>> Stacey Arnold: In this third part of the series,
I'll describe the process for submitting results
information to ClinicalTrials.gov.
Topics for this session include an overview of results
reporting to ClinicalTrials.gov
via the protocol registration and results system,
or PRS, including the objectives of reporting
and the components of results submissions.
We'll also review key points to consider when reporting results.
The ClinicalTrials.gov Results Database
was designed to satisfy legal requirements
for the sharing of clinical trial results information.
The database aims to promote objective,
standardized reporting
and to facilitate good reporting practices,
including publishing and regulatory guidelines.
The database provides structured tabular data entry
to ensure complete reporting
and consistent display of data elements
and to facilitate the quality assurance
review of the information submitted to ClinicalTrials.gov.
This consistent structure supports detailed searches
of the ClinicalTrials.gov database.
As with registration, results are manually entered
or uploaded into the PRS database
for eventual posting to ClinicalTrials.gov.
Results can be submitted once data collection
has been completed for at least one primary outcome measure
and for records that have been previously
registered on ClinicalTrials.gov.
Results are posted to ClinicalTrials.gov
once they have undergone a review process
like the one performed for registration information,
meaning they must pass an automated system
validation process,
and quality assurance review by ClinicalTrials.gov staff.
Results submissions included scientific information
provided in four modules, including participant flow,
baseline and demographic characteristics,
outcome measures and statistical analyses and adverse events.
An additional module, limitations, and caveats,
provides a free text field where data submitters
can provide information about considerations
for interpreting the reported data.
There are also two modules for administrative information
including contact information for the point of contact
for the study results,
and a description of any agreements
between the principal investigator
and the study sponsor,
including ones that restrict the PI from discussing
or publishing study results.
The participant flow module includes a table
that resembles the consort flow diagram
that often serves as the first figure
in a clinical trial publication.
It tracks the progress of participants through the trial
according to the arms or groups to which they've been assigned.
An arm represents a unique experience, for example,
receipt of a single intervention or the sequence
and interventions for the duration of the trial.
Studies specific milestones, multiple periods,
and reasons for participant dropout can all be listed.
An example of how a consort flow diagram
is translated into a participant flow table is shown to the left.
The baseline characteristics
module provides demographic and baseline data
for the entire population of the trial
as well as each charm or comparison group.
Age, sex, race, ethnicity,
and any measures assessed at baseline
that are used in the analysis of the primary
outcome measures are required to be included.
Examples of each type of measure are shown to the left.
The outcome measures and statistical analysis
module presents data by arm or comparison group
and accommodates categorical, continuous,
and time to event data.
Examples of outcome measure and statistical analysis tables
are shown to the left.
Three types of outcome measures are reported in this module
including primary outcome measures,
which represent the analyses of greatest importance in the study
and typically include the assessment
used in the power calculation,
secondary outcome measures which are of lesser importance
than the primary outcomes but are of interest
in evaluating the effects of the interventions,
and other pre specified outcome measures
which are exploratory in nature. A well planned outcome measure
specifies four levels of analysis
that identifies a domain for the analysis in this example,
anxiety, defines a specific measurement tool
to explore the domain,
like the Hamilton anxiety rating scale,
indicates a specific metric for determining
an effective interventions such as change from baseline
and identifies a method for aggregating collected data,
like report of the proportion of participants
with a greater than or equal to 50 percent decrease
in the measured scale score.
The adverse events module lists all collected events,
whether anticipated or unanticipated,
that result in death, are serious, or are non-serious
and occurring above a frequency
threshold of less than or equal to 5 percent
in any study arm or comparison group.
Examples of all three adverse events tables
are shown to the left.
An additional section, the study documents section,
is required to be included at the time of results submission.
For studies with the primary completion date on
or after January 18, 2017,
a full protocol and accompanying statistical analysis plan
are required to be submitted and informed consent forms
must also be posted for trials
that are subject to the Revised Common Rule.
The statistical analysis plan can be included
as part of a single document with the protocol
or as a separate document.
These documents must represent all amendments
approved by a human subject's review board
that apply to all study locations,
they must be accompanied by a cover page
that indicates the official title for the study,
the NCT number assigned by ClinicalTrials.gov
at the time of trial registration,
and the date of the document version.
Data submitters can redact this information
including personally identifiable information,
and trade secrets
or other confidential commercial information
unless the information is otherwise required
to be submitted.
The uploaded documents must be in the archival PDF/A format
and will be made public on ClinicalTrials.gov,
so they are also required to be in English.
Inclusion of the informed consent form
on ClinicalTrials.gov is optional.
However, ClinicalTrials.gov is one of two federal websites
that satisfy the requirement of the Revised Common
Rule that clinical trials conducted
or supported by a Common
Rule department or agency be posted
on a publicly available federal website
within a specific timeframe.
The compliance date for this provision was January 21, 2019,
and Regulations.gov is the second site
that satisfies the requirements.
There are three main points to consider
when reporting results to ClinicalTrials.gov.
These include the manner
in which the data will be prepared for submission,
the considerations needed to satisfy review criteria,
and the relationship of reporting results
to ClinicalTrials.gov
to publishing results in scientific journals.
Summarizing results for submission
of ClinicalTrials.gov is similar in complexity
to preparing results for journal publication.
The process requires an understanding
of the study design and analytic plan,
a basic understanding of the principles
of clinical trial conduct and analysis,
and access to the necessary data.
Ideally, results should be prepared for submission
by the study's principal investigator or statistician.
The submitted information must be accurate and precise,
as well as understandable and informative
for someone who is a reader of the medical literature,
but not an expert in the field.
It's recommended that someone who is not familiar
with the study review the information for clarity
and comprehension
prior to submission to ClinicalTrials.gov.
It is important to note that meeting the requirements
for reporting to ClinicalTrials.gov
does not necessitate a change
in study design or study procedures.
The reporting results should reflect what was planned
and collected as part of the study
as designed to meet the research objectives.
Results are intended for readers of the medical literature
and not the lay public.
This is different from information provided
during registration,
which should be understandable to a lay audience
to facilitate recruitment of study participants.
Results provided and data tables should be informative
with minimal narrative text.
Conclusions and discussion of the data are not permitted.
The database is intended for report of just the facts
that is just the summary level data and results submission
is not required for all registered trials
only those that are subject to the final rule,
NIH policy, or other funding policies.
The ClinicalTrials.gov quality assurance team reviews records
for apparent validity, meaningful entries, logic,
and internal consistency and will return a record
with comments requiring the resolution of major problems
when the following types of issues arise.
When there's a lack of apparent validity,
such as an outcome measure
that reports a mean of 263 hours of sleep per day,
when a description of an analysis
is too big to be meaningful.
For example, when an outcome measure
reports the results of a scaled assessment
without sufficient information to interpret the result,
when data are inconsistent with the description of the analysis,
for example, when an outcome measure
reports account of participants
rather than a median and full range or a time to event.
When information throughout a record is inconsistent,
for example,
when a study designated as observational indicates
that randomization was used to assign participants
to interventions,
or when a trial design is unclear.
For example, when participants suddenly appear
in an outcome measure analysis
who were not included in the participant
flow or baseline characteristics modules.
With ClinicalTrials.gov in peer reviewed journal publications
seek to ensure accurate and informative results reporting.
However, they differ in important ways.
ClinicalTrials.gov results
reporting does not reject submissions.
While peer reviewed journals can refuse to publish research
that isn't deemed high quality or interest to readers.
ClinicalTrials.gov permits the disclosure
of all outcome measures that were assessed,
while journals might limit the focus
to the report of critical aspects of a study,
thereby excluding some outcome measures.
And ClinicalTrials.gov does not permit extensive narrative text.
It is intended for tabular summary level data only.
In contrast, journal articles rely upon narrative
text and conclusive language
to provide context for reported results
and to allow for interpretation of comparative analyses.
In summary, the
ClinicalTrials.gov Results Database
was designed to fulfill legal requirements,
facilitate structured data entry,
and support detailed searches of results information.
Results are reported in four scientific modules
that reflect the flow of participants through a study,
their baseline characteristics,
the results of outcome measure analyses
in which they participate,
and any serious adverse events frequent,
non-serious adverse events or deaths
that occur over the course of the study.
There are also three types of supporting documentation
that can or should be appended, including the study protocol,
the statistical analysis plan, and the informed consent form.
Results should be prepared for submission
by someone who understands the study design and analytic plan.
Results submissions to ClinicalTrials.gov
serve to supplement journal publication
by allowing a board of all analyses and studies.
Now I'll ask a couple of questions
to review the material that we covered.
True or False?
Results reporting is required for all trials
that have been registered on ClinicalTrials.gov.
This is false -- results submission is not required
for registered studies that are not subject to the final rule,
NIH policy, or other funding policies.
True or False?
When reporting results on ClinicalTrials.gov researchers
can describe conclusions drawn from analyses
of all pre specified outcome measures,
even ones that aren't reported in journal publications.
This is false -- ClinicalTrials.gov
does not permit study records to include conclusive language
or discussion of trial results.
I hope you've learned about the types of information
included in results submissions to ClinicalTrials.gov
and how these submissions differ from journal publications.
Thank you for your attention.