ARCHIVE Data and safety monitoring
Section 2
Which PCTs Should Have a DMC? – ARCHIVED
While FDA regulations require sponsors to monitor their trials, there are different ways this can be accomplished. One method is an independent DMC, sometimes also referred to as a Data and Safety Monitoring Board (DSMB). These committees are independent of the trial sponsor and investigators; they should have no vested interest in the trial or its outcome. Current US Food and Drug Administration (FDA) regulations impose no requirements for the use of DMCs except for research studies conducted in emergency settings in which the requirement for informed consent has been waived (21 CFR 50.24(a)(7)(iv)). Funding agencies impose broader requirements, as discussed later.
FDA guidance advises considering the following when determining whether a study warrants using a DMC:
- Is it a large, multicenter study of long duration?
- Is the study endpoint such that a finding at interim analysis might ethically require termination of the study before its planned completion?
- Are there a priori reasons for a particular safety concern (e.g., particularly invasive treatment?)
- Is there prior information suggesting the potential for serious toxicity due to the study treatment?
- Is the study being performed in potentially fragile or vulnerable populations (e.g., children, pregnant women, very elderly, terminally ill, those with diminished mental capacity)?
- Is the study being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a less serious endpoint?
If a study has one or more of these characteristics, the FDA recommends that sponsors consider the use of a DMC to further protect study participants.
Additional considerations include whether review by a DMC is practical (e.g., due to study length) and whether a DMC can help ensure the scientific validity of a trial. Examples of studies that may not need a DMC include short-term studies where a DMC is unlikely to have the opportunity to make a difference and studies with less serious outcomes (e.g., symptom relief) in which early termination is unlikely to be appropriate. As many PCTs will be large, multicenter studies with serious clinical outcomes, it is likely that most of these will warrant use of a DMC (Ellenberg et al 2015).
Research sponsors may have their own policies outlining the type of data monitoring required and which studies must have a DMC. For example:
- NIH policy requires most NIH-funded randomized trials to have a DMC if they are multicenter and pose any material risk to participants.
- PCORI policy states that a DMC should be appointed if required by the IRB, regulatory agency, or determined appropriate “after considering factors such as potential risks; target study subject population, nature, and size; and the research project’s scope and complexity.”
PCT investigators should work with their sponsor(s) to implement an appropriate data monitoring plan for the study and determine whether a DMC (or DSMB or independent monitoring committee) will be used. The NIH Collaboratory has made available brief descriptions of the data monitoring plans for all NIH Collaboratory Trials as part of the publicly available ethics and regulatory documentation for these trials. The data monitoring details are excerpted in the table below. Not all NIH Collaboratory Trials use an independent DMC, but all have a data monitoring plan that was discussed with the NIH sponsor and determined to be in compliance with their policies. More details on data monitoring for some of these trials are explored throughout the chapter.
| NIH Collaboratory Trial | Minimal risk? | Uses a DMC? | Monitoring plan |
|---|---|---|---|
| ABATE Infection | Yes | No | The sponsor approved the trial’s data monitoring plan, and study-related event forms were distributed to all participating sites. |
| ACP PEACE | Yes | Yes | The DSMB has members with expertise in advance care planning (ACP), cluster trial design, biostatistics, EHR data and health data access, and geriatrics. The DSMB will identify any safety issues every 6 months. |
| BackInAction | Yes | Yes | For the conduct phase, the trial will establish an independent monitoring committee (IMC) comprising experts in chronic pain, internal medicine, family medicine, qualitative research, and clinical trials. The IMC will review adverse events/serious adverse events and data on recruitment and retention efforts every 6 months. |
| EMBED | Yes | No | The trial has an independent study monitor for data monitoring and oversight. |
| FM TIPS | Yes | Yes | For the conduct phase, the sponsor will establish a DSMB for data monitoring through a contract research organization. |
| GGC4H | Yes | Yes | The trial has established an IMC that monitors and evaluates the safety of study participants; monitors the performance of the study; and assures adherence to the reporting of any adverse events and serious adverse events. |
| HiLo | No | Yes | A DSMB has been established. In addition, a site management and monitoring team reviews enrollment reports weekly during the enrollment phase. Any concerns will be communicated with the unit staff and members of the steering committee. |
| ICD-Pieces | Yes | Yes | The study team tracks and regularly informs the DMC of safety events, including the primary outcome (all-cause unplanned hospitalization), secondary outcomes (cardiovascular events, emergency department visits, and death), and safety events that are possible outcomes of the interventions. The team tracks the primary outcome rates by healthcare system and reports these to the sponsor and DMC quarterly. |
| LIRE | Yes | No | Two safety officers reviewed study data at regular intervals for any safety concerns. |
| NOHARM | Yes | Yes | A DSMB reviewed the oversight protocol and reviews progress and safety issues periodically. For the conduct phase, the study team will adhere to the sponsor’s requirements for monitoring and oversight. |
| Nudge | Yes | Yes | A DSMB has been established. The study team continuously monitors responses to the text messages and has a weekly call with the pharmacist team to discuss patient responses to the text messages to ensure that any clinical messages from patients are responded to appropriately. |
| OPTIMUM | Yes | Yes | For the conduct phase, the trial will establish an independent DSMB. |
| PPACT | Yes | No | An independent monitor identified by the study team and sponsor reviewed subject accrual, serious adverse events, and clinician/patient compliance with treatment every 6 months. |
| PRIM-ER | Yes | No | The trial has a 3-member IMC to monitor patient safety and the performance of the clinical study in meeting its stated objectives. The IMC will be engaged at periodic intervals during the course of the study as outlined in the charter. |
| PROVEN | Yes | Yes | The trial had a full DSMB. The statisticians were able to review unblinded interim data, but the PIs remained blinded. |
| SPOT | Yes | Yes | The trial was monitored by a standing DSMB at the sponsor. |
| STOP CRC | Yes | No | The trial’s safety monitoring plan consisted of semi-annual review of study progress and adverse events by 2 independent monitors--a statistician and a gastroenterologist--who were approved by the sponsor. |
| TiME | Yes | Yes | An external DSMB appointed by the sponsor reviewed study progress, outcome event rates, and routinely performed laboratory tests as indicators of safety. |
| TSOS | Yes | Yes | The trial has a DSMB providing oversight. Outcomes monitored included adverse events (medication side effects, death), suicidality, loss to follow-up, and demographics. |
Source: NIH Collaboratory Trial ethics and regulatory documentation. For more information on the NIH Collaboratory Trials, including study population and primary outcome, see the NIH Collaboratory Trials table in the What Is a Pragmatic Clinical Trial chapter.
In sections that follow, we review special considerations for data monitoring in PCTs, including monitoring protocol adherence when information on “real-world” use is desired, issues associated with use of EHR data such as data quality and timeliness, complexities of monitoring adverse events in PCTs, whether PCTs should ever be stopped early due to futility, and any particular perspectives or expertise that may be useful on a DMC charged with monitoring PCTs.
SECTIONS
sections
- Introduction – Data and Safety Monitoring ARCHIVED
- Which PCTs Should Have a DMC? – ARCHIVED
- Monitoring Protocol Adherence – ARCHIVED
- Data Issues With Monitoring PCTs – ARCHIVED
- Monitoring for Serious Adverse Events – ARCHIVED
- Futility Assessment V. 2 – ARCHIVED
- Futility Assessment – ARCHIVED
- Case Study: Planning for Monitoring PCTs – ARCHIVED
- Including Stakeholder Perspectives – ARCHIVED
- Special Training and Resources for DMCs of Pragmatic Trials – ARCHIVED
- Additional Resources – ARCHIVED
Resources
Grand Rounds Presentations:
The DSMB Role in Pragmatic Trials: NIMH Progress and Challenges
REFERENCES
Ellenberg SS, Culbertson R, Gillen DL, Goodman S, Schrandt S, Zirkle M. 2015. Data monitoring committees for pragmatic clinical trials. Clin Trials. 12:530–536. doi:10.1177/1740774515597697.
current section : Which PCTs Should Have a DMC? – ARCHIVED
- Introduction – Data and Safety Monitoring ARCHIVED
- Which PCTs Should Have a DMC? – ARCHIVED
- Monitoring Protocol Adherence – ARCHIVED
- Data Issues With Monitoring PCTs – ARCHIVED
- Monitoring for Serious Adverse Events – ARCHIVED
- Futility Assessment V. 2 – ARCHIVED
- Futility Assessment – ARCHIVED
- Case Study: Planning for Monitoring PCTs – ARCHIVED
- Including Stakeholder Perspectives – ARCHIVED
- Special Training and Resources for DMCs of Pragmatic Trials – ARCHIVED
- Additional Resources – ARCHIVED