SMG 4101 (06/11/2018) 1 

SMG 4101

FDA STAFF MANUAL GUIDES, VOLUME IV – AGENCY PROGRAM DIRECTIVES

COMBINATION PRODUCTS

INTER-CENTER CONSULT REQUEST PROCESS

Effective Date: June 11, 2018

Change: November 13, 2023

1. Purpose

2. Scope

3. Background

4. Roles and Responsibilities

5. Procedures

6. Process Monitoring and Improvement

7. References

8. Effective Date

9. History

Attachment A - Inter-Center Consult Request 

Process Map

Attachment B – External Study: Combination 

Products Coalition

1. PURPOSE

The purpose of this document is to describe the procedures for when and how to 

request, receive, process, and track the progress of Inter-Center Consult Requests 

(ICCRs) between the Center for Biologics Evaluation and Research (CBER), Center 

for Drug Evaluation and Research (CDER), and Center for Devices and Radiological 

Health (CDRH). Henceforth, this will be referred to as the ICCR process. This SMG 

outlines the standardized ICCR process across the medical product Centers to 

enable efficient and effective collaboration.1

2. SCOPE

The ICCR process covers inter-center consults that occur between CBER, CDER, 

and CDRH for combination products and non-combination products.2 If staff have 

1 CBER, CDER, CDRH, and OCP also coordinate on regulations and guidance that pertain to 

combination products. See SMG 4103 Expectations and Procedures for Engagement among Medical 

Product Centers and Office of Combination Products on Regulations and Guidance Pertaining to 

Combination Products. 2 Combination products are defined in 21 CFR 3.2(e). The term Part 3 combination product (hereafter 

“combination product”) includes:
SMG 4101 (06/11/2018) 2 

questions about this document, they should contact their Center Product Jurisdiction 

Officers (PJOs) or the Office of Combination Products (OCP).

In addition to describing the ICCR process, this document describes:

• Roles and responsibilities for the Lead Center, the Consulted Center(s), and 

OCP;

• The process for determining if an inter-center consult is needed;

• Critical steps in the ICCR process; and

• Standard critical elements to be included in a consult request.

3. BACKGROUND

Consultation with another Center may be needed for the review of a product. Such 

consultation between Centers, for example for premarket applications3 or in 

postmarket, may occur when a unique aspect of a product’s indication, formulation, 

design, or performance raises concerns that require review by another Center, or 

when the expertise to review a particular aspect of the product resides in another 

Center. In such instances, a consult is requested by one Center to another. This 

ensures a comprehensive review of the product.

In 2015, an external study (Attachment B) identified the need for a comprehensive 

strategy for managing combination product review and underscored the importance 

of cross-center collaboration. This study highlighted issues that had the potential to 

delay approval. The findings of the external study were confirmed by an internal 

(1) A product comprised of two or more regulated components, i.e., drug/device, biologic/device, 

drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and 

produced as a single entity;

(2) Two or more separate products packaged together in a single package or as a unit and comprised of 

drug and device products, device and biological products, or biological and drug products;

(3) A drug, device, or biological product packaged separately that according to its investigational plan or 

proposed labeling is intended for use only with an approved individually specified drug, device, or 

biological product where both are required to achieve the intended use, indication, or effect and where 

upon approval of the proposed

product the labeling of the approved product would need to be changed, e.g., to reflect a change in 

intended use, dosage form, strength, route of administration, or significant change in dose; or

(4) Any investigational drug, device, or biological product packaged separately that, according to its 

proposed labeling, is for use only with another individually specified investigational drug, device, or 

biological product, where both are required to achieve the intended use, indication, or effect.

3 For purposes of this SMG, unless otherwise stated, the term premarket application includes 

investigational new drug application (IND), new drug application (NDA), abbreviated new drug application 

(ANDA), investigational device exemption (IDE), premarket approval application (PMA), premarket 

notification (510(k)), humanitarian device exemption (HDE), biologics license application (BLA), request 

for classification submitted under section 513(f)(2) of the Federal Food, Drug, and Cosmetic Act (De Novo 

request), presubmissions (e.g., pre-NDA, Q-submission) or supplements/amendments to any of these 

applications (as applicable).
SMG 4101 (06/11/2018) 3 

study. A comprehensive assessment revealed several opportunities for improvement 

related to combination product review processes.

To address the issues identified in the studies and facilitate inter-center interactions, 

FDA developed and piloted a new ICCR process for premarket combination product 

review beginning in August 2016. The objectives of the pilot were to improve intercenter coordination for combination products and enhance the timeliness and 

consistency of inter-center reviews. Based on outcomes of the pilot and internal 

stakeholder feedback, the new process was implemented throughout CBER, CDER, 

CDRH, and relevant groups in FDA’s Office of the Commissioner (OC), and the 

process was expanded to all inter-center consults. The process outlined in this SMG 

is based upon the results of the pilot and addresses the mandate in Section 3038 of 

the 21st Century Cures Act to ensure timely and effective review that involves more 

than one Agency Center.

4. ROLES AND RESPONSIBILITIES

A. Lead Center: The Center that has primary review responsibility for the product. 

This Center is responsible for identifying early in the review process whether the 

application or product issue necessitates an inter-center consult.4

B. Lead Center Consult Requester: The person in the Lead Center who fills out 

and submits an ICCR. The consult requester serves as the administrative point of 

contact for the consult request (e.g., location of review materials) and when 

additional information is needed from the external stakeholder 

(sponsor/applicant/manufacturer).

C. Lead Center Submission Contact: The person(s) in the Lead Center who 

serves as the point of contact for technical questions regarding the application or 

issue. The Lead Center Submission Contact and the Lead Center Consult 

Requester may or may not be the same.

D. Consulted Center: The Center that will provide the necessary expertise to the 

Lead Center. After the consult is completed, the Consulted Center is responsible 

for closing out the ICCR.

E. Consulted Center Receiver: The person(s) in the Consulted Center who is 

assigned to receive ICCRs (e.g., by monitoring a specific email inbox) and assist 

with triage and reviewer assignment within the Consulted Center.

4 To aid in determining whether an Inter-Center consult is needed for certain combination products, 

agreements between the Centers exist that outline circumstances when a consult is or is not needed. 

When the Lead Center is unsure whether a combination product is covered by such an agreement, the 

Lead Center should contact its PJOs for a determination. In addition, when a combination product is not 

covered by any agreement and the Lead Center is considering not issuing a consult, the Lead Center 

should consult its PJOs, who should work with the relevant Center(s) to determine whether a consult is 

necessary.
SMG 4101 (06/11/2018) 4 

F. Assigned Consulted Center Reviewer: The person in the Consulted Center 

who is assigned to conduct the review and provide a review memo or other 

deliverable in response to the consult request.

G. Center Product Jurisdiction Officers (PJOs): The contact(s) within each 

Center for product classification, Center jurisdiction, and combination product 

information. The PJOs also serve as administrative support for Center 

stakeholders using the ICCR process.

H. Office of Combination Products (OCP): The Agency office that administers the 

overall ICCR process and assists the Centers, when needed. For combination 

products, OCP oversees the statutory requirements for coordinating inter-center 

reviews by overseeing the timeliness of premarket reviews and the alignment of 

Centers’ feedback to industry. OCP may serve in the same capacity for noncombination products, typically at the request of Centers.

5. PROCEDURES

The figure in Attachment A illustrates the general flow of the ICCR process, including 

the specific roles and responsibilities of the Lead Center, Consulted Center, and 

OCP. OCP and each Center's PJOs are resources for Center staff regarding the 

ICCR process. The Center PJOs should typically be contacted first for questions 

related to whether a product is a combination product, for assistance in identifying 

the appropriate Consulted Center Receiver, or for questions related to a Center’s 

internal process for managing ICCRs. Center PJOs will engage OCP when needed 

in these discussions.

The ICCR process in brief is as follows:

a. Identify the product as a combination product or a non-combination 

product (Lead Center)

This should be done within the first few days of the receipt of the application 

or issue and, when applicable, documented within the Lead Center’s records 

system. 

b. Identify need for expertise and initiate consult (Lead Center)

The specific expertise needed for the consult, where that expertise resides, 

and the complexity of the request dictate the process for the request (see 

section d. below). Every effort should be made to identify the need for a 

consult as early in the review process as possible.5 The Lead Center should 

provide the Consulted Center adequate time to complete the review while still 

ensuring that necessary due dates are met (e.g., any user-fee goal dates 

associated with the submission). OCP participation in discussions may be 

5 Staff should refer to internal process documents for specific timelines.
SMG 4101 (06/11/2018) 5 

requested directly by the external stakeholder or by either the Lead or the 

Consulted Center(s).

c. Draft/prepare consult request (Lead Center)

At a minimum, the Lead Center Consult Requestor should include the 

following information in an ICCR to enable the Consulted Center to efficiently 

assess the scope of the request and identify appropriate reviewer(s):

i. Application and product information (application number and type (if 

applicable); product name(s); indications for use; and description of the 

product(s));

ii. Specific questions for which expertise is being requested and what is 

needed (i.e., deliverables being requested) from the Consulted Center;

iii. Location of review materials (e.g., links to electronic documents) and 

specific details on where the question/relevant product information can be 

found (sections, page numbers, etc.);6

iv. Requested due date for the Consulted Center’s review or other 

deliverable, established to allow Lead Center to meet applicable user-fee 

commitments or other Center or Agency policies or requirements;

v. Any known interim milestones before consult completion (e.g., internal 

meetings, external stakeholder meetings, interactive review due dates, 

filing decision dates, draft memos, slides, minutes) for which feedback or 

participation from the Consulted Center may be needed; and

vi. Contacts (e.g., Lead Center Submission Contact) for the Consulted Center 

to follow up with if additional information is needed.

d. Submit consult (Lead Center)

i. For routine consults,7 the consult request is sent to the relevant Consulted 

Center Receiver. OCP maintains a list of Consulted Center Receivers 

accessible to all staff. If the Lead Center Requester has questions about 

the Consulted Center Receiver, he/she can contact the Lead Center PJOs 

for assistance.

6 When access to electronic systems and databases is needed to complete a consult review, the process 

to gain access to the Lead Center’s electronic systems and databases should be expedited. Staff with 

questions about such access may contact their PJOs or OCP.

7 A routine consult is one in which Lead Center staff knows which group(s) in the Consulted Center 

has/have the desired expertise. One application or issue may require multiple routine consults within the 

same Consulted Center (e.g., separate consult requests issued for facility inspection, clinical, and/or 

product design considerations).
SMG 4101 (06/11/2018) 6 

ii. For non-routine consults,8 ICCRs are initially sent to OCP. Prior to sending 

such a consult request to OCP, the Lead Center Requester should contact 

their Center PJOs for assistance. OCP schedules and coordinates a 

consult orientation meeting with the Lead Center and potential Consulted 

Center(s). During the consult orientation meeting, the Centers and OCP 

will discuss what expertise from the potential Consulted Center(s) is 

necessary for review of the product and/or issue.

After the consult orientation meeting, the Lead Center will submit any 

necessary consult requests to the identified Consulted Center(s) as discussed 

during the orientation meeting. Once all necessary ICCRs are submitted, the 

process and engagement between Centers follow that of a routine consult, 

outlined below.

e. Assign reviewer (Consulted Center)

Upon receipt of an ICCR, the Consulted Center Receiver assigns a reviewer 

in the ICCR electronic tracking system, which will automatically notify the 

Lead Center of the reviewer assignment. If an assigned reviewer cannot 

address all the questions in the consult request or if an ICCR has been sent 

to the wrong Consulted Center Receiver, the Consulted Center should 

expeditiously communicate the issue to the Lead Center so that the ICCR can 

be reassigned or redirected.9

Assigned reviewers from the Consulted Center are considered members of 

the Lead Center review team. The Lead Center will inform assigned reviewers 

from the Consulted Center of the other review team members. The Lead 

Center will invite assigned reviewers from the Consulted Center to internal 

and stakeholder meetings. Their supervisors may also be invited to these 

meetings.

f. Consult review (Consulted Center)

The scope of the Consulted Center’s review should include the specific 

requests from the Lead Center and be limited to these requests. If a 

Consulted Center believes there are additional review considerations for 

which the Lead Center did not request a consult and for which the Consulted 

Center has expertise, the scope of the consult should be discussed with the 

Lead Center. If the Lead Center determines that additional expertise is 

8 A non-routine consult is any consult where another Center’s input is needed, but the interaction is not 

straightforward. Non-routine consults typically occur when the scope of the consult is large/complex (e.g., 

multiple groups may need to interact), or when novel products or issues that present challenging 

questions regarding the scope or content of the consult or groups that may need to provide input are 

involved.

9 Staff should refer to internal process documents for specific details and timelines.
SMG 4101 (06/11/2018) 7 

necessary to inform the regulatory decision-making process, then additional 

consult requests may be issued.

The Lead Center is responsible for communication with the external 

stakeholder in accordance with the Lead Center’s processes. This includes 

sending requests on behalf of the Consulted Center for additional information 

or clarification to the external stakeholder. The Lead Center should 

expeditiously notify the Consulted Center when the response is received. The 

Consulted Center’s review of the information obtained does not require a new 

ICCR and should be incorporated into the final deliverable provided by the 

Consulted Center. New ICCRs are required for review of responses in a 

resubmission after an action has been taken (e.g., Complete Response, 

major deficiency).

User-fee and other goals are commitments that apply to the entire Agency. 

Therefore, the Consulted Center and its Assigned Reviewer(s) should make 

every effort to meet the consult due date identified by the Lead Center to 

ensure that goal dates are met. If the Consulted Center anticipates that a due 

dates will be missed, the Consulted Center must notify the Lead Center to 

discuss alternatives as soon as possible and, as necessary, update the ICCR 

with a new due date.

g. Complete consult (Consulted Center)

Centers may choose to interact with each other on draft or informal work 

products prior to finalizing the consult, and this can be done on an as-needed 

basis. Final deliverables (e.g., final written review, response to meeting 

questions) should go through appropriate signoff procedures within the 

Consulted Center before being provided to the Lead Center. Assigned 

Consulted Center Reviewers are responsible for ensuring their management 

has appropriate documentation to ensure timely signoff (e.g., application, 

previous consulting reviews) by the requested consult due date. Once the 

consult is complete, the Consulted Center sends the final deliverable to the 

Lead Center and closes out the ICCR in the ICCR electronic tracking system.

h. Incorporate consult (Lead Center)

If the Lead Center accepts the Consulted Center’s consult recommendation, 

the Lead Center incorporates the recommendation in developing 

communications with the external stakeholder, determining application 

approvability, or taking other FDA action. If the Lead Center disagrees with 

the recommendations, it should reach out to the Consulted Center to discuss 

the disagreement prior to taking a regulatory action. If disagreements cannot 

be resolved, see i. below.
SMG 4101 (06/11/2018) 8 

Copies of any communications with the external stakeholder (e.g., minutes, 

action letters) that are related to or result from the consult should be sent 

electronically to the Consulted Center in a timely manner.

i. Informal and Formal Dispute Resolution (Lead and Consulted Centers)

If the Consulted Center feels that rejection of information provided in a consult 

will affect the assessment of safety, efficacy, and/or quality of the product 

under review, it is encouraged to try to resolve these disagreements 

informally at the inter-center review team level and continue through the next 

level signatory if agreement cannot be reached. The outcome of any such 

discussions should be documented in the administrative record of the 

application. If the Lead Center and Consulted Center(s) cannot resolve the 

difference of opinion informally, the cross-center scientific or regulatory 

dispute resolution process may be initiated (see SMG 9010.2 Cross-Center 

Dispute Resolution at the FDA).

j. Archive consult (Lead Center)

The Lead Center is responsible for archiving the final deliverable from the 

Consulted Center (e.g., written consult memorandum) in the appropriate Lead 

Center administrative file. The Lead Center is also responsible for confirming 

that the combination product code in the Lead Center systems and databases 

appropriately reflects the type of combination product (see 5.a. above).

Communication between staff in the Lead and Consulted Centers should be 

frequent. Informal communication should ideally occur on a one-to-one basis 

between review staff, without the need for prior supervisory approval. For 

complex products and development programs, the Lead Center should 

schedule additional planning meetings as necessary to ensure an efficient 

review process. Such communications may involve discussion of updates to 

the product application, information requests to and from external 

stakeholders, attendance and discussions at milestone/review meetings, and 

interim review findings, among others.

6. PROCESS MONITORING AND IMPROVEMENT

OCP will maintain centralized resources on the Agency intranet for staff, including 

training materials on the ICCR process. OCP and the Centers will periodically review 

and update these resources as needed. The Centers will ensure that established 

timelines for ICCR activities are clear and predictable and will communicate target 

timelines for identifying the need for an inter-center consult, submitting a consult 

request, and assigning a reviewer for the consult.

Quantitative and qualitative data will be collected by OCP and the Centers to 

evaluate the need for process improvements. Data collected may include:
SMG 4101 (06/11/2018) 9 

 

• Number of inter-center consults requested;

• Circumstances under which consults are needed for combination products;

• Timeliness of consult interactions, as compared to any established benchmarks 

(e.g., time from application receipt to consult request submission, time from 

consult request submission to reviewer assignment);

• Input on ICCR format and usability (e.g., through staff feedback, audits, 

monitoring users request for assistance with ICCR tasks); and

• Quality of the consult requests or reviews (e.g., through staff feedback, audits, 

collection of user complaints).

OCP will periodically review ICCR data and conduct additional assessments (audits, 

etc.) as needed to ensure the ICCR process supports timely, consistent, and 

effective review of combination products.

7. REFERENCES

U.S. Food and Drug Administration. Combination Product Review Inter-Center 

Consult Process Study. April 17, 2015. Available at: 

http://www.fda.gov/downloads/CombinationProducts/GuidanceRegulatoryInformatio

n/UCM467128.pdf. Accessed October 31, 2016.

8. EFFECTIVE DATE

The effective date of this guide is June 11, 2018.

9. Document History – SMG 4101, “Inter-Center Consult Request Process” 

STATUS 

(I, R, C)

DATE 

APPROVED

LOCATION OF 

CHANGE 

HISTORY

CONTACT

APPROVING 

OFFICIALS

Initial 7/31/02 N/A N/A Steering Committee:

J. Morrison,

K.Cook,

S.Lard,

H. Rosecrans

S. Unger

Center Directors:

K. Zoon

J. Woodcock

D. Feigal

Revision 2/14/03 Added interim 

procedures for 

M. Kramer D. Feigal

J. Goodman
SMG 4101 (06/11/2018) 10

STATUS 

(I, R, C)

DATE 

APPROVED

LOCATION OF 

CHANGE 

HISTORY

CONTACT

APPROVING 

OFFICIALS

combination 

products tracking; 

Modified IRCR 

Form to denote 

type of product

J. Woodcock

M. Kramer

Correction 7/1/03 Updated fax 

number of Office of 

Combination 

Products

M. Kramer New approval not 

required; technical 

correction to OCP fax 

number only

Correction 6/18/04 Updated fax 

number of Office of 

Combination 

Products

M. Kramer New approval not 

required; technical 

correction to OCP fax 

number only

Revision 6/11/18 Substantive 

revision of entire 

document to reflect 

revised inter-center 

consult process.

Office of Combination 

Products (OCP)

combination@fda.gov

Jonette Foy, Associate 

Director for Policy, CDRH

Diane Maloney, 

Associate Director for 

Policy, CBER

Thinh Nguyen, Office 

Director, Office of 

Combination Products

Douglas Throckmorton, 

Deputy Center Director 

for Regulatory Programs, 

CDER

Rachel Sherman, 

Principal Deputy 

Commissioner

Change 11/13/2023 Attachment B Office of Combination 

Products (OCP)

combination@fda.gov

James Bertram, Director

OCP
SMG 4101, Attachment A - Inter-Center Consult Request Process Map
1227 25th St. NW

Suite 700

Washington, DC 20037

combinationproducts.com

202.861.1881

Improving Patient Care through Better Combination Product Regulation 

Recommendations to FDA Centers from the Combination Products Coalition 

May 23, 2014 

Executive Summary: Combination product regulation is at a crossroads. To ensure it proceeds 

on the right path – one that improves the public health by promoting innovation – reforms are 

needed to: 

(1) Improve coordination among FDA participants in combination product reviews (i.e., 

Divisions, Offices, and Centers); 

(2) Improve communication with sponsors; and 

(3) Improve scientific and regulatory justifications supporting Agency data requests to 

ensure optimal decision-making that facilitates patient access to new and better therapies. 

Among the areas that would benefit from these reforms is the usability testing review process, 

where innovators have observed significant shifts in requirements over the last few years. The 

problems that innovators have had with usability testing requirements have their origin in different 

philosophies among Centers – specifically, CDRH generally favors simulated-condition “human 

factors” testing to evaluate product usability, whereas CDER increasingly favors “actual use” 

testing that (1) is more likely to delay patient access to therapies, and (2) often provides little or 

no benefit over the information gained through human factors testing. However, issues with 

communication, coordination, and justifications provided with requests, are transforming 

philosophical differences into impediments to innovation and creating patient access issues. 

Appendix A presents a case for usability testing that emphasizes human factors testing, 

which is generally considered the best approach to assess combination product usability and its 

impact on safety and effectiveness. Appendix A also addresses those aspects of coordination, 

communication, and scientific justification that should be improved. To that end of improving the 

regulatory system, and thereby improving patient access to innovative new therapies, we 

recommend that FDA: (1) Adopt traditional, simulated-use human factors testing as the policy for 

combination product testing across Centers; (2) Develop and implement an Agency-wide policy 

that allows bridging of combination products that use different injectors (e.g., prefilled syringe and 

pen injector) – but the same liquid injectable drug, dose, and route & process of administration –

based on nonclinical testing and human factors studies; (3) Require human factors validation 

testing only with participants from the indicated patient group (or an appropriate surrogate group) 

for the combination product; (4) Provide sponsors with comments from all reviewers in all Centers 

before human factors validation studies commence.

 
1227 25th St. NW

Suite 700

Washington, DC 20037

combinationproducts.com

202.861.1881

Introduction 

Over the last few years, manufacturers (innovators) have run into unexpected regulatory 

road blocks when pursuing combination product approvals. Ad hoc FDA data requirements and 

surprising requests during the latter part of Agency reviews are keeping medically significant 

product enhancements and better therapies out of physicians’ and patients’ hands. If this 

continues, innovation will decline to the detriment of the public health. But with some reasonable 

improvements, FDA can change direction and put combination product regulation on the right 

path. 

 The Combination Products Coalition (CPC) has made attempts in the past to support the 

FDA in making improvements to these regulations, but these efforts have not resulted in the 

improvements that are needed. These efforts are evidenced in the proactive submission of 

documents prepared by the CPC, such as the CPC – drafted guidance document regarding “FAQs 

on Pre-Clinical and Clinical Research on Combination Products” submitted in February 2009, the 

Human Factors Matrix submitted in December 2012, and the Labeling Matrix submitted in April 

2013. Additionally, the Office of Combination Products and the CPC hold an annual meeting to 

review ongoing activities and priorities of both organizations. During these discussions, the CPC 

routinely offers to provide assistance to the FDA in driving these priorities. The CPC commits to 

support the FDA in implementing the recommendations contained herein, to the extent possible.

 

In the following pages, the Combination Products Coalition (“CPC”) explores the problems 

innovators are now facing during the FDA review process. We start by summarizing key results 

of an innovator survey and interviews that were recently completed by the CPC and conclude with 

general suggestions for improving the regulatory process. We also include, as an Appendix to this 

paper, a detailed analysis of specific problems innovators face with usability testing, and suggest 

improvements FDA can make which will help assure the safety, efficacy, and availability of 

combination products. We call out usability testing in the Appendix because it represents perhaps 

the single largest trouble spot in combination product regulation today in terms of delaying access 

to important new products for patients. 

We hope, as you read this paper, you will come to appreciate the importance of setting 

combination product regulation on the path towards increased growth, innovation, and safety, 

particularly with respect to usability testing. The CPC has been heavily involved with combination 

product regulatory issues for over a decade, and our members have deep roots in both device and 

drug regulation dating back decades more. Our consensus is that the problems innovators are 

facing today with usability testing exceed anything we have seen previously and that resolving 

these issues must be made an Agency priority. We hope to work with you in the coming months 

to set regulation on the right path, and allow patients to benefit from more innovations. 
3

II. CPC Survey Results 

During March-April 2014, the CPC conducted an online survey of combination product 

innovators. Survey respondents had cumulative experience with more than 80 separate 

combination product marketing applications. 

Five results from the survey stood out – three related to regulatory review process 

problems, and two quantifying delays and costs that are associated with these problems (which 

translates to delaying or otherwise limiting patient access to therapies). These results are 

summarized in Table I, and illustrate the pervasiveness of the difficulties innovators face, and the 

significant consequences these difficulties have on research and development.

Table I: Key Survey Results

Regulatory Process Problems that Delay

Patient Access to Combination Products

Quantitative Impact of Process Problems 

on Combination Product Development

 100% of respondents stated that they had 

experienced problems with combination 

product regulation during Agency reviews.

 80% of respondents stated that significant 

problems were caused by “surprise” 

requests made late in the review cycle. 

 50-85% of respondents stated that when a 

conflict arose with a Center around a 

combination product issue, the Center 

would communicate its position without 

offering scientific and regulatory support 

for its position.

 70% of innovators reported delays as the 

result of problems during combination 

product reviews. These delays ranged 

from 1-3 months (15%) to 6-12 months 

(25%) to 12+ months (33%).

 Survey participants said that the problems 

with combination products resulted in 

significant consumptions of human 

resources to resolve combination product 

problems. Sponsors noted that to solve 

problems, they needed to expend:

o “Effort=thousands of man-hours; 

Cost=hundreds of thousands USD”

o “Too many hours to count”

o “A team of 5 people of a label change, 

3 months incl. review – net time: 9 

man months plus scrapped material”

o “A team of 15 people for redoing a 

usability study for color 

differentiation, 8 months incl. review –

net time: 3-5 man years”

o “Ballpark - $150K” plus “1500 FTE 

hours of employee time.”

o “~5-10% additional effort over that of 

a traditional NDA/BLA submission”
4

IV. Interviews 

To learn more about the origins of the problems unearthed in the survey, we conducted 

follow-up interviews with willing survey participants to discuss the kinds of issues they 

encountered. From these interviews and the survey we identified three interrelated root causes for 

the process problems: 

 A lack of coordination and consistency between FDA groups, both across Centers and 

within Centers; 

 A lack of timely communication with sponsors (e.g., groups within FDA getting involved 

in reviews late in the process, and completing reviews later than expected); and 

 The absence of adequate scientific and regulatory justifications for decisions, which may 

reflect communication issues (i.e., FDA is not providing sufficient explanations) or 

substantive issues (i.e., FDA is not reaching scientifically supportable conclusions). 

Many companies had similar stories about reviews that went awry, often well into the FDA review 

process. Some also expressed strong belief that there was significant value in Agency input, but 

that the value often was diminished as the result of coordination and communication problems 

(e.g., Agency units reaching contradictory conclusions on requirements, or communicating 

differences in opinion after extensive investment in development). In the following sections, we 

present some of examples of what we were hearing in italics and summarize the root causes 

associated with each to illustrate the problems and their origins.

Example 1: A Surprise during a Combination Product Review 

A sponsor is navigating the approval process for a combination product, and conducts 

several human factors formative studies (early stage “stress testing” to evaluate subjects’ use of 

the device and labeling to identify areas for improvement). The sponsor then:

 Submits its formative study data and proposed labeling from FDA, and receives feedback 

from CDER division reviewers, Division of Medication Error Prevention and Analysis 

(DMEPA), and CDRH; 

 Conducts additional formative studies based on that feedback and provides the results to 

FDA along with a revised instructions for use (“IFU”) and a summative (final) study 

protocol to validate the use of the final device and labeling; and after receiving apparent 

agreement with the approach 

 Conducts a summative (final) study in accordance with the protocol to validate its IFU,

and submits what it believes are good results to FDA. 

After conducting its summative study, another group within CDER that had not been 

involved with the review to that point – the Division of Medical Policy Programs (“DMPP”) –

recommends significant revisions to the IFU. The specific reasons for the recommendations are 

not provided, and FDA does not provide substantive guidance on next steps the sponsor should 

take. Unfortunately, a sponsor who took great care to ensure the usability of its device, and

worked diligently with FDA throughout to incorporate Agency input, was sent back to the 

drawing board based on late input from a different group, and was left with more questions than 

answers. 
5

What went wrong? 

 Lack of Coordination: The sponsor did its due diligence, conducted studies, worked 

collaboratively with FDA throughout. However, there was a lack of coordination between 

DMPP and other reviewers, which led to an unexpected change in Agency position very 

late in the review process. Simply including DMPP early in the process would have allowed 

its recommendations to be addressed in early stage formative studies, and may have 

avoided all of the problems. 

 Lack of Communication: There were at least three groups within CDER, plus CDRH, 

involved in this review. It was the responsibility of these groups to adopt a single “FDA” 

policy and to communicate that to the innovator early enough so it could address the 

position by, e.g., revising its IFU before summative testing began. 

 Lack of Justification: The sponsor conducted several studies to develop an IFU with input 

from multiple Divisions at multiple points, and then conducted an extensive summative 

validation study which showed good results. In light of this, a significant shift in position 

based on the DMPP review should have been accompanied by a very detailed rationale 

from FDA explaining the need for changes.

Example 2: Ineffective Meetings with FDA 

A. A sponsor schedules a meeting to discuss a combination product review with CDRH 

and CDER. CDRH is supposed to provide CDER with an evaluation of a data package 

a few days prior to the meeting, CDER reported in the meeting that CDRH only recently 

provided their comments on the package to CDER. Having not had time to review 

CDRH’s evaluation, CDER refuses to answer any questions relating the issues, making 

the meeting fruitless. 

What Went Wrong? 

 Lack of Coordination: The Agency should be prepared to speak to development issues 

on which it agreed to meet. Better coordination between CDER and CDRH could have 

prevented the problem. 

B. In another instance, a sponsor schedules a meeting to discuss a summative human factors 

study protocol. The CDER project manager is not able to tell the sponsor which different 

groups at FDA are involved in the review, forcing the sponsor to (a) figure out who is 

participating in the review (which it does through individuals outside of FDA), and (b) 

request their attendance at the meeting. The sponsor proceeds as best it can, and learns 

shortly before the meeting that of the five (5) different groups at FDA evaluating the 

protocol, a crucial individual from one group was missed and not specifically invited to 

attend (when the sponsor discusses with other people within the Agency they confirm that 

person was essential, and do not understand why they would not be invited). The sponsor 

then needs to scramble to make the meeting meaningful by getting everyone in the room.
6

What Went Wrong?

 Lack of Coordination: The Agency should have been sufficiently coordinated to bring 

the right people to a meeting without putting the responsibility on the shoulders of the 

sponsor to identify those right people.

 Lack of Communication: The Agency should have shared who should attend the 

meeting with the sponsor. 

Example 3: Unexplained Requests 

A. A sponsor consults CDRH regarding requirements for usability testing for a combination 

product and is told that standard human factors studies would be sufficient (e.g., 

recommendations from “CDRH Guidance: Medical Device Use-Safety: Incorporating 

Human Factors Engineering into Risk Management”); studies are conducted and deemed 

acceptable by CDRH. The sponsor then receives a request for actual use testing from 

CDER. The sponsor explains why actual use testing is not necessary – past experiences 

with these kinds of devices and success of human factors testing, the inability to separate 

out user risk from other risks with actual use studies, etc. CDER responds that it disagrees 

with the sponsor’s and CDRH’s position, but does not address the merits of the sponsor’s 

arguments.

What Went Wrong?

 Lack of Justification: Human factors testing is a science that has developed over 

decades to assess the usability of products and identify potential failure modes to 

mitigate the risks they cause. In light of this, the substantive arguments made by the 

sponsor, and the fact that CDRH reached a different conclusion regarding the need for 

actual use testing, a detailed justification for CDER’s disagreement should have been 

provided. 

B. A sponsor conducts formative studies with trained and untrained users; untrained users 

are included to “stress test” the use of the product, and develop the best possible labeling 

prior to conducting a summative study to validate the product and its labeling. The sponsor 

designs a summative study which includes trained users only, as training is one of the 

conditions prescribed by the proposed labeling. CDER insists that an untrained arm be 

included in the trial, although the value of including the arm at this stage of development 

is unclear. CDER offers no explanation for its request. 

What Went Wrong? 

 Lack of Justification: Under the Food, Drug, and Cosmetic Act, FDA is required to 

judge products for approval under the conditions “prescribed, recommended, or 

suggested” in proposed product labeling. The sponsor in this case recognized the need 

for training, and included a training requirement as one such condition. Thus, although 

inclusion of untrained users in formative studies was valuable in developing data and 

designing training, their inclusion in a summative study was unnecessary. 
7

V. Recommendations 

As illustrated above, combination product innovators have had several problems 

navigating the path to product approval. Unfortunately, these problems delay access to innovative 

therapies that help patients and improve the public health. These are not problems with the 

products themselves. 

What should FDA do to improve the situation? At a high level, the following steps would 

make a substantial improvement to the regulatory process for combination products by directly 

addressing the three root causes above. The CPC is available to assist, to the extent possible, in 

implementing these recommendations. 

1. Improve Coordination within FDA. FDA should improve its internal coordination to 

ensure consistent decision-making. The Agency should develop cross-Center policies for 

issues impacting combination product regulation (like usability testing), so the different 

groups are coordinated as much as possible in advance. 

In addition, the Agency should ensure that groups involved in the review across all Centers 

work together from the start. There should be specific time points that all groups are 

required to provide input to a single FDA position on each issue (as opposed to several 

different Center, Office, or Division positions) reached shortly thereafter. To facilitate this 

process, we recommend having a single team leader who is responsible for collecting all 

feedback from all the groups within the Centers, and who is responsible for ensuring that 

the Agency develops a single coordinated response at each stage of review. To the extent 

that the groups do not see eye to eye, the team leader must have the authority to bring 

together the parties and develop a single FDA position. Given the role of the Office of 

Combination Products (OCP), CPC respectfully suggests that this role might naturally 

reside within OCP, provided that they are given the authority to ensure interCenter 

coordination. However, CPC acknowledges that it is the Agency’s prerogative to decide 

the proper location and authority of this important team leader position. 

2. Improve Communication with Sponsors. Once the different groups within FDA are 

coordinated, they will need to communicate with sponsors. Communication includes 

guidance and regulations (general communications to all sponsors addressing standards 

and procedures related to product development and approval) and also communications 

with individual sponsors during product development and review. In all instances guidance 

must come from the three Centers (CDER, CDRH, and CBER) and OCP to ensure every 

Center recognizes and follows the guidance or provides reasonable justification for 

deviations from the guidance. Recommendations made to individual sponsors must reflect 

unified FDA positions developed through intra-FDA coordination. 

One guidance document the Agency must develop is a comprehensive procedural guidance 

which includes a list of “touch points” and timeframes which specifies points where FDA 

and sponsors plan to address key issues during combination product development and 

review. This may include, e.g., touchpoints and timelines related to feedback protocols for 

review (e.g., for a summative study), and pre-meeting information. This procedural 
8

guidance should respect the regulatory timelines of each lead center review process as 

appropriate (i.e., PMA, NDA, BLA, 510(k), etc.). 

The team leader should collect feedback for the sponsor and ensure that feedback is 

consistent and represents the FDA position, and is provided at designated touch points. 

3. Improve Justifications for Decisions. Improvements in justifications will build on 

improvements in coordination and communication. Once the Agency is coordinating (to 

assure uniformity) and communicating (to ensure sponsors understand the Agency’s 

thinking) much of the work should be done. What will remain is for FDA to keep an open 

mind when a sponsor makes a well-reasoned proposal. 

 Improvements in coordination, communication, and justifications would benefit all aspects 

of the combination product review process and, thereby, bring better products to patients. 

However, one aspect of review where this is especially true, and where problems have been most 

significant, is the issue of usability testing. In Appendix A, we address this specific issue, and 

hope it will serve as an area of focus as the Agency moves to put combination product reviews on 

the right path. 

Coordinate

Communicate

Justify

Requests Improvements Build on One Another 

to Create a System That Fosters 

Innovation & Brings New Therapies 

to Patients More Quickly
1227 25th St. NW

Suite 700

Washington, DC 20037

combinationproducts.com

202.861.1881

Appendix A --Usability Testing Issues in the FDA Review Process 

Usability testing plays a pivotal role in the approval process of combination products, 

especially for those therapeutics that are combined with a drug delivery device (e.g., an

autoinjector). Because usability of these products is determined almost exclusively by the function 

of the device constituent that delivers the therapeutic, historically the Agency followed the lead of 

CDRH and its applicable guidances in evaluating these issues.1 The CDRH approach to usability 

testing focuses on human factors simulated-use studies—participants use the device constituent 

part in a simulated environment designed to mimic typical use scenarios under the observation of 

a human factors expert, who can identify and understand potential misuse. Using these 

environments, studies are conducted in phases using “formative testing” to evaluate opportunities 

to improve device features and labeling for product use, and “summative testing” to establish the 

safety and effectiveness of performance in the hands of the intended users according to the 

product’s proposed conditions of use. This approach has developed over many years, and is 

supported by a significant body of scientific literature.2

More recently, however, groups within CDER have sometimes pressed innovators to use 

actual use studies—in which actual patients use the device on themselves to deliver the drug or 

biologic constituent part in a clinical setting. Actual use studies have several limitations3

 and under 

the CDRH regulatory approach are typically reserved for those situations where the device or use 

environment being evaluated is “particularly challenging or poorly understood.”4 This creates a 

regulatory inconsistency: if an innovator is dealing with a device-only product, it is subject to 

CDRH’s human factors testing standards, but when the same product is combined with a specific 

drug, groups within CDER may impose an entirely different set of requirements (which are more 

burdensome without increased benefit), creating review inconsistencies that ultimately delay 

access to important therapies by unnecessarily lengthening the combination product approval 

process. 

CDER also tends to position these requests and others related to usability testing as nonnegotiable conditions for approval, but in many cases without reasoned justifications for its 

positions, leaving sponsors to wonder what is driving the Agency’s concerns and how to address 

them. If sponsors are provided with FDA’s detailed concerns, they would have opportunity to 

provide alternate suggested approaches to satisfy FDA’s concerns which more closely align with 

 

1

 U.S. FOOD & DRUG ADMIN., DRAFT GUIDANCE: APPLYING HUMAN FACTORS AND USABILITY ENGINEERING TO 

OPTIMIZE MEDICAL DEVICE DESIGN (2011) [hereinafter FDA, DRAFT GUIDANCE: APPLYING HUMAN FACTORS]; U.S.

FOOD & DRUG ADMIN., MEDICAL DEVICE USE-SAFETY: INCORPORATING HUMAN FACTORS ENGINEERING INTO RISK 

MANAGEMENT (2000) [hereinafter FDA, MEDICAL DEVICE USE-SAFETY] (final guidance). 

2

 ANSI/AAMI HE75, 2009/(R) 2013 Human Factors Engineering—Design of Medical Devices. 

3

 See discussion herein. 

4

 FDA, Draft Guidance: Applying Human Factors, supra note 1, §§ 10, 10.2, at 23, 27. 
10

the Least Burdensome Approach. Further, sponsors also struggle with a lack of communication 

and coordination amongst Centers, Offices, and Divisions of the Agency. It is not uncommon for 

an innovator to be coordinating with some groups at FDA only to later hear from a new group that 

wants to impose a different set of requirements (as detailed in the examples).

Through our survey and conversations with innovators, we have identified four particular 

areas within usability testing that are most affected by the following issues, which are considered 

below: 

(1) CDER requests for usability testing to be incorporated in clinical trials; 

(2) CDER requests for studies to “bridge” two combination products that use different 

injectors; 

(3) Subject population selection for usability testing; and 

(4) Requests for labeling revisions which come late in the FDA review cycle. 

We consider each of these below. 

A. Actual use Testing of Device Constituent Part During Clinical Trials 

In pivotal safety and efficacy trials for combination products, CDER has begun requesting 

actual use data for combination products instead of allowing simulated-use human factors testing 

to supplement clinical data on corresponding drug or biologic constituent parts. Traditionally, 

human factors testing performed in accordance with CDRH guidance5

 and recognized consensus 

standards (IEC62366, AAM/ANSI-HE-75) has provided scientifically rigorous means for 

innovators to demonstrate that the intended users of a device constituent part can safely and 

effectively perform the relevant task as intended in the expected use environment. 

Recently, some groups within CDER have requested that sponsors collect actual use data 

during pivotal clinical studies in addition to conducting traditional simulated-use human factors 

studies. However, no substantive explanation is provided for deviating from established human 

factors testing under simulated conditions. Human factors study is a science that has developed 

over decades and has been used to evaluate a variety of important items, including medical devices 

and combination products. Human factors testing is tailored to identify the most important 

problems with device or combination product use, and allow for development of optimal products 

and instructions that help patients get the best possible care. Actual use testing, on the other hand, 

may often fail to provide the kinds of observational data and insights that human factors testing 

can because it is not sufficiently tailored to detect and evaluate the causes of device problems. 

Also, the chance of detecting rare events would typically be low without a very large number of 

subjects. Thus, the lack of explanation as to why actual use testing is necessary makes it difficult 

for sponsors to respond to CDER concerns because of the many reasons that argue for using 

 

5

 FDA, MEDICAL DEVICE USE-SAFETY, supra note 1; see also FDA, DRAFT GUIDANCE: APPLYING HUMAN FACTORS, 

supra note 1, § 10. 
11

simulated-use testing instead of actual use testing. Other advantages of human factors, simulated 

use testing are listed below6: 

 Simulated-use testing has a focused endpoint pertaining solely to the subject’s interaction 

with the device and no other constituent part, increasing the probability of identifying 

usability issues. By contrast, clinical trials typically entail multivariate endpoints based on 

drug or biologic action. Device-related endpoints, which are readily determinable in 

simulated-use studies because an error must originate with use of the device constituent 

part, become unclear when combined with non-device endpoints because the observer 

cannot always discern a device failure from a drug or biologic failure. Additionally, a 

failure may be due to the interaction of the drug and the device making the detection of 

device problems quite confounded. Such confusion may result in false error reports, 

leading to inefficiency and delay. 

 Human factors experts typically observe simulated-use studies, as opposed to formal 

clinical trials, which are observed by clinicians. While human factors experts are trained 

specifically to notice errors in device use, clinicians often cannot distinguish a device error 

from other errors. Also, post-trial interviews with participants in a controlled human 

factors environment can provide important information when conducted by a highly trained 

and experienced human factors expert. 

 Simulated-use studies allow participants to make errors safely, allowing ample opportunity 

to observe close calls or potential patterns of misuse. In clinical trials, sponsors must 

provide participants the greatest protection possible by ensuring that they receive extensive 

training with a combination product to prevent any harm due to user error. However, 

simulated-use studies involve more basic training that more closely mimics post-market 

conditions, where a patient may receive initial training with a combination product, but the 

training may be inadequate or the patient may forget, and allows human factors experts to 

observe “naturally-occurring” user errors. The additional training participants receive in 

the clinical environment dramatically decreases the probability of identifying an error 

because an over-trained user is less likely to make a mistake. 

 Investigators in drug clinical trials, often being medical specialists as opposed to device 

specialists, are not necessarily trained or experienced in the assessment of device-related 

problems and, particularly when the administration is un-witnessed, cannot differentiate a 

device problem from a drug problem, or the interaction between the two. Thus, the data in 

actual use trials are often dependent on patient reports of issues which are uninformed by 

knowledge of what a device can or cannot do. For example, a patient may report that the 

device malfunctioned when a dose was not delivered; however, the problem could be that 

a temperature sensitive drug product was not allowed to come to room temperature before 

an administration was attempted. 

 

6

 All of the factors in the following paragraphs were reviewed with human factors experts. The experts agreed that 

simulated-use studies have distinct advantages over actual use studies with respect to these factors and the ability to 

identify device-associated risks. 
12

 A greater and more characteristically varied population may participate in simulated-use 

studies. Clinical studies are tightly regulated and recruitment is restricted to limited 

populations. Those restrictions do not apply to simulated-use studies, and consequently, 

sponsors may recruit more participants with a greater variety of characteristics (e.g., age, 

intelligence, general health, ability) that may affect device use. 

 Simulated-use studies imitate real-life situations as well as clinical studies. FDA places 

much emphasis in its guidance on the ability of validation studies to represent real-life 

scenarios. At first glance, clinical studies appear superior because a participant will use 

the combination product in a clinical environment if necessary, but often, the participant 

will use the product unobserved and in her own home. However, according to human 

factors experts, simulated-use studies may be, and often are, conducted in the participant’s 

home if those environmental factors will reveal more about methods of use. Although 

observation may affect a participant’s use of the device constituent part, the effect may be 

reduced, or eliminated, by conducting the test in modern simulation labs, which allow 

unobtrusive observation. 

 Simulated-use studies are significantly less expensive than clinical studies. With costs 

ranging from $47,000 per patient, on average, to as high as $85,000 per patient,7 clinical 

trials, which involve highly specialized teams and regulatory requirements, are often 

expensive undertakings. By contrast, simulated-use testing or simple bench trials cost far 

less to set up and conduct because patient recruitment and testing parameters have fewer 

restrictions. Lower costs can translate to lower burdens and greater innovation, which

benefits patients. 

 Simulated-use studies can eliminate unnecessary risks from exposures to investigational 

drug therapies because they do not require that a patient receive drug. 

In light of these benefits, the CPC asks FDA to publish guidance (or regulation) that adopts 

traditional, simulated-use human factors testing as the standard for usability testing across all 

Centers for all device constituents. In addition, consistent with Good Guidance Practices, FDA 

should only allow requests for actual use studies when reviewers (a) identify specific unassessed 

risks or facts relating to a particular product that make actual use testing necessary, and (b) receive 

supervisory approval for the request.8

 

7 D.J. Stewart & R. Kurzrock, Fool’s Gold, Lost Treasures, and the Randomized Clinical Trial, 13 

BIOMEDCENTRAL CANCER 193 (2013), available at http://www.biomedcentral.com/content/pdf/1471-2407-13-

193.pdf. 

8 See Food, Drug and Cosmetic Act § 701(h)(1)(B) (“The Secretary shall ensure that employees of the Food and Drug 

Administration do not deviate from . . . guidances without appropriate justification and supervisory concurrence.”).
13

B. Bridging Studies for Combination Products 

Innovators may modify drug delivery systems between completion of Phase III pivotal 

trials and submission of an application for drug approval to help improve patient adherence, easeof-use, or other attributes. Manufacturers may also develop modifications after product approvals 

to improve patient ease-of-use, convenience, etc. When making these modifications, the innovator 

must determine whether the changes impact product safety or effectiveness. Comments from some 

CDER reviewers suggest that an actual use, clinical bridging study where patients are required to 

use the device on themselves (e.g., inject themselves with medication)—as opposed to simulateduse studies where participants use the device in an artificial environment (e.g., inject saline into 

injection pads)—is necessary to demonstrate that the previously collected safety and efficacy data 

apply to the modified, to-be-marketed product. The practical problems with the approach can be 

significant, especially for drugs that may be used on a weekly, monthly, or as-needed schedule,

where it could take a very long time to accumulate enough events for analysis. Moreover, for the 

reasons detailed below, the approach should generally be unnecessary. 

Under the Food, Drug and Cosmetic Act (“FDCA”), FDA approves an injectable drug 

based on safety and effectiveness of: (1) the drug and (2) its delivery into the body. Once the 

safety and effectiveness of a given dose is established, the only questions to answer in a bridging 

study for delivery devices are: (1) whether the modified device will deliver an equivalent dose of 

drug using the same route of administration to produce bioequivalent results; and (2) whether a 

person can use the modified device as well as (or better than) the previously used device. Simple 

design evaluation and bench testing of the modified delivery device will validate accurate and 

consistent delivery of the set dose, answering the first question more effectively than clinical 

studies.

The second question requires usability testing to identify any risks of human error that may 

be a result of the modification to the delivery device. Simulated-use studies are particularly wellsuited for bridging studies because the endpoint focuses solely on usability of the delivery device. 

Once the safety and effectiveness of the drug is established, whether a bridging study participant 

injects himself with the actual drug or injects an injection pad, the same relevant information will 

be collected with regard to injector use. 

Therefore, FDA should develop an Agency-wide guidance or regulation allowing 

innovators to bridge products that use the same drug and dose, but a different injector (e.g., prefilled syringe, pen injector, autoinjector) without repeating the drug clinical study, provided that: 

(1) The product is a liquid injectable; 

(2) The administration process (including route of delivery, approximate injection depth, 

needle gauge and length) and volume delivered remain the same; and 

(3) The innovator can demonstrate product usability is not impacted by employing simulateduse testing with injection pads. 

Actual use studies should not be required unless medical reviewers: 

(1) Can provide a reasoned basis why simulated-use testing would be insufficient; 

(2) Agree that the methodological issues inherent to an actual use study would allow the study 

to provide better information; and 

(3) Receive supervisory approval to request actual use data. 
14

C. Subject Populations for Usability Studies 

 Recently, some CDER reviewers have required that summative studies include: (1) 

untrained users for a combination product that requires training (and where the innovator seeks 

approval only for trained use); and (2) medical professionals to test combination products (e.g., 

pre-filled syringes) whose labels specify patient self-administration. Though the addition of these 

additional patient groups may seems innocuous, they unnecessarily increase regulatory burdens 

(which discourages innovation) and potentially raise “red herring” questions that shift the focus of 

the review away from the statutory standards of approval. 

 We do note that non-indicated users often play a role in formative testing as a product and 

its labeling is being developed. But once the summative testing phase is reached – the phase which 

validates the proposed use of the to-be-marketed product and labeling – the focus must be on the 

indicated population. Under the FDCA, innovators are required to demonstrate the safety and 

effectiveness of products when used under conditions “prescribed, recommended, or suggested” 

in labeling to receive FDA approval for those uses. Thus, in the summative phase of testing, 

expanding usability tests that validates the safety and effectiveness of a device constituent part to 

include users outside the scope of the labeled indications does not provide information bearing on 

approval and should not be required. 

Therefore, FDA should adopt an Agency-wide guidance or regulation that limits requests 

for non-indicated study populations to formative studies (these populations should generally not 

be included in summative studies).9

 Any deviation from this request should require the FDA 

reviewer to: (1) provide a reasoned basis why testing with the indicated population would be 

insufficient; and (2) receive supervisory approval to request inclusion of a non-indicated 

population in the study. 

D. Agency Labeling Recommendations 

 Some CDER reviewers have been providing input on patient instructions for use very close 

to PDUFA

10 action dates, and well past completion of human factors testing. These late 

recommendations sometimes require changes to the instructions for use, which, if adopted, may 

undermine reliance on prior human factors testing and associated use-related risk analyses. 

Moreover, CDRH sometimes objects to product labeling alterations based on reviewer input unless

 

9

 By “non-indicated” we mean users that would not be representative of the abilities of the indicated population. 

There may be instances where it is reasonable, or even necessary, to include individuals do not suffer from the 

indicated disease state in the human factors study. For example, if an indicated patient population is very small, an 

innovator may identify a “surrogate” test population that has characteristics similar to the indicated patient 

population with regard to ability to use the device and take required training (if any). 

10 Prescription Drug User Fee Act, Pub. L. No. 102-571, 106 Stat. 4491 (1992) (reauthorized by Food and Drug 

Administration Safety and Innovation Act, Pub. L. No. 112-144, 126 Stat. 993 (2012)). 
15

the innovator conducts new human factors testing with the new labeling – studies that will take 

months and delay approval.11

 Expert FDA assessments of labeling have value, and are often part of the instruction 

development process prior to a human factors usability study. However, once a validation has 

proceeded to the summative phase, new FDA reviews and comments can cause significant delays, 

and should only be included in reviews under extraordinary circumstances. Therefore, reviewers 

from all involved Centers should coordinate their efforts and provide combined comments on 

proposed instructions for use before human factors studies commence. FDA should adopt a 

guidance or regulation that ensures reviewers override human factors validation results only if they 

can identify actual data or information suggesting that the wording of a relevant instruction is 

likely to cause harm to a user, and receive approval from their supervisor. 

* * * * *

FDA should adopt the suggestions above because they will improve patient access to 

innovative products. However, regulatory concerns the Agency must consider also weigh in favor 

of reform. First, unjustified requests for studies (which several requests described above appear 

to be) fail to meet Administrative Procedure Act (“APA”) standards because they lack the kind of 

reasoned basis that is required for all Agency decision-making. Also, absent true need, requests 

for supplemental usability studies may be considered “arbitrary and capricious” under APA 

standards if human factors testing provides better safety and effectiveness data than actual use 

studies (which, as explained above, it would in most cases). This makes it all the more imperative 

that FDA reviewers consider all options, including those proposed by sponsors, and explain their 

reasoning when making decisions. 

Second, innovation-delaying requests, such as requests for unnecessary actual use studies,

are not consistent with the least burdensome principles. Under those principles, FDA must 

establish a regulatory regime that allows innovators to receive approval or clearance for their 

products without the burden of unnecessary testing.12

 In situations where approval is being 

delayed based on CDER requests related to a device constituent (e.g., actual use studies when 

human factors testing is sufficient), the Agency undermines these principles. However, if the 

Agency embraces these principles, it will allow patients to realize significant benefits from 

innovation more quickly. 

Finally, because FDA is taking an ad hoc approach to regulation, it runs the risk of treating 

similarly situated parties differently, which violates the APA.13 Establishing a uniform standard 

that clearly defines the roles and responsibilities of all Centers and that is based upon scientific 

 

11 The CPC’s Combination Product Survey found that almost 80% of respondents received late requests in the 

review process and over 50% received conflicting information regarding Instructions for Use. 

12 Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144 §§ 602, 901, 126 Stat. 993, 1051, 

1082 (2012). 

13 5 U.S.C. § 706(2)(A) (2012); see also Bracco Diagnostics, Inc. v. Shalala, 963 F. Supp. 20, 27–28 (D.D.C. 1997) 

(holding that FDA’s failure to treat similarly situated innovators or products equally is arbitrary and capricious in 

violation of the Administrative Procedure Act). 
16

reasoning will help ensure FDA regulates all similarly situated innovators and products equally 

and will prevent the Agency from making arbitrary and capricious requests during the review 

process. 

Recommendations 

In summary, a cross-Center set of policies should be created through regulation or guidance 

(including procedural guidance) to: 

1. Adopt traditional, simulated-use human factors testing as the policy for combination 

product testing across Centers, and only allowing reviewers to request actual use studies 

only if they: (a) can point to specific unassessed risks or facts regarding a product that make 

actual use testing necessary; and (b) receive supervisory approval to make the request. 

2. Develop and implement an Agency-wide policy that allows bridging of combination 

products that use different injectors (e.g., prefilled syringe and pen injector) – but the same 

liquid injectable drug, dose, and route & process of administration – based on nonclinical 

testing and human factors studies. Actual use studies would only be required if medical 

reviewers: (a) can provide a reasoned basis for why standard, simulated-use human factors 

testing to evaluate drug delivery differences with a design evaluation would be insufficient; 

(b) agree that the methodological issues inherent to an actual use study would allow the 

study to provide better information; and (c) receive supervisory approval to request the 

actual use data. 

3. Require human factors validation testing only with participants from the indicated patient 

group (or an appropriate surrogate group) for the combination product unless a medical 

reviewer (a) can provide a reasoned basis for deviating from this policy based on specific 

facts, and (b) receives supervisor approval for deviating from the policy. 

4. Provide sponsors with comments from all reviewers in all Centers before human factors 

validation studies commence. Decisions to override human factors validation results 

should only be made if an FDA reviewer (a) can point to published information that 

suggests, based on objective evidence (e.g., study data that contradicts a sponsor’s human 

factors validation results), that the wording in the validated label would cause patient harm, 

and (b) receives supervisor approval. 

These changes will create a better environment for innovation that improves therapeutic 

options for patients.