for PK analyses and for pharmacodynamic impact, non-PK blood draws, eye exams, endocrine follow-up, and other specialized examinations for safety assessment and/or for data collection [1][2][3][4]. In phase II and III studies, Roche et.…”

“…Several authors [1,2] have discussed issues that emerge as a result of the monitoring directive, including an exponential growth in tests, the rigidity of the rules governing the proper follow-up of patients, and duplication of tests on multiple occasions. In a paper published in 2002 [2], it was estimated that one full-time equivalent research staff was required for enrollment of every 10 patients in a moderate-intensity phase III study.…”

“…Progressively more intensive monitoring is being used in cancer clinical trials research [1,2]. Monitoring of patients in clinical studies via tabulation of adverse events, follow-up of laboratory tests, electrocardiograms (ECGs), scans, and specialized testing (e.g., ophthalmology exams, pharmacokinetic [PK] sampling) generally serves one of two purposes: (a) ensuring patient safety while on an experimental drug and (b) data collection and analysis that are not required for the direct clinical management or safety of the patient but are incorporated to more fully evaluate the drug for research purposes.…”

U.S. Food and Drug Administration Inspections of Clinical Investigators: Overview of Results from 1977 to 2009

“…It has been well documented that the complexity of clinical trials has increased substantially in this period of time (9)(10)(11)(12)(13)(14)(15). Hence, the purpose of this review was to describe the frequency with which compliance problems are observed, with the rationale for the study being that compliance in the face of increasing protocol complexity might present challenges that should be ascertained, so that they can be addressed.…”

Considerations for hospital approval of human participant research

“…Jamerson 5 also makes the case for hospital departmental review and involvement, assessment of the ability to integrate study activities into the hospital structure, assessment of the resources needed to support the research, determination of whether the hospital will contribute financially to the research, and explicit decision making regarding the assumption of institutional risk. Despite the recognition that US patients increasingly live with multiple chronic conditions 6 and that clinical trial protocols have become more procedure and resource intensive and costly, [7][8][9] there has not been a corollary recognition of the increasing need for hospitals to understand and manage research activities occurring within their facilities. Our organization is a hospital system with 9 acute care hospitals, including an academic teaching hospital (affiliated with a university medical school) with a Level 1 Trauma Center, 1 specialty rehabilitation hospital, numerous specialized clinics, and a LifeFlight Program with a 6-helicopter fleet (Geisinger, Danville, PA).…”