Fabry Disease: 
Developing 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DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only.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 90 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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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) Patroula Smpokou at 240-402-
9651 or (CBER) Office of Communication, Outreach, and Development at (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) 
 
August 2019 
Clinical/Medical 
30042664dft.docx 
08/06/19   
Fabry Disease: 
Developing Drugs for 
Treatment 
Guidance for Industry 
 
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Food and Drug Administration 
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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) 
 
August 2019 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION..................................................................................................1 
II.  BACKGROUND ....................................................................................................1 
III.  KEY CONSIDERATIONS FOR CLINICAL TRIALS .....................................3 
A.  Eligibility Criteria ............................................................................................................. 3 
B.  Trial Design and Efficacy Endpoints ............................................................................... 4 
1. Trial Design ......................................................................................................................... 4 
2. General Considerations for Efficacy Endpoints .................................................................. 5 
3. Specific Considerations for Efficacy Endpoints .................................................................. 5 
a.  Neuropathic and gastrointestinal symptoms ................................................................. 5 
b.  Renal disease ................................................................................................................ 6 
c.  Cardiac disease ............................................................................................................. 6 
 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Fabry Disease:  Developing Drugs for Treatment 
2  Guidance for Industry1 
3   
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page. 
11   
12   
13   
14  I.  INTRODUCTION 
15   
16  The purpose of this guidance is to provide recommendations to sponsors regarding clinical trial 
17  design features that can support approval of drugs and biological products intended for the 
18  treatment of Fabry disease (FD).2 
19   
20  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
21  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
22  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
23  the word should in Agency guidances means that something is suggested or recommended, but 
24  not required. 
25   
26   
27  II.  BACKGROUND 
28   
29  FD is a rare, X-linked, slowly progressive, lysosomal storage disorder caused by pathogenic 
30  variants (disease-causing mutations) in the galactosidase alpha (GLA) gene resulting in absent or 
31  deficient activity of the lysosomal enzyme -galactosidase A (-Gal A). The -Gal A enzyme 
32  breaks down glycosphingolipids within lysosomes. -Gal A deficient activity leads to 
33  progressive intralysosomal accumulation of the undegraded substrate globotriaosylceramide 
34  (GL-3, also known as Gb3), a glycosphingolipid. FD is characterized by chronic 
35  symptomatology (e.g., gastrointestinal symptoms, neuropathic symptoms including pain, 
36  hypohidrosis or anhidrosis), slowly progressive organ damage eventually leading to chronic renal 
37  disease and renal failure, cardiovascular disease (e.g., hypertrophic cardiomyopathy, heart 
                                                 
1 This guidance has been prepared by the Division of Gastroenterology and Inborn Errors Products in the Center for 
Drug Evaluation and Research in cooperation with the Center for Biologics Evaluation and Research at the Food and 
Drug Administration.  
 
2 For purposes of this guidance, unless otherwise specified, references to drugs include drugs submitted for approval 
or approved under section 505(b) or (j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and biological 
products submitted for licensure or licensed under section 351 of the Public Health Service Act, other than 
biological products that also meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)). 
 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  failure, myocardial infarction, arrhythmias), cerebrovascular disease (strokes), and early 
39  mortality.3   
40   
41  FD is divided into two subtypes based on age of symptom onset and extent of organ 
42  involvement:4 
43   
44    Classic FD presents in patients with absent or minimal residual -Gal A enzyme activity 
45  (less than 1 percent of mean normal). Childhood-onset clinical manifestations in classic 
46  FD include chronic gastrointestinal symptoms (e.g., diarrhea, abdominal pain, 
47  constipation), neuropathic pain crises involving the extremities (acroparesthesias), 
48  proteinuria, and hypohidrosis or anhidrosis leading to heat and exercise intolerance. 
49  Angiokeratomas on the skin and cornea verticillata (corneal whorls) on ophthalmologic 
50  slit lamp exam, both asymptomatic, are also sometimes observed. Adult-onset 
51  manifestations in classic FD include progressive renal failure, cardiac disease (e.g., 
52  hypertrophic cardiomyopathy, heart failure, myocardial infarction, arrhythmias), and 
53  stroke, which cause chronic morbidity and early mortality. The highest concentrations in 
54  tissues and plasma of the substrate GL-3 and of its degradation product, 
55  globotriaosylsphingosine (lyso-GL-3), are typically seen in patients with classic FD. 
56   
57    Nonclassic (late-onset) FD is more prevalent than classic FD.5 Patients with late-onset 
58  FD have some residual -Gal A enzyme activity, which is highly variable (greater than 1 
59  percent of mean normal). Late-onset FD presents clinically in adulthood with renal, 
60  cardiac, and/or cerebrovascular disease; has a highly variable age-of-symptom onset; and 
61  follows a highly variable rate of progression.6 Within the late-onset subtype, patients may 
62  have only single organ involvement.7 Patients with late-onset FD (and female patients) 
63  show variable levels in tissues and plasma of the substrate GL-3 and its degradation 
64  product, lyso-GL-3. 
65   
66  Despite its X-linked inheritance, FD affects both males and females, although to different 
67  degrees. In general, male patients with the classic subtype experience the most severe clinical 
68  manifestations, multi-organ disease, faster disease progression, and an earlier age of symptom 
69  onset compared to male patients with the late-onset subtype and to female patients. In female 
                                                 
3 Germain, DP, 2010, Fabry Disease, Orphanet J Rare Dis, 5:30, doi: 10.1186/1750-1172-5-30. 
 
4 Germain, DP, 2010, Fabry Disease, Orphanet J Rare Dis, 5:30, doi: 10.1186/1750-1172-5-30; Spada M, Pagliardini 
S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, and Desnick RJ, 2006, High Incidence of Later-
Onset Fabry Disease Revealed by Newborn Screening, Am J Hum Genet, 79(1):3140; and Ortiz A, Germain DP, 
Desnick RJ, et al., 2018, Fabry Disease Revisited: Management and Treatment Recommendations for Adult 
Patients, Mol Genet Metab,123(4):416427. 
 
5 Ortiz A, Germain DP, Desnick RJ, et al., 2018, Fabry Disease Revisited: Management and Treatment 
Recommendations for Adult Patients, Mol Genet Metab, 123(4):416427. 
 
6 Ortiz A, Germain DP, Desnick RJ, et al., 2018, Fabry Disease Revisited: Management and Treatment 
Recommendations for Adult Patients, Mol Genet Metab, 123(4):416427. 
 
7 Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ, 2006, High 
Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening, Am J Hum Genet, 79(1):3140. 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
70  patients, disease severity and age of symptom onset depend, at least partly, on tissue-specific X 
71  chromosome inactivation. The spectrum of organ involvement and disease severity in female 
72  patients with FD can range from completely asymptomatic to the severe phenotype seen in male 
73  patients with classic FD. Overall, the rate of disease progression is highly variable in male 
74  patients with late-onset FD and in female patients.  
75   
76   
77  III.  KEY CONSIDERATIONS FOR CLINICAL TRIALS 
78   
79  A.  Eligibility Criteria 
80   
81  All eligible patients should have a confirmed diagnosis of FD based on both biochemical testing 
82  and molecular genetic testing (as outlined below). Of note, both plasma and leukocyte -Gal A 
83  activity should be assayed given that some pathogenic GLA variants affect intracellular 
84  trafficking and secretion of -Gal A such that the reduction in -Gal A enzyme activity in plasma 
85  may be more pronounced than within leukocytes. Clinical trials should allow enrollment of both 
86  male and female patients. As early as feasible, sponsors should consider enrolling pediatric 
87  patients with FD in clinical trials.   
88   
89  Criteria for confirming the diagnosis of FD should include, at a minimum, the following:8 
90   
91    In symptomatic male patients:  
92   
93    Absent or minimal -Gal A enzyme activity (i.e., less than 1 percent of the mean 
94  normal) in both plasma and isolated peripheral leukocytes.  
95   
96    When -Gal A enzyme activity is low but not absent (i.e., greater than 1 percent of 
97  the mean normal), identification of a clinically significant9 GLA variant (mutation). 
98   
                                                 
8 Mehta A and Hughes DA, 2017, Fabry Disease. In: Adam MP, Ardinger HH, Pagon RA, et al., editors, 
GeneReviews, Seattle (WA): University of Washington, Seattle, accessed July 30, 2018, 
https://www.ncbi.nlm.nih.gov/books/NBK1292/; and Arends M, Wanner C, Hughes D, et al., 2017, Characterization 
of Classical and Nonclassical Fabry Disease: A Multicenter Study, J Am Soc Nephrol, 28(5):16311641. 
 
9 Richards S, Aziz N, Bale S, et al., 2015, Standards and Guidelines for the Interpretation of Sequence Variants: A 
Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association 
for Molecular Pathology, Genet Med, 17(5):405424. Laboratory reports of genetic testing results may include the 
terms likely pathogenic or pathogenic to characterize whether a given GLA variant (mutation) causes FD. For the 
purposes of this guidance, the term clinically significant includes variants considered either pathogenic or likely 
pathogenic. 
 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
99    In symptomatic female patients:  
100   
101    Identification of a clinically significant10 GLA variant. This is needed as -Gal A 
102  enzyme activity may range from normal to absent because of the presence of both 
103  normal and abnormal copies of the GLA gene in tissues.  
104   
105  In cases where the GLA variant is considered a variant of uncertain significance,11 additional 
106  biochemical and/or histopathological evidence should be used to establish the diagnosis of FD 
107  (e.g., elevated plasma lyso-GL-3, demonstration of tissue GL-3 inclusions or other). 
108   
109   
110  B.  Trial Design and Efficacy Endpoints 
111   
112  1.  Trial Design 
113   
114  Given the rarity of FD, sponsors can use a single adequate and well-controlled trial (as described 
115  in 21 CFR 314.126), showing a clinically meaningful treatment effect on core clinical aspects of 
116  FD, as the basis for drug approval when accompanied by confirmatory evidence. A parallel-
117  group design should be used with an appropriate concurrent control group (placebo or active 
118  treatment). Sponsors should consider stratifying at randomization by known prognostic factors, 
119  such as sex and age. If the drug is intended to slow or arrest disease progression but not reverse 
120  it, the trial should be of sufficient duration to observe disease progression in the control group. 
121  There are special considerations regarding the length of long-term follow up for gene therapy 
122  products.12 
123   
124  Importantly, all laboratory tests conducted in a clinical development program should be 
125  performed using appropriately validated methods to ensure reliability of the results and should be 
126  conducted at a central laboratory. 
127   
                                                 
10 Richards S, Aziz N, Bale S, et al., 2015, Standards and Guidelines for the Interpretation of Sequence Variants: a 
Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association 
for Molecular Pathology, Genet Med, 17(5):405424. See footnote 9. 
 
11 Richards S, Aziz N, Bale S, et al., 2015, Standards and Guidelines for the Interpretation of Sequence Variants: a 
Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association 
for Molecular Pathology, Genet Med, 17(5):405424. 
 
12 See the draft guidance for industry Long Term Follow-Up After Administration of Human Gene Therapy Products 
(July 2018). When final, this guidance will represent the FDAs current thinking on this topic. 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.  
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
128  2.  General Considerations for Efficacy Endpoints 
129   
130  Demonstration of clinical benefit on any core disease manifestation (e.g., renal disease, 
131  cardiovascular disease, cerebrovascular disease, gastrointestinal symptoms, neuropathic 
132  symptoms, pain) can be the basis for traditional approval.13 When selecting efficacy endpoints, 
133  the sponsor should consider the natural history and time course of the selected disease 
134  manifestation(s) assessed, the drugs mechanism of action and the target organ(s), and the target 
135  FD patient population or subpopulation. For instance, certain clinical outcome assessments may 
136  not be appropriate for use in pediatric FD patients based on their age or symptom presence or 
137  absence or severity. Similarly, classic FD and late-onset FD patients often have differences both 
138  in the presence of disease manifestations (some late-onset FD patients may only have renal 
139  disease or only cardiac disease) and in the rate of disease progression. Given the multisystemic 
140  nature of FD, the highly variable rate of disease progression (especially in late-onset FD patients 
141  and in female patients), and the heterogeneity of clinical manifestations, sponsors could consider 
142  combining multiple clinical outcomes for assessment in clinical trials. Specifically, sponsors 
143  could consider the use of a composite endpoint such that changes in symptoms and/or functional 
144  outcomes could be captured across a variety of FD manifestations. The choice of such endpoints 
145  could be based on baseline symptom presence and severity in enrolled patients. FDA strongly 
146  encourages sponsors to engage in early discussions (as early as the pre-investigational new drug 
147  application phase) with the appropriate review division regarding the selection of efficacy 
148  endpoints and when considering combining efficacy outcomes for demonstration of efficacy. 
149   
150  3.  Specific Considerations for Efficacy Endpoints 
151   
152  a.  Neuropathic and gastrointestinal symptoms 
153   
154  Sponsors can establish drug effectiveness with the demonstration of clinically meaningful 
155  improvement in neuropathic symptoms, including pain, or gastrointestinal symptoms (abdominal 
156  pain, diarrhea, constipation). Sponsors should select well-defined and reliable instruments for 
157  assessments of changes in such symptoms in accordance with the recommendations of the 
158  guidance for industry Patient-Reported Outcome Measures: Use in Medical Product 
159  Development to Support Labeling Claims (December 2009). FDA strongly encourages sponsors 
160  to engage early with the appropriate review division for selection of the most appropriate clinical 
161  outcome assessment instruments. FDA encourages the development of publicly available, fit-for-
162  purpose, patient-reported outcome instruments that can be used across multiple drug 
163  development programs in FD to facilitate and accelerate drug development in this disease.14 
164   
                                                 
13 The term traditional approval denotes the longstanding route of drug approval based on the demonstration of 
clinical benefit or an effect on a surrogate endpoint known to predict clinical benefit.  That term is distinguished 
from accelerated approval, which is associated with use of a surrogate endpoint or intermediate clinical endpoint that 
is reasonably likely to predict clinical benefit to support drug approval. 
 
14 See the draft guidance for industry and FDA staff Qualification Process for Drug Development Tools (January 
2014). When final, this guidance will represent the FDAs current thinking on this topic. 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  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
165  b.  Renal disease 
166   
167  Sponsors could use the demonstration of a sustained treatment effect on a specified magnitude of 
168  loss of renal function (e.g., a 30 percent decline in glomerular filtration rate (GFR), assessed via 
169  a widely accepted estimating equation for GFR or measured GFR) or on the rate of loss of renal 
170  function as the basis for traditional drug approval. In general, sponsors of trials using rate of loss 
171  of renal function as an endpoint (e.g., a comparison of the annualized change in estimated GFR 
172  (eGFR) between the treatment arms) should assess whether the treatment effect continues to 
173  accrue across the various stages of renal disease by enrolling patients with different levels of 
174  renal function at baseline. In addition, the trial duration should be sufficient (generally at least 24 
175  months) to evaluate for long-term effectiveness and to obtain a more reliable estimate of the 
176  treatment effect on the rate of change in eGFR. 
177   
178  In general, programs should collect information on progression to end-stage renal disease 
179  requiring chronic dialysis or renal transplantation while acknowledging that such events are 
180  likely to be uncommon in clinical trials of early-stage renal disease in FD given the slowly 
181  progressive nature of FD.  
182   
183  Sponsors can use histological reduction of GL-3 inclusion burden in biopsied kidney interstitial 
184  capillaries (KIC) as a surrogate endpoint reasonably likely to predict clinical benefit to support 
185  accelerated approval. If a sponsor plans to use a surrogate endpoint based on histological 
186  assessment of GL-3 inclusions, FDA encourages the sponsor to engage in early discussion with 
187  the appropriate review division to more precisely define such an endpoint (including the 
188  magnitude of change in that endpoint) that would be reasonably likely to predict clinical benefit. 
189  When assessing (counting) KIC GL-3 inclusions in histology specimens, the sponsor should use 
190  validated and standardized assay methodologies, and scoring of KIC GL-3 inclusions should be 
191  conducted by experienced pathologists in a blinded and systematic fashion. In general, 
192  postmarketing studies to verify and describe the clinical benefit should already be underway at 
193  the time of submission of a marketing application. FDA encourages sponsors to engage in early 
194  discussion with the appropriate review division regarding trial design features of such 
195  postmarketing studies.  
196   
197  Patients concomitant therapies that could affect renal function or the measurement of renal 
198  function (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers) should 
199  be optimized before trial enrollment, and doses of such therapies should remain stable for the 
200  duration of the trial.  
201   
202  Although proteinuria is an important prognostic marker in patients with renal diseases in general, 
203  including FD, it is not clear whether treatment effects on proteinuria predict treatment effects on 
204  important renal outcomes in FD. At this time, additional evidence is needed to support the use of 
205  proteinuria as a validated or reasonably likely surrogate endpoint for clinical benefit in FD.   
206   
207  c.  Cardiac disease 
208   
209  Endpoints that assess treatment effects on cardiovascular hospitalization, functional capacity 
210  (e.g., exercise capacity), and/or cardiovascular symptoms can be used to provide evidence of 
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
211  effectiveness in treating the cardiac manifestations of FD. At this time, additional evidence is 
212  needed to support the use of left ventricular mass index and global longitudinal strain as 
213  validated or reasonably likely surrogate endpoints for clinical benefit in FD.  
7