Human Factors Studies and Related Clinical Study Considerations in Combination Product Design and Development

Human Factors Studies and Related

Clinical Study Considerations in

Combination Product Design and

Development

Draft Guidance for Industry and

FDA Staff

This guidance document is for comment purposes only.

Submit one set of either electronic or written comments on this draft guidance by the date

provided in the Federal Register notice announcing the availability of the draft guidance.

Submit electronic comments to http://www.regulations.gov. Submit written comments to the

Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers

Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with the docket

number listed in the notice of availability that publishes in the Federal Register.

Additional copies of this guidance are available from the Office of Combination Products

website at http://www.fda.gov/CombinationProducts/default.htm.

For questions on the content of this guidance, contact the Office of Combination Products at

[email protected] or [email protected].

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Devices and Radiological Health,

Center for Drug Evaluation Research,

Center for Biologics Evaluation and Research, and

Office of Combination Products in the Office of the Commissioner

February 2016

Contains Nonbinding Recommendations

Table of Contents

I. INTRODUCTION............................................................................................................. 2

II. BACKGROUND ............................................................................................................... 3

III. HUMAN FACTORS ......................................................................................................... 5

A. Glossary and Concepts ......................................................................................... 5

B. Evaluation of Use-Related Risk ........................................................................... 6

1. Critical Tasks ........................................................................................................ 7

2. Intended Users and Use Environment ................................................................ 8

3. Training ................................................................................................................. 8

C. Human Factors-Formative Studies ..................................................................... 9

D. Human Factors Knowledge Task Studies ......................................................... 12

E. Human Factors Validation Studies ................................................................... 10

1. Human Factors-Simulated Use Validation Studies ......................................... 10

2. Human Factors-Actual Use Validation Studies ............................................... 10

IV. PROCESS CONSIDERATIONS ................................................................................... 12

A. Considerations on Whether to Submit Combination Product Human Factors

Study Data ........................................................................................................... 12

B. Considerations for Design Changes After HF-Validation .............................. 14

C. Human Factors Information to Submit in a Combination Product

Investigational Application ................................................................................ 14

D. Marketing Application Review of HF Studies and Certain Labeling ............ 15

V. RELATIONSHIP OF HUMAN FACTORS AND MAJOR CLINICAL STUDIES

OF THE COMBINATION PRODUCT ........................................................................ 16

VI. HOW TO OBTAIN ADDITIONAL INFORMATION ............................................... 17

APPENDIX A: USER TASK FAILURE EXAMPLES ........................................................ 18

Contains Nonbinding Recommendations

Human Factors Studies and Related Clinical Study Considerations 1

in Combination Product Design and Development

Draft Guidance for Industry and FDA Staff 5

This draft guidance, when finalized, will represent the current thinking of the Food and Drug 7

Administration (FDA or Agency) on this topic. It does not establish any rights for any person 8

and is not binding on FDA or the public. You can use an alternative approach if it satisfies the 9

requirements of the applicable statutes and regulations. To discuss an alternative approach, 10

contact the FDA staff responsible for this guidance as listed on the title page. 11

I. INTRODUCTION AND SCOPE 14

This document provides guidance to industry and FDA Staff on the underlying principles of 16

human factors (HF) studies during the development of combination products as defined under 21 17

CFR Part 3. This guidance describes Agency recommendations regarding HF information in a 18

combination product investigational or marketing application and clarifies the different types of 19

HF studies; the recommended timing and sequencing of HF studies; and how HF studies are part 20

of the process to maximize the likelihood that the combination product user interface is safe and 21

effective for use by the intended users, uses, and environments. In addition, the guidance 22

describes how HF studies relate to other clinical studies. The guidance also provides process 23

considerations for HF information in investigational or marketing applications to promote 24

development and timely review of safe and effective combination products. 25

This guidance focuses on HF issues related to combination products that are comprised of a drug 27

or biological product and a device (also referred to in this guidance as medical device) for review 28

in an investigational or marketing application submitted to the Center for Biologics Evaluation 29

and Research (CBER), the Center for Devices and Radiological Health (CDRH), or the Center 30

for Drug Evaluation and Research (CDER). The application types include an investigational 31

device exemption application (IDE), an investigational new drug application (IND), biologics 32

license application (BLA), new drug application (NDA), or premarket approval application 33

(PMA). However, the principles and recommendations may be applicable to combination 34

products reviewed under other types of applications (e.g., premarket notification (510(k)) or 35

abbreviated new drug application (ANDA)) as appropriate.

This guidance has been prepared by the Office of Combination Products in the Office of Special Medical Programs

in the Office of the Commissioner in association with the Center for Biologics Evaluation and Research, the Center

for Drug Evaluation and Research, and the Center for Devices and Radiologic Health.

The applicability of HF studies for certain combination product design changes under the 510(k) or ANDA

program are beyond the scope of this document. Applicants who are considering whether the combination product

design change would change the center assignment should contact the Office of Combination Products

(combination@fda.gov

) for questions on the center assignment. For information on the application types within a

center, contact the respective center jurisdiction officers at CDERproductjurisdiction@fda.hhs.gov ,

CDRHproductjurisction@fda.hhs.gov, or cberombusmana@fda.hhs.gov. Applicants preparing to submit a

combination product for review under an ANDA that may include HF studies should contact the CDER Office of

Contains Nonbinding Recommendations

Related information is available in the Agency Guidance Applying Human Factors and Usability 37

Engineering to Optimize Medical Device Design

and the Agency Draft Guidance Safety 38

Considerations for Product Design to Minimize Medication Errors.

Additionally, this guidance 39

supplements other existing guidance documents developed by CBER, CDRH, CDER, and the 40

Office of Combination Products (OCP) that describe other aspects of product development. (See 41

Section VI for a list of some additional guidance documents.) 42

FDA’s guidance documents, including this guidance, do not establish legally enforceable 44

responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be 45

viewed only as recommendations, unless specific regulatory or statutory requirements are cited. 46

The use of the word should in FDA’s guidances means that something is suggested or 47

recommended, but not required. 48

II. BACKGROUND 50

Combination products, as described in 21 CFR Part 3, are comprised of any combination of a 52

drug and a device; a device and a biological product; a biological product and a drug; or a drug, a 53

device, and a biological product.

The constituent parts of a combination product retain their 54

regulatory status (as a drug, device, or biological product) after they are combined. Accordingly, 55

a combination product remains subject to the regulatory requirements associated with its 56

constituent parts. 57

Generally, HF studies are conducted to evaluate the user interface of a product. FDA often 59

receives requests to clarify how HF concepts apply to the development of a combination product 60

when one of the constituent parts is a device. Inquiries include: 61

• What types of HF studies might need to be conducted for the combination product? 63

• When is the appropriate time to perform HF Validation studies? 64

• What is the role of HF studies as compared to other types of clinical studies? 65

• Are additional HF studies necessary when the design of the combination product 66

changes? 67

Other general inquiries relate to regulatory considerations for combination products such as 69

when a HF study is subject to review and approval by an institutional review board (IRB),

and 70

how HF studies are considered in User Fee determinations.

Generic Drugs at GenericDrugs@fda.hhs.gov regarding controlled correspondence subject to the Generic Drug User

Fee Act (GDUFA) performance goals to discuss considerations related to HF studies.

Guidance for Industry and FDA Staff, Applying Human Factors and Usability Engineering to Optimize Medical

Device Design, accessible at

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM259760.

pdf.

Draft Guidance Safety Considerations for Product Design to Minimize Medication Errors, accessible at

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM331810.pdf

FDA’s draft guidance documents represent FDA’s proposed approach on the topics.

For purposes of this document the term “drug” also refers to biological products unless otherwise indicated.

Clinical studies regulated under 21 CFR Part 312 (IND requirements) or Part 812 (IDE requirements) and clinical

studies intended to support an investigational or marketing application are subject to applicable requirements under

21 CFR Parts 50 and 56. See 21 CFR 50.1(a), 50.20, 56.101(a), and 56.103. As used in this document, clinical

Contains Nonbinding Recommendations

For medical devices, the use of human factors and usability engineering (e.g., applying the 72

knowledge of human behavior, abilities, and limitations to the design of a medical device) plays 73

a key role in maximizing the likelihood that the device will be safe and effective for use by the 74

intended users, for the intended uses, and for the intended use environments. Under the medical 75

device design control requirements described in 21 CFR 820.30, design validation must include a 76

risk analysis where appropriate. As part of the risk analysis, device manufacturers should 77

identify and analyze potential use-related hazards, including lessons learned from reported errors 78

with similar products, and as appropriate, incorporate and validate design features that mitigate 79

or eliminate these hazards. This assessment informs the device design development to eliminate 80

or minimize use errors that could cause harm or compromise medical treatment. 81

For a drug product, goals for reducing use-related hazards are reflected in the process and data 83

that support selection of the drug formulation, assurance of product quality,

drug risk 84

management activities,

and in pharmaceutical quality system principles.

Drug development 85

should take into account the user interface and factors that can reduce the risk for medication 86

errors; i.e., features to enhance patient safety. Such features include product appearance, 87

identification markings (such as imprint codes on solid oral dosage forms), container closure, 88

packaging configurations, labeling (including labels on containers and cartons), and 89

nomenclature.

The Prescription Drug User Fee Act IV (PDUFA IV)

provides that one of the 90

development goals is to ensure drug safety by prospectively designing a drug that minimizes the 91

risk for errors made by intended end users.

study has the same meaning as investigation or clinical investigation as defined in Parts 50, 56, 312, and 812, as

applicable.

For information on user fee assessment under the Prescription Drug User Fee Act (PDUFA) for applications

containing clinical studies, see FDA Guidance Submitting Separate Marketing Applications and Clinical Data for

Purposes of Assessing User Fees accessible at

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079320.pdf

As described in that document the term “clinical data, for purposes of assessing user fees, encompasses a broad

range of studies that are purported to be adequate and well-controlled investigations submitted in support of

approval. This includes [1] study reports or literature of what are explicitly or implicitly represented by the

applicant to be adequate and well-controlled trials for safety or effectiveness; or [2] reports of comparative activity

(other than bioequivalence and bioavailability studies), immunogenicity, or efficacy, where those reports are

necessary to support a claim of comparable clinical effect. As applicable, FDA will determine whether a HF study

would meet these criteria.

See Guidance for Industry Q8(R2) Pharmaceutical Development accessible at

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073507.pdf

See Guidance for Industry Q9 Quality Risk Management accessible at

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073511.pdf

See Guidance for industry Q10 Pharmaceutical Quality System accessible at

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM073517.pdf

As defined in FD&C Act section 201(m), “labeling” means “all labels and other written, printed, or graphic

matters (1) upon any article or any of its containers or wrappers, or (2) accompanying such article.” As defined in

FD&C Act section 201(k), “label” means “a display of written, printed, or graphic matter upon the immediate

container of any article.”

See information under Item-IX accessible at

http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119243.htm

Measures for designing such a drug could address, among other things, concerns regarding: look-alike and sound-

alike proprietary names; unclear label abbreviations, acronyms, and dose designations; and other label and

packaging design that may lead to user error.

Contains Nonbinding Recommendations

For a combination product that includes drug and device constituent parts, both the device design 94

control requirements and drug development expectations apply to the entire combination 95

product.

Therefore, when evaluating a combination product, the design of the product user 96

interface should be assessed in HF studies if needed to ensure that use-related hazards associated 97

with the product are eliminated or mitigated to reduce patient adverse events and medication 98

errors attributable to use-related errors. This document focuses on human factors considerations 99

for combination products to promote consistency in their design, development and review. 100

101

III. HUMAN FACTORS 102

103

A. Glossary and Concepts 104

105

For purposes of this document, the following definitions and concepts apply to HF studies, the 106

final finished combination product, and the major clinical study. For additional information on 107

these terms see the sections that follow the glossary. For related definitions see Agency 108

guidance Applying Human Factors and Usability Engineering to Optimize Medical Device 109

Design.

110

111

1. Human Factors Study (or HF Study): A study conducted with representative users to 112

assess the adequacy of the combination product user interface design to eliminate or 113

mitigate potential use-related hazards. Typically, HF studies are part of an iterative 114

design process that is driven by the complexity of the combination product and the nature 115

of the safety considerations. The HF study evaluates: (i) the ability of the user to perform 116

critical tasks, and (ii) the ability of the user to understand the information in the 117

packaging and labeling, such as product labels or instructions for use, that inform the 118

user’s actions and that are critical to the safe and effective use of the combination product 119

(e.g., product preparation, administration, maintenance and disposal, or what actions to 120

take if an adverse reaction occurs). Both types of evaluations may be part of the HF 121

Formative and HF Validation studies described below. 122

123

a. HF Formative Study: A study conducted on a combination product prototype user 124

interface at one or more stages during the iterative product development process to 125

assess user interaction with the product and identify potential use errors. HF 126

Formative studies are iterative and inform the need for user interface changes (e.g., 127

product design or labeling changes) and inform the content of the HF Validation 128

study. For additional information on HF Formative studies see Section III.C. 129

130

HF Validation Study:

A study conducted to demonstrate that the final finished 131

combination product user interface can be used by intended users without serious use 132

errors or problems, for the product’s intended uses and under the expected use 133

conditions. The study should demonstrate that use-related hazards for the final 134

finished combination product (see glossary item A.2 below) have been eliminated or 135

that the mitigation for residual risks is acceptable; i.e., the benefit of product use 136

For combination products that include a device constituent part, design controls must be applied to the

combination product. See 21 CFR 4.4; 78 FR 4307 (Jan. 27, 2013). Current Good Manufacturing Practice

Requirements for Combination Products is accessible at

https://www.federalregister.gov/articles/2013/01/22/2013-

01068/current-good-manufacturing-practice-requirements-for-combination-products.

Contains Nonbinding Recommendations

outweigh the residual risk of the product. The study participants are representative of 137

the intended users and the study conditions are representative of expected use 138

conditions. 139

140

2. Final Finished Combination Product: The final finished combination product is the 141

product intended for market and submitted in the marketing application. This term 142

applies to the combined final device, drug, and/or biological product configuration 143

including all product user interfaces (e.g., proposed packaging, labels and labeling, 144

including training programs). 145

146

3. Major Clinical Study (or Major Clinical Trial): As opposed to a HF study, a major 147

clinical study is a larger scale clinical study that occurs during a later phase of 148

combination product development. Major clinical studies provide the primary support for 149

the safety and effectiveness of a product for a proposed indication (e.g., adequate and 150

well-controlled studies

In addition to adequate and well-controlled studies, other 151

types of later phase larger scale clinical studies may also be considered major clinical 152

studies; e.g., a long-term extension study. . 153

154

B. Evaluation of Use-Related Risk 155

156

Consistent with a risk-based design and development paradigm, the foundation for HF study 157

designs, testing and evaluation should be a use-related risk analysis of a combination product. A 158

use-related risk analysis is a crucial step to help identify use-related hazards associated with the 159

combination product, as well as to characterize high-risk hazards so they can be mitigated or 160

eliminated through improved product interface design. The use-related risk analysis will help 161

identify critical tasks that should be evaluated in a HF study, inform the priority of testing the 162

tasks in a HF study, and determine if there are specific use scenarios to include in testing. A 163

variety of methods can be used to develop and analyze use-related hazards. Two methods 164

frequently used are Failure Mode and Effects Analysis (FMEA) and Fault Tree Analysis 165

(FTA).

166

167

The use-related risk analysis should take into account: all the intended uses, users, and use 168

environments; therapeutic or diagnostic procedures associated with the use of the combination 169

product; similar products used within the environments; and any associated medical factors that 170

may affect the safe use of the combination product. In addition, if previous models of the same 171

or similar combination products exist, the risk analysis should incorporate information on known 172

use-related problems with those products. This information can be obtained from the applicant’s 173

own experience as well as from public sources such as literature, adverse event reports, and 174

product safety communications. 175

176

See CFR 314.126.

The term Major Clinical Study is consistent with other terms such as “phase-3 clinical study,” “key clinical

study,” and “pivotal studies or trials.”

For more information on FMEA, FTA and other risk analysis methods, see Guidance for Industry and FDA Staff,

Applying Human Factors and Usability Engineering to Optimize Medical Device Design, accessible at

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationsandGuidance/Guidancedocuments/UCM259760.

pdf.

Contains Nonbinding Recommendations

1. Critical Tasks 177

178

The use-related risk analysis should identify critical tasks.

Critical tasks are user tasks that, if 179

performed incorrectly or not performed at all, would or could cause harm to the patient or user, 180

where harm is defined to include compromised medical care. Thus, categorizing a task as 181

critical is dependent on the unique considerations for each combination product. The Agency 182

expects the risk analysis for the combination product to include an identification of all the critical 183

tasks required for using the combination product, the consequences for failing to perform each 184

critical task correctly, and the strategies that have been applied in the design of the user interface 185

to eliminate or reduce risks to acceptable levels. Such an assessment should include 186

considerations of the indication, the users, the environment and other conditions that might 187

influence the importance of a particular task. Some examples of critical tasks to illustrate this 188

concept include: 189

190

• The patient being able to successfully self-administer a drug at the prescribed dose 191

identified in the labeling. Failure to successfully perform this task could harm the patient 192

due to mis-dosing, under-dosing, overdosing, or inability to deliver a dose. 193

• The user being able to safely dispose of a used syringe. Failure to successfully perform 194

this task could result in needle sticks. 195

• The patient being able to appropriately navigate the user interface for a patient-controlled 196

analgesia (PCA) delivery system. Failure to successfully perform this task could result in 197

missed doses, inappropriate repeat doses, or overdoses. 198

• The user being able to understand instructions for inserting a capsule into an inhaler to 199

release the drug, and being able to insert the capsule. Failure to successfully perform this 200

task could result in the patient swallowing the capsule instead of inhaling the contents, 201

lack of treatment effect, or medication related adverse events. 202

• The user being able to distinguish a product from others of similar appearance. Failure to 203

successfully perform this task could result in delivery of the wrong drug. 204

• The user being able to complete a series of several critical tasks required to prepare and 205

administer a reconstituted drug from a combination product kit containing a prefilled 206

diluent syringe, drug vial, empty syringe, needle, transfer device and infusion pump. 207

These tasks could include preparing the drug under sterile conditions, connecting the 208

system, and introducing the reconstituted drug solution into an infusion pump. Failure to 209

successfully complete any of these tasks could result in medication errors and/or use- 210

related infection. 211

212

Appendix A identifies task failures that may occur with general categories of combination 213

products such as injectors and inhalers. The information can be used to guide the applicant when 214

conducting a risk analysis, which is recommended for any combination product being developed. 215

Additionally, these task failure examples may apply to other types of combination products, and 216

can be used as a reference to help identify and evaluate hazards for other combination products. 217

218

For additional information on critical tasks, see Sections 7.3 and 7.4 of Applying Human Factors and Usability

Engineering to Optimize Medical Device Design at

http://www.fda.gov/RegulatoryInformation/Guidances/ucm259748.htm

Contains Nonbinding Recommendations

2. Intended Users and Use Environments 219

220

Prior to performing a risk analysis, it is important to identify all intended users and use 221

environments for the combination product. Intended users may be categorized into distinct user 222

groups by their different characteristics (e.g., use responsibilities, tasks performed, age ranges, 223

skills, or experience levels). For combination products, distinct user groups generally are health 224

care professionals (HCPs) and lay users (non-health care professionals). Within these two 225

groups there are likely further subgroups based on different tasks, roles, abilities and education. 226

Subgroups of the HCP user population can include those with significantly different roles (e.g., 227

nurses, pharmacists, physicians, emergency medical technicians, home health care providers). 228

Also, within the HCP user population there may be individuals that have experience with the use 229

of similar products and individuals that do not (e.g., injector-experienced vs naïve) or that do or 230

do not have experience with similar appearing products with different instructions for use or 231

different hazards. In addition, both the professional role and experience of HCPs can influence 232

interactions with a product. These various differences may justify treating HCPs as distinct user 233

groups that should be evaluated in the HF study as such. 234

235

Lay users (non-health care professionals) are those who use the product for self-administration 236

(the patient) or those who administer the product to others as a caregiver (e.g., a family member, 237

sports coach). Within this population, experience of individual users with similar products or 238

products under development may vary widely. For example, when considering a drug-239

autoinjector combination product, some lay users may be naïve to the use of any autoinjector or 240

may be naïve to the use of certain types of autoinjectors; e.g., those for single dose disposable 241

versus single patient reusable products. Also, lay users may have experience with a different 242

product that might influence their interaction. As a result of these differences, there may be 243

distinct subgroups that should be considered in the use-related risk analysis. As applicable, the 244

HF study should incorporate separate subgroups of lay users. 245

246

Environments of use can have diverse characteristics that affect the users’ interactions with the 247

product. Thus, the intended environment of use is another important consideration in designing a 248

HF study. Combination products may be used in various professional health care / clinical 249

settings that include emergency departments, intensive care units, inpatient bedsides, procedure 250

suites, outpatient clinics, mobile units, and stocking and storage locations. Likewise, they can 251

also be used in non-clinical settings including homes, schools, offices, and various modes of 252

transportation (e.g., ambulances, airplanes). These environments may vary with respect to 253

temperature, lighting and noise levels, ambient activity levels, number of people in the vicinity, 254

and the availability of associated/accessory medication or devices. Also, a combination product 255

that is intended for home use may be confused with other family member or pet medications 256

stored in the same location. Such environmental conditions may lead to use errors. These 257

environmental factors should be considered in the use-related risk analysis, and included within 258

the design of the HF study as appropriate when they present a use hazard. 259

260

3. Training 261

262

Training is often proposed as a way to mitigate or control risks. However, before determining if 263

training is appropriate for the combination product, first it is important to eliminate risks that are 264

inherent to the product design. If there are residual risks, the next step is to determine if training 265

Contains Nonbinding Recommendations

is needed. For example, for a new product that is developed as similar to or an alternative to a 266

currently marketed product with use techniques that are well understood by the users, then 267

training may not be necessary. Such an example might be a prefilled syringe with a staked 268

needle for use by a health care professional. On the other hand, if there are residual risks for 269

which training may be appropriate, the next step is to consider whether there is an opportunity 270

for training, and if so, whether there is an expectation that training will routinely and consistently 271

occur, before the first use of the combination product. In cases where training would be 272

appropriate but is not expected to routinely or consistently occur, the HF study should evaluate 273

the user interface in the absence of training.

274

275

For combination products when training is expected or needed to control or mitigate residual 276

use-related hazards, it is important to determine what the training is likely to encompass and how 277

it will be performed, who is responsible for conducting the training, and how to ensure 278

consistency in the training method. Consider, for example, a combination product being 279

developed for a hospital-based surgical procedure. A risk analysis might determine that HCP 280

training is required prior to the first use of the product to minimize the risk of errors related to 281

assembling all the combination product constituent parts, preparing the treatment area and the 282

surgical device constituent part before beginning the procedure, administering the drug 283

constituent part(s), monitoring patient responses after using the product, and/or managing 284

interactions across multiple users during the procedure. Due to the nature of the product and its 285

use environment, all users would be expected to receive training before using the product. The 286

HF study would evaluate the adequacy of the training in minimizing these potential risks. In this 287

case, it is likely that FDA would not expect the HF study to evaluate the absence of training. 288

289

In addition, when considering training to mitigate residual risks associated with the user 290

interface, it is important to consider how frequently the training will occur, as well as the length 291

of time between the training session(s) and product use. For some combination products, 292

training and first product use is separated by days, weeks, or months. As such, a significant 293

amount of time may elapse between the training session and product use. Retention of 294

information from the first, and possibly the only, training a user receives can decrease over time 295

(i.e., training decay). For example, for a combination product designed for once a week self-296

injection, post-training information retention one week later can be anticipated to be lower than it 297

would one hour later. If the risk analysis shows that training decay is a source of use-related 298

error, then the HF study design should evaluate the effect of training decay. The HF Validation 299

study should simulate the effect training decay may have on the users; e.g., simulate the training 300

decay by separating the training and simulated use testing by several hours or days. The protocol 301

should justify the interval to simulate the training decay. 302

303

C. Human Factors Formative Studies 304

305

HF Formative studies are designed to evaluate early combination product prototypes, taking into 306

consideration the identified use-related hazards. HF Formative study results guide prototype 307

design changes to eliminate or mitigate use-related hazards identified during the product 308

development process. The use of iterative HF Formative studies optimizes the design of the 309

As appropriate, if user training is necessary, applicants should discuss what methods are appropriate to ensure the

provision of training.

Contains Nonbinding Recommendations

combination product user interface for safety, and minimizes the risk of first discovering use 310

problems during late stages of development (e.g., during an HF Validation study, during a major 311

clinical study, or after finalizing commercial plans.). 312

313

Iterative HF Formative studies and related design modifications are performed until the user 314

interface design appears to be sufficiently optimized for safety and ready for HF Validation 315

testing. Iterative modifications to the user interface may include changes to the physical design 316

attributes, changes to the packaging and labeling (including instructions for use) and changes to a 317

training program. The results of HF Formative studies should inform the design of the final 318

finished combination product. None of the individual subjects in the HF Formative studies 319

should participate in the HF Validation studies to avoid the potential for bias. For information 320

on HF Knowledge Task studies, see Section III.E; for information on HF Validation studies, see 321

Section III.D below. 322

323

D. Human Factors Validation Studies 324

325

HF Validation studies demonstrate that the final finished combination product user interface 326

would maximize the likelihood that the product will be safely and effectively used by intended 327

users, for the intended uses in the intended use environments. There are two types of HF 328

Validation studies: HF Simulated-Use and HF Actual-Use Validation. For most combination 329

products, FDA expects that a HF Simulated-Use Validation study will be sufficient to assess the 330

adequacy of the user interface. 331

332

1. Human Factors Simulated-Use Validation Studies 333

334

The HF Simulated-Use Validation study focuses on confirming that the design of the 335

final finished combination product (i.e., after iterative prototype design changes) user 336

interface adequately mitigates or eliminates the identified use-related risks. Simulation 337

methods for these studies vary and may include the use of a manikin, injection pads, 338

placebo, and other elements intended to simulate the patient, the procedure, or the 339

environment of use. 340

341

The conditions of the HF Simulated-Use Validation study should be sufficiently realistic 342

so that the results HF-Simulated-Use Validation represent relevant aspects of actual use 343

of the product once introduced into the market. Tasks to be performed in the HF 344

Simulated-Use Validation study should include those critical tasks identified in a use-345

related risk analysis that may be associated with user interface problems. The study 346

design should provide for the identification of any unanticipated hazards or unexpected 347

use behaviors that were not previously identified. 348

349

2. Human Factors Actual-Use Validation Studies 350

351

As noted above, FDA expects that for most combination products, a HF Simulated-Use 352

Validation study will be sufficient to assess the adequacy of the user interface design. 353

However, there are rare circumstances when it is difficult to simulate the conditions of 354

use, physical characteristics of the product, or environment of use. Thus, a HF Actual-355

Use Validation study may be needed to confirm the adequacy of the user interface design. 356

Contains Nonbinding Recommendations

HF Actual-Use Validation studies either (1) use the final finished combination product 357

(including the drug, not a placebo) in a simulated use setting or (2) use the final finished 358

combination product in a real (not simulated) environment of use. 359

360

• A HF Actual-Use Validation study of the combination product that includes the 361

actual drug in a simulated use setting may be necessary when the drug can affect 362

the user’s ability to perform a critical task. For example, for a drug that causes 363

coughing on inhalation which could result in incomplete dosing, inhaler designs 364

to minimize the risk of not completing an inhalation could not be evaluated 365

without use of the actual drug. This type of assessment using the drug-device 366

combination product would otherwise occur in a simulated-use setting. 367

368

• The other type of HF Actual-Use Validation study in a real environment of use. 369

For example, based on the hazard analysis and results of an HF Simulated-Use 370

Validation, it may be appropriate to evaluate in a real environment of use use-371

related risks associated with a complex combination product intended for use in 372

crisis/emergency settings or with a combination product that has a complex 373

operating procedure. In these instances, the user’s tasks could be influenced by 374

the presence of noise, rapidly changing circumstances, distractions, etc. 375

Therefore, the need for a HF Actual-Use Validation study is determined on a 376

case-by-case basis. FDA recommends that applicants for combination products 377

discuss with FDA the availability of simulation techniques and whether HF 378

Simulated-Use Validation and HF Actual-Use Validation studies are needed to 379

evaluate the user interface.

380

381

Regardless of the type of HF Validation study, if use errors or problems (e.g., failures, “close 382

calls,” use difficulties, and/or new findings) are identified in an HF Validation study, these 383

should be evaluated to (1) identify the root cause(s), (2) determine the potential for harm 384

(including the clinical significance of such errors or problems and the potential for compromised 385

medical treatment), and (3) determine whether additional measures to eliminate or mitigate 386

hazards are necessary. Regardless of the type of HF Validation study, if the HF Validation study 387

shows that additional measures are necessary to address the risk of failures that are deemed 388

clinically significant, then the HF Validation study will be considered failed. Changes to the 389

user interface may be needed to eliminate or mitigate hazards and a new HF Validation study 390

should be performed to evaluate the changes, with the goal of demonstrating that the 391

modifications minimize the risk to acceptable levels without creating additional hazards. 392

393

Also, if the product design changes or the user population changes, then the completed HF 394

Validation study may or may not be applicable to the design change. A use-related risk analysis 395

should be completed and, dependent upon the findings of the risk analysis, a new HF Validation 396

study may be advisable to support that the modifications continue to minimize the risk without 397

The term “HF Actual-Use Validation study” has a different meaning than similar terms such as “user study” or

“actual use study”. The term “HF Actual-Use Validation study” applies to only the evaluation of the user interface

and associated critical tasks. In contrast, the terms “actual use” or “user study” (without the “HF” qualifier) often

refer to clinical studies such as a major clinical study to evaluate safety and effectiveness of prolonged home use or

to an open label safety study. Those studies have different purposes or mixed purposes and are outside the scope of

this document. FDA recommends against referring to these different or mixed purpose studies as HF studies.

Contains Nonbinding Recommendations

creating additional hazards. If the product design remains unchanged but the applicant seeks to 398

add a new user population, then as applicable, a new use-related risk analysis and new HF 399

Validation study should be performed. See Section V for the relationship of the HF Validation 400

study to the major clinical study. 401

402

E. Human Factors Knowledge Task Studies 403

404

In situations when the understanding of the information provided in a combination product’s 405

labels or labeling is a critical task to using a product safely and effectively, a study to assess the 406

user’s understanding of such information (Knowledge Task study) is appropriate. Knowledge 407

Task studies may occur as part of the HF formative, or HF validation process. However, in 408

comparison to other types of HF studies in which critical task performance is assessed by 409

observing user interaction with the product, Knowledge Task studies focus on the understanding 410

and interpretation of important information in the user interface that will be applied to make use-411

related decisions. The users’ understanding of the labeling is evaluated by questioning test 412

participants and assessing whether the information has been understood. 413

414

Knowledge Task studies may focus on particular aspects of labeling. For example, a Knowledge 415

Task study could evaluate: 416

417

• HCP’s understanding of their roles and responsibilities when introducing a 418

combination product as part of a new procedure, or associated with complex 419

medical/surgical procedures that involve many different HCPs; 420

• The user’s ability to select the appropriate task from a lengthy set of instructions 421

that include different options; 422

• The user’s understanding of how to identify defective or expired product; 423

• The user’s awareness and understanding of the combination product’s pertinent 424

safety information provided in the instructions for use; 425

• The user’s ability to recognize clinical signs, identified in the instructions for use, 426

that would prompt medical attention; e.g., shortness of breath, allergic reaction, 427

weakness, signs of disease progression; or 428

• The user’s understanding of the diagrams provided in the labeling. 429

430

Certain types of Knowledge Task studies are also used in the development of non-prescription 431

products.

Generally, these are quantitative studies that evaluate whether results are statistically 432

significant. 433

434

IV. PROCESS CONSIDERATIONS 435

436

A. Considerations for Submission of Combination Product Human Factors 437

Study Data 438

439

For the following two groups of combination products, generally human factors data should be 440

submitted: (1) products for use outside the health care environment or by laypersons (e.g., 441

For further information about such studies for non-prescription drug products, see Guidance to Industry Label

Comprehension Studies for Nonprescription Drug Products, accessible at

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm143834.pdf

Contains Nonbinding Recommendations

home-use products, products for self-administration by patients or lay-caregivers) and (2) 442

combination products having a device constituent part for which human factors data should be 443

submitted. For combination products that do not fall within these two categories, a risk analysis 444

for the combination product should be completed and the use-related risks reviewed to assess the 445

need for HF studies (see section III.B). If the use-related risk analysis identifies the need for HF 446

studies, then a HF Validation study should be conducted and the results submitted for review. 447

For example, a syringe is not on the list of high priority devices for human factors review, and 448

the following illustrates certain considerations for when a HF Validation study may be needed 449

for a prefilled syringe. 450

451

• A prefilled syringe with a staked needle and needle guard for use by HCPs in an acute 452

care setting: 453

o If the syringe, needle and needle guard design is commonly used and well 454

understood (absent other use-related risk concerns for the combination product as 455

a whole), FDA would not expect a HF Validation study for such products. During 456

the investigational phase when the applicant determines that a HF Validation 457

study may not be needed, the applicant should submit its risk analysis and 458

justification to support the basis of the applicant’s conclusion, and seek Agency 459

comment on the assessment. 460

o If the syringe, needle and needle guard are of a unique/novel design, there are use 461

experience concerns with similar products, or there are other factors that increase 462

the use-related hazard, then an HF Validation study should be conducted. 463

464

• The same prefilled syringe with needle guard for use by patients with neuromuscular 465

disorder or visual impairment: 466

o Because the user characteristics and associated medical symptoms present unique 467

user profiles that may affect safe use of the product, an HF Validation study 468

should be conducted to demonstrate that the product design adequately mitigates 469

the risks for its intended use in these patients, and use environments. 470

471

• The same prefilled syringe with needle guard and a unique application of color to 472

distinguish it from different drugs in similar prefilled syringes to help prevent medication 473

errors: 474

o Even if factors such as indications for use, intended users, and use environment 475

remain unchanged, based on the use-related risk analysis, an HF Validation study 476

may be necessary to ensure that HCPs can readily distinguish the new syringe 477

from similar prefilled syringes containing different drugs. As appropriate, such a 478

study might focus on knowledge-based tasks. 479

480

• The same prefilled syringe with needle guard that is used with various tubing, connectors, 481

pumps and other device components in a high risk procedural setting: 482

o A HF Validation study is likely necessary to assess the entire system. As 483

applicable, the HF Validation study may include detailed assessments of the 484

instructions, diagrams, training or other aspects that might become part of a 485

postmarket safety program. 486

487

Contains Nonbinding Recommendations

Other scenarios and alternative approaches are possible. As with all product development, FDA 488

encourages applicants to contact the Agency to discuss the specific product proposals. 489

490

B. Considerations for Design Changes After HF Validation 491

492

FDA recognizes that combination product design changes may occur premarket or postmarket 493

after HF Validation studies have been completed. For example, during premarket development 494

the results of a clinical trial may reveal design flaws that were not detected in HF Formative or 495

HF Validation studies. Similarly, during postmarket development an applicant may plan a 496

design change to the marketed combination product, for example, to respond to use-related 497

safety reports, complaints/problems, to address a manufacturer-initiated postmarket corrective 498

and preventative action plan, or to meet the needs of an expanded indication or user population. 499

500

Some modifications to a product’s internal design or to some of its external features may not 501

need validation in a HF study (e.g., a change in a material that does not affect user interface). 502

However, design changes made after HF Validation that relate to identified critical tasks or may 503

result in new use-related errors or hazards that could lead to harm should have new HF 504

Validation study assessments. 505

506

When making design changes, the applicant should conduct an updated use-related risk 507

assessment of the new design. FDA encourages applicants to follow the HF principles outlined 508

in this document. Conceptually, this analysis should consider such things as: 509

510

• Does the design change alter the user interface in any way (e.g., audible, tactile, color 511

recognition, user instructions, etc.)? 512

• Does the design change alter an existing critical task or add a new critical task? 513

• Does the design change alter the expected users or their knowledge base? 514

515

To facilitate discussion with FDA, the applicant should provide a proposal about what, if any, 516

additional HF testing is needed. The proposal should include a detailed description of why the 517

change is being made, a description of what specifically is changing, a use-related risk analysis 518

of the new design, and where appropriate a proposal for evaluating potential risk mitigations of 519

the new design and the effects of the change. 520

521

When making a design change to a combination product, FDA encourages applicants to 522

expeditiously identify the change plans and to discuss with the Agency the types of HF and other 523

clinical or non-clinical studies that may be applicable before the applicant’s approval of the 524

design change.

(Also, see Section IV.A for further information that may be useful in 525

considering the HF implications of a design change.) 526

527

C. Review of Human Factors Information in Combination Product 528

Investigational Applications 529

530

The combination product’s specific use-related risk analysis generally informs the Agency’s 531

expectations for whether HF information on a combination product should be submitted in an 532

The use of other types (i.e., non-HF) of studies (e.g., clinical, pharmacokinetic, or non-clinical studies) to evaluate

combination product design changes is beyond the scope of this document.

Contains Nonbinding Recommendations

investigational application. The risk analysis itself should be submitted in the investigational 533

application for the combination product. If the applicant determines from the risk analysis that a 534

HF study is not needed, the applicant should provide the use-related risk analysis along with the 535

justification for this conclusion. If the use-related risk analysis indicates that a HF study is 536

necessary, FDA encourages applicants to submit the following HF information for feedback 537

before commencing the HF Validation study: 538

539

• Use-related risk analysis and any updated risk analysis of design changes; 540

• A summary of HF Formative study results and analysis; 541

• A summary of changes made to the product user interface after the HF Formative studies, 542

including how the results from the HF Formative studies were used to update the user 543

interface and use-related risk analysis; 544

• The draft HF Validation study protocol; and 545

• Intend-to-market labels and labeling (including instructions for use if any are proposed) 546

that will be tested in the HF Validation study. 547

548

When this information is submitted to the investigational application, FDA will review the 549

information, including the use-related risk analysis and the draft HF Validation study protocol, 550

and intends to provide comments or recommendations to increase the likelihood of an acceptable 551

HF study design that will adequately test for potential use failures. Also, during Agency review 552

of draft HF Validation study protocols that include product labeling (e.g., instructions for use), 553

FDA intends to provide preliminary comments on the user interface labels and labeling being 554

However, final labeling is determined after review of the entire marketing application that 555

includes information beyond that in the HF Validation study. 556

557

D. Review of HF Studies and Certain Labeling in Marketing Applications 558

559

As applicable, FDA will review HF Validation study results submitted in the marketing 560

application to assess whether the data confirm validation of the user interface and certain aspects 561

of the proposed labels and labeling (e.g., instructions for use). FDA cautions applicants 562

leveraging a master file for HF data, that in some instances the master file data may suffice for 563

one constituent part alone, but not for the combination product as a whole (e.g., device with a 564

specific drug/biological product). The applicant should determine whether sufficient information 565

would be available in the master file or whether the applicant should conduct and submit 566

additional HF studies for the combination product as a whole. 567

568

During FDA review of labeling

in a marketing application, FDA may determine that the final 569

user interface labeling should differ from the HF Validated labeling. This may occur, for 570

example, based on the results of the major clinical trial, other safety data or medication error 571

data, new nomenclature considerations, and labeling content and format requirements. The 572

labeling assessment also considers current postmarket experience with the same or similar 573

products, which might indicate that modification of the instructions for use is appropriate to 574

mitigate a risk. After review of the marketing application, depending on the potential impact of 575

resulting labeling differences on performance of critical tasks, an additional HF Validation study 576

Labeling review includes consideration of labeling claims that might be provided by a HF study (e.g., user

preference or ease of use) and whether the data support those claims.

Contains Nonbinding Recommendations

may be needed to ensure that the changes minimize the use-related risks without creating 577

additional hazards. 578

579

V. RELATIONSHIP OF HUMAN FACTORS AND MAJOR CLINICAL STUDIES 580

OF THE COMBINATION PRODUCT 581

582

As explained in preceding sections of this document, HF studies of a combination product are 583

conducted as part of the product design controls process. An appropriate HF development 584

program will maximize the likelihood that the combination product user interface is safe and 585

effective for use by the intended users, uses and use environments. However, the HF Validation 586

study is not sufficient to establish the safety and effectiveness of the combination product for the 587

proposed indication. Specifically, data from the major clinical study(ies) establish the 588

combination product’s safety and effectiveness for the proposed indication and the complete 589

labeling summarizes the essential scientific information needed for the safe and effective use of 590

the product.

591

592

Therefore, ideally, before conducting the major clinical study(ies), the HF Validation study 593

should be conducted on the final finished combination product, including the user interface (e.g., 594

instructions for use, training materials, and any other user labeling, if applicable). The HF 595

Validated product would then be ready for further evaluation in the major clinical study(ies) that 596

will be submitted in the marketing application. Noting that in some cases it may be appropriate 597

to conduct your human factors studies in parallel to your major clinical studies or after your 598

clinical studies to address modifications to your product. 599

600

FDA recognizes that in some circumstances the data to support safety and efficacy of the 601

combination product may adequate without the inclusion of the final finished combination in a 602

major clinical trial. For certain products, the sequencing of the HF study prior to the clinical 603

study may be less critical to inform our understanding of the product’s safety and efficacy, 604

allowing for greater flexibility in the timing of the human factors validation study relative to a 605

major clinical studies. In other cases, a sponsor may encounter a need to change the combination 606

product design in the course of the development program, even after clinical studies have been 607

completed. The type and extent of data to support such changes depend on the nature of change, 608

development stage, and other contextual factors, and FDA would consider the totality of the data 609

provided to support the approvability of the combination product in any such circumstances. 610

However, for certain combination products, we might expect or encourage you to use the final 611

finished combination product in your major clinical studies. In such cases, we recommend that 612

you conduct the HF-Validation study on the final finished combination product prior to the major 613

clinical studies. 614

615

And, in all cases, we encourage you to discuss your combination product development plans with 616

the Agency as appropriate and consider such discussion as a component of your development 617

meeting, including the pre-IND, IDE and EOP2 meetings 618

619

See 21CFR 201.56(a)(1).

Contains Nonbinding Recommendations

VI. HOW TO OBTAIN ADDITIONAL INFORMATION 620

621

FDA encourages applicants to request early discussions with FDA regarding their HF program 622

and the type of HF studies that might be appropriate or necessary in the planned submission. 623

Additionally, if applicants anticipate design changes during product development before launch, 624

FDA strongly encourages meetings during the early planning stages. Discussion topics might 625

include how to add a new configuration to the development plan and/or how to bridge to existing 626

data. Such discussions should provide clarity on the applicant’s development plan and provide 627

transparency on FDA recommendations and expectations on HF studies and sequence of the 628

development program. Where appropriate, the applicant may request focused meetings for more 629

detailed discussions. For a combination product, applicants should submit meeting requests to 630

the lead center using the process and procedures of the lead center. The meeting request should 631

indicate that the discussion is for a combination product and request participation of all relevant 632

centers and Office of Combination Products as appropriate. Additional information on 633

requesting meetings is provided in the last two guidance documents listed below. 634

635

The following FDA documents may be useful: 636

637

• Guidance for Industry and FDA Staff – Applying Human Factors and Usability 638

Engineering to Optimize Medical Device Design; 639

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocument640

s/ucm259748.htm 641

• Draft Guidance for Industry – Safety Considerations for Product Design to Minimize 642

Medication Errors; 643

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid644

ances/UCM331810.pdf 645

• Draft Guidance for Industry – Safety Considerations for Container Labels and Carton 646

Labeling Design to Minimize Medication Errors; 647

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc648

es/ucm349009.pdf 649

• Guidance for Industry – Label Comprehension Studies for Nonprescription Drug 650

Products; 651

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc652

es/ucm143834.pdf 653

• Draft Guidance for Industry – Format and Content of Proposed Risk Evaluation and 654

Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications; 655

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc656

es/ucm184128.pdf 657

• Guidance for Industry – Formal Meetings Between FDA and Sponsors or Applicants; 658

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc659

es/ucm153222.pdf 660

• Guidance for Industry and FDA Staff – Requests for Feedback on Medical Device 661

Submissions: The Pre-Submission Program and Meetings with Food and Drug 662

Administration Staff; 663

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedo664

cuments/ucm311176.pdf 665

666

Contains Nonbinding Recommendations

APPENDIX A: USER TASK FAILURE EXAMPLES 667

668

Table 1 and Table 2 below provide examples of some user task failures that typically apply to 669

injection and inhalation combination products. Table 1 applies to combination products with 670

injectors (e.g., pen injectors, autoinjectors, prefilled syringes), and Table 2 applies to 671

combination products with certain inhalation systems (e.g., nebulizers and inhalers). 672

673

In addition to the examples in these tables, there may be knowledge tasks that require user 674

understanding of information that is not typically or easily evaluated through observation of 675

simulated use. Knowledge tasks are derived from the product labeling (including user manual, 676

Medication Guide, labels on the device itself) and training package. 677

678

The tables do not present comprehensive all-inclusive lists. If the combination product requires 679

users to perform tasks not contained in the tables that could result in harm if not performed 680

correctly, then those tasks should be included in the HF Validation study. Also, depending upon 681

the product design, only certain tasks may be applicable to a specific combination product. The 682

critical tasks may change depending on the indications, use environments, user populations that 683

have unique or novel risks, and other characteristics and features of the combination product. 684

Therefore, a use-related risk analysis should be performed before identifying tasks for evaluation 685

in a HF Validation study. Once identified, those tasks should be used to construct the HF 686

Validation study. 687

688

689

690

691

(Intentionally blank)692

Contains Nonbinding Recommendations

693

Table 1: Examples of Critical Tasks for Combination Products that Deliver Dose by Injection

User Task

Possible Task Failures and Use Errors

Possible Hazard / Harm Resulting

from Failures/Use Errors

Understand how to dose

the product

 Misunderstanding dosing instructions

 Not aware of dosing instructions

 Overdosing

 Under dosing

 Missed dose

Understand how to

administer the product

 Improper technique while interacting

with the product during dosing

 Cannot complete injection

 Overdosing

 Under dosing

 Missed dose

 Needlestick injury

 Accidental exposure to others

Product differentiation

 Select incorrect product

 Wrong drug delivered

Open packaging

 Damage to device

 Loss of instructions or components

 Inability to open package

 Delay of therapy

 Missed dose

 Over or under dosing



User injury

Evaluate device and drug

prior to dosing

 Failure to check injector window for

drug condition

 Expired or adulterated drug used

 Use device that is not functional for

dose delivery

 Use damaged needle

 Painful injection

 Reduced drug efficacy

 Delay of therapy

 Missed dose

 Infection

Prepare injection site

 Not cleaning/disinfecting injection site

 Infection

Prepare/mix the dose for

injection

 Mix or Measure the product incorrectly

 Wrong drug amount drawn into the

syringe

 Reduced drug efficacy

 Under dosing

 Overdosing

Prime injector/syringe

for injection.

 Not priming at all or priming

incorrectly

 Inaccurate dosing



Under dosing

Select injection site

 Identify incorrect injection site

 Painful injection

 Lack of drug efficacy



Local or systemic adverse events

Remove syringe needle

cover

 Do not remove needle cover or injector

cap

 Missed dose



Delay of therapy

Attach needle

 Do not attach needle

 Missed dose

 Delay of therapy

Remove injector cap

 Do not remove injector cap

 Missed dose



Delay of therapy

Hold injector/syringe in

correct orientation

 Hold injector/syringe incorrectly

 Inject upside down

 Needle stick injuries

 Delay of therapy

 Reduced drug efficacy

Depress syringe plunger/

activate autoinjector

(press injection button)

 Unable to depress the plunger

 Unable to activate injector fully

 Unable to determine if dose delivered

 No dose

 Under dosing

Hold syringe or injector

at injection site

 Premature removal of syringe/injector

 Wet injection (drug solution on surface

of injection site)

 Under dosing

 Missed dose

Verify dose delivery

 Not verifying complete dose delivery

 Under dosing

 Missed dose

Dispose/clean/store

syringe/injector

 Improper disposal/storage

 Inject degraded product

 Do not clean reusable device

 Needle stick injuries

 Contamination /transmission of

disease (infection)

 Reduced drug efficacy

 Delay of therapy

 Drug diversion

 Exposure of non-users

Contains Nonbinding Recommendations

694

able 2: Examples of Critical Tasks for Combination Products that Deliver Dose by Inhalation

User Task

Possible Task Failures and Use Errors

Possible Hazard / Harm Resulting

from Failures/Use Errors

Understand how to

administer the product



Improper technique while using the

product during dosing

Cannot complete inhalation



Overdosing

Under dose

Missed dose

Accidental exposure to others

Understand how

the product

to dose



Misunderstanding dosing instructions

Not aware of dosing instructions



Overdosing

Under dosing

Missed dose

Open packaging



Damage to device

Loss of instructions or components

Inability to open package



Delay of therapy

Missed dose

Wrong dose

User injury

Assemble product



Assembled incorrectly

Unable to assemble



Choking on device components

Delay of therapy

Missed dose or dosing error

Evaluate device and drug

prior to dosing



Expired or adulterated drug used

Use device that is not functional for dose

delivery

Use damaged product



Reduced drug efficacy

Delay of therapy

Missed dose or dosing error

Set up dose; prime

product



Not preparing dose for inhalation

Not priming at all or priming incorrectly



Under dosing or overdosing

Choking on dose capsule (if

present)

Missed dose

Use device to deliver

dose



Improper inhalation technique

Improper seal of mouth on mouthpiece



Under dosing or over-dosing

Missed dose or dosing error

Coughing

Waiting a specific

amount of time between

doses for multiple breath

dosing

 Not waiting long enough between doses



Under dose

Lack of efficacy

Disassemble, maintain,

 Failing to clean or maintain.

 Delay of therapy

store, and clean reusable  Storing at wrong temperature or under  Under dosing or overdosing

device components other incorrect conditions



Infection

Reduced drug efficacy

Dispose of device as per

instructions.

 Failing to properly dispose of device



Diversion of drug

Exposure to non-users

695