re: docket no. fda-2015-d-4848; human factors … · as the device hf final guidance notes, human...

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May 3, 2016

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

RE: Docket No. FDA-2015-D-4848; Human Factors Studies and Related Clinical Study

Considerations in Combination Product Design and Development; Draft Guidance

for Industry and Food and Drug Administration Staff

Dear Sir or Madam:

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 treatment. Our members range from the smallest to

the largest medical technology innovators.

AdvaMed appreciates the opportunity to comment on the draft guidance entitled “Human

Factors Studies and Related Clinical Study Considerations in Combination Product Design

and Development.” Our general comments are set forth below, and our specific comments

are in the attachment.

The relationship between this and other guidance documents, regulations, and standards:

This draft guidance is meant to complement the recently issued guidance for medical devices

(“Applying Human Factors and Usability Engineering to Medical Devices: Guidance for

Industry and FDA Staff,” issued 2/3/16), referred to hereafter as the “Device HF Final

Guidance.” Since June 2011, industry has relied on this guidance in understanding how to

best apply human factors and usability engineering to our combination products. While we

are pleased to see the collaboration between the Office of Combination Products and the

Centers in preparing this guidance for industry on the special considerations for human

factors information submitted in investigation and marketing applications, we would like to

better understand the relationship between these guidance documents and what additional

information this new guidance provides above and beyond the Device HF Final Guidance as

well as other guidance documents and standards related to human factors. The two FDA

human factors guidance documents are redundant for combination products that are regulated

as devices. It is overly burdensome, for example, to require combination products to conduct

two different risk analyses and submit two different sets of data to FDA.

For combination products, much of the same principles for HF studies apply as for devices,

such as the planning process (identifying intended users and use environments before critical

task identification), the use of commercially-equivalent product in the summative study, and

the simulation of an actual use environment, including training if applicable. It was not

FDA-2015-D-4848

May 3, 2016

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apparent why a combination product should be managed differently or why the review

process for these studies should be any different than for a device. Many of the comments in

the attached address some instances where terminology in this guidance is defined differently

than in other documents, or where information found elsewhere could not be found in this

draft guidance. Closer alignment between this guidance and existing documents may help

prevent increase in time or duplication of efforts by both applicants and FDA, for example,

by increasing the scope, formality, and time for investigational and marketing application

reviews.

Considering human factors studies to be a type of clinical study:

The title of this guidance is “Human Factors Studies and Related Clinical Study

Considerations…” (emphasis added). This title and many other instances throughout the

document (e.g., line 22, “the guidance describes how Human Factors studies relate to other

clinical studies” or the use of the adjective “major” before “clinical study” throughout the

document) imply that a human factors (HF) study is another type of, or minor, clinical study.

As the Device HF Final Guidance notes, human factors data can be collected as part of a

clinical study, but a human factors study is not the same as, nor a type of, clinical study.

There are distinct differences between the objectives and endpoints of human factors or

clinical studies. Whereas a clinical study assesses the safety and efficacy/effectiveness of a

drug product or a device for a proposed indication, a HF study of a drug-device combination

product assesses the safety and efficacy of the user interface of a combination product

regardless of the safety or efficacy of the drug product or device. Unless HF data are

collected as part of a clinical study, a HF study does not use the same type of study materials

as does a clinical study: A clinical study involves the clinical use of actual active drug

products or finished devices whereas a HF study uses samples without active drug product or

active drug product use assessed without delivery to a human (e.g., use of an injection

training pad, an aerosol/spray delivery to a controlled space or a device without its drug

constituent part). Most importantly, a HF study has predetermined participant demographics,

may involve a range of user training conditions, and relies on HF behavioral experts to

observe task deviations, user errors, near misses/close calls, and operational difficulties, and

to conduct knowledge probes about them. These study elements are typically not possible in

clinical studies or home use studies.

The regulatory implication of considering a HF Study to be a clinical study is that, for any

device modifications validated with a HF study, filing supplements may be considered to be

efficacy Prior Approval Supplements, with longer review times and submission costs for

combination products regulated as drugs. Additionally, as implied in footnote 7 in the draft

guidance, to consider a HF study to be a type of clinical study would require a case-by-case

decision about whether PDUFA IV User Fees apply. We recommend that the final guidance

address the type of drug or device supplement appropriate for a device change that is

supported with HF study data in a combination product regulated as a drug.

FDA-2015-D-4848

May 3, 2016

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Concerns about recommendations for combination products that are more prescriptive than

similar recommendations for devices, and which shift the accountability for design control,

risk assessment, and change control from the applicant to the FDA:

We appreciate that the intent of this guidance to answer questions specific to combination

products, and, as described in the Introduction and Scope, to promote timely review of

combination products. We disagree, however, that the FDA should assume the responsibility

for reviewing design changes, determining whether HF studies are necessary, and

determining appropriate tasks and study users. We would like to see more emphasis on the

use of formative study results. Per 21 CFR Part 4 and 21 CFR §820.30(g), applicants are

already expected to make risk-based decisions that are most appropriate for their products

and target users and validate that the user interface of a combination product is effective via

testing under actual or simulated use conditions. By transferring this accountability from

applicants to the FDA, the FDA takes on an increased burden of time and responsibility for

making decisions, translating to a longer application review than necessary or what is

currently expected for devices.

Thank you for the opportunity to submit these comments.

Sincerely,

/s/

Sharon A. Segal, Ph.D.

Vice President, Technology and Regulatory Affairs

Attachment

ADVAMED COMMENTS “Human Factors Studies and Related Clinical Study Considerations in

Combination Product Design and Development”

Page 1 of 13

Line(s) No. – Line or lines numbers of the guidance

Change – Proposed change to the guidance

Reason – Reason/Rationale for proposed change

Line(s)

No. Change Reason

1. 1

Revise title of guidance to read as follows:

“Human Factors Studies and Related Clinical Study

Considerations”

See discussion in cover letter regarding the

implication of considering human factors studies to

be a type of clinical study.

2. 14

Limit the scope by exempting integrated combination

products that are regulated as devices.

Alternatively, clarify in Section B (line 155) that risk

analyses and human factors testing performed as part

of medical device design controls (21CFR part

820.30) are sufficient for human factors as well as

other risks for these types of combination products.

Integrated combination products such as drug-eluting

stents, heparin-coated cannulae and steroid-eluting

leads do not have human factors concerns that are

unique to combination products. Following the

standard FDA Guidance, “Applying Human Factors

and Usability Engineering to Medical Devices” and

compliance with medical device design controls in

21CFR part 820.30 are sufficient to address human

factors considerations for integrated combination

products that are regulated as devices, such as drug-

eluting or coated stents, cannulae and leads.

3. 22-23

Revise to read as follows:

“In addition, the guidance describes how HF studies

relate to other clinical studies.”




4. 37, 38,

109, 110

Revise title of listed guidance to

“Applying Human Factors and Usability Engineering

to Medical Devices. Guidance for Industry and

Food and Drug Administration Staff.” Also update all

footnotes that reference this guidance to have correct

Title listed is incorrect based on document associated

with link in guidance.



Page 2 of 13

Line(s)

No. Change Reason

title.

5. 65


“What is the role of HF studies as compared to other

types of clinical studies?”




6.

71,

footnote

7, last line

As applicable, FDA will determine whether a HF

study would meet these criteria.

Whether a HF study would meet these criteria

depends on whether the objectives, interventions, or

study materials are the same as those of a clinical

trial, for instance, if the study protocol involves

actual delivery (e.g., injection) of drug product or

placebo to humans.




7. 74


“maximizing the likelihood that of safe and effective

use of the device by the intended users will be safe

and effective for use by the intended users, for the

intended uses, and for the intended use environments.




8. 112


"1. Human Factors Study (or HF Study): A study of

human capabilities (physical, sensory, emotional, and

intellectual) and limitations to the design and

development of devices, systems, and environmentsA.

A HF study that assesses usability studies the

characteristics of the user interface that establish

effectiveness, efficiency, ease of user learning and

user satisfactionB. Other HF studies include heuristic

reviews, user inquiries, diary studies, and

ethnographic research. HF studies are conducted

The draft guidance’s definition of a Human Factors

(HF) study is narrower than the definition in the ISO

62366 standard (i.e., the ISO standard is inclusive of

more than just usability).



Page 3 of 13

Line(s)

No. Change Reason

with representative users..."

"A usability study HF study evaluates (i) the

ability..."

A ANSI/AAMI HE75:2009

B ISO/IEC 62366: 2007

9. 124, 131

Include in glossary definitions for the terms

"prototype" and "final finished" combination product

as follows:

Prototype: simple mock-ups, preliminary prototypes

or more advanced prototypes

Final Finished Product: initial production units, lots,

or batches, or their equivalents, manufactured using

the same methods and procedures expected to be used

for ongoing production. The studied samples must be

representative in use and risk to those of the expected

commercial product.

Align (or provide) definition of terms like “final

finished product” and “prototype” with those defined

in 21CFR Part 4 and § 820.30(g). “Final” might be

interpreted to mean the final design tested in Design

Validation or the final finished product that is

produced from a validated production line. "Final"

might also be confused with similar terms such as

"finished" device, considered per 21CFR Part 4 as a

device that is a constituent part of a combination

product. For the purposes of the phrase “or their

equivalents,” samples used in a HF Study can be

representative of a final finished device and still

undergo manufacturability changes that have no

impact on function as assessed in bench testing. (See

comment 10 below.)

10. 131-133

Revise to read as follows:“A study conducted to

demonstrate that the final finished combination

product user interface or representative training

materials can be used by intended users without

serious errors or problem, for the product’s intended

uses and under the expected uses, (Representative

training materials may be used in final validation of

the user interface.)”

These HF studies are typically occurring more than 1

year prior to market launch (given the typical review

cycle for a PMA) and might need to be repeated to

meet the requirement for actual training materials. In

addition, if testing of actual training materials are

required, future changes made to training materials

would need to have a regulatory assessment, possible

repeating of HF testing, and submission of PMA



Page 4 of 13

Line(s)

No. Change Reason

supplements. “Representative is reasonable and

consistent with the medical device HF guidance and

expectations for test articles for all other types of

testing. (See comment 9 above.)

11. 131

Revise definition of HF Validation Study to read as

follows:

“Human factors validation testing is generally

conducted under conditions of simulated use, but

when necessary, human factors data can also be

collected under conditions of actual use or as part of a

clinical study.”

Define “HF Validation Study” as is done in the

Device HF Final Guidance (Sec. 8). This definition

also distinguishes a HF study from a clinical study.

12. 131

Add new footnote to definition of HF Validation

Study(or HF Summative A

Study): A Human factors validation testing is sometimes

referred to as “summative usability testing.”

However, summative usability testing can be defined

differently and some definitions omit essential

components of human factors validation testing as

described in this guidance document.

The term “summative human factors study,”

commonly used in the industry, has been replaced

with “human factors validation study” here (and in

the Device HF Final Guidance); this change is

opposite to that made in the ANSI/AAMI/IEC 62366-

1:2015 standard, which replaced “usability

validation” with “summative evaluation.” Without

suitable explanation as to why these terms have been

chosen or that the terms are synonymous, there may

be potential for confusion.

13. 145


“…including required training programs”

To more closely follow the Device HF Final

Guidance, “training provided to the human factors

validation test participants should approximate the

training that actual users would receive” (Sec. 8.1.4);

trainers or additional materials accompanying an IFU

that would not be required to be used prior to using

the product, should not be required in a HF study.

Conversely, even if the proposed labeling indicates



Page 5 of 13

Line(s)

No. Change Reason

training is required, applicants who make a risk-based

decision not to include an untrained study group

should not then be mandated to include untrained

subjects, as has been our experience with

combination product HF studies.

14. 147-153


“3. MajorClinical Study (or MajorClinical Trial):

While HF validation testing is generally conducted

under conditions of simulated use, when necessary

human factors data can also be collected under

conditions of actual use or as part of a clinical studyA.

Human factors studies are not, however, a type of

clinical study. A clinical study (or clinical trial)

assesses the safety and efficacy of a drug product or

device for a proposed indication, whereas a HF study

assesses the safety and efficacy of the user interface

of a device or combination product.

ADevice HF/UE Final Guidance




15. 177

Section III.B.1 (identifying the critical tasks) should

occur after identifying users & use environments

(currently described in III.B.2.).

Describe the HF study planning process in the same

order as that conducted in typical development

practice, and as described in the Device HF Final

Guidance.

16. 179


“The use-related risk analysis should identify critical

tasks18

. Previously unidentified risks observed during

Human Factors formative studies should be included

in the risk analysis and may serve to identify

additional critical tasks. Critical tasks are user tasks

Applicants should be encouraged to conduct

formative studies to shape the design, risk analysis,

and identification of hazards and potentially critical

tasks and to revisit risk analysis results after a

formative study to help determine the need for and

scope of a HF Validation Study.



Page 6 of 13

Line(s)

No. Change Reason

that…. “

17. 194

Remove this example from the list and/or move to a

separate category: The user being able to safely

dispose of a used syringe. Failure to successfully

perform this task could result in needle sticks.

Applicants should use risk analysis to determine if

steps a user would follow independent of a particular

device (e.g. aseptic technique or standard disposal

practices) are considered critical.

18. 212

Add an additional bullet item

The user being able to appropriately work with a

software application that can affect the product

To include information related to the study of

combination products containing software

components

19. 221-222


“Intended users may be categorized into distinct user

groups by their different characteristics (e.g., use

responsibilities, tasks performed, age ranges, skills,

or experience levels)” or by different drug

indications, in the case of a drug-device combination

product.”

Similar to how the Device HF Final Guidance

identifies the dependence of usability on

"comorbidities (i.e., multiple conditions or diseases),"

we would like this guidance to point out that an

important characteristic of a user group, particularly

for a drug-delivery combination product, could be the

very disease state for which the product is indicated.

For example, if a hand-held device has been

approved for one indication but is going to treat a

new indication, a disease for which difficulty

grasping is a characteristic of users with that disease,

evaluating the validity of previous usability results

may be warranted.

20. 274

Add the following sentences after “…training.”19

” on

line 274:

”If you anticipate that most or all users would receive

minimal or no training, then the test participants in

the human factors validation test should not be

See comment on Line 145 above.



Page 7 of 13

Line(s)

No. Change Reason

trained.” Untrained subjects are not required if it has

previously been determined that untrained users will

have increased difficulty using the product.”

21. 304

Add to Section C a statement that indicates, in the

case that a design problem is solved and the formative

study verifies that the solution has mitigated a

potential user risk, applicants may conclude, in the

formative study report, that the design issue has been

solved and the design is ready for a summative study

(perhaps with a greater or different population of

users), or that no summative study is necessary if

applicable.







22. 312


“…clinical study, or after finalizing commercial

plans.). The study design should provide for the

identification of any unanticipated hazards or

unexpected use behaviors that were not previously

identified.”







23. 318


“…the results of HF Formative studies inform the

design of the final finished combination product and

are inputs to the initial risk analysis and identification

of critical tasks.







24. 319

Replace with: “Individual subjects who participate in

HF Formative studies may participate in the HF

Validation study but new participants should also be

recruited in order to avoid the potential for bias”








Page 8 of 13

Line(s)

No. Change Reason


25. 346

Move the following text to just before line 382:

“The study design should provide for the

identification of any unanticipated hazards or

unexpected use behaviors that were not previously

identified.”

This text is applicable to both types of Validation

studies

26. 362 Avoid use of “simulated” to define “actual-use”

study.

Using the term “simulated” to define “actual-use”

testing may be confusing in the attempt to

differentiate the terms “actual use,” “user study,”

(without the “HF” qualifier), and “HF Actual-Use

Validation Study.”

27. 369-380

Specify whether an actual drug would be used, and

whether it would be administered to a human.

Provide an example like that provided in the previous

paragraph.

Enhance description of an actual-use validation

study.

Helpful to avoid multiple interpretations by

applicants or the FDA as to how to interpret what

might be considered a “complex” product.

28. 369


“The other type of HF Actual-Use Validation study is

conducted in a real environment of use.”

Editorial -- Incomplete sentence, fragment, needs

clarification

29. 440-444

Revise to add footnote at the end of Line 444 as

follows:

“For the following two groups of combination

products, generally human factors data should be

submitted: (1) products for use outside the health care

environment or by laypersons (e.g., home-use

products, products for self-administration by patients

or lay-caregivers) and (2) combination products

Clarify which devices have a “constituent part”

requiring HF data. Suggest referencing the alternate

guidance document.



Page 9 of 13

Line(s)

No. Change Reason

having a device constituent part for which human

factors data should be submitted.[INSERT FOOTNOTE]

”

Footnote: “List of Highest Priority Devices for

Human Factors Review,” Draft Guidance for

Industry and Food and Drug Administration Staff

Feb 3, 2016.”

30. 441

Clarify the exclusion of OTC combination products

by adding a statement to the Introduction and Scope:

“This guidance does not apply to combination

products containing nonprescription drugs marketed

without an approved application (e.g., under a

monograph).”

The first group is combination products for use

outside the healthcare environment, such as at home.

Many types of OTC combination products which are

not reviewed in applications are used outside the

healthcare environment. Therefore, while the Scope

of this draft guidance does state that the focus is

combination products reviewed in an investigational

or marketing application, we recommend adding an

explicit exclusion.

31. 442

Provide further clarification on how an applicant

determines whether that device constituent requires

HFS data would be helpful, for example, by reference

to the Draft Guidance “List of Highest Priority

Devices for Human Factors Review.”

The second group is “combination products that

contain a device constituent requiring HFS data.”

Without this clarification, the second group appears

to overlap with the first group (line 441) since

combination products with a device constituent could

also be used outside the healthcare environment.

32. 440-447

Indicate (within the guidance or in the examples)

whether Design Validation data would be sufficient

for evaluating the usability of certain devices.

Clarify that a risk analysis should be completed for all

products (not just certain types).

For example, for products intended to be used by

medical professionals in a surgical setting (such as

surgeons, circulating/scrub nurses), Design

Validation may be sufficient.

Per QSRs, a risk analysis would be completed for all

combination products during development.

33. 444-445 Revise to read as follows:

“a risk analysis for the combination product should be





Page 10 of 13

Line(s)

No. Change Reason

completed following formative HF studies and the

use-related risks reviewed to assess the need for HF

Validation (Summative) studies (see section III.B). If

the use-related risk analysis identifies the need for HF

Validation (Summative) studies, then a HF Validation

studies study should be conducted and the results

submitted for review.”





34. 476-477


“based on the use-related risk analysis, applicants

should determine whether differences are sufficiently

obvious to obviate the need for an HF Validation

study may be necessary”

Provide option (but not requirement) to applicants

that if, in the course of the design and development

process, an Applicant determines there is ambiguity

about whether a HF Validation Study is required,

then Applicants can (but are not required) to seek

advice from the FDA via the meeting process.

35. 503-505


“Applicants should determine, via their risk analysis

procedures, whether However, design changes made

after HF Validation that relate to identified critical

tasks or may result in new use-related errors or

hazards that could lead to harm should have new HF

Validation study assessments.”







36. 516

Insert before line 516:

If applicants determine there is ambiguity about

whether additional HF testing is needed, they can

(but are not required) to seek advice from FDA.







37. 522-525


“If after When making a design change to a

combination product, applicants are unclear what

Adding a time-consuming step of preparing briefing

documents and scheduling/conducting formal

meetings is not feasible when design changes are



Page 11 of 13

Line(s)

No. Change Reason

FDA encourages applicants to expeditiously identify

the change plans and to discuss with the Agency the

types of HF and other clinical or non-clinical studies

that may be applicable, FDA encourages applicants to

review the changes with the Agency before the

applicant’s approval of the design changes are

validated.22

typical and frequent in the development process and

when there is already a process in place to manage

these changes. The request for a summary of changes

made to the device during the formative studies (i.e.

during device development) goes beyond the

information typically required by FDA in a device

submission. Development activities during the

iterative design process need not be reviewed as long

as the final device design is adequately supported by

verification and validation activities, including a HF

study. A comprehensive list and discussion of design

changes made in response to these historical studies

and design changes made for other reasons (such as

material or manufacturing changes), may be

burdensome and may not effectively explain why the

final design was chosen and studied in the HF

Validation Study.

38. 523-524


“HF, and other clinical studies, or non-clinical

studies”




39. 528-556

Remove or revise section IV.C

Or,

provide expected review periods more aligned with

IND review requirements in the event an applicant

determines an investigational application is the most

appropriate route for FDA review of a protocol.

Reconsider the expectation that the FDA review HF

information in an IND submission. In our

experience, FDA has routinely requested 3-4 months

for its reviews submitted in an IND information

amendment, and resolution of the FDA’s feedback

when received can and has taken additional months,

whereas IND applications with study protocols have

defined statutory FDA review periods of 30 days

wherein comments from FDA would be expected.

We would like to know if FDA is now planning to



Page 12 of 13

Line(s)

No. Change Reason

review HFS protocols in 30 days.

40. 546 Remove requirement to include “intend to market”

labeling.

Per the Device HF Final Guidance, we agree the user

interface of the products tested in the summative

study should represent the final design. However, the

requirement to include "intend to market" labeling

may not be feasible. Regulatory submissions for

combination products regulated as drugs are often

prepared months or years before a product is

launched, and changes may be made in labeling

between the investigational stage and commercial

launch. Applicants should then be able to make the

determination whether the label change warrants any

additional usability testing. Final labeling may not be

in place at such an early investigational application

stage since studies may not have been conducted to

develop them; if labeling is to be included in a HF

study, it may likely be draft labeling. Carton labeling

is not finalized until a product is submitted for

approval, and text font and placement is often revised

by FDA in its final review.

41. 573-574

Provide expanded guidance regarding when a human

factors study data can be leveraged for different

products.

We would like to see guidance for users who wish to

leverage HF study data between:

- products which utilize the same device component

but deliver different drug products

- product that undergoes minor device design

changes that do not impact usability

42. 583


“HF studies of a combination product are conducted

as part of the product design controls development

21 CFR Part 820.30 does not specifically require a

human factors study.



Page 13 of 13

Line(s)

No. Change Reason

process”)”

43. 586-591


“However, the HF Validation study is not sufficient

to establish the safety and effectiveness use of the

combination product for the proposed indication.”




44. 593-599

Add a comment that HF study could be, but is not

required to be, conducted in parallel or after a clinical

study.

The results of one study would not impact the other

as HF studies and clinical studies have different

measures and outcomes.

45. 596

In cases where HF data could be collected from a

clinical study, provide further guidance (than what is

stated here) regarding what methods are

recommended for collecting these usability data.




46. 602

Revise to read:

.” .. combination product may be adequate without

the inclusion . . . “

Editorial -- Missing the word “be.”

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