Monitoring the conduct of a trial

The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events

Declaration of Helsinki. Principle 13

According to Emanuel and colleagues (1), respect for potential and enrolled subjects comprises five elements: respecting participants' informational privacy interests; permitting participants to withdraw from the trial without penalty; providing enrolled participants with any new information that may affect their willingness to remain in the trial; monitoring participants' safety, particularly with respect to the occurrence of adverse events; and providing participants information about the outcome of the trial.

The checklist addresses two items that are necessary to fulfill this requirement for the ethical conduct of research: the trial monitoring plan and the means whereby the results of such monitoring will be made readily available to research ethics committees. Committees have obligations towards participants that are encompassed in the notion of continuing review (2), which is particularly important during the time participants are being recruited, research-related interventions are being applied, and interim results are collected and analyzed.

Because controlled trials typically involve multiple centers, each of which may recruit only a few participants, research ethics committees may not be able to acquire a contextually meaningful sense of the overall experience of trial participants. In industry-sponsored trials, committees may receive a large volume of unaggregated adverse event reports emanating from other centers, but be unable to determine their significance. Morse and colleagues (3) have reported on the deliberations of a group of professionals with expertise in various aspects of clinical trials, confirming the challenges committees face in the context of multicenter trials. They describe certain actions and requirements that should be fulfilled by the various parties involved in clinical trials, which are adapted and summarized in the following table.

Actions and requirements for clinical trial monitoring
A formal, systematic plan is required for each trial.
The plan must be included in the application for research and approved by the research ethics committee.
The plan should provide for the provision of aggregated data summaries, and an explanation of the severity and relatedness of adverse events to the trial interventions, to research ethics committees at pre-specified intervals.
Independent Data and Safety Monitoring Committees (DSMB) should be constituted when applicable. The means whereby summaries of its deliberations will be provided to research ethics committees at regular intervals must be declared.
A summary of the DSMB's governance structure, and its operational and statistical approach to interim results analysis, should be pre-specified and elaborated on in the research application

The trial monitoring plan

The complexity and intensity of safety monitoring should be proportionate to the potential risks, and the number of participants and centers involved in the trial. Small, single-institutional trials in which anticipated risks associated with the trial-related interventions are limited (severity and frequency) may necessitate only a monitoring group consisting of the primary investigator, a statistician, and an individual independent of the trial, such as a member of the research ethics committee. The plan should declare when interval reports of aggregated data will be provided to the committee. This may be related to specified time intervals or the number of subjects enrolled.

In the U.S., the F.D.A. requires the submission of Annual Reports from sponsors of drug trials conducted under an IND (Investigational New Drug) application (4). The reports must include summary information such as the number of subjects enrolled to date; the number of subjects withdrawn from the trial; a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system; a list of subjects who died during the reporting interval, with the cause of death; and a list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related.

For trials conducted under an IND, the monitoring plan should include a provision for transmittal of this annual report, or equivalent report, to the committee at pre-specified intervals.

Establishment of a Data and Safety Monitoring Board

Because controlled trials vary substantially in nature and scope, there are no definitive indications for establishment of a DSMB. Factors that should be considered when deciding on the potential applicability for interim results monitoring include the nature of the outcomes evaluated; the likely temporal relationship between the occurrence of measured outcomes and the estimated time period during which subjects will be accrued for the trial; and the nature of the known risks associated with the research interventions. The application for research should elaborate on the applicability of a DSMB for the proposed trial. To this end, research ethics committees and investigators should reference a decision in relation to guidelines proposed by Cairns and colleagues (5), which are adapted and summarized in the table below.

A DSMB is needed for a clinical trial whenever any one of the following are present
The trial has the power to detect statistically significant differences in tangible outcomes (mortality and significant morbidity).
When the risks asociated with the therapeutic components are not known. This is particularly applicable to pivotal phase 3 trials of investigational agents.
When the therapeutic components in either arm are known to be associated with severe adverse effects. This includes trials intended to evaluate approved agents for new medical indications.

When a DSMB is planned, certain information concerning its governance and monitoring plan should be provided in the application for research: the DSMB should be independent of the sponsor, and its members should not have any potentially disqualifying conflicts of interest in the outcome of the trial. Members with appropriate qualifications for defined roles should be chosen. The trial may be associated with more than one statistician, and they may be blinded or unblinded with respect to which outcomes are related to the arms of the trial. Guidance concerning this is available (6,7), and the choice for the proposed trial should be an informed one.

The application for research should list the name and affiliations for each DSMB member, and each should be associated with a declaratory statement concerning conflicts of interest, if any. The role fulfilled by each member should be stated.

The DSMB is responsible for periodic evaluation of the trial results, and may need to stop the trial for reasons of efficacy, safety or futility. Both significant positive and negative trends (8) necessitate careful evaluation. The DSMB has to balance the interests of the trial's participants against the need to acquire statistically valid results. The DSMB will evaluate interim results on a statistical basis (frequentist or bayesian), and should also consider the statistical evaluation in light of other information such as results of related trials, and an up-to-date Systematic Review pertinent to the trial (9).

Statistical techniques appropriate for trial monitoring have been described, and stopping guidelines for trial should be formulated in light of the nature of the trial, the nature of the interventions evaluated, and the nature of the adverse events and toxicity that may occur (10-11).

The application for research should specify the statistical techniques that will be used for interim results monitoring, and the stopping guidelines that will be used for the trial.

Communication of trial monitoring results and protocol changes to research ethics committees

In multicenter trials, information concerning interim results monitoring and protocol changes are typically transmitted to the principal investigator at each participating center. The investigator is responsible for providing this information to the committee, and ensuring that proposed protocol changes are reviewed and approved before they are instituted. Local research ethics committees recognize that this process of communication is unreliable and inefficient. Individual centers often become involved in the trial at different times relative to trial inception. Thus, this information should be made directly available -- on a continuing basis -- to local committees by the research sponsor. The availability of electronic communication and the Internet makes this feasible.

The feasibility and utility of using the Internet for the conduct of clinical trials has been established. Marks and colleagues (12) have described the web-based conduct of clinical trials wherein many trial-related functions are accomplished : site administration; center and subject recruitment; submission of data (electronic Case Report Forms) ; randomization; establishment of a "virtual" pharmacy for provision of drugs to participating centers; site monitoring; maintenance of security; and adverse event reporting. Many other items of information of interest to investigators, participants and the public may be provided. It would be technologically trivial for research ethics committees requirements to be included in this Web-based trial format. Involved committees could be notified by E-mail when new and pertinent information has been posted on the trial's Web site. The reader is referred to an example of this in the context of the INVEST (INternational VErapamil/trandolapril STudy) study for hypertension (13).

A multicenter clinical trial should be associated with a Web site wherein up-to-date trial-related information required by research ethics committees is provided. Committees should strongly encourage the conduct of Web-based clinical trials.


References available online are hyperlinked

1. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000; 283:2701-2717

2. 45 CFR 46.109(e). IRB review of research (Continuing Review).

3. Morse MA, Califf RM, Sugarman J. Monitoring and Ensuring Safety During Clinical Research JAMA 2001: 285:1201-1205.

4. IND. Annual Reports. Title 21 Part 312.33

5. Cairns JA, Hallstrom A, Held P. Should all trials have a Data Safety and Monitoring Committee? Am Heart J 2001; 141:156-63.

6. Wittes J. Data Safety Monitoring Boards Biopharmaceutical Report 2000; 8:1-6.

7. Snapinn SM. Comment on "Data Safety Monitoring Boards" Biopharmaceutical Report 2000; 8:7-8.

8. DeMets DL, Pocock SJ, Desmond GJ. The agonsing negative trend in monitoring of clinical trials Lancet 1999; 354:1983-88.

9. Chalmers I. Using systematic reviews and registers of ongoing trials for scientific and ethical trial design, monitoring, and reporting. In, Egger M, Davey SG, Altman DG (editors) Systematic Reviews in Health Care: Meta-analysis in Context. London. BMJ Books. 2001, pp 429-443

10. Bolland K, Whitehead J. Formal approaches to safety monitoring of clinical trials in life-threatening conditions Stat Med 2000; 19:2899-2917.

11. Freidlin B, Korn EL, George SL. Data Monitoring Committees and Interim Monitoring Guidelines Control Clin Trials 1999; 20:395-407.

12. Marks RG, Conlon M, Ruberg SJ. Paradigm shifts in clinical trials enabled by information technology Stat Med 2001; 20:2683-2696.

13. The INVEST trial