DEPARTMENT OF HEALTH AND HUMAN
SERVICES
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REVIEW MEMORANDUM
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Division of General and Restorative DevicesOrthopedic Devices Branch,
HFZ-410 |
Food and Drug
Administration Office of Device Evaluation 9200 Corporate Boulevard Rockville, MD 20850 |
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Date: |
April 19, 2004 |
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To: |
File |
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From: |
Medical Officer
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Subject: |
Hip Guidance Document Submission: Clinical
Trial Design for Hip replacement Systems |
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Sponsor: |
Orthopedic Surgical Manufacturers Association |
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Contact: |
Joel Batts
813-877-4469 |
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Docket # |
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Background
Once a year, FDA publishes, both in the Federal Register and on the Internet, a list of possible topics for future guidance document development or revision during the next year according to 21 CFR IB-10.115(5). This document is the Orthopedic Surgical Manufacturers Association’s (OSMA’s) response to this list and discussion between industry, and professional societies about the needs for assisting in getting new devices to the public in accordance to the MDUFMA goals. In accordance with 21 CFR IB-10.115(3), anyone can submit drafts of proposed guidance documents for FDA to consider. These documents are termed "Guidance Document Submissions"(GDS) and are submitted it to Dockets Management Branch of FDA.
FDA is required to
acknowledge receipt of the "Clinical Hip" GDS and provide public
access to it on the Dockets web site, per the FDA's Good Guidance Practices
(GGPs) at 21 CFR 10.115.
The subject of this GDS is a clinical
study design for evaluating hip joint replacement systems, an all encompassing
term, to include both conventional hip arthroplasty prostheses (cemented and
noncemented) and modern technological improvements on the conventional designs. It contains
three objective performance criteria as a composite patient success criterion
and a performance benchmark for study success.
This is the Office of Device Evaluation’s
first GDS which is one of the reasons for presenting it to the advisory
panel. There are many examples of
objective performance criteria used for preclinical data comparisons. In addition, there exist examples where
acceptable endpoint criteria based on meta-analysis of medical literature are
used as a control against which the safety and effectiveness of emerging
technological devices are measured.
Examples include cardiac heart valve devices, cardiac ablation catheters
and intraocular ophthalmic lens devices.
It should be emphasized that
this is not a petition for
reclassification of the hip replacement systems. The devices that may be affected include those described as
classified devices by 21 CFR 888.3310.,888.3320, 888.3330, 888.3340, 888.3350, 888.3353,
888.3358 and 888.3410 and potential unclassified new types of devices. This information is not intended to supplant
current guidances which define standard preclinical investigations that
characterize hip replacement prostheses.
Any subsequent guidance that develops would be used to supplement those
guidances.
The Premise
The ideal and preferred vehicle for establishing safety and effectiveness for any device is the randomized clinical trial. However, FDA’s regulations implementing section 513(a)(3) of the Act establish a hierarchy of valid scientific evidence. Under 21 CFR 860.7(c)(2), endorsed by the US Preventive Services Task force Quality of Evidence (USPSTF–HHS) includes
- well-controlled
investigations,
- partially controlled
studies,
- studies and objective
trials without matched controls,
- well documented case
histories, and
- reports of significant
human experience with a marketed device,
from which it can fairly and responsibly be concluded
by qualified experts that there is reasonable assurance of the safety and
effectiveness of a device under its condition of use.
Depending on the availability of data from previous studies
of these devices and previously studied similar devices in comparable
populations, other sources of valid
scientific evidence to show safety and effectiveness on this list can be
considered in an effort to provide a less burdensome approach to premarket
applications. Such an approach is one
of the intentions of this document. It
proposes to provide a standardized method for designing clinical trials
intended to evaluate the safety and effectiveness of hip joint replacement
systems, with minimum benchmark achievement goals for patient and study
success, in an effort to provide a least burdensome approach to manufacturers
and facilitate FDA review. A fundamental concept underlying “least
burdensome” concept is that safety and effectiveness be demonstrated by
appropriate and valid scientific information, evidence, or data. Least burdensome
is not intended as a way for either the FDA or Industry to "cut corners"
regarding the generation of data to support a marketing application.3
The underlying rationale for
this document is a long history of knowledge and understanding of conventional
hip joint arthroplasty dating to before the 1960s. Currently, there is considerable
cumulative experience on prosthetic hip joint clinical performance, given the
40 years of clinical evolution and an implantation rate of approximately 300,000
or more devices/year.7 Over
the past 10-20 years total hip arthroplasty has become the standard of care for
end stage arthritic and other medical conditions affecting the weight bearing
surfaces of the hip joint. Improved
quality of life, through the reduction of pain and return to function are well
accepted outcomes in the professional, scientific and patient communities. There is an abundance of literature with
long-term follow-up available that documents the safety and effectiveness for
conventional hip arthroplasty which allows comprehensive review and
understanding by the industry, physicians and FDA. This understanding allows for the development of benchmark
criteria, by which to measure new emerging technologies in the least burdensome
way.
How can the FDA
use this GDS?
Guidance, by definition, represents FDA's current
thinking on a topic; therefore FDA may revise a GDS as deemed appropriate
before issuing it as an FDA guidance document.
FDA defines guidance documents as those prepared for FDA staff,
regulated industry, and the public that describe the agency's interpretation of
or policy on a regulatory issue.
Therefore, the FDA presents this GDS to the advisory
panel for input to assist in developing a framework for a future guidance. It
is important to note that devices with a novel design, new material or
indication for use may or may not be included in the guidance eventually
developed from this meeting. If not specifically included, a novel design would
be required to provide valid scientific evidence, such as a randomized clinical
trial to demonstrate the safety and effectiveness or to support a specific device
claim.
What is the Panel’s
charge?
The panel will be asked to
make a recommendation on the adequacy of the objective clinical endpoint
criteria described for the proposed duration described in this GDS to support
the safety and effectiveness or specific device claim(s) in a future marketing
application. While the proposed GDS
provides many elements necessary for a clinical study guidance document (patient/study
success criteria, a proposed duration, etc.), we are concerned that other
elements do not appear to be included. In order to move forward toward an
appropriate guidance for clinical studies for hip replacement systems, we will
ask the panel to consider what was proposed in the GDS, to discuss acceptable specific
endpoint criteria and acceptable endpoints at a specific point in time, and to identify
additional information that should be included for a future guidance on the
topic of hip replacement systems.
Summary:
This GDS proposes a
standardized minimum patient success benchmark, based on 3 “variables” (Harris
hip score (HHS), revisions and device-related complications), for prospective
clinical trials that are intended to demonstrate the safety and effectiveness
of hip replacement devices intended to treat hip joint disease that has
resulted in pain and disfunction in patients.
This benchmark was developed
by clinical consensus by a group of orthopaedic surgeons who specialize in
total hip joint replacement surgery.
The consensus is based on their cumulative practice experience and a
literature search aimed at discovering the failure modes of total hip joint replacement devices
recorded in clinical studies of various hip replacement system (HRS)
designs. The literature search was
conducted using MeSH headings and sorted by the “Levels of Evidence,” a
hierarchy of scientific evidence described by the Journal of Bone and Joint
Surgery8 that categorizes research studies in terms of
validity and reliability of evidence.
Review:
This
document is intended to facilitate study design and provide consistency that
will provide a least burdensome approach for review and introduction of new
devices to market. It is focused on
patient and study success, and only general areas of study design.
The GDS
does not include a description of how studies were included or excluded and
what the results of the meta-analysis were in terms of numbers of patients,
length of follow-up, implant survival, revision rate, adverse event rates, and
outcomes of assessment scales for pain, function and global satisfaction
FDA
acknowledges the efforts of the team of expert orthopaedic surgeons who were
charged with answering six questions to arrive at a consensus for the proposed benchmarks. Although the document addresses a list of
complications and a minimal acceptable HHS, it appears to only partially
address the minimally acceptable percent difference in clinical success as
defined in the GDS between an HRS composite endpoint under study and the proposed
consensus benchmark composite endpoint at the proposed time of the final
postoperative evaluation. Also, the
GDS does not appear to address what the minimal acceptable change in HHS at the
final postoperative evaluation in comparison to baseline (question #2, GDS page
6) and the measures to be performed on postoperative radiographs with the
minimal acceptable quantities of those measures (question # 4, GDS page 6).
A. Device related complications = 0 %
B.
HHS at 12 months greater
or equal to 80
C.
Revision surgeries = 0 %
Study success is achieved when 95% of patients are deemed patient successes at one year.
While the absence of
revisions and device-related complications is expected at one year, an HHS
score of 80 may be too low a target for a one year time point. We are aware of large studies evaluating hip
replacement devices report HHSs of 90 or better early in patient followup.4,5 Thus, we will be requesting recommendations
in respect to pain and function objective performance criteria (e.g., the appropriateness
if the proposed HHS of >80 at one year or some other level for an objective
performance criteria at another time point.).
Although the GDS does not
specify which evaluations are repeated at which interval, the sponsor proposes
data collection postoperatively at baseline, 6 weeks, 6 months, and 12 months. When queried in the past, the panel has previously
recommended that 2 year data is not sufficient to understand the performance
and safety of a joint prosthetic, even judging that 2 year data was an
inadequate surrogate for long term performance. FDA has always recommended that data be collected at a minimum of
2 years and to collect data until the last enrolled patient has had his 24
month evaluation, as this allows for the collection of some data beyond 2
years. This GDS does not appear to
have provided an adequate rationale or data to support the proposed objective
performance criteria at 1 year. We will
be asking for recommendations regarding the combination of the proposed
objective performance criteria and the proposed time of the last evaluation.
Statistical Plan
For a full statistical analysis review,
please see the statistician’s review.
The advantage of having a predetermined sample size is
that sponsors would be better able to financially plan financially clinical
trials, presumably reducing the cost of research and development. The
proposed statistical plan includes a determination of sample size based on a
delta of 4% with a confidence interval, between 91.7 and 97.5. This would allow a 5% failure rate at one
year. This proposal appears to be more liberal
than several large consensus and meta analyses that demonstrate that implant
survival is greater than 95% at 10 years for cemented components and approximately
98% at 5 year follow up for uncemented components4,5. Based on the Power calculation in Appendix
V, if the observed rate was 90% or 93% success, the null hypothesis would not
be rejected, but the lower confidence interval could be 85%- 89% which may not
be consistent with what is reported in practice or in the literature. We will be seeking recommendations on
whether the proposes composite success rates at earlier time points (e.g., one
year, 18 months, 2 years, etc.) are acceptable based on long-term information regarding
success rates.4,5,6. This GDS does not appear to address the
treatment and analysis of patients requiring bilateral treatment or patients
who are lost to follow-up. Other issues
not specifically addressed in this GDS include what the primary analysis will
be and how covariates will be considered and/or addressed.
Outcome Evaluation tools and Secondary Endpoint
Considerations
Although the document has
suggested that radiographic and other secondary endpoint considerations should
be conducted, no specific evaluations are proposed. In addition, OSMA proposes that some hip replacement designs may
not conform well to standard, accepted techniques without citing examples or
why this would be true. OSMA proposes
that radiographic failures would be reported without discussing how this
assessment characterizes the failure of a device, or which scales are
appropriate for use in the approach proposed in the GDS.
Adverse Events
Appendix IV lists the most
common complications determined as a result of review of the articles provided
in Appendix III. Not all complications
are addressed for all materials and designs, particularly those with newer
bearing surfaces and designs. This
includes ceramic head or liner fractures.
The table does not include the denominator for the number of hip
procedures, the types of devices (bearing surfaces and materials, designs) that
were included in the analysis for this evaluation describes or the type of
study the data comes from. In addition,
in contrast to that proposed in the GDS, FDA would include surgical technique
(labeling for the device) as part of the device-related events.
Discussion
We will be seeking a
recommendation regarding the proposed clinical objective performance criteria as
an alternative to other forms of valid scientific evidence such as a randomized
clinical trial. We will also be
accepting recommendation(s) regarding items discussed above that should be
included to be complete and useful for evaluating the safety and effectiveness
of these HRS devices for the purposes of supporting marketing applications.
This GDS proposed by OSMA brings
several factors to the forefront in support of the proposed approach. This approach, which employs objective
clinical performance criteria, would be a singular allowance in orthopaedic
devices due to the long history of consistent
device performance reported in peer reviewed literature and by professional
experience. It is supplemented by some
well-developed bench, preclinical and clinical
performance evaluations in standard use that characterize these
devices well. Continuing professional
society surveillance of the reliability of prosthetic devices with periodic
international professional society meetings also exists which is dedicated to the
evaluation of hip prostheses as the technology evolves. Moving forward with this equivalent of
objective performance criteria can encourage the development and testing of new
technology in the advance of the treatment of hip arthritis in a timely manner.
With a historical control, as proposed in this GDS, the resulting study becomes a one-armed observational study and since there is no randomization, any comparative statistical inference is compromised. An advantage of a randomized trial design is that confounding factors, such as selection biases, are counteracted because of the randomization. If there is no randomization, there is a greater need to check for and avoid potential confounding factors that lead to bias in the trial. Thus, there need to be tools in place to mitigate the biases that exist inherently with historical controls. The use of historical controls and a study of the past assume that the knowledge gathered can answer new clinical questions. The assumption is that a review of the literature allows complete and adequately detailed records for review. A meta-analyses based on published reports is subject to publication bias as negative clinical studies are less likely to be published. With a vast historical experience based on the patients and medical thinking of the past, there is a strong possibility of temporal bias. Baseline conditions of a population change over time. What naturally follows is a question of the capacity and soundness of a comparison between historical controls and future patients to be treated. The concern associated with those factors that have changed since the time of the historical review is whether the historical criteria applied to a new device may not discern whether the device is inferior to concurrent treatment. All of the factors discussed above should be considered in the discussion of the GDS as proposed and presented to the FDA in order to effectively move a future guidance for the clinical evaluation of hip replacement systems forward.
References:
1.
Dawson, B,
Trapp, RG, Basic and Clinical Biostatistics 3rd ed,. New York: Lange, 2001, pp. 7-23, 63-72, 250-3.
2.
Guyatt,
G Rennie D, eds., Users Guides to Medical Literature: A manual for Evidence based Clinical
Practice, Chicago: AMA Press, 2002, p. 426.
3.
The Least Burdensome
Provisions of the FDA Modernization Act of 1997: Concept and Principles; Final
Guidance for FDA and Industry. 9/30/2002 http://www.fda.gov/cdrh/ode/guidance/1332.pdf
4.
Total Hip
Replacement, NIH Consensus Statement,
September 12-14, 1994, 12(5): 1-31.
5.
Malchau H, Herberts P, Eisler T, Garellick G, Soderman P, The Swedish Total Hip Replacement Register., J Bone Joint Surg Am.,
2002, 84-A Suppl 2:2-20.
6.
Weinstein, J. The Dartmouth Atlas of Musculoskeletal
Health Care,
Chicago, IL: AHA Press, 2000.
7.
National Center for
Health Statistics, 1991 to 2000 National Hospital Discharge Survey.
8.
Wright JG,
Swiontkowski MF, Heckman JD,.
Introducing levels of evidence to the journal.
J Bone Joint Surg Am,.
2003, Jan; 85-A(1):1-3.