Food and Drug Administration

Center for Drug Evaluation and Research

Summary Minutes of the
Anesthetic and Analgesic Drug Products Advisory Committee Meeting
November 24-25, 2014

Location: The FDA White Oak Campus, Building 31, The Great Room (Rm. 1503),
White Oak Conference Center, Silver Spring, Maryland.

Topic: The committee discussed the risk of serious neurologic adverse reactions
associated with epidural steroid injections (ESI) administered to reduce inflammation for
pain management. The committee also considered the efficacy of ESI and the overall
risk benefit balance of injecting steroids in the epidural space to treat pain. These
considerations will assist the Agency in our discussions of possible regulatory options,
including but not limited to changes to the product labeling.

These summary minutes for the November 24-25, 2014, meeting of the Anesthetic and
Analgesic Drug Products Advisory Committee of the Food and Drug Administration
were approved on December 18, 2014.

I certify that I attended the November 24-25, 2014, meeting of the Anesthetic and
Analgesic Drug Products Advisory Committee of the Food and Drug Administration and
that these minutes accurately reflect what transpired.

/s/ /s/
______________________________ _______________________________
Stephanie L. Begansky, PharmD Randall Flick, MD
Designated Federal Officer, AADPAC Chairperson, AADPAC

Page 1 of 7
 Summary Minutes of the Anesthetic and Analgesic Drug Products
Advisory Committee Meeting
November 24-25, 2014

The following is the final report of the Anesthetic and Analgesic Drug Products Advisory
Committee meeting held on November 24-25, 2014. A verbatim transcript will be available in
approximately six weeks, sent to the Division of Analgesia, Anesthesia and Addiction Products
and posted on the FDA website at:
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndA
nalgesicDrugProductsAdvisoryCommittee/ucm390304.htm.

All external requests for the meeting transcript should be submitted to the CDER Freedom of
Information Office.

The Anesthetic and Analgesic Drug Products Advisory Committee of the Food and Drug
Administration, Center for Drug Evaluation and Research, met on November 24 and 25, 2014, at
the FDA White Oak Campus, Building 31, The Great Room (Rm. 1503), White Oak Conference
Center, Silver Spring, Maryland. Prior to the meeting, the members and temporary voting
members were provided the briefing materials from the FDA. The meeting was called to order
by Randall Flick, MD (Chairperson). The conflict of interest statement was read into the record
by Stephanie Begansky, PharmD (Designated Federal Officer). There were approximately 100
people in attendance on November 24th and approximately 60 in attendance on November 25th.
There were 16 Open Public Hearing (OPH) speaker presentations.

Issue: The committee discussed the risk of serious neurologic adverse reactions associated with
epidural steroid injections (ESI) administered to reduce inflammation for pain management. The
committee also considered the efficacy of ESI and the overall risk benefit balance of injecting
steroids in the epidural space to treat pain. These considerations will assist the Agency in our
discussions of possible regulatory options, including but not limited to changes to the product
labeling.

Attendance:

Anesthetic and Analgesic Drug Products Advisory Committee Members Present (Voting):
Randall P. Flick, MD, MPH (Chairperson); David S. Craig, PharmD, BCPS; Charles W. Emala
Sr., MS, MD; Jennifer G. Higgins, PhD, CCRP (Consumer Representative); Gary A. Walco,
PhD, ABPP; James H. Ware, PhD; Ursula Wesselmann, MD, PhD

Anesthetic and Analgesic Drug Products Advisory Committee Members Not Present
(Voting): Jeffrey L. Galinkin, MD, FAAP; Alan D. Kaye, MD, PhD; Rafael V. Miguel, MD;
Cynthia Wong, MD;

Anesthetic and Analgesic Drug Products Advisory Committee Member Present (Non-
Voting): Richard L. Leff, MD

Page 2 of 7
 Temporary Members (Voting): Brian T. Bateman, MD, MSc; Brian Bradley, CRNA, MS;
Susan R. Broyles (Patient Representative); James C. Eisenach, MD; John T. Farrar, MD, MSCE,
PhD; Tobias Gerhard, PhD, RPh; S. Raymond Golish, MD, PhD; Scott Horn, DO; Jeffrey R.
Kirsch, MD; John D. Loeser, MD; John Markman, MD; Edward Michna, MD, JD, RPh; Michael
Sprintz, DO; Andreas Reimold, MD; Michael H. Weisman, MD; Lynda J-S Yang, MD, PhD

FDA Participants (Non-Voting): Mary Parks, MD; Judy Racoosin, MD, MPH; Sally Seymour,
MD; Scott Proestel, MD; CDR Laurelle Cascio, PharmD

Open Public Hearing Speakers: Lazmaiah Manchikanti, MD for David Bryce, MD; Lazmaiah
Manchikanti (American Society of Interventional Pain Physicians); Roland Chalifoux, DO (West
Virginia Society of Interventional Pain Physicians); Dennis Capolongo (End Depo Now); Scott
Glaser, MD; Ray Baker, MD (International Spine Intervention Society); Jeff Ebel (Clint
Pharmaceuticals); John Dombrowski, MD (American Society of Anesthesiologists); Kenneth
Candido, MD for Mahendra Sanapati, MD; Larry Dalton, DO (Florida Society of Interventional
Pain Physicians); Terri Anderson (NFFE Local 60 and Arachnoiditis Society for Awareness and
Prevention); Dawn Fickel; DJ Kennedy, MD (North American Spine Society); Kenneth Zahl,
DO; Gary Snook; Sarah Sorscher (Public Citizen)
_____________________________________________________________________________

The agenda was as follows:

Day 1: Monday, November 24, 2014

8:00 a.m. Call to Order and Introduction of Randall P. Flick, MD, MPH
Committee Chairperson, AADPAC

8:05 a.m. Conflict of Interest Statement Stephanie L. Begansky, PharmD

Designated Federal Officer, AADPAC

8:15 a.m. FDA Introductory Remarks Sally Seymour, MD

Deputy Director for Safety
Division of Pulmonary, Allergy, and
Rheumatology Products (DPARP)
Office of Drug Evaluation II (ODE II)
Office of New Drugs (OND), CDER, FDA

8:35 a.m. GUEST SPEAKERS’ PRESENTATIONS

Epidural Injections: Are They Effective? Steven P. Cohen, MD

Professor of Anesthesiology and Critical Care
Medicine
Director of Medical Education, Pain Medicine
Division
Johns Hopkins School of Medicine

Page 3 of 7
 GUEST SPEAKERS’ PRESENTATIONS (CONT.)

An Overview of Complications Charles E. Argoff, MD

Associated with Epidural Steroid Professor of Neurology
Injections Albany Medical College
Director, Comprehensive Pain Center
Albany Medical Center

9:55 a.m. Clarifying Questions

10:25 a.m. BREAK

10:40 a.m. FDA PRESENTATIONS

Epidural Steroid Injections (ESIs): CDR Laurelle Cascio, PharmD

Postmarketing Serious Neurological Safety Evaluator
Adverse Events Reported to the FDA Division of Pharmacovigilance II (DPV II)
Adverse Event Reporting System Office of Surveillance and Epidemiology (OSE)
(FAERS) CDER, FDA

Overview of the Published Medical Jane L. Gilbert, MD, PhD

Literature Medical Officer, DPV I, OSE, CDER, FDA

11:10 a.m. Drug Utilization Patterns for Epidural Rajdeep Gill, PharmD
Steroid Injections: Years 2009-2013 Drug Utilization Analysis Team Leader (Acting)
Division of Epidemiology II, OSE, CDER, FDA

11:30 a.m. Clarifying Questions

12:00 p.m. LUNCH

1:00 p.m. FDA PRESENTATIONS (CONT.)

Safe Use Initiative John Whyte, MD, MPH

Director
Professional Affairs and Stakeholder
Engagement (PASE)
Office of the Center Director, CDER, FDA

1:05 p.m. GUEST SPEAKER PRESENTATION

Safeguards to Prevent Neurologic James P. Rathmell, MD

Complications During Epidural Steroid Chief, Division of Pain Medicine, Department
Injection of Anesthesia, Critical Care and Pain Medicine
Massachusetts General Hospital
Professor of Anesthesia
Harvard Medical School
1:30 p.m. Clarifying Questions

Page 4 of 7
2:00 p.m. Open Public Hearing

3:30 p.m. BREAK

3:45 p.m. Charge to the Committee Judith A. Racoosin, MD, MPH

Deputy Director for Safety
Division of Anesthesia, Analgesia, and
Addiction Products (DAAAP)
ODE II, OND, CDER, FDA

4:00 p.m. Questions to the Committee/Committee Discussion

5:00 p.m. ADJOURNMENT

Day 2: Tuesday, November 25, 2014

8:00 a.m. Call to Order and Introduction of Randall P. Flick, MD, MPH
Committee Chairperson, AADPAC

8:05 a.m. Conflict of Interest Statement Stephanie L. Begansky, PharmD

Designated Federal Officer, AADPAC

8:15 a.m. Questions to the Committee/Committee Discussion (cont.)

10:15 a.m. BREAK

10:30 a.m. Questions to the Committee/Committee Discussion (cont.)

12:00 p.m. ADJOURNMENT

Questions to the Committee:

1. DISCUSSION: Discuss your understanding of the evidence regarding the benefits of

epidural corticosteroid injection administered to reduce inflammation for pain management.
Considerations in the discussion may include the following:

a. Medical condition being treated

b. Location of the injection
c. Injection method
d. Corticosteroid formulation

Committee Discussion: The committee indicated that the evidence regarding the benefits of
epidural corticosteroid injection administration seem to be modest, with substantial variation
from patient to patient. It was stated that the benefit has to be placed in context of risks, and
consideration must be given to alternative therapies based on individual patients. The
committee also stated that there is a lack of sufficient data to suggest that any one medical
condition being treated, injection location, injection method, or formulation had better
efficacy. Please see the transcript for details of the committee discussion.

Page 5 of 7
2. DISCUSSION: Discuss your understanding of the evidence regarding the risks of epidural
corticosteroid injection administered to reduce inflammation for pain management,
particularly the potential neurological sequelae. Considerations in the discussion may include
the four factors listed in question 1 above.

Committee Discussion: The committee indicated that there did not appear to be adequate
evidence to suggest that the risks of epidural corticosteroid injection administration were
worse for any one specific medical condition being treated. However, the weight of the
evidence suggests an increased risk associated with transforaminal injections into the
cervical spine, principally with particulate corticosteroid formulations. Please see the
transcript for details of the committee discussion.

3. VOTE: Based on your discussions of the evidence regarding the benefits and risks of
epidural corticosteroid injection administered to reduce inflammation for pain management,
do you think there are any clinical situations for which a contraindication is warranted?

As per 21 CFR 201.57c(5), a drug should be contraindicated only in those clinical situations
for which the risk from use clearly outweighs any possible therapeutic benefit. Only known
hazards, and not theoretical possibilities, can be the basis for a contraindication.

Vote: Yes = 15 No = 7 Abstain = 1

a. DISCUSSION: If you voted yes, describe the clinical situation warranting the
contraindication.

Committee Discussion: The majority of the committee agreed that a contraindication is

warranted for transforaminal cervical injections of particulate corticosteroids. One
committee member stated that the cervical transforaminal approach as presented has
small to moderate benefit at most and while the associated risk may also be small, it is
significant when it happens. The committee further stated that to limit a contraindication
to cervical transforaminal injections of particulate corticosteroid formulations may be
overly specific, and the contraindication may be better applied to settings in which intra-
arterial or intrathecal injection are more likely to occur. These settings may include, but
are not limited to, cervical transforaminal approaches. Please see the transcript for
details of the committee discussion.

b. DISCUSSION: Please explain the basis for your recommendation and any additional
recommendations for other labeling changes (e.g., limitation of use, addition of a boxed
warning, modification of the current warning statement, etc.).

Committee Discussion: In general the committee agreed that there should be a

contraindication for transforaminal injection of particulate corticosteroids into the
cervical spine, and that a warning should remain in the label of all injectable
corticosteroids with some modifications. The committee members who voted “No” stated
that the evidence regarding the risks and benefits of epidural corticosteroid injections is

Page 6 of 7
 not strong enough to support a contraindication. Many of those who voted “No” also
indicated that a contraindication may be overly broad and that a warning or limitation of
use, particularly for cervical transforaminal corticosteroid injections with particulate
formulations, may be warranted. The committee member who abstained from the vote said
that the voting question as written will reduce access to epidural steroid injections for the
broader population and not to those at the highest risk.

Further recommendations were made by the committee surrounding labeling changes.

Some committee members noted that the current class warning should be removed for
lumbar epidural injections; however, others stated that the class warning should be kept
in place and removal at this point would be misleading and falsely indicate that there is
evidence of safety. Another committee member stated that the current label has a sufficient
warning across the class but the Agency should consider adding additional warnings to
particulate corticosteroids regarding transforaminal cervical injections. One member
suggested that a black box warning should be in place to warn of the threat of intra-
arterial injection of particulate corticosteroids. Some committee members noted that the
current warning should be updated to state that the safety and effectiveness of epidural
administration of corticosteroids have not been established “by the FDA.” Please see the
transcript for details of the committee discussion.

4. DISCUSSION: Discuss any additional recommendations you have on this topic.

Committee Discussion: The preponderance of additional recommendations and comments

related to the need for more research and pre-clinical studies. It was the committee’s sense
that preclinical studies would help to clarify the mechanism of risk, especially with
particulate steroids, and should be undertaken. The committee noted that these studies are
fairly straightforward and could be funded with very little research investment. One
committee member warned that pharmacoepidemiological data may be able to be used for
upper bounds to estimate a risk of catastrophic neurological complications, but any
comparisons beyond that, even between steroid formulations and routes of administration,
would be very difficult to do with proper adjustment for confounding factors. Please see the
transcript for details of the committee discussion.

The meeting was adjourned at approximately 5:02 p.m. on November 24, 2014 and at 11:35 a.m.
on November 25, 2014.

Page 7 of 7