UNITED STATES OF AMERICA
FOOD AND DRUG ADMINISTRATION
CENTER FOR DEVICES AND RADIOLOGICAL HEALTH
ORTHOPEDIC AND REHABILITATION DEVICES PANEL
MEETING
FRIDAY, SEPTEMBER 9, 2005
The
meeting came to order at 8:30 a.m. in Salons A, B, and C of the Hilton
Washington, D.C. North, 620 Perry Parkway, Gaithersburg, MD. Dr. Sanjiv H. Naidu, Acting Panel Chair,
presiding.
PRESENT:
SANJIV H. NAIDU, M.D., PH.D. ACTING PANEL CHAIR
CHOLL W. KIM, M.D., PH.D. VOTING MEMBER
SALLY A. RUDICEL, M.D. VOTING MEMBER
FERNANDO DIAZ, M.D., PH.D. CONSULTANT
MICHAEL J.
YASZEMSKI, M.D., PH.D. CONSULTANT
PAMELA ADAMS, M.S., R.A.F., C.Q.M. INDUSTRY REP.
CONNIE F. WHITTINGTON, M.S.N., R.N.CONSUMER REP.
JANET L. SCUDIERO,
M.S. EXECUTIVE SEC.
MARK MELKERSON, M.S. FDA
I-N-D-E-X
Call To Order................................... 3
Appointment of Temporary Panel Chair and Conflict
of Interest Statement........................... 4
Panel Introductions and Conflict of Interest.... 8
Open Public Hearing............................. 9
Orthopedic
Surgical Manufacturers' Association,
Sally Maher, Esq., President 11
Hal
Mathews, M.D................... 18
Spine
Wave, Inc.
Ronald
K. Smith, Director of Quality Systems
and Regulatory Affairs 25
Zimmer
Spine
Reginald
Davis, M.D., Greater .......... Baltimore
Medical
Center 33
Abbott
Spine, Emerging Technologies Research and Development
Paul
McAfee, M.D., Towson Orthopedics .. Association,
Baltimore 43
Brent
Blumenstein, Ph.D., TriArc ....... Consulting,
Seattle 48
Stryker
Spine, Inc.
Eeric
Truumees, M.D., of Weisman, Gitlin, and
Herkowitz of William Beaumont
Hospital........................... 57
North
American Spine Society
Philip
Schneider, M.D.............. 65
St.
Francis Medical Technologies, Inc.
Paul
Anderson, M.D., University of ..... Wisconsin 71
Spine
Arthroplasty Society
Stephen
Hochschuler, M.D........... 82
FDA Presentation
Jonathan
H. Peck, Orthopedic Devices Branch 89
Panel Deliberation, Lead Discussant, Michael J.
Yaszemski, M.D., Ph.D............................................... 103
FDA Questions................................. 111
P-R-O-C-E-E-D-I-N-G-S
8:04
a.m.
MS.
SCUDIERO: Good morning. We are ready to begin this meeting of the
Orthopedic and Rehabilitation Devices Panel.
I am Jan Scudiero, the Executive Secretary of this panel and a reviewer
in the Division of General Restorative and Neurological Devices. We have the usual housekeeping first. If you haven't already one so, please sign
the attendance sheets that are on the tables by the door and pick up your
agenda information.
The
next tentatively scheduled meeting of the panel that was tentatively scheduled
for November 3rd and 4th is canceled because there is no agenda item ready for
panel review.
Upcoming
panel meetings are announced on our Advisory Panel web site, in the Federal
Register, and on the telephone information line. Please monitor the panel web site for future meeting
information. Information goes up on
this site first before the other two locations.
Finally,
as a curtesy to the others in the room please turn off or silence your cell
phone during the meeting.
Dr.
John Kirkpatrick is unable to be with us today.
I
will now read into the record two agency statements prepared for this meeting,
the Appointment for Temporary Panel Chair Statement, and the Conflict of
Interest Statement.
"I
appoint Sandra H. Naidu, M.D., Ph.D., a voting member of the Orthopedic and
Rehabilitation Devices Panel as Acting Panel Chair for the September 8th and
9th, 2005, meeting of the panel."
This is signed by Daniel G. Schultz, M.D., Director, Center for Devices
and Radiological Health on September 7th.
The
Conflict of Interest Statement. The
Food and Drug Administration is convening today's meeting of the Orthopedic and
Rehabilitation Devices Panel of the Medical Devices Advisory Committee under
the authority of the Federal Advisory Committee Act of 1972.
The
Advisory Panel meeting provides transparency into the agency's deliberative
processes. With the exception of the
industry representative all members of the panel are special government
employees or regular federal employees from other agencies subject to the
federal conflict of interest laws and regulations.
FDA
has determined that members and consultants of this panel are in compliance
with the federal conflict of interest laws including, but not limited to, Part
18 of the U.S. Code, Section 208, and Part 21 of the U.S. Code, Section
355(n)(4).
Under
Part 18, U.S. Code, Section 208 applicable to all government agencies, and Part
21 U.S. Code Section 355(n)(4) applicable to FDA Congress has authorized FDA to
grant waiver to special government employees who have financial conflicts when
it is determined that the agency's need for particular individual services
outweighs his or her potential conflict of interest.
Members
and consultants who are special government employees at today's meeting have
been screened for potential financial conflicts of interest of their own as
well as those imputed to them including those of their employer, spouse, or
minor child.
These
interests may include investments, consulting, expert witness testimony,
contracts, grants, teaching, speaking, writing, patents and royalties, and
primary employment.
Today's
agenda involves a discussion on the design of clinical studies for spine
devices indicated for the treatment of mild to moderate low-back pain. In accordance with Part 18 U.S. Code Section
208(b)(3) a waiver was granted to Dr. Sally Rudicel.
A
copy of the written conflict of interest waiver statements may be obtained by
submitting a written request to the agency's Freedom of Information Act, Room
12A30 of the Parklawn Building. In addition, Ms. Pamela Adams is
participating as the industry representative acting on behalf of all related
industry and is employed by Etex Corporation.
Finally,
in interest of the public transparency with respect to all other participants,
we ask that they publicly disclose prior to making any remarks any current or
previous financial involvement with a firm whose products they may wish to
comment upon.
This
statement will be available for review at the registration table during the
meeting and will be included as part of the official meeting transcript.
Dr.
Naidu.
DR.
NAIDU: Good morning. My name is Sanjiv Naidu and I'm the Acting
Chairperson of the Orthopedic and Rehab Devices Panel. I am Professor of Orthopedics at the Penn
State College of Medicine. I'm an
orthopaedic surgeon and also a material scientist.
At
this meeting the panel will be responding to FDA's questions on the design of
clinical studies for spinal devices to treat mild to moderate low back
pain. Before we begin, I would like to
ask our distinguished panel members who are generously giving their time to
help FDA in the matter being discussed today, and also the other FDA staff
seated at this table to introduce themselves.
Please state your name, your area of expertise, your position, and
affiliation
Why
don't we start off with Mr. Melkerson.
MR.
MELKERSON: I am Mark Melkerson. I am the Acting Director of the Division of
General Restorative and Neurological Devices and I'm a biomedical engineer.
DR.
YASZEMSKI: I'm Mike Yaszemski and I'm
professor of Orthopedics and Biomedical Engineering at Mayo Clinic in
Rochester, Minnesota. I'm past chair of
this panel.
DR.
RUDICEL: I'm Sally Rudicel. I'm Associate Professor at Tufts University
and I work at Tufts New England Medical Center in Boston.
DR.
KIM: I'm Choll Kim. I'm an Assistant Professor of Orthopedic
Surgery at the University of California, San Diego. I'm the Director of the Spine Research Lab and Spine Fellowship
Program at UCSD Medical Center.
DR.
DIAZ: I am Fernando Diaz, Professor of
Neurosurgery at Wayne State University.
MS.
WHITTINGTON: I'm Connie Whittington.
I'm an Orthopedic Clinical Nurse Specialist at Piedmont Hospital in Atlanta
where I serve as the Coordinator for Research.
DR. NAIDU: Thank you, panel members.
We will now proceed with the open public hearing portion of the
meeting. Prior to the meeting eight
organizations and manufacturers asked to speak at the open public hearing. They will speak in order of the request to
speak. Each organization and
manufacturer has 10 minutes to address the panel. We do have a speaker timer.
We
ask you to speak clearly into the microphone as the transcriptionist is
dependent on this means of providing an accurate record of this meeting. Please state your name and the nature of any
financial interest you may have in this or any other medical device
company.
Ms.
Scudiero will now read the open public hearing statement.
MS.
SCUDIERO: Both the Food and Drug
Administration and the public believe in a transparent process for information
gathering and decision making. To
ensure such transparency at the open public hearing session of the advisory
committee meeting, FDA believes that it is important to understand the context
of any individual's presentation.
For
this reason, FDA encourages you, the open public hearing speaker, at the
beginning of your statement to advise the committee of any financial
relationship you may have with the sponsors, which is not relevant for today
exactly, its product, and, if known, it direct competitors.
For
example, this financial information may include the sponsor's payment of your
travel, lodging, or other expenses in connection with your attendance at the
meeting.
Likewise,
FDA encourages you at the beginning of your statement to advise the committee
if you do not have any such financial relationships. If you choose not to address the issue of financial relationships
at the beginning of your statement, it will not preclude you from speaking.
Sally,
did you provide your statement?
DR.
RUDICEL: Yes, I did.
MS.
SCUDIERO: Thank you.
DR.
NAIDU: The first open public hearing
presenters are representing the Orthopedic Surgical Manufacturers Association,
OSMA. Ms. Sally Maher, Esq., the
President of OSMA, will speak first and Dr. Mathews will follow her.
Ms.
Maher, I suppose you know the timer pretty well?
MS.
MAHER: Yes. Ms. Feinway said I could have two minutes of theirs.
DR.
NAIDU: Okay. So the two-minute warning will not apply to you.
MS.
MAHER: Thank you. Good morning. My name is Sally Maher and I'm the President of the Orthopedic
Surgical Manufacturers Association.
OSMA is a trade association comprised of greater than 30 medical device
companies who produce more than 85 percent of all orthopaedic implants intended
for clinical use in the United States today.
We greatly appreciate
the opportunity to address this distinguished panel.
In
the interest of time I will focus my comments on three regulatory points, the
least burdensome provisions of the FDA Modernization Act, regulatory thresholds
for PMA approval, and a definition of valid scientific evidence. Dr.
Hal Mathews from the Medical College of Virginia will provide further comments
from a medical perspective.
In
1997 Congress signed into law the FDA Modernization Act of '97. Congress stated that the central purpose of
the act was to ensure the timely availability of safe and effective new
products that will benefit the public and to ensure that our nation continues
to lead the world in new product innovation and development.
The
law states that FDA shall consider in consultation with the applicant the least
burdensome appropriate means of evaluating device effectiveness. It would have a reasonable likelihood of
resulting in approval.
FDA
has defined least burdensome to mean a successful means of addressing a
premarket issue that involves the most appropriate investment of time, effort,
and resources on the part of the industry and the FDA. We believe that is critical to keep in mind
today the intent of Congress in passing this law, as well as the language in
law and FDA's implementing regulations.
In
that regard we wanted to share with you three important provisions that are
contained in the least burdensome guidelines.
FDA's guidance document states that if clinical data are needed, FDA and
industry should consider alternatives to randomized controlled clinical trials
when potential bias associated with the alternative controls can be
addressed. Among the alternatives
listed are study designs, employing nonconcurrent controls such as historical
controls, objective performance criteria, and patients as their own control.
The
least burdensome guidance document also discusses the use of modern statistical
methods such as phasing analysis to achieve a least burdensome path to
market. Also, the use of scientifically
valid surrogate endpoints and the use of Bayesian analyses can predict
longer-term data based on shorter-term follow-up thereby allowing a PMA
application to be filed early.
Another
important consideration is the role of post-marketing information to assure
long-term device safety and effectiveness thus reducing premarket burden. When considering a clinical study design for
the devices that are the subject of today's discussion, we would like to remind
the panel of the regulatory threshold that has been established for PMA
approval, a reasonable assurance of safety and effectiveness.
FDA's
explanation of reasonable assurance of safety and effectiveness is based on
providing valid scientific evidence. It
is noteworthy for this panel that several alternatives to randomized control
clinical trials are included in FDA's definition of what constitutes valid
scientific evidence.
Finally,
I would like to provide some brief comments regarding the specific questions
that are before you today. With regard
to Question 1, it is OSMA's opinion that the decision regarding the time to
surgically intervene should be dictated by the standard of care for the
specific indication.
We
note there are guidelines published by the American Academy of Orthopedic
Surgeons in this regard, as well as recent publication in the Journal of
Neurosurgery which outlines treatment guidelines for degenerative disc disease.
Furthermore,
in answering this question, one must consider the standard of care, the
intended use of the device, the patient population for which the sponsor seeks
approval for the device to treat, the risk of the investigational device, and
the health benefits that the sponsor seeks to prove.
With
regard to Question 2, OSMA believes that the panel cannot categorically assign
a control treatment group to each device category. First, the demonstration of effectiveness might involve
alternatives to randomized controlled clinical trials such as historical
controls using patients as their own control, or use of a concurrent
nonrandomized group control.
Second,
this decision should be based on the intended patient population and the health
benefits that the sponsor is seeking approval to promote. As with the selection of the comparison
treatment or control group, the determination of the clinical trial entry
requirements should be based on the study objectives.
With
regard to Question 3, OSMA believes that endpoints cannot be categorically
assigned to each device type. Rather, a
sponsorship proposes a set of endpoints that they believe will yield valid
scientific data to support the study hypothesis and the intended use of the
device.
Particularly
for early intervention motion preserving devices, study sponsors should be able
to use a shorter-term data to demonstrate safety and effectiveness rather than
placing all the emphasis on long-term follow-up which historically derives from
the time to develop a fusion mass.
Patients
want relief from their pain and they want to go back to work. Therefore, we believe that shorter-term
endpoints should be considered valid in supporting PMA approval for the subject
devices.
With
regard to Question 4, OSMA supports the option to allow both smaller changes in
pain and function scores and flexibility in the traditional delta between
comparisons or treatment groups based on the study objectives and the proposed
claims to the device.
In
conclusion, the OSMA member companies would like to leave you the following two
points. We believe that the questions
and issues presented to the panel today are too complex and multi-dimensional
to make any conclusive determinations in just one morning session.
The
clinical trials' issues outlined in FDA's questions should not be discussed
without serious consideration for the least burdensome provisions of the FDA
Modernization Act, the threshold for PMA approval, and the definition of valid
scientific evidence.
We
greatly appreciate the opportunity to address this distinguished panel today
and hope our remarks will be taken into your consideration as you discuss
this. I have given you a much thicker
speech that you should read and enjoy before the end of the day. Dr. Mathews will discuss the clinical
perspectives. Thank you.
DR.
MATHEWS: Thank you. Good morning. My name is Dr. Hal Mathews, and I am a spinal surgeon from
Richmond, Virginia. Although OSMA has
paid a portion of my travel expenses today, my comments reflect my personal
views, and they are not necessarily consistent with the views of each of the
orthopedic companies comprising OSMA.
I
would like to focus my comments today on a clinician's perspective of the four
specific questions that FDA has posed to this panel and the three different
types of implants being considered today.
First,
FDA is seeking input on the clinical study of early surgical interventions in
lumbar degenerative disc disease. Three
different types of implants are to be considered are interspinous process
spacers, nucleus replacements, and pedicle screw/dynamic stabilization systems.
Through the years, I have
consulted with companies on product designs and clinical study designs. In the past, we have tried to force‑fit
studies into a certain design to decrease the amount of time needed to gain
regulatory approval.
As
a collaborative, forward‑looking exercise, I believe the guidance
provided by the Agency should not map designs to device types, but should be
flexible enough to assist in resolving study design questions for the early
intervention under discussion today as well as for those that may not yet be
conceived of or designed.
With
respect to the first question about the appropriate time needed before
intervention with an implantable device, it is my opinion that symptomatic
lumbar degenerative disc disease can be viewed as a continuum, depending on the
severity or progression of the disease.
In
my practice, conservative care options for patients early in this continuum
would include rest, change in activity status, exercises, physiotherapy,
NSAIDs, and possibly steroid injections.
I believe that these patients could become surgical candidates if their
symptoms did not subside over several weeks of treatment or if an identified
pathology, such as an annular tear with or without herniation, progresses.
These
patients may be candidates for nucleus replacement if their symptoms do not
relent after several weeks. These
patients could also receive a pedicle screw system if their symptoms are longer‑standing
or if the annulus needs retensioning.
The
FDA's second question pertains to the appropriate control groups for studies
involving the three subject devices. I
have to point out that a device could treat multiple indications, and I believe
that appropriate controls have to be based on indications and treatment goals,
not necessarily on the devices themselves.
Also,
we should not automatically jump to the requirement for a randomized,
controlled clinical trial. It is
legitimate to design studies with patients as their own controls or with
historical controls. Conservative care
controls may also be appropriate if handled adequately in the protocol, such
as, for example, existing care data from other physicians or a treatment cross‑over.
Regardless
of the control chosen, care must be taken to make sure that it represents an
appropriate comparison treatment. For
example, it would be inappropriate to utilize a more invasive control that is a
standard of care for a later stage of degenerative disc disease if the
investigational treatment is intended for an earlier stage of
degeneration. I would recommend
guidelines similar to those of AAOS guidelines as references in designing
protocol criteria.
The
FDA's third question to this panel focuses on the selection of appropriate
study endpoints, when to evaluate these endpoints, and the importance of
certain radiographic measures. First, I
need to emphasize that these are not spinal fusion devices; rather they provide
spinal stability, thereby reducing or eliminating the patients' symptoms. Historically,
FDA has desired 12‑ to 24‑month data as a prerequisite for device
approval. One possible reason for this is that they believe that it takes this
long for the spine to fuse. However,
short‑term data may be sufficient for approvals of these devices when
stability, and not fusion, is the objective.
I
believe that 12‑month data, perhaps even less, would be adequate to
determine the safety and effectiveness of early intervention non‑fusion
devices. If the FDA desired longer term data for added comfort with their
approval decision, post‑approval patient follow‑up studies could be
employed.
I
also believe that device effectiveness should be based more on alleviating
patient pain and restoring function rather than on radiographic measures. Spinal stability without pain relief is not
an effective device treatment.
Conversely, both patient and surgeon may be satisfied even if the
radiographic criteria are not met but the patient is pain‑free and has
resumed the desired lifestyle.
Therefore,
I recommend that tools such as Oswestry, Visual Analog Scale, and SF‑36
scales be used alone or together to evaluate patient outcome. Perhaps, there
are other, more newly validated, and perhaps more sensitive, tools that would
detect early post‑operative treatment benefits. Patient satisfaction, perceived treatment effect measures, and
work or activity status may also be incorporated.
When
analyzing and interpreting the data, emphasis should be placed on early
postoperative time points since these types of devices are intended to provide
benefits to the patients early on.
Finally,
I would not recommend that radiographic criteria serve as a primary
endpoint. For these devices,
radiographic data is "nice‑to‑know" information that
should be collected and presented. However, the approvability of the device
should not hinge on it.
FDA's
last question relates to the threshold for determining device
effectiveness. Since the types of
spinal implants being discussed here today are generally intended for earlier
states of lumbar degenerative disease and, in some cases, require less surgical
trauma and rehabilitation, the success criteria and statistical approach should
take into consideration these differences.
In
conclusion, I hope this panel and the FDA have found my comments useful. I believe the safety and effectiveness of
these devices can be determined via a number of approaches, all of which appear
to be less burdensome than current IDE study designs. I advocate smaller studies based on shorter‑term
endpoints. Device approvals can be
accompanied with requirements for longer‑term post‑market patient
observations.
My
final comment to you is to encourage innovation and flexibility in study
designs. With the types of devices
being discussed here today and for those of the future, there cannot be a
"one size fits all" randomized controlled study solution. Study measurements will have to be molded
around the product indications, the intended patient population, and the study
objectives. I encourage everyone to be open to novel ideas.
I
appreciate your attention. I will be here most of the day and would be glad to
try to answer any questions you may have. Thank you.
DR.
NAIDU: Thank you, Dr. Hallett.
Next
we have representatives from Spine Wave.
First is Mr. Ronald Smith, Director of Quality Systems and Regulatory
Affairs and then Mr. Pafford will follow.
MR.
SMITH: Actually, just a point of
clarification. Mr. Pafford will not be
speaking. I will be speaking to all the
points.
DR.
NAIDU: Thank you.
MR.
SMITH: Good morning. Good morning. My name is Ronnie Smith and I
am Director of Quality Systems and Regulatory Affairs at Spine Wave, Inc. Spine
Wave is a small medical device company located in Shelton, Connecticut.
Having
spent the past few years developing a nuclear replacement device, Spine Wave
appreciates the opportunity today to present our thoughts on issues surrounding
the time course of treatment for patients that would be possible candidates for
nucleus replacement or augmentation surgery.
During
the next few minutes, I would like to briefly introduce our nucleus replacement
technology so that you may have a better understanding of how this device when
used in two distinct indications, each with different conservative care regimes
fits into the continuum of care for the spine patient.
Specifically,
I will speak to its use as a nucleus "augmentation" device for
patients facing surgery for herniated nucleus pulposus as well as a nucleus
"replacement" device for patients with chronic degenerative disc
disease. In closing I will also discuss the company's position
regarding the appropriate time for surgical intervention for these types of
devices for each of these distinct uses.
Spine
Wave's NuCore Injectable Nucleus is an in situ curing material that is designed
to have properties that mimic those of the natural nucleus pulposus. The
material adheres to the existing nucleus pulposus and to the annulus and, once
cured, mimics the human disc nucleus in protein content, water content, pH and
mechanical properties.
Unlike
most other types of nucleus replacement devices that we are aware of, the
NuCore device replaces only what has been removed. Therefore, the size of the implanted device is determined by the
amount of nuclear material the surgeon removes.
The
shape of the implanted device is determined by shape of the space into which
the NuCore material is injected. This
is distinct from many other nucleus replacement devices, which are typically
preformed devices either produced from preformed hydrogel or other Spine Wave
panel Comments.
This also differentiates the NuCore from other
products that are injected into a containment system which determines the
amount and size of the replacement.
The
physical, chemical and mechanical properties of the NuCore Injectable Nucleus
allow for multiple potential intended uses within what is referred to
generically as lumbar "degenerative disease." For example, one indication for Spine Wave's
technology includes replacement or augmentation of nucleus pulposus material
through injection into the void created after a standard discectomy for a
herniated nucleus pulposus.
Disc
nucleus herniations are generally "acute" events; unlike the
"classic," chronic degenerative disc disease paradigm. These acute herniation patients may present
with unremitting low back pain in addition to sciatica. When nucleus material is herniated from a
disc, or if a surgeon removes nucleus material from the disc, the mechanics of
that disc and at the operated level change and the conditions are established
for subsequent degeneration.
Even
though patients undergoing removal of the nucleus material without replacement
in a conventional discectomy procedure may often yield a good "short term
result" based on pain scores, studies have shown that many of these
patients go on from the acute herniation to subsequent degeneration as well as
re‑herniation and re‑operation.
As
with other nuclear replacement devices being developed, the NuCore Injectable
Nucleus also has potential benefit in the treatment of those patients who have
"chronic" degenerative disc disease. These devices are intended for
patients with mild to moderate low back pain with classic signs of degenerative
disc disease, as opposed to the acute herniation injury described
previously. These patients, if left untreated, may progress through more
severe stages of degeneration, which may ultimately require fusion or disc
arthroplasty.
With
either of these two distinct intended uses for the NuCore Injectable Nucleus,
this device would be considered by FDA to be a "Nucleus Replacement
Device." However, while both sets
of patient populations would be diagnosed generally as having degenerative disc
disease according to FDA definitions, the treatment modalities for each
population would be distinctly different.
As
such, if each intended use were to be studied clinically, they would likely
each use a different control group for comparison.
Therefore, in giving its recommendations to the
Agency, we would urge the panel to be aware that nucleus replacement devices
may be intended for different clinical indications.
The
type and duration of conservative care that a patient should receive prior to
use of such a device should be dictated by the clinical condition being
treated, not a technology classification.
The surgical treatment guidelines for acute disc
herniations are very different from those for chronic degenerative disc
disease, particularly with respect to conservative therapy timing.
A
patient with a herniated disc has generally suffered an acute "event"
as opposed to a chronic or progressive "disease" and the consequences
of this event can progress rapidly and with great severity. It is for this reason that we feel that the
most appropriate course of action for the treating physician is to follow
guidelines, such as those established by the American Academy of Orthopedic
Surgeons, Washington State, or by the Agency for Healthcare Research and
Quality that apply to the condition being treated.
All
of these guidelines establish a course of treatment only after establishing a
differential diagnosis. According to the AAOS guidelines, these differential
diagnoses are:
1.
Herniated Nucleus Pulposus (HNP)
2.
Unremitting Low Back Pain (LBP)
3.
Spondylolysis or Lytic Spondylolisthesis or
Degenerative
Spondylolisthesis/Stenosis (SLIP)
4.
Spinal Stenosis
As
outlined by the AAOS guideline, a full course of nonoperative treatment for
each diagnosis should first be considered for mild to moderate conditions
unless it is clear that the patient falls into the clinically severe
category. In the case of a diagnosis of
herniated nucleus pulposus, initial nonoperative treatment for mild to moderate
conditions is recommended for four to six weeks.
If
unresolved, the HNP patient should be referred to a specialist for further
discussion of treatment options, including operative treatments such as
discectomy. However, if the patient
presents with a profound/progressive neurological deficit, disabling leg pain
or loss of bowel and bladder control, therefore falling into the
"clinically severe category," the patient moves directly into a
management decision between the patient and physician regarding continued
nonoperative treatment versus operative treatment.
These
patients may or may not have completed the outlined conservative treatment
course but it would be a disservice to these patients to be denied the possible
benefit from new technologies simply because they didn't meet a
"time" requirement established by an Agency guideline.
In
contrast, the agency has typically required the conservative treatment period
to be six months for studies which are intended to treat any degree of
degenerative disc disease in the lumbar region. The agency's recommendation clearly does NOT correlate with AAOS
guidelines for management and treatment of patients with acute herniated
nucleus pulposus.
It
is for this reason that we would recommend the agency adopt a guideline such as
the AAOS guideline which was established by physicians that are experts in the
field of spine surgery to not only define patients who are appropriate
candidates for surgical intervention, but to establish an appropriate course of
treatment and time frame for this treatment.
Criteria
for inclusion of patients in the clinical study of a new device should be
determined through such guidelines by the surgeon, and should be tailored the
specific indication and patient population under study.
In
conclusion, we appreciate the panel considering these points and would like to
again thank FDA for the opportunity to make these comments. Thank you.
DR.
NAIDU: Thank you, Mr. Smith. Representing Zimmer Spine we have Dr.
Reginald Davis of the Greater Baltimore Medical Center. Dr. Davis.
DR.
DAVIS: Good morning. My name is Reginald Davis. I'm a neurosurgeon in clinical
practice. For today's discussion I am a
Zimmer paid consultant being reimbursed for my time away from my practice. I am involved in several clinical
trials. I currently am one of the
principal investigators for the Dynesys IDE study currently ongoing in the USA.
The
comments I will make are my own composition.
The words and thoughts belong to me and me alone. I appreciate this opportunity to represent
my own thought processes to this panel.
Lumbar
degenerative disease actually represents a broad spectrum of a complex cascade
of processes. They are unique
characteristics specific for each individual portion of the anatomy of the
spine that has to be considered independently if a proper algorithm is going to
be proposed.
The
disc has a specific pattern of degeneration.
Initially with the mild disease there is maintenance of disc height,
relative maintenance of hydration so there is minimal radiographic findings
even though there may be significant pain.
As
the cascade progresses with moderate disc disease we see loss of this disc
height, loss of this hydration. Some
annular fissures may occur. There may
be some end plate changes or early modic changes.
As
the progression continues you get into the severe cases which are characterized
by disc space collapse, vacuum phenomenon.
Similar stratification, a similar process occurs with the other
structures of the spine, the sets, the ligaments leading to stenosis and
lateral recess encroachment, even the vertebral body with development of
sclerosis, osteocytosis.
All
of these have to be characterized and there is a summation of the
characterization of each of the anatomical structures that can lead then to a
characterization of the overall lumbar disc disease such that severe disease
across the board will result in a diagnosis of severe lumbar disc disease.
With
this stratification I think a logical algorithm or logical nature is going to
be developed to promote guidelines for how these devices can be looked at. The patients likewise can be stratified. The patients themselves have a physical
component. They can be healthy to
chronically ill with multiple co-morbidities.
Patients
themselves can be robust to fragile, young to elderly. They cover a broad spectrum and these are
independent of the disease process. The
disease process itself can be acute occurring within days to weeks. It can be chronic or end stage having
progressed or grown out of the course of many, many years.
Psychologically
patients also stratify themselves ranging in characteristics from well
adjusted, self assured to psychologically impaired, co-dependent, and very
dysfunctional. The socioeconomic
support structure of the patient also comes into play with the psychology. They can have good family support, good
church support, good economic backup all the way to complete collapse and total
failure of the socioeconomic support.
This
allows stratification of the patients into good or excellent physical
specimens, average or poor.
Psychologically the patient is stratified into well adjusted, moderately
maladjusted or severely maladjusted.
These variables are actually independent of the lumbar disc disease
process itself. This allows a selection
bias for the best study outcome. Only the better patients will get
enrolled in study even though this may not truly represent our own personal
clinical experience. Subsequently, there is a possible
discrepancy that develops between these study results and the subsequent
clinical results. I think that any
ongoing consideration to guidelines must take this into consideration as well.
The
treatment options likewise form a spectrum.
That allows stratification with proper analysis. The nonoperative treatments, medications,
rest, physical therapy, pain procedures including injections and some minor
ablation procedures such as rhizotomies and IDEs.
Decompression
would be the next major category with tubular decompression being the least
invasive all the way through to major laminectomy and facetectomy which may
introduce an element of instability.
Then
fusion. Even the fusion can be
substratified into minimally invasive.
Posterior or anterior fusion.
And then posterior and anterior fusion, so-called 360, are representing
the most severe surgical invasiveness or treatment option in this
category.
Such
the stratification comes in to nonoperative and minimal surgery, which tend to
be out-patient, not invasive, minimal blood lost basically characterized
by no disruption of the native anatomy. Certainly disruption of the fascial planes
but nothing else.
Moderate
surgical interventions then would be moderate disruption of native anatomy or
removal of some of the bony structures.
This tends to be an in-patient procedure with moderate blood loss. Major surgical intervention would then be a
significant disruption of the anatomy with significant removal of some
anatomical structures and significant alteration of the physiology.
With
these stratifications in mind, the devices themselves allow for
stratification. Based on invasiveness
they can be minimally invasive to totally invasive. Based on reversibility the device itself can be removed with the
native anatomy being left relatively intact resuming native physiology.
They
can be revised or not be revised. They
can be removed with placement of a new device or a similar device or totally
revised to a different category, or they are permanent requiring a totally
different approach for revision.
Then
there is the familiarity of technique.
It ranges in spectrum from very well known familiar technique to all
surgeons to requiring novel approach or techniques. Subsequently the device’s stratification has the following characteristics showing minimal fascial disruption,
the reversible, revisable with familiar techniques.
Moderate
acuity devices do require bone disruption.
Removable, revisable still but perhaps with some residual physiology
alteration. And then variation on a
known technique. The major devices or
interventions will require removal of major anatomical structure with
subsequent significant alteration of the physiology. They are not reversible or easily removable and require a novel
approach or brand new technique, a substantial learning curve for the surgeon.
I
think the evaluations themselves if they are well known and well accepted can
also be stratified on the basis of minimal, moderate, and major, VAS, ODI,
SF-36. Certainly the data that's
obtained is worthwhile. However, how
it's applied can be stratified and individualized for each device in each
patient group as study outcome.
Radiographic
study needs to be tailored specifically for that portion of the anatomy that's
being structured and is used for screening or used for staging of the disease
process itself but in and of itself should not be used as an endpoint for
device acceptance. Then standard
criteria appropriately applied, I think, will be the key to flexibility.
We
need to be able to apply these in equivalence studies versus superiority
studies depending on the study design.
Then being able to analyze the trend of net change versus the overall
average value which will vary from patient acuity to patient acuity.
Utilizing
all of these characteristics and proper analyses I think that a rational matrix
can be obtained. If we look at the
spectrum and stratification and apply these across the board, then the
guidelines kind of define themselves based on the individual device.
For
example, as my experience is with the Dynesys, stratification of this pedicle
screw based device for treatment of these syndromes, it is revisable and it is
reversible. It has a familiar
technique. It does require bone
disruption. Therefore, this represents
a moderate intervention and should be applied in moderate instances and
moderate patients.
The
moderate disease characteristics would be radiographic evidence of moderate
degenerative disease with some tubal body collapse, neural impingement with
subsequent symptomatology. The ligament
has laxity which may lead to a spinal lithosis and moderate facet changes as
evidenced by CT.
The
patient would also have a sub-acute to chronic onset having failed physical
therapy of at least six weeks but more in the course of three months so this
would not be immediate intervention but more the moderate onset intervention.
The
treatment options and, therefore, the control group or the control surgical
group should also be of a moderate category so this can be compared to a major
decompression which is perhaps a little less than the Dynesys and, as such, the
Dynesys would have to demonstrate superiority given this matrix.
Or
it can be compared to a moderate intervention of posterior fusion in which case
they are fairly equivalent and, as such, utilizing the analog scales and the
various in modalities for assessment equivalence, would have to be
demonstrated. I feel that especially in the face of fusion that this would have
a time frame of one to two years.
However,
for some of the minimal devices that time frame should be modified
accordingly. With acute intervention,
acute treatment options, and comparison to acute processes, I think the time
frame and the analyses should also be acute.
I
thank you for your attention and hope that you will take into consideration
that in order to move forward with proper guidance, guidelines for these
devices flexibility and analysis of each individual criteria would have to be
the rule of thumb. Thank you.
DR.
NAIDU: Thank you, Dr. Davis.
Next
representing Abbott Spine, Emerging Technologies Research and Development will
be Dr. Paul McAfee of Towson Orthopedic Association, and Brent Blumenstein of
TriArc Consulting.
Dr.
McAfee.
DR.
McAFEE: Thanks very much. I'm a consultant for Abbott Spine. I do not have a financial interest in the
products. I drove from Baltimore.
I'm
going to show some slides that highlight some of the points. We've had very productive dialogue over the
past year with the FDA so my comments will be more specific than many of the
other talks.
In
short, we've had an approved IDE to start and the control group was total disc
replacement and PLIF with pedicle screws.
But our investigators at our 20 investigator sites felt that the control
group was a larger magnitude of procedure than the Wallis. Essentially myself and Dr. Blumenstein are
going to present what we feel to be a good experimental design for the control.
The
inventor is J. Sčnčgas. It's a nonrigid
fixation system. It does not use
pedicle screws and is intended for degenerative changes less than Pfirrmann
State V. Both N. Simon and Brian
Cunningham have shown that the Wallis reduces the extremes of flexion and
extension by 35 percent.
The
advantages of the Wallis, it's largely a soft tissue procedure can be performed
as outpatient, no general anesthesia required.
There's no spinal column structural removal, only the interspinous
ligaments. The rehabilitation is much
faster. It's on the one to two-week
scale versus three to six months recovery for spinal fusion. The device can be removed without requiring
a fusion or anterior rate vessel dissection.
It
is a very safe procedure. This is a 16-year
survivorship experience from Sčnčgas.
They obtain follow-up on 58 percent of the patients and the survivorship
at 16 years was 82.7 percent. Only five
devices were actually required to be removed.
This is very competitive and compares very well with what I have had the
opportunity to present to the panel a year ago. This is the reoperations on the Charité, 4.9 percent versus the
BAK fusion control of 8.1 percent.
Now,
there is also an international study on the Wallis in six different countries, 262
patients with a minimum of one-year follow-up.
It is intended for degenerative changes less severe than either the
Charité or a PLIF. It's Modic Stage 1
or less. There has to be less than 50
percent loss of disc space height.
The
VAS going from a mean of about 70 down to 15 is very competitive with the
functional outcomes at one year for either fusion or disc replacement. One definite advantage with some of the data
the company has collected, there's 55 matched sets of MRI, pre-op and at one
year. It does show in a majority of
cases rehydration of the nucleus pulposus.
There is the opportunity for regeneration or repair of the disc by
protecting the extreme range of motion.
For
example, on this picture of this 36-year-old woman you would match up the
hydration signals at L3-L4, and L5-S1.
You match up the hydration signal of the uninvolved level. I think you can see some definite changes
and rehydration at L4-L5.
So
our preferred experimental design is not the Wallis versus conservative physical
therapy, but it's the Wallis versus conservative treatment plus a rescue
procedure. The rescue procedure can be
invoked as early as eight weeks. The
rescue procedure is a fusion or arthroplasty.
It's not a cross-over to a Wallis.
The rescue is permanent and with no clear revision strategy. It has the potential for the neurologic
morbidity and vascular problems.
One
of the key concepts we want to get across is that if you look at the randomized
study, 205 Charité patients versus 99 of BAKs.
There is a durability of response that occurs at six months so at six
months both the VAS and the Oswestry were very predictive of the 24-month
results.
We
feel once a patient crosses over -- I'm sorry, once a patient is rescued, then
you need to get a good response and if that response is maintained for six
months, then that is worth something clinically. The advantages are, aside from the reversibility of the Wallis,
the fact that it's just largely under the fascial posteriorly, does not involve
any dissection of the neural elements as a PLIF would.
It
can be placed through a two-inch incision on out-patient. It leaves the option for fusion and total
disc replacement completely open. I
hate to use the cliché but it does not burn any bridges.
On
the left is Pfirrmann's classification which is not widely used but at
Pfirrmann Stage 1 in the upper left, that's fine to use physical therapy and
epidural injections. In the lower left
is a collapsed disc. That's fine to do
a PLIF and a disc replacement but we attempt to treat patients with Pfirrmann
II, III, and IV so we are addressing the strategy to those patients with the
intermediate amount of degeneration.
On
the right is Pollintine's work. It's
very important to show that you go all the way up to a degenerative Stage IV
before you get irreversible changes in the facet joints so you have three
stages of degenerative changes involving the anterior column. Our device and other interspinous devices
are aimed at trying to intervene earlier and preserve those posterior facet
joints.
Thanks
very much. In summary, just with my
theme of being specific, I would try to go for a delta of 15 percent versus 10
percent. I feel this is justified
because the procedure can be done on an out-patient, local anesthesia, faster
rehab, and it's more reversible.
Secondly,
as a clinician I'm willing to accept a five percent lower success rate for the
Wallis versus the more invasive total disc replacement or PLIF due to the fact
that it's reversible and it's largely superficial just under the lumbar facet
anywhere from L1 to L4. Thanks very
much.
DR.
NAIDU: Thank you, Dr. McAfee
DR.
BLUMENSTEIN: I'm Brent Blumenstein,
statistical consultant to Abbott and they do pay me. What I wanted to do
today was to propose a design for this class of devices. The purpose of this chart is to show the
three relevant types of devices that we are talking about here, the current
focus on what I've labeled for this presentation as early invasive
intervention.
The
point here is that there is a radiant of invasiveness, risk, and whether or not
subsequent interventions are possible.
This has an influence on what type of outcome one focuses on. For conservative care you're looking for
durable success of some kind which is a good thing. With this new class of devices we are also looking for durable
success which is also a good thing.
Whereas
in the traditional late invasive interventions the focus is usually on failure
to realize success or a failure to sustain success. These are really bad things as opposed to good things. So what we propose as an outcome of interest
to be in a trial is what we call a durable response. This is the realization of the state of response for all
assessments spanning at least X months.
The
criteria for state of response has specific elements discussed by others. It's for changes and things like that. You can put whatever you wish in here. We are proposing that this X be six
months. That is, if someone has a
response that it be observed for at least six months to be called a
response.
We
feel this is clinically meaningful relative to the characteristics of the type
of device that we're talking about here.
If you have a group of patients treated with one of those devices, a
high proportion of this durable response implies efficacy. So that's all well and good but when we get
to the statistical considerations we want to take it one step further.
What
we have here is the proposed statistical input of time to durable
response. The reason we do this is
because the speed at which these responses occur is actually quite relevant to
the type of device that we're talking about today. What we mean here is the time interval from randomization until
the date where the durable response is observed to start.
It
is important to realize that when you convert a dichotomous endpoint of a
durable response to a time to that endpoint that you have to take certain
things into consideration. One of them
is that this is subject to competing risk.
Competing risk is something that prevents observation of the endpoint
and that would be death or revision or whatever.
That
is, these things prevent you from observing a durable response. A competing risk is not the same thing as
sensoring due to lack of follow-up. What we want to do with this proposed
endpoint is to look at the cumulative incidence of these in our statistical
considerations now that the vertical axis has dropped here.
This
is proportion, this is time, and this is the proportion of patients in each of
these two arms that have experienced the durable response to the specific point
in time dating from the date of randomization.
At one year you have this percent of patients in the control arm and this
percent of patients in the investigational arm having achieved a durable
response.
So
when we think about control arms for trials of early invasive intervention, we
find out that we don't have a predicate at this time and, therefore, we really
can't think about a superiority or non-inferiority trial against the
predicate. What we are left with is
conservative care or late intervention.
If
we think about using late invasive intervention as our control arm, we have to
think about that it's okay if the late invasive intervention is superior to the
early invasive intervention because the early has lower risk and it also
doesn't preclude subsequent intervention.
The
issue here is defining an acceptable degree of inferiority. That would be the separation at a
prespecified time. For example, 24
months in this cumulative incidence that we're talking about. We would call this an acceptable inferiority
trial as compared to a non-inferiority trial.
Here
is the representation of what it might look like. This is the investigational arm.
It has a very rapid increase to a plateau of success. Whereas, the control arm has a slower
increase followed by a possibly higher ultimate outcome.
This
is inferior at this point in time, for example, and so the acceptable
inferiority has to do with this margin that you are willing to accept given the
less invasiveness and potential for revision.
Now,
if we think about taking instead the control as just conservative care as
opposed to the late invasive intervention, we can think about that as the time
to durable response outcome is appropriate.
We can think of this as being a superiority trial. What
we immediately come up against is what if the early intervention is almost
surely superior to conservative care?
In other words, almost a given thing.
Also, this trial wouldn't address long-term effects. In other words, the reversing of the early
invasive intervention.
So
what we are proposing instead is a conservative care with rescue. What this does is it allows the control arm
to catch up to the early invasive intervention when we are almost surely
superior to just conservative care.
What we have here is a rescue implemented in the control arm only.
This
rescue should not be the early invasive intervention. In other words, the so-called "crossover" would not be
applicable to this. The rescue would be
something more, a late invasive intervention.
What
we are going to propose is two endpoints and the primary endpoint we are
calling it a short-term endpoint and it's just time to durable response from
the first intervention. In the early
invasive intervention is what we mean by the first intervention in the
investigational arm.
Conservative
care is the intervention of interest for this endpoint in the control arm. This would be just to compare the cumulative
incidence curves for that primary endpoint.
This would be what it would look like.
We would have a more rapid and a higher investigational arm cumulative incidence
of durable response, whereas the control arm would be lower. We would probably win on that one.
But
the co-primary endpoint that captures the long-term outcome would be a durable
response cumulative incidence at time Y where we are going to define Y as
1. What we're talking about here is
that the conservative care durable response includes the rescue intervention
and ignores conservative care failure.
What we are doing is deferring what we consider to be the intervention
that might cause a durable response.
It
could be either conservative care or the rescue procedure. What we would do here would be compare the
durable response cumulative index at time Y.
We are proposing Y as 1 year because the early invasive intervention
likely has a rapid onset of benefit and fewer complications.
Some
more considerations. The requirement
for superiority of the investigational arms and for this co-primary endpoint
seems onerous. In other words, I'm not
sure that you could really expect an early invasive intervention to be superior
in the long run to the late. We've
already discussed this point before.
So
we could test for either noninferiority or this acceptable inferiority
trial. This is the situation where the
outcome would be equivalent. That is,
we have a rapid onset but a flattening versus the same long-term outcome but
less speed in getting there. This is
the situation where the investigational arm has a rapid plateau but the control
arm is slower to get there but it gets there higher. This is maybe the acceptable inferiority margin.
So
there are other issues to solve. Many
of these will be discussed today, eligibility, criterion for implementing the
rescue intervention, which rescue interventions are used, and should the
investigational arm also be allowed to be a rescue. We think not. Then
there's this secondary endpoint that you would measure would be there as
supportive such as time to failure of the device.
In
summary, what we are recommending is the control arm be conservative care with
rescue, that the primary endpoint for short-term should be a time to durable
response from the first intervention analyzed using cumulative incidence
methodology, and that the co-primary endpoint would be a long-term
endpoint. It would be a cumulative
incidence difference at 1 year between the two arms. This could be either set up as noninferiority or as acceptable
inferiority.
I'll
be around today.
DR.
NAIDU: Thank you, Dr. Blumenstein.
Next
representing Stryker Spine we'll have Dr. Eeric Truumees of Weisman, Gitlin,
and Herkowitz of William Beaumont Hospital.
Dr.
Truumees.
DR.
TRUUMEES: Good morning. My name is Eeric Truumees. I'm a local spine surgeon in private
practice with Weisman, Gitlin, and Herkowitz.
I also maintain an active academic practice and run a biomechanics
laboratory at William Beaumont Hospital in Royal Oak, Michigan.
I'm
a paid consultant with Stryker Spine and they funded my travel and lodging
costs in order to attend this meeting.
I greatly appreciate the opportunity to address this distinguished panel
today and comment on the questions posed by the panel.
First,
I would like to acknowledge the FDA's concerns. The human study of these new, early intervention devices creates
novel challenges for clinical trial design.
Prudent and ethical study of medical devices in degenerative conditions
requires appropriate attempts at non‑operative management. Further, appropriate operative
intervention is offered once our patient's symptomatic progression has become
clear. That is, early surgery may be
unnecessary surgery in the sense that some patients' symptoms could improve
without surgery. Finally, to understand the real effects of implantation of a
given device on that patient's clinical status requires careful study with
appropriate comparison groups and sensitive outcomes measures.
While
I agree with concerns that generated the questions we are here to address, I
feel that these questions make false assumptions about this category of
devices. Global answers are being sought for groups of implants that have very
little in common.
FDA
seeks to prescribe relatively uniform approaches to the study of these new
devices. In so doing, the marked differences in the goals, intended patient
population, mechanism of action, and the level of surgical morbidity are
ignored.
Overall,
clinical goals and expected outcomes are much different. Rather than establish a list of acceptable
controls for the study of a particular implant group, I would argue that
controls, non‑operative treatment periods, and outcomes measures should
reflect the patient population, disease state under study, and device claims.
With
regards to Question 1, the standard of care is best set by physicians,
investigators and study sponsors and not by a regulatory body. While there are
a host of reasons Regulatory Bodies should not prescribe care to patients
individually or in groups, the most important lies in the heterogeneity of the
patients studied. More specifically, lumbar degenerative
disease is not a linear progression of symptoms and radiographic findings.
Patients
with similar symptoms will vary markedly in their radiographic appearance. Similarly, patients with similar radiographs
may have markedly different symptom profiles.
Lumbar degenerative disease is best characterizes as a matrix of
symptoms, functional effects, and pathoanatomic findings.
In
patients with painful disc degeneration and identical symptoms and MRI
findings, for example, the rate at which their facets degenerate or they lose
back muscle can be very different. An
appropriate time line for operative intervention in someone that is clinically
stable is very different from the patient that has marked functional decline.
As
a physician, I make decisions for a particular patient at a particular time in
the progression of their condition. I
look at how symptoms affect a patient's life and perform a risk/benefit
analysis of the various types of treatment options available.
We
can't presume that withholding intervention with a patient will protect them
from overly aggressive treatment. Nor
can we assume that the disease manifestations or pathology will become clear
over time. Delayed intervention in some
cases may require a more invasive approach later.
That is, unlike with fusion surgery, waiting too
long may preclude effective utilization of these new and novel treatment
modalities.
Although
some non‑surgical treatment is always appropriate, we need to understand
that the percutaneous placement of some implants are really blurring the lines
between traditional nonoperative care and operative management. In some cases conservative management may be
physical therapy, injection therapy, or may even be relatively less invasive
surgery types.
Furthermore,
one can not dictate in advance of the emergence of a new device whether a four-week
or four-month per of nonoperative care appropriate and what types of
nonoperative care are appropriate for your patient group.
With
regards to Question 2, an appropriate control group should be chosen by the
investigators and the sponsor based on the patient population under study and
health benefit the sponsor is seeking approval to promote. The natural histories of all of the various
types of painful degenerative lumbar disease remain insufficiently
documented.
As
such, the establishment of formal lists that allow controls for the study of a
given class of early intervention device would be misguided. Even within the subgroups of nuclear
replacement, for example, are devices that are implanted percutaneously and
others that require formal, open surgery. These differences in approach will
lead to differences in the ideal control groups for the individual devices
discussed.
With
the opportunity to investigate the effectiveness of early intervention devices,
nonoperative care may not always be an appropriate control group. However, in cases where a nonoperative
control is used, from a patient care point of view, these must be allowed to
cross over when appropriate. I believe that "appropriate" must be
decided by the investigator and would be very difficult to define in a general
guidance.
With
regard to Question #3, as an investigator in several IDEs, I believe that study
endpoints cannot be categorically assigned to each device type. Because of the marked differences and the
goals of these devices, the sponsor in collaboration with clinician
investigators should be free to propose a set of endpoints that they believe
will yield data to support their study hypotheses.
Interspinous
process devices, for example, are not a homogenous group. They have very different goals. One seeks to treat patients with neurogenic
symptoms in a stop‑gap approach to delay more invasive intervention such
as laminectomy. Others seek to limit
painful motion in patients with mechanical pain. This difference in surgical
goals should lead to very different outcomes measures and evaluation time
points.
Along
the same lines, we may use more subtle outcomes measures and demand far longer
follow‑up for devices seeking to prevent post‑operative adjacent
segment change than we would for a similarly configured dynamic rod device
implanted to alleviate the low back pain.
For the majority of devices, pain relief and functional outcomes remain
primary measurements for success.
Radiographic results are secondary endpoints.
As
to the length of follow-up, points less than 24 months are sometimes
appropriate, again, depending on the intended use and proposed benefits of the
device. Twenty‑four month
endpoints are appropriate for morbid, open spinal reconstruction procedures
requiring fusion.
For
many patients undergoing these procedures, ultimate symptom resolution and
return of full function doesn't occur until much later after the surgery. Given the less invasive surgical strategies
for some of these novel implants, outcome measures might become clearer much
sooner. Therefore, the endpoints should
match the proposed benefit of the device.
With
regard to Question #4, I support the option to allow study sponsors and
statisticians to specify study design based on the population studied and the
objectives of the device rather than refer to standardized approach based on
the outward appearance of the implant.
The
challenge for industry, clinician investigators, as well as FDA, is to design
and execute studies in a least burdensome fashion. That occurs in a complex clinical and regulatory environment in
which some requirements seem to be at odds with one another.
In
the end, our common goals are to help patients improve their quality of life or
prevent further deterioration, and to do so with treatments and/or devices for
which there is a reasonable assurance of safety and effectiveness.
Again,
rather than standardizing study designs based on the implant design,
investigators and sponsors welcome the opportunity to work with the Agency to
define study designs appropriate for the patient group implanted and the
specific goals of the device. That is,
less risky surgeries with lower morbidity should really have smaller -- be appropriate
to have smaller clinical benefits.
Thank
you for your time today. I hope my
remarks were of value. I'll be
available for questions as the day goes on.
DR.
NAIDU: Thank you, Dr. Truumees.
Next
representing North American Spine Society is Dr. Philip Schneider.
Dr.
Schneider.
DR.
SCHNEIDER: Thank you. Hello.
Good morning. As you can see, I
am not Dr. Marjorie Eskay‑Aurbach as you have on your agenda. My name is Dr. Phil Schneider, and I am
replacing Dr. Aurbach.
I
am an orthopaedic spine surgeon in private practice, about 15 minutes from
here. I may be, geographically, the
closest spine surgeon to the FDA. No
one is paying my travel expenses. I
live 10 minutes from here. However, the
price of gasoline these days I might have to rethink it in the future.
I
have a keen interest in research. I
serve as an Assistant Professor of Orthopedic Surgery at Howard University and
have been involved in numerous IDE studies, both as an investigator and as a
data safety monitor officer.
I
am here today because I am representing the North American Spine Society, the
largest spine organization in America.
The 3,000 members actually up to 4,000 members now that we have share
similar interests as I do; that is, patient care, research, and education.
NASS
is comprised of both surgeons and non‑surgeons, representing the various
fields of spinal care, including orthopaedic surgery, neurosurgery, psychiatry,
radiology, and anesthesiology. Our
members have one primary interest: to provide the very best quality medical
care to our patients. The end result
should be less pain and better function, resulting in a better quality of life
for our patients.
Like
you, we recognize that the landscape of spinal care is rapidly changing. Consequently, the way we study spinal care
may need to also change. From reading
your four proposed questions, it is clear that you already appreciate this.
Regarding
your first question about time to intervention, this will depend on patient
pathology. However, since the devices
you are inquiring about are designed for earlier intervention, the time to
intervention may logically occur at an earlier time in the disease process.
For
example, six months of non‑operative treatment may be reasonable before a
spinal fusion, but may be too long for one of the less invasive procedures
being discussed today. Degenerative
disc disease represents a wide spectrum of intra discal disorders, and each
stage needs to be specifically addressed. Different
levels of disease require differing approaches to conservative treatment.
Your
second question about controls is something that I think about a lot. Fusion, as a control in a randomized study,
may not be the best model when investigating these less intrusive devices.
There are several reasons for this.
Firstly,
fusion may be a much more aggressive treatment than is warranted for the
pathology being studied. This has some
ethical concerns. Secondly, these
devices can be used for differing levels of degenerative disc disease, and the
controls may need to be different for various disease states. And, thirdly, the goal of treatment is not
to ankylose the spine. The goal is to
provide a stable platform that allows motion. Fusion is the antithesis of this.
The
North American Spine Society is committed to the application of evidence‑based
medicine evaluation to both the current practice of operative and non‑operative
spine care as well as the evaluation of new technology.
Although
well‑designed, prospective, randomized, blinded studies are most helpful
in drawing conclusions when comparing treatments, it remains important that all
of the scientific evidence is critically examined, including other levels of
evidence. Despite the limitations and
greater influence of bias and confounding factors in such studies, these still
provide information which should also be given consideration.
Since
the devices we are talking about today are not for fusion, but are for motion
preservation, endpoints (your third question) will likely occur sooner than the
traditional 24 months used in fusion studies.
When you think about it intuitively, motion preservation occurs
immediately, whereas with fusions, it is a lengthy process. Endpoints
need to be flexible depending on the device being studied and the level of
disease being treated. Some devices may require only short follow‑up, and
some devices may require very long follow‑up depending on the control
being used. It may also be instructive
to shorten the follow‑up on motion‑sparing devices, while still
rigorously following the patients in a post‑market environment.
Again, endpoints should not be set in stone. Pain relief is the goal.
Finally,
your fourth question has to do with changes in study design for mild to
moderate disc disease. With earlier
intervention for lesser disease, smaller changes in outcome scores would be
inevitable and expected. This needs to
be accounted for.
A
15-point drop in Oswestry score may be impossible, while a 15 percent drop may
be more realistic. A percentage drop
from pre‑op screening would make sense.
While Oswestry is a good assessment tool, others can also be
valuable. This includes VAS, SF‑36,
and the NASS Outcome Assessment Tool.
With
regards to increasing the delta value over 10 percent, this certainly may be
appropriate depending on the control being used. A higher delta value would allow more studies to proceed because
of easier recruitment abilities.
The
North American Spine Society applauds you in your attempts to improve on the
design and process of spine research in the United States. Our goal as an organization is to provide
the very best care to our patients.
This may mean intervening in their disease process at an earlier stage
in different ways.
The
North American Spine Society would like to sincerely offer its assistance to
FDA in any way we can. We are prepared
to provide experts in different fields of spine care to work with you on
developing specific protocols, outcome tools, controls, etc. for the spectrum
of conditions within degenerative disc disease. Thank you very much.
DR.
NAIDU: Thank you, Dr. Schneider.
Next
representing St. Francis Medical Technologies is Dr. Paul Anderson of the
University of Wisconsin.
Dr.
Anderson.
DR.
ANDERSON: Good welcome. I welcome the opportunity to address the panel. I am a board certified orthopedic surgeon
and associate professor of orthopedics and neurological surgery at the
University of Wisconsin. I am a consultant to St. Francis Medical who paid my
travel expenses and electronic.
The
questions that the panel has been asked to address relate to devices intended
to treat lumbar degenerative disc disease in patients with mild to moderate
"back pain." Back pain may be
the primary complaint in patients with isolated disc involvement. However, in the case of degenerative
conditions such as spinal stenosis, patients may experience back and leg
pain. These are important distinctions
the panel needs to take into consideration while debating such issues as study
entry criteria and study endpoints based on device type.
Also,
the appropriate use of clearly defined terminology in clinical trial design is
of paramount importance and too often overlooked. The unintentional misuse of terms such as success and failure can
dramatically impact the interpretation of study outcomes and present issues as
"black and white" when, in reality they frequently are not when
patients are concerned, as I will attempt to illustrate.
I
would like to comment today on several issues that are fundamental to the
panel's discussion and must be considered when determining the structure of
clinical trials for these types of patients. These issues include:
The
definitions of success and failure in clinical trial design.
The
selection of the appropriate control group that allows for valid, quantitative
comparison to the treatment group.
The
selection of valid study endpoints in patients with mild to moderate symptoms.
Defining
"success" and "failure" in patients with mild to moderate
symptoms is open to much debate in the research community. Until we agree on definitions that are both
clinically reasonable and scientifically valid, we have no solid foundation
upon which to judge the effectiveness of devices in this patient
population. Secondly, the definition of
a clinically significant response to treatment in patients with mild to
moderate symptoms is fundamental to determining success and deserves equal
attention.
In
20 years of treating patients with spinal disorders and involved in numerous
clinical trials, I have found that patients consider surgery because they have
significant impairment in their quality of life and have weighed the possible
benefits against the risks. This is a
highly personal choice for the patient.
Some
patients are willing to undergo a less invasive procedure but will not undergo
a major procedure even if it offers a chance of higher success. Other patients view the risks of any
surgical intervention as too great and would be satisfied with some level of
improvement by continuing with non‑operative therapy. Is it appropriate to consider this patient a
failure if the patient is satisfied with this outcome within the context of his
or her choice of treatment? Probably
not.
We
all know that patients must undergo a minimum amount of non‑operative therapy
before we consider a more invasive procedure.
This does not mean that a patient has "'failed" nonoperative
therapy at some arbitrary time point if he elects to continue with this
therapy. The only certain failure point
is the patient's decision to abandon nonoperative care and undergo
surgery.
Unlike
patients with herniated disks and discogenic low back pain where there are well
established guidelines for timing of intervention, with patients with lumbar
spinal stenosis there is no established length of time to surgery.
Is
it appropriate to use the same criteria for determining a successful outcome in
a patient treated nonoperatively, to a patient who has elected to undergo a
major procedure like a spine fusion?
No. The patient who elects to undergo an invasive procedure has the
reasonable expectation of more than just a small degree of improvement.
In
measuring outcomes the most important metric is the patient's satisfaction with
his outcome in the context of his treatment.
Patient‑reported outcomes measures are now a mainstay in clinical
research and include general health, disease‑specific outcomes and
patient satisfaction. The weakness of most of these is the
absence of valid measurements of what constitutes a clinical difference,
especially in patients with mild to moderate symptoms.
Outcomes
research experts are now incorporating a patient's satisfaction with treatment
or a patient's assessment of whether the treatment helped as a yardstick for
determining a successful outcome.
As Walsh and colleagues noted in their
recent paper on the responsiveness of the ODI, MODEMS and SF‑36 outcomes
measures, "While there is no gold standard to measure an actual change, it
is difficult to argue that no improvement has occurred if both the patient and
clinician independently and simultaneously report improvement."
The
authors therefore used the patient's perceived improvement as the criterion to
measure the sensitivity and specificity of these outcomes measures and have
established satisfaction as a gold standard.
So
how do we determine clinical success in patients with mild to moderate
symptoms? The consensus among outcomes
experts is that the "minimum clinically important difference" or
"MCID" is the appropriate standard to define clinical success. This standard is particularly relevant when
applied to patients with mild to moderate symptoms where the risk of false
negatives is significant due to "ceiling" effects that may occur when
less severe disease states are being evaluated.
Clinically
significant levels of improvement need be defined and should not be chosen
arbitrarily. An absolute 15 point
change from baseline in the ODI score at two‑year follow‑up was
chosen by FDA for back pain studies as clinically significant and is now
accepted as the "conventional" standard to define clinical success.
In
my review of the literature I find only one article, by Mannion and colleagues,
in which the minimum clinically important difference is validated for the
ODI. It turns out the authors
determined a "good outcome" is defined by a cut‑off value of 11
points using ROC analysis, not 15 points, and the minimum clinically important
difference for an individual patient is 9 points.
This
validation was based not on 2‑year data, but 6‑month data. The authors of this paper, which include
Jeremy Fairbank who developed the ODI, also recommend a percent change from
baseline rather than absolute amount of improvement for consideration. They
further acknowledge that the cutoff value for patients treated conservatively
may range from 4 to 6 points, much lower than the 11 points for patients
treated operatively.
Finally,
the ODI has been reported to be more sensitive in detecting change in patients
with more severe disability and less sensitive in detecting change in patients
with mild to moderate disability.
Based on careful review of the literature, there
is no evidence that a 15‑point change from baseline in the ODI score is a
scientifically valid measure of the minimum clinically important difference in
patients with mild to moderate symptoms.
Therefore,
I believe it is imperative that we validate the appropriate thresholds of
clinical significance that we use to define success in an individual
patient. There are outcomes measures in
which thresholds for improvement were determined as part of the clinical study
validating the instrument, thus providing guidance for how to interpret
outcomes. For example, in patients with spinal stenosis, the Zurich
Claudication Questionnaire has statistically validated values for clinically
significant improvement.
Next,
we need to take into account the large difference in risk profiles between
current operative treatment and non‑operative therapy. This makes the
dilemma for patients with mild and moderate symptoms especially difficult. And this is why the advent of new devices
and procedures, which offer the possibility of improving outcomes without
adding to, or possibly lessening surgical risk, important and desired by
patients.
In
designing the clinical trials to evaluate new devices, the dilemma for
investigators is choosing the appropriate control therapy. The consensus of the clinical literature on
degenerative lumbar spinal stenosis is clear that nonoperative therapy is the
standard of care for patients with mild to moderate symptoms.
From
an ethical standpoint, it may not be appropriate to randomly assign a patient
with mild to moderate symptoms to an invasive and risky surgical procedure when
good outcomes are not well established and the risk‑benefit ratio may not
be in the patient's best interest.
Patients
with degenerative lumbar spinal stenosis are elderly and may have medical
comorbidities that increase the risks of surgery and diminish efficacy. Ethically, you must select investigational
and control therapies that have the potential to offer comparable
risk-benefit. For the at-risk elderly
population in particular, nonoperative care is a particularly appropriate
control for minimally invasive investigational procedures.
Nonoperative
care is a particularly appropriate control for interspinous spacers since
neither treatment exposes patients to the risks of neural injuries and general
anesthesia, and future treatment options remain open should they be necessary. On the other hand, interbody fusion was the
appropriate control for artificial disc studies, since both treatments expose
the patient to a similar level of risk.
In
conclusion, I believe the clinical studies we undertake to evaluate devices
must take into account:
(1)
The risks and benefits of any therapy have to be balanced and considered when
selecting appropriate control groups for clinical trials of new therapies.
(2)
The terminology used to define success and failure, study endpoints, and other
critical elements of a well‑designed study protocol must be clearly and
consistently applied for each patient population.
(3)
A patient's level of satisfaction with his treatment is the most clinically
meaningful measure of treatment response and provides a valid basis to
determine thresholds when defining a successful response to treatment.
(4)
The strengths and limitations of outcome instruments must be recognized in
order to select clinically significant endpoints that match the patient disease
state and demographics and the types of devices under study.
I
would like to thank you for this opportunity to address the panel.
DR.
NAIDU: Thank you, Dr. Anderson.
The
last speaker for this open public session will be Dr. Stephen Hochschuler
representing the Spine Arthroplasty Society.
He is the 1st Vice President of the Society.
Dr.
Hochschuler.
DR.
HOCHSCHULER: Thank you. Good morning. My name is Stephen
Hochschuler. I am a board certified orthopedic surgeon practicing spinal
surgery. I am a member of the AAOS, ISSLS, NASS and Co-founder and Chairman of
The Texas Back Institute. I am here today as a founding board member and 1st
Vice‑President of the Spine Arthroplasty Society.
I
have come to this hearing to help address issues relating to Spinal Arthroplasty.
Spinal surgery has changed over the past several
years from stabilization associated with fusion to stabilization via motion
preservation.
With
this evolution it has become evident from the FDA posed questions to be
discussed today, as well as concerns voiced by practicing spine surgeons and
patients, that there needs to be a reconsideration of FDA approved clinical
studies. Do the study protocols of
yesterday apply today? Do the requisite needs of safety and efficacy merit the
cost of the study?
For
example, is it possible to utilize computer modeling and previous controlled
double blind studies analyzing historical data from one arm of such study to
compare to a new device in a stand alone trial? I believe it's time to rethink the entire analytical process to
expedite the development of new technologies while protecting our patients.
Over
the past several years, largely due to the Internet, patients have become more
enlightened and empowered as to their medical decisions. It is not only important
to consider what we as scientists and clinicians hold important but also what
our patients value.
Is
prolonged pain and suffering associated with the inability to work and partake
in one's social environment while undergoing "Conservative Care"
merited? Is a minimally invasive,
minimally destructive, reversible operative procedure less conservative than
our traditional definition of conservative care?
We
in the USA have prided ourselves in delivering the best medical care in the
World. Nevertheless, our citizens more and more utilize non‑FDA
alternative medical therapies. Why is
this? Is our approval process part of the problem?
The
Spine Arthroplasty Society was founded approximately five years ago. At the time I had a particularly
ethnocentric opinion that outside the USA studies were inferior. Since, I have learned that although they
might not be perfect, the data is worth considering and the CE Mark process as
well.
Today,
The FDA has elected to evaluate how studies should be organized to determine
the safety and efficacy of nuclear replacements, interspinous process devices,
and pedicle screw based dynamic stabilization systems. All three technologies are key to the
development of spine stabilization surgeries associated with maintenance of
spinal motion.
Questions that have arisen and need to be
addressed include:
(1)
Is the proposed device considered minimally invasive, minimally destructive and
readily reversible or salvaged? These
types of devices will be justified earlier in the continuum of care. The traditional six months of failed
conservative care prior to surgery is likely to compromise the potential
efficacy of these devices and the low risk and preservation of options justify
earlier use. One possible explanation
for the relatively low success rates of fusion/arthroplasty may be that we wait
too long to intervene.
(2)
Does the proposed devise have the potential to prevent the degenerative cascade
as described by Dr. Kirkaldy‑Willis?
Early intervention could have long-term benefits. Once the cascade has resulted in loss of
disc height, chronic muscle spasm and facet disease, surgery is much less
likely to be successful.
(3)
Is six weeks to three months of incapacitating low back pain as defined by the
Visual Analog Scale, Oswestry Index, etc., enough to merit surgical
intervention? It depends on the nature
of the surgery and the risk profile of the device. If a product is minimally invasive and doesn't burn bridges, then
earlier use should be considered.
(4)
Is continued conservative care after three months more intrusive to a patient's
well being than a minimally invasive, reversible procedure?
It becomes unethical to prohibit a patient from
surgical care if they aren't responding to conservative management alone.
These
patients must be told when they enroll into a conservative care study that if
they don't respond to it, then they can pursue surgery and still be in the
study.
(5)
Would an early, minimally invasive, motion preservation surgical intervention save
the patient the grief of being unemployed with all the concomitant family,
social and financial issues?
Again,
early intervention with these types of devices may break the degenerative
cascade and get patients back to work sooner.
We know from numerous studies that the longer someone is incapacitated
with back pain, the less likely they are to make full recovery. Early intervention allows them to
rehabilitate that much sooner.
(6)
The cost of a worker's compensation low back claim is substantial. The indirect costs are noted to be three
times the direct costs. Would the
device under consideration allow an earlier return to work and save society a
significant financial burden?
Very possibly yes.
(7)
Last, and perhaps most important, what criteria are our patients most
interested in after safety and efficacy issues are addressed.
(a)
Relief of Pain.
(b)
Return to Function to include: Work, Leisure Time, Sleep and Sex.
(c)
Prevention of downstream degeneration associated with the potential exacerbation
of pain and disability.
Patients
don't want to hurt anymore; they want to live their lives. I recognize that as a representative of The
Spine Arthroplasty Society, I have made a statement rather than address the
specific FDA questions posed. Obviously
we do not have all the answers today, but this meeting is a good start. My
main concern is that practical, cost saving, expeditious decisions are made
without compromising the safety of our patients. Thank you for allowing me this audience.
DR.
NAIDU: Thank you, Dr. Hochschuler.
This
will conclude the open public session.
We will take a 10-minute break.
We will reconvene at 9:45.
(Whereupon,
at 9:37 a.m. off the record until 9:56 a.m.)
DR.
NAIDU: It's almost 10:00. I would like to call this meeting back to
order. Before we proceed with the FDA
presentation, is there anybody else in the public that would like to address
the panel at this point? If so, please
come forward. State your name and
affiliation.
Before
we precede further, Ms. Adams, would you please introduce yourself?
MS.
ADAMS: Good morning. I'm Pamela Adams. I'm with Etex Corporation and I'm the industry representative to
the panel.
DR.
NAIDU: Thank you, Ms. Adams. At this point we will proceed with the FDA
presentations on this topic. The FDA
presenter is Mr. Jonathan Peck.
Mr.
Jonathan Peck.
MR.
PECK: Thank you. Good morning. My name is Jonathan Peck.
I'm a reviewer in the Orthopedic Devices Branch in the Office of Device
Evaluation. I would like to take this
opportunity to thank the members of the panel for being here today to help FDA
out with our questions on this topic. I would also like to thank the
presenters this morning. The
information you shared is essential to a productive discussion this afternoon.
I
would like to give a special thanks to two of my colleagues, Dr. Kristen Mills
and Mr. Justin Eggleton for all their hard work and help in preparing for this
meeting.
Today
we will be discussing clinical trial design for devices intended to treat mild
to moderate lumbar degenerative disease.
I'll start out with some brief background information and then I'll move
into discussion of issues related to intended study population, potential control
groups, and study endpoints to these clinical trials. Finally, I'll present FDA's questions for the panel.
It
is estimated that 60 to 80 percent of the adult population will experience low
back pain at sometime in their lives with up to 5 percent experiencing this
pain on a yearly basis. Chronic low
back pain is one of the most common reasons for physician visits in the United
States. It's one of the leading causes
of employee absenteeism and disability.
It accounts for relatively large percentage of all U.S. healthcare
expenditures.
The
causes of low back pain are multifactorial and the specific pain generator
typically cannot be isolated. Normal
aging of the lumbar spine involves a sequence of degenerative changes that
likely start at a biochemical and cellular level and then turn into the changes
that we see clinically.
The
functional spine unit is made up of the intervertebral discs, the two facet
joints, the ligamentous structures, and the vertebral bodies. Each component of this complex undergoes
changes with aging and degeneration.
It's
hard to know what a bulging or degenerated disc means clinically as was shown
in the study by Boden. As you can see,
the majority of patients over the age of 60 that Boden looked at show some
radiographic signs of disc disease without showing any symptoms.
Now
I'll discuss the continuum of treatment options. The vast majority of patients with low back pain are successfully
managed nonoperatively. A wide variety of nonoperative treatments are available
including physical therapy, medications, and injections. But there is really no set treatment
protocol.
On
the other side of the spectrum, if symptoms persist or progress despite
nonoperative management, surgery becomes an option. The standard of care for most patients for whom surgery has been
deemed necessary has been spinal fusion and/or a decompressive procedure. Total disc replacement has become a more
recent option.
Over
time less invasive procedures have been developed to treat disc herniation and
more minimally invasive approaches for laminectomy and spinal fusion have
evolved. I just want to clarify that this treatment continuum was
meant to organize treatments based on the level of invasiveness and it does not
necessarily directly correlate with the disease continuum.
Recently
new devices have been reported in the literature that fits somewhere in between
nonoperative care and more invasive surgical options. You have heard about a
number of these devices in earlier presentations and read about several of them
in the literature provided in the panel pack.
Some of these new devices
have been proposed for use in patients who based on current surgical options
would have been treated with nonoperative care.
These
new devices are all intended to stabilize the affected functional spinal unit
while maintaining some degree of motion.
These devices are quite variable in design, function, and region of
implantation so we have broken them out into three design categories for your
consideration. The first group consists of spacers between adjacent spine
processes. The second group is nucleus
replacements and the third group is systems that are pedicle screw based.
Currently
there are several parameters that FDA is relatively comfortable with to
determine patient inclusion for lumbar spinal studies. For example, we typically like to see that a
patient receive six months of nonoperative care prior to inclusion.
With
regard to baseline pain and function levels, for example when using the
Oswestry disability index we prefer a baseline score 40 but have accepted 30
with an appropriate rationale. We are
also relatively comfortable with the radiographic findings we expect to see for
inclusion.
With
regard to the new devices it may make sense to alter some of these inclusion parameters
to capture patients that fall earlier in the disease continuum. This is something we are going to ask you to
discuss.
Before
moving into our main discussion, I just want to outline the main topics that
our questions will be centered around.
We will be asking you about intended patient population, potential
control groups, appropriate study endpoints, and miscellaneous questions about
study design.
Many
patients suffering from more mild to moderate disease may not be ideal surgical
candidates who warrant treatment with a permanent spinal implant. The associated risks may not be appropriate
for patients with mild to moderate disease and the benefits may not last long
enough to have warranted to the intervention.
The question will be for these types of devices how do we define the
patients to study?
There
are multiple control options for these studies. One such option is nonoperative care control. These control arms are designed to include
various combinations of medications, physical therapy, patient education, and
injections. An additional option for nonoperative care control is a
crossover or secondary treatment design which is also referred to as a rescue
procedure in the earlier presentations. The other control option would be
surgery in the form of fusion, total disc replacement, laminectomy, etc.
FDA sees potential limitations with
both nonoperative and surgical control options. If a patient has exhausted nonoperative care options, then it may
not be appropriate to randomize that patient to receive nonoperative care and
it could lead to a low success rate in the control group.
On
the other hand, if patients are not allowed to exhaust nonoperative options,
any outcomes observed during the trial may not be due to the device. In addition, it may not be ethical to treat
patients with mild disease with an implanted device.
Also,
compared to surgical intervention nonoperative care introduces potentially
significant bias due to placebo effects.
On the other hand, considering surgical control option, patients with
mild to moderate disease do not necessarily meet the criteria established for
fusion, disc replacement, laminectomy, etc.
We
have concerns about randomizing these patients to an invasive procedure that
they might not need. In addition,
regarding the crossover and secondary treatment designs, we aren't sure how to
objectively define when a subsequent intervention is warranted so we will be
asking you to discuss appropriate control group options.
Traditionally,
studies of spinal devices compare some or all of the following endpoints at the
24-month time point. Pain and function
scores, quality of life assessments, radiographic evidence of fusion or motion,
adverse events including secondary surgical procedures, and neurological
assessments.
A
number of pain and function assessments, for example, the Visual Analog Scale
and the Oswestry Index have become commonly accepted as endpoints in clinical
trials. These traditional spinal study
endpoints may not be the most appropriate endpoints to evaluate patient's mild
to moderate disease at baseline.
With
regard to pain and function assessments, the ceiling effect may come into play
given the potentially lower baseline scores.
FDA believes it is important for these studies to show durability in
response to the device. We are
concerned that the subjective nature of the pain and function assessments may
not capture the true treatment effect.
We will be asking you what the most appropriate clinically significant
endpoints are for these studies.
FDA
is concerned with studies that are not designed to demonstrate a mechanism of
action. Some proposed mechanisms of
action are the device may delay or halt the progression of DDD. The device may maintain or restore disc
height. Device may increase canal
foraminal dimensions or the device may delay or eliminate the need for more
invasive surgical options while providing equivalent results.
FDA
believes demonstrating a mechanism of action may be valuable, especially if
patients suffering from mild to moderate disease are studied and conservative
care is used as a control.
That's
the end of the FDA presentation. Would
it be helpful for me to go over the questions now or should we wait until
later?
DR.
NAIDU: Why don't we just go over the
questions briefly so that we have an idea as to what to address.
MR.
PECK: Okay. Now, when considering the questions, please consider that you may
have different conclusions for each of the three device types listed and the
two disease states listed as well. When
formulating your response, please clarify whether the answer is specific to
either device type,
disease state or if your answer is more general.
Here
are the main topics the questions are based on.
Question
No. 1, Intended Population. Considering
the natural history of lumbar degenerative disease, please discuss appropriate
time to intervene with a permanently implanted device intended to treat mild to
moderate disease. Then please discuss
the characteristics that should be used to define appropriate candidates for a
clinical study.
At
a minimum, please consider the
type and amount of nonoperative care a patient
should receive prior to inclusion and specific baseline criteria (e.g., ODI,
VAS, neurologic findings, radiographic criteria) that patients should meet
prior to inclusion in a spinal device clinical trial.
Question
No. 2, Control Groups. Based on the
population of appropriate surgical candidates discussed in Question No. 1,
please discuss the control options, nonoperative or operative, for
each of these device types. Please consider that a clinical study must
be designed to demonstrate a treatment effect.
For
example, it must be designed to show that any observed clinical outcome is due
to the device rather than other confounding factors and treatments. When considering this issue, please consider
the following dilemma. On one hand, in
order to warrant surgical intervention patients should have exhausted
nonoperative therapy options. However,
on the other hand, a patient should not be randomized to a control treatment
that they have already "failed."
Also, remember that these
patients may not meet the currently used criteria for surgical
intervention. Please comment on the use
of "crossover" and secondary treatment designs. Specifically, please comment on how to
define patients who have "failed" the first treatment and thus are
eligible to go on to the second treatment.
Question
3, Endpoints. Please discuss the most
appropriate clinically significant endpoints to evaluate subjects with mild to
moderate lumbar degenerative disease.
Please discuss what value, if any, there is in demonstrating a faster
response as opposed to comparing responses at the final study evaluation time
point, which has traditionally been 24 months.
If
demonstrating a faster response is
considered important, please discuss the length
of time the response should last to consider
the device a success. Please also discuss the value of potential mechanism of action endpoints. Which of the proposed endpoints might the
sponsor be able to demonstrate and how.
For
example, should restoration of disc height and hydration be shown through
objective radiographic criteria?
Finally, please discuss the endpoints for demonstrating if earlier
intervention is warranted because it alters or delays the course of the
disease.
Our
final question has to do with Study Design.
Please discuss what changes to traditional spinal device study designs
might be appropriate given the less invasive nature of many of these devices as
well as the mild to moderately affected patient population. Please discuss the appropriate final time
point to evaluate study endpoints to make a determination of study
success.
Please
discuss whether it is appropriate to define a smaller change in pain and
function scores as clinically significant given that these devices may pose
less risk and that the inclusion criterion score may be lower and the ceiling
effect may come into play.
Depending
on the study control, please discuss noninferiority versus superiority. Also, please discuss whether an increased
delta may be appropriate depending on the control.
DR.
NAIDU: Thank you, Mr. Peck. If you could go back and post the first
question up before I introduce the panel.
We will now begin the panel discussion.
Dr. Michael Yaszemski will open this part of the meeting with his
remarks to help us focus.
Yes,
Mr. Melkerson.
MR.
MELKERSON: Just one point of
clarification. In the description that
we've described of different device types, it was brought up in the
presentation that it should be based upon the claims. It should be pointed out that the device types we have listed
have made various claims associated with their design so when you are
addressing the questions you can either approach it from device by device or by
the claims associated with that device because of those three device types were
identified we have various claims made for each of the three device types.
DR.
NAIDU: Thank you, Mr. Melkerson.
Dr.
Yaszemski.
DR.
YASZEMSKI: Thanks, Dr. Naidu. I would like to make an introduction to the
panel discussion that we are about to have.
I think that as part of that discussion I'm going to start with my
conclusion so we can go from there. My
conclusion is that it's not appropriate at this time to provide strict answers
to any of these questions.
I
think we're too early in the evaluation of these types of devices to make any
global statements that will then bind either physicians or patients or device
manufacturers into a narrow pathway.
I
think what it is appropriate to do is to provide our thoughts together with our
clinical and industry colleagues as to a framework for evaluation of each
device that comes down the line, the questions to ask for each device and each
patient inclusion group that will then get to these four questions that we'll
discuss today.
That's
going to be the gist of what I have to say.
I think that the over-arching criterion that we should look for is
equipoise for each patient. When Dr.
Blumenstein talked before, he talked about the time of randomization and the
decisions to be made.
I
think for each individual patient when a physician and a patient are together
and making that decision to randomize, at that point the two choices available
must be equal in their risks and benefits to the patient to the best of our
knowledge.
I
think that as we answer these questions specifically, we should be trying to
get to that point. Are we presenting patients
with, as best as we can tell, equal options whether we choose the control or
the study for whatever device is under consideration at the time.
To
get to that, to get to equipoise at the time of randomization, I think that
there are two issues from which our discussion of the questions will flow. They are, No. 1, clinically appropriate care
and, No. 2, scientific validity, in that order. I think that the clinically appropriate care gets to the
equipoise. Each patient that comes here
to think about one of these devices there are three classes of devices and
several classes of disease processes. Depending upon the mix of the disease
process the particular patient's position along the path of that disease
process, where they are stage wise, and the device under consideration, each of
those mixes is going to be different for each device and each set of inclusion
criteria for the studies that are proposed.
With
scientific validity when we do get to the study it will be less than ideal if
after the study is done and the data are looked at that they are not valid to
the point that we can make scientific conclusions so I think that we need to
keep those things in mind as we deliberate.
Is the care appropriate and are the data going to be scientifically
valid?
Let
me look next at just two examples to say why I think that this group is
heterogeneous enough that we can't
provide anywhere near firm or rigid guidelines. The disease process and its natural history, the anticipated
clinical path, are going to be different whether the person is -- the two
examples I'm going to use are a young person previously asymptomatic who has
had some event and has a combination of back and leg pain, the typical
herniated disk person, early in the disease process. The second, a
person who has degenerative spondylolisthesis and spinal stenosis who has been
going along and is less and less able to get through his or her activities of
daily living. I think that these two
somewhat extremes demonstrate the heterogeneity of the patient groups and how
we will have to apply the conditions of equipoise in these varying situations.
The
disease, that is one. Then the second
-- excuse me. That discussion will be
focusing on the disease process. The
second will be on the device itself.
Each of these devices has different risk benefits. There is a different surgical risk depending
upon, as we've heard many of the presenters this morning, whether it's
minimally invasive or traditional surgical procedure.
These
devices span that spectrum. There is a
different anesthetic risk. Some of them
can be put in under local anesthesia and some of them require general
anesthesia. The reversibility I think
is also important because that reversibility includes two things from what I've
heard this morning and from what I've read.
That
is, what existing anatomy is altered when putting the device in that will stay
altered when you take the device out and how do you have to take this device
out. As we've heard this morning, some
of the interprocess spacer devices will be different to take out, for example,
than a prosthetic nucleus, a noninjectable prosthetic nucleus.
Now,
the examples again that I gave I would like to give to just frame out
subsequent discussion here. I would
like to give two examples where I think the answers to the questions will be
widely different.
First,
let's look at that 21-year-old patient who has had his or her first episode of
pain and has a herniated disk, back and leg pain. The leg pain is getting a little better. Back still hurts four weeks out. We ask the question is six weeks of
treatment long enough after which we invoke some device.
Let's
look at the other patient. She's a
70-year-old person with degenerative spondylolisthesis and spinal
stenosis. She has neurogenic
claudication. She has had it for a while.
She has gone through a number of nonoperative treatments. She has had a couple of injections. They have lasted for a while. The extent of her relief is getting slower
and slower. You see her at this time and then ask is four more weeks or six
more weeks of treatment enough.
I
would propose to you that the answer to is six weeks enough very different for
both those patients. I would propose
that in the first case. It's not
appropriate to go to any minimally invasive procedure. In the second case it might be.
Now,
let's look at devices. Pedicle-based
systems, interspinous spacers, and prosthetic disc nucleus, both injectable and
implantable. The pedicle screw based
systems can be put in percutaneous or open.
The questions I might ask when asking the risk benefit analysis for
them, if they are open or percutaneous we may have to retract the muscles to
put them in.
If
we retract the paraspondis muscles how long is it going to take to do so. The risk, although it's minimal in
experienced hands, there always is some risk to vascular or neurologic
structures putting a pedicle screw in.
They can be removed. They can be
removed percutaneously or they can be removed open.
Let's
look at the interspinous spacers. They
can be put in under a local anesthetic.
The risk to nervous and vascular structures, as we've heard this
morning, is very small and they can be removed with very little alteration to
the normal anatomy.
Let's
look at the prosthetic fixed disc nuclei.
If the PDN is an injectable PDN and the study under consideration is one
in which a discectomy is already being done, the risk of surgery and anesthetic
that has already been made. That
decision has already been made. They
are taking care of the patient. This
study might be having the PDN during surgery.
If,
however, it's a degenerative disc disease patient who is not otherwise getting
an operation, that same injectable PDN has to undergo different scrutiny than
it does in a case where a surgeon has already elected to proceed with the
decompression.
If
the PDN is not injectable but implantable and has to go in either posteriorly
or anteriorly, this presents a different situation than the injectable PDN. I say these things not to get us to an
answer but to emphasis the great heterogeneity in the patient population and of
devices that has to be considered each time a device proposal comes in front of
the FDA.
Again,
I'll restate my conclusion. We are too
early, I think, in the assessment of these devices to make any rigid
criteria. I think that a matrix of
considering the specific disease, the inclusion criteria for the patients
proposed for a study is going to result in an appropriate decision on the
answer to these four questions.
Then
with time since it's quite apparent that these devices are going to continue to
come for approval and for patient use, I think patterns will emerge that will
allow firmer answers for the four questions.
Thanks, Dr. Naidu.
DR.
NAIDU: Thank you, Dr. Yaszemski. Let's just go on straight to the panel
questions at this point. The questions
are fairly detailed, I think. This will
lead us to the discussion as well.
I
would like to start off with Dr. Kim.
Dr. Kim, if you could address the first question that's posed to us with
respect to the nuclear replacement devices, the spacers, and the pedicle screw
system. For each if you could outline
your opinion, I would appreciate it.
DR.
KIM: First of all, I want to echo Dr.
Yaszemski's comments that there is such a wide variety of implants and diseases
and various combinations that it's probably too early to make any specific
recommendations or requirements.
I
would say that I agree with virtually everybody that has made a presentation
today that a standard six-month number of preoperative or pretreatment trial of
conservative therapy is probably not a number that we should be relying
on. It makes sense for certain disease
types but for some of these other disease entities and implants that may be too
long, or it may be too short.
A
general guideline, I think, is important because it decreases the uncertainty
that the study sponsors and the investigators face whenever they come to these
PMA meetings so I think it would be beneficial to have some type of
guidelines. I don't have any specific
numbers but things like herniated disc it doesn't seem reasonable to have to
wait six months with nonoperative treatment because that is not how we take
care of these patients in our clinics.
That would be something that may benefit from a shorter nonoperative
treatment time period.
On
the other end of the spectrum is something like lumbar stenosis. We know that is a very slow gradual process
and six months seems very reasonable.
In some cases depending on the implant we may want to recommend even
longer times although six months seems reasonable.
I
just want to echo what people have said that the FDA needs to be a little bit
more flexible in making certain requirements and especially now where all the
spinal implant devices are so different than what we have been looking at. We need to really work together with the
study sponsors to come to some agreements almost on a case-by-case basis.
If
I have to try to make some generalizations for nucleus replacement devices,
that's a hard one because the two indications that I see is to replace the
nucleus after a discectomy so if you are treating somebody for a herniated
disk, waiting six months doesn't seem reasonable.
But
if you are treating somebody with a nucleus replacement device for low back
pain, waiting six weeks doesn't seem reasonable. Low back pain is a difficult entity to describe in the first
place in terms of its natural history so something like that waiting six months
would be reasonable so it would depend on what the study sponsor claims the
purpose of this device will be for.
Interspinous
process spacers tend to be for stenosis patients so the six-week period is not
reasonable and six-month period would be more reasonable. Then, finally, the pedicle screw dynamic
stabilizers again depends on the disease entity that they are proposing to
treat in the particular PMA. I would go
by the same guidelines that things like a herniated disk doesn't have to wait
six months but a treatment for low back pain or stenosis would need to wait
longer.
DR.
NAIDU: Thank you, Dr. Kim.
Dr.
Diaz.
DR.
DIAZ: As I was flying here, I was
trying to figure out what would be a sensible way to make a rational decision
and a rational comment about how to deal with this very complex problem. I think Dr. Yaszemski put it out very
clearly that we are not dealing with a homogeneous population. This is a very heterogeneous population at
best.
Not
only is a heterogeneous in a sense of scope of disease but in quality of
manifestations and type of individuals that it presents on. I cannot envision how we can come up with
one solution that fits all with this approach that we are asked to take
today.
I
don't think we can provide you with a single recipe for a solution that will
address all the questions that not only the patient population presents, the
clinical manifestations have, or the devices are used to treat these problems
are really giving us an opportunity to participate in the case of these
patients. I believe that the only way
that we can provide a sensible answer is addressing each and every one of the
problems individually.
I
believe that if we are talking about the young individual who has been a rugby
player, as I heard this morning in the elevator, who has been beating his
brains against somebody else's knees for months and comes in with back pain and
may have an acutely ruptured disc is going to have the same possible solution
as grandma who has been gradually deteriorating over the last 10 years.
She
has had manifestations that even though subtle are real but have not been
terribly incapacitating to her to the point where she has been able to function
reasonably well, although gradually losing ground and eventually coming to see
us because we don't have a solution to her problem.
Coming up with a study time to decide
when to intervene on these patients I think has to be individualized. The young athlete that has an acute sprain
in the back and may have nothing other than myofascial pain even though we
treat that patient for six weeks and we say there are MRI changes that show
that there may be an annular tear, if it were me after I played football and I
had an injury like that, I know I got better with not doing anything and I have
been able to continue to do well for many years.
I
don't think that there is a real solution to the time dilemma that this
question presents and to try to come up with a broad answer to be all inclusive
for all of these devices and all of these problems I think is asking too much.
DR.
NAIDU: Thank you, Dr. Dias.
Dr.
Rudicel.
DR.
RUDICEL: I think I would agree with
what everyone else on the panel has said.
I guess I would like to add that I think with these complex problems
that we have to think outside the box.
For example, I don't think a randomized trial, while it is certainly the
gold standard, but that may not always be the answer for how to deal with these
issues and how to conduct a study so I think we have to think in different ways
of dealing with this and certainly dividing up the patient population each
device has something different that we are trying to treat.
I
think it's difficult to compare conservative treatment with surgical
treatment. I think looking at different
study designs for doing that can be quite helpful. Also, I think we do
have some historical controls for these different problems that can be of
benefit.
We
do have a lot of information for the natural course of disease in some of these
problems and I don't think we want to ignore that. I would agree with the panel that it is a myriad of problems and
we can't come up with one solution for that.
DR.
NAIDU: Thank you, Dr. Rudicel.
Ms.
Whittington.
MS.
WHITTINGTON: I agree with the comments
from the other panel members in that these patients certainly have different
diseases and different problems that need to be addressed in different ways.
As
I sit and listen, I think it's also important that we consider that many of the
patients that the surgeons are seeing have already been exposed to a period of
conservative treatment by their primary care physician or practitioner and that
discounting that and looking at research that's done would potentially be
inappropriate, as well because of the delay of treatment to patients who would
benefit from earlier treatment.
There
was also discussion about guidelines that may already be available for
evaluating or timing treatments from the American Academy of Orthopedic Surgeons
so taking that into consideration would also be important when the panel
decides or evaluates research that's submitted by different companies.
DR.
NAIDU: Thank you, Ms. Whittington.
Ms.
Adams.
MS.
ADAMS: My comments are offered from an
industry perspective but I would say that I agree with most of the panel
members about the issues of heterogeneity that we are struggling with here. From an industry standpoint we are helped by
FDA issuance of guidance documents.
We
rely on them, we look to them, we try to follow them, and they are useful to
us. I'm a little concerned that this
may not be the appropriate approach for these types of devices and it may be
too early to be thinking about setting standards for such a large range of
devices, disease cases, patients, etc.
The
other thing I would just like to say is that from an industry standpoint I
think we rely really heavily on clinicians and the physicians that we work with
as investigators to give us their ideas about standard of care, about times to
intervene, about what the appropriate endpoints might be.
I
think that in this early stage with these types of devices that may still be
the best approach. We are as an
industry a little uncomfortable about thinking about regulatory answers to
these sorts of things just because there is so much that we still need to learn
from clinicians and there is so much information that we need to rely on from
principal investigators.
As
tricky as it is and as much as it may not be the answer that would be useful to
the FDA, I really think that this is a very difficult thing for us to give one
size fits all.
DR.
NAIDU: Thank you. Can I give my comments?
MR.
MELKERSON: Sure.
DR.
NAIDU: This is a very challenging
question. We have three devices that we
have to be concerned about. One is
nuclear replacement devices, the other one is the spacers, and lastly we have
to address the pedicle screw system.
The
spacers, the interspinous ligament spacers are supposed to be less invasive
like the Back Stop devices, the Wallis device.
They work on the premises that there is going to be distraction across
the space so the theme here is that it is less invasive. It can be done with local anesthesia.
How
about the nuclear devices? They come in
two flavors. Apparently they are
injectable at times. At times they will
need open surgical approaches. It also
comes in many flavors. Costarica
himself said the nuclear devices may have to withstand as much as 100 million
cycles of load over 40 years. They come in many flavors. It could be polyurethane. It could be elastin silk polymers,
copolymers. They come in hydrogels,
polycarbonate urethane, plastic polymers that are injectable to polymerize at
66 degrees Celsius. Even though there
is no actual curing occurring it is injected.
That
is, molded into the disc space which is technique dependent because the
surgeons don't have a mold of the space so instead of cutting a metal mold, the
spine itself is actually serving as a mold.
They may not be benign devices even though it appears that unless we
inject this material, it may be benign.
It may not do anything.
I
don't think these things have been characterized adequately in the literature
as well. There are reports as far as
oxygen degradation reports. I think
polymer characterization is an important issue here. That goes back to preclinical issues.
Now,
coming back to the appropriate time to intervene, it is the general consensus
of the panel that the patient population is quite varied. Some numbers that come up for a young
patient with acute disc herniation six months may be too long a time. Early
intervention may be appropriate. I do
agree with that. People with spinal
stenosis a more definitive time of six months as FDA has already required it
would be more appropriate. Those are my
thoughts. Have we addressed the first
question adequately?
MR.
MELKERSON: Let me possibly redirect it
a little bit. What we are looking at
here is suggestions on inclusion/exclusion criteria. We are talking homogeneity of the group devices. If a sponsor wants to study a particular
device and they want to pursue a particular group, you have talked about
herniated disc acute. You have talked
about degenerative processes.
Suggestions
in terms of giving not only FDA but the industry guidance of instead of trying
to have a very heterogenous population, would the suggestion then be from the
panel then to try to limit your studies to stenosis, herniated disc acute.
In
other words, when we're looking at this question, it is trying to address how
we advise and work with sponsors to identify inclusion/exclusion criteria for
them to study to get to a point where you then can compare it to a control
group.
The
time to intervene question is looking at when we are trying to help people
design studies, where are we going with inclusion/exclusion criteria to be
appropriate candidates. There is a
suggestion then to keep it -- have them limit their groups based on, say, acute
herniation or degenerative processes. I
would kind of turn it back to the panel.
That
is where the intent of this question was, not trying to lock you down and say,
"We need X, Y, and Z for each study design." What are the points to consider in giving
advice to companies that are. In other
words, it may be premature to initiate guidance at this time but the studies,
and we are being approached with those studies at this time, what advice then
would you have in that vein.
DR.
NAIDU: Dr. Yaszemski.
DR.
YASZEMSKI: I think it would be
appropriate to match both the disease and the device in each study and start
with that. For example, a posterior
motion limiting device to the neutral zone for back pain associated with
degenerative disc disease and start that with a description and have the
inclusion and exclusion criteria flow from there.
So
I think that even saying that, I still can't find myself giving you a number
because I think that number is going to depend on what that device is, what the
intended target audience is, and what the inclusion/exclusion criteria
are.
At
the point of seeing that for each application, I think then clinical and
scientific criteria could be applied to that combination of disease patient
group and device to come up with an appropriate number. I think that number is going to vary widely
for the different combinations of diseases and devices that we've talked about
today.
DR.
NAIDU: Dr. Rudicel, anything to add?
DR.
RUDICEL: I think age criteria obviously
as well. Otherwise, nothing else.
DR.
NAIDU: Dr. Kim.
DR.
KIM: I would agree as well. It is worthwhile from a scientific basis to
try to get as clean a data as possible so that we can make a solid conclusion
as to the results. I would recommend
that we focus on each disease entity assuming that the device being studied is
appropriate for that entity and that is what it's designed for.
Some
devices are designed for two things so the question arises if one device treats
two different things, should we just include both those things in the same
study. That depends but let's assume
two extremes. One is stenosis and the
other is herniated disc. I think we should
have two separate inclusion criteria.
If you are going to go through that trouble, it's probably cleaner to
have two separate studies. That's what
I would vote for.
Also,
I get a sense that this problem is so big that we are not wanting to try to
come up with a number but I would encourage us to work with the study sponsors
and investigators to come up with something so that there is not such a wide
variability in the different studies that we are going to be evaluating at this
panel. Just for selfish reasons I want
to be able to come to a solid decision.
It will be difficult if two very similar devices have two very different
inclusion criteria.
DR.
NAIDU: Thank you, Dr. Kim.
Dr.
Diaz.
DR.
DIAZ: I think the answer to your
question is one word, specificity. You
have to look at what problem you are trying to resolve and apply the possible
tool to solve it. Once you have
identified those two things, then your inclusion criteria are narrow. The broader the inclusion criteria, the
bigger the population that is required and the less likely that you will get a
good answer.
I
think if we can narrow the question to one problem, one device, one
application, then you can come up with a very well tailored-down solution to
the problem and it will give you a better yes or no answer rather than making
it fishnet.
DR.
NAIDU: Thank you, Dr. Diaz.
Ms.
Whittington.
MS.
WHITTINGTON: I agree with the
panel. I have nothing further to add.
DR.
NAIDU: Ms. Adams.
MS.
ADAMS: I have only one other thought to
add, is that Dr. Mathews talked about smaller studies, shorter-term
endpoints. I like the idea of
specificity and I think maybe we may be moving towards a place where we are
talking about companies working with clinicians to look at some specific
state. We should also be considering
looking at a variety of studies that are smaller and have shorter endpoints so
that we can get more data.
DR.
NAIDU: Thank you, Ms. Adams.
Mr.
Melkerson, in general with regards to Question 1, again, the time criteria is
quite varied. The specific
recommendation will go to the fact that the disease process be matched to the
device. For example, if somebody has
stenosis, go with the distraction device.
If somebody has a disc issue, go with the nuclear replacement
device. That way we can narrow the
patient population down and develop more stringent criteria. Does that adequately address it?
MR.
MELKERSON: I believe so. Thank you.
DR.
NAIDU: Thank you. Let's proceed on with Question No. 2. Would you mind reading it, please? Thank you.
MR.
PECK: Based on the population of
appropriate surgical candidates discussed in Question No. 1, please discuss the
control options, nonoperative or operative, for each of these device types. Please consider that a clinical study must
be designed to demonstrate a treatment effect.
For
example, it must be designed to show that any observed clinical outcome is due
to the device rather than other confounding factors and treatments. When considering this issue, please consider
the following dilemma. On one hand, in
order to warrant surgical intervention patients may have results to
nonoperative therapy options. However,
on the other hand, a patient should not be randomized to a control treatment
that they have already "failed."
Also, remember that these
patients may not meet the currently used criteria for surgical intervention. Please comment on the use of
"crossover" and secondary treatment designs. Specifically, please comment on how to
define patients who have "failed" the first treatment and thus are
eligible to go on to the second treatment.
DR.
NAIDU: Thank you. Dr. Kim, would you like to lead off, please?
DR.
KIM: The question is to whether or not
we need controls. The answer is an
overwhelming yes. The question is what
type of controls. I think that's what
we're talking about. Probably the
biggest concern that most sponsors have is do these controls need to be
randomized.
I
think the answer to that is clearly no.
We can use historical data. We
can use crossover data. We can use a
number of different things. We need to
be flexible but we need to be stringent in our analysis and in the end that is
going to require reliable data.
So
when we sit down and decide on a study whether or not the control is adequate,
it always depends on the disease entity to be treated and what is the current
accepted treatment. Sometimes the
answer to that is not obvious as we can see.
I don't think, at least myself as a panel member, will be able to sit
down today and tell you what the answers are.
In the end I think we
need to spend more time and we need to be more focused not on a case-by-case
basis but on a disease entity and type of implant basis. In some cases we should consider having
three groups. If we are in a situation
where you have a device to be studied and the two potential controls are either
nonoperative treatment or fusion, for example, even that may be an appropriate
type of study.
I'm
sorry to say I can't give a specific recommendation but I do want to emphasis
that the FDA needs to be flexible and, again, work with the study sponsors and
investigators to come up with an acceptable study design.
DR.
NAIDU: Thank you, Dr. Kim.
Dr.
Diaz.
DR.
DIAZ: I guess in this situation I'm
going to be the bad apple. I believe
that the only way we can come up with an answer is if we compare apples to apples. I think a study design of this nature
requires the assessment of the best possible treatment versus a new option.
If
the only available best overall treatment now for this disease process or any
of these processes is nonoperative, that has to be the control because we don't
know that there is anything better yet.
If we are looking for a scientific answer, we have to compare what we
have now with what we are proposing. In
my mind the control has to be always nonoperative versus operative.
I
disagree completely that a historical control is adequate. In my mind if we want to come up with a
scientific answer, we have to have concurrent controls. Otherwise, we will not answer the question
and we will leave it open for somebody else to criticize us.
I
think we have to have concurrent controls that are randomized as best as
randomization can be done. I have seen
far too many studies that have been approved and then shot down scientifically
because they lack concurrent randomized controls.
The
randomization into the study in my mind should be done probably relatively
early. We are not really in a position
right now to tell how long a nonoperative treatment is. Since what we are trying to answer is
whether nonoperative is better or as good or not as good as surgery, then I
think on early entry into the study is acceptable because that is a question we
will answer with this study.
If
we choose six weeks, three months, two days, I don't think it's quite as
important as including that nonoperative branch as a very important point of
comparison with the operative component.
Once we have come up with
that answer, we will know that if our nonoperative group got better at three
months or six months, then we will be able to say when the study population
that was operated on and got a better result we can say these people will improve
with medical therapy or nonoperative therapy if they do so within six
months. If they don't, then surgery
should be indicated. I think that time
limit is more applicable to the future implementation of the device used.
I
am in total disagreement with crossover allowance. In my mind a crossover allowance is not scientific. To me somebody that fails treatment can and
should be treated outside the study but should be considered a study failure,
not entered into the study branch on the other side of the population. If there is crossover treatment, they should
be given the treatment but taken out of the study.
DR.
NAIDU: Thank you, Dr. Dias.
Dr.
Rudicel.
DR.
RUDICEL: I think theoretically what
you're saying is right and is the most ideal way to get a really pure
answer. I think in reality that
sometimes doesn't work which is why I was making the point of thinking outside
the box. And it may even be things like
starting people early in a trial and there may be a second point beyond that at
which randomization might occur as well.
I
also agree with you about the crossovers.
I think they are treatment failures even though they deserve to have the
treatment offered. It's complex and I
still believe concurrent controls are certainly the best but I think we do have
some good current historical controls so I think there is a place for that as
well.
DR.
NAIDU: Thank you, Dr. Rudicel.
Dr.
Yaszemski.
DR.
YASZEMSKI: Receive from this discussion
that the issues of time to treatment and control groups are interrelated. If the person who is the patient has reached
what they consider the end of nonoperative care and the timing allowed by the
inclusion criteria of the study aims at that time, whatever that time be, then
they are not going to be at a point where they are going to want to be
randomized to a nonoperative arm which brings up why there is an issue of
operative versus nonoperative controls.
I
think that I am going to agree with Dr. Diaz that to have a valid assessment of
whether early intervention is appropriate, it needs a nonoperative control but
that also implies that the time at which you make that decision has to be
sooner so as we got to that spectrum we've been looking at, six weeks to six
months, if we are going to have nonoperative controls, then we would have to
have the ability to offer to persons earlier in the course of treatment and not
at a point where they've had enough and are looking for a different kind of
treatment and will not accept a nonoperative control.
I
think that will eliminate the issue of the crossover because people when
entered into early are still at a point where they are thinking, "Well, is
there equipoise? Is it equally
beneficial to me to either continue to try nonoperative therapies or to try one
of these early interventions." If
you allow the studies to enroll patients at that point in their care, then I
think the issue of crossover will go away.
I would agree with allowing an earlier time point if and when a
nonoperative control arm is approved.
DR.
NAIDU: Thank you, Dr. Yaszemski.
Ms.
Whittington.
MS.
WHITTINGTON: I agree with Dr.
Yaszemski. I think certainly what we're
hearing today offers or provides patients earlier treatment than we have
historically had for back pain and that's a whole different ball of wax for
everyone to deal with.
Earlier
treatment will allow people to select operative treatment earlier. I agree that there should not be a rescue
procedure included in the results. They
should be a failed treatment.
Otherwise, we have no good comparison.
I
think we have seen in other studies that having a good control group is the one
thing that we depend on to help us -- one of the things that we depend on to
help us in making decisions as to the applicability of the study summary to
other patient populations.
DR.
NAIDU: Thank you, Ms. Whittington.
Ms.
Adams.
MS.
ADAMS: Well, I think I agree with Dr.
Rudicel in her comment to Dr. Diaz in that I understand the pure approach he's
interested in. I think there are real
practical considerations here. One of
the things we talked about yesterday that strikes me is that we have different
-- we have a referral system and so we are talking about, as I understand it,
primary care physicians and specialist.
Where do we talk about when
a patient is entering this whole continuum of care and at what point they think
they failed or that sort of thing.
That's one concern. The other is
that I thought Dr. Anderson's point was very good in that if you are thinking
about control groups, these patients have very different opinions and personal
strategies regarding what they do and don't want to undergo.
How
we dial that all in is also a complicating factor, I think. I don't have a particular answer but I do
have concerns along those ways and I'll leave it at that.
DR.
NAIDU: Ms. Adams, thank you.
I
would have to concur with Dr. Diaz. I
think an ideal study would require a nonoperative control group. He has said little concern about the
crossover and I do have to concur with that as well. I don't think crossover should be allowed. I think they should be treated as treatment
failures.
Lastly,
Dr. Yaszemski points out clearly that if you do limit the nonoperative time,
rather than prolonging it to six months, maybe even shorter, the issue of
crossover may go away. In general the
panel believes that randomized nonoperative controls would be a reasonable
control group and, in fact, is a needed control group to judge the efficacy of
the device that is being implanted.
Have
we addressed that question adequately?
MR.
MELKERSON: Actually, my staff has given
me a couple of questions, but I want to ask one of my own questions first. We have been talking about nonoperative
controls or surgical controls in terms of study designs.
Now,
in discussions if they are ready for surgery, are there for these devices --
we're talking about devices. Are there
surgical treatments that could be considered to be used as controls of these
minimally invasive earlier intervening devices and how would that figure into
your discussions in terms of a control group?
DR.
NAIDU: Dr. Diaz, would you like to
address that?
DR.
DIAZ: Yes. In my mind we are trying to open a new chapter in the management
of spine disease. We are trying to look
at something that has not been really treated commonly surgically. Again, I have to be a purist in that
regard.
I
don't think there is any surgically comparable group that exists currently, at
least in the U.S., that has been approved or accepted by standard of care as
appropriate for the care of these limited or intermediate back pain patients.
So,
in my mind, no, I would not accept the surgical comparison because we don't
know that there is a surgically acceptable treatment yet. In my mind it should be nonoperative and
operative for each one of these devices.
DR.
NAIDU: Thank you, Dr. Diaz.
Dr.
Yaszemski.
DR.
YASZEMSKI: Nothing to add.
DR.
NAIDU: Dr. Rudicel.
DR.
RUDICEL: Nothing to add.
DR.
NAIDU: Dr. Kim.
DR.
KIM: Dr. Diaz' comments are all
excellent but I would personally not want to pigeonhole the investigators to
that type of requirement in case a particular study and device has an operative
control.
The
one that I can think of is using a nucleus replacement device to fill the void
that you would after a discectomy that control so the disease would be
herniated disc, the device would be the disc replacement device to try to
prevent, for example, long-term back pain or progression of degeneration. In
that case, to make the control group with leg pain or radiculopathy be a
nonoperative control, I don't think that would be very beneficial so most of
the time it will be nonoperative treatment, particularly if the sponsors and
investigators claim that this treatment is for a group of patients that are bad
enough to be suffering but not bad enough to warrant surgery. Then the appropriate control is nonoperative
but there are going to be instances where that is not the case so my vote is
not to pigeonhole it at this point as of yet.
DR.
NAIDU: Thank you, Dr. Kim.
Ms.
Whittington.
MS.
WHITTINGTON: I have nothing to add.
DR.
NAIDU: Ms. Adams.
MS.
ADAMS: Just one thought and that is
that we have heard things about smaller studies, earlier time points. We have also heard things about randomized
controls, nonoperative controls, and specificity. All of these things are at play.
I'm a little bit concerned that if we give advice back from t his panel
that says we need to be specific, we need to be randomized, we need to have
controls. We are talking about long
lead times for most of these devices and these are things that we need to dial
in.
DR.
NAIDU: Thank you, Ms. Adams.
Mr.
Melkerson, you've heard varied responses -- yes, go ahead.
MR.
MELKERSON: Could Mr. Stiegman actually
ask his question? I'm having difficulty
reading his writing.
MR.
STIEGMAN: Glen Stiegman, Branch Chief,
Orthopedic Devices Branch. One of the
issues that we keep coming up with when trying to figure out a control for this
is we go through the continuum and look at how the device is indicated. We agree that these devices can't be
generalized across the board and they are looking for specific answers.
However,
when looking at those early option devices maybe for acute rugby player, and
not good looking rugby players but acute disease rugby players, is it really
ethical to implant this device? You are
going through a surgery, the risk of surgery.
I think Dr. Yaszemski hinted
at it, weighing the risk and benefit of the two controls and investigational
arm. If there is an option or a chance
that this patient may get better through conservative care, should they be
randomized to get a surgery?
DR. NAIDU: Would anybody like to address that? Dr. Yaszemski.
DR.
YASZEMSKI: I would say that's the
person's decision. If the patient meets
the inclusion criteria, it doesn't mean you are going to randomize them. It means you offer it to them and if they
feel they are still at a point where they may get better, they will choose not
to participate in the study.
I
would say as long as from clinical view we feel there is equipoise in the
treatments from a scientific view, the data that emanates from the study will
be valid, then presented to the patients and they will decide whether to sign
up or not.
DR.
NAIDU: Thank you, Dr. Yaszemski.
Dr.
Rudicel.
DR.
RUDICEL: Yeah. I would completely agree. I mean, I think we wouldn't have any
innovation at all if we said it was never ethical to offer patients
options. That is really part of the
ongoing studies. We do as much as we
can beforehand to approve safety and efficacy and then offering patients that
option is what is going to lead us to find new treatment modalities that will
be beneficial.
DR.
NAIDU: Thank you.
Dr.
Kim.
DR.
KIM: I agree with both Dr. Yaszemski
and Dr. Rudicel.
DR.
NAIDU: Dr. Diaz.
DR.
DIAZ: I think the purpose of the FDA,
as I have understood it in the last five years of participating in these
panels, is to look at two questions: is the device safe and is it effective? If the questions that we have to answer are
premised on those two concepts, then doing a scientific study that answers
those questions is a must.
That
is why we have to in my mind be relatively strict in including individuals that
are limited in scope of need and particular in a type of problem for a specific
device. We offer it to the patient. We say, "This is the potential benefits
to you and these are the potential risks.
It is up to you to help us decide if this is the right treatment for
people like you. We don't know that
this works any better than aspirin. Do
you want to participate or do you not?"
DR.
NAIDU: Thank you, Dr. Diaz.
Ms.
Whittington.
MS.
WHITTINGTON: As the consumer
representative on the panel, I really emphasize the fact that we cannot take
patient choice out of the potential for an invasive procedure. To do that would not be appropriate in any
way.
DR.
NAIDU: Thank you, Ms. Whittington.
Ms.
Adams.
MS.
ADAMS: No comments.
DR.
NAIDU: Did we answer your question?
MR.
STIEGMAN: Yes. Thank you.
My second chicken scratch comment was -- I mean, like I said before, you
can't really generalize these devices.
However, we have discussed acute devices that there is an immediate need
for and then those like stenosis that may be more long-term where six-month
entry criteria is needed.
I
still really haven't heard and maybe this answer doesn't exist yet but what
would be the control for at least those two groups of patients? I mean, if it's acute, should we have the
conservative care? I mean, I would like
to hear the panel actually say that. If
it's an acute type indication, should conservative care be used.
Or
if it's long-term and it's minimally invasive surgery and six-month
conservative care entry criteria, should bigger surgery such as either disc
replacement or fusion be used.
Basically, two different categories of indications.
DR.
RUDICEL: Could you clarify that
again? You want to know if there should
be conservative care?
MR.
STIEGMAN: I guess from what I've heard
from discussion from Question 1, I heard two sorts of devices discussed, one
for acute care and one for more long-term where six-month inclusion criteria
will be needed or conservative care criteria will be needed.
What
would you suggest or what would be your input on control for those two types of
scenarios? I don't know if I
specifically heard that discussion or, at least, not to my satisfaction.
DR.
NAIDU: Dr. Yaszemski.
DR.
YASZEMSKI: I'll take one of them. I'll choose what you have referred to as the
long care one and, if I might, I'll rephrase that. I wouldn't call it long-term care. I would call it treatment for a disease that develops slowly and
steadily, i.e., the stenosis patient as I think you are getting at.
I
think that you have come to an example now of the general to the specific. You have asked for a specific mix of
patient, their position along the disease spectrum, their symptoms, the chronic
symptoms, if you will, the spinal stenosis and claudication, and a type of
device. In this case I would think you
would be talking about perhaps the interspinous devices that will flex the
functional spinal unit.
I
would say that this would be an example of this particular mix. I think that this is the way it's going --
from my perspective this is the way it's going to have to be addressed. What we can do here is a frame work to which
we can apply to specific mixes of patient device and proposed treatment.
I
would say that this type, a person who comes in with spinal stenosis, I would
shorten the time to which I would offer that person entry into a study for an
interspinous process device because these persons typically have
comorbidities. They have heart
disease. They have lung disease. To offer them something that can be done
under local anesthesia I think is a big plus for them.
In
my practice, if I saw a study available that would allow me at the time I went
from activity modification, anti-inflammatories, physical therapy for a
stenosis patient to injections for a stenosis patient, I would think there
would be equipoise of treatment to offer that person entry into a study that
would allow them an interspinous device.
I think the risks to
them would be low enough.
That
is just one guy's opinion and I think this mix of all these factors is going to
occur with everyone of these proposals like you just said. So I would shorten the time for this
particular patient and include it with nonoperative treatments such as
injections.
DR.
NAIDU: Thank you, Dr. Yaszemski.
Dr.
Rudicel.
DR.
RUDICEL: I just wanted to add to that
that a person like that also may be coming to the physician when they are well
into the course of their disease. It
may be that there are some instruments, maybe the SF-36 or some type of
instruments that can give a bit of an indication of just how much their
symptoms are affecting their life which is the most important thing.
But
I would agree they need to come to treatment much sooner than the football
player that herniates a disc acutely so that, you know, it would be good if
there is a way of measuring at what point in their disease process they are
entering the medical system. I think
that affects the entrance into the study and treatment.
DR.
NAIDU: Thank you, Dr. Rudicel.
Dr.
Kim.
DR.
KIM: I would agree with those comments.
DR.
NAIDU: Dr. Diaz.
DR.
DIAZ: I just noticed a little fragment
of your comments that bothered me a little bit. The issue that I picked on was that if this patient has been
treated conservatively for six, eight, 10, 12 weeks, is that an acceptable
control to that patient already and should that patient be then treated
surgically and can we use the person as his own or her own historical
control?
In
my mind that is not acceptable because the way that I treat back pain, which
may include a six-pack per night, hot packs locally, and resting on the beach
may not be the same as Dr. Yaszemski who treats them with nonsteroidal
anti-inflammatories, physical therapy, ultrasound, and epidural
injections. So a rose is not a rose is not a rose here. Conservative treatment does not mean the
same thing to all of us. It is a very
different thing. It is not the same for
a primary care as it is for a spine specialist. We need to make -- if we are going to answer the question, we
have to answer the question directly.
Is
it appropriate? The operative word here
is appropriate. Is appropriate
conservative therapy better, worse, or equal to operative treatment? If that is the question we want to answer,
then all of these patients should be treated equally. They should be entered early into the study and they should be
given the same management.
If
nonoperative treatment is good, we'll know it then but it will be the
appropriate nonoperative treatment. To
me of all the four questions you gave us, this is the easiest one to answer
because it applies to everybody. In my
mind there is a very simple answer to this.
It is nonoperative versus operative specifically driven to each
individual population.
DR. NAIDU: Thank you, Dr. Diaz.
Ms.
Whittington.
MS.
WHITTINGTON: I think Dr. Diaz brings up
a good point. What he's talking about
is evidence-based practice and evidence-based guidelines. That is an issue across the board, not only
with this disease but other diseases and practitioners, orthopedic surgeons,
neurosurgeons, and primary care physicians need to be providing care at the
same level.
Until
we can get to that point, I'm afraid that Dr. Diaz is right, that patients that
are included in these studies have to undergo what those guidelines are from
the point that they are entered in the study.
If prospectively that changes and people truly are using the same
guidelines in conservative management of these patients early in their disease,
then that could potentially change but that is not in the playing field right
now I don't believe.
DR.
NAIDU: Dr. Kim, you had something to
add?
DR.
KIM: I'm sorry. We're going out of turn but I just want to
bring up a point. All those points are
very valid scientifically, but the reality is that there are going to be
instances when a new device is very, very promising and whether we like it or
not, these devices are already being used outside the U.S.
If
as a panel member I was presented with data from outside the United States that
had valid outcome measures, was well controlled whether randomized or not, and
the disease entity had a good historical control, for example, lumbar stenosis,
the results of that are very well known historically, then I would feel
uncomfortable making that device undergo a stringent randomized control trial
that would take four or five years when we have enough data to reasonably say
that this is safe and it is effective based on the data that we have at
hand.
Most
of here are M.Ds., Ph.Ds. so I think we are all scientists, but at the same
time we are also clinicians and I just want to reemphasize that, at least, from
this seat that being stringent and scientific is not necessarily what the goal
of the FDA necessarily needs to be, at least from my perspective.
DR.
NAIDU: Thank you.
Ms.
Whittington.
MS.
WHITTINGTON: I think that is a good point. Certainly spinal stenosis has radiographic
indications that may be different than a disc herniation early on. Maybe that needs to be addressed in the
application criteria or identification for patients. Good point. Thank you.
DR.
NAIDU: Ms. Adams.
MS.
ADAMS: Well, I like Dr. Kim's
idea. I think it's a creative approach
and I think it is something that should be considered. I think one of the biggest concerns I have
through this whole discussion is that we're talking about people who have probably
failed conservative care and how do you dial them in and put them into a
control group.
I
think that's a real challenge so I like your idea. I can certainly imagine that somebody would say, "I would
really be interested in one of these earlier intervention devices as opposed to
jumping to surgery. I think that is a
great suggestion.
DR.
NAIDU: Thank you, Ms. Adams.
Dr.
Diaz.
DR.
DIAZ: I think we need to be very
careful with straying too far from the straight and narrow. One of the major problems we deal with right
now in healthcare in the U.S. is reimbursement. The FDA recently approved the use of Charité device. Now we have had a great deal of problem betting
reimbursement by a variety of reimbursing agencies claiming that the study used
was inappropriate, not well controlled, and not scientifically based. Patients
may not be reimbursed for a procedure that helps them because a movement exists
now to indicate that the studies that the FDA found to be appropriate
satisfactory and sufficient to answer both questions of safety and efficacy may
be actually trumped by people who do not think that they were appropriately
done.
If
we allow too many of these less scientific approaches in the use of these
things, even though industry wants us to get this out to the public quickly, we
may end up not being able to use it because we did not do the appropriate
relatively rigid studies that we need to do to answer those critics out there
who will prevent us from using them later.
Even
though there are studies outside the U.S. that may suggest that these devices
are useful, if we set up our study criteria as such that there can be people
who have failed their branch of treatment and can be taken out of that
treatment and treated as a failure but given the option of surgical treatment,
we are serving our population well.
We
have answered that conservative therapy is inadequate and we have provided the
patient with the care that he or she needs.
The U.S. population demands that we do this right. I don't think that being rigid is
inappropriate in something like this.
DR.
NAIDU: Thank you, Dr. Diaz.
Dr.
Rudicel.
DR.
RUDICEL: I just want to make a comment
that I disagree a little with what Dr. Diaz is saying, and I completely agree
with Dr. Kim in terms of having some other options. I would not judge what the payers of medical care, what kind of
judgment they are going to make about safety and efficacy because I think what
they are looking to answer is very different from what we are looking to answer
so I wouldn't use that as a judgment for whether a device is good or not good.
DR.
NAIDU: Thank you, Dr. Rudicel.
Dr.
Yaszemski.
DR.
YASZEMSKI: I'm going to submit that
we're all saying the same thing. I
think that the issue of U.S. versus non-U.S. studies should be based on whether
there is good evidence-based medicine regardless of where the study comes
from. If the study is from outside the
United States, and after scrutiny it appears that it's a good study, then it's
appropriate to use that data.
DR.
NAIDU: Thank you.
Mr.
Melkerson.
MR.
MELKERSON: One last point of
clarification. This is to Dr.
Diaz. I have heard enrolling patients
in conservative treatment. Some of the
study designs have already failed appropriate conservative treatment and then
compared one of these interventions.
Are you making a distinction between those two groups? In other words, should the studies be
enrolling at the same time or is there a distinction in your mind?
DR.
DIAZ: In my mind there is really no
distinction. In my mind appropriate
care needs to be defined beforehand.
Once we know what the nonoperative appropriate treatment is and we
implement that, the comparison of nonoperative with operative is relatively
easy and uniform. I cannot accept what
somebody else has given us as appropriate nonoperative control and include that
as my criteria because it may not be the same.
It may be a lot better but it could also be a lot worse.
DR.
NAIDU: Okay. Ms. Adams, did you have anything to add?
MS.
ADAMS: Well, I would just like to go
back and echo what Dr. Rudicel said. I
am very concerned about us comparing the bar for reimbursement in SEMUS with
what Congress has advocated FDA to do with respect to safety and efficacy
studies. They are very, very
different. It may well be that we'll
see SEMUS get the same kind of Congressional advocacy pushing them in a
different direction than they are. I
think we should be careful of not talking about reimbursement as part of this
panel consideration.
DR.
NAIDU: Thank you, Ms. Adams.
MR.
MELKERSON: I think you've addressed our
question on controls. Thanks.
DR.
NAIDU: Would you mind posing Question
No. 3?
MR.
PECK: Please
discuss the most appropriate clinically significant endpoints to evaluate
subjects with mild to moderate lumbar degenerative disease. Please discuss what value, if any, there is
in demonstrating a faster response as opposed to comparing responses at the
final study evaluation time point, which has traditionally been 24 months for
spinal studies.
If
demonstrating a faster response is
considered important, please discuss the length
of time the response should last to consider the device a success. Please also discuss the value of potential
mechanism of action endpoints. Which of
the proposed endpoints might the sponsor be able to demonstrate and how.
For
example, should restoration of disc height and disc hydration be shown through
objective radiographic criteria?
Finally, please discuss the endpoints for demonstrating if earlier
intervention is warranted because it alters or delays the course of the
disease.
DR.
NAIDU: Thank you. I would like to ask Dr. Kim to start off,
please.
DR.
KIM: Thank you. Let me try to address this in two
questions. The first question is study
endpoints. Do we need to wait 24 months
for every single study? I think Dr.
McAfee made a compelling argument that in certain circumstances you don't have
to wait 24 months. We can get a lot of
data at six months which will be reliably the same at 24 months.
I
think the number 24 months should not be strict. It should be variable depending on the disease entity and the
device treated. Having said that, we
also never answer the question of long-term efficacy. That came up dramatically at the Charité panel meeting where this
is a motion sparing device. It's going to be loaded constantly so
what happens at 10 to 20 years or even 30 years, that is an important very
relevant question. The question is how
should we deal with that. I don't think
it's fair to expect the sponsors and the investigators to do 10 to 20-year
studies.
In
terms of study time points we can go shorter but, at the same time, I think we
need a more robust mechanism to look at things long-term. Right now we are using the post-market
surveillance and I would recommend that we change that term from surveillance
to post-market studies and be a little bit more strict on that end to try to
address those two very different questions.
That is for the study time points.
In
terms of the outcomes, there are numerous outcomes but the few things that I
notice is that it is hard for a panel member like myself to determine whether
or not a study is efficacious if multiple different study parameters or
outcomes measures are being used. Even
though they may be imperfect, I would encourage the FDA and the sponsors to
agree upon certain types of or certain specific outcome parameters so that we
feel comfortable making some sound data analysis decisions.
Then,
finally, the question of mechanism of action, the rate at which this device
improves patient outcomes. I think that
should be specific. If the sponsor
investigator claims that this device will (a) help patients within six weeks
whereas the alternative treatment takes six months, then that should be a study
parameter we look at and use that as a gauge of whether or not this is
successful.
The
same thing with mechanism of action. If
they claim that this prevents future disc degeneration or allows the disc to rehydrate,
that should be a study success criteria.
That is how I would deal with those issues.
DR.
NAIDU: Dr. Diaz.
DR.
DIAZ: I think Question 1 and Question 3
are basically similar in nature. They
are too broad to really give you a specific answer. I think that each individual pathology state that we are
addressing needs to have its own endpoint follow-up criteria and success
measures in relation to the device that is being used.
If
we are looking at a resolution of spinal stenosis symptomatology in an elderly
individual and we are addressing it with an interspinous blocking device, then
we may have an answer within six weeks.
If
we are talking about a dynamic stabilization with any of the various dynamic
instruments that have been presented, the answer may not be as easy to obtain
in six weeks and may require six months because the intervention is much more
invasive. I think it needs to be
tailored to the disease process and to the tool use.
DR.
NAIDU: Thank you, Dr. Diaz.
Dr.
Yaszemski.
DR.
YASZEMSKI: Thanks. I'll start by commenting on the
process. We now understand a little bit
it's one process, early degenerative disc disease. The part of the question that says, "An assessment might be
to halt the progression of the degenerative process," highlights a
difficulty here. It's not going to get
halted.
The
point is that it's going to go on so success, I think, needs to include an
appreciation that the process is going to continue. Hence, I think it would tend to make we feel this question about
earlier time points is important. If
the person is uncomfortable with their current symptoms because the care hasn't
worked, I think it would be reasonable to look at whether the time change of how
long it takes them to get better has occurred.
It
is a difficult question to distill down to a few words. I do think earlier time points are
important. I think that what you are
going to look at is going to be different for all of them. For example, in this case we're using the
interspinous process spacer for early DDD as opposed to another use for it in
the spinal stenosis patient.
For
early DDD this would be -- the interspinous process spacer would be something
that is not going to preclude further surgery, minimally alters the anatomy,
can be taken out quite easily if its affect stops and it will affect neither
the facet joints, which will get typical degenerative changes or the
intervertebral disc.
On
the other hand, a nucleus replacement is going to affect the intervertebral disc. It's not going to affect the facet joints
other than their motion. The pedicle
screw base systems will affect the facet joints in that likely some insult to
their anatomy, some insult to their capsule in putting the pedicle screw base
system, is going to occur and whether that has a longer term affect on the
degenerative changes in the facet joints, we're not going to know that over a
short period of time.
On
the other hand, if that pedicle screw base system limits motion to the neutral
zone, it may have a beneficial affect both on the facet degenerative process
and the disc. It's a long-winded answer
to say that a quick -- to answer this question, Mark, I think is very
difficult. I think that we have to be
intentionally vague and you have to look at each of these submissions
individually.
DR.
NAIDU: Thank you, Dr. Yaszemski.
Dr.
Rudicel.
DR.
RUDICEL: What I would add is that I
think looking at patient-oriented outcomes is clearly important. We spent a long time in the academy in the
'90s looking at establishing validated instruments that everyone could use so
that your comments would be answered where we are always using similar outcome
measures.
It's
difficult but there are instruments.
Which of those we need to use I'm not sure of in the spine but I think
you would want to work closely with NASS because they have done a lot of work
in this area. Getting standardized
approaches is what is essential.
I
would maintain that radiographs are of some importance but certainly way down the
ladder what we really care about is how patients are functioning, what their
pain level is, and what they are able to do.
Clearly there are floor and ceiling effects depending on the age groups. The 20-year-old is much different than the
70-year-old but I think standardization and patient oriented outcomes are of
most importance.
DR.
NAIDU: Thank you, Dr. Rudicel.
Ms.
Whittington.
MS.
WHITTINGTON: I would echo what Dr.
Rudicel just said. Certainly the
patient reported outcomes are the most crucial. In looking at those I would agree that the emphasis of utilizing
the same validated tools across all studies would be helpful in specific
devices.
More
importantly looking not at the specific numbers that people score on those but
the percent change is the area of most importance, that improvement as
perceived by the patient. Also, Dr. Yaszemski's comments about the
importance of looking at applying these tools at a much earlier time because we
are looking at a mild to moderate disease and not a severe disease what is what
we have historically been looking at is also crucial.
In
determining those time variations again across studies or time increments would
be really important so that we are comparing apples to apples. There certainly is also the need for
radiographic and neurological assessment on the part of the physician as well
but I would again lend emphasis to the patient reported outcome.
DR.
NAIDU: Thank you, Ms. Whittington.
Ms.
Adams.
DR.
RUDICEL: Could I just add one
thing? I'm sorry. I think it's also being shown generally in
orthopedics that simpler instruments are working better than the longer complex
ones. I think one of my suggestions to
industry would be not to try to reinvent the wheel and develop your new
instrument for whatever new device you are developing but rather looking at
NASS or what has already been done because a new instrument just, you know,
clouds the issue.
DR.
NAIDU: Thank you, Dr. Rudicel.
Ms.
Adams.
MS.
ADAMS: Thanks for that comment, Dr. Rudicel. I agree with you. I think we all want the same thing. We want instruments that are validated so I think it's a great
point. There is some good work that has
been done in those areas.
The
only things I would add to this is that I think we ought to consider, even
though they're not here and we haven't discussed them, valid surrogate
endpoints, looking at Bayesian statistics to predict longer-term outcomes with
shorter-term measures. All those kinds
of things that we talked about as options to try and get data earlier.
The
last thing I would add is that the issue of evaluating the mechanism of action
sure seems like a complicated one since in many cases we don't seem to even
understand the source of the pain so that's a tricky one.
DR.
NAIDU: Thank you, Ms. Adams.
Mr.
Melkerson, in general with regards to Question No. 3 the panel's consensus is
that in general for these devices we do not need 24 months of follow-up like we
have for total disc replacement and spinal fusion devices. However, these may be device dependent.
Six
months may be adequate. Six weeks may
be adequate. That has to be
defined. It has to be device dependent. Therefore, in general the study endpoints
will be shorter but, nevertheless, this does not preclude the fact that
post-market surveillance the long-term outcome may well need to be appended to
the stipulation that you would formulate.
Lastly,
the mechanism of device should be specific to the device, although it appears
that the panel is kind of split on what you use for objective criteria with
regards to that. Radiographs are
important. It appears that if the
device states that it distracts the interspinous space, it will show by CT
scan.
There
are some panel members who feel that should be shown. There are other panel members who say that you are better off
with the patient outcome questionnaire rather than relying on the radiographic
parameters. As far as progression of
the disease, who knows. I mean, this
will go on most likely, as Dr. Yaszemski has said. Is the device going to stop it?
Mostly likely no. Have we
adequately answered all the questions?
MR.
MELKERSON: Just a clarification on the
issue of earlier time points. You
identified and earlier time point may be appropriate and we're talking about
premarket/post-market balance. Should
there be some demonstration of maintenance of that correction or improvement as
part of a premarket requirement versus a post-market requirement. You had suggested maybe six months and I
think Dr. McAfee had identified maybe a year.
That
would be a question that I would turn back to the panel in terms of when you're
talking about earlier time points should there be at least some duration of
effect shown premarket prior to putting other things off for longer term. That is, how long does the duration of
effect last.
DR.
NAIDU: Dr. Kim, would you like to
address that?
MR.
MELKERSON: And just a little caveat to
that question. In terms of when you are
looking at these earlier time points, what duration of effect before you would
go on to another surgical procedure may enter into that mix.
I
just kind of throw that out in your thought processes. In other words, if it's a duration of
effect, what is appropriate for a patient.
In other words, justify that this surgical intervention is as good as
nonoperative care in terms of preventing going on to a more invasive surgical
procedure.
DR.
NAIDU: Dr. Kim, would you like to
address that?
DR.
KIM: That's a really difficult
question. Yes, if that is an issue in
terms of the analysis for the particular device and disease entity, then we
should do longer-term premarket approval.
The question is what number is it.
I really like the analysis Dr. McAfee gave with the Charité that things
seem to plateau at about six months.
I
would want to look at data like that a little bit more to get a good idea of
how solid that six-month or 12-month data is.
Again, I like six months, I like 12 months. Twenty-four months is even better but it may be too burdensome. To answer your question, yes, we should look
at premarket parameters to look at durability.
The question is how long we need to look at it. That is going to require a little bit more
study that probably the data is out there.
Then
how long should we wait. I think the
answer to that is completely dependent on the answer to the first
question. We just have to find out how
durable an implant is within a reasonable degree of certainly.
DR.
NAIDU: Dr. Yaszemski.
DR.
YASZEMSKI: I think, Mark, my answer
would depend upon what the risk to putting a particular device in was and what
the alteration of normal anatomy was and how easy it is to remove the device.
On
the one end of the spectrum if it's very low risk to insert under local
anesthesia, disrupts normal anatomy very little and can be removed with minimal
risk, I wouldn't ask for long-term results at all. I would say if it provided quick relief of the symptoms and
lasted a short time, whatever you define as short, I would be okay with that.
I
wouldn't ask for -- to put a number on it I wouldn't even ask for six months if
it were easy to do and low risk. On the
other hand, if it was risky to put in and risky to take out and altered the
anatomy a lot, I would want to know that it's going to last longer. For longer I would make the one or two-year
number.
DR.
NAIDU: Thank you, Dr. Yaszemski.
Dr.
Rudicel.
DR.
RUDICEL: I would concur with that.
DR.
NAIDU: Thank you.
Dr.
Diaz.
DR.
DIAZ: I think the only comment I have
to make on that is really are we talking about early success response or are we
talking about delayed sustained response.
If it is early response that we are looking at, the device used and type
may give you a very wide spectrum of responses.
The
simple device that requires minimal implantation effort may give you a quicker
answer to a very specific problem shortly.
As opposed to the one that requires a lot of intervention with a lot of
local tissue damage that requires time for healing in and of itself.
If
we are talking about duration or length of duration of response, sustained
response, then I think we are looking at a totally different thing because, as
was mentioned earlier, this is not a static process. It is a dynamic process.
Even though we may intervene surgically to try to slow it down, we are
not stopping it.
So
the durability of a procedure may be addressed again individually to the
specific device with the understanding that the process in and of itself has a
fairly steady rate of progression that we may alter to a certain point and we
don't really know what the natural history of the problem is in addition to
what the intervention will do to that natural process.
DR.
NAIDU: Thank you, Dr. Diaz.
Ms.
Whittington.
MS.
WHITTINGTON: I have nothing to add.
DR.
NAIDU: Ms. Adams.
MS.
ADAMS: (No response.)
DR.
NAIDU: Have we adequately answered
that? It appears as if co-primary
endpoints seem to be reasonable for some devices, whereas the other devices
which are less invasive we may not need to stress the co-primary
endpoints. In fact, we may not even
need the one-year or two-year data for those.
MR.
MELKERSON: Just a quick response to Dr.
Diaz. Some of the questions are aimed
at some of the claims sponsors want to make so I appreciate your looking at
early claims versus later claims because some of them have actually said we
stopped degenerative process so the duration question comes into play.
The
review staff has also asked part of this question was related to the types of
evaluations done, ODI, ZZQ evaluations.
I've already heard patient satisfaction. Are there other types of studies or should we just be going to
the professional societies and looking at their mechanisms?
NASS
identified one of their own. Any
comments on those as far as adequacy for these types of devices? In general, if I'm not mistaken, many of
them were looked at more for the more invasive type devices. The question is are they relatable to these
devices?
DR.
NAIDU: Thank you.
Dr.
Yaszemski, would you like to start off on that?
DR.
YASZEMSKI: Mark, I'm not sure I can
give a straight answer to that. Again,
my response is going to be that heterogeneity is going to require considering a
particular mix of device indication and risk.
I'm going to stay vague and not directly answer.
DR.
NAIDU: Thank you.
Dr.
Rudicel.
DR.
RUDICEL: I think that is a very good
question and I'm not really qualified to answer that either. I would certainly look to -- I know several
people in the spinal world I would look to to help answer that. I think that is probably what should be
done.
DR.
NAIDU: Thank you, Dr. Rudicel.
Dr.
Kim.
DR.
KIM: I agree. I don't think we can make a decision today but we should probably
formulate a panel of experts to come to a decision at some point because there
are instruments out there that are being used very frequently compared to other
instruments and we should make a decision on that.
DR.
NAIDU: Thank you, Dr. Kim.
Dr.
Diaz.
DR.
DIAZ: I think it needs to be process
and disease specific device tailored and with a recommendation from
professional societies.
DR.
NAIDU: Dr. Whittington.
MS.
WHITTINGTON: Again, I think NASS is a
good source of that but ensuring that there are validated tools, that there are
some generic tools like an SF-36 that I think probably are too generic for this
patient population quite frankly but I think utilizing those resources. Patient satisfaction is not the only thing
to be evaluated here but patient pain and functionality are the two most
crucial pieces to evaluate.
DR.
NAIDU: Thank you, Ms. Whittington.
Ms.
Adams.
MS.
ADAMS: No comment.
DR.
NAIDU: Have we adequately addressed
that issue?
MR.
MELKERSON: I think we've --
MR.
PECK: One point of clarification
maybe. On the mechanism of action
point, it seems like the panel is saying you definitely agree if the sponsor
makes a claim that should be validated in the study.
However,
if we get an application and it doesn't make any specific mechanism of action
claims, our concern is that if we are comparing these patients to these earlier
conservative care as a control, we are going to be left with patients that get
better in the investigation but we're not going to be sure if it was due to
just them getting -- the fact that they might have gotten better anyway if they
continued with conservative care. That
was one of our main concerns with mechanism of action.
DR.
NAIDU: Thank you. Dr. Yaszemski.
DR.
YASZEMSKI: Now I can offer a thought
because that is a specific question. I
think I'm going to get back to what Dr. Diaz said before. We'll answer that with an appropriate design
study that has an appropriate control group.
That is a straightforward question.
DR.
NAIDU: Dr. Kim, anything to add?
DR.
KIM: (No response.)
DR.
NAIDU: Dr. Diaz?
DR.
DIAZ: No.
DR.
NAIDU: Anybody else?
MR.
MELKERSON: I think you have adequately
addressed this question. Thank you.
DR.
NAIDU: Thank you. Would you mind posting Question No. 4,
please.
MR.
PECK: Please discuss what changes to
traditional spinal device study designs might be appropriate given the less
invasive nature of many of these devices as well as the mild to moderately
affected patient population. Please
discuss the appropriate final time point to evaluate study endpoints to make a
determination of study success.
Please
discuss whether it is appropriate to define a small change in pain and function
scores as clinically significant given that these devices may pose less risk
and that the inclusion criterion score may be lower and the ceiling effect may
come into play.
Depending
on the study control, please discuss noninferiority versus superiority. Also, please discuss whether an increased
delta may be appropriate depending on the control.
DR.
NAIDU: Thank you. I think that we have already answered some
of these questions but I would like Dr. Diaz to field this question.
DR.
DIAZ: I cannot answer it any better
than in Question 3. I think the study
duration, the appropriateness of response, the outcome superiority or
inferiority needs to be tailored to the disease process and to the device
used.
If
we use appropriate criteria that have been selected with the help of the
professional societies, that will answer not only the clinical improvement
criteria that we need to know, but also the anatomical criteria that some of
these devices claim to make a change to, then that has to be applied to each
and every one of these problems and tailored accordingly.
DR.
NAIDU: Thank you.
Dr.
Kim.
DR.
KIM: This is a very difficult question
as well. Sitting here it is painfully
obvious that we do not have enough information to say with any degree of
reasonable certainty that we know what numbers represent success.
The
numbers that we have we have because we needed to have them to look at the past
PMAs but I think it's an opportunity now to go to literature and try to better
define and validate the degrees, the numbers that better represent what is
successful and not successful in the study using the particular instruments
that we are recommending be used.
The
second question is whether or not a smaller change in pain and function is
clinically significant. I think that
speaks to the first question. If I was
faced with a situation where -- that was brought up in one of the
presentations, one treatment is much more dangerous. Yet, if it's successful, the outcome is greater than a much safer
minimally invasive option but the overall success is slightly less, I would not
be against that type of success criteria.
DR.
NAIDU: Thank you, Dr. Kim.
Dr.
Rudicel.
DR.
RUDICEL: I don't really have much to
add except that clearly I think we are going to have to alter what is
considered successful. I think
definitely a different delta may be indicated.
DR.
NAIDU: Thank you, Dr. Rudicel.
Dr.
Yaszemski.
DR.
YASZEMSKI: I think that in general if
the treatment is less invasive, if it's earlier on, than I would tend toward
liking this improvement of 10 points over the traditional 15 points; for
example, the Oswestry. I would tend
toward liking a larger delta value in return for earlier intervention with a
more minimally invasive treatment. And
add the caveat that not everything we are talking about here is minimally
invasive. This would be for those that
are minimally invasive.
DR.
NAIDU: Thank you, Dr. Yaszemski.
Ms.
Whittington.
MS.
WHITTINGTON: I have nothing to add.
DR.
NAIDU: Ms. Adams.
MS.
ADAMS: Well, this may surprise you but
I agree with Dr. Diaz that we should be basing these parameters on the device,
the disease, and the study objectives.
I think it's a great idea and certainly well worth considering that with
earlier intervention for lesser diseases.
As Dr. Schneider said, smaller changes in outcome scores are inevitable
and should be expected so I think it should be considered.
DR.
NAIDU: Mr. Melkerson, to summarize the
panel's thoughts on this, in general the panel believes that if the device is
less invasive, smaller changes in pain level may be acceptable, higher delta
values may be acceptable. Again,
everything should be just based on a specific device and the mechanism of
action. Again, not all the devices that
we are talking about today are of the same mechanism. I mean, some are definitely less invasive than others so, again,
they have to be again device specific.
Is
there anything else that you would like us to address?
MR.
MELKERSON: Just because we keep using
the term minimally invasive and less invasive, just for clarification to make
sure that we are understanding correctly, what you're calling less invasive are
the stenosis type spacer products that can be done under local? How would you grade the nucleus replacement
products whether injectable or noninjectable and the pedicle screw base
systems?
DR.
NAIDU: Why don't we go around the table
and try to get an opinion with regards to that.
Dr.
Yaszemski.
DR.
YASZEMSKI: If it's an injectable
nucleus replacement first. If it's
injectable and done at the time of a surgery that is already being done, I
don't think there's any increase in risk.
It's already an open surgical procedure. If it's an injectable percutaneous nucleus replacement, I would
call that minimally invasive.
If
it's an open surgically implanted nucleus replacement, I would consider that a
standard surgical procedure and neither minimally nor less invasive. The pedicle screw systems, if they can be
applied under sedation and local anesthesia percutaneously as some are, I would
consider that less invasive.
If
they require an open surgical procedure, I would consider that a normal
surgical procedure neither minimally nor less.
Finally, the interspinous process spacers I would consider them
minimally invasive.
DR.
NAIDU: Thank you, Dr. Yaszemski.
Dr.
Rudicel.
DR.
RUDICEL: I don't have anything to add.
DR.
NAIDU: Dr. Kim.
DR.
KIM: I concur with Dr. Yaszemski.
DR.
NAIDU: Dr. Diaz.
DR.
DIAZ: I concur also.
DR.
NAIDU: Ms. Whittington.
MS.
WHITTINGTON: I concur.
DR.
NAIDU: Ms. Adams.
MS.
ADAMS: No additional comments.
DR.
NAIDU: Have we answered that question
adequately?
MR.
MELKERSON: I believe so. Thank you.
DR.
NAIDU: Thank you. At this point I would like to thank the
panel members for traveling long distances and for all their time that has been
put toward this meeting. I would like
to adjourn the meeting at this point.
MR.
MELKERSON: Before we adjourn, I would
like to thank the speakers who spoke today on this topic. We know it was a difficult topic, both for
the panel and for the audience as well as for the FDA. Again, we would like to thank the panel
members and Dr. Sanjiv Naidu for standing in for Dr. John Kirkpatrick. Thank you.
DR.
NAIDU: Thank you.
(Whereupon,
at 11:48 a.m. the meeting was adjourned.)