Fabry Disease: Developing 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Administrative draft guidance, not enacted legislation.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.

30042664dft.docx
08/06/19
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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

Fabry Disease:
Developing 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
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)
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Draft — Not for Implementation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	1
Guidance for Industry1
2
3
4
5
This draft guidance, when finalized, will represent the current thinking of the Food and Drug	6
Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not	7
binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the	8
applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible	9
for this guidance as listed on the title page.	10
11
12
13
I. 	INTRODUCTION	14
15
The purpose of this guidance is to provide recommendations to sponsors regarding clinical trial	16
design features that can support approval of drugs and biological products intended for the	17
treatment of Fabry disease (FD).2	
18
19
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.	20
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only	21
as recommendations, unless specific regulatory or statutory requirements are cited. The use of	22
the word should in Agency guidances means that something is suggested or recommended, but	23
not required.	24
25
26
II. 	BACKGROUND	27
28
FD is a rare, X-linked, slowly progressive, lysosomal storage disorder caused by pathogenic	29
variants (disease-causing mutations) in the galactosidase alpha (GLA) gene resulting in absent or	30
deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A). The α-Gal A enzyme	31
breaks down glycosphingolipids within lysosomes. α-Gal A deficient activity leads to	32
progressive intralysosomal accumulation of the undegraded substrate globotriaosylceramide	33
(GL-3, also known as Gb3), a glycosphingolipid. FD is characterized by chronic	34
symptomatology (e.g., gastrointestinal symptoms, neuropathic symptoms including pain,	35
hypohidrosis or anhidrosis), slowly progressive organ damage eventually leading to chronic renal	36
disease and renal failure, cardiovascular disease (e.g., hypertrophic cardiomyopathy, heart	37
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)).

Contains Nonbinding Recommendations
Draft — Not for Implementation
2
failure, myocardial infarction, arrhythmias), cerebrovascular disease (strokes), and early	38
mortality.3	
39
40
FD is divided into two subtypes based on age of symptom onset and extent of organ	41
involvement:4	
42
43
• 	Classic FD presents in patients with absent or minimal residual α-Gal A enzyme activity	44
(less than 1 percent of mean normal). Childhood-onset clinical manifestations in classic	45
FD include chronic gastrointestinal symptoms (e.g., diarrhea, abdominal pain,	46
constipation), neuropathic pain crises involving the extremities (acroparesthesias),	47
proteinuria, and hypohidrosis or anhidrosis leading to heat and exercise intolerance.	48
Angiokeratomas on the skin and cornea verticillata (corneal whorls) on ophthalmologic	49
slit lamp exam, both asymptomatic, are also sometimes observed. Adult-onset	50
manifestations in classic FD include progressive renal failure, cardiac disease (e.g.,	51
hypertrophic cardiomyopathy, heart failure, myocardial infarction, arrhythmias), and	52
stroke, which cause chronic morbidity and early mortality. The highest concentrations in	53
tissues and plasma of the substrate GL-3 and of its degradation product,	54
globotriaosylsphingosine (lyso-GL-3), are typically seen in patients with classic FD.	55
56
• 	Nonclassic (late-onset) FD is more prevalent than classic FD.5 Patients with late-onset	57
FD have some residual α-Gal A enzyme activity, which is highly variable (greater than 1	58
percent of mean normal). Late-onset FD presents clinically in adulthood with renal,	59
cardiac, and/or cerebrovascular disease; has a highly variable age-of-symptom onset; and	60
follows a highly variable rate of progression.6 Within the late-onset subtype, patients may	61
have only single organ involvement.7 Patients with late-onset FD (and female patients)	62
show variable levels in tissues and plasma of the substrate GL-3 and its degradation	63
product, lyso-GL-3.	64
65
Despite its X-linked inheritance, FD affects both males and females, although to different	66
degrees. In general, male patients with the classic subtype experience the most severe clinical	67
manifestations, multi-organ disease, faster disease progression, and an earlier age of symptom	68
onset compared to male patients with the late-onset subtype and to female patients. In female	69
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):31–40; 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):416–427.
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):416–427.
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):416–427.
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):31–40.

Contains Nonbinding Recommendations
Draft — Not for Implementation
3
patients, disease severity and age of symptom onset depend, at least partly, on tissue-specific X	70
chromosome inactivation. The spectrum of organ involvement and disease severity in female	71
patients with FD can range from completely asymptomatic to the severe phenotype seen in male	72
patients with classic FD. Overall, the rate of disease progression is highly variable in male	73
patients with late-onset FD and in female patients.	74
75
76
III. 	KEY CONSIDERATIONS FOR CLINICAL TRIALS	77
78
A. 	Eligibility Criteria	79
80
All eligible patients should have a confirmed diagnosis of FD based on both biochemical testing	81
and molecular genetic testing (as outlined below). Of note, both plasma and leukocyte α-Gal A	82
activity should be assayed given that some pathogenic GLA variants affect intracellular	83
trafficking and secretion of α-Gal A such that the reduction in α-Gal A enzyme activity in plasma	84
may be more pronounced than within leukocytes. Clinical trials should allow enrollment of both	85
male and female patients. As early as feasible, sponsors should consider enrolling pediatric	86
patients with FD in clinical trials.	87
88
Criteria for confirming the diagnosis of FD should include, at a minimum, the following:8	
89
90
• 	In symptomatic male patients:	91
92
− 	Absent or minimal α-Gal A enzyme activity (i.e., less than 1 percent of the mean	93
normal) in both plasma and isolated peripheral leukocytes.	94
95
− 	When α-Gal A enzyme activity is low but not absent (i.e., greater than 1 percent of	96
the mean normal), identification of a clinically significant9 GLA variant (mutation).	97
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):1631–1641.
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):405–424. 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.

Contains Nonbinding Recommendations
Draft — Not for Implementation
4
• 	In symptomatic female patients:	99
100
− 	Identification of a clinically significant10 GLA variant. This is needed as α-Gal A	101
enzyme activity may range from normal to absent because of the presence of both	102
normal and abnormal copies of the GLA gene in tissues.	103
104
In cases where the GLA variant is considered a “variant of uncertain significance,”11 additional	105
biochemical and/or histopathological evidence should be used to establish the diagnosis of FD	106
(e.g., elevated plasma lyso-GL-3, demonstration of tissue GL-3 inclusions or other).	107
108
109
B. 	Trial Design and Efficacy Endpoints	110
111
1. 	Trial Design	112
113
Given the rarity of FD, sponsors can use a single adequate and well-controlled trial (as described	114
in 21 CFR 314.126), showing a clinically meaningful treatment effect on core clinical aspects of	115
FD, as the basis for drug approval when accompanied by confirmatory evidence. A parallel-	116
group design should be used with an appropriate concurrent control group (placebo or active	117
treatment). Sponsors should consider stratifying at randomization by known prognostic factors,	118
such as sex and age. If the drug is intended to slow or arrest disease progression but not reverse	119
it, the trial should be of sufficient duration to observe disease progression in the control group.	120
There are special considerations regarding the length of long-term follow up for gene therapy	121
products.12	
122
123
Importantly, all laboratory tests conducted in a clinical development program should be	124
performed using appropriately validated methods to ensure reliability of the results and should be	125
conducted at a central laboratory.	126
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):405–424. 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):405–424.
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 FDA’s 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.

Contains Nonbinding Recommendations
Draft — Not for Implementation
5
2. 	General Considerations for Efficacy Endpoints	128
129
Demonstration of clinical benefit on any core disease manifestation (e.g., renal disease,	130
cardiovascular disease, cerebrovascular disease, gastrointestinal symptoms, neuropathic	131
symptoms, pain) can be the basis for traditional approval.13 When selecting efficacy endpoints,	132
the sponsor should consider the natural history and time course of the selected disease	133
manifestation(s) assessed, the drug’s mechanism of action and the target organ(s), and the target	134
FD patient population or subpopulation. For instance, certain clinical outcome assessments may	135
not be appropriate for use in pediatric FD patients based on their age or symptom presence or	136
absence or severity. Similarly, classic FD and late-onset FD patients often have differences both	137
in the presence of disease manifestations (some late-onset FD patients may only have renal	138
disease or only cardiac disease) and in the rate of disease progression. Given the multisystemic	139
nature of FD, the highly variable rate of disease progression (especially in late-onset FD patients	140
and in female patients), and the heterogeneity of clinical manifestations, sponsors could consider	141
combining multiple clinical outcomes for assessment in clinical trials. Specifically, sponsors	142
could consider the use of a composite endpoint such that changes in symptoms and/or functional	143
outcomes could be captured across a variety of FD manifestations. The choice of such endpoints	144
could be based on baseline symptom presence and severity in enrolled patients. FDA strongly	145
encourages sponsors to engage in early discussions (as early as the pre-investigational new drug	146
application phase) with the appropriate review division regarding the selection of efficacy	147
endpoints and when considering combining efficacy outcomes for demonstration of efficacy.	148
149
3. 	Specific Considerations for Efficacy Endpoints	150
151
a. 	Neuropathic and gastrointestinal symptoms	152
153
Sponsors can establish drug effectiveness with the demonstration of clinically meaningful	154
improvement in neuropathic symptoms, including pain, or gastrointestinal symptoms (abdominal	155
pain, diarrhea, constipation). Sponsors should select well-defined and reliable instruments for	156
assessments of changes in such symptoms in accordance with the recommendations of the	157
guidance for industry Patient-Reported Outcome Measures: Use in Medical Product	158
Development to Support Labeling Claims (December 2009). FDA strongly encourages sponsors	159
to engage early with the appropriate review division for selection of the most appropriate clinical	160
outcome assessment instruments. FDA encourages the development of publicly available, fit-for-	161
purpose, patient-reported outcome instruments that can be used across multiple drug	162
development programs in FD to facilitate and accelerate drug development in this disease.14	
163
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 FDA’s 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.

Contains Nonbinding Recommendations
Draft — Not for Implementation
6
b. 	Renal disease	165
166
Sponsors could use the demonstration of a sustained treatment effect on a specified magnitude of	167
loss of renal function (e.g., a 30 percent decline in glomerular filtration rate (GFR), assessed via	168
a widely accepted estimating equation for GFR or measured GFR) or on the rate of loss of renal	169
function as the basis for traditional drug approval. In general, sponsors of trials using rate of loss	170
of renal function as an endpoint (e.g., a comparison of the annualized change in estimated GFR	171
(eGFR) between the treatment arms) should assess whether the treatment effect continues to	172
accrue across the various stages of renal disease by enrolling patients with different levels of	173
renal function at baseline. In addition, the trial duration should be sufficient (generally at least 24	174
months) to evaluate for long-term effectiveness and to obtain a more reliable estimate of the	175
treatment effect on the rate of change in eGFR.	176
177
In general, programs should collect information on progression to end-stage renal disease	178
requiring chronic dialysis or renal transplantation while acknowledging that such events are	179
likely to be uncommon in clinical trials of early-stage renal disease in FD given the slowly	180
progressive nature of FD.	181
182
Sponsors can use histological reduction of GL-3 inclusion burden in biopsied kidney interstitial	183
capillaries (KIC) as a surrogate endpoint reasonably likely to predict clinical benefit to support	184
accelerated approval. If a sponsor plans to use a surrogate endpoint based on histological	185
assessment of GL-3 inclusions, FDA encourages the sponsor to engage in early discussion with	186
the appropriate review division to more precisely define such an endpoint (including the	187
magnitude of change in that endpoint) that would be reasonably likely to predict clinical benefit.	188
When assessing (counting) KIC GL-3 inclusions in histology specimens, the sponsor should use	189
validated and standardized assay methodologies, and scoring of KIC GL-3 inclusions should be	190
conducted by experienced pathologists in a blinded and systematic fashion. In general,	191
postmarketing studies to verify and describe the clinical benefit should already be underway at	192
the time of submission of a marketing application. FDA encourages sponsors to engage in early	193
discussion with the appropriate review division regarding trial design features of such	194
postmarketing studies.	195
196
Patients’ concomitant therapies that could affect renal function or the measurement of renal	197
function (e.g., angiotensin converting enzyme inhibitors, angiotensin receptor blockers) should	198
be optimized before trial enrollment, and doses of such therapies should remain stable for the	199
duration of the trial.	200
201
Although proteinuria is an important prognostic marker in patients with renal diseases in general,	202
including FD, it is not clear whether treatment effects on proteinuria predict treatment effects on	203
important renal outcomes in FD. At this time, additional evidence is needed to support the use of	204
proteinuria as a validated or reasonably likely surrogate endpoint for clinical benefit in FD.	205
206
c. 	Cardiac disease	207
208
Endpoints that assess treatment effects on cardiovascular hospitalization, functional capacity	209
(e.g., exercise capacity), and/or cardiovascular symptoms can be used to provide evidence of	210

Contains Nonbinding Recommendations
Draft — Not for Implementation
7
effectiveness in treating the cardiac manifestations of FD. At this time, additional evidence is	211
needed to support the use of left ventricular mass index and global longitudinal strain as	212
validated or reasonably likely surrogate endpoints for clinical benefit in FD.	213