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DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 
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 
 
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:  
2  Considerations for Optimizing and Standardizing Diet  
3  in Clinical Trials for Drug Product Development 
4  Guidance for Industry1 
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16  I.  INTRODUCTION 
17   
18  This guidance describes the Food and Drug Administrations (FDAs) current recommendations 
19  for optimizing and standardizing dietary management in clinical trials for drug products intended 
20  to treat inborn errors of metabolism when dietary management is important for metabolic 
21  control.2  Optimizing and standardizing dietary management in patients diagnosed with inborn 
22  errors of metabolism before they enter clinical trials and during clinical trials reduces an 
23  important source of bias and variability, improves interpretability, and may allow for smaller and 
24  more efficient clinical trials. 
25   
26  This guidance does not address scenarios in which dietary optimization and standardization may 
27  be infeasible (e.g., diseases with prominent neuropsychiatric symptoms).  For those programs, 
28  bias from differential dietary management can best be addressed with randomization and 
29  blinding.  This guidance also does not address general issues of statistical analysis or clinical trial 
30  design.  Those topics are addressed in the ICH guidances for industry E9 Statistical Principles 
31  for Clinical Trials (September 1998) and E10 Choice of Control Group and Related Issues in 
32  Clinical Trials (May 2001), respectively.3 
33   
34  This guidance revises the draft guidance of the same name issued on July 24, 2018.  This 
35  revision clarifies that: 
 
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. 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
36    Drug products should be studied in conjunction with dietary management for conditions 
37  where dietary management is the current standard of clinical care. 
38   
39    The most informative design is a randomized, double-blind clinical trial that includes a 
40  concurrent control group (approved drug or placebo).   
41   
42    Metabolic control may be evaluated by biochemical analytes and clinical assessment as 
43  substantiated by current clinical standards of care.   
44   
45    Dietary optimization should be based on dietary standards for the relevant population and 
46  account for the severity of the patients metabolic defect and the patients age, growth, 
47  and general health status. 
48   
49    Baseline dietary management standards among patients from different countries should 
50  be explained in the protocol.  
51   
52  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
53  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
54  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
55  the word should in Agency guidances means that something is suggested or recommended, but 
56  not required. 
57   
58   
59  II.  BACKGROUND 
60   
61  Dietary management is an important treatment modality and standard of care for several inborn 
62  errors of metabolism where specific enzymatic defects result in reduced or absent metabolism of 
63  a variety of dietary components, with subsequent accumulation of toxic metabolites and organ 
64  damage.  Dietary management involves restricting particular food components, for example: 
65   
66    Restricting protein for patients diagnosed with urea cycle disorders or organic acidemias 
67   
68    Limiting food containing certain fats in patients diagnosed with some fatty acid oxidation 
69  defects 
70   
71    Limiting carbohydrates in patients diagnosed with certain primary mitochondrial diseases 
72   
73    Removing dietary galactose in patients diagnosed with classical galactosemia 
74   
75    Limiting phenylalanine in patients diagnosed with phenylketonuria 
76   
77  In some inborn errors of metabolism, dietary management includes supplementation with special 
78  formulas that lack specific components (e.g., amino acids or galactose) and the recommendation 
79  to ingest vitamins or cofactors that are important and unique to the patients metabolic pathway 
80  deficiency.  
81   
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
82  The goal of dietary modification is to improve or restore biochemical and physiologic 
83  homeostasis by restricting the dietary precursors that generate intermediary products of 
84  metabolism that may accumulate and lead to toxicity in specific diseases. 
85   
86  Drug products (e.g., enzyme replacement therapy, enzyme substitution therapy) should be 
87  studied in conjunction with dietary management for conditions that use dietary management as 
88  part of clinical care.  Clinical trials for these drugs typically include measurements of metabolite 
89  concentrations (primarily in serum and urine) as endpoints, which are the same assessments used 
90  to inform dietary changes and to determine whether dietary management has been optimized.  
91  Consequently, dietary changes during these trials can affect efficacy results and pose significant 
92  interpretability challenges, particularly when the clinical trial does not anticipate or appropriately 
93  account for the confounding effect of diet in the design and analyses of trial results.  This 
94  confounding can add to the existing challenges in designing and conducting successful clinical 
95  trials in rare diseases, such as the limited availability of patients (thus, the small size of clinical 
96  trials), the heterogeneity of clinical phenotypes, the challenges with selecting appropriate 
97  efficacy endpoints, and the lack of precision of dietary assessments.  Inadequate dietary 
98  management or insufficient documentation of dietary changes during a trial can make 
99  interpretation of trial results particularly difficult when the treatment effect of the new drug 
100  product is not large.  
101   
102   
103  III.  RECOMMENDATIONS 
104   
105  A.  Optimizing, Standardizing, and Maintaining Diet Stability in Clinical Trials 
106   
107  Sponsors should consider the following recommendations for optimizing, standardizing, and 
108  maintaining the diets of patients before they enter clinical trials: 
109   
110    When optimizing a patients dietary management before trial entry, sponsors should take 
111  into account the specific condition that is being treated; the severity of each patients 
112  metabolic defect; the patients age, growth, and general health status; the duration needed 
113  to assess whether the patients dietary management is appropriate and optimized for the 
114  patients individual medical needs; and the complexity of, and the patients/familys 
115  ability to understand and comply with, the prescribed diet.  
116   
117    Sponsors should assess and systematically document patient adherence to the dietary plan 
118  during the trial.  Protocols should include standard measures to verify adherence to the 
119  dietary plan (e.g., periodic testing for specific metabolites over time based upon age-
120  related standards, appropriate growth assessments, etc.). 
121   
122    Sponsors should evaluate the patients ability and likelihood of complying with the 
123  recommended diet to ensure that patients with a high likelihood of maintaining a stable 
124  diet during the trial are enrolled. 
125   
126    The duration of the run-in period for diet optimization should be justified.  
127   
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
128    Given the global nature of rare disease trials, sponsors should have an awareness of and 
129  clearly state the differences in standards in baseline dietary management among patients 
130  from different countries. 
131   
132  Sponsors should consider the following dietary recommendations for subjects who are 
133  participating in the treatment phase of the clinical trial: 
134   
135    During the trial, patients should maintain a stable diet, and any changes should be 
136  documented in a diary and accompanied by the reasons for the changes.   
137   
138    Sponsors should follow the same principles of dietary management across clinical sites 
139  according to protocol-defined and allowed dietary modifications.  For consistency, the 
140  trial protocol should define clearly both the dietary goals and the dietary management, 
141  including use of standardized household measurements and scale-measuring devices for 
142  estimating volume and weight of food, whenever possible.  
143   
144    Protocols should include precise definitions of diet stability during the trial, including 
145  magnitude of allowed deviations generally anticipated in the prescribed diet, such as  
146  5% or other change in total daily protein.  This definition should be scientifically justified 
147  and supported by evidence that a certain dietary deviation will not affect the clinical and 
148  laboratory outcomes assessed in the trial.  
149   
150    Patients should enter the treatment phase of the trial during a period of stable metabolic 
151  control as evaluated by appropriate biochemical analytes (e.g., ammonia, plasma amino 
152  acids, urine organic acids, plasma acylcarnitines, total and free carnitine) and clinical 
153  assessments.  Sponsors should document baseline dietary information (total daily protein, 
154  lipid, carbohydrate, and total daily caloric intake) over an appropriate time period (e.g., 3 
155  days) at enrollment. 
156   
157  B.  Procedures and Intercurrent Illnesses 
158   
159  Patients with inborn errors of metabolism often require increased caloric intake for procedures or 
160  assessments requiring sedation that can include dental care, adenoidectomy or gastrostomy tube 
161  placement, in addition to intercurrent illnesses that may precipitate a change in metabolic status 
162  (e.g., metabolic decompensation with need for dietary and/or pharmacologic changes).  Ideally, 
163  sponsors should anticipate and address elective surgeries and procedures before enrolling 
164  patients in clinical trials.  However, protocols also should specify a standardized approach to 
165  dietary management for unanticipated intercurrent procedures, illnesses, and metabolic events 
166  that may occur during the trial.  Adherence to this approach should be documented 
167  systematically and addressed in the statistical analysis plan, including how these intercurrent 
168  events will impact the efficacy and safety assessments and clinical interpretation of data.  
169   
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
170  C.  Clinical Trial Design 
171   
172  Sponsors should consider the following recommendations for clinical trial design when an 
173  investigational drug is compared with an approved drug or placebo as add-on to dietary 
174  management.  General considerations include the following: 
175   
176    The most informative design is a randomized, double-blind clinical trial that includes a 
177  concurrent control group (approved drug or placebo).  Dietary management should be 
178  consistent across all trial arms such that regardless of treatment arm, all patients should 
179  be receiving optimized standard of care, including dietary management.  
180   
181    Sponsors can consider different types of controlled, randomized clinical trial designs 
182  (e.g., crossover, randomized withdrawal, delayed start).  An active-controlled 
183  noninferiority design is one possible approach if there is an already approved therapy and 
184  it is possible to justify a noninferiority margin.4  Sponsors should discuss the specific trial 
185  designs with FDA for concurrence before initiating the trial. 
186   
187    Changes in dietary management during a trial can introduce variability, reducing the 
188  potential to find benefit for an effective treatment.  Dietary changes made to account for 
189  growth or disease exacerbation should be prespecified and clearly documented. 
190   
191    Sponsors should discuss with FDA any performance-based or clinical outcome 
192  assessment tools for endpoints intended to establish substantial evidence of effectiveness, 
193  including those that may be influenced by dietary changes, before implementing those 
194  assessments in a trial(s). 
195   
196  To allow for unbiased comparative efficacy assessments when trials involve dietary 
197  management, the use of a concurrent blinded control arm is an essential aspect to the clinical trial 
198  design.  Comparisons to a nonconcurrent, historical control group have important limitations for 
199  the following reasons: 
200   
201    Standards for dietary management can change over time.  An optimized diet for a 
202  historical control group may differ from an optimized diet for a concurrent control group 
203  or a treatment group in a given trial.  This difference can introduce bias in comparisons, 
204  as differences in dietary practice can affect the results of the clinical outcomes. 
205   
206    Differences in the frequency and type of dietary instructions can lead to differences in 
207  dietary management and compliance between treatment groups, which can bias efficacy 
208  analyses.   
209   
210    Differences in patient documentation of diet can limit the ability to compare dietary 
211  management and compliance between treatment groups. 
212   
 
4 See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness (November 2016). 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
213    Differences in patient baseline characteristics between the historical control group and 
214  the treatment group, some of which may be unmeasured, can limit the ability to conduct 
215  reliable comparisons.  
216   
217    The standards of disease management, including management of concurrent or related 
218  conditions, change over time.  Changes in disease management compared with a 
219  historical control group can also introduce bias.  
220   
221    The types and performance characteristics of laboratory assays used to measure 
222  metabolic biomarkers/endpoints among the groups can change over time.  It is important 
223  that sponsors account for these changes when using these assays to evaluate biochemical 
224  parameters of metabolic control and to assess dietary compliance or dietary optimization 
225  and response to treatment. 
226   
227  D.  Challenges and Limitations of Diet Assessments 
228   
229  Although assessments of dietary intake have been used to document dietary practices and to 
230  verify the patients diet adherence, available tools that measure dietary components have 
231  limitations.  Sponsors should consider the following: 
232   
233    Dietary questionnaires use crude measures of portion size, frequency of consumption, 
234  and broad food groupings and are only a general estimate of dietary intake.  Thus, day-to-
235  day and week-to-week variation in diets could lead to a range of estimates of long-term 
236  dietary intake.5  
237   
238    Food diaries (e.g., 3-day diet) are commonly used in the clinical management of patients 
239  with inborn errors of metabolism.  The inherent variability of patient/family recall in a 
240  food diary may introduce imprecision into a clinical trial and should be avoided.  Using 
241  standardized dietary forms (written or electronic) designed or vetted by metabolic 
242  dietitians and physicians can greatly facilitate dietary documentation in a clinical trial and 
243  is strongly encouraged. 
244   
245    Sponsors should encourage families and patients to document their diet frequently during 
246  the trial to support the routine documentation obtained during the 3 days before clinical 
247  site visits. 
 
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. 
6