Office of the Executive Vice President for Research
and Innovation
Jouett Hall – Suite 202
University of Louisville
Louisville, KY 40292-0001
Office: 502-852-8373 Fax: 502-852-8375

Monday, February 1, 2016
Kristina Borror, Ph.D., Director
Division of Compliance Oversight
Office for Human Research Protections
1101 Wootton Parkway, Suite 200
The Tower Building
Rockville, MD 20852
Dear Dr. Borror:
SUBJECT:

Human Subject Protections under Federalwide Assurance 00002211
Principal Investigator: Susan Harkema, Ph.D.

Research Project:
IRB#12.0151

IRB#066.07

Title:
H133N110007: Baclofen with Locomotor
Training: The Effect on Function and
Neuroplasticity in Chronic Incomplete Spinal Cord
Injury (Baclofen)
Spinal Epidural Electrode Array to Facilitate
Standing and Stepping after Spinal Cord Injury
(EPI ORIGINAL)

IRB#13.0625

Recovery of Cardiovascular Function with Epidural
Stimulation after Human Spinal Cord Injury (CV EPI)

IRB#268.07

Activity-Dependent Rehabilitation Model to Improve
Bone and Muscle after SCI (NMES)

Sponsor:
National Institute on Disability,
Independent Living and
Rehabilitation Research (NIDILRR)
National Institutes of Health
Christopher Reeves Paralysis
Foundation
Kessler Foundation
Helmsley Charitable Trust
Christopher and Dana Reeve
Foundation
Craig H. Nielsen Foundation
New Jersey Commission on Spinal
Cord Research
Craig H. Nielsen Foundation

Brief Study Summary: To determine the impact and interaction of oral Baclofen (an FDA approved drug) and locomotor
training (LT) on gait, spasticity, neuromuscular activation during voluntary movements and stepping, cardiovascular
function, pulmonary function, and quality of life in persons with chronic, motor incomplete Spinal Cord Injury (SCI) in a
prospective, controlled, randomized study. This proposal outlines a randomized (1:1), two-group, four-month
longitudinal design to determine if outcomes of LT alone will be significantly different than Baclofen with LT. A total of
60 patients will be randomized into one of two (n=30 each) treatment groups, measuring a baseline and again following
20, 40, 60 and 80 sessions.
This letter is to address your correspondence to the University of Louisville dated 11/9/2015, concerning allegations
made regarding subject safety in four research studies being conducted by Dr. Susan Harkema. This letter specifically
addresses the Baclofen study, IRB#12.0151.
The University of Louisville Human Subjects Protection Program was contacted on Wednesday, September 16, of
allegations of possible adverse events by the study physician ten associated with this research study, Dr. Steve Williams.
Dr. Williams met with the Assistant Director of the HSPP Office, Christy LaDuke, and the two research compliance
monitors, Lisa Schaffer and Beverly Taft.

 Dr. Kristina Borror
Baclofen Study - H133N11 0007: Baclofen with Locomotor Training: The Effect on Function and
Neuroplasticity in Chronic Incomplete Spinal Cord Injury
IRB#12.0151

Dr. Williams’ allegations caused the HSPP Office to establish a proposed audit plan, and to allow the research
compliance monitors to review the study files prior to beginning an audit. The research compliance monitors cleared
their schedules and were given approval to conduct an unannounced audit to begin on Monday, October 19, 2015.
On Friday, October 16, 2015, the University of Louisville received an email from Dr. Dawn Carlson, NIDILRR, indicating
that Dr. Carlson had received a letter dated 10/15/15 from Dr. Dan Graves, Project Director, for the Baclofen study at
the University of Louisville. The study is funded by the National Institute on Disability, Independent Living and
Rehabilitation Research (NIDILRR), and Dr. Graves is the listed Principal Investigator on the grant. Dr. Harkema
is a co-investigator on this grant.
Additionally, from the IRB perspective, all IRB submissions for the Baclofen study were made with Dr.
Harkema as the Principal Investigator. Dr. Carlson requested that the University of Louisville respond to
allegations of possible adverse events and subject injuries contained in the letter from Dr. Graves.
Dr. Harkema was notified on Friday, October 16, of the email received from Dr. Carlson. When notified of the
request, the investigator, Dr. Susan Harkema, immediately voluntarily placed the Baclofen study on hold, so that the
allegations could be investigated, and subject safety assured.
The Human Subjects Protection Program began an audit of this study on Monday, October 19, 2015. Research
Compliance Monitors, Lisa Schaffer and Beverly Taft, began a records review of the Baclofen study. On Wednesday,
October 21, they met with Dr. Harkema concerning their preliminary findings in reviewing the research records.
Research Compliance Monitors reviewed research records in the Kentucky Spinal Cord Injury Research Center (KYSCIRC,
located at the Frazier Rehabilitation Institute, associated with KentuckyOne Health, a part of Catholic Health Initiatives.
Records review continued throughout the two week period October 19–October 22 and October 26-October 30.
Research Compliance Monitors began drafting a preliminary report of findings for review by the University of Louisville
Biomedical IRB.
On Monday, November 9, 2015, your letter was received in the Executive Vice President for Research and Innovation
office and was distributed to those engaged in compliance oversight: Director, Human Subjects Protection Program;
Director, Office of Research Integrity; and Interim Director, Clinical Contracts Division.
Once the preliminary observations were reviewed by the IRB Chair, Laura Clark, MD, and Vice Chair, Julie Goldman, MD,
the preliminary findings were scheduled for review at the 11/19/15 meeting of the Biomedical IRB. Sixteen preliminary
audit observations were reported to the IRB and Board determinations were voted on by the Biomedical IRB. All
observations are documented below. University of Louisville local process allows the Principal Investigator 10 working
days to respond to IRB observations/findings. Due to Thanksgiving holiday closures at the University of Louisville,
responses were due back to the Biomedical IRB by Wednesday, December 9, 2015.

Page 2 of 7

 Dr. Kristina Borror
Baclofen Study - H133N11 0007: Baclofen with Locomotor Training: The Effect on Function and
Neuroplasticity in Chronic Incomplete Spinal Cord Injury
IRB#12.0151

Summary of Observations Presented at the 11/19/15 Biomedical IRB meeting include the following:
1

2

3

4

5

FINDING DETAIL
Not all subjects listed completed/performed 80 locomotor
training sessions. Should they be listed as complete? (i.e.,
Some subjects had an evaluation after 20 sessions and were
listed as completed.)
November 9, 2015 letter from OHRP alleged non-compliance
with protocol. Protocol stated, “80 LT sessions.” PI failed to
modify protocol to indicate evaluation at end of 20 visits to
ensure continued participation. There is no confirmation
within protocol that subjects would be continued after
insurance covered visits were completed.
Subjects didn’t sign the Baclofen study (12.0151) screening ICF
before they were enrolled.
• 233_CDL
• 132_CMB
• 213_CMN

The protocol indicates Dr. Harkema is blinded to study drug.
In the Frazier Rehab Database (ITW) it notes if subject remains
on Baclofen. The Physical Therapist and study MD must know
which drug subject is currently on. Notes on screening and
consent log in research record states if subject was on
Baclofen at time of completion or withdrawal. If Dr. Harkema
& blinded physical therapist have access to the ITW system
they can see which subjects are on study drug. All subject
current medications are listed in the ITW system.
At the time of audit, there were not inclusion/exclusion
worksheets on file for any of the enrolled subjects. Dr.
Harkema received training from the research compliance
monitors concerning documenting inclusion criteria for each
enrolled subject.
No follow-up records are present in the research records. It is
nearly impossible to see which protocol procedures have been
completed. Dr. Harkema states that records are in the cardinal
database and Systemax. Systemax is a KentuckyOne Catholic
Health Initiative database that pulls data from the ITW
system. Research compliance monitors were unable to see
records for study sessions or MD visits related to the protocol.

Page 3 of 7

Notes
Protocol non-compliance
The protocol (draft format) has been
modified to clarify the number of
sessions for completion of the study
for data analysis. This protocol will be
submitted if the study is allowed to
continue with enrollment.
IRB currently allowing PI to keep study
open until DHHS makes their final
determination. Enrollment hold
remains in effect.
Protocol non-compliance
Educated site re: consenting subjects
to correct informed consent.
(Completed by research compliance
monitors)
Screening information for the three
subjects that did not sign Baclofen
Screening Consent Form was extracted
from previous clinic documentation or
from the Human Locomotor Research
Center research procedures.
Protocol non-compliance
Throughout the audit process and in
order to respond to allegations of IRB
non-compliance Dr. Harkema has been
required to review clinical medical
records including baclofen status.
Blinding did follow the protocol as
written.

Resolution
No

Serious non-compliance
Source documents were provided for
each subject confirming their eligibility.

Yes

Serious non-compliance with protocol
Site provided missing follow-up source
documentation. Most of the
procedures were completed. Board
has requested a deviation for those
missing protocol procedures either not
completed or missing from research
medical record.

No

Yes

Yes

 Dr. Kristina Borror
Baclofen Study - H133N11 0007: Baclofen with Locomotor Training: The Effect on Function and
Neuroplasticity in Chronic Incomplete Spinal Cord Injury
IRB#12.0151

6

7

8

9

10

FINDING DETAIL
No study medication compliance is noted in the subjects
records, nor information regarding titration or if study drug
was stopped. Per protocol, the physical therapist is to assess
on a daily basis study medication compliance. Research
compliance monitors were also unable to identify any
documentation about study drug visit cards, mentioned in the
protocol.

Adverse events for the study have not been tracked or
monitored by the research team. Research compliance
monitors have compiled a list of 151 AEs from the ITW
database.
11 subjects signed the incorrect consent forms.
• 123_BPR- screening consent- No difference in content.
ICF was stamped different due to CR
• 125_DDI main consent- subject was later re-consented to
correct ICF
• 156_BDO screening consent should have been consented
to contained Research Authorization. Subject did sign
Research Authorization at time of initial consent
• 156_BDO main consent- should have been consented to
ICF that contained Research Authorization and
Neurorecovery Scale. Subject did sign Research
Authorization at time of initial main consent.
• 243_DKB & 244_BLI- screening consent should have been
version 12/11/14 stamped 12/15/14-4/18/15. The only
difference was Yukishia Austin’s name. She is the research
nurse.
• 185_CTC, 243_DKB, 242_DTC, 213_CMN, 233_CDL main
consent should have been 12/11/14 stamped 12/15/144/18/15. The only difference was Yukishia Austin’s name
Subject 724-CQA signed screening and main ICF on the same
day, December 14, 2012. Per the protocol page 8, there will
be a mandatory minimum three-day waiting period before the
main ICF is signed. This requirement was later removed from
the protocol approved 5/14/13.
Subject 724-CQA signed the research authorization 6 days
after screening and main consent form was signed.

Page 4 of 7

Notes
Serious non-compliance
Educated site about documentation by
research team on study drug
compliance. (Completed by research
compliance monitors).
Upon determination by DHHS
regarding study enrollment submit an
amendment to the protocol and
standard operating procedures stating
one entity (physical therapist) will
monitor study medication and on what
time period (daily, every 7 days, every
re-evaluation, etc). Standard operating
procedures need revised to reflect
where medication is filled.
Non-compliance
The study MD verified in writing that
all the adverse events were not related
to baclofen or study procedures.
No subjects currently enrolled. Closure
amendment requested. IRB currently
allowing PI to keep study open until
DHHS makes their final determination.

Resolution
No

Non-compliance
Protocol Deviation submitted.

Yes

Non-compliance
No research procedures completed in
that 6 day period.

Yes

Yes

No

 Dr. Kristina Borror
Baclofen Study - H133N11 0007: Baclofen with Locomotor Training: The Effect on Function and
Neuroplasticity in Chronic Incomplete Spinal Cord Injury
IRB#12.0151

11
12

13

14
15

16

FINDING DETAIL
The PI has placed the study on hold. PI has requested that she
be allowed to restart subject enrollment.
Study MD was not documenting lab values for the research
protocol as being clinically significant or non-significant.
Records reflecting that the study MD approved enrollment for
the randomized subjects was not present for all subjects.
Many of the source documents didn’t have a date or signature
showing when they were completed.
There were inconsistencies noted in what was covered by
insurance or what was covered by the study grant. This
includes physical therapy assessments and the Baclofen. What
the auditors recommend is that this be reviewed by someone
with financial expertise. This includes what was told or not
told to the subjects. Initial Billing Compliance Table (BCT)
showed Research paying for all procedures and Amend-7120
(approved 6/11/13) changed the BCT to reflect insurance pays
for all procedures except study drug & lab tests. See
attachment I regarding the compliant that was sent to Dr.
Graves.
CVs needed for Drs. Harkema, Angeli, Kaelin, Darryn Atkinson,
Heather Tolle, Cassidy Raibert, Steve Williams, James Ochsner,
Amy Goins, Amanda Oakley
Local Institutional requirements-Proof of training; CVs.
Training needs to be completed by Darryl Kaelin, M.D.
Address the issue of non-compliance in the OHRP letter dated,
November 9, 2015. Specifically for study 12.0151 item 2d, “A
subject involved in the "Baclofen" Study complained of
ongoing right knee pain since participating in the study that
was so severe she needed to sleep with joint cushioned
between two pillows. On exam this subject had a visibly
displaced leg, and an x-ray revealed a deformed tibial plateau
fracture.”
Need a clear explanation of all the databases being utilized to
record research findings and medical records for this study.
Explain the following databases: Centrix, Cardinal database,
Purple database, ITW, Systemax, and ULP database.
Who established these databases? Who owns or manages
these databases? What info is stored in each database? Is the
information stored de-identified information? How is it used?
What records are kept in each of the databases? How many
research subjects are in each database? Are the databases
password protected?
Who has access to each database? If the database is for
research purposes, provide an excel spreadsheet with field
names. Clinical databases not approved by the IRB cannot be
mined for research purposes unless that database is covered
by an IRB approved protocol.

Page 5 of 7

Notes
Board voted to continue with
enrollment hold until final
determination by DHHS.
January 2016 two different education
sessions were given to the
investigators and study team
members.

Resolution
No

12/15/15 letter from Dr. Kevyn
Merten, University of Louisville,
Assistant VP Research & Innovation
stated, “Study drug and lab tests
included in budget, but physical
therapy assessments in form of
locomotor training not included and
are not coverable via funding from the
grant.”

Yes

All required training & CV’s have been
received.
Possible non-compliance
The study MD reviewed the case and
confirmed the fracture was not study
related. The fracture occurred months
after the research participant
completed the study.

Yes

The Research Compliance Monitors
and the Director of the HSPPO will
oversee that this issue is resolved.
Further information will be reported to
an IRB Chair.

Yes

Yes

Yes

 Dr. Kristina Borror
Baclofen Study - H133N11 0007: Baclofen with Locomotor Training: The Effect on Function and
Neuroplasticity in Chronic Incomplete Spinal Cord Injury
IRB#12.0151

Responses for the above observations were received from the Investigator on December 3, 2015, and those responses
were reviewed by the Biomedical IRB on Thursday, December 10. Additional clarifications and supporting documents
were requested from the investigator after the December 10 IRB meeting.
The Biomedical IRB has reviewed investigator responses at the meetings of 12/10/15, 01/07/16, and 01/28/16.
Repeated educational sessions have been given to Dr. Harkema, the new study physician, Dr. Darryl Kaelin, key
personnel and members of the study staff.
Dr. Harkema has answered most audit observations appropriately with a few noted outstanding items to be completed.
It is expected that the remaining items will be handled in the same manner: responses provided, responses reviewed by
the Biomedical IRB, and observations closed.
Overall Observations: The Research Compliance Monitors did find several instances of non-compliance and serious
non-compliance based on federal regulations and local institutional standard operating procedures. Research
Compliance Monitors provided instruction to the Principal Investigator, key study personnel and study team members
throughout the audit process. This investigator has responded in an appropriate manner to the IRB concerning all audit
findings and will continue to provide follow up on open observations. Ultimately, the expectation is that all issues will
be resolved to the satisfaction of the Biomedical IRB.
Findings of the Human Subject Protections Program: The University of Louisville Human Subject Protections Program
found that allegations concerning subject safety were unfounded and no subjects were injured who participated in the
Baclofen study. All subjects who were enrolled and who received Baclofen have been appropriately weaned from
Baclofen, an FDA approved drug, being used for the approved indication in this research study. Research Compliance
Monitors noted turnover in qualified study personnel throughout the history of the study. Also noted was the
competence of the current clinical and regulatory staff.
Follow Up on Provided Corrective Action Plans and Continuation Review Cycle: Research Compliance Monitors have
recommended that the corrective action plans provided for this study be monitored at each continuation review cycle.
Since no subjects were harmed in this research study, the continuation review cycle will remain at annual review. If
NIDILRR finds that the study should be continued, this recommendation will not be needed.
Institutional Goal: The institutional goal would be to allow Dr. Harkema to complete this funded research study.
However, that final determination will not be made until the University of Louisville hears from NIDILRR whether the
study may continue. If NIDILRR discontinues funding and closes this study to accrual, the University of Louisville will
comply with that decision.
Preliminary Observations and Responses for each IRB request are included in the Audit Report that accompanies this
letter. Attachments A-P provide information received and noted within the Audit Report.
Dr. Harkema’s direct response to OHRP and all other items requested by OHRP are being provided as zip files that
accompany this letter. The following requested items are included:
a) The IRB-approved research protocol and any applicable grant applications.
b) The IRB-approved informed consent documents.
Page 6 of 7

 Dr. Kristina Borror
Baclofen Study H133N11 0007: Baclofen with Locomotor Training: The Effect on Function and
Neuroplasticity in Chronic Incomplete Spinal Cord Injury
-

IRB#12.0151

c) The relevant IRB minutes including initial review, continuation review, review of changes to the research or to
the informed consent document, and review of any adverse or unanticipated events.
d) All correspondence between the IRB and investigators.
e) All continuing review reports.
f) A list of subjects (code numbers only) and dates of enrollment.
g) A chronological summary of the dates of the IRB’s actions.
h) A copy of any publications or presentations which were derived from this research project.
i) Any other pertinent information.
The University of Louisville and its affiliated institutions hold investigators responsible for conducting research with
human subjects as outlined in 45 CFR 46,21 CFR 50 And 56,21 CFR 312, and affirm our commitment to the protection of
human subjects. If you should have any questions about this information, please feel free to contact me at (502) 8528373 or Rebecca Higgins, Director, Human Subjects Protection Program at (502) 852-6956.
Sincerely,

William M. Pierce, Jr., Ph.D.
Executive Vice President for Research and Innovation
Cc:

Dr. Susan J. Harkema, Professor, Department of Neurological Surgery
Kelly Neese, Regulatory Coordinator, Kentucky Spinal Cord Injury Research Center
Dr. Laura D. Clark, Chair, UofL Biomedical Institutional Review Board
Dawn Carlson, Ph.D., NIDILRR, U.S. Department of Health and Human Services, Washington, DC
Joanne Less, Ph.D., Director, Office of Good Clinical Practice, U.S. Food and Drug Administration
Mr. John Tschida, Director, National Institute on Disability, Independent Living and Rehabilitation Research
Mr. Jeffrey Rodamar, Protection of Human Subjects Coordinator, U.S. Department of Education
Ms. Sarah Carr, Office of Science Policy, National Institutes of Health
Gregory Postel, M.D., Interim Executive Vice President for Health Affairs, University of Louisville
Toni Ganzel, M.D., M.B.A, F.A.C.S., Dean, School of Medicine, University of Louisville
Pamela W. Feldhoff, Ph.D., Associate Vice President for Research and Innovation, University of Louisville
Kevyn E. Merten, Ph.D., Assistant Vice President for Research and Innovation, University of Louisville
David D. King, JD, Associate University Counsel, University of Louisville
Haring Nauta, M.D., Interim Chair and Professor, Department of Neurological Surgery
Scott Whittemore, Ph.D., Professor and Vice Chairman for Research, Department of Neurological Surgery, and
Scientific Director, Kentucky Spinal Cord Injury Research Center
Allison G. Ratterman, Ph.D., Director, Research Integrity Program, University of Louisville
David Gary, Director, Human Research Protection Program, CHI Institute for Research and Innovation (CIRI),
Catholic Health Initiatives
Katy Wane, JD, MPH, CHRC, Director, Clinical Research Compliance, KentuckyOne Health, part of Catholic Health
Initiatives

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