Gastroparesis: Clinical Evaluation of Drugs for Treatment Guidance for Industry

Administrative draft guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

6/21/2019
Gastroparesis:
Clinical Evaluation of
Drugs for Treatment
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 Maureen Dewey at 301-796-0845.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2019
Clinical/Medical
Revision 1

Gastroparesis:
Clinical Evaluation of
Drugs for Treatment
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., 4th 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
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
August 2019
Clinical/Medical
Revision 1

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	ENDPOINTS AND TRIAL DESIGN FOR GASTROPARESIS CLINICAL
TRIALS.............................................................................................................................. 3
A. 	Trial Design .................................................................................................................................... 3
B. 	Trial Populations............................................................................................................................ 4
C. 	Approach for Outcome Assessment Measures ............................................................................ 5
D. 	Trial Endpoints .............................................................................................................................. 6
1. Primary Endpoints ........................................................................................................................... 6
2. Secondary/Other Endpoints ............................................................................................................. 6
3. Defining Clinically Meaningful Within-Patient Changes in Sign and Symptom Scores.................. 6
E. 	Statistical Considerations .............................................................................................................. 7
REFERENCES.............................................................................................................................. 9

Contains Nonbinding Recommendations
Draft — Not for Implementation
1
Gastroparesis:	1
Clinical Evaluation of Drugs for Treatment	2
Guidance for Industry1
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
The purpose of this guidance is to assist sponsors in the clinical development of drugs for	19
treating idiopathic and diabetic gastroparesis.2 Specifically, this guidance addresses FDA’s	20
current recommendations regarding clinical trial designs and clinical endpoint assessments to	21
support developing gastroparesis drugs.	22
23
This draft guidance is intended to serve as a focus for continued discussions among the	24
responsible FDA divisions in the Office of New Drugs, pharmaceutical sponsors, the academic	25
community, and the public.3	
26
27
This guidance revises the draft guidance for industry of the same name issued in July 2015.	28
Changes from the previous draft reflect FDA’s current thinking about developing clinical	29
outcome assessment tools and statistical considerations for using those tools to assess primary	30
and secondary efficacy endpoints.	31
32
This guidance does not address detailed patient-reported outcome (PRO) instrument	33
development and validation; these topics are addressed in the guidance for industry Patient-	34
1 This guidance has been prepared by the Division of Gastroenterology and Inborn Errors Products in the Center for
Drug Evaluation and Research at the Food and Drug Administration.
2 For the purposes of this guidance, all references to drugs include both human drugs and therapeutic biological
products unless otherwise specified.
3 In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that
arise during the development of drugs to treat gastroparesis.

Contains Nonbinding Recommendations
Draft — Not for Implementation
2
Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims	35
(December 2009).4	
36
37
More details regarding statistical analysis and clinical trial design are addressed in the ICH	38
guidances for industry E9 Statistical Principles for Clinical Trials (September 1998) and E10	39
Choice of Control Group and Related Issues in Clinical Trials (May 2001), respectively.	40
41
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	42
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	43
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	44
the word should in Agency guidances means that something is suggested or recommended, but	45
not required.	46
47
48
II. 	BACKGROUND	49
50
Gastroparesis is a disorder characterized by delayed gastric emptying (DGE) in the absence of	51
mechanical obstruction. Symptoms are chronic with episodic exacerbation (Parkman et al.	52
2004). The idiopathic form of the disorder, which accounts for the greatest number of cases	53
(Karamanolis et al. 2007), predominantly affects young adult females. Gastroparesis is also	54
frequently associated with diabetes (diabetic gastroparesis), which likely occurs because of	55
impaired neural control of gastric motility (Parkman et al. 2004). In addition, acute	56
hyperglycemia has the potential to slow gastric emptying and decrease the effects of prokinetic	57
drugs (Camilleri 2010).	58
59
The core signs and symptoms of gastroparesis are nausea (92 to 96 percent), vomiting (68 to 88	60
percent), postprandial fullness (54 to 77 percent), early satiety (42 to 86 percent), and upper	61
abdominal pain (36 to 85 percent) (Hoogerwerf et al. 1999; Anaparthy et al. 2009). Patients may	62
experience any combination of signs and symptoms with varying degrees of severity. Pain is	63
more prevalent in patients with idiopathic gastroparesis than it is in patients with diabetic	64
gastroparesis. Patients with diabetic gastroparesis may experience further derangement of	65
glucose control because of unpredictable gastric emptying and altered absorption of orally	66
administered hypoglycemic drugs.	67
68
Because the signs and symptoms of gastroparesis overlap with other gastrointestinal conditions,	69
gastroparesis may be incorrectly diagnosed as bowel obstruction, functional dyspepsia, irritable	70
bowel syndrome, or peptic ulcer disease. In a patient with signs and symptoms suggestive of	71
gastroparesis, a finding of DGE in the absence of an obstruction or alternative diagnosis provides	72
critical support for the diagnosis of gastroparesis and can be assessed using either gastric	73
emptying scintigraphy, the gastric emptying breath test, or the SmartPill motility testing system.	74
75
There is an urgent medical need for development of safe and effective therapies to treat patients	76
with gastroparesis.	77
78
4 We update guidances periodically. To make sure you have 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
3
III. 	ENDPOINTS AND TRIAL DESIGN FOR GASTROPARESIS CLINICAL	79
TRIALS	80
81
Primary efficacy assessments for adequate and well controlled trials must be well defined and	82
reliable.5 Because gastroparesis is a symptomatic condition, a well-defined and reliable PRO	83
instrument that measures all the clinically important signs and symptoms of gastroparesis would	84
be the ideal primary efficacy-assessment tool in clinical trials used to support labeling claims for	85
treating gastroparesis.6 However, we are currently not aware of such a measure. Until an	86
appropriate PRO instrument for gastroparesis becomes available, sponsors should consider the	87
strategies discussed in the following sections when designing gastroparesis clinical trials.	88
Sponsors may also wish to review FDA’s Center for Drug Evaluation and Research Clinical	89
Outcome Assessment (COA) Drug Development Tool Qualification Program web page for	90
information on qualified tools or tools currently under development.	91
92
Sponsors may wish to include and evaluate well-defined PRO instruments assessing the relevant	93
and important signs and symptoms in early drug development — and evaluate the results in	94
dose-ranging phase 2 trials or stand-alone noninterventional studies — to support their future use	95
in phase 3 trials. We encourage early and regular discussions with FDA regarding the	96
development of these PRO instruments.	97
98
Because gastroparesis manifests as more than one core sign or symptom, the effect of new drugs	99
intended to treat gastroparesis on each core sign and symptom should be assessed. Early phase	100
trials should help inform which of the core signs and/or symptoms should be included as	101
prespecified endpoints intended to support labeling claims, based on which signs or symptoms	102
the treatment is likely to improve. It is important to show that even drugs intended to treat only a	103
subset of the core signs or symptoms, based on the mechanism of the drug, do not worsen the	104
remaining signs or symptoms of gastroparesis. For example, a drug may be expected to improve	105
gastroparesis-related nausea and vomiting but not abdominal pain based on its mechanism of	106
action. In this scenario, clinical studies should demonstrate that nausea and vomiting improved	107
and that the treatment did not worsen the symptoms of abdominal pain, postprandial fullness, and	108
early satiety.	109
110
The following sections provide recommendations regarding trial design, trial populations,	111
outcome assessment measures, trial endpoints, and statistical considerations.	112
113
A. 	Trial Design	114
115
In general, the trial design should consist of a randomized, double-blind, placebo-controlled trial	116
and should include a 1- to 2-week screening period. The screening period can be used for	117
investigators to establish the presence and persistence of trial-entry criteria and for patients to	118
gain experience completing the PRO instruments employed in the trial and demonstrate adequate	119
5 21 CFR 314.126.
6 See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to
Support Labeling Claims.

Contains Nonbinding Recommendations
Draft — Not for Implementation
4
understanding of and compliance with completing these instruments. The screening period	120
assessments of gastroparesis signs and symptoms can serve as the baseline values used in the	121
analyses of the primary endpoint (see section III. D., Trial Endpoints). FDA recommends a	122
baseline assessment period of at least 7 days. The primary endpoint should measure the change	123
in signs and symptoms from baseline over a treatment period of at least 12 weeks’ duration.	124
125
Trial designs should address the need for maintenance treatment to prevent recurrence of signs or	126
symptoms.	127
128
Endpoint assessment should be based on patients’ daily reporting to avoid recall error, and the	129
protocol should state whether rescue medication (i.e., protocol-specified therapy for continued	130
exacerbation of symptoms that is standardized across study sites) is allowed. Daily diaries	131
should be collected throughout the entire trial.	132
133
In addition, we recommend a randomized, controlled, long-term safety study of 12 months’	134
duration, with appropriate prespecified provisions for rescue medications, which should be	135
conducted before submitting a new drug application.	136
137
B. 	Trial Populations	138
139
Idiopathic and diabetic gastroparesis patients should be studied in separate clinical trials. In	140
general, diabetic gastroparesis patients experience the same core signs and symptoms as patients	141
with idiopathic gastroparesis, but individual signs and symptoms may occur more often or with	142
greater severity in one population compared with the other, and the degree of diabetic control can	143
also confound results. To fully describe safety and efficacy in each population, we recommend	144
separate trials. Because idiopathic and diabetic gastroparesis are closely related conditions, a	145
single phase 3 trial in each population with demonstration of reliable and clinically meaningful	146
results may support approval for both indications.7	
147
148
We recommend that trial-entry criteria include the following:	149
150
• 	The trial populations should have a clinical diagnosis of idiopathic or diabetic	151
gastroparesis (for the individual trials) based on a documented history of gastroparesis	152
symptoms, exclusion of other potential etiologies, and DGE (Abell et al. 2008;	153
Parkman et al. 2004). To optimize the ability to demonstrate a treatment effect, the	154
trial should enroll patients with higher symptom severity (moderate to severe).	155
Because there are currently no accepted definitions of gastroparesis severity, the	156
sponsor should provide a justification for the severity index selected, including what	157
defines moderate and severe symptoms.	158
159
• 	Diabetic gastroparesis patients should have controlled and stable blood glucose levels.	160
Patients prone to acute hyperglycemic events may confound interpretation of the	161
therapeutic effect of the drug.	162
163
7 See the guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and Biological
Products (May 1998).

Contains Nonbinding Recommendations
Draft — Not for Implementation
5
• 	Patients on opioids should be excluded because opioid use may affect gastrointestinal	164
motility and potentially confound results.	165
166
C. 	Approach for Outcome Assessment Measures	167
168
Until a well-defined and reliable PRO instrument that measures all the clinically important signs	169
and symptoms of gastroparesis is available, we recommend that the five core signs and	170
symptoms of gastroparesis — nausea, vomiting, postprandial fullness, early satiety, and	171
abdominal pain — be included as endpoints in well-controlled clinical trials (Karamanolis et al.	172
2007; Hoogerwerf et al. 1999; Anaparthy et al. 2009). Sponsors should identify and empirically	173
justify the questionnaire items (and their wording) used to assess signs or symptoms of	174
gastroparesis that will be included in the trial.8	
175
176
Each sponsor should propose a primary endpoint definition (see section III. D. Trial Endpoints)	177
and a method for measuring each of the five signs and symptoms as described below. Piloting	178
the proposed instrument(s) in phase 2 trials can provide an opportunity to evaluate the ability of	179
the instrument(s) to detect change, provide guidelines for interpretation of clinically meaningful	180
within-patient change, and confirm the endpoint definition. Pilot results can further inform plans	181
for implementation of the proposed instrument(s) in the phase 3 trials. Wording of the	182
questionnaire should be carefully thought out so the questions or requests do not overlap in their	183
measurement concepts (e.g., postprandial fullness and early satiety), and the concepts should be	184
well-defined so that they are interpreted in a consistent way by patients (i.e., the questionnaire	185
should include definitions for postprandial fullness, early satiety, or other terms that may vary in	186
their interpretation among patients). Each core sign and symptom should be separately measured	187
and documented in the clinical trial.	188
189
The sponsor should also specify the mode of data collection that will be used by patients to	190
record their daily signs and symptoms (e.g., electronic diary).	191
192
All signs and symptoms except vomiting should be rated by severity. For example, question or	193
request item responses can range from 0 for no symptom to 4 for the most severe symptom	194
(0=none; 1=mild; 2=moderate; 3=severe; and 4=very severe) or have a numerical rating scale	195
from 0 to 10, where 0 reflects the absence of the symptom and 10 reflects the worst possible	196
symptom experience. When possible, the rating scale should be consistent across the core signs	197
and symptoms. We recommend that reporting of vomiting in a daily symptom diary be	198
measured by frequency rather than severity. Frequency should be reported as the exact number	199
of times over a 24-hour period, and a clear definition of what is considered “one time” of	200
vomiting should be provided to patients to ensure consistency both within and between patients	201
in reporting the number of times vomiting has occurred. The severity of nausea, postprandial	202
fullness, early satiety, and abdominal pain should be recorded based on the patient’s worst	203
experience over a 24-hour period.	204
205
8 See the guidance for industry Patient-Reported Outcome Measures: Use in Medical Product Development to
Support Labeling Claims.

Contains Nonbinding Recommendations
Draft — Not for Implementation
6
D. 	Trial Endpoints	206
207
1. 	Primary Endpoints	208
209
Changes in patient-reported signs and symptom scores should form the basis of the primary	210
efficacy assessment in therapeutic trials for idiopathic and diabetic gastroparesis. The primary	211
endpoint should be based on patients’ core signs and symptoms or a subset of them. Gastric	212
emptying time should not be used as a primary efficacy endpoint because changes in gastric	213
emptying time are not associated with the changes in the clinically important signs and	214
symptoms in patients with gastroparesis.	215
216
The primary endpoint should measure change in signs and symptoms from baseline. The	217
analysis plan should include an evaluation of treatment effect throughout the 12-week study	218
period.	219
220
We recommend the use of an endpoint that is based on core signs and symptoms. This may be	221
based on prespecified core signs and symptoms or a symptom severity summary score	222
(excluding vomiting) and vomiting frequency (collected as a continuous variable). The primary	223
endpoint should not be limited to a single sign or symptom. If sponsors propose a summary	224
score, they should evaluate question-level (or request-level) responses to determine whether	225
individual questions (or requests) overly influence the total score. Currently, we do not have	226
evidence to recommend one approach over the other. Scores based on severity should be	227
analyzed separately from those based on frequency (e.g., vomiting).	228
229
2. 	Secondary/Other Endpoints	230
231
FDA recommends that changes from baseline in the individual signs and symptoms that are not	232
assessed as part of the primary endpoint be measured as secondary endpoints. Therefore, the	233
primary and secondary endpoints should include an evaluation of all five core signs and	234
symptoms. Change in gastric emptying time can be measured as a secondary endpoint if desired	235
(Abell et al. 2008). The prespecified plan should address an analysis of the remaining core signs	236
or symptoms that are not included in the primary endpoint.	237
238
3. 	Defining Clinically Meaningful Within-Patient Changes in Sign and Symptom	239
Scores	240
241
To aid in the interpretation of the results, sponsors should determine the amount of change that is	242
meaningful to patients, in a total summary score or in individual sign and symptom scores.	243
Ideally, this should be based on actual data and established in advance of phase 3 trials, so	244
clinically meaningful within-patient change thresholds may be prespecified. There are two	245
clinically meaningful change thresholds of interest: one for a clinically important improvement	246
from baseline and one for a clinically important deterioration from baseline. Depending on the	247
proposed mechanism of action of the drug and trial objectives, a proposed threshold can specify	248
some level of improvement in each of the five core signs and symptoms, or it can specify some	249
level of improvement in a subset of those core signs and symptoms. Worsening of core signs	250

Contains Nonbinding Recommendations
Draft — Not for Implementation
7
and symptoms would be inconsistent with the expected clinical benefit and taken into account	251
when evaluating benefit and risk.	252
253
We recommend the use of an anchor-based approach, typically using phase 2 trial data, to	254
estimate clinically meaningful change. For this approach, we recommend including in phase 2	255
and 3 trials multiple anchor scales, such as patient global impression of severity (PGIS) and	256
patient global impression of change (PGIC) scales, with the intent of providing accumulated	257
evidence to help interpret a clinically meaningful within-patient score change. In contrast to a	258
PGIC scale, a PGIS scale is not subject to recall error and can also be used to assess change from	259
baseline data. The PGIS scale is the preferred anchor scale over the PGIC scale; however, there	260
is no perfect anchor scale, and it is helpful to include multiple anchor scales for anchor-based	261
analyses.	262
263
The following item, which could be asked of patients (following the assessment schedule and	264
recall period of the prespecified endpoint) and at baseline, is an example of a PGIS scale:	265
266
“Please choose the response below that best describes the severity of your gastroparesis	267
symptoms over the [insert appropriate recall period here].”	268
269
Sponsors can consider the following response options to this item: 0=none; 1=mild;	270
2=moderate; 3=severe; and 4=very severe.	271
272
The following item, which could be asked weekly of patients, is an example of a PGIC scale:	273
274
“Please choose the response below that best describes the overall change in your	275
gastroparesis symptoms since you started taking the study medication.”	276
277
Sponsors can consider the following response options to this item: much better, a little better, no	278
change, a little worse, much worse.	279
280
Sponsors should determine the clinically meaningful within-patient change threshold range using	281
anchor-based methods (e.g., patient global impression scale as an anchor), supplemented with	282
empirical cumulative distribution functions (eCDFs) of within-patient score change. Separate	283
eCDF curves should be generated for each meaningful anchor category (e.g., improved, no	284
change, worsened) using data pooled across trial arms.	285
286
E. 	Statistical Considerations	287
288
To evaluate daily diary assessments created during a trial, an adequate number of the	289
assessments should be available. The sponsor can determine this number based on evidence	290
derived from the particular PRO assessment used in the trial. For example, if a weekly summary	291
score is used, in general, the sponsor should provide assessments from at least 4 of the 7 days.	292
However, evidence from a particular PRO assessment may support the need for data from a	293
higher number of days for that instrument to provide reliable results.	294
295

Contains Nonbinding Recommendations
Draft — Not for Implementation
8
The efficacy analysis plan should clearly define how patients who take rescue medication will be	296
considered in the final analysis. Sponsors also should propose methods for handling missing	297
data, including missing rescue medication data and missing PRO data at both question or request	298
and instrument levels, in the analysis plan. Sponsors should consider different approaches before	299
the trial is initiated and the properties of these approaches should be evaluated.	300
301
We recommend that sponsors analyze the primary and secondary endpoints as continuous or	302
ordinal variables; we do not recommend the use of percentage change. In general, a traditional	303
responder analysis would not be appropriate unless the targeted response is complete resolution	304
of signs and symptoms. In addition, we encourage the use of baseline values and other	305
covariates to improve the efficiency of primary and secondary endpoint analyses.	306
307
Additionally, sponsors should submit supportive descriptive analyses (i.e., graphs of eCDFs of	308
within-patient change from baseline for primary and secondary endpoints by treatment arm) for	309
FDA review.	310

Contains Nonbinding Recommendations
Draft — Not for Implementation
9
REFERENCES	311
312
Abell TL, RK Bernstein, T Cutts, G Farrugia, J Forster, WL Hasler, RW McCallum, KW Olden,	313
HP Parkman, CR Parrish, PJ Pasricha, CM Prather, EE Soffer, R Twillman, and AI Vinik, 2006,	314
Treatment of Gastroparesis: A Multidisciplinary Clinical Review, Neurogastroenterol Motil	315
18:263–283.	316
317
Abell TL, M Camilleri, K Donohoe, WL Hasler, HC Lin, AH Nauer, RW McCallum, T Nowak,	318
ML Nusynowitz, HP Parkman, P Shreve, LA Szarka, WJ Snape, and HA Ziessman, 2008,	319
Consensus Recommendations for Gastric Emptying Scintigraphy: A Joint Report of the	320
American Neurogastroenterology and Motility Society and the Society of Nuclear Medicine, Am	321
J Gastroenterol, 103:753–763.	322
323
Anaparthy R, N Pehlivanov, J Grady, H Yimei, and PJ Pasricha, 2009, Gastroparesis and	324
Gastroparesis-Like Syndrome: Response to Therapy and Its Predictors, Dig Dis Sci,	325
54(5):1003–1010.	326
327
Hoogerwerf WA, PJ Pasricha, AN Kalloo, and MM Schuster, 1999, Pain: The Overlooked	328
Symptom in Gastroparesis, Am J Gastroenterol, 94:1029–1033.	329
330
Karamanolis G, P Caenepeel, J Arts, and J Tack, 2007, Determinants of Symptom Pattern in	331
Idiopathic Severely Delayed Gastric Emptying: Gastric Emptying Rate or Proximal Stomach	332
Dysfunction? Gut, 56:29–36.	333
334
Parkman HP, WL Hasler, and RS Fisher, 2004, American Gastroenterological Association	335
Technical Review on the Diagnosis and Treatment of Gastroparesis, Gastroenterology,	336
127(5):1592–1622.	337
338
Parkman HP, K Yates, WL Hasler, L Nguyen, PJ Pasricha, WJ Snape, G Farrugia, KL Koch, J	339
Calles, TL Abell, RW McCallum, L Lee, A Unalp-Arida, J Tonascia, and F Hamilton, 2011,	340
Similarities and Differences Between Diabetic and Idiopathic Gastroparesis, Clin Gastroenterol	341
Hepatol, 9:1056–1064.	342