[Federal Register Volume 79, Number 93 (Wednesday, May 14, 2014)]
[Notices]
[Pages 27623-27626]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-11048]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-P-1107]


Oxiplex[supreg]/SP Gel; FzioMed, Incorporated's Petition for 
Review of the Food and Drug Administration's Denial of Premarket 
Approval; Notice of Meeting

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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    This notice announces a forthcoming meeting of a public advisory 
committee of the Food and Drug Administration (FDA). The topic to be 
discussed is the Center for Device and Radiological Health's (CDRH's) 
denial of a premarket approval application (PMA) for Oxiplex[supreg]/SP 
Gel (OXIPLEX) submitted by FzioMed, Inc.--the sponsor for OXIPLEX. The 
meeting will be open to the public.
    Name of Committee: Medical Devices Dispute Resolution Panel of the 
Medical Devices Advisory Committee.
    General Function of the Committee: To provide advice and 
recommendations to the Agency on scientific disputes between CDRH and 
sponsors, applicants, and manufacturers.
    Date and Time: The meeting will be held on June 10, 2014, from 8 
a.m. to 6 p.m.
    Location: The meeting will be held at the Hilton Washington DC/
North, salons A, B, C, and D of the Ballroom, 620 Perry Pkwy., 
Gaithersburg, MD. The hotel's telephone number is 1-301-977-8900.
    Contact Person: Pamela D. Scott, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 3611, Silver Spring, MD 20993, 301-796-5433, FAX: 
301-847-8510, email: [email protected], or FDA Advisory 
Committee Information Line, 1-800-741-8138 (301-443-0572 in the 
Washington, DC area), and follow the prompts to the desired center or 
product area. Please call the Information Line for up-to-date 
information on this meeting. A notice in the Federal Register about 
last minute modifications that affect a previously announced advisory 
committee meeting cannot always be published quickly enough to provide 
timely notice. Therefore, you should always check the Agency's Web site 
and call the appropriate advisory committee hot line/phone line to 
learn about possible modifications before coming to the meeting.
    Procedure: Interested persons may present data, information, or 
views, orally or in writing, on issues pending before the committee. 
Written submissions from persons other than FzioMed and CDRH may be 
made to the docket on or before June 3, 2014. Submit electronic 
comments to http://www.regulations.gov. Submit written comments to the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD, 20852. It is only necessary 
to send one set of comments. Identify all written and electronic 
comments and submissions with the docket number found in brackets in 
the heading of this document. All written and electronic comments and 
submissions will be considered to be publicly disclosable.
    Oral presentations from persons other than FzioMed and CDRH will be 
scheduled between approximately 12:45 and 1:15 p.m. on June 10, 2014. 
If you wish to make an oral presentation during the meeting, you should 
register on or before May 27, 2014. Send registration information 
(including name, title, firm name, address, telephone, email, and FAX 
number), and requests to make oral presentations to Pamela D. Scott 
(see Contact Person). You should provide the docket number appearing in 
the heading of this notice. You also should submit a brief summary of 
the presentation, including the discussion topic(s) that will be 
addressed and the approximate time requested for your presentation. The 
amount of time to be allotted to each presenter may be limited to 
provide opportunities to as many persons wishing to present as 
possible. If the number of registrants requesting to speak is greater 
than can be reasonably accommodated during the scheduled open public 
hearing session, FDA may conduct a lottery to determine the speakers 
for that session. We encourage individuals and organizations with 
common interests to consolidate or coordinate their presentations to 
allow adequate time for each request for presentation. Pamela D. Scott 
will notify interested persons regarding their request to speak by June 
2, 2014. On the day of the meeting scheduled open public speakers 
should identify themselves at the registration desk.
    After the scheduled speakers have spoken, the Chair of the advisory 
committee may ask them to remain if the advisory committee wishes to 
question them further. The Chair may recognize unscheduled speakers 
should time allow.
    Persons attending FDA's advisory committee meetings are advised 
that the Agency is not responsible for providing access to electrical 
outlets.

SUPPLEMENTARY INFORMATION: 

I. Background

    FDA is announcing that, in accordance with section 515(g)(2) of the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 360e(g)(2)), 
a public advisory committee will review CDRH's denial of a PMA for 
OXIPLEX submitted by FzioMed--the sponsor for OXIPLEX.
    On August 21, 2007, FzioMed submitted a PMA (PMA P070023) for 
OXIPLEX. OXIPLEX is an absorbable, clear, viscoelastic gel designed to 
be applied in the lower back during lumbar spine surgery. The device's 
proposed indication is for use as a surgical adjuvant in adult patients 
with primary leg pain and severe baseline back pain undergoing first 
surgical intervention (i.e., open or endoscopic posterior lumbar 
laminectomy, laminotomy, or discectomy) for diagnosed unilateral 
herniation of lumbar intervertebral disc material associated with 
radiculopathy. The proposed intended use is for one-time use, up to 3 
milliliters, after hemostasis during wound closure, as an adjunct to 
primary surgical intervention to improve patient outcomes by reducing 
leg pain, back pain and neurologic symptoms.
    On October 9, 2012, CDRH issued a decision upholding a not 
approvable letter in response to the PMA P070023 for OXIPLEX. CDRH 
determined that PMA P070023 is not approvable based on its conclusion 
that the data and information offered in support of the PMA do not 
provide a reasonable assurance that the device is safe and effective 
under the conditions of use prescribed, recommended, or suggested in 
the proposed labeling, as required by section 515(d)(2) of the FD&C 
Act.
    On November 5, 2012, FzioMed requested administrative review of 
CDRH's decision to uphold its not approvable letter. Submitted in the 
form of a petition for reconsideration under 21 CFR 10.33 (see Sec.  
814.44 (21 CFR 814.44(f)(2))), FzioMed's petition for review (petition) 
stated that, in accordance with Sec.  814.44(f), FzioMed

[[Page 27624]]

considered the decision to uphold the not approvable letter to be a 
denial of approval of PMA P070023 under Sec.  814.45. Pursuant to 
section 515(d)(4) of the FD&C Act, FzioMed requested review of this 
denial under section 515(g)(2) of the FD&C Act (petition is available 
in Docket No. FDA-2012-P-1107).
    Accordingly, as required by Sec.  814.45(e)(3), CDRH issued an 
order denying approval of the PMA for OXIPLEX on October 21, 2013. 
Pursuant to section 515(g)(2) of the FD&C Act, on October 25, 2013, FDA 
granted FzioMed's petition for review of the order denying PMA P070023. 
In accordance with section 515(g)(2) of the FD&C Act, the Office of the 
Commissioner is referring PMA P070023 and the basis for the order 
denying its approval to the Medical Devices Dispute Resolution Panel 
(the panel), an advisory committee of experts established, in part, to 
receive referrals of petitions for advisory committee review under 
section 515(g)(2)(B) of the FD&C Act. The panel for this review will 
consist of nine persons, qualified by training and experience to 
evaluate the clinical and scientific basis of CDRH's order denying 
approval of the PMA. After independent study of the data and 
information furnished to it by the Office of the Commissioner, and 
other data and information before it, the panel will, during the 
meeting, discuss, evaluate, make recommendations, and vote on the 
issues in dispute based on the statement of issues described below. A 
transcript of the meeting will serve as a report and recommendation 
with respect to CDRH's order denying approval. (See section 
515(g)(2)(A) of the FD&C Act.) Together with the underlying data and 
information before the panel, the transcript of the meeting will be 
submitted to FDA's Chief Scientist, who is an official authorized to 
perform all delegable functions of the Commissioner and is the 
Commissioner's designee for this matter.
    The Office of the Commissioner will make the transcript of the 
meeting public in accordance with section 515(g)(2)(C) of the FD&C Act. 
The Office of the Commissioner will also provide a copy of the 
transcript to FzioMed and CDRH and will offer FzioMed and CDRH the 
opportunity to submit comments on the panel's recommendations before a 
final order is rendered. In accordance with section 515(g)(2)(C) of the 
FD&C Act, the Chief Scientist will issue an order either affirming or 
reversing the order denying PMA P070023 and, if appropriate, approving 
or denying approval of the PMA.

II. Meeting Issues and Process

A. Issues

    The scientific questions for the panel relate to whether the 
information provided by FzioMed is sufficient to provide a reasonable 
assurance of safety and effectiveness for OXIPLEX's proposed 
indications. Key to a determination regarding effectiveness is whether 
the product will provide clinically significant results to a 
significant portion of the target population. (See 21 CFR 860.7(e).)
    Over the course of CDRH's review of OXIPLEX, FzioMed submitted data 
from four peer-reviewed, published clinical studies in an effort to 
demonstrate safety and effectiveness. The clinical studies included a 
pilot study and a pivotal study, both of which were conducted in the 
United States, and two studies conducted outside of the United States 
in China and Italy (the OUS studies). The pivotal study was a 
randomized, controlled, double-blinded multicenter study designed to 
evaluate the efficacy of OXIPLEX in the reduction of postoperative pain 
and symptoms and to evaluate the safety of applying OXIPLEX during 
lumbar disc surgery by comparing a group of patients undergoing lumbar 
surgery alone and a group undergoing the same surgery with the use of 
OXIPLEX. FzioMed maintains that, although the pivotal study did not 
show a statistically significant reduction in leg pain for OXIPLEX in 
the study patient population as a whole, the study did demonstrate 
OXIPLEX to be effective for the subgroup of patients with leg pain and 
severe baseline back pain (SBBP):

    For those subjects with both leg pain and severe baseline back 
pain, which comprised 55% of the total study population, . . . 
improvement in leg pain from baseline to the 6-month visit was 
statistically significantly greater for Oxiplex subjects compared to 
control subjects (P=0.0123), with an 18% greater improvement in leg 
pain in the Oxiplex group compared to controls. (Petition at 7-8.)

In addition, FzioMed submitted data from the two OUS studies that, 
according to FzioMed, provide confirmatory evidence of the safety and 
efficacy of OXIPLEX in the severe back pain subgroup.

    In denying PMA P070023, CDRH concluded that the effect observed in 
the SBBP subgroup in the pivotal study was not adequate to support 
approval because it stemmed from what CDRH characterized as FzioMed's 
``exploratory subgroup analysis.'' CDRH further determined that the OUS 
studies do not confirm the results of improvement shown in 
postoperative leg pain in the SBBP subgroup from the pivotal study 
because: (1) Differences in subject population and study endpoints 
among the three studies preclude pooling the data; (2) the Chinese 
clinical study was not initially designed to assess the treatment 
effect in the SBBP subgroup, and review of the quartile of patients 
with the most severe baseline back pain in the study did not 
demonstrate a treatment effect for OXIPLEX at either the 30- or 60-day 
endpoint; and (3) the Italian clinical study was not truly randomized, 
resulting in important baseline differences between the control and 
treatment groups that preclude meaningful comparison between the two 
groups, and few study subjects had baseline back pain of the severity 
considered in the SBBP subgroup of the pivotal study.
    FzioMed contests the scientific bases for CDRH's determination that 
the evidence from the pivotal study and the two OUS studies does not 
provide a reasonable assurance of the device's safety and effectiveness 
for the device's proposed indications. First, FzioMed contends that the 
agency should place greater weight on the treatment results for the 
SBBP subgroup in the pivotal study. While acknowledging that ``severe'' 
was not prospectively defined in identifying the SBBP subgroup, the 
company notes that the statistical analysis plan did prospectively 
identify baseline back pain as a covariate for analysis. FzioMed 
maintains that analysis of this subgroup was justified and executed in 
a manner consistent with the approved statistical analysis plan. 
Second, FzioMed maintains that differences in study population among 
the clinical studies submitted to FDA actually strengthen support for 
the effectiveness of OXIPLEX:

    The fact that consistent results were observed using the LSOQ 
[Lumbar Spine Outcomes Questionnaire] and the Visual Analogue Scale 
(VAS), and that these results were demonstrated at short (60 days), 
intermediate (6 months) and long-term (3 years) follow-up intervals 
supports the robustness of the data and confirms that the results 
observed in the U.S. pivotal study did not occur by chance. 
(Petition at 13.)

    Third, FzioMed argues that CDRH improperly rejected the submitted 
OUS studies as confirmatory evidence of safety and effectiveness, based 
on, among other things, inappropriate subgroup analyses and improper 
restrictions on study design.
    CDRH and FzioMed have agreed that, in order to demonstrate 
clinically significant results for a significant portion of the target 
population from the adjunctive use of OXIPLEX for the proposed SBBP 
indications, the

[[Page 27625]]

submitted information must demonstrate, based on patients' self-
assessment under validated pain scales, at least a 10 percent 
difference in the mean leg pain reduction from baseline pain to 6-month 
postoperative residual pain in favor of Oxiplex, when the mean 
difference between the treatment and control groups is divided by the 
mean reduction in leg pain in the control group. This assumes at least 
a 50 percent reduction in baseline to 6-month residual pain in the 
control group.
    Questions for the panel to consider relative to safety and 
effectiveness are:
    1. With respect to the pivotal study:
    a. Is it scientifically and statistically valid to rely on analysis 
of the SBBP subgroup of the pivotal study to support, in part, a 
determination of reasonable assurance of effectiveness for the proposed 
SBBP indications?
    b. Did CDRH give the effect observed in the SBBP subgroup of the 
pivotal study sufficient weight in evaluating OXIPLEX's effectiveness 
for the proposed SBBP indications?
    2. With respect to the Chinese clinical study (Confirmatory Study 
1):
    a. Is it scientifically and statistically valid to rely on analysis 
of the SBBP subgroup as confirmatory evidence of effectiveness for the 
proposed SBBP indications?
    b. In evaluating whether OXIPLEX provides clinically significant 
results for the proposed SBBP indications, is it scientifically and 
statistically valid to look at the treatment effect for OXIPLEX 
observed for the quartile of patients (N=17) with the most severe 
baseline back pain (VAS score >=6.2) at the 30- and 60-day endpoints?
    3. With respect to the Italian case series (Confirmatory Study 
2): Does the study design enable a scientifically and 
statistically valid comparison between the treatment and control groups 
for the proposed SBBP indications?
    4. Do the differences in study design for the pivotal study and the 
OUS studies prevent considering all three studies in the aggregate to 
evaluate whether OXIPLEX provides statistically and clinically 
significant results for the proposed SBBP indications?
    5. When reviewed in total, do the data and other information 
submitted for OXIPLEX provide a reasonable assurance of effectiveness 
for the proposed SBBP indications (i.e., do the data and information 
demonstrate, based on patients' self-assessment under validated pain 
scales, at least a 10 percent difference in the mean leg pain reduction 
from baseline pain to 6-month post-operative residual leg pain in favor 
of OXIPLEX, when the mean difference between the treatment and control 
groups is divided by the mean reduction in pain in the control group, 
assuming at least a 50 percent reduction in baseline to 6-month 
residual pain in the control group)?
    6. When reviewed in total, do the data and other information 
submitted for OXIPLEX provide a reasonable assurance of safety for the 
proposed SBBP indications? For there to be ``reasonable assurance of 
safety,'' valid scientific evidence must enable a determination that 
the probable benefits to health from use of OXIPLEX for the proposed 
SBBP indications outweigh any probable risks.

B. Process

    Although no statute or regulation requires that separation of 
functions be applied to this review proceeding under section 515(g)(2) 
of the FD&C Act, FDA is adopting the following measures to ensure 
impartiality and promote efficiency. First, the Office of the 
Commissioner has formed two teams. The first, the Substantive Team, 
handles all decisions on any issues or matters that either relate 
directly to the merits of the review proceeding or are the subject of a 
dispute between CDRH and FzioMed, which are both parties to this 
proceeding. The second team, the Administrative Team, handles all 
undisputed procedural matters related to the administration of the 
panel meeting. The Administrative Team ensures that it keeps the 
parties apprised of all significant procedural decisions. Moreover, the 
Administrative Team refers the parties to the Substantive Team if 
either or both of the parties have concerns about the manner in which 
the Administrative Team has resolved a procedural issue.
    To promote efficiency and facilitate the flow of information 
between the Office of the Commissioner and the parties, the agency is 
not requiring that all communications between the parties and the 
Office of the Commissioner be made part of the public record. However, 
until the Office of the Commissioner issues an order either affirming 
or reversing the order denying approval of PMA P070023, the Office of 
the Commissioner will not engage, and has not engaged, in any 
communication concerning the merits of the review proceeding with 
anyone participating as a party to the hearing or any person outside 
the agency unless the communication is made part of the public record. 
Communications between the parties and the Administrative Team that are 
not part of the public record will be limited to discussion of 
procedural issues and questions.
    For the purposes of this proceeding, members of CDRH are considered 
to represent CDRH unless specifically designated to advise the Office 
of the Commissioner as a member of the Substantive Team or 
Administrative Team. All other members of FDA are available to advise 
and participate with the Office of the Commissioner on matters related 
to this proceeding.
    At the meeting, each party will be provided 1 hour and 45 minutes 
during the first portion of the meeting to present relevant information 
or views orally. The parties may use the allotted time as desired, 
consistent with an orderly meeting, and may be accompanied by 
additional persons, who may present relevant information or views. The 
parties will subsequently be allowed 15 minutes for rebuttal. During 
the panel's open discussion, the panel members may pose questions to, 
or seek requests for clarification from, FzioMed and/or CDRH. 
Thereafter, each party will be allocated 15 minutes for summation, 
after which panel deliberation and voting will occur.
    FDA welcomes the public's attendance at this advisory committee 
meeting and will make every effort to accommodate persons with physical 
disabilities or special needs. If you need special accommodations due 
to a disability, please contact AnnMarie Williams, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, rm. 3611, Silver Spring, MD 20993, 301-796-
5966, FAX: 301-847-8505, email: [email protected] in 
advance of the meeting.
    FDA is committed to the orderly conduct of its advisory committee 
meetings. Please visit our Web site at http://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/ucm111462.htm for procedures 
on public conduct during advisory committee meetings.
    Because this is a public meeting before an advisory committee, it 
is subject to our regulations concerning the policy and procedures for 
electronic media coverage of public agency administrative proceedings 
(21 CFR 10.200 through 10.206). These procedures are primarily intended 
to expedite media access to our public proceedings. Representatives of 
the electronic media may be permitted, subject to certain limitations, 
to videotape, film, or otherwise record our public administrative 
proceedings, including the testimony of witnesses in the proceedings. 
Accordingly, the parties and nonparty participants, and all other 
interested persons, are directed to Sec.  10.200 through 10.206, for a 
more

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complete explanation of those regulations' effect on this meeting.
    Documents filed in this matter are available for public review 
under Docket No. FDA-2012-P-1107 in the Division of Dockets Management 
(see Procedure) between 9 a.m. and 4 p.m., Monday through Friday. 
Persons with access to the Internet may obtain documents at http://www.regulations.gov. FDA intends to make background material, including 
briefing materials for the panel provided by CDRH and FzioMed, 
available to the public no later than 2 business days before the 
meeting. If FDA is unable to provide the background material prior to 
the meeting, the background material will be made publicly available at 
the location of the advisory committee meeting, and the background 
material will be available in the Division of Dockets Management (see 
Procedure) and at http://www.regulations.gov after the meeting.
    Notice of this meeting is given under the Federal Advisory 
Committee Act (5 U.S.C. app. 2).

III. Transcripts

    Please be advised that as soon as a transcript is available, it 
will be accessible at http://www.regulations.gov. It may be viewed at 
the Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD.

    Dated: May 9, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-11048 Filed 5-13-14; 8:45 am]
BILLING CODE 4160-01-P