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Overview: Clinical Research in the Emergency Department

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Clinical Research in the
Emergency Department
Jim Quinn MD MS
Associate Professor of Surgery/Emergency Medicine
Research Director Emergency Medicine
Overview
• Goals for research in academic emergency
medicine
• Problems/solutions for researchers in
emergency medicine
• Problems/solutions for research
implementation
• The new clinical research unit in the ED at
Stanford
Academic Emergency Medicine
• Outstanding residency and clinical
operations
• Research lags behind educational and
clinical performance
• Excellence in education, clinical operation
and research will lead to departmental status
at the university
• Departmental status will lead to more
academic and fiscal freedom
Improving Research
How Do We Get There
•
-
Obstacles
Too busy
No training in research
Too few mentors/role models
No interest
Improving Research
How Do We Get There
• Solutions
1) Recruit researchers
2) Develop researchers
- Personal and academic investment
- Expose EM residents to advantages of
academic career
- Funding through grants and career
development awards
Research During Residency
• Train residents to appreciate research efforts,
critically evaluate a study
- Study design, methodology, statistics
• Exposure to opportunities for an academic
career
• Some will decide to do research fellowships
and pursue academic medicine
Research During Residency
•
•
•
-
Start early (1st year)
Develop own idea
Develop that idea with a faculty mentor
avoid doing research for them
find mentors with common interest
Research curriculum and support to facilitate
project development
• Research Director- support and direction
Research Curriculum
Structure and Support to Develop Your Idea
• Curriculum (tried and tested)
- 12 hours – 6 sessions with core reading and homework
designed to develop your project
• Textbook
- “Designing Clinical Research” - Hulley and Cummings
- small paperback readable
• Help identify mentors and sources of data
The Five Page Protocol
Goal for the Research Curriculum
• Concise protocol
- More concise than an NIH submission, but
often sufficient for small intramural grants
- Discipline approach to planning the study
- Provide the materials and answers for IRB
submission
- Completed by the end of first year
- Implement in years 2 and 3
Organization
The Five Page Protocol
• Page One
- Title, Specific objectives, significance
• Pages 2-5
- Overview of design (RCT, observational cohort/ cross
sectional, case/control)
- Study subjects: selection criteria, exclusions, accessible
populations, plans for sampling and recruitment
- Measurement – predictor and outcome variables
- Statistical issues – sample size, proposed analysis
- Quality control and data management
- Timetable
- Ethical considerations
Research Development
• Residents
- EMF: Resident Research Grants - $5,000
- EMF, SAEM: Research Fellowships $75,000
- T and F awards from NIH
Faculty
- Career development awards
SAEM, EMF, K awards from NIH
What is a Career Development Award ?
п‚џ Funding to protect your time so that you can
develop your research skills
п‚џ Research may be:
п‚џ Clinical
п‚џ Basic Science
NIH Awards for Individuals with a Health-Professional Doctorate
Institutional
Training Grants (T32)
Short-Term
Training Grant
(T35)
Medical
School
Postdoctoral
Fellowships (F32)
Internship/Residency
Specialty
Scientist Development
Program (K12)
Mentored Clinical Scientist
Development Award (K08)
Senior Fellowships
(F33)
Independent
Investigator
Career Enhancement
Award Stem Cells (K18)
Midcareer Investigator
in Patient-Oriented
Research (K24)
Mentored Patient-Oriented
Research CDA (K23)
Benefits of a Career Development Award ?
•
•
•
•
Protected time
Extra Training
Step towards independence
New relationships
Myth: NIH Grants/Study Sections
• Emergency medicine proposals, especially
clinical research, will not be evaluated
fairly, nor will they be funded consistently,
until the NIH has a study section devoted to
emergency medicine.
• NIH grants are rare and hard to get
What is Important to Study
Section Members?
• Study section members don’t care what department
the investigator is in.
• Study section members care about:
– The match between the proposed work and the
goals of the program
– The quality of the proposal
– Investigator’s track record and preliminary data
– The institutional research environment
Selected NIH Panel
Recommendations
• “The NIH must ensure fair and effective
reviews of extramural grant applications for
support of clinical research: panels that review
clinical research
– (a) must include experienced clinical
investigators and
– (b) at least 30-50% of the applications
reviewed by these panels must be for clinical
research.”
Selected NIH Panel
Recommendations
• “The NIH should improve the quality of
training for clinical researchers by requiring
grantee organizations to provide formal
training experiences in clinical research and
careful mentoring by experienced clinical
investigators.”
Does NIH Fund EM Research?
• A search of currently funded federal
grants using the CRISP database and key
words “Emergency” yielded 204 new
grants in the years 2000-2002.
• Accurate numbers of grants submitted by
specialty are difficult to find and
interpret. No separate statistics are
maintained for Emergency Medicine.
Research Options
•
•
•
-
Basic Science
Translational Research
Clinical Research
Large database
Retrospective reviews
Clinical trials/Prospective cohorts
Myth: Large Databases
• Large administrative databases
contain large amounts of
clinically useful information.
Large Databases
• In general, large databases are collected:
– For non-research purposes (e.g., claims
and billing databases)
– With no specific research question in
mind (e.g., trauma center databases)
Large Databases
• Large databases often lack the specific
outcome and risk stratification variables
needed for a particular study, requiring
assumptions and approximations to be
made.
• Large databases often have a substantial
proportion of missing or incorrect data
which may reflect recording bias or other
sources of bias.
Large Databases
• Even small biases, together with a large
sample size, may yield results with
impressively small p values that are,
nonetheless, artifacts.
• Without independent methods for checking
the accuracy and completeness of the data,
these biases may be difficult to detect.
Clinical Trials
• Prospective trials
• Designed to answer specific questions
• More likely to answer the question correctly
Problems Implementing Clinical Research
• Where did all the patients go?
“ The best way to eliminate disease
is to study it”
• Nobody cares
• IRB/HIPAA issues
• Department too busy, too many protocols
“Tragedy of the Commons”
•
A “Metaphor” to describe the sub-optimal
use of a collectively shared resource
“best strategies for individuals conflict with
the common good”
Clinical Research Unit
Goal – “conduct efficient and effect research in the
chaotic environment of the ED for the common
good”
- Comprehensive database of all ED patients
- Real time data infrastructure
- Real time notification and enrollment
- Research director, research coordinator, volunteers
- Research committee to oversee all projects to
ensure adequate resources
Clinical Research Unit
Real Time Data Infrastructure
- HIPPA complaint ED Research database
- Hosted by SOM: secure, redundancy
- Allows for instant notification directly from
database
- Web based enrollment
- Eventually paperless
- https://emerg-med.stanford.edu/
Clinical Research Unit
Research Coordinator and Volunteers
•
•
-
Volunteers
Undergrads and med students
Help screen and enroll patients
Deal with paper flow
Coordinator
oversees volunteers: schedules
patient follow-up
resource for data and chart acquisition for ED
studies.
Clinical Research Unit
Research Committee
• Meets monthly – 30-60 minute meetings
after faculty meeting 2nd Wednesday
• Open meetings
• Oversees and approves all protocols in ED
• Consists of research director, resident
representation, at least 2 volunteer faculty
members
Clinical Research Unit
Funding and Resources
• Coordinator – 50% time primarily from
grant funding
• New funding and studies could increase to
100%
• Non-EM researchers/industry will have to
pay to use our data infrastructure/research
unit
Clinical Research Unit
Registering Protocols
• Send e-mail with protocol to Dr.Quinn
• Protocol will be reviewed at research committee
for:
- IRB approval
- Funding Source
- Resource Utilization
- Benefit to EM
- All external protocol will need to have an EM
faculty as an investigator/supporter on the protocol
Next Step
• Identify current projects utilizing ED
patients/resources
• Hire coordinator – Completed Dec/Jan
• Volunteer recruitment - Ongoing
• First committee meeting in December
Clinical Research Unit
The First Studies
• Dog Bite Study
- Requires prospective enrollment of patients
and consent
• NET-2
- Surveillance study to be part of large NINDS
study, no consent
Are Prophylactic Antibiotics
Beneficial in Dog Bites?
• Controversial
1) Meta analysis- Ann Emerg Med – 1994
- Recommend treating
2) Cochrane Review 2004
- Recommend Not Treating
3) Current recommendation is to treat high
risk wounds
Are Prophylactic Antibiotics
Beneficial in Dog Bites?
• Is it worth doing the study?
- Over 1,000 patients needed in a multi-center
trial at great cost to determine a 5%
difference (less power on sub group
analysis)
- Is 5% an important difference?
Are Prophylactic Antibiotics Beneficial in Dog Bites?
Value of Cost- Benefit Models
The models done ahead of a trial can;
1) Clearly define important outcomes to
measure
2) Help determine MCID for sample size
3) Sometimes provide the answer
Dog Bite: Cost – Benefit Model
SE
Uncom pl icat ed
i nptu nc
W TP1 - CO ST1
l ongse
NoSE
W TP2 - CO ST2
#
SE
W TP3 - CO ST3
Di sabil ity
InptR x
co mpd is
fail
l ongse
NoSE
W TP4 - CO ST4
R ecover
#
NoSE
co mprec
W TP5 - CO ST5
Nodi s
C om plica ted
Out ptRX
l ongno se
#
SE
W TP6 - CO ST6
#
#
Out ptR x
Deat h
W TP7 - CO ST7
#
SE
W TP8 - CO ST8
Out ptrecover
#
l ongse
NoSE
FaceR xi nf
W TP9 - CO ST9
#
F aceR xi nf
SE
Uncom pl icat ed
i nptu nc
W TP10 - CO ST10
l ongse
NoSE
W TP11 - CO ST11
#
SE
W TP12 - CO ST12
Di sabil ity
InptR x
co mpd is
#
Rx
l ongse
NoSE
R ecover
W TP13 - C13
#
NoSE
co mprec
W TP14 - C14
Nodi s
l ongno se
C om plica ted
#
SE
W TP15 - C15
#
#
Deat h
B ite
W TP16 - C16
#
short SE
FaceR xnoi nf
#
W TP17 - C17
sh ort se
noshortSE
W TP18 - C18
#
NoR x
[+]
Clinical Data
Variable
Baseline Infection Rate Facial Bites
(FaceNoRxInf)
Infection Rate - prophylactic
antibiotics – facial bites (FaceRxInf)
Baseline Infection Rate
Hand Bites (HandNoRxInf)
Infection Rate - prophylactic
antibiotics – Hand Bites (HandRxInf)
Baseline Infection Rate
Other Area (extremity and trunk)
(OtherNoRxInf)
Infection Rate - prophylactic
antibiotics – other areas
% of infected wounds considered for
outpt Rx (OutPtRx)
Failure Rate of outpt antibiotics (Fail)
Risk of Complicated Inpt Course (1Inptunc)
Risk of disability after hand
infection/surgery (CompDis)
Risk of Death w/ complicated infection
(1-CompRec)
Antibiotic Side Effects (ShortSE;
LongSE)
Estimate
Evidence
Range Analyzed
10%
Retrospective Review
5% - 10%
5.60%
(95% CI 3.8 –8.2%)
Meta-analysis of RCT
3.2% - 10%
36%
Retrospective Review
10% - 50%
8.30%
(95% CI 1.8 – 34.2%)
Meta-analysis of RCT
18% - 34.2%
17%
Retrospective Review
10% - 30%
9.50%
(95% CI 6.5% - 13.95)
Meta-analysis of RCT
6.5% - 14%
90%
Physician Opinion
50% - 90%
5 % - 15%
RCT for outpt treatment of
cellulitis
10% - 30%
1- 4%
Retrospective review
2% - 10%
5%
Surgeon’s opinion
1% - 10%
3%
Survey Estimate
2% - 3%
5% - 34%
RCT
5% - 34%
Potential No.
of Subjects
Entered
in Trial
No. With
Known
Results
(%)†Wound > 24 hr old
569
98
62 (63.3)
11 (17.7)
Oxacillin
Wound > 24 hr old Children Hospitalized patients Bone involvement
—
63
47 (73.0)
2 (4.3)
No
Penicillin
Wound > 24 hr old Adults Sutured wounds Facial wounds
80
58
55 (94.8)
2 (3.6)
Pittsfield,
Massachusetts7
Yes
Cloxacillin
Dicloxacillin
Erythromycin
Wound > 8 hr old Involved, bone, tendon, nerves Cannot take capsule
medication
150
36
33 (91.7)
3 (9.1)
Manchester, United
Kingdom16
Yes
Trimethoprim/sulfa
methoxazole
Age < 3 yr Problems requiring antibiotics
—
113В§
78 (69.0)
11 (14.1)
Chicago17
Yes
Penicillin
Adults Hospitalized patients
—
39
39 (100.0)
3 (7.7)
Middlesbrough,
United Kingdom18
Yes
Amoxicillin/clavula
nate
Wound > 24 hr old Age < 6 yr Tendon or joint involvement
1,334
185В¶
96 (51.9)
44 (45.8)
No
Dicloxacillin
Cephalexin
Erythromycin
Wound > 12 hr old Age < 1 yr Wounds of hands or feet Puncture wounds
Immunocompromised host Immunosuppressive medication
759
191
185 (96.9)
6 (3.2)
783
594 (75.9)
82 (13.8)
Double
Blind?
Antibiotic
Exclusions*
Fresno,
California15
Yes
Penicillin
Kansas City,
Missouri5
Yes
Philadelphia6
Location of Study
Fort Hood, Texas19
No.
Infected
(%)
Antibiotic
Control
Location of Study
Total
Infected (%)
Total
Infected (%)
Relative Risk
95% CI
Fresno, California15
30
3 (10)
32
8 (25)
0.40
0.12-1.37
Kansas City, Missouri5
22
2 (9)
24
0 (0)
Philadelphia6
25
1 (4)
30
1 (3)
1.20
0.08-18.23
Pittsfield, Massachusetts7
15
1 (7)
18
2 (11)
0.60
0.06-5.99
Manchester, United Kingdom16
55
3 (5)
58
8 (14)
0.40
0.11-1.41
Chicago17
19
2 (11)
20
1 (5)
2.11
0.21-21.36
Middlesbrough, United
Kingdom18
51
17 (33)
45
27 (60)
0.56
0.35-0.88
Fort Hood, Texas19
89
1 (1)
96
5 (5)
0.22
0.03-1.81
0.56
0.38-0.82
Summary
'
—
Willingness to Pay Data
Survey
Question
2
Bite
Location
Hand, Face,
Other
Willingness to Pay to:
Median Range
Avoid side effects of a 10-day course of antibiotics
$40
3
Face
Lower risk from 4% to 2% that face wound will scar and need plastic surgery
$50
4
Other
Lower risk from 2% to 1% that leg wound will scar and need plastic surgery
$10
5
Hand
Lower risk from 4% to 1% that hand wound will scar and need plastic surgery
$20
6
Hand
Decrease chance of chronic pain in dominant hand from 4% to 1%
$200
7
Hand
Decrease chance of chronic pain in non-dominant hand from 4% to 1%
$100
8
Face, Other
Decrease 0.0006% risk of death from extremely rare infection by 50%
$10
9
Hand
Decrease 0.002% risk of death from rare infection by 75%
$20
10
Face
Take pills for 3 days to decrease need to take the same pills for 10 days from 10% to 6%
$5
11
Hand
Take pills for 3 days to decrease need to take the same pills for 10 days from 16% to 10%
$25
12
Other
Take pills for 3 days to decrease need to take the same pills for 10 days from 36% to 8%
$10
13
Face
Take a pill to decrease chance of hospitalization for 3 days from 2% to 1%
$15
14
Other
Take a pill to decrease chance of hospitalization for 3 days from 4% to 2.2%
$15
15
Hand
Take a pill to decrease chance of hospitalization for 3 days from 10% to 2.3%
$100
16
Face
Take a pill to decrease chance of hospitalization for 10 days from 0.4% to 0.2%
$3
17
Other
Take a pill to decrease chance of hospitalization for 10 days from 0.8% to 0.5%
$4
18
Hand, Other
Take a pill to decrease chance of hospitalization for 3 days from 2% to 0.5%
$25
$7 to
$250
$10 to
$400
$0 to
$20
$0 to
$250
$0 to
$3000
$0 to
$2500
$0 to
$200
$0 to
$200
$0 to
$40
$0 to
$100
$0 to
$30
$0 to
$50
$0 to
$150
$15 to
$300
$0 to
$100
$0 to
$100
$0 to
$200
Cost Data
Diagnosis / Procedure
Charge
(1997)
Charge Payment Range
(2000) (2000)
$1,849Cellulitis of the face
$4,357 $4,624 $2,312
$4,624
$1,763Cellulitis of the hand
$4,153 $4,407 $2,204
$4,407
Other Skin & Subcutaneous
$2,027$4,776 $5,068 $2,534
Locations
$5,068
$4,474Septicemia (except in labor) $10,540 $11,185 $5,593
$11,185
Incision and Drainage of skin
$3,031$7,141 $7,578 $3,789
and subcutaneous tissue
$7,578
Other skin and breast
$4,665$10,991 $11,663 $5,832
procedures, OR
$11,663
Medication
Augmentin (per pill)
$4.76
$2-$6
Source
HCUP Nationwide
Inpatient Sample
HCUP Nationwide
Inpatient Sample
HCUP Nationwide
Inpatient Sample
HCUP Nationwide
Inpatient Sample
HCUP Nationwide
Inpatient Sample
HCUP Nationwide
Inpatient Sample
www.pillbot.com
In 2000
Dollars
4623.52
4407.04
5068.15
11185
7577.82
11663
Base Case
Face
Hand
Other
Branch
WTP
Cost
WTP - Cost
Rx
NoRx
Rx
NoRx
Rx
NoRx
44.1
10.7
75.3
92.3
49.4
18.9
70.8
65.7
87.4
229.4
100.1
118.8
-26.7
-55
-12.1
-137.1
-50.7
-99.9
Incremental
Difference
28.3
125
49.2
Extreme Scenario (based on sensitivity runs)
Face
Hand
Other
Branch
WTP
Cost
WTP - Cost
Rx
NoRx
Rx
NoRx
Rx
NoRx
12.9
6.2
44.1
39.9
18.2
10.6
116
146.4
253.2
506.2
184.2
269.3
103.1
140.2
-208.8
-466.3
-166
-258.7
Incremental
Difference
37.1
257.5
92.7
Sensitivity Analysis on
FaceRxinf
-10.0
Rx
-15.0
NoRx
E xpected V alue
-20.0
-25.0
-30.0
-35.0
-40.0
-45.0
-50.0
-55.0
0. 0320
0. 0490
0. 0660
FaceRxinf
0. 0830
0. 1000
Are Prophylactic Antibiotics Beneficial in Dog Bites?
Value of Cost- Benefit Models
• Model determined 1% difference may be important as far
as cost
• An RCT to determined this would not be reasonable
But….
- The model is based on assumptions and best available data.
- Sensitivity analysis can determine the errors associated
with assumptions
- Better model estimates will improve the accuracy of the
results.
Are Prophylactic Antibiotics
Beneficial in Dog Bites
• Funding – NIAMS
• Design Cost Benefit Analysis with Clinical Trial Data
• Start Aug 2003 UCSF add Stanford November 2004, Study
will run through June 2006
• Patient randomized to 3 days of Augmentin or Placebo
• Goal 100 – 125 patients outcomes (the largest trial)
- 37 patients with complete F/U to date
• Goal is to define and measure accurately all outcomes
(infections, side effects, hospitalizations etc.) in the model
• Re-run the model and sensitivities to come up with the best
recommendations.
Are Prophylactic Antibiotics Beneficial in Dog Bites?
Outcomes
• Infection
- Defined as to whether the patient on followup was treated for an infection with
antibiotics
• Related physician/hospital: visits,
admissions, treatments
• Side effects
- Self limited: patient self treated
- Required physician visit/treatment
How Can I Help?
• Expect a call when a dog bite comes in
• Volunteers will do the enrolment if they are
present, but will ask you some questions
and will need physician help with attaining
the consent
• We will walk you through enrollment if the
volunteers are not present
• If you are too busy we will come in
Summary
• Academic Emergency Medicine is growing
• Research is an integral part
• Division of Emergency Medicine at
Stanford has made a commitment to the
research program
Questions and Answers
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