The closeout phase starts with the
final follow-up visit of the first participant enrolled and lasts
until all analyses have been completed. It is evident that well
before the scheduled end of the trial, there needs to be a detailed
plan for this phase if the study is to be completed in an orderly
manner. Importantly, one must be prepared to implement or modify
this plan prior to the scheduled termination since unexpected trial
results, either beneficial or harmful, may require the trial to be
stopped early.
This chapter addresses a number of
topics on the closeout process. Although many of them relate
primarily to large single-center or multicenter trials, they also
apply to smaller studies. The topics discussed include technical
procedures for the termination of the trial, cleanup and
verification of data, dissemination of trial results, storage of
study material, and post-study follow-up. Obviously, the details of
the closeout plan have to be tailored to each particular
trial.
Fundamental Point
The closeout of a clinical trial is usually a
fairly complex process that requires careful planning if it is to
be accomplished in an orderly and effective fashion.
Termination Procedures
Planning
Many details of closeout will depend on
factors that only become known once the trial is underway or
participant enrollment is completed. Nevertheless, general planning
for the closeout ought to start early. There are arguments for
initiating this process on day one of the trial. Data management
processes can be optimized for rapid database finalization at the
end the trial. One major issue is that the trial may not continue
through its scheduled termination. Greater-than-expected benefit or
unexpected harm may lead to early termination. A more subtle reason
is that developing plans for closeout after the trial is well
underway may be interpreted by the blinded investigators as a
signal of imminent trial termination. Thus, another recommendation
is to develop the general closeout plans prior to the first meeting
of the data monitoring committee [1].
The closeout phase needs its own
written protocol or operating procedures with respect to
termination activities, dissemination of results, and data cleanup
and storage. The literature on the topic of closeout is scant but
there are a few good descriptions of the process [2].
Scheduling of Closeout Visits
If each participant in a clinical trial
is to be followed for a fixed period of time, the closeout phase
will be of the same duration as the enrollment phase. If
recruitment took 2 years, the closeout phase would last 2 years.
This fixed follow-up design may not be desirable, since terminating
the follow-up of some participants while others are still being
actively followed can create problems. In some blinded trials, the
code for each participant is broken at the last scheduled follow-up
visit. If the unblinding must occur over a span of many months or
years, there is the possibility of the investigator learning
information that could suggest the identity of the drugs taken by
participants still actively followed in the trial. This may happen
even if drug codes are unique for each participant. The
investigator may start associating a certain symptom or
constellation of symptoms and signs with particular drug
codes.
An alternative and frequently used plan
involves following all participants to a shortened closeout period
to avoid the problems described above. Another advantage of this
design is the added power of the trial and more information about
the effects of longer intervention. The follow-up period is
extended beyond the minimum time for all but the last participant
enrolled. In a trial with 2 years of uniform recruitment, the
additional follow-up period would increase by an average of up to 1
year. In addition, this approach might be more cost-efficient when
clinic staff is supported solely by the sponsor of the trial. With
all participants followed to a shortened closeout period, full
support of personnel can be justified until all participants have
been seen for the last time. In trials where the participants are
phased out after a fixed time of follow-up, an increase in the
staff/participant ratio may be unavoidable.
Despite the problems with following all
participants for a fixed length of time, this approach may be
preferable in certain trials, particularly those with a relatively
short follow-up phase and when the effect of the intervention is
believed to be restricted to a short period of time. In such
studies, there may be no realistic alternative. In addition, it may
not be logistically feasible to conduct a large number of closeout
visits in a short time. Depending on the extent of data collection
at the last visit and availability of staff and weekly clinic
hours, seeing 100–150 participants at a clinic may require a month
or 2. A decision on the type of follow-up plan should be based on
the scientific question as well as logistics.
Final Response Ascertainment
At trial termination, it is important
in any trial to obtain, to the extent possible, response variable
data on every enrolled participant. It is particularly so in trials
where the main response variables are continuous, such as
laboratory data or a performance measure. By necessity, the
response variable data must be obtained for each participant at the
last follow-up visit because it marks the end of treatment and
follow-up. If the participant fails to show up for the last visit,
the investigator will have missing data. When the response variable
is the occurrence of a specific event, such as a nonfatal stroke or
death, the situation may be different if the information can be
obtained without having the participant complete a visit.
If a participant
suffers an event after his or her last follow-up visit, but before
all participants have been seen for the final visit, the study must
have a firm a priori rule
as to whether that response variable should be included in the data
analysis. For the participants who complete their participation,
the simplest solution is to let the last follow-up visit denote
each participant’s termination of the trial. For participants who
do not show up for the last visit, the investigator has to decide
when to make the final ascertainment. If death is a response
variable, vital status is usually determined as of the last day
that the participant was eligible to be seen. The counting rule
must be clearly specified in the study protocol or the manual of
procedures.
Another approach is to have a common
cut-off date (for example, the date of the first planned final
follow-up visit). A common cut-off date—such as was used in the
Apixaban for Reduction in Stroke and Other Thromboembolic Events in
Atrial Fibrillation (ARISTOTLE) trial [3]—may be an advantage for clear definitions in
the statistical analysis and for dealing with participants who may
never appear for their final visits. In favor of a variable cut-off
date (used in most trials) is that including all events until the
last participant’s final visit allows maximal capture of the
exposure period and therefore optimizes the precision of the
estimate of the intervention effect. It is possible that the timing
of the final visit could be affected by assignment to intervention
or control and therefore could create bias when a variable cut-off
date is used, although this would likely be small.
A number of means have been used to
track participants and to determine their vital status. These
include the use of a person’s identification number (e.g., Social
Security number in the United States) or contact with relatives,
employers, or health care providers. It has been discovered that
participants have died through searching obituaries. Electronic
medical records and various other electronic databases can be
searched, with appropriate permissions. In countries with national
death registries, including the United States, mortality
surveillance is simpler and probably more complete than in
countries without such registries. Agencies that specialize in
locating people have been used in several trials. As has been used
in many trials, the Digitalis Investigation Group trial
[4] used a search agency, but the
searches were limited to records only. It used directory
assistance, credit header reports, property records, obituary
searches, database mailing lists for magazine subscriptions, and
other similar means. No personal contact was allowed. These
constraints probably limited the success of finding participants
lost to follow-up. This process can be sensitive, since a search
may be looked upon as an intrusion into the privacy of the
participant. The integrity of a trial and the importance of its
results plus the participant’s initial agreement to participate in
the trial have to be weighed against a person’s right to protect
his or her privacy. Investigators should consider including in the
informed consent form a sentence stating that the participant
agrees to have her vital status determined at the end of the trial
even if he or she has by then stopped participating actively or
withdrawn general consent. It pays to initiate the process of
obtaining information on vital status on inactive participants well
in advance of the closeout phase.
The uncertainty of the overall results
rises as the number of participants for whom response variable data
are missing at trial termination increases. For example, assume
that death from any cause is the primary response variable in a
trial and the observed mortality is 15% in one group and 10% in the
other group. Depending on study size, this group difference might
be statistically significant. However, if 10% of the participants
in each group were lost to follow-up, the observed outcome of the
trial may be in question.
The Anti-Xa Therapy to Lower
Cardiovascular Events in Addition to Standard Therapy in Subjects
with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction
51 (ATLAS ACS 2–TIMI 51) trial of rivaroxaban following acute
coronary syndromes [5] highlights
the importance of completeness of follow-up data. The trial had a
primary outcome of cardiovascular death, myocardial infarction, and
stroke, using an on-treatment plus 30-day analysis with an
intention-to-treat sensitivity analysis. In the original data from
which the primary manuscript was published and the first United
States Food and Drug Administration (FDA) filing was made
[5], 1509 (or about 10%) of 15,526
participants had incomplete follow-up, and 799 participants had
incomplete follow-up limiting the observation period of up to 30
days after early discontinuation. For the primary analysis, there
was a 1.8% absolute and a 16% relative risk reduction with
rivaroxaban (p = 0.008)
that was counterbalanced by more major bleeding. There was a 0.8%
lower mortality with rivaroxaban than placebo (p = 0.04) in the primary analysis. The
FDA review raised important issues about missing data
[6]. First, when the FDA declared
that the 10% missing data made it impossible to interpret the
mortality data, the sponsor was able to go back to the sites and
establish vital status for 843 of 1338 patients with a missing
status at the end of the trial, showing that it was possible to
have more complete follow-up with more intense effort. When this
was done, 22 additional rivaroxaban and 9 additional placebo
participants were found to have died, and the p-value increased from 0.045 to 0.076
(for the main “stratum 2” with background thienopyridine therapy).
Secondly, it was more common to have missing data in the
rivaroxaban arm than in the placebo arm, raising further questions
about interpretability. Third, there were three sites in India with
questionable data that could neither be verified nor proven to be
fraud, which raised additional questions about whether to exclude
these data. To address the potential impact of the missing data
with regard to mortality, the FDA presented a variety of imputation
scenarios to address the missing data in stratum 2 [7] (see Table 19.1). Using the
conservative approach of assuming the same mortality for all
patients with missing data, the p-values increased from 0.076 to 0.100.
Table
19.1
ATLAS ACS 2–TIMI 51 trial mortality data
with various imputations (adapted from an FDA slide presentation at
a January 16, 2014 Cardiovascular and Renal Drugs Advisory
Committee meeting [7])
Imputed mortality rate used for missing
data
|
Mortality rates when applied (placebo vs.
rivaroxaban) (%)
|
Additional deaths imputed
|
Hazard ratio (95 % confidence
interval)
|
Nominal p-value
|
---|---|---|---|---|
No imputation
|
3.80 vs. 3.20
|
0
|
0.85 (0.71–1.02)
|
0.076
|
Observed rate for each treatment
group
|
3.80 vs. 3.20
|
5 vs. 11
|
0.85 (0.71–1.02)
|
0.087
|
Pooled rate for all participants
|
3.40 vs. 3.40
|
5 vs. 12
|
0.86 (0.72–1.03)
|
0.093
|
Placebo rate
|
3.80 vs. 3.80
|
5 vs. 13
|
0.86 (0.72–1.03)
|
0.100
|
Another example of the problem of
participants being lost to follow-up, and specifically of
withdrawal of consent, comes from the Comparison of Medical
Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION)
trial [8] of defibrillator versus
pacemaker versus best medical care. Withdrawal of consent was four
times higher in the medical care group than in the other two groups
when the trial was terminated and follow-up ended. At a
recommendation by the data safety and monitoring board, the
investigators approached the participants who had withdrawn their
consent and obtained their permission to collect data on vital
status and hospitalizations retrospectively for the duration of the
trial. This was done at a substantial extra cost and loss of time
and stresses the importance of prevention of withdrawal of
consent.
It is a mistaken concept that when a
participant goes off study medication or intervention that he or
she is out of the study and thus no longer followed, or at least
not followed beyond some short period of time such as 7 days and 30
days. In the Adenomatous Polyp Prevention on Vioxx (APPROVe) study,
participants who stopped their study medication (rofecoxib) due to
adverse effects and other reasons were not followed beyond 14 days
of going off drug [9]. In the
re-analysis, the problem with this “informative censoring” was
revealed and a full extra year of follow-up of all randomized
participants after stopping study treatment was added. This
analysis suggested that the excess of drug-induced major
cardiovascular events observed during rofecoxib treatment continued
to increase during the first year after treatment was stopped. The
adjusted hazard ratio for the extra year was 1.41 (95% confidence
interval [CI] 0.77–2.59), in addition to the hazard ratio of 2.12
(95% CI 1.20–3.74) on treatment and during the following 14
days.
The National Academy of Sciences,
prompted by FDA officials, has published a comprehensive statement
concerning missing data in clinical trials with a focus on phase
III confirmatory trials [10]. The
report states that “there is no ‘foolproof’ way to analyze data
subject to substantial amounts of missing data; that is, no method
recovers the robustness and unbiasedness of estimates derived from
randomized allocation of treatments. Hence, the panel’s first set
of recommendations emphasizes the role of design and trial conduct
to limit the amount and impact of missing data” [10]. We stress the need to have systems in place
from the beginning of the trial to minimize missing response
variables, which for phase III trials begins with carefully
structuring the informed consent to allow follow-up, at least for
vital status, even if a participant otherwise withdraws from study
procedures.
Transfer of Post-trial Care
Termination of a long-term study can
be difficult due to the bonding that often develops between
participants and clinic staff. The final visit needs to be
carefully planned to deal not only with this issue, but also with
the need in many trials to inform the participants of which
medication they were on (in a blinded study), their individual
study data, and the overall study findings (often at a later time).
Referral of the participant to a regular source of medical care is
another important issue (see Chap. 2).
If the closeout is extended over a
long period, as it would be if each participant were followed for
the same duration, any early recommendation to an individual
participant would have to be based on incomplete follow-up data,
which may not reflect the final conclusions of the trial. Moreover,
any information given could “leak” to participants still actively
treated, thus affecting the integrity of the trial. Although it is
highly desirable to provide each participant with a recommendation
regarding continued treatment, doing so may not be possible until
the study is completely over and the trial results have been
published. When unblinding occurs over a span of months or years,
the investigator is in the uncomfortable position of ending a
participant’s involvement in the trial and asking him or her to
wait months before being told the study results and being advised
about what to do. On the other hand, if the incomplete results are
clear cut, it would be easy to arrive at such recommendations.
However, in such an instance, the investigator would be confronted
with an ethical dilemma. How can the investigator recommend that a
participant start, continue, or discontinue a new intervention
while keeping other participants active in the trial? For this
reason, we generally prefer a shortened period of trial
closeout.
Data and Other Study Material
Cleanup and Verification
Verification of data may be
time-consuming, and it can conflict with the desire of the
investigator to publish his findings as early as possible. While
publication of important information should not be delayed
unnecessarily, results should not be put into print before key data
have been verified. Despite attempts to collect complete,
consistent, and error-free data, perfection is unlikely to be
achieved. Traditional monitoring systems are likely to reveal
missing forms, unanswered items on forms, and conflicting data. In
isolated cases, they may also uncover falsification of individual
data [11, 12] and, in the worst cases, fabrication of all
data on fictitious participants [13–15]. Data
cleanup and verification typically continue for months after
completion of the closeout visits, although the use of electronic
records has substantially reduced the burden of this cleanup and
verification. It is necessary to be realistic in the cleanup
process. This means “freezing” and “locking” the files at a
reasonable time after the termination of participant follow-up and
accepting some incomplete data. Obviously, the efforts during
cleanup should be directed toward the most critical areas—those
crucial to answering the primary questions and serious adverse
effects.
We strongly recommend that study forms
and data be continuously monitored throughout a trial as pointed
out in Chap. 11. Data editing should be initiated
as soon as possible, because it is difficult to get full staff
cooperation after a trial and its funding are over. Early
monitoring may reveal systematic problems that can be corrected.
Staff feedback is also important. Approaches for statistical
process control audits are now available, and they have been shown
to reduce the overall database error rates significantly
[16].
Any clinical trial may be faced with
having its results reviewed, questioned, and even audited.
Traditionally, this review has been a scientific one. However,
since regulatory and special interest groups may want to look at
the data, the key results should be properly verified, documented,
and filed in an easily retrievable manner. The extent of this
additional documentation of important data will depend on the
design of each trial. Electronic data provide verification
opportunities that are more efficient than paper records, but
storage remains important. Various models have been used. In one
multicenter study, the investigators were asked at the end of
follow-up to send a list of all deceased participants along with
date of death to an office independent of the data coordinating
center. In other trials, key data were independently audited before
the results were published. Common to all models is an attempt to
maintain credibility.
Procedures for data cleanup and
verification in trials conducted for regulatory approval add
substantially to the trial cost and complexity. Many such trials
collect a large quantity of data. Final verification of these data
is both time-consuming and costly [17, 18]. As
noted in Chap. 11, investigators should, when
designing such trials, both limit the amount of data and decide
which data are essential and require full final verification.
Storage
Investigators should consider storing
various kinds of material after a trial has ended. One set of
documents—such as the trial protocol, manual of procedures, study
forms, and the analytic material, including electronic
records—should be kept by the investigator and sponsor. In
addition, a list containing identifying information for all
participants who enrolled in a trial ought to be stored at the
institution where the investigation took place. Local regulations
sometimes require that individual participant data such as copies
of study forms, laboratory reports, electrocardiograms, and X-rays
be filed for a defined period of time with the participants’
medical records. Storage of these data electronically clearly eases
the problem of inadequate space. The actual trial results and their
interpretation should be published and then can be retrieved
through a library search, although it is all-to-common for trial
results to remain unpublished [19]. As of 2012, less than two-thirds of
National Heart, Lung, and Blood Institute (NHLBI)-sponsored
clinical trials were published within 30 months [20]. Recognition of this major problem, pressure
from sponsors and the clinical trial community to publish all trial
results, and transparency and data sharing are all important steps
to dealing with lack of publication (see Chap. 20).
In planning for a new trial, an
investigator may want to obtain unpublished data from other
investigators who have conducted trials in a similar population or
tested the same intervention. Tables and figures in actual
manuscripts seldom include everything that may be of interest. The
situation is changing with online material available on journal
websites. Many journals now publish full protocols, forms, manuals,
and even raw data [21]. However,
no uniform mechanism exists today for getting access to such study
material from terminated trials. If information is available, it
may not be in a reasonable and easily retrievable form. Substantial
cooperation is usually required from the investigators originally
involved in the data collection and analysis [22], and standards for data sharing and open
access to trial data are evolving [23] (see Chap. 20).
The storage of biological material has
raised new issues as it relates to genetic analyses. Biospecimens
from well-characterized populations followed for long durations in
clinical trials are in demand. These can be used to determine
whether participant subgroups with a specific genotype are more
likely to benefit or to experience serious adverse effects. The
availability of these specimens for specific analysis depends on
the wording of the informed consent (see Chap. 2). Patient privacy has to be
considered, as always.
Storage of biomaterials may be costly.
Freezers must be maintained, and a system for labeling and
retrieving specimens or aliquots without damaging the remaining
material must be implemented. Unlike with retrieval and
distribution of data, many specimens may only be used once.
Therefore, investigators need to develop a system for deciding when
and how to use or distribute biospecimens. The cost and benefit, as
well as the duration of storage must be considered. Central
specimen repositories have been created to which investigators may
be able to send their materials.
In summary, most trials collect an
excess of study material, and it may not make sense to store
everything. The investigator has to consider logistics, the length
of the storage period, and cost. He also has to keep in mind that
biological material, for example, deteriorates with time and
laboratory methods change.
Dissemination of Results
The reporting of findings from a small
single-center trial is usually straightforward. The individual
participants are often told about the results shortly after the
last follow-up visit, and the medical community is informed through
scientific publications. However, there are situations that make
the dissemination of findings difficult, especially the order in
which the various interested parties are informed. Particularly in
multicenter studies where the participants are referred by
physicians not involved in the trial, the investigators have an
obligation to tell these physicians about the conclusions,
preferably before they read about them in the newspaper or are
informed by their patients. In trials with clinics geographically
scattered, investigators may have to be brought together to learn
the results. In certain instances, the sponsoring party has a
desire to make the findings known publicly at a press conference or
through a press release. However, although an early press
conference followed by an article in a newspaper may be politically
important to the sponsor of the trial, it may offend the
participants, the referring physicians, and the medical community.
They may all feel that they have a right to be informed before the
results are reported in the lay press. Companies may perceive a
fiduciary responsibility to let the public know the “top line”
results of a trial once they know them in order to control the risk
of leaks.
We have had good experiences from the
following sequence. First, the study leadership informs the other
investigators who, in turn, inform the participants. Second, the
private physicians of the participants are also told of the
findings. Third, the results are then published in the scientific
literature, after which they may be more widely disseminated in
other forums. With journals now being available electronically,
publication can be timed to coincide with presentation of the
results at major scientific meetings.
However, there are sometimes
unavoidable long delays between the presentation of trial findings
at a scientific meeting and the publication of the full trial
reports in peer-reviewed journals. The medical community may be
placed in difficult positions by having to make treatment decisions
if the lay press reports on elements of findings many months prior
to the publication of the trial data in full. The messages released
by the lay press are typically very simple. To minimize this
problem, three recommendations have been made [24]: (1) “congress organizers should insist that
published abstracts contain sufficient data to justify the
conclusions of the presentation,” (2) “investigators should not
present results of any study that is likely to influence clinical
management until they are in a position to write a full paper,” and
(3) “journal editors must be willing…to expedite the publication of
such papers.” These recommendations are reasonable, but there may
be exceptions.
In order to facilitate expedited
translation of research results, the National Institutes of Health
(NIH) introduced a data sharing policy in October 2003
[25] that has since been updated
[26]. The agency’s position is
that “Data should be made as widely and freely available as
possible while safeguarding the privacy of participants, and
protecting confidential and proprietary data.” The risk of wide
dissemination of databases is that other investigators might
analyze the data and arrive at different interpretations of the
results. However, after a certain period of time has passed to
allow for the trial investigators to analyze and publish, further
analysis and discussion of various interpretations of trial data
are usually scientifically sound and ought to be encouraged.
In special situations, when a therapy
of public health importance is found to be particularly effective
or harmful in a trial sponsored by the NIH, physicians and the
public need to be alerted in a timely manner. The NIH would
promptly post a release on its news website [27]. When the Adenoma Prevention with Celecoxib
trial sponsored by the National Cancer Institute was terminated due
to a 2.5-fold increased risk of major fatal and nonfatal
cardiovascular events for participants taking celecoxib compared
with those on a placebo, the release was issued the day after the
decision was made to stop treatment [28]. Three months later, the results were
published in The New England
Journal of Medicine [29].
At the NIH, individual institutes may
also issue their own press releases. These are generally released
to coincide with the publication of an article in a medical
journal. However, institutes, with journal permission, have issued
brief press announcements prior to journal publication. To avoid
criticism from physician groups, an institute may also notify the
leadership of relevant medical societies before the release. The
United States National Library of Medicine also releases timely
scientific news on its MedlinePlus website [30]. These releases are not limited to
NIH-sponsored research.
The FDA also informs physicians and
the public about regulatory actions and news. FDA MedWatch Safety
Alerts for Human Medical Products are posted on the website
[31]. Included are brief summaries
of products in question and FDA alerts. This and the general FDA
drug website [32] provide
recommendations and information for health care providers as well
as information for patients to consider. If a serious adverse event
has been uncovered by investigators in a trial, the FDA and other
regulatory agencies or the trial sponsor may communicate this
information to medical professionals, and thereby indirectly to the
lay public, through a “Dear Healthcare Provider” letter.
Wide dissemination of trial findings
to the public by investigators and study sponsors is increasingly
common, even if the results are of modest scientific or public
health importance. Press releases have become part of highly
orchestrated marketing campaigns in both industry- and
government-funded trials. We strongly support making trial results,
and indeed data, widely available, with the expectation that broad
discussion (and reanalysis as appropriate) will assist clinicians
and the public in arriving at appropriate decisions as to the value
of a trial’s intervention.
As emphasized in Chap. 1, clinical trials must be
registered. Worldwide, there are a large number of registries
[33–35]. Until the enactment of the FDA Amendments
Act (FDAAA) in September 2007, the registration was limited to
design information from the trial protocols [35]. The FDAAA expanded the scope to include a
trial results database with information on participant demographics
and baseline characteristics, primary and secondary outcomes, and
statistical analyses. These data should be posted within 12 months
of trial completion. The database should also be linked to
publically available information from the FDA website. This would
include summary safety and effectiveness data, public health
advisories, and action packages for drug approval. Serious and
frequent adverse effect data observed during a trial are to be
added within 2 years.
Post Study Follow-up
There are three main reasons for
short-term follow-up after completion of the intervention period.
One is to find out how soon treatment-induced changes in laboratory
values or symptoms return to pretrial level or status. The effect
of the intervention may last long after a drug has been stopped,
and abnormalities revealed by laboratory measurements or adverse
drug effects may not disappear until weeks after the intervention
has ended. Second, for certain drugs, such as beta-blockers and
steroids, the intervention should not be stopped abruptly. A
tapering of the dosage may require additional clinic visits. Third,
clinical events may occur differentially in the study groups after
the intervention is stopped due to lingering drug effects or to a
hazard in switching patients back to standard of care
[36]. Drug effects may be seen for
weeks or months after treatment is stopped or there may be
unfavorable withdrawal reactions [9]. These activities are separate from the moral
obligation of the investigator to facilitate, when necessary, a
participant’s return to the usual medical care system, to ensure
that study recommendations are communicated to his or her private
physician, and at times to continue the participant on a beneficial
new intervention.
Long-term post-study follow-up of
participants is a rather complex process in most, but not all,
countries. The investigators and the sponsor have to decide what
should be monitored. Mortality surveillance can be cumbersome
globally but can easily be performed in selected regions, for
example in Scandinavia. Usually, the justification for long-term
post-study surveillance is based on a trend or unexpected finding
in the trial or from a finding from another source. Since most
clinical outcome trials of chronic therapies are relatively short
in duration, extended follow-up can provide important additional
information.
Obtaining information on nonfatal
events is even more complicated and, in general, its value is
questionable. However, a classical illustration that post-study
follow-up for harm can prove valuable is the finding of severe
adverse effects attributed to diethylstilbestrol. The purported
carcinogenic effect occurred 15–20 years after the drug was
administered and occurred in female offspring who were exposed in
utero [37]. Similarly, use of
unopposed estrogen has been reported to be associated with an
increased risk of endometrial cancer 15 or more years after therapy
was stopped [38]. One article
reported an association between in utero exposure to valproate, an
antiepileptic drug, and impaired cognitive function in offspring at
3 years of age [39].
In 1978, the results of a trial of
clofibrate in people with elevated lipids indicated an excess of
cases of cancer in the clofibrate group compared with the control
group [40]. The question was
raised whether the participants assigned to clofibrate in the
Coronary Drug Project also showed an increase in cancer incidence.
This was not the case [41]. Only
3% of deaths during the trial were cancer-related. Subsequently, a
World Health Organization study of clofibrate reported that
all-cause mortality was increased in the intervention group
[42]. At the same time, Coronary
Drug Project investigators decided that post-study follow-up was
scientifically and ethically important, and such a study was
undertaken. No increase in cancer incidence was noted in the
clofibrate group [43]. A more
recent example is the Women’s Health Initiative, which extended
follow-up for 5 years after it reached its scheduled termination in
2005. This example brings up a question: should investigators of
large-scale clinical trials make arrangements for surveillance in
case, at some future time, the need for such a study were to arise?
The implementation of any post-study surveillance plan has
challenges. A key one is finding a way to keep participants’ names
and addresses, or their Social Security or other national
identification numbers, in a central registry without infringement
upon the privacy of the individuals. The investigator must also
decide, with little evidence, on the optimal duration of
surveillance after the termination of a trial (e.g., 2, 5, or 20
years).
Another issue of post-study
surveillance relates to a possible beneficial effect of
intervention. In any trial, assumptions must be made with respect
to time between initiation of intervention and the occurrence of
full beneficial effect. For many drugs, this so-called “lag time”
is assumed to be zero. However, if the intervention is smoking
cessation, a lipid-lowering drug, or a dietary change, and if the
response variable is coronary mortality, the lag time might be a
year or longer. The problem with such an intervention is that the
maximum practical follow-up may not be long enough for a beneficial
effect to appear. Extended surveillance after completion of active
treatment may be considered in such studies. At the scheduled
termination of the Multiple Risk Factor Intervention Trial, the
results favored the special intervention group over usual care but
did not reach statistical significance [44]. Almost 4 years later, a statistically
significant effect emerged [45]. A
late benefit was also evident in a passive follow-up phase after
stopping enalapril versus placebo in the Studies of Left
Ventricular Dysfunction (SOLVD) [46].
The post-study surveillance in the
Coronary Drug Project [43] showed
unexpected benefit in one of the intervention groups. At the
conclusion of the trial, the participants assigned to nicotinic
acid had significantly fewer nonfatal re-infarctions, but no
difference in survival was detected. Total mortality after an
average of six-and-a-half years in the trial on drug, plus an
additional 9 years after the trial, however, was significantly
lower in the group assigned to nicotinic acid than in the placebo
group. There are several possible interpretations of the Coronary
Drug Project finding. It may be that this observation is real, and
that the benefit of nicotinic acid simply took longer than expected
to appear. Of course, the results may also be due to chance, a
possibility that seems more likely with the lack of benefit and
evidence of harm with niacin in the much larger Heart Protection
Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events
(HPS2-THRIVE) trial [47]. A major
difficulty in interpreting the data relates to the lack of
knowledge about what the participants in the intervention and
control groups did with respect to lipid lowering and other
regimens in the intervening 9 years.
Knowledge of the response variable of
interest for a substantial portion of participants is required if
long-term surveillance after completion of regular follow-up is to
be worthwhile. The degree of completeness attainable depends on
several factors, such as the response variable itself, the length
of surveillance time, the community where the trial was conducted,
and the aggressiveness of the investigator. Many of the very large
trials have successfully monitored participants (or subsets
thereof) after closeout to determine whether behavioral effects of
the study intervention have been sustained or participants have
adhered to recommendations regarding continued treatment.
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