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

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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

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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

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Improving ResearchHow Do We Get There

• Obstacles
• Too busy
• No training in research
• Too few mentors/role models
• No interest

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Improving ResearchHow 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

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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

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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

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Research CurriculumStructure 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

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The Five Page ProtocolGoal 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

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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

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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

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What is a Career Development Award ?

• Funding to protect your time so that you can
  develop your research skills
• Research may be
• Clinical
• Basic Science

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NIH Awards for Individuals with a
Health-Professional Doctorate
Institutional Training Grants (T32)
Senior Fellowships (F33)
Postdoctoral Fellowships (F32)
Short-Term Training Grant (T35)
Independent Investigator
Medical School
Internship/Residency Specialty
Career Enhancement Award Stem Cells (K18)
Scientist Development Program (K12)
Midcareer Investigator in Patient-Oriented
Research (K24)
Mentored Clinical Scientist Development Award
(K08)
Mentored Patient-Oriented Research CDA (K23)
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Benefits of a Career Development Award ?

• Protected time
• Extra Training
• Step towards independence
• New relationships

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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

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What is Important to Study Section Members?

• Study section members dont 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
• Investigators track record and preliminary data
• The institutional research environment

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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.

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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.

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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.

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Research Options

• Basic Science
• Translational Research
• Clinical Research
• Large database
• Retrospective reviews
• Clinical trials/Prospective cohorts

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Myth Large Databases

• Large administrative databases contain large
  amounts of clinically useful information.

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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)

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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.

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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.

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Clinical Trials

• Prospective trials
• Designed to answer specific questions
• More likely to answer the question correctly

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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

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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

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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

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Clinical Research UnitReal 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/

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Clinical Research UnitResearch 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.

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Clinical Research UnitResearch 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

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Clinical Research UnitFunding 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

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Clinical Research UnitRegistering 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

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Next Step

• Identify current projects utilizing ED
  patients/resources
• Hire coordinator Completed Dec/Jan
• Volunteer recruitment - Ongoing
• First committee meeting in December

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Clinical Research UnitThe 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

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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

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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?

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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

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Dog Bite Cost Benefit Model
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Clinical Data
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Location of Study Double Blind? Antibiotic Exclusions Potential No. of Subjects Entered in Trial No. With Known Results () No. Infected ()
Fresno, California15 Yes Penicillin Wound gt 24 hr old 569 98 62 (63.3) 11 (17.7)
Kansas City, Missouri5 Yes Oxacillin Wound gt 24 hr old Children Hospitalized patients Bone involvement 63 47 (73.0) 2 (4.3)
Philadelphia6 No Penicillin Wound gt 24 hr old Adults Sutured wounds Facial wounds 80 58 55 (94.8) 2 (3.6)
Pittsfield, Massachusetts7 Yes Cloxacillin Dicloxacillin Erythromycin Wound gt 8 hr old Involved, bone, tendon, nerves Cannot take capsule medication 150 36 33 (91.7) 3 (9.1)
Manchester, United Kingdom16 Yes Trimethoprim/sulfamethoxazole Age lt 3 yr Problems requiring antibiotics 113 78 (69.0) 11 (14.1)
Chicago17 Yes Penicillin Adults Hospitalized patients 39 39 (100.0) 3 (7.7)
Middlesbrough, United Kingdom18 Yes Amoxicillin/clavulanate Wound gt 24 hr old Age lt 6 yr Tendon or joint involvement 1,334 185 96 (51.9) 44 (45.8)
Fort Hood, Texas19 No Dicloxacillin Cephalexin Erythromycin Wound gt 12 hr old Age lt 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)





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Antibiotic 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
Summary ' 0.56 0.38-0.82
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Willingness to Pay Data
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Cost Data
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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.

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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.

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Are Prophylactic Antibiotics Beneficial in Dog
Bites?Outcomes

• Infection
• Defined as to whether the patient on follow-up
  was treated for an infection with antibiotics
• Related physician/hospital visits, admissions,
  treatments
• Side effects
• Self limited patient self treated
• Required physician visit/treatment

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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

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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

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Questions and Answers