| Comment Record|
Dr. Thomas Louis ||
2001-11-25 12:09:11 |
| Comments for FDA General |
1. General Comments
+ heightened awareness within the scientific community
of problems in clinical trial conduct and analysis
that might lead to inaccurate and/or biased results,
especially when early termination for efficacy is a
possibility, and demand for approaches to protect
against such problems.
COMMENT: The intended point is important, but the wording is a bit confusing. One needs a multidisciplinary group to discuss the formal and informal aspects of deciding to stop or modify a trial. The DMC serves as that multidisciplinary group, taking fiduciary responsibility for trial participants.
All clinical trials require safety monitoring (21 CFR
312.32(c)), but not all trials require monitoring by a formal
committee external to the trial organizers and investigators. As
noted earlier, DMCs have generally been established for large,
randomized multisite studies that evaluate interventions
intended to prolong life or reduce risk of a major adverse
health outcome such as a cardiovascular event or recurrence of
cancer. Because monitoring of accumulating results is almost
always essential in such trials, DMCs should be established for
controlled trials with mortality or major morbidity as a primary
or secondary endpoint. They may also be helpful in settings
where trial participants may be at elevated risk of such
outcomes even if the study intervention addresses lesser
outcomes such as relief of symptoms. Although DMCs may prove
valuable in other settings as well, a DMC is not needed or
advised for every clinical study. Several factors are relevant
to determining whether or not to establish a DMC for a
particular trial. These relate primarily to safety,
practicality, and scientific validity.
COMMENT: State that the default option should be that a DMC is constituted, that the burden of proof should be on not having one.
The oversight of a DMC in addition to typical
sponsor-conducted safety monitoring can provide further
protection of study participants. A trial that is large, of
long duration, and multi-center raises more possibilities
of safety concerns because of the greater overall exposure
and because prolonged exposure may cause adverse effects
not readily recognized as such. DMCs may be more important
in these trials.
COMMENT: DMCs help with more than safety. Frequently, they help identify important trial modifications, review management issues and increase the credibility of a study.
Most DMCs are composed of clinicians with expertise in
relevant clinical specialties and at least one
biostatistician knowledgeable about statistical methods for
clinical trials and sequential analysis of trial data. Some
DMCs may include a medical ethicist knowledgeable about the
design, conduct, and interpretation of clinical trials.
Prior DMC experience is helpful, but not essential,
although it is
that at least some members have
prior DMC service. Some trials may require participation of
other types of scientists; for example, a study in which
the investigational drug has variable absorption or
excretion might include a clinical pharmacologist on the
DMC; toxicologists, epidemiologists, and laboratory
scientists could be included in particular cases. One or
more individuals (often non-scientists) who may help bring
to the DMC the perspectives of the population under study
may be a useful addition in some settings. That individual
should not be participating in the trial, but could be
someone with the disease under study or a close relative of
such an individual, for example. DMCs for international
trials should have representation from participating
countries or regions to the extent practical
ADD(relevant written and oral language skills are essential).
representation of gender and ethnic groups may be of
particular importance for some trials. All appointees
should be prepared to maintain confidentiality of the
interim results they have reviewed (see Section 4.2).
The study sponsor usually appoints the DMC chair. Prior DMC
experience is more important for the chair than for other
DMC members, as members will look to the chair for
leadership on administrative as well as scientific issues.
DELETE(If the DMC includes only one statistician, however, it is desirable for the statis-tician to have had prior DMC experience as well)
ADD(It is very important that at least one statistician has had prior DMC experience.)
The chair should be
ADD(effective in developing a proper process, in)
facilitating discussion, integrating differing points of
view and moving toward consensus on recommendations to be
provided to the trial sponsors. It is particularly
important for the chair to make a firm commitment to
participate for the duration of the trial.
Sponsors should establish procedures to ensure the
confidentiality of the interim data (see Section 220.127.116.11.).
ADD(DMC members should commit to keeping results confidential.)
4.2.1. Interim Data
The interim unblinded data will be most securely
protected from inadvertent or inappropriate access by
the sponsor if it is prepared for analysis by an
entity group independent of the sponsor and investigators
(see Section 6.4). The lead investigators, the study
Steering Committee, or the sponsor generally develops
the analytical plan, but these individuals should
generally not be involved in the actual preparation of
the interim results, for reasons discussed in Section
6.4. They should, however, work with the statistician
who will be preparing and presenting the interim
analyses prior to the first analysis of unblinded data
to develop a template for the interim reports.
COMMENT: This is a bit off the mark. In multi-center trials, the statistical center is not independent of the investigators. Rather, the. center ensures that it acts independently in this aspect of the clinical trial.
4.2.2. Interim Reports to the DMC
Any part of the interim report to the DMC that
includes comparative effectiveness and safety data
presented by study group, whether coded or uncoded,
COMMENT: Some readers won't know what this means.
should generally be available only to DMC members
during the course of the trial, including any
follow-up period-that is, until the blind is broken.
If such reports are shared with the sponsor, it may
become impossible for the sponsor to make potentially
warranted changes in the trial design or analysis plan
in an unbiased manner (see Section 6.3).
COMMENT: Make the foregoing more definitive: results should not be shared unless an agreed process has been followed (in extreme circumstances).
4.3.1. Considerations for Standard Operating
18.104.22.168 Meeting Schedule and Format
COMMENT: Meeting frequency should err on the side of more frequent until the study is well underway. If necessary, frequency can then be modified.
Face-to-face meetings are generally preferable,
but telephone meetings may be necessary in some
situations, particularly when new information
must be urgently considered. In some settings,
when the DMC has already had numerous meetings
and the committee is very familiar with the trial
and the analytical issues, telephone meetings may
COMMENT: Telephone meetings require special considerations to ensure that only those permitted to be on the call are on the call.
22.214.171.124 Meeting Structure
Attendance at meetings raises the same
confidentiality issues as access to interim
reports to the DMC. Although confidentiality of
the interim data should be maintained, the DMC
may interact with the study sponsor and/or trial
lead investigators to clarify issues relating to
the conduct of the trial, potential impact on the
trial of external data, or other topics. In order
to permit such interaction without compromising
confidentiality, many DMC meetings include an
open session in which information in the open
report is discussed. These non-confidential data
may include, for example, status of recruitment,
baseline characteristics, ineligibility rate,
accuracy and timeliness of data submissions, and
aggregated safety and outcome data.
COMMENT: Some will argue that even aggregate outcome data should not be pre-sented in the open meeting. This issue will be an important discussion item in the Nov. 27th meeting.
Section 6 describes the risks to study integrity
when sponsor representatives have access to
unblinded interim data and attend closed sessions
of DMC meetings. In settings in which sponsors
choose to permit its representatives or other
non-DMC members to attend the closed session
despite the risks of such arrangements, the DMC
should have the option of conducting an
executive closed session with no participants
other than DMC members.
COMMENT: It should be in only extraordinary circumstances that such attendance is allowed.
4.3.2. Statistical Methods
Nevertheless, protection of Type I error is
important even when there is a stated intention to
stop early only for futility reasons since interim
review of outcome data always raises the possibility
that the DMC may find early results so persuasive that
it would recommend early termination of the trial.
COMMENT: Consider recommending that a fully sequential monitoring plan be used, one that has boundaries as though monitoring were to occur after every endpoint is re-ceived. These boundaries are very little wider than the six-look boundaries and allow assessment of the trial as necessary.
COMMENT: How should the type I error be allocated? Should there be 0.05 for the main endpoint and a separate 005 for AEs, etc.?
126.96.36.199 Consideration of External Data
COMMENT: A policy is needed for sharing of information between two DMCs
monitoring related, active trials.
6.1. Desirability of an Independent DMC
ADD( 4. Enhances the credibility of the trial.)
6.2. Value of Sponsor Interaction with the DMC
COMMENT: The sponsor may be the federal government and all considerations in this section apply with equal force in that situation.