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701 Pennsylvania Avenue, NW Suite 800
Washington, D.C. 20004–2654
Tel: 202 783 8700 Fax: 202 783 8750
www.AdvaMed.org
Bringing innovation to patient care worldwide
October 17, 2018
Division of Dockets Management Staff (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Room 1061
Rockville, MD 20852
Re: Docket No: Docket No. FDA–2018–D–2896: Osteoarthritis: Structural Endpoints
for the Development of Drugs, Devices, and Biological Products for Treatment; Draft
Guidance for Industry; Availability
Dear Sir/Madam:
On behalf of the Advanced Medical Technology Association (AdvaMed), we are pleased
to submit these comments in response to the Food and Drug Administration’s (FDA’s)
request for comments on the draft guidance entitled, “Osteoarthritis: Structural
Endpoints for the Development of Drugs, Devices and Biological Products for
Treatment.”
AdvaMed represents manufacturers of medical devices, diagnostic products, and health
information systems that are transforming health care through earlier disease detection,
less invasive procedures, and more effective treatments. These members range from the
smallest to the largest medical technology innovators and companies. AdvaMed’s nearly
400 members manufacture the vast majority of all medical technology products sold in
the U.S. AdvaMed advocates for a legal, regulatory and economic environment that
advances global health care by assuring worldwide patient access to the benefits of
medical technology. The Association promotes policies that foster the highest ethical
standards, rapid product approvals, appropriate reimbursement and access to international
markets.
AdvaMed has both general and specific comments in tabular format below.
General Comments
AdvaMed supports FDA’s intent to develop guidance on treatment of the underlying
pathophysiology and structural progression of osteoarthritis (OA). However, this
guidance on OA structural endpoints alone fails to provide sufficient clarity. FDA
appears to want to address structural endpoints yet still validates structural endpoints as
surrogates of pain and function so the guidance document is not independent. FDA
should combine this guidance with future guidance on treatment of OA symptoms
including pain or functional impairment.
Division of Dockets Management
October 17, 2018
Page 2 of 8
Given the extreme brevity and limited information in the draft guidance, we recommend
that FDA remind sponsors of the availability of the pre-submission meeting process to
obtain updated information and agreement on what FDA believes may be needed to
demonstrate safety and effectiveness for a particular product, in this case, for the
treatment of OA.
We also recommend that FDA include a definition for the term “structural endpoints”
which is used repeatedly throughout the guidance document. For the development of
drugs, devices, and biological products for the treatment of osteoarthritis, AdvaMed
recommends that the definition be the following:
“Structural endpoint” is defined as an outcome that can be measured objectively
to determine whether the intervention being studied is capable of altering disease
progression or abnormal function or morphology of a joint. This may include
measures based on imaging or biomarkers.
Lastly, we encourage the addition of FDA’s thinking regarding the development of in
vitro diagnostics and the identification of biomarkers for osteoarthritis to this guidance.
For the development of in vitro diagnostics for osteoarthritis, AdvaMed recommends that
the definition of “structural endpoints” be the following:
“Structural endpoint” is defined as the method of objectively measuring structural
disease progression or abnormal function or morphology of a joint. This includes
diagnostic accuracy of qualitative or quantitative IVDs that can diagnose and/or
indicate disease severity or progression.
Specific Comments
AdvaMed’s specific comments can be found in the attached table.
Sincerely,
/s/
Tara Federici
Vice President
Technology and Regulatory Affairs
AdvaMed Comments on Draft Guidance on Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices and Biological Products for Treatment
10/17/2018 Page 3 of 8 Docket Number FDA-2018-D-2896
Edit # ID # Change Reason
1 N/A
Add a definition for the term ‘Structural Endpoints’ and include a
definition for in vitro diagnostics for osteoarthritis:
For the development of drugs, devices, and biological
products for treatment of osteoarthritis:
“Structural endpoint” is defined as an outcome that can be
measured objectively to determine whether the intervention
being studied is capable of altering disease progression or
abnormal function or morphology of a joint. This may
include measures based on imaging or biomarkers.
For the development of in vitro diagnostics for
osteoarthritis:
“Structural endpoint” is defined as the method of objectively
measuring structural disease progression or abnormal
function or morphology of a joint. This includes diagnostic
accuracy of qualitative or quantitative IVDs that can
diagnose and/or indicate disease severity or progression.
The term ‘structural endpoints’ is used throughout the document
without definition. A definition should be added or, at minimum,
examples of what is meant by structural endpoints. Reference #5
alludes to the possibility of using biomarkers as a means to
measure structural endpoints, but it is unclear.
Given the current research environment, there is an increasing
likelihood that biomarkers could be identified as valid measures
of structural endpoints.
2 N/A
Additional guidance is needed for the development of In Vitro
Diagnostic (IVD) devices for osteoarthritis.
There is a significant challenge faced when using patient
reported outcomes (PROs) or standard imaging techniques to
correlate IVD performance because PROs and imaging used in
the current Standard of Care are subjective and most likely less
sensitive or specific to the different stages of OA than the method
being developed.
AdvaMed Comments on Draft Guidance on Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices and Biological Products for Treatment
10/17/2018 Page 4 of 8 Docket Number FDA-2018-D-2896
Edit # ID # Change Reason
Sponsors developing IVDs in this space would benefit from
guidance on regulatory pathways for bringing IVDs to market that
do not have a predicate and are also unable to be correlated to a
currently used PRO or standard imaging method due to the
inadequacy of the current approach for determining OA staging
and progression.
3 N/A
Update draft guidance document to address use of biomarkers as
an endpoint for the treatment of osteoarthritis.
Given the current research environment, there is an increasing
likelihood that biomarkers could be identified as valid outcome
measures for accelerated approval of medical products intended
for the treatment of OA.
4 2
Add the following to the end of the guidance title:
Osteoarthritis: Structural Endpoints for the Development of
Drugs, Devices and Biological Products for Treatment or
Diagnosis
This guidance can also be used to provide guidance to
manufacturers of potential In Vitro Diagnostic (IVD) devices that
could aid in the measurement of structural severity or progression
of osteoarthritis.
5 19 Strike and replace the following:
Replace “his” by “this”
The word “this” is misspelled in the text.
6 23 - 24
Add the following:
To date, FDA review of products intended Approvals for the
treatment of OA to date have been based on patient-reported
outcome measures that assess pain and function.
No non-surgical product has been approved with the indication of
both pain AND function for the treatment of OA. The approvals to
date (HA and steroid) have only had pain as the primary
endpoints in their clinical trials, and they are approved for the
treatment of pain associated with OA.
AdvaMed Comments on Draft Guidance on Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices and Biological Products for Treatment
10/17/2018 Page 5 of 8 Docket Number FDA-2018-D-2896
Edit # ID # Change Reason
7 28 - 29
Clarify intent of the following:
“This guidance does not address improvement of symptoms of
OA, such as pain or functional impairment.”
It is unclear if this statement can be interpreted to mean that FDA
believes an OA treatment can be developed that does not
address the symptoms and whether there is a path forward for
OA treatment that does not demonstrate improved symptoms. If
symptomatic improvement is a necessary component for any OA
treatment, then that should be clearly stated.
8 29
Strike and replace the following:
This guidance does not address improvement of symptoms of
OA, such as pain or functional impairment. FDA recognizes the
importance of these outcomes indications, which will be
addressed in future guidance.
As written, it is unclear if FDA recognizes the improvement of
symptoms associated with OA as a meaningful indication for use.
9 47
Add the following:
“Sponsors should consider the following regarding structural
endpoints for developing medical products for the treatment or
diagnosis of OA:”
Expand the scope of the guidance to also include In Vitro
Diagnostics (IVDs) i.e., diagnosis of OA. The guidance highlights
the issues with the current structural endpoints for OA.
Considering the treatment of OA is heavily reliant on the
structural endpoints, it would make sense to use IVDs
(biomarkers or other technologies) to identify and diagnose OA
severity and progression. Sponsors of products intended for
treatment could then utilize the IVDs to measure the ability of the
treatment to alter OA disease progression.
AdvaMed Comments on Draft Guidance on Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices and Biological Products for Treatment
10/17/2018 Page 6 of 8 Docket Number FDA-2018-D-2896
Edit # ID # Change Reason
10 54
Strike and replace the following:
However, there are several ongoing issues with developing such
products, including the multifactorial and complex
etiopathogenesis of the disease, the well-recognized discordance
between structural changes and signs/symptoms/function, the
lack of standard definitions of methods to objectively measure
disease progression, and correspondingly, the absence of
endpoints to reliably assess the ability of a product to alter OA
disease progression.
Even if we had a standard definition, if we are unable to
objectively measure OA progression, the definition will still be
applied subjectively.
11 61
Strike and replace the following:
Because of the complex and variable pathologic changes through
which OA impairs function and leads to long-term disability and/or
joint replacement, at this time it is unclear what magnitude of
change in structural endpoints would translate to a clinically
meaningful benefit to patients (i.e. e.g., reliably predict both
reduced pain and increased function or prolonged time to end-
stage disease surgical joint replacement).
It appears that examples are being presented, which makes
sense given that prediction of both pain and function and
prolonging the time to end-stage disease are likely not the only
two ways of demonstrating a clinically meaningful benefit to
patients.
In addition, a key message of this guidance is that structural
endpoints are not well defined. Hence, “end-stage disease” is
also subjective with no standard definition. The result of end-
stage disease is typically a joint replacement and prolonging the
need for joint replacement would generally be considered a
slowing of OA progression.
AdvaMed Comments on Draft Guidance on Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices and Biological Products for Treatment
10/17/2018 Page 7 of 8 Docket Number FDA-2018-D-2896
Edit # ID # Change Reason
12 65
Add the following:
To accept structural endpoints as valid primary outcome
measures for accelerated approval, there should be substantial
confidence, either based on empirical evidence from randomized,
controlled comparisons from clinical trials and/or based on a
comprehensive understanding of the disease process and
product mechanism of action, that an effect on the candidate
structural endpoint will reliably predict an effect on the clinical
outcomes of interest.
To clarify that this statement is referring to the use of a structural
endpoint as a primary outcome measure intended to serve as a
surrogate endpoint.
A clinical trial for a potential OA treatment product can measure
the “clinical outcome of interest” (e.g., improvement of pain and
reduced functional impairment) as the primary endpoint, in order
to achieve an indication for the treatment of osteoarthritis. In the
same trial, a structural endpoint may be independently measured
as a secondary endpoint in order to make support claims
regarding the disease modifying potential of the product. In this
case, the objective of improving clinical outcomes may be
independently demonstrated, and the validity of the structural
endpoint as an outcome measure would not need to be based on
evidence that the structural endpoint can predict an effect on the
clinical outcome of interest.
13 65
Strike the following:
To accept structural endpoints as valid outcome measures for
accelerated approval, there should be substantial confidence,
either based on empirical evidence from randomized, controlled
comparisons from clinical trials and/or based on a comprehensive
understanding of the disease process and product mechanism of
action, that an effect on the candidate structural endpoint will
reliably predict an effect on the clinical outcomes of interest.
This guidance is not only applicable for products which would be
reviewed using an accelerated pathway. The validity of an
outcome measure in a clinical study is not affected by the
approval pathway.
AdvaMed Comments on Draft Guidance on Osteoarthritis: Structural Endpoints for the Development of Drugs, Devices and Biological Products for Treatment
10/17/2018 Page 8 of 8 Docket Number FDA-2018-D-2896
Edit # ID # Change Reason
14 72 - 73
Strike and replace the following:
The ultimate goal of treatments related to inhibition of structural damage or targeting the underlying pathophysiology associated with OA is to avoid or significantly delay the complications of joint failure and the need for joint replacement, and also or to reduce the deterioration of function and or worsening of pain.
Although both endpoints: 1. Delay in joint failure/replacement and
2. reduction function/pain are clinically relevant and have a
degree of interdependency, the patient would benefit if either of
them is achieved independently. Hence it should be sufficient to
demonstrate that inhibition of structural damage or targeting the
underlying pathophysiology achieves improvement in one OR the
other endpoint.