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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request for comments on the draft guidance entitled, “Osteoarthritis: Structural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.

http://www.advamed.org/

Division of Dockets Management

October 17, 2018

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Given the extreme brevity and limited information in the draft guidance, we recommend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 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.




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.




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.




10 54


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


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.




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.




14 72 - 73


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.

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