23257339dft.docx
06/03/21
Oral Drug Products
Administered Via Enteral
Feeding Tube: In Vitro Testing
and Labeling Recommendations
Guidance for Industry
DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.
Comments and suggestions regarding this draft document should be submitted within 60 days of
publication in the Federal Register of the notice announcing the availability of the draft
guidance. Submit electronic comments to https://www.regulations.gov. Submit written
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630
Fishers Lane, Rm. 1061, Rockville, MD 20852. All comments should be identified with the
docket number listed in the notice of availability that publishes in the Federal Register.
For questions regarding this draft document, contact (CDER) Mohamed Ghorab at 240-402-8940
or (CDRH) CDRH product jurisdiction officer at [email protected]
.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Devices and Radiological Health (CDRH)
June 2021
Pharmaceutical Quality/CMC
Oral Drug Products
Administered Via Enteral
Feeding Tube: In Vitro Testing
and Labeling Recommendations
Guidance for Industry
Additional copies are available from:
Office of Communications,
Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
10001 New Hampshire Ave., Hillandale Bldg., 4
th
Floor
Silver Spring, MD 20993-0002
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs
and/or
Office of Policy
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 66, Room 5431
Silver Spring, MD 20993-0002
Email: CDRH-Guidance@fda.hhs.gov
https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/guidance-documents-
medical-devices-and-radiation-emitting-products
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Devices and Radiological Health (CDRH)
June 2021
Pharmaceutical Quality/CMC
Contains Nonbinding Recommendations
Draft — Not for Implementation
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 3
III. IN VITRO TESTING RECOMMENDATIONS TO EVALUATE DRUG
PRODUCT SUITABILITY FOR ADMINISTRATION VIA ENTERAL TUBE ...... 4
A. In Vitro Testing Development Considerations ............................................................................ 5
1. Selection of Enteral Tubes ............................................................................................................... 5
2. Dispersion Media and Dispersion Preparation ............................................................................... 6
3. In Vitro Method Development .......................................................................................................... 7
B. Testing Type Recommendations ................................................................................................... 8
1. Recovery Testing .............................................................................................................................. 8
2. Sedimentation Volume and Redispersibility Testing ........................................................................ 8
3. In-Use Stability in Designated Dispersion Media ........................................................................... 9
4. Particle Size Distribution Study ..................................................................................................... 10
5. Acid Resistance Testing for Drug Products With an Enteric Coating ........................................... 10
6. Dissolution Testing for Extended-Release Drug Products ............................................................ 10
C. Data Submission for Drug Product Applications...................................................................... 11
1. Additional Considerations for NDA Submissions .......................................................................... 11
2. Additional Considerations for ANDA Submissions ....................................................................... 11
IV. LABELING RECOMMENDATIONS.......................................................................... 13
A. Oral Drug Product Recommended for Administration Via Enteral Tube ............................. 13
B. Oral Drug Product NOT Recommended for Administration Via Enteral Tube ................... 16
GLOSSARY................................................................................................................................. 17
REFERENCES ............................................................................................................................ 18
APPENDIX: RECOMMENDED REPORT FORMAT FOR SUBMISSION OF IN
VITRO TESTING RESULTS TO SUPPORT ENTERAL TUBE ADMINISTRATION ... 19
Contains Nonbinding Recommendations
Draft — Not for Implementation
1
Oral Drug Products Administered Via Enteral Feeding Tube: 1
In Vitro Testing and Labeling Recommendations 2
Guidance for Industry
1
3
4
5
6
7
This draft guidance, when finalized, will represent the current thinking of the Food and Drug 8
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 9
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 10
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 11
for this guidance as listed on the title page. 12
13
14
15
16
I. INTRODUCTION 17
18
This guidance provides recommendations regarding in vitro testing of oral drug products, other 19
than solutions, administered via enteral feeding tube (hereinafter enteral tube). These products 20
represent a wide range of oral dosage forms including, but not limited to, granules, pellets, 21
powders, suspensions, capsules, and tablets. The recommendations for in vitro testing apply to 22
products that are subject to the following and submitted under section 505 of the Federal Food, 23
Drug, and Cosmetic Act (21 U.S.C. 355) and 21 CFR parts 312 and 314:
2
24
25
• New drug applications (NDAs) (original or supplemental) where applicants are seeking 26
and/or revising enteral tube administration instructions and related information in 27
labeling 28
29
• Abbreviated new drug applications (ANDAs) where the reference listed drug (RLD) 30
contains enteral tube administration instructions and related information in labeling 31
32
• Investigational new drug applications where the investigational drug product is 33
administered or planned for administration via enteral tube 34
35
1
This guidance has been prepared by the Office of Pharmaceutical Quality in the Center for Drug Evaluation and
Research in cooperation with the Center for Devices and Radiological Health at the Food and Drug Administration.
2
The principles and recommendations in this guidance may also be relevant to products that are subject to biologics
license applications that are developed or marketed as oral dosage forms (other than solutions) where the applicant is
seeking labeling instructions for administration via enteral tube. Applicants seeking licensure for these products are
encouraged to contact the Agency regarding their development plans.
Contains Nonbinding Recommendations
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2
Specifically, the guidance covers: 36
37
• In vitro testing recommendations to ensure oral drug product quality and, as applicable, 38
bioequivalence to the RLD when evaluating a drug product’s suitability for 39
administration via enteral tube 40
41
• Appropriate content and format for submission of in vitro testing results regarding 42
administration via enteral tube 43
44
• Recommendations on how to incorporate information about administration via enteral 45
tube in drug product labeling when supported by in vitro testing results
3
46
47
The guidance does not cover recommendations involving: 48
49
• Oral solutions, which do not present the same risk of forming occlusions when 50
administered via enteral tube as other oral dosage forms containing solid or insoluble 51
components 52
53
• Clinical study design to support enteral tube administration 54
55
• Physical characteristics of enteral tubes (e.g., connector design), which are covered in the 56
guidance for industry Safety Considerations to Mitigate the Risks of Misconnections with 57
Small-bore Connectors Intended for Enteral Applications (February 2015)
4
58
59
Providing recommendations for in vitro testing of oral drug products administered via enteral 60
tube will support the development of clear, product-specific enteral tube administration 61
instructions in labeling for administration to patients unable to ingest oral drug products. The 62
goal is to establish applicable in vitro methodology and provide information in drug product 63
labeling for safe and effective administration of oral drug products through enteral tubes. 64
65
Applicants
5
are encouraged to discuss testing approaches that differ from those recommended in 66
this guidance with the applicable review or assessment staff before conducting the studies. 67
68
The contents of this document do not have the force and effect of law and are not meant to bind 69
the public in any way, unless specifically incorporated into a contract. This document is intended 70
only to provide clarity to the public regarding existing requirements under the law. FDA 71
guidance documents, including this guidance, should be viewed only as recommendations, unless 72
3
The recommendations in this guidance are limited to applicants for drug products seeking or bearing labeling
instructions for administration via enteral tube. As of the time of publication of this guidance, no nonprescription
drug product is labeled for administration via enteral tube. Therefore, with respect to nonprescription drug products,
only those applicants seeking such labeling statements should follow the recommendations for in vitro testing to
evaluate the drug products’ suitability to be administered via enteral tube.
4
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
.
5
For the purposes of this guidance, the term applicant includes application holder, manufacturer, and sponsor.
Contains Nonbinding Recommendations
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specific regulatory or statutory requirements are cited. The use of the word should in Agency 73
guidance means that something is suggested or recommended, but not required. 74
75
76
II. BACKGROUND 77
78
Enteral tubes are critical for patients who are unable to swallow oral dosage forms because of 79
medical conditions or therapies that may compromise swallowing or the function of the proximal 80
gastrointestinal system (e.g., feeding disorders, severe intellectual disabilities, neurological 81
disorders, cancers). These patients rely on enteral tubes for their nutrition and drug treatment 82
needs. This need spans patient care settings from intensive care units and other acute care 83
settings to chronic residential care facilities and patients’ homes. Enteral tube feeding at home is 84
becoming widespread, with an estimated patient prevalence of 1,385 per 1 million U.S. 85
inhabitants (Mundi et al. 2017). It is essential that each drug product administered via enteral 86
tube is delivered in a manner that preserves the correct dose and the drug’s expected safety and 87
effectiveness profile, including any labeled modified-release
6
characteristics, and does not 88
compromise the integrity of the tube. Although some FDA-approved drug products include 89
instructions for enteral tube administration in their labeling, the administration instructions and 90
in vitro testing to support administration via enteral tube are not sufficiently widespread or 91
consistent (Ren et al. 2017). 92
93
Enteral tubes differ in tube diameter (inner and outer), tube composition, inner tube geometry, 94
tube length, port number, connector type, port geometry (closed versus open distal tip), and 95
number and location of eyes. Enteral tubes are composed of a variety of materials, including 96
polyurethane, polyvinylchloride, and silicone. Table 1 summarizes common enteral tube types 97
and their typical size ranges. In general, enteral tube size is designated by the diameter of the 98
outer tube in French (Fr) units. Some enteral tubes can be inserted through the nose and are 99
intended for short-term use, typically less than 4 weeks. Enteral tubes for chronic use (greater 100
than 4 weeks) are placed percutaneously into the stomach or jejunum using an open surgical, 101
endoscopic, or radioimaging technique. 102
103
Table 1. Types and Characteristics of Enteral Tubes 104
Type
Outer Tube Diameter (Fr*
,
**)
Nasogastric
5-18
Nasoduodenal
3.5-12
Nasojejunal
3.5-12
Gastrostomy
12-30
Gastrojejunal
12-22
Jejunostomy
12-18
* Fr = French 105
** 3 Fr = 1 millimeter 106
107
Clinical data suggest enteral tube occlusions and clogs occur in 23 to 35 percent of cases during 108
routine use (Bourgault et al. 2003; Dandeles and Lodolce 2011; Blumenstein et al. 2014). The 109
6
Terms that appear in bold type upon first use are defined in the Glossary.
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risks of enteral tube occlusion increase under a number of conditions, including, but not limited 110
to, the following (Bourgault et al. 2003; Shipley et al. 2016): 111
112
• Presence of insoluble ingredients 113
• Aggregation in dispersion media 114
• Selection of an inappropriate vehicle to serve as the dispersion media
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115
• Inadequate flushing of the enteral tube before and after drug product administration 116
• Inadequate drug product dispersion before administration 117
• Larger particle size 118
• Drug product-enteral tube interactions 119
• Departures from drug product labeling or enteral tube instructions 120
121
The Agency recognizes the need for consistent in vitro testing to ensure safe and effective 122
delivery of drug products that may be administered via enteral tube and to identify drug products 123
that cannot be administered through an enteral tube without altering the safety and effectiveness 124
profile of the drug product or compromising the integrity of the tube. 125
126
127
III. IN VITRO TESTING RECOMMENDATIONS TO EVALUATE DRUG 128
PRODUCT SUITABILITY FOR ADMINISTRATION VIA ENTERAL TUBE 129
130
Given the inherent challenges of administering oral drug products via enteral tubes, it is critical 131
that in vitro testing to evaluate drug product suitability for enteral tube administration be 132
completed before the initiation of any clinical studies intended to support enteral tube 133
administration claims in labeling. Performing controlled in vitro testing before the initiation of 134
clinical studies will aid in developing appropriate administration instructions for clinical studies 135
and potentially identify drug product-specific risks associated with enteral tube administration. 136
137
The in vitro testing recommended in this guidance should be performed for oral drug products 138
other than solutions by: (1) applicants for new drugs, whether by original or supplemental 139
application, seeking to add labeling instructions for administration via enteral tube; and (2) 140
applicants for generic drugs where the RLD labeling includes instructions for administration via 141
enteral tube. The results of in vitro testing to support the use of enteral tube administration 142
should be submitted to the Agency as part of original or supplemental drug applications in which 143
enteral tube administration labeling claims are sought. Completion of the recommended testing 144
should demonstrate whether or not a drug product is suitable for enteral tube administration. 145
More evidence may be needed to demonstrate suitability and/or compatibility for administration 146
via enteral tube for a solid oral dosage form known to contain insoluble components than for an 147
oral drug product that completely dissolves in the directed dispersion media. 148
149
Applicants seeking labeling instructions for administration via enteral tube should consider 150
multiple factors when determining how to perform in vitro enteral tube administration testing 151
during drug product development including: 152
7
See the draft guidance for industry Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General
Considerations for Selection and In Vitro Methods for Product Quality Assessments (July 2018). When final, this
guidance will represent the FDA’s current thinking on this topic.
Contains Nonbinding Recommendations
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153
• The active pharmaceutical ingredient’s (API’s) site of absorption from the 154
gastrointestinal tract 155
156
• Whether the drug has a narrow therapeutic index 157
158
• Whether the drug product is a delayed-release or extended-release dosage form
8
159
160
• The aqueous solubility of the API and inactive ingredients 161
162
• Whether the API or inactive ingredients may adhere to the enteral tube material (Jory et 163
al. 2017) 164
165
The Agency recommends applicants consider the following test development recommendations 166
and test types when conducting testing to demonstrate that oral drug products are suitable for 167
administration via enteral tube. The data generated from the following studies should be included 168
in a report to support enteral tube administration as a valid alternative method of drug product 169
delivery.
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170
171
A. In Vitro Testing Development Considerations 172
173
The following testing recommendations are based on an expectation that the drug product will be 174
prepared for in vitro testing in the same manner as it will be prepared for administration via 175
enteral tube to a patient in planned clinical studies, or prepared as described in labeling submitted 176
for approval, as applicable. 177
178
1. Selection of Enteral Tubes 179
180
If an applicant intends to recommend multiple tube types (e.g., nasogastric (NG), gastrostomy 181
(G)) or sizes (e.g., Fr 10-16) for administration of its drug product, the recommended testing 182
should, at minimum, be performed with the smallest intended enteral tube size for each type of 183
material or design (see section III.B.4., Particle Size Distribution Study, for testing data that may 184
be helpful in the selection of tube size). For example, if an applicant intends the labeling to 185
include instructions for drug product administration with both NG (Fr 8 and above) and G tubes 186
(Fr 12 and above), NG tubes should be tested at Fr 8 and G tubes should be tested at Fr 12. 187
188
Enteral tubes may be made with different materials (e.g., polyvinylchloride, silicone, 189
polyurethane) and different designs (e.g., various numbers of ports and/or eyes, retention 190
8
The term modified-release is defined in United States Pharmacopeia (USP) General Chapter <1151>
Pharmaceutical Dosage Forms. “Modified-release is a term used when the rate and/or time of release of the drug
substance is altered as compared to what would be observed or anticipated for an immediate-release product. Two
modified-release profiles, delayed-release and extended-release, are recognized.”
9
The studies described in this guidance may be suitable for inclusion in various sections of the electronic common
technical document, depending on the context of the submission. Therefore, the Agency recommends inclusion of a
summary report in Module 2, with a link to the full testing report. See also the Appendix of this guidance for test
report format.
Contains Nonbinding Recommendations
Draft — Not for Implementation
6
balloons, open or closed distal end). Such differences may affect the inner tube diameter and/or 191
flow of material through the tubes (Kurien et al. 2015). For in vitro testing, applicants should 192
consider the material and design of the various enteral tubes that may be used for drug product 193
administration, and test a representative selection of tubes to ensure complete delivery of the 194
drug product in the recovery test. FDA recommends that applicants test at least three different 195
enteral tube configurations for all tube types proposed in the labeling and provide justification 196
for the enteral tubes selected for testing. Note that for G tubes, at least one tube should be tested 197
with an inflated balloon configuration. 198
199
2. Dispersion Media and Dispersion Preparation 200
201
Various dispersion media such as purified water, apple juice, milk, and liquid nutritional 202
supplements may be used as vehicles for oral drug product administration and to flush enteral 203
tubes. The properties of the dispersion media may vary between brands or formulations. 204
Variations may include pH, concentration, ingredients, and preparation method, among others. 205
Therefore, applicants should consider the different types and properties of the vehicles that may 206
be used for drug product administration and evaluate the risk due to potential variations in the 207
dispersion media used. This analysis should form part of the basis for justifying the 208
administration conditions, including dispersion media. Detailed instructions describing how the 209
drug product is prepared for enteral tube administration should be documented including: 210
211
• Dispersion medium (e.g., type of water such as purified water (including distilled water 212
and water for injection); type of liquid food; brand of juice)
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213
214
• Volume and temperature of the dispersion medium 215
216
• Holding/soaking time between dispersion and administration through the enteral tube 217
218
• Number of potential administrations through the tube based on proposed administration 219
instructions (e.g., once per day, every four hours) 220
221
• Details regarding the preparation and dispersion method of the drug product (e.g., crush, 222
suspend, dissolve, shaking method), including any equipment used in preparation or 223
dispersion 224
225
• The pH of the medium before and after dispersion 226
227
• Flush volume used before and after drug product administration 228
229
• Tube and syringe used (e.g., brand item number, material, brand, inner and outer tube 230
diameter, with or without balloon (filled according to the tube manufacturer’s 231
instructions), number of eyes, length of the tube, syringe tip type) 232
233
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Tap water is not recommended as a dispersion medium in the laboratory setting due to its variability as described
in this guidance.
Contains Nonbinding Recommendations
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• Holding position of the tube and holding position of the syringe (e.g., horizontal, 234
vertical) 235
236
• Method, analytical site, and testing dates for each of the tests 237
238
The pH for different types of water (e.g., distilled, sterile, and other types of bottled water) may 239
vary between 5.5 to 8.5. When water is used as the dispersion medium, particularly for modified-240
release dosage forms or for products containing pH-sensitive coating excipients, the pH within 241
the preparation container, oral syringe, or enteral tube might adversely affect the integrity of the 242
enteric coating or dissolution of drug products. Therefore, in these cases, we recommend testing 243
using water with different pH values (e.g., pH 5.5, 7.0, 8.5) for in vitro enteral tube studies even 244
if labeling will specify a particular type of water. Similarly, when juice is used as the dispersion 245
medium, multiple types of juice should be studied, even if labeling will specify a particular type 246
of juice. 247
248
3. In Vitro Method Development 249
250
Development of in vitro methods should follow a risk-based process. In vitro testing conditions 251
should be justified based on the drug product formulation and its proposed method of 252
administration. For example, successful testing on the smallest tubing diameter recommended for 253
use in the drug product labeling would obviate the need to perform testing through tubing with 254
larger diameters. Likewise, performing the testing at the initial (time zero) and final time points 255
proposed before administration (e.g., holding/soaking time) would also reduce the need for 256
testing holding/soaking time points that fall between those two extremes. Applicants should also 257
consider the dose strengths of their drug products to select the formulation at highest risk of 258
forming occlusions for testing and should provide their rationale. 259
260
The following is a general overview of the in vitro testing method recommendations: 261
262
• The enteral tube should be prepared according to the tube manufacturer’s instructions 263
(e.g., flushing the tube or inflating the balloon). 264
265
• The drug product (e.g., granules from capsule, tablet (crushed or not)) should be prepared 266
in the dispersion medium (e.g., purified water, apple juice, or milk), and rotated gently 267
until the drug product is completely dispersed with no particles visible that are large 268
relative to the tube inner diameter. 269
270
• The drug product dispersion should be transferred into an oral syringe, the oral syringe 271
(or funnel, if applicable) should be connected to the enteral tube, and the dispersion 272
should be passed through the enteral tube into a collection container. After administration 273
of the dispersion using the enteral tube, the enteral tube and syringe should be flushed 274
with a specified amount of the dispersion medium. 275
276
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B. Testing Type Recommendations 277
278
The type and extent of testing should be a risk-based decision focused on the characteristics of 279
the individual drug product. For example, if additional procedures are needed during testing to 280
demonstrate that the drug product can be delivered by enteral tube, the applicant should provide 281
a detailed description of these procedures. 282
283
There are additional testing considerations for modified-release dosage forms. In vitro testing of 284
modified-release products should demonstrate that preparation of the drug product for 285
administration via enteral tube does not adversely affect the drug content assay or release 286
characteristics (e.g., dissolution), where appropriate. 287
288
These testing recommendations do not replace conventional drug product quality 289
characterization studies or in vivo bioequivalence studies for the drug product that are typically 290
conducted. 291
292
1. Recovery Testing 293
294
The purpose of recovery testing is to determine the percentage of a dose of a drug that 295
successfully passes through an enteral tube when the drug product is prepared and administered 296
as specified or proposed in the product labeling. Recovery testing should be performed to 297
support enteral tube administration. Applicants should determine the percentage of drug 298
recovered at the tube exit relative to the initial dose of the drug product using a validated 299
analytical method. The study should be conducted using an adequate number of samples and 300
justification for the selected sample size should be provided. The tube and syringe should be 301
examined visually, and any aggregation, buildup, clogging, or other observations should be 302
recorded. The percentage of drug recovered at the tube exit relative to the initial dose should 303
meet appropriate drug product release specifications for new drugs. For generic drugs, the 304
percentage should be calculated as described in section III.C.2., Additional Considerations for 305
ANDA Submissions. Applicants should provide video or photographs of the contents of the 306
syringe and tube before, during, and after testing. 307
308
If a drug product will be administered multiple times in a 24-hour period, applicants should 309
mimic the directed dosing regimen and record drug recovery after each individual administration 310
(i.e., the same tube should be used for sequential administrations of the drug product). 311
312
If the dispersion medium is water, recovery testing should be performed with material recovered 313
from the enteral tube using water with different pH values (e.g., pH 5.5, 7.0, 8.5) and various 314
soaking times to support the intended delivery time. The pH values of the drug product 315
dispersion should be measured upon initial dispersion and after delivery through the enteral tube. 316
317
2. Sedimentation Volume and Redispersibility Testing 318
319
Sedimentation volume and redispersibility testing should be performed to assess the 320
sedimentation potential of a drug product within an enteral tube to support enteral tube 321
administration. Insoluble components of a drug product have the potential for sedimentation that 322
Contains Nonbinding Recommendations
Draft — Not for Implementation
9
may increase the risk of clogging. For convenience, instead of an enteral tube, a syringe can be 323
used for this test. To test sedimentation volume, the syringe should be loaded with drug product 324
dispersion and allowed to settle. Applicants should record the sedimentation volume and 325
duration of test (e.g., holding/soaking time). Markings on the syringe can be used for the 326
measurement. 327
328
Redispersibility of the drug product dispersion should be evaluated to determine if settled solids 329
can be redispersed for administration (e.g., by shaking after the maximum directed soaking 330
time). The syringe that was used for the sedimentation volume test above should be used to test 331
redispersibility. Applicants should provide a qualitative description of the test product (e.g., 332
particle aggregation and particles adhering to the syringe walls). Representative photographs of 333
the syringe contents should be taken at various intervals throughout the testing process. 334
335
Sedimentation volume and redispersibility tests performed during product development or 336
included as part of routine testing of the drug product (e.g., for oral suspensions) may be 337
sufficient to serve as the sedimentation volume and redispersibility tests recommended in this 338
guidance to support enteral tube administration. 339
340
3. In-Use Stability in Designated Dispersion Media 341
342
When labeling instructions for administration via enteral tube specify an in-use holding/soaking 343
time before administration via enteral tube, in vitro testing as described in this guidance should 344
include in-use stability testing through this in-use period.
11
Applicants should perform in-use 345
stability testing in the proposed dispersion media to demonstrate that the drug product dispersion, 346
when prepared for enteral tube administration, is chemically and physically stable (i.e., as 347
indicated by the dissolution profile) throughout the specified soaking time at the recommended 348
or proposed storage conditions. Chemical stability of the drug product dispersion under proposed 349
storage conditions for enteral tube administration should be monitored at predetermined time 350
intervals. The drug content and degradation products of the API should be determined using a 351
stability-indicating method or methods. The results of the stability studies should provide 352
assurance for the stability of the drug product dispersion during the proposed soaking period. 353
354
For extended holding times before administration of over 4 hours at room temperature or over 24 355
hours under refrigeration, applicants should include microbiological studies in support of the 356
proposed storage conditions. For microbial testing and acceptance criteria for non-sterile aqueous 357
drug products for oral use, see United States Pharmacopeia (USP) General Chapter <1111> 358
Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical 359
Preparations and Substances for Pharmaceutical Use, USP General Chapter <61> 360
Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests, and USP 361
General Chapter <62> Microbiological Examination of Nonsterile Products: Tests for Specified 362
Microorganisms. 363
364
11
See the ICH guidance for industry Q1A(R2) Stability Testing of New Drug Substances and Products (November
2003) for additional information about in-use stability testing.
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4. Particle Size Distribution Study 365
366
Particle size is a key attribute affecting the passage of a drug product through an enteral tube 367
during administration. The particle size distribution study evaluates one mechanism by which a 368
formulation could block the tube and predicts the risk of blockage. Particle size distribution 369
studies should be conducted for modified-release dosage forms and other formulations where 370
particle size may indicate a high risk for forming tube occlusions. Following the enteral tube 371
preparation procedure outlined in section III.A.3., In Vitro Method Development, applicants 372
should determine the particle size of the drug suspension before and after delivery through the 373
enteral tube. Particle size should be determined using a validated method that is sufficiently 374
reproducible and sensitive (e.g., laser diffraction method with the particle size data at the D10, 375
D50, and D90 levels). 376
377
5. Acid Resistance Testing for Drug Products With an Enteric Coating 378
379
Acid resistance testing is used to ensure the integrity of the enteric coating of delayed-release 380
dosage forms during administration via enteral tube.
12
Acid resistance testing should be 381
performed on drug products with an enteric coating. The test should be performed under acidic 382
conditions (pH 1.2 or 0.1 N HCl for 1–2 hour(s) per drug product release specification) after the 383
drug product is incubated in the dispersion medium and delivered through the enteral tube. The 384
percentage of drug released into the acidic medium should conform to the acceptance criteria set 385
in the drug product specification. Applicants should consider the potential for degradation of the 386
API if it is acid-labile. 387
388
6. Dissolution Testing for Extended-Release Drug Products 389
390
Dissolution testing should be performed for extended-release dosage forms to demonstrate that 391
preparation and delivery via enteral tube does not affect the timing of drug release from the 392
dosage form. Dissolution testing should be performed after administration through a combination 393
of an oral syringe and an enteral tube in dissolution media specified in the drug product 394
specification. The pH values of the drug product dispersion should be measured before and after 395
delivery through the enteral tube. The amount of drug released into each recommended 396
dispersion medium should also be quantitated after passing through the enteral tube. After 397
collection of the drug product dispersion at the enteral tube exit, the particulates collected into a 398
dissolution vessel should be transferred using the testing conditions specified in the drug product 399
specification and the amount of drug released should be determined at time points per the drug 400
product specification. The amount of drug released (after passage through the enteral tube) 401
divided by the labeled content of the drug product and expressed as a percentage should conform 402
to the acceptance criteria set in the drug product specification. 403
404
12
A tablet that is enteric-coated would not likely be appropriate for enteral tube administration because crushing to
disperse the drug would disrupt the function of the enteric coating, whereas a capsule containing enteric-coated
beads may be suitable for enteral administration.
Contains Nonbinding Recommendations
Draft — Not for Implementation
11
C. Data Submission for Drug Product Applications 405
406
In addition to the test results, applicants should submit test protocols and the analytical methods 407
used for the in vitro enteral tube studies recommended in section III.B., Testing Type 408
Recommendations. The test protocols should incorporate the recommendations in section 409
III.A.2., Dispersion Media and Dispersion Preparation. Detailed method validation reports for 410
the analytical techniques used should be submitted to demonstrate adequacy for the intended 411
purpose. If the method validation reports for the analytical techniques used are provided 412
elsewhere in the application, a link or reference to that location in the submission should be 413
provided. Individual data, mean values, standard deviations, and coefficients of variation (CV %) 414
for each test should be submitted. Test results should be submitted in the format described in the 415
Appendix. 416
417
The tubing and syringe used for in vitro testing should be examined visually for any aggregation, 418
adherence, or clogging, and the observations reported with supporting visual information (video 419
and/or photographs). For recovery studies, applicants can provide videos that document the 420
testing process and associated observations. If application of additional force to the syringe 421
compared to that used for initial flushing with dispersion medium is needed during the testing to 422
ensure complete recovery, it should be documented, and an explanation should be provided. 423
424
1. Additional Considerations for NDA Submissions 425
426
For NDAs, the in vitro testing recommendations provided in section III.B., Testing Type 427
Recommendations, are intended as the initial step to demonstrate that a new drug product is 428
suitable for administration via enteral tube. Clinical studies involving enteral tube administration 429
of a new drug product are outside the scope of this guidance, but if applicable, generally should 430
be conducted after the recommended in vitro studies demonstrate the suitability of a new drug 431
product for enteral tube administration and the appropriate administration instructions have been 432
established. For a new drug product seeking labeling instructions for administration via enteral 433
tube, the proposed labeling statement in the DOSAGE AND ADMINISTRATION section 434
should be developed based on, and be supported by, the results of enteral tube administration 435
testing. To ensure adequate investigations, FDA encourages early communication with the 436
review division to discuss in vitro testing and any clinical study protocol design. When 437
submitting the in vitro test and any clinical study results, applicants should provide the enteral 438
tube administration instructions, including the recommended enteral tube type, size, brand, part 439
number, and the size of the oral syringe used. This information should be submitted at the time 440
the claim for enteral tube administration is sought (e.g., in the original NDA submission, or in a 441
supplement if clinically indicated). 442
443
2. Additional Considerations for ANDA Submissions 444
445
For ANDAs, the in vitro testing recommendations provided in section III.B., Testing Type 446
Recommendations, are intended to demonstrate that a generic drug product is therapeutically 447
equivalent to the RLD when administered according to the RLD product labeling enteral tube 448
Contains Nonbinding Recommendations
Draft — Not for Implementation
12
administration instructions.
13
The enteral tube administration instructions provided in the 449
DOSAGE AND ADMINISTRATION section of labeling for the RLD should guide development 450
of the in vitro enteral tube administration testing procedures for the planned generic drug 451
product. If the RLD is discontinued and the reference standard (RS) is being used for 452
bioequivalence testing, the enteral tube administration instructions in the labeling of the RS 453
should guide development of the in vitro enteral tube administration testing procedures.
14
454
455
When performing the recommended in vitro testing to ensure bioequivalence to the RLD (or RS 456
if the RLD is discontinued or otherwise unavailable) after administration via enteral tube, 457
applicants should describe the testing conditions including: the number of units of the test and 458
reference drug products used; enteral tube type, size, brand, and part number; and the size of the 459
oral syringe used. 460
461
For comparative in vitro testing (e.g., recovery testing, acid resistance testing, and sedimentation 462
testing), applicants should prepare the enteral tube studies based on the procedure outlined in the 463
most current FDA-approved drug product labeling using 12 units each of the test (T) and 464
reference (R) drug products dispersed in the dispersion medium for 0 minutes and for the 465
maximum allowable holding/soaking incubation time in accordance with the drug product 466
labeling, unless the testing conditions set forth in the relevant product-specific guidance for 467
generic drug development state otherwise. All in vitro enteral tube tests should be performed on 468
unexpired T and R batches of the drug product. When labeling instructions specify immediate 469
administration after preparation, the Agency recommends performing comparative in vitro 470
enteral tube testing at both 0- and 15-minute soaking times. For recovery testing, applicants 471
should determine the percentage of drug recovered at the tube exit relative to the initial dose for 472
both the T and R products using a validated analytical method. Applicants should calculate the 473
T/R recovery ratio and the 90 percent confidence interval of the T/R recovery ratio. 474
475
This information should be provided in the original ANDA submission. For additional insight on 476
the recommended in vitro testing reporting format, see the Bioequivalence Summary Tables for 477
In Vitro Feeding Tube Testing.
15
Any recommendations for in vivo bioequivalence studies 478
involving administration via enteral tube will be communicated in the respective product-specific 479
guidance for generic drug development.
16
480
481
482
13
The regulations under 21 CFR 314.3 define therapeutic equivalents as follows: “approved drug products that are
pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the
same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.”
14
See the draft guidance for industry Updating ANDA Labeling After the Marketing Application for the Reference
Listed Drug Has Been Withdrawn (July 2016). When final, this guidance will represent the FDA’s current thinking
on this topic.
15
https://www.fda.gov/media/98853/download
16
Product-specific guidances are published on the Product-Specific Guidances for Generic Drug Development web
page at https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm
.
Contains Nonbinding Recommendations
Draft — Not for Implementation
13
IV. LABELING RECOMMENDATIONS 483
484
A. Oral Drug Product Recommended for Administration Via Enteral Tube 485
486
If there are adequate data that support administration of the drug product via enteral tube, the 487
drug product labeling should include sufficient information to ensure that the health care 488
provider, patient, and/or caregiver have the essential information to administer the drug product 489
safely and effectively via enteral tube. The DOSAGE AND ADMINISTRATION section of 490
labeling should include, as applicable:
17
491
492
• Information on which dosage form(s) and strength(s) are suitable for administration via 493
enteral tube. 494
495
• Recommended enteral tube characteristics, such as the following: 496
497
‒ Type (e.g., NG, G) 498
499
‒ Size range (expressed in French units) 500
501
‒ Any other tube characteristic that affects passage of the drug product dispersion 502
through the tube (e.g., material composition) 503
504
• Recommended drug product and enteral tube preparation instructions before 505
administration. For example: 506
507
‒ Dispersion media (e.g., type of water, milk, apple juice) 508
509
‒ Details regarding the method of drug product dispersion (e.g., crush to a fine powder, 510
suspend, dissolve, shaking method) 511
512
‒ Volume of dispersion media and soaking time of drug product dispersion before 513
administration 514
515
‒ Preparation of the enteral tube (e.g., flushing the tube) 516
517
‒ Other recommended preparation information (e.g., shaking the syringe immediately 518
before administering the drug product dispersion, a physical description of the desired 519
dispersion) 520
521
• Recommended administration instructions. These can include, but are not limited to: 522
523
‒ Volume and rate of administration of the drug product dispersion for each strength (if 524
different) 525
17
See the guidance for industry Dosage and Administration Section of Labeling for Human Prescription Drug and
Biological Products — Content and Format (March 2010).
Contains Nonbinding Recommendations
Draft — Not for Implementation
14
526
‒ Holding positions of the syringe and tube during administration 527
528
‒ Instructions regarding any residual drug product in the mixing container, syringe, or 529
enteral tube 530
531
‒ Information regarding the timing of administration, such as in relation to continuous 532
enteral feeding or the appropriate interval prior to the administration of a different 533
drug product. 534
535
• Instructions on maintenance of the enteral tube following administration (e.g., flushing of 536
the tube) 537
538
• Instructions for storage of residual drug product dispersion during the in-use period, if 539
applicable. 540
541
Clinically relevant information about dispersion media, preparation procedures, syringe 542
characteristics, soaking times, and enteral tube characteristics that adversely affect drug delivery, 543
if applicable, should be presented in the appropriate section(s) or subsection(s) of labeling (e.g., 544
DOSAGE AND ADMINISTRATION section, WARNINGS AND PRECAUTIONS section, 545
Pharmacokinetics subsection of the CLINICAL PHARMACOLOGY section). 546
547
If applicable, the DOSAGE AND ADMINISTRATION section should cross-reference the 548
Pharmacokinetics subsection of the CLINICAL PHARMACOLOGY section of labeling, where 549
a succinct summary of the relevant data (e.g., enteral tube characteristics, dispersion media or 550
soaking times) that affect the pharmacokinetics of the drug product should be included.
18
551
552
Provided below are examples of instructions for the preparation and administration of a drug 553
product dispersion via enteral tube in the DOSAGE AND ADMINISTRATION section of 554
labeling. 555
556
Example 1 557
558
To administer DRUG-X tablets (all strengths) via nasogastric tube (French size 8 or 559
larger) follow these steps [see Clinical Pharmacology (12.3)]: 560
561
• Place one tablet in a catheter-tip syringe and draw up 20 mL of distilled water. 562
563
• Shake gently to allow for a quick dispersal. 564
565
• After the tablet has dispersed, swirl the catheter-tip syringe gently to keep the 566
microgranules from settling, and immediately inject the mixture through the 567
18
See the guidance for industry Clinical Pharmacology Section of Labeling for Human Prescription Drug and
Biological Products — Content and Format (December 2016).
Contains Nonbinding Recommendations
Draft — Not for Implementation
15
nasogastric tube into the stomach. Do not save the water and microgranule mixture 568
for later use. 569
570
• Refill the catheter-tip syringe with approximately 10 mL of distilled water, shake 571
gently, and flush the tube. 572
573
• Refill the catheter-tip syringe again with 10 mL of distilled water, swirl gently, and 574
administer. 575
576
Example 2 577
578
To administer DRUG-X capsules via nasogastric (French size 8 or larger) or gastrostomy 579
tube (French size 12 or larger): 580
581
• Open the capsule and empty the entire contents of the capsule into a clean container 582
with 30 mL of distilled water. 583
584
• Gently swirl the mixture in the container for 30 seconds or longer until all of the 585
powder is uniformly dispersed in the liquid. 586
587
• After the capsule’s contents have dispersed, draw up the mixture into a catheter tip 588
syringe. Apply steady pressure to dispense the contents of the syringe into the 589
nasogastric or gastrostomy tube within 15 minutes of preparation. Do not keep the 590
mixture for later use. 591
592
• If residual drug remains in the syringe or tube, draw up 10 mL of distilled water into 593
the syringe, swirl it around, and administer through the tube. 594
595
• Flush the tube with at least 10 mL of distilled water. 596
597
If applicable, FDA-approved patient labeling (e.g., Instructions for Use
19
) should include 598
detailed patient-use instructions for the preparation, administration, handling, storage, and 599
disposal of the drug product dispersion administered via enteral tube.
20
600
601
19
See the draft guidance for industry Instructions for Use — Patient Labeling for Human Prescription Drug and
Biological Products and Drug-Device and Biologic-Device Combination Products — Content and Format (July
2019). When final, this guidance will represent the FDA’s current thinking on this topic.
20
The Instructions for Use are considered part of the drug product user interface. As such, additional data, such as
data from human factors studies, could be used to inform the development of the instructions for use for an NDA
drug product. The discussion of human factors considerations is outside the scope of this guidance. For additional
information on development of the user interface and human factors considerations, see the draft guidance for
industry and FDA staff Human Factors Studies and Related Clinical Study Considerations in Combination Product
Design and Development (February 2016). When final, this guidance will represent the FDA’s current thinking on
this topic.
Contains Nonbinding Recommendations
Draft — Not for Implementation
16
B. Oral Drug Product NOT Recommended for Administration Via Enteral 602
Tube 603
604
If, in the development of an oral drug product intended for administration via enteral tube, 605
testing identifies no successful method for preparation and administration of the drug product via 606
enteral tube, then the DOSAGE AND ADMINISTRATION section of labeling should state this 607
and provide a brief rationale, if appropriate. As applicable, relevant information supporting the 608
recommendation against enteral tube administration should be succinctly summarized in other 609
subsections or sections of labeling (e.g., DESCRIPTION section, Pharmacokinetics subsection 610
of the CLINICAL PHARMACOLOGY section) and a cross-reference to that information should 611
be provided in the recommendation. 612
613
Provided below are examples of statements recommending against administration of an oral drug 614
product via enteral tube in the DOSAGE AND ADMINISTRATION section of labeling. 615
616
Example 1 617
618
Do not administer DRUG-Y via nasogastric, gastrostomy, or other enteral tubes because 619
it may cause obstruction of enteral tubes. 620
621
Example 2 622
623
Do not administer DRUG-Y for Oral Suspension via nasogastric, gastrostomy, or other 624
enteral tubes, because its chemical constituents may interact with the device material [see 625
Description (11)]. 626
627
If applicable, FDA-approved patient labeling (e.g., Instructions for Use,
21
Medication Guide,
22
628
Patient Package Insert) should include patient-use instructions that the drug product should not 629
be administered via enteral tube along with the reason why not. 630
631
21
See footnote 19.
22
21 CFR part 208
Contains Nonbinding Recommendations
Draft — Not for Implementation
17
GLOSSARY 632
633
Delayed-release: A formulation that achieves a delay in the release of the drug substance for 634
some period of time after initial administration. 635
636
Dispersion media: A qualified liquid substrate used to disperse a drug product for delivery 637
through an enteral tube. 638
639
Enteric coating: A polymer barrier applied on drugs intended for oral administration that 640
prevents their dissolution or disintegration in the gastric environment. 641
642
Extended-release: A formulation that makes the drug available over an extended period of time 643
after ingestion. This allows a reduction in dosing frequency as compared to that presented by a 644
conventional dosage form (e.g., a solution or an immediate-release dosage form). 645
646
Flush volume: A predetermined quantity of liquid used to purge an enteral tube before and/or 647
after the administration of a drug product in the directed dispersion media. 648
649
Holding position of the syringe: The specific orientation (e.g., horizontal, vertical) at which a 650
syringe must be maintained to ensure adequate administration of a drug product in the directed 651
dispersion media. 652
653
Holding position of the tube: The specific orientation (e.g., horizontal, vertical) at which an 654
enteral tube must be maintained to ensure adequate administration of a drug product in the 655
directed dispersion media. 656
657
Modified-release: When the rate and/or time of release of the drug substance is altered as 658
compared to what would be observed or anticipated for an immediate-release product. Two 659
modified-release profiles, delayed-release and extended-release, are recognized. 660
661
Soaking time: A qualified duration of time that demonstrates adequate dispersion of an oral 662
dosage form in the specified dispersion media. 663
664
Therapeutic index: A ratio of the median toxic dose to the median effective dose of a specific 665
drug product. 666
667
Contains Nonbinding Recommendations
Draft — Not for Implementation
18
REFERENCES 668
669
Blumenstein I, YM Shastri, and J Stein, 2014, Gastroenteric Tube Feeding: Techniques, 670
Problems and Solutions, World J Gastroenterol, 20:8505–8524. 671
672
Bourgault AM, DK Heyland, JW Drover, L Keefe, P Newman, and AG Day, 2003, Prophylactic 673
Pancreatic Enzymes to Reduce Feeding Tube Occlusions, Nutr Clin Pract, 18:398–401. 674
675
Dandeles LM and AE Lodolce, 2011, Efficacy of Agents to Prevent and Treat Enteral Feeding 676
Tube Clogs, Ann Pharmacother, 45:676–680. 677
678
Jory C, R Shankar, K Oak, J Oates, and M Wilcock, 2017, Going Down the Tubes! Impact on 679
Seizure Control of Antiepileptic Medication Given Via Percutaneous Feeding Tubes, Epilepsy 680
Behav, 74:114–118. 681
682
Kurien M, H Penny, and DS Sanders, 2015, Impact of Direct Drug Delivery Via Gastric Access 683
Devices, Expert Opinion on Drug Delivery, 12:3, 455-463 (doi: 684
10.1517/17425247.2015.966683). 685
686
Mundi M, A Pattinson, MT McMahon, J Davidson, and RT Hurt, 2017, Prevalence of Home 687
Parenteral and Enteral Nutrition in the United States, Nutr Clin Pract, 32:799–805. 688
689
Ren P, Cui M, Anand O, Xia L, Zhao ZJ, Sun D, Sharp T, Conner DP, Peters J, Jiang W, Stier E, 690
and Jiang X, 2017, In Vitro Approaches to Support Bioequivalence and Substitutability of 691
Generic Proton Pump Inhibitors Via Nasogastric Tube Administration, AAPS J, 19(6):1593–692
1599. 693
694
Shipley K, AM Gallo, and WL Fields, 2016, Is Your Feeding Tube Clogged? Maintenance of 695
Gastrostomy and Gastrojejunostomy Tubes, Medsurg Nurs, 25:224–228. 696
697
698
Contains Nonbinding Recommendations
Draft — Not for Implementation
19
APPENDIX: 699
RECOMMENDED REPORT FORMAT FOR SUBMISSION OF IN VITRO TESTING 700
RESULTS TO SUPPORT ENTERAL TUBE ADMINISTRATION 701
702
Test Report Information 703
704
Complete test reports for nonclinical in vitro testing should include: the objective of the test, 705
description of the test methods and procedures, predefined pass/fail criteria, test results, and 706
discussion of conclusions. 707
708
A. Summary Table 709
710
To facilitate the assessment of submissions, FDA recommends that all submissions containing in 711
vitro testing reports also include a tabular summary of the testing performed and results obtained, 712
following the list in B. Test Reports. 713
714
B. Test Reports 715
716
Complete test reports should include clear, detailed descriptions of: 717
718
1. Test performed 719
720
2. Test objectives 721
722
3. Test methods and procedures. The following should be included: 723
724
a. Test sample information 725
726
The sample tested should be described. 727
728
b. Test sample size/selection 729
730
The report should provide a scientific rationale to support the number of samples 731
tested. The test sample selection should consider both inter- and intra-lot variability 732
(e.g., by examining multiple manufacturing lots if appropriate). 733
734
c. Test protocol 735
736
The test protocol should contain enough detail that an individual familiar with the 737
testing will be able to interpret the purpose of the test, how the test was performed, 738
and whether the test protocol and method are appropriate to evaluate the results of the 739
testing. The test protocol should describe the test parameters, including an 740
explanation of and rationale for critical test parameters. The test protocol should also 741
include acceptance criteria with scientific or clinical justification for the relevancy of 742
the acceptance criteria. 743
744
Contains Nonbinding Recommendations
Draft — Not for Implementation
20
Inclusion of the test protocol is unnecessary if FDA-recognized consensus standards 745
that include test methods are used during testing even when a Declaration of 746
Conformity to the standard is not provided.
1
Instead, the report should include a full 747
citation for the standard including the version, the extent to which the standard was 748
followed, and any deviations from the standard. If the FDA-recognized consensus 749
standard includes testing options (e.g., what to test, which test methods to use, 750
performance limits to assess conformity), applicants should include explanations for 751
the choices and selections made. 752
753
4. Predefined pass/fail criteria 754
755
The report should include all specifications or acceptance and rejection criteria used as 756
well as a clinical or scientific justification for the specifications or acceptance and 757
rejection criteria. 758
759
5. Test results 760
761
The report of test results should include: 762
763
a. Data points 764
765
The report should include all data points collected for the tests performed and a 766
summary of the data (e.g., minimum, maximum, average, and standard deviation). 767
Applicants should consider using consistent units throughout the testing. If data 768
values are rounded, then the significant digit to which they were rounded should be 769
specified. 770
771
b. Data analysis 772
773
Applicants should analyze the data, including any outlying points and anomalous 774
results, and explain whether the data meet acceptance criteria. FDA recommends that 775
applicants conduct data analyses for the test results using statistical analyses, when 776
appropriate, and specify whether the acceptance criteria were met. If the data analysis 777
demonstrates that the acceptance criteria were not met for either individual samples or 778
entire sample populations, applicants should: discuss the potential reasons for test 779
failure; determine if re-testing is appropriate; identify risk mitigation measure(s); and 780
provide justification for why the testing results should be considered acceptable and 781
supportive of the proposed labeling regarding administration via enteral tube. 782
783
1
See the guidance for industry and FDA staff Recognition and Withdrawal of Voluntary Consensus Standards
(September 2020). 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
.
Contains Nonbinding Recommendations
Draft — Not for Implementation
21
c. Protocol deviations 784
785
The report should describe any protocol deviations, the activities executed to 786
determine the source of the deviation, and any effect on the test results and their 787
interpretation. 788
789
6. Discussion of conclusions 790
791
Applicants should describe the conclusions drawn from the test results and the clinical 792
significance of the conclusions. 793
