Inborn Errors of Metabolism That Use Dietary Management: Considerations for Optimizing and Standardizing Diet in Clinical Trials for Drug Product Development: Draft Guidance for Industry

Administrative draft guidance, not enacted legislation.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.

25036902dft.docx
06/29/23
Inborn Errors of Metabolism That
Use Dietary Management:
Considerations for Optimizing and
Standardizing Diet in Clinical Trials
for Drug Product Development
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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) Division of Rare Diseases and
Medical Genetics, Dina Zand at 240-402-2538, or (CBER) Office of Communication, Outreach
and Development, 800-835-4709 or 240-402-8010.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 2023
Clinical/Medical
Revision 1

Inborn Errors of Metabolism That
Use Dietary Management:
Considerations for Optimizing and
Standardizing Diet in Clinical Trials
for Drug Product Development
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
and/or
Office of Communication, Outreach, and Development
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 71, Room 3128
Silver Spring, MD 20993-0002
Phone 800-835-4709 or 240-402-8010
Email, ocod@fda.hhs.gov
https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-
guidances
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 2023
Clinical/Medical
Revision 1

TABLE OF CONTENTS
I. 	INTRODUCTION..................................................................................................1
II. 	BACKGROUND ....................................................................................................2
III. 	RECOMMENDATIONS.......................................................................................3
A. 	Optimizing, Standardizing, and Maintaining Diet Stability in Clinical Trials ............ 3
B. 	Procedures and Intercurrent Illnesses............................................................................. 4
C. 	Clinical Trial Design ......................................................................................................... 5
D. 	Challenges and Limitations of Diet Assessments ............................................................ 6

Contains Nonbinding Recommendations
Draft — Not for Implementation
1
Inborn Errors of Metabolism That Use Dietary Management:	1
Considerations for Optimizing and Standardizing Diet	2
in Clinical Trials for Drug Product Development	3
Guidance for Industry1
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
I. 	INTRODUCTION	16
17
This guidance describes the Food and Drug Administration’s (FDA’s) current recommendations	18
for optimizing and standardizing dietary management in clinical trials for drug products intended	19
to treat inborn errors of metabolism when dietary management is important for metabolic	20
control.2 Optimizing and standardizing dietary management in patients diagnosed with inborn	21
errors of metabolism before they enter clinical trials and during clinical trials reduces an	22
important source of bias and variability, improves interpretability, and may allow for smaller and	23
more efficient clinical trials.	24
25
This guidance does not address scenarios in which dietary optimization and standardization may	26
be infeasible (e.g., diseases with prominent neuropsychiatric symptoms). For those programs,	27
bias from differential dietary management can best be addressed with randomization and	28
blinding. This guidance also does not address general issues of statistical analysis or clinical trial	29
design. Those topics are addressed in the ICH guidances for industry E9 Statistical Principles	30
for Clinical Trials (September 1998) and E10 Choice of Control Group and Related Issues in	31
Clinical Trials (May 2001), respectively.3	
32
33
This guidance revises the draft guidance of the same name issued on July 24, 2018. This	34
revision clarifies that:	35
1 This guidance has been prepared by the Division of Rare Diseases and Medical Genetics in the Center for Drug
Evaluation and Research (CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER) at
the Food and Drug Administration.
2 For this guidance, the term drug products includes both human drugs and biological drug products regulated by
CDER and CBER unless otherwise specified.
3 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
2
• 	Drug products should be studied in conjunction with dietary management for conditions	36
where dietary management is the current standard of clinical care.	37
38
• 	The most informative design is a randomized, double-blind clinical trial that includes a	39
concurrent control group (approved drug or placebo).	40
41
• 	Metabolic control may be evaluated by biochemical analytes and clinical assessment as	42
substantiated by current clinical standards of care.	43
44
• 	Dietary optimization should be based on dietary standards for the relevant population and	45
account for the severity of the patient’s metabolic defect and the patient’s age, growth,	46
and general health status.	47
48
• 	Baseline dietary management standards among patients from different countries should	49
be explained in the protocol.	50
51
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	52
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	53
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	54
the word should in Agency guidances means that something is suggested or recommended, but	55
not required.	56
57
58
II. 	BACKGROUND	59
60
Dietary management is an important treatment modality and standard of care for several inborn	61
errors of metabolism where specific enzymatic defects result in reduced or absent metabolism of	62
a variety of dietary components, with subsequent accumulation of toxic metabolites and organ	63
damage. Dietary management involves restricting particular food components, for example:	64
65
• 	Restricting protein for patients diagnosed with urea cycle disorders or organic acidemias	66
67
• 	Limiting food containing certain fats in patients diagnosed with some fatty acid oxidation	68
defects	69
70
• 	Limiting carbohydrates in patients diagnosed with certain primary mitochondrial diseases	71
72
• 	Removing dietary galactose in patients diagnosed with classical galactosemia	73
74
• 	Limiting phenylalanine in patients diagnosed with phenylketonuria	75
76
In some inborn errors of metabolism, dietary management includes supplementation with special	77
formulas that lack specific components (e.g., amino acids or galactose) and the recommendation	78
to ingest vitamins or cofactors that are important and unique to the patient’s metabolic pathway	79
deficiency.	80
81

Contains Nonbinding Recommendations
Draft — Not for Implementation
3
The goal of dietary modification is to improve or restore biochemical and physiologic	82
homeostasis by restricting the dietary precursors that generate intermediary products of	83
metabolism that may accumulate and lead to toxicity in specific diseases.	84
85
Drug products (e.g., enzyme replacement therapy, enzyme substitution therapy) should be	86
studied in conjunction with dietary management for conditions that use dietary management as	87
part of clinical care. Clinical trials for these drugs typically include measurements of metabolite	88
concentrations (primarily in serum and urine) as endpoints, which are the same assessments used	89
to inform dietary changes and to determine whether dietary management has been optimized.	90
Consequently, dietary changes during these trials can affect efficacy results and pose significant	91
interpretability challenges, particularly when the clinical trial does not anticipate or appropriately	92
account for the confounding effect of diet in the design and analyses of trial results. This	93
confounding can add to the existing challenges in designing and conducting successful clinical	94
trials in rare diseases, such as the limited availability of patients (thus, the small size of clinical	95
trials), the heterogeneity of clinical phenotypes, the challenges with selecting appropriate	96
efficacy endpoints, and the lack of precision of dietary assessments. Inadequate dietary	97
management or insufficient documentation of dietary changes during a trial can make	98
interpretation of trial results particularly difficult when the treatment effect of the new drug	99
product is not large.	100
101
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III. 	RECOMMENDATIONS	103
104
A. 	Optimizing, Standardizing, and Maintaining Diet Stability in Clinical Trials	105
106
Sponsors should consider the following recommendations for optimizing, standardizing, and	107
maintaining the diets of patients before they enter clinical trials:	108
109
• 	When optimizing a patient’s dietary management before trial entry, sponsors should take	110
into account the specific condition that is being treated; the severity of each patient’s	111
metabolic defect; the patient’s age, growth, and general health status; the duration needed	112
to assess whether the patient’s dietary management is appropriate and optimized for the	113
patient’s individual medical needs; and the complexity of, and the patient’s/family’s	114
ability to understand and comply with, the prescribed diet.	115
116
• 	Sponsors should assess and systematically document patient adherence to the dietary plan	117
during the trial. Protocols should include standard measures to verify adherence to the	118
dietary plan (e.g., periodic testing for specific metabolites over time based upon age-	119
related standards, appropriate growth assessments, etc.).	120
121
• 	Sponsors should evaluate the patient’s ability and likelihood of complying with the	122
recommended diet to ensure that patients with a high likelihood of maintaining a stable	123
diet during the trial are enrolled.	124
125
• 	The duration of the run-in period for diet optimization should be justified.	126
127

Contains Nonbinding Recommendations
Draft — Not for Implementation
4
• 	Given the global nature of rare disease trials, sponsors should have an awareness of and	128
clearly state the differences in standards in baseline dietary management among patients	129
from different countries.	130
131
Sponsors should consider the following dietary recommendations for subjects who are	132
participating in the treatment phase of the clinical trial:	133
134
• 	During the trial, patients should maintain a stable diet, and any changes should be	135
documented in a diary and accompanied by the reasons for the changes.	136
137
• 	Sponsors should follow the same principles of dietary management across clinical sites	138
according to protocol-defined and allowed dietary modifications. For consistency, the	139
trial protocol should define clearly both the dietary goals and the dietary management,	140
including use of standardized household measurements and scale-measuring devices for	141
estimating volume and weight of food, whenever possible.	142
143
• 	Protocols should include precise definitions of diet stability during the trial, including	144
magnitude of allowed deviations generally anticipated in the prescribed diet, such as ±	145
5% or other change in total daily protein. This definition should be scientifically justified	146
and supported by evidence that a certain dietary deviation will not affect the clinical and	147
laboratory outcomes assessed in the trial.	148
149
• 	Patients should enter the treatment phase of the trial during a period of stable metabolic	150
control as evaluated by appropriate biochemical analytes (e.g., ammonia, plasma amino	151
acids, urine organic acids, plasma acylcarnitines, total and free carnitine) and clinical	152
assessments. Sponsors should document baseline dietary information (total daily protein,	153
lipid, carbohydrate, and total daily caloric intake) over an appropriate time period (e.g., 3	154
days) at enrollment.	155
156
B. 	Procedures and Intercurrent Illnesses	157
158
Patients with inborn errors of metabolism often require increased caloric intake for procedures or	159
assessments requiring sedation that can include dental care, adenoidectomy or gastrostomy tube	160
placement, in addition to intercurrent illnesses that may precipitate a change in metabolic status	161
(e.g., metabolic decompensation with need for dietary and/or pharmacologic changes). Ideally,	162
sponsors should anticipate and address elective surgeries and procedures before enrolling	163
patients in clinical trials. However, protocols also should specify a standardized approach to	164
dietary management for unanticipated intercurrent procedures, illnesses, and metabolic events	165
that may occur during the trial. Adherence to this approach should be documented	166
systematically and addressed in the statistical analysis plan, including how these intercurrent	167
events will impact the efficacy and safety assessments and clinical interpretation of data.	168
169

Contains Nonbinding Recommendations
Draft — Not for Implementation
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C. 	Clinical Trial Design	170
171
Sponsors should consider the following recommendations for clinical trial design when an	172
investigational drug is compared with an approved drug or placebo as add-on to dietary	173
management. General considerations include the following:	174
175
• 	The most informative design is a randomized, double-blind clinical trial that includes a	176
concurrent control group (approved drug or placebo). Dietary management should be	177
consistent across all trial arms such that regardless of treatment arm, all patients should	178
be receiving optimized standard of care, including dietary management.	179
180
• 	Sponsors can consider different types of controlled, randomized clinical trial designs	181
(e.g., crossover, randomized withdrawal, delayed start). An active-controlled	182
noninferiority design is one possible approach if there is an already approved therapy and	183
it is possible to justify a noninferiority margin.4 Sponsors should discuss the specific trial	184
designs with FDA for concurrence before initiating the trial.	185
186
• 	Changes in dietary management during a trial can introduce variability, reducing the	187
potential to find benefit for an effective treatment. Dietary changes made to account for	188
growth or disease exacerbation should be prespecified and clearly documented.	189
190
• 	Sponsors should discuss with FDA any performance-based or clinical outcome	191
assessment tools for endpoints intended to establish substantial evidence of effectiveness,	192
including those that may be influenced by dietary changes, before implementing those	193
assessments in a trial(s).	194
195
To allow for unbiased comparative efficacy assessments when trials involve dietary	196
management, the use of a concurrent blinded control arm is an essential aspect to the clinical trial	197
design. Comparisons to a nonconcurrent, historical control group have important limitations for	198
the following reasons:	199
200
• 	Standards for dietary management can change over time. An optimized diet for a	201
historical control group may differ from an optimized diet for a concurrent control group	202
or a treatment group in a given trial. This difference can introduce bias in comparisons,	203
as differences in dietary practice can affect the results of the clinical outcomes.	204
205
• 	Differences in the frequency and type of dietary instructions can lead to differences in	206
dietary management and compliance between treatment groups, which can bias efficacy	207
analyses.	208
209
• 	Differences in patient documentation of diet can limit the ability to compare dietary	210
management and compliance between treatment groups.	211
212
4 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016).

Contains Nonbinding Recommendations
Draft — Not for Implementation
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• 	Differences in patient baseline characteristics between the historical control group and	213
the treatment group, some of which may be unmeasured, can limit the ability to conduct	214
reliable comparisons.	215
216
• 	The standards of disease management, including management of concurrent or related	217
conditions, change over time. Changes in disease management compared with a	218
historical control group can also introduce bias.	219
220
• 	The types and performance characteristics of laboratory assays used to measure	221
metabolic biomarkers/endpoints among the groups can change over time. It is important	222
that sponsors account for these changes when using these assays to evaluate biochemical	223
parameters of metabolic control and to assess dietary compliance or dietary optimization	224
and response to treatment.	225
226
D. 	Challenges and Limitations of Diet Assessments	227
228
Although assessments of dietary intake have been used to document dietary practices and to	229
verify the patient’s diet adherence, available tools that measure dietary components have	230
limitations. Sponsors should consider the following:	231
232
• 	Dietary questionnaires use crude measures of portion size, frequency of consumption,	233
and broad food groupings and are only a general estimate of dietary intake. Thus, day-to-	234
day and week-to-week variation in diets could lead to a range of estimates of long-term	235
dietary intake.5	
236
237
• 	Food diaries (e.g., 3-day diet) are commonly used in the clinical management of patients	238
with inborn errors of metabolism. The inherent variability of patient/family recall in a	239
food diary may introduce imprecision into a clinical trial and should be avoided. Using	240
standardized dietary forms (written or electronic) designed or vetted by metabolic	241
dietitians and physicians can greatly facilitate dietary documentation in a clinical trial and	242
is strongly encouraged.	243
244
• 	Sponsors should encourage families and patients to document their diet frequently during	245
the trial to support the routine documentation obtained during the 3 days before clinical	246
site visits.	247
5 Greenwood DC, MS Gilthorpe, and JE Cade, 2006, The Impact of Imprecisely Measured Covariates on Estimating
Gene-Environment Interactions, BMC Med Res Methodol, 6:21.