9.8 - Monitoring and Interim Reporting for Trials9.8 - Monitoring and Interim Reporting for Trials
Here are some practical issues as they relate to single-center trials. Typically, an investigator for a single-center trial needs to submit an annual report to his/her IRB. The report should address whether the study is safe and whether it is appropriate to continue.
The report should include the following topics:
- Compliance with governmental and institutional oversight,
- Review of eligibility (low frequency of ineligible patients entering the trial),
- Treatment review (most patients are adhering to the treatment regimen),
- Summary of response,
- Summary of survival,
- Adverse events,
- Safety monitoring rules (possibly statistical criteria for evaluating safety endpoints), and
- Audit and other quality assurance reviews.
A multi-center trial is one in which there are one or more clinical investigators at each of a number of locations (centers). Obviously, multi-center trials are of great importance when the disease is not common and a single investigator is capable of recruiting only a handful of patients.
Advantages of a multi-center trial (Pocock, 1983) include the following:
- Larger sample size and quicker patient accrual,
- Broader interpretations of results because of the multiple participants involved in the study across various geographic regions, (this adds to external validity), and
- Increased scientific merit of the trial because of collaborations among experienced clinical scientists involved in the design and implementation of the study.
Of course there is a down side... Disadvantages of a multi-center trial include the following:
- Planning is more complex,
- The study is going to be more expensive,
- More effort to needs to go into ensuring compliance to clinical protocol across all centers,
- Quality control must be implemented for taking measurements and recording data,
- You need a data coordinating center (DCC) for storing, monitoring data and organizing investigators,
- A need develops to keep all investigators involved and motivated,
- Avoidance of passive investigators,
- Compromise between quantity and quality of centers, and
- A need for strong leadership.
The NIH requires a Data and Safety Monitoring Board (DSMB) to monitor the progress of a multi-center clinical trial that it sponsors. Although the FDA does not require a pharmaceutical/biotech company to construct a DSMB for its multi-center clinical trials, many companies are starting to use DSMBs on a regular basis.
There are several advantages that a DSMB provides, such as yielding a mechanism for protecting the interests and safety of the trial participants, while maintaining scientific integrity. The manner in which it is constructed should ensure that the DSMB is financially and scientifically independent of the study investigators so that decisions about early stopping or study continuation are made objectively. Depending on the circumstances, a DSMB may be composed of anywhere from three to ten experts in medicine, statistics, epidemiology, data management, clinical chemistry, and ethics. None of the study investigators should be a part of the DSMB. In addition, the DSMB should not be masked to treatment assignment when it is evaluating a clinical trial. Although investigators and statisticians may submit information and materials to the DSMB for their study, most of the deliberations made by the DSMB are kept confidential. The DSMB reports directly to the sponsor of the multi-center trial (the NIH or the company) and does not report to the investigators.
A DSMB typically examines the following issues when assessing the worth of a multi-center clinical trial:
- Are the treatment groups comparable at baseline?
- Are the accrual rates meeting initial projections and is the trial on its scheduled timeline?
- Are the data of sufficient quality?
- Are the treatment groups different with respect to safety and toxicity data?
- Are the treatment groups different with respect to efficacy data?
- Should the trial continue?
- Should the protocol be modified?
- Are other descriptive statistics, graphs, or analyses needed for the DSMB to make its decisions?
The major disadvantage of a DSMB holding the decision-making authority in a multi-center clinical trial, instead of the investigators, is that expertise may be sacrificed in order to maintain impartiality. Investigators gain valuable knowledge during the course of the trial and it is not possible to provide the DSMB with the totality of this knowledge. Nevertheless, the advantages of a DSMB seem to outweigh this disadvantage during the conduct of a multi-center trial.
A comprehensive book on the aspects of DSMBs is available: Ellenberg, SS. Fleming, TR. DeMets, DL. 2002, Data Monitoring Committees in Clinical Trials, New York, NY: Wiley.