Transcript Slide 1

Everything You Need to Know
About
Clinical Trials Registration and
Results Reporting Requirements
Deborah A. Zarin, M.D.
ClinicalTrials.gov
October 2009
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Background
2
February 27, 2009
Recent Events
February 26, 2009
Kaplan-Meier estimates for ulcer complications according to traditional
definition. Results are truncated after 12 months, no ulcer complications
occurred after this period. Adapted from Lu 2001.
Source: Jüni P, Rutjes AW, Dieppe PA. BMJ. 2002 Jun 1;324(7349):1287-8.
Zarin DA, Tse T. Medicine. Moving toward transparency of clinical trials. Science. 2008 Mar 7;319(5868):1340-2.
Levels of “Transparency”
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Zarin DA, Tse T.. Science. 2008 Mar 7;319(5868):1340-2.
Reasons to Register Clinical Trials
and Report Results
• Human Subject Protections
– Allows potential participants to find studies
– Assists ethical review boards and others to determine
appropriateness of studies being reviewed (e.g., harms, benefits,
redundancy)
– Promote fulfillment of ethical responsibility to human volunteers –
research contributes to medical knowledge
• Research Integrity
– Facilitates tracking of protocol changes
– Increases transparency of research enterprise
• Evidence Based Medicine
– Facilitates tracking of studies and outcome measures
– Allows for more complete identification of relevant studies
• Allocation of Resources
– Promotes more efficient allocation of resources
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ClinicalTrials.gov—the basics
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History of ClinicalTrials.gov
• FDAMA 113 (1997): Mandates Registry
– IND trials for serious and life-threatening diseases or
conditions
• ClinicalTrials.gov Launched in February 2000
• Calls for Increased Transparency of Clinical Trials
– Maine State Law; State Attorneys General
– Journal Editors (2004)
• ClinicalTrials.gov Accommodates Other Policies
• FDAAA 801 (2007): Expands Registry and Adds
Results Database
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New Registrations
Continue to Increase
Number of New Records Since May 1, 2005
90000
80000
70000
R
E
C
O
R
D
S
60000
50000
40000
30000
20000
10000
0
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ClinicalTrials.gov Statistics
(as of 10/05/09)
Number
Total
Type of Trial
Observational
Interventional*
– Drug & Biologic
– Surgical Procedure
– Behavioral, Gene
Transfer, Other
– Device
International Sites (172 countries)
US only
Non-US only
US & Non-US mixed
Missing
Percent
79,605
100%
12,956
66,649
54,208
8,470
16%
83%
13,369
4,742
37,271
28,263
5,686
8,385
47%
35%
7%
11%
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*231 “delayed posting” device trials included in “total,” but excluded from other statistics
ClinicalTrials.gov Statistics (cont.)
(as of 10/05/09)
Number
Percent
10,777
25,737
43,091
79,605
14%
32%
54%
Trials by Sponsor
US Federal (including NIH)
Industry
University, Other
Total
User Statistics
Page Views per month
Unique visitors per month
60 Million
900,000
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Value-Added Links
Search Interface
Legal and other requirements
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ICMJE Policy
• Editorial 2004 and updates
• Registration required for manuscript
consideration for following:
– Interventional studies
– Any phase
– Any intervention
• ClinicalTrials.gov or WHO Primary registry
• Registration prior to enrollment first
participant
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Public Law 110-85
Sec.801 Expanded Clinical Trial Registry
• Enacted on September 27, 2007
• Requires Trial Registration (Dec 2007)
– Phase II-IV drug and device trials for all diseases
– Data elements: ClinicalTrials.gov + ~ WHO/ICMJE
• Requires Results Reporting (Sept 2008)
– Trials of FDA-approved or cleared drugs and devices
– “Basic” Results: Baseline Characteristics, Primary &
Secondary Outcomes, Statistical Analyses
– Adverse Events (Sept 2009)
– “Expansion” of results by rulemaking (Sept 2010)
• Added enforcement provisions
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Enforcement Provisions
• Notices of non-compliances
• Civil monetary penalties up to $10,000/day
• Withholding of NIH grant funds
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Key Terms
• Applicable Clinical Trials
– Interventional trials
– Phase 2-4 drug, biologic, device
– >= one site in U.S.
– Ongoing as of 9/27/07, or later
• Responsible Party
– Sponsor, grantee
– PI if designated
• Primary Completion Date
Key Milestones: FDAAA - Sec.801
Expanded Clinical Trial Registry
• December 26, 2007
– New registration requirements effective
– Linking to existing results
• September 27, 2008
– “Basic Results” reporting requirements effective
• April 2009 - Public Meeting
• September 27, 2009 – Adverse Events
• September 27, 2010 – Rulemaking Due
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Key Points: Memo from Dr. Kington,
Acting Director, to NIH Grant Awardess
• “For grants, NIH is generally not the sponsor …
and, as such, NIH would not be the responsible
party.”
• “Responsible parties who have not yet
registered their clinical trials should do so
immediately.”
• “Thank you for your attention to this important
matter and your commitment to helping enhance
the transparency of NIH funded clinical trials.”
Basic Results Database
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Basic Results Database:
General Characteristics
• Results of “applicable clinical trials” of
FDA-approved/cleared medical products
• Generally, submission within 12 months of
the earlier of estimated or actual trial
completion date (of primary outcome)
• Delayed Submission of Results
– Seeking initial approval
– Seeking approval of a new use
– Extensions for “good cause”
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Adverse Events
• If the Secretary fails to issue regulation by March 2009,
default provisions take effect in September 2009
• SERIOUS ADVERSE EVENTS
– Table of anticipated & unanticipated serious adverse events
– Grouped by organ system
– Number and frequency of event in each clinical trial arm
• FREQUENT (other) ADVERSE EVENTS
–
–
–
–
Table of anticipated & unanticipated adverse events
Exceed a frequency of 5 percent within any trial arm
Grouped by organ system
Number and frequency of event in each trial arm
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Basic Results Modules
•
•
•
•
•
Participant Flow
Baseline and Demographic Characteristics
Outcome Measures
Adverse Events (summary data)
Other Information
– “Certain Agreements” Restricting Results
Disclosure
– Overall Limitations and Caveats
– Results Point of Contact
Current Status – “Basic Results”
(as of 02/06/09)
• Functional Web-based Data Entry System
• Launched in September 2008
• 662 Results Records have been submitted
• Industry: 449 records from > 100 data
providers
• NIH: 24 records
• Rate of submission continues to increase
• 40 records per week now
• Anticipate about 150 per week
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Sample Posted Results
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Participant Flow
“A table ..., including the number of patients
who dropped out of the clinical trial and the
number of patients excluded from the
analysis, if any.”
[Sec. 282(j)(3)(C)(i)]
Reasons Not Completed
An Investigational Drug on Clinical
Outcomes in Patients With Aortic Stenosis
NCT00092677
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Arms
Milestone
Reasons Not Completed
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Baseline Measures
“A table of the demographic and baseline
data collected overall and for each arm of
the clinical trial…”
[Sec. 282(j)(3)(C)(i)]
“Default” Required
Measures
User-Specified
Measure
Categories
Outcome Measure
“…a table of values for each of the primary
and secondary outcome measures for each
arm of the clinical trial…”
[Sec. 282(j)(3)(C)(ii)]
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Categories
Statistical Analysis
“…a table of values for each of the primary
and secondary outcome measures…,
including the results of scientifically
appropriate tests of the statistical
significance of such outcome measures.”
[Sec. 282(j)(3)(C)(ii)]
Statistical Analysis
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Statistical Analysis
Statistical Analysis
Serious Adverse Events
“A table of anticipated and unanticipated
serious adverse events grouped by organ
system, with number and frequency of such
event in each arm of the clinical trial.”
[Sec. 282(j)(3)(I)(iii)(I)]
Frequent Adverse Events
“A table of anticipated and unanticipated
adverse events that are not included in the
[Serious Adverse Events] table … that
exceed a frequency of 5 percent within any
arm of the clinical trial, grouped by organ
system, with number and frequency of such
event in each arm of the clinical trial.”
[Sec. 282(j)(3)(I)(iii)(II)]
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Definition of Adverse Event
• Definition: Unfavorable changes in health,
including abnormal laboratory findings,
that occur in trial participants during the
clinical trial or within a specified period
following the trial.
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Definition of Serious AE
• Serious Adverse Events include adverse
events that result in death, require either
inpatient hospitalization or the
prolongation of hospitalization, are lifethreatening, result in a persistent or
significant disability/incapacity or result in
a congenital anomaly/birth defect.
•
Other important medical events, based upon appropriate medical
judgment, may also be considered Serious Adverse Events if a trial
participant's health is at risk and intervention is required to prevent
an outcome mentioned.
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Design Features
• Tables are “constructed” by the data
provider
– Columns are pre-set as study arms, but can
be changed by the data provider
– Rows are measures—some are pre-set,
others are customized for each study
– Type of measure determines specific design
of “cells”
• Attempt to balance fixed structure with
flexibility
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http://prsinfo.clinicaltrials.gov/fdaaa.html
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Issues in Reporting Results
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ICJME
“…will not consider results posted in the
same primary clinical trials register in which
the initial registration resides as previous
publication if the results are presented in the
form of a brief, structured (<500 words)
abstract or table.”
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Who is the Audience?
PI and Clinical Research Team
Other Medical Researchers in same field
Other Medical Researchers in other fields
Other Readers of the medical literature
Science Writers
Lay Public (readers of consumer health literature)
Quality Assurance Challenges
• Data tables will be the public
representation of the study—must be clear
and informative;
• NLM QA Focuses on:
– Apparent Validity (when possible)
– Meaningful Entries
– Internal consistency/logic
– Format
What Does QA Address?
• Data must make sense
– Measure name, units, and data must match
– No invalid entries
• E.g., 823 hours/day; “time to survival”
– No illogical tables
– No missing parameters or data
• Tables should convey study design,
conduct and analysis
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Tables Must Be Informative
• Scales should include:
– Full name
– Construct or domain (e.g., pain)
– Direction of scores (Best/Worst Value)
– Other information as necessary
• Measures Have Useful Descriptions
• Avoid Abbreviations
Measure Information Must be
Precise and Accurate
• Avoid misuse of terms, e.g.,
– proportion
– ratio
– incidence
• State what is being measured and how
– Do not provide results in measure description
field
Data in All Tables Must be
Internally Consistent and Logical
• Participants must “flow”
• “Number analyzed” must be consistent
with participant flow data
• Avoid Illogical Entries
Illogical Results Table
Number of Participants
Analyzed
[units: participants]
Treatment Satisfaction
Questionnaire
After 18 Weeks of Treatment
[units: Score]
Mean ± Standard Deviation
Drug X,
Week 10
Drug X, Change
from Week 10 to 18
88
80
81 ± 17.46
7.9 ± 12.16
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Unclear Outcome Measure
Measure Name
Measure
Description
Time Frame
Time to Disease-Free Survival
Time from date of treatment to date of
survival
5 years
Number of Participants
Analyzed
[units: participants]
Time to Disease-Free Survival
[units: participants]
Drug A
648
Drug B
645
246
277
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Problematic Entry
Number of Participants
Analyzed
[units: participants]
Hours Per Day of Sleep
[units: Average Hours per
Day]
Mean ± Standard Deviation
Intervention X
Control
28
27
823 ± 92
864 ± 106
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Problematic Entry
Measure
Name
Measure
Description
Clinician Assessment After Injection
Time Frame
8 months
Physician’s assessment of: SIJ pain
[5 point-Likert scale], Change of finger
to floor [cm] and Schober test [mm]
Number of Participants
Analyzed [units: participants]
Clinician Assessment After
Injection
[units: Units on a scale]
Sacroiliac Injection
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100
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Informative Entry
Measure Name
Measure
Description
Pregnancy Rate (Pearl Index)
Pearl Index = (100)*(number of
pregnancies)*(4 cycles/year)/number of
91-day cycles completed.
Time Frame
After the onset of treatment and within 14
days after the last combination pill
(approx. 1 year of treatment)
DR-1011
Number of Participants Analyzed
Pregnancy Rate (Pearl Index)
[units: Pregnancies per 100 woman
years exposure]
1735
2.74
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Informative Entry
Measure Name
Time to Progressive Disease
Measure
Description
Time from study enrollment to the first date of
disease progression. Time to disease
progression was censored at the date of
death if death was due to other cause.
Time Frame
Every other 21 day cycle (6-8 cycles) and
every 3 months during follow-up
Drug X
Number of Participants Analyzed
50
Time to Progressive Disease
[units: weeks]
Median ( 95% Confidence Interval )
45.1
( 37.9 to 56.9 )
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Number of Records Posted Without Revision
Number of Results Records
without Revision by Quarter Posted
120
106
100
80
60
40
27
20
8
10
0
08Q4
09Q1
09Q2
09Q3
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Quarter Posted
Results Posting - Caveats
• Posting does not assure that all review
criteria were met
• Data provider is responsible for ensuring that
records meet review criteria
• ClinicalTrials.gov may note issues and
request revisions after results have been
posted publicly
• Additional comments may suggest
improvements, but are not necessarily
“required” changes prior to posting
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Lessons Learned from Early
Submissions of Basic Results
• Data Providers must be able to
understand the study design and data
analysis
– Typically, the investigator and a
statistician will need to be involved
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Interesting Scientific Issues
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Interventional vs. Observational
– Interventional: studies in human beings in which individuals
are assigned by an investigator based on a protocol
to receive specific interventions. Subjects may receive
diagnostic, therapeutic or other types of interventions. The
assignment of the intervention may or may not be random. The
individuals are then followed and biomedical and/or health
outcomes are assessed.
– Observational: studies in human beings in which biomedical
and/or health outcomes are assessed in pre-defined groups of
individuals. Subjects in the study may receive diagnostic,
therapeutic, or other interventions, but the investigator does
not assign specific interventions to the subjects of the
study.
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Interventional or Observational?
• Example: Evaluation of PillCam™ Colon
Capsule Endoscopy (PCCE) in the
Visualization of the Colon
– Capsule Endoscopy versus Colonoscopy for
the Detection of Polyps and Cancer
– Van Gossum et al. NEJM (2009)
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Interventional
(as of 8/3/09)
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Observational
(before 8/3/09)
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How Should You Describe the
Outcome Measures?
Level of Detail
Low
• Anxiety
• Hamilton Anxiety Rating Scale
• Hamilton Anxiety Rating Scale at 12 weeks
• Change in Hamilton Anxiety Rating Scale at 12 weeks from
baseline
• Proportion of patients with improvement in Hamilton Anxiety
Rating Scale at 12 weeks from baseline
• Proportion of participants with a change of ≥11 points at 12
weeks from Baseline on the Hamilton Anxiety Rating Scale
High
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Goals for Registration of
Outcome Measures
• Inform potential participants
• Provide details to inform other researchers,
systematic reviewers, etc.
• Monitor integrity of research
– Track additions/deletions
– Track significant changes
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CLASS Study Data by Follow-up Period
Kaplan-Meier estimates for ulcer complications according to traditional
definition. Results are truncated after 12 months, no ulcer complications
occurred after this period. Adapted from Lu 2001.
95
Source: Jüni P, Rutjes AW, Dieppe PA. BMJ. 2002 Jun 1;324(7349):1287-8.
ENHANCE: Prespecified Endpoints
1
2
3
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Source: Kastelein JJ et al. Am Heart J. 2005 Feb;149(2):234-9.
Bottom Line—Reporting
Outcome Measures
• Be as specific as possible
• Primary and Secondary outcome
measures
– Designation should be consistent with
statistical analysis plan
• “Other prespecified” and “post hoc” should
be used for measures that are not in the
statistical analysis plan
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Outcome Measure Statistics
ClinicalTrials.gov (as of 8-27-09)
• 701 Results records posted
• 1,592 POMs
– Mean:
– Median:
– Range:
2.3
1
1-71
• 3,402 “Secondary” OMs
–
–
–
–
498 Results records with ≥ 1
Mean:
5
Median:
2
Range:
0-85
“Other Pre-specified”: 43 Records, 156 OMs, Range: 1-31
“Post-Hoc”: 11 Records, 18 OMs, Range: 1-6
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Diagnostic Accuracy Studies
• Studies in which the results are generally
displayed in a “2 x 2 table”
– Columns: “with disease” and “without disease”
based on a reference standard
– Rows: “test positive” and “test negative”
based on the experimental diagnostic test.
• ClinicalTrials.gov can be used to create
2 x 2 tables
Applicable Clinical Trials?
• Components involve devices and/or drugs
– ImageChecker DMax computer-aided detection
system, version 8.1 (Hologic/R2 Technology)
Gilbert FJ et al. N Engl J Med 2008;359:1675-84.
Device or Procedure?
• What Is the Intervention Type?
– Device
– Procedure/Surgery
• Example: The Stress Incontinence
Surgical Treatment Efficacy Trial
– Burch Colposuspension versus Fascial Sling
to Reduce Urinary Stress Incontinence
– Albo ME et al. NEJM (2007)
Procedure: Burch Modified Tanagho
Procedure: Autologous Fascia Sling
Bottom Line
• Determine who is the Responsible Party
• Register prior to enrollment (or within 21d):
– Phase 2-4 interventional trials that include a drug,
device or biologic
– Regardless of whether or not the trial is being used to
support an FDA application
• Report results:
– Any trial described above once the drug, device or
biologic has been approved; OR
– Within one year of “primary completion date”
• Keep all information up to date!
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Next Steps
• September 27, 2010: Expansion by
Rulemaking
• Expect announcement in October about
plans for rulemaking
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Key Issues in Expansion
• Expand results reporting to trials of unapproved
products?
• Include narrative summaries? Can it be done
w/out being promotional and misleading?
– Technical
– Lay Language
• Data Quality Verification
– Process (e.g., Pilot Quality Control Project)
– External Sources
• Full protocol versus extract “necessary to help
evaluate the results”
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EMEA & Unapproved Products
• Publically Accessible Results Database
– Required no later than 6 months after trial
completion (i.e., last patient, last visit)
– Applies to EU-regulated clinical trials of
medicines, regardless of authorization status
– Applies to trials of pediatric and adult drugs
• Interaction to harmonize EudraCT and
ClinicalTrials.gov databases & policies
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Resources
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Finding Results at ClinicalTrials.gov
• From Homepage
– Go to “Search for Clinical Trials”
– Select “Advanced Search”
– Select “Studies with Results” from the menu
for the Study Results field
– Select study record from results list
– Click “Study Results” tab
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Additional Information
(at http://prsinfo.clinicaltrials.gov/fdaaa.html)
• "Basic Results" Data Element Definitions
• Helpful Hints - tips on entering results
data, including examples of common study
models (e.g., crossover design)
• Detailed Review Items - describes items
evaluated by the QA/QC staff at NLM
• Common Errors - overview of common
types of errors identified in submitted
records with "basic results"
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Additional Background
• Tse T, Williams RJ, Zarin DA. Update on
registration of clinical trials in
ClinicalTrials.gov. Chest 2009;136:304-5.
• Tse T, Williams RJ, Zarin DA. Reporting
basic results in ClinicalTrials.gov. Chest
2009;136:295-303.
• Zarin DA, Tse T. Moving toward transparency
of clinical trials. Science 2008;319:1340-2.
• Wood AJ. Progress and deficiencies in the
registration of clinical trials. N Engl J Med
2009;360:824-30.
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Additional Information
• Email LISTSERV and other FDAAA
information:
– http://prsinfo.clinicaltrials.gov/fdaaa.html
• Other general information:
– http://prsinfo.clinicaltrials.gov
• Questions?
– [email protected]
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