Application of Human 
Factors Engineering 
Principles for  
Combination Products: 
Questions and Answers 
 
 
Guidance for Industry and FDA Staff 
 
Additional copies are available from: 
Office of Combination Products 
Food and Drug Administration 
WO32, Hub/Mail Room # 5129 
10903 New Hampshire Avenue 
Silver Spring, MD 20993 
(Tel) 301-796-8930 
(Fax) 301-847-8619 
http://www.fda.gov/combination-products 
 
For questions regarding this document, contact the Office of Combination Products at 301-796-8930 
or combination@fda.gov. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Office of Combination Products (OCP), Office of the Commissioner 
Center for Devices and Radiological Health (CDRH) 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 September 2023 
 
  Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  SCOPE ............................................................................................................................... 2 
III.  BACKGROUND ............................................................................................................... 3 
IV.  QUESTIONS AND ANSWERS ....................................................................................... 5 
Q-1.    What guidance is available for medication error considerations to inform the 
design of a combination product? ............................................................................... 5 
Q-2.    Could a drugs properties affect how a user interacts with a combination product 
that includes that drug? ............................................................................................... 5 
Q-3.    How do the general definitions in the guidance for industry and FDA staff 
Applying Human Factors and Usability Engineering to Medical Devices apply to a 
combination product? .................................................................................................. 5 
Q-4.    What is the definition of a final finished combination product? ............................. 6 
Q-5.    What is the definition of a combination product critical task and how are 
combination product critical tasks identified? .......................................................... 6 
Q-6.    How does FDA evaluate HF validation study results? ............................................. 8 
Q-7.    Is there a difference between the use-related risk analysis (URRA) to support the 
user interface and other types of risk analysis? ........................................................ 9 
Q-8.    What considerations may apply for training as part of the user interface for 
combination products? ................................................................................................ 9 
Q-9.    What is the difference between an HF actual-use validation study and an actual-
use/clinical home-use study? ..................................................................................... 10 
Q-10.  Are there any considerations for formative HF evaluation protocols or formative 
HF study results? ....................................................................................................... 11 
Q-11.  What HF information and/or data should be provided to support initiating  
clinical investigations for a combination product? ................................................. 11 
Q-12.  Does FDA expect the HF validation study that supports market authorization to 
be conducted at a certain development phase of the combination product? ........ 12 
Q-13.   What HFE principles should be considered when modifying a combination 
product? ...................................................................................................................... 13 
Q-14.   What are FDA review processes for combination product draft HF validation 
study protocols and draft labeling? .......................................................................... 13 
Q-15.   How do I obtain information from and provide information to FDA on my 
combination product HF program? ......................................................................... 14 
 
  Contains Nonbinding Recommendations 
 
Application of Human Factors Engineering Principles for 
Combination Products:  Questions and Answers  
Guidance for Industry and FDA Staff 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION 
 
This document contains questions and answers for industry and FDA staff on the application of 
human factors engineering (HFE) principles to the development of combination products as 
defined under 21 CFR part 3.1  This guidance finalizes the February 2016 draft version entitled 
Human Factors Studies and Related Clinical Study Considerations in Combination Product 
Design and Development.  This guidance provides information in a question and answer format 
and clarifies how the unique aspects of a combination product influence the considerations 
within the HFE process.   
 
This guidance should be used in conjunction with the guidance for industry and FDA staff 
Applying Human Factors and Usability Engineering to Medical Devices2 and with the guidance 
for industry Safety Considerations for Product Design to Minimize Medication Errors.3  
Additionally, this guidance supplements other existing guidance documents developed by the 
Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological 
Health (CDRH), the Center for Drug Evaluation and Research (CDER), and the Office of 
Combination Products (OCP) that describe other aspects of product development.   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.    
 
 
1 For additional information on combination products see https://www.fda.gov/combination-products.  Applicants 
with questions on combination product center assignment should contact the Office of Combination Products 
(combination@fda.gov). 
2 February 2016.  For additional information on human factors evaluation for medical devices, see the draft guidance 
for industry and FDA staff Content of Human Factors Information in Medical Device Marketing Submissions 
(December 2022).  When final, that guidance will represent FDAs current thinking on the topic.  We update 
guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
3 April 2016.  
1 
 
  Contains Nonbinding Recommendations 
 
II.  SCOPE 
 
This guidance focuses on considerations for the application of HFE principles to combination 
products comprised of a medical device4 combined with a drug or a biological product submitted 
for review in CBER, CDRH, or CDER.5  This guidance discusses, among other things, the 
definition of a combination product critical task, considerations for combination products due to 
the use of drug and device constituent parts6 together, training as part of the user interface, and 
human factors (HF) validation data to support the combination product user interface that may be 
included in a premarket submission. 
  
Consistent with development of medical devices, the successful development of a combination 
product that includes a device constituent part applies the appropriate HFE principles and 
processes throughout the entire product development process and product lifecycle changes.  
Because the application of HFE principles and processes is similar for such combination 
products and medical devices, this document does not focus on general HFE principles or the 
general design considerations for formative and validation studies.7      
 
This document does not address HF considerations for combination products submitted under 
section 505(j) of the Federal Food, Drug, and Cosmetic Act in an abbreviated new drug 
application (ANDA)8 or submitted in a BLA under section 351(k) of the Public Health Service 
Act for a proposed biosimilar or interchangeable biosimilar biological product.9  This document 
 
4 For purposes of this guidance, the term medical device is used interchangeably with the term device and has the 
same meaning as this term which is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act. 
5 As appropriate for the center, the application types include an investigational device exemption application (IDE), 
investigational new drug application (IND), biologics license application (BLA) submitted under section 351(a) of 
the Public Health Service Act, new drug application (NDA), premarket approval application (PMA), De Novo 
classification request, and premarket notification (510(k)).  For information on the application types within a center, 
contact the respective center product jurisdiction officers at CDERProductJurisdiction@fda.hhs.gov, 
CDRHProductJurisdiction@fda.hhs.gov, or CBERProductJurisdiction@fda.hhs.gov.  For further information on 
what application type may be appropriate for a combination product, see the guidance for industry and FDA staff 
Principles of Premarket Pathways for Combination Products (January 2022). 
6 For purposes of this guidance, the term drug also refers to a biological product and the term drug constituent part 
also refers to a biological product constituent part unless otherwise indicated.  See 21 CFR 4.2 for the definition of 
constituent part.  
7 For information on general HFE principles and general design considerations for formative and validation studies, 
see the guidance for industry and FDA staff Applying Human Factors and Usability Engineering to Medical 
Devices.  See also the guidance for industry Safety Considerations for Product Design to Minimize Medication 
Errors.   
8 Although human factors considerations for combination products submitted in an ANDA are beyond the scope of 
this guidance, certain principles described in this guidance may apply to these products on a case-by-case basis.  
Applicants preparing to submit a combination product for review in an ANDA are strongly encouraged to contact 
FDA via controlled correspondence and/or a pre-ANDA meeting request to discuss the applicants proposed 
product.  For additional information, see the draft guidance for industry Comparative Analyses and Related 
Comparative Use Human Factors Studies for a Drug-Device Combination Product Submitted in an ANDA (January 
2017).  When finalized this guidance will represent FDAs current thinking on this topic.    
9 Applicants preparing to submit a combination product for review in a BLA under section 351(k) are encouraged to 
interact with FDA.  For additional information, see the draft guidance for industry Formal Meetings Between the 
FDA and Sponsors or Applicants of BsUFA Products (August 2023).  When finalized this guidance will represent 
FDAs current thinking on this topic.  For related information, see Q-15. 
2 
 
  Contains Nonbinding Recommendations 
 
does not address label comprehension studies for non-prescription uses.10  Further, this document 
does not address when an HF study may be subject to the requirements under 21 CFR part 50 
(human subject protection), part 56 (review and approval by an institutional review board (IRB)), 
part 312 (investigational new drug applications), or part 812 (investigational device exemptions) 
or how HF studies are considered in user fee determinations.11 
 
 
III.  BACKGROUND 
 
Combination products, as described in 21 CFR part 3, are comprised of two or more different 
types of products (i.e., a combination of a drug, device, and/or biological product with one 
another).  The regulatory requirements for combination products arise from the statutory and 
regulatory requirements applicable to drugs, devices, and biological products, which retain their 
discrete regulatory identities when they are constituent parts of a combination product.12  At the 
same time, combination products comprise a distinct category of products that can be subject to 
specialized regulatory requirements, where appropriate.13 
 
Medical devices are subject to design control requirements identified in 21 CFR 820.30 that 
include design validation and a risk analysis where appropriate.14  As codified at 21 CFR 
4.4(b)(1)(ii), Current Good Manufacturing Practice Requirements for Combination Products, 
combination products that include a device constituent part are subject to design controls.15  In 
the context of a drug-device combination product, as part of the HFE process, design controls 
should include a use-related risk analysis (URRA) of the combination product as a whole, not 
just the device constituent part or the drug constituent part for its use in the combination product 
(Figure 1).   
 
Further, beyond use-related risks associated with the device alone, there can be use-related risks 
associated with the drug.  Also, there may be use-related risks associated with the combination 
product as a whole that do not exist for the device alone or drug alone.  These different use-
related risks may influence the user interface design inputs and the HFE assessment. 
 
 
10 If your combination product includes a non-prescription drug, the following guidance on this topic may be 
helpful:  guidance for industry Label Comprehension Studies for Nonprescription Drug Products (August 2010).  
11 For information on user fee assessment under the Prescription Drug User Fee Act (PDUFA) for applications 
containing clinical studies, see the guidance for industry Submitting Separate Marketing Applications and Clinical 
Data for Purposes of Assessing User Fees (December 2004).  For related information, see Q-15. 
12 See combination product current good manufacturing practice and post marketing safety reporting rules, 78 FR 
4307-23 (2013) (21 CFR part 4, subpart A) and 81 FR 92603-26 (2016) (21 CFR part 4, subpart B). 
13 Ibid. 
14 See 21 CFR 820.30(g). 
15 Also, see guidance for industry and FDA staff Current Good Manufacturing Practice Requirements for 
Combination Products (January 2017). 
 
3 
 
  Contains Nonbinding Recommendations 
 
 
Combination Product 
 
Device    Drug 
Specialized Considerations for Combination Products 
 
Figure 1:  Drug-Device Combination Product Risk Considerations 
 
 
HFE is the application of knowledge about human behavior, abilities, limitations, and other 
characteristics of the users to the design of products to help ensure safe and effective use of the 
product.16  This includes consideration of the intended user population characteristics, including 
concomitant diseases and conditions, and limitations that may impact the use of the combination 
product.  For example, for a digital health combination product intended for use in a geriatric patient 
population,  common characteristics or limitations may include decreased vision/hearing, varying 
literacy levels, and cognitive decline.  Furthermore, the design of the combination product should 
take into account, among other things, the use environment(s), including any limitations (e.g., limited 
internet /cellular phone service). 
 
A key goal of applying HFE principles during development is to ensure that the user interface 
supports the safety and effectiveness of the combination product as a whole.  The user interface 
for a combination product includes all points of interaction between the combination product and 
the user(s), including displays, controls, packaging, product labels, carton labeling, instructions 
for use, and training, if applicable.  Applicants should consider how the design of the user 
interface could affect the user interactions with the combination product and result in harm, 
including an interaction that could result in a medication error.17   
 
The following questions and answers address certain topics relevant to HFE considerations for 
combination products, including how the characteristics of drug and device constituent parts, 
user population(s), and potential for medication errors inform the design of the combination 
product user interface and impact HFE considerations for combination products.   
 
 
16 See definition in the guidance for industry and FDA staff Applying Human Factors and Usability Engineering to 
Medical Devices, section III. 
17 The guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to Minimize 
Medication Errors (May 2022), defines a medication error as any preventable event that may cause or lead to 
inappropriate medication use or medication-related patient harm while the medication is in the control of the health 
care professional, patient, or consumer (see also the National Coordinating Council for Medication Error Reporting 
and Prevention, https://www.nccmerp.org/about-medication-errors).  
4 
 
  Contains Nonbinding Recommendations 
 
IV.  QUESTIONS AND ANSWERS 
 
Q-1.    What guidance is available for medication error considerations to inform the design 
of a combination product? 
 
The guidance for industry Safety Considerations for Product Design to Minimize Medication 
Errors provides a set of principles for using a systems approach to minimize medication errors 
relating to product design, including container closure design, to enhance patient safety.  That 
guidance further explains how HFE principles apply to the design of medical products to 
minimize medication errors, including those that may lead to patient harm, and provides 
examples of medical product designs that have resulted in postmarket medication errors.18  
 
 
Q-2.    Could a drugs properties affect how a user interacts with a combination product 
that includes that drug? 
 
Yes, the drugs properties may influence and affect whether a user can successfully complete 
tasks when using the combination product.  For example, the presence of a chemically irritating 
drug or a viscous drug formulation in combination with an injector-device may increase the risk 
for local pain on injection, either from drug toxicity or the fluid pressure in the interstitial tissue.  
Local pain has the potential to influence a users ability to complete an injection task, resulting in 
a dose omission or under-dose.  Also, high drug viscosity could increase the injection delivery 
time of the drug through the needle and increase the length of time the user must hold the 
injector in place (hold time) to administer the drug.  The increase in hold time could reduce a 
users ability to complete an injection task and result in an under-dose.  The potential effect(s) of 
drug properties should be considered when identifying, evaluating, and managing the use-related 
risk for the combination product.   
 
 
Q-3.    How do the general definitions in the guidance for industry and FDA staff Applying 
Human Factors and Usability Engineering to Medical Devices apply to a combination 
product?   
 
The general definitions in the guidance for industry and FDA staff Applying Human Factors and 
Usability Engineering to Medical Devices reflect HFE principles that are applicable to the 
combination product as a whole, and not just to the device constituent part, and may be 
referenced to support applying HFE to a combination product.  However, for a combination 
product, there are two unique definitions:  the final finished combination product and 
combination product critical task (see Q-4 and Q-5 for details). 
 
 
 
 
18 Also see the guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to 
Minimize Medication Errors.    
 
5 
 
  Contains Nonbinding Recommendations 
 
Q-4.    What is the definition of a final finished combination product? 
 
A final finished combination product is the product intended for market and submitted in the 
marketing application.  This term includes the user interface for the combination product (e.g., 
proposed packaging, labels and labeling, and training, if applicable). 
 
 
Q-5.    What is the definition of a combination product critical task and how are 
combination product critical tasks identified? 
 
A combination product critical task is a user task which, if performed incorrectly or not 
performed at all, would or could cause harm to the patient or user, where harm is defined to 
include compromised medical care.  
 
Although the combination product critical task definition is similar to the stand-alone device 
critical task definition,19 it differs in the level of harm.  Specifically, for a stand-alone device, a 
user task with the potential to result in serious harm is considered a critical task, and this 
definition remains unaltered.  Also, the stand-alone drug definition of medication errors remains 
unchanged (see Q-1).   
 
However, as discussed in section III, there may be use-related risks associated with the 
combination product as a whole that do not exist for the device alone or the drug alone.  
Therefore, combination product critical tasks reflect the use-related risks resulting from both the 
drug and device constituent parts used together as a combination product.  For a combination 
product critical task, compromised medical care includes consideration of medication errors.20 
 
A comprehensive URRA can aid in the identification of combination product critical tasks.  
Consistent with HFE principles, the comprehensive URRA should include a systematic 
evaluation of all the tasks involved in using the combination product (i.e., based on a task 
analysis), reflecting the use errors that may occur or the tasks that may not be completed (i.e., 
task failures), and the potential clinical consequences of use errors and task failures.  Applicants 
should comprehensively consider the harm in the context of the combination product 
indication(s), intended use, use environment,21 user interface, and the users.22   The Agency is 
particularly interested in the assessment of tasks that directly: 
 
 
19 Guidance for industry and FDA staff Applying Human Factors and Usability Engineering to Medical Devices, 
section 3.2.  
20 See footnote 17. 
21 For the purpose of this guidance, use environment is the setting in which the product is used (e.g., home, hospital, 
first response) and the focus is the impact that the setting has on the users ability to interface with the product. 
22 For additional considerations and further information regarding the URRA, see the guidance for industry and FDA 
staff Applying Human Factors and Usability Engineering to Medical Devices, the guidance for industry Safety 
Considerations for Product Design to Minimize Medication Errors, and the draft guidance for industry and FDA 
staff Contents of a Complete Submission for Threshold Analyses and Human Factors Submissions to Drug and 
Biologic Applications (September 2018) (when finalized this guidance will represent FDAs current thinking on this 
topic).  FDA intends to issue additional guidance on URRAs (see PDUFA VII commitment letter).    
6 
 
  Contains Nonbinding Recommendations 
 
1.  Impact dosing (e.g., overdose, underdose, or missed dose), including those that may lead 
to lack of treatment response; 
 
2.  Impact administration of the product (e.g., wrong site of administration, improper 
preparation of drug/biologic before administration); or 
 
3.  Have the potential to result in harm (e.g., physical injury, adverse events, events that may 
need patient monitoring to confirm no harm, or events that may lead to hospitalization) 
 
Furthermore, in their URRA, sponsors should consider whether their product may be a time 
sensitive or time urgent product.  For time sensitive or time urgent products (e.g., emergency-use 
autoinjector), most or all tasks are likely combination product critical tasks because of their 
potential impact on delivering life-saving medication.   
 
Once the combination product critical tasks are identified, the combination product critical tasks 
should be appropriately evaluated further as part of the human factors engineering process.  FDA 
will evaluate a sponsors identified combination product critical task list as part of the review of  
an HF validation study protocol.  Sponsors should submit their URRA with the identification of 
combination product critical tasks when they submit their HF validation study protocol.23  
 
The following provides hypothetical examples of some considerations for combination product 
critical tasks: 
 
  Example 1- Consider an autoinjector for repeat use that includes a task to remove the cap.  
If a user cannot initially remove the cap, then the user is initially delayed in the sequence 
of tasks.  However, there is no sense of urgency associated with completion of tasks for 
this hypothetical combination product and the user ultimately removes the cap.  In cases 
where the timeliness of the injection is not linked to physical injury, its unlikely that 
FDA would consider this task to be a combination product critical task.24 
 
  Example 2 - Consider an autoinjector for a non-urgent, repeat use where the user must 
complete the task of pushing the needle end against the skin to activate the injection 
sequence and administer the dose.  In this example, a user does not complete the task of 
pushing to activate the full injection sequence because the user did not know s/he needed 
to push the needle all the way down, and thus fails to administer the dose.  The omission 
of a single dose is a medication error that may not result in an immediate change in 
clinical signs or symptoms; however, it is reasonable to consider the potential for 
repeated dose omission medication errors over the course of treatment.  The treatment for 
 
23 For additional information see the draft guidance for industry and FDA staff Contents of a Complete Submission 
for Threshold Analyses and Human Factors Submissions to Drug and Biologic Applications.  When finalized this 
guidance will represent FDAs current thinking on this topic.  Also, for more information on how to obtain 
feedback, see Q-15. 
24 Applicants should be aware that even if a task is not a combination product critical task, the collected HF data for 
that task may still be important in FDAs consideration of design validation (see 21 CFR 820.30(g)).  In this 
example, if the root cause of users initially not being able to remove the cap is linked to the force specification, then 
FDA may further consider whether the specification has been appropriately validated. 
7 
 
  Contains Nonbinding Recommendations 
 
that patient may be compromised and could result in harm to the patient.  Thus, the task 
of pushing the needle end against the skin to activate the full injection sequence would be 
considered a combination product critical task.  
 
  Example 3 - Consider a drug suspension co-packaged with a vial adaptor and an 
administration device that requires a task where a user must vigorously shake a powder 
mixed with a liquid vehicle for 60 seconds to achieve a homogenous suspension.  The 
task of shaking vigorously for 60 seconds would be considered a combination product 
critical task because an inability to achieve a homogenous suspension can directly result 
in an improper (inaccurate) dose being administered to a patient (e.g., under or overdose 
medication error).   
 
  Example 4 - Consider an on-body infusion system that can deliver a medication 
continuously to a patient with congestive heart disease to reduce the likelihood that the 
patient will be hospitalized.  The patient must know how to refill the drug cartridge, 
apply the system to the body, activate the system, and be able to determine whether the 
drug is infusing and if the device constituent part is performing as expected (e.g., delivery 
status, refill alerts).  Each of these tasks associated with the drug administration process 
would be considered combination product critical tasks because failure of any one of 
these tasks could lead to an improper dose being administered (e.g., underdose 
medication error).  Further, such medication error could result in exacerbation of 
congestive heart failure that may lead to subsequent hospitalization.   
 
  Example 5 - Consider an inhaler that requires the patient to place a drug capsule into the 
inhaler, where it is aerosolized for inhalation.  Swallowing the capsule instead of placing 
it in the inhaler would be considered a medication error, even if swallowing the capsule 
may not cause immediate clinical signs or symptoms.  It is a medication error because 
swallowing the capsule is an incorrect route of administration and could result in harm 
(i.e., non-treatment of the pulmonary disorder).  The task of placing the drug capsule into 
the inhaler would be considered a combination product critical task. 
 
 
Q-6.    How does FDA evaluate HF validation study results? 
 
From a practical perspective FDA recognizes that it may be impossible to design a user interface 
that is completely error-proof or risk-free, and some residual use-related risk may remain.  The 
HF validation study results should be considered within the overall benefit-risk assessment of the 
combination product.  All risks that remain after HF validation testing should be thoroughly 
analyzed by the applicant to determine whether additional modifications to the combination 
product user interface are warranted.  FDA will evaluate the HF validation study results to 
determine whether the combination product user interface design has been optimized such that 
the use-related risks have been sufficiently reduced.25  
 
 
 
25 See also section 8.1.7, Residual Risk, in the guidance for industry and FDA staff Applying Human Factors and 
Usability Engineering to Medical Devices. 
8 
 
  Contains Nonbinding Recommendations 
 
Q-7.    Is there a difference between the use-related risk analysis (URRA) to support the 
user interface and other types of risk analysis? 
 
Yes, the URRA26 is a subset of the full engineering risk analysis for the device constituent part 
and combination product as a whole (including the drug constituent part).  For the purposes of 
this guidance, the URRA is the systematic use of available information to identify use-related 
hazards and to estimate the use-related risk.  Additionally, the URRA should consider the 
intended use, as well as reasonably foreseeable misuse, and should focus on the users, use 
environment, user interface, and user tasks.  When an applicant for a combination product is 
submitting a URRA, FDA recommends submitting it as a separate risk analysis and not with the 
full engineering risk analysis.27   
 
 
Q-8.    What considerations may apply for training as part of the user interface for 
combination products? 
 
During product HFE development, a determination should be made regarding whether training 
will be part of the user interface.  This determination should be based on an analysis of the 
intended users, use environments, and uses of the proposed combination product and whether 
training will occur consistently.28   
 
Combination products are used in a variety of use environments and by different intended users, 
such as, hospital surgery rooms by a health care provider (HCP), emergency first responder 
settings by HCP, in-home procedures by HCP, and outside of a health care environment (e.g., 
home, schools) by patients and lay caregivers.  Likewise, how training is provided varies with 
how the product is distributed (e.g., to a health care facility or to the patient).  For products 
dispensed to the patient, the patient may be trained at the HCPs office (e.g., with printed 
materials, with a training version of the product, or with the actual product), or training may 
occur at the pharmacy upon patient request.  Also, in some instances the user may not receive 
training.  Furthermore, some combination products are used daily, other combination products 
are used intermittently (e.g., weekly, monthly) or on an as needed basis (e.g., an emergency-use 
injector to treat anaphylaxis).  In addition, for infrequently used products, the memory of 
knowledge and information gained through training can decrease over time (training decay).  All 
of these factors should be considered in determining the most appropriate training program for 
the combination product. 
 
Because of the range of combination products, user interfaces, use environments, intended users, 
and training locations, FDA recommends HF validation training considerations such as the 
following: 
 
 
26 For information on risk analysis tools such as failure mode effects analysis (FMEA) or fault tree analysis (FTA), 
see the guidance for industry and FDA staff Applying Human Factors and Usability Engineering to Medical 
Devices. 
27 For additional information see section 6, Preliminary Analyses and Evaluations, in the guidance for industry and 
FDA staff Applying Human Factors and Usability Engineering to Medical Devices. 
28 For additional information see section 8.1.4, Participant Training, in the guidance for industry and FDA staff 
Applying Human Factors and Usability Engineering to Medical Devices. 
9 
 
  Contains Nonbinding Recommendations 
 
  If training is part of the user interface design requirements, the training program itself 
should be validated.  The training program validation should include the procedures used 
to ensure consistent and reliable training is provided for all intended users.  The training 
program validation should also include the method for training the trainers.  The 
combination product HF validation study submission should include the intended training 
program, including any repeat training, if applicable, and all materials the users are to 
receive with the final finished combination product.29     
 
  If the training is not part of the user interface design requirements, then the combination 
product user interface design should support safe and effective use without training. 
 
  If the training is optional or the provision of training cannot be ensured, then the 
combination product HF validation study may test both trained and untrained users to 
evaluate risk mitigation for both user populations.  In some instances (e.g., if the 
untrained users are the higher risk scenario), it may be acceptable to test only untrained 
users.   
 
 
Q-9.    What is the difference between an HF actual-use validation study and an actual-
use/clinical home-use study? 
 
HF actual-use validation studies to validate the user interface may occur in circumstances when 
the combination product use, use environments, or other aspects are particularly complicated, 
poorly understood, or difficult to simulate.  Also, HF actual-use validation studies may occur 
when simulated-use test methods are otherwise inadequate to evaluate users interactions with 
the final finished combination product.  Compared to the HF simulated-use validation study, the 
HF actual-use validation study assesses the user interface in representative patients who receive 
actual medical care.  As with other HF studies, these HF actual-use validation studies are 
observed by an HF evaluator.     
 
FDA emphasizes that the HF actual-use validation study is different from, and should not be 
confused with, other clinical studies that involve the actual use of the study product.  
Specifically, there can be different investigations of clinical safety and effectiveness of products 
where a clinical study participant self-administers an investigational product at home over the 
duration of a clinical investigation (e.g., a standalone drug oral tablet; for a combination product 
investigation, a drug prefilled autoinjector).  These other studies have a range of different 
descriptive terms (e.g., phase 1, 2, 3; clinical home-use; patient handling studies; actual-use 
studies; open-label use; open-label safety use).  In those contexts, the term actual use has been 
a source of confusion.  In this guidance, FDA emphasizes that these other clinical studies have 
different purposes and are outside the scope of this document because they are designed to 
establish safety and effectiveness of the proposed product.  In the studies described in this 
 
29 For additional information on providing information to support FDA review of the proposed training, see the draft 
guidance for industry and FDA staff Contents of a Complete Submission for Threshold Analyses and Human 
Factors Submissions to Drug and Biologic Applications.  When finalized this guidance will represent FDAs current 
thinking on this topic. 
 
10 
 
  Contains Nonbinding Recommendations 
 
paragraph, the user interface is not observed by an HF evaluator and the studies are not HF 
actual-use validation studies.   
 
In instances where an applicant may want to collect HF actual-use validation data as part of a 
clinical study, given the HF actual-use validation study and the clinical study have different 
primary objectives and endpoints, the Agency recommends that the applicant submit their 
proposal to the Agency for review and comment.  Applicants should carefully consider whether 
differences in study participant training and/or supervision of study participants or other aspects 
of the clinical study design may negatively impact the ability of the HF actual-use data to 
validate the user interface.30  
 
 
Q-10.  Are there any considerations for formative HF evaluation protocols or formative HF 
study results? 
 
Overall, formative31 HF evaluations should be part of the applicants HFE process and will play 
an important role in identifying user needs and how the user interface affects user interactions.  
HF formative evaluations are iterative throughout development; i.e., from early prototypes to the 
stage when the user interface of the entire combination product is finalized.  Therefore, FDA 
generally reviews formative HF information in the following two circumstances: 
 
  Summaries of formative HF evaluations as background information to support review of 
a draft HF validation study protocol. 
 
  Formative HF evaluations as part of the overall HF process and HF report that is 
provided in the marketing application for a combination product.  This informs FDA on 
how the user interface design was developed for optimization with respect to safe and 
effective use, as well as important outcomes of the evaluations such as understanding of 
user interactions and identifying combination product critical tasks.   
 
 
Q-11.  What HF information and/or data should be provided to support initiating clinical 
investigations for a combination product? 
 
In an investigational application (IND or IDE), one of FDAs objectives in reviewing clinical 
investigation protocols before implementation is to help protect the rights, safety, and welfare of 
human subjects (subjects).  Consistent with HFE principles as part of combination product 
development, the applicant should consider whether the risk of incorrect use or failure to perform 
user tasks with the combination product could cause harm to subjects.  For this assessment FDA 
recommends the following:  
 
 
30 For additional information on HF actual-use validation studies, see the guidance for industry and FDA staff 
Applying Human Factors and Usability Engineering to Medical Devices, section 8.3 (the actual use testing 
described in this section of the guidance is the same as the HF actual-use validation studies discussed in Q-9). 
31 For information on formative evaluations, see the guidance for industry and FDA staff Applying Human Factors 
and Usability Engineering to Medical Devices, sections 3.3 and 6.4.3. 
11 
 
  Contains Nonbinding Recommendations 
 
  To minimize the risk of harm in a clinical investigation, before beginning a clinical 
investigation, applicants should conduct a URRA in the context of the risk mitigation 
measures to be used in the clinical investigation. 
 
  If the results of the applicants URRA suggest that the use-related risks to the subjects 
are: 
 
-  Acceptable (i.e., URRA results would not preclude proceeding with the clinical 
investigation), FDA may request the URRA if there are questions regarding safety of 
the subjects.   
 
-  Unacceptable (i.e., URRA results would preclude proceeding with the clinical 
investigation), then before beginning the clinical investigation, the applicant should 
submit the URRA results and the applicants rationale for using HF validation for 
purposes of a clinical investigation,32 to demonstrate that the applicants proposed 
measures adequately mitigate the risks.  Assuming FDA agreement with the URRA 
results and agreement that HF validation is appropriate, then FDA recommends the 
applicant submit a draft HF validation study protocol for FDA feedback before 
proceeding with HF validation.  Further, to assess the HF risk mitigations, FDA 
recommends submission of the HF study results to the IND/IDE, before beginning the 
clinical investigation. 
 
In some circumstances the applicants URRA may show that the use-related error would not 
result in subject harm, but could jeopardize the evaluability of the study results.  In such 
circumstances if the applicant wishes to seek FDAs feedback, the applicant may request 
feedback in accordance with the procedures associated with the application type (see Q-15 for 
additional information regarding meeting requests with FDA).   
 
 
Q-12.  Does FDA expect the HF validation study that supports market authorization to be 
conducted at a certain development phase of the combination product? 
 
An HF validation study is generally conducted before submission of the marketing application, 
once the final design of the user interface has been determined.  The HF validation study report 
is submitted to the marketing application to support that the combination product can be used 
safely and effectively by intended users, for its intended uses, and in the expected use 
environment(s).33  Applicants should conduct the appropriate iterative HF studies throughout the 
development process, but the HF validation study is generally conducted with the final finished 
combination product.  If the HF validation study is not conducted with the final finished 
combination product,34 the user interface evaluated in the HF validation study should be 
sufficiently representative of the user interface of the final finished combination product.  In such 
 
32 Note, this validation is not for the purpose of the final finished combination product validation. 
33 For applicants leveraging a master file for HF data, in some instances, the master file data may suffice for one 
constituent part alone, but not for the combination product as a whole. 
34 For example, if it is determined that an HF validation study is needed prior to the start of a clinical investigation, 
as described in Q-11. 
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  Contains Nonbinding Recommendations 
 
circumstances, the applicant should provide a justification for relying on the representative test 
product as an acceptable surrogate for the final finished combination product (also see Q-13).   
 
 
Q-13.   What HFE principles should be considered when modifying a combination product? 
 
When planning a combination product design change, the URRA should include all aspects of 
the combination product to be modified and all elements of the combination product that may be 
affected by the modifications.  This may occur when a manufacturer is modifying a combination 
product:  (1) after completion of the clinical investigations to establish safety and effectiveness 
but before marketing authorization, (2) after an HF validation study identified unacceptable 
residual use-related risks, or (3) after the product is on the market.  Consistent with HFE 
principles, whether any additional HF validation study should be conducted is based on the 
acceptability of the results of the URRA of the proposed modifications.  In some instances, the 
new HF validation study may be limited in scope to evaluate those use scenarios and 
combination product critical tasks that are impacted by the modifications.35 
 
FDA notes that the data and information needed to support a combination product design change 
(e.g., prefilled syringe to an autoinjector, or associated change in the drug constituent part) may 
involve more than an HFE assessment and such other data are beyond the scope of this 
document.36 
 
 
Q-14.   What are FDA review processes for combination product draft HF validation study 
protocols and draft labeling? 
 
Draft HF validation study protocols will be reviewed in the time frame consistent with the lead 
center review program and user fee commitments or policies associated with the application 
type.   
 
When labeling is submitted as part of the draft HF validation study protocol, a comprehensive 
labeling review will be performed by the labeling leads in each center to provide 
recommendations to the applicant prior to conducting the HF validation study.37  This is done to 
minimize the likelihood of labeling revisions being needed after completion of the HF validation 
study. 
 
 
 
35 For additional information on the principles of risk analysis and HF validation study of modified products, see 
section 8.2, Human Factors Validation Testing, in the guidance for industry and FDA staff Applying Human Factors 
and Usability Engineering to Medical Devices. 
36 For additional information see the draft guidance for industry Bridging for Drug-Device and Biologic-Device 
Combination Products (December 2019).  When finalized this guidance will represent FDAs current thinking on 
this topic.     
37 See FDA MAPP 6701.1, Procedures for DMEPA Intra-Center Consult to DMPP on Patient-Oriented Labeling 
Submitted with Human Factors Validation Study Protocols, available at 
https://www.fda.gov/media/131008/download. 
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  Contains Nonbinding Recommendations 
 
Q-15.   How do I obtain information from and provide information to FDA on my 
combination product HF program?  
 
FDA encourages applicants to request early discussions with FDA regarding their HF program 
and the type of HF studies that might be appropriate or necessary in the planned submission.    
Additionally, if applicants anticipate design changes during product development before launch, 
FDA strongly encourages meetings during the early planning stages.  Discussion topics might 
include how to add a new presentation to the development plan and/or how to bridge to existing 
data.  Such discussions should provide clarity on the applicants development plan and on FDAs 
recommendations and expectations for HF studies and the sequence of the development program.  
Where appropriate, the applicant may request HF-focused meetings for more detailed 
discussions.38  For a combination product, applicants should submit meeting requests, and any 
other information, as appropriate, for feedback or review as discussed in this guidance, to the 
lead center using the process and procedures of the lead center for the application type.  The 
meeting request should indicate that the discussion is for a combination product and request 
participation of all relevant centers and OCP, as appropriate.   
 
38 For information on requesting FDA feedback see the guidance for industry and FDA staff Requesting FDA 
Feedback on Combination Products (December 2020).  For information on PDUFA submissions and meetings see 
the draft guidance for industry Formal Meetings Between FDA and Sponsors or Applicants of PDUFA Products 
(December 2017) (when finalized this guidance will represent FDAs current thinking on this topic).  For 
information on requesting meetings for device application types, see the guidance for industry and FDA staff 
Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program (June 2023).   
 
 
 
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