Pediatric Rare Diseases--A Collaborative Approach for Drug Development Using Gaucher Disease as a Model; Draft Guidance for Industry: Draft Guidance for Industry

Administrative draft guidance, not enacted legislation.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.

Pediatric Rare Diseases —
A Collaborative Approach for
Drug Development Using
Gaucher Disease as a Model
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DRAFT GUIDANCE
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft
guidance.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 Hong Vu at 301-796-7401.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2017
Rare Diseases
16252414dft.docx
11/28/17

Pediatric Rare Diseases —
A Collaborative Approach for
Drug Development Using
Gaucher Disease as a Model
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/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
December 2017
Rare Diseases

TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
A. 	Disease Characteristics and Response to Treatment .................................................................. 2
B. 	Unmet Needs in Pediatric Gaucher Disease ................................................................................ 3
III. 	NONCLINICAL AND CLINICAL CONSIDERATIONS............................................ 3
A. 	Nonclinical Models of Gaucher Disease ....................................................................................... 3
B. 	Endpoint Assessments in Gaucher Disease .................................................................................. 4
C. 	Long-Term Clinical Aspects ......................................................................................................... 5
D. 	The Use of Extrapolation of Efficacy for Pediatric Gaucher Disease ....................................... 5
IV. 	PROPOSED MULTI-ARM, MULTI-COMPANY TRIAL FOR PEDIATRIC
GAUCHER DISEASE ...................................................................................................... 6
GENERAL REFERENCES AND GUIDELINES ................................................................... 10

Contains Nonbinding Recommendations
Draft — Not for Implementation
1 	Pediatric Rare Diseases —
2 	A Collaborative Approach for Drug Development
3 	Using Gaucher Disease as a Model
4 	Guidance for Industry1
5
6
7
8
9 	This draft guidance, when finalized, will represent the current thinking of the Food and Drug
10 	Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not
11 	binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the
12 	applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible
13 	for this guidance as listed on the title page.
14
15
16
17
18 	I. 	INTRODUCTION
19
20 	The emergence of concomitant trials for multiple investigational drug products for the treatment
21 	of rare diseases can pose significant challenges to effective drug development due to the limited
22 	number of patients worldwide with any given rare condition. The purpose of this guidance is to
23 	facilitate drug development in pediatric rare diseases. In particular, it discusses a new possible
24 	approach to enhance the efficiency of drug development in pediatric rare diseases using Gaucher
25 	disease as an example. This new approach consists of a controlled, multi-arm, multi-company
26 	clinical trial, which aims to facilitate the development of multiple drug products in a time
27 	efficient manner while minimizing the number of patients necessary to be treated with placebo.
28 	The general principles presented should be viewed as a proposal only, and the principles
29 	underlying the proposal may be extended to other areas of drug development in rare diseases. Of
30 	note, the specific recommendations regarding drug development for Gaucher Disease apply only
31 	to systemic (i.e., non-neurological) manifestations of Gaucher disease in treatment-naïve patients
32 	with Type I and Type III phenotypes, across all the pediatric ages (i.e., up to 18 years of age).
33
34 	Modified approaches may be proposed, but the sponsor should justify the specific choice of each
35 	new strategy. Given that rare disease drug development tends to require global involvement, and
36 	the potential differences in requirement between the FDA and other regulatory agencies,
37 	sponsors are advised to consult the appropriate regulatory agency(ies) prior to initiation of such
38 	trials.
39
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. This guidance adapts with minor
modifications the 2017 update of the 2014 Food and Drug Administration – European Medicines Agency
Collaborative Approach document titled “Gaucher Disease — A Strategic Collaborative Approach From EMA and
FDA.”
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40 	In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
41 	Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only
42 	as recommendations, unless specific regulatory or statutory requirements are cited. The use of
43 	the word should in Agency guidances means that something is suggested or recommended, but
44 	not required.
45
46
47 	II. 	BACKGROUND
48
49 	A. 	Disease Characteristics and Response to Treatment
50
51 	Gaucher disease is one of the most common lysosomal storage disorders, estimated to affect
52 	6,000 individuals in the United States.2 It meets the U.S. regulatory definition of an orphan
53 	disease (i.e., fewer than 200,000 affected individuals).
54
55 	Historically, Gaucher disease has been classified into three phenotypes. Although nowadays
56 	many view Gaucher disease as a spectrum of manifestations, and alternative classifications have
57 	been proposed on the basis of absence or presence of neurological symptoms (the latter further
58 	subdivided into acute or chronic forms), the following phenotypes continue to be commonly
59 	referenced:
60
61 	 	Type I refers to the somatic, non-neurological form (the most prevalent)
62 	 	Type II refers to the acute, infantile neuronopathic form, usually lethal in infancy
63 	 	Type III refers to the chronic, neuronopathic form (it may have somatic manifestations as
64 	well)
65
66 	In Gaucher disease, the age at onset of symptoms tends to correlate with clinical severity and
67 	subsequent outcomes. A lower residual level of enzyme activity generally results in earlier onset
68 	and greater severity of disease manifestations.
69
70 	The underlying biology of Gaucher disease is the same in adults and children. However, clinical
71 	manifestations in children differ from those seen in adults, both in presentation and disease
72 	course. Disease-modifying factors such as type of genetic mutation, residual enzyme activity,
73 	and epigenetic factors may further influence disease presentation and rates of clinical
74 	progression.
75
76 	The current standard of care in the pediatric Gaucher population in the United States consists of
77 	enzyme replacement therapy (ERT), which is used to treat the non-neurological (i.e., somatic)
78 	manifestations of the disease in patients with Type I and Type III phenotype. Despite the
79 	availability of ERT, other therapies with different mechanisms of action may still offer
80 	complementary or additive clinical benefit.
81
82 	Given that ERT is the current standard of care, placebo-controlled trials of new generation ERTs
83 	in pediatric patients with Type I Gaucher disease are not considered ethical because of
2 https://rarediseases.org/rare-diseases/gaucher-disease/
2

Contains Nonbinding Recommendations
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84 	demonstrated clinical improvements with the currently available ERT. However, new non-ERT
85 	investigational drug products may be studied using a placebo add-on design while continuing
86 	current ERT management.
87
88 	B. 	Unmet Needs in Pediatric Gaucher Disease
89
90 	Studies conducted thus far have not adequately addressed all the major medical needs across all
91 	pediatric age groups. For example, few patients younger than 2 years of age have been enrolled
92 	in clinical trials. Additionally, the disease’s impact on growth rate, bone, and pulmonary
93 	manifestations has not been fully studied with available ERT therapy. Another unmet medical
94 	need is that of drug products with more practical routes of administration. Developing age
95 	appropriate oral pharmaceutical drug products (e.g., substrate reduction therapies) could be
96 	beneficial across all pediatric ages and may add benefit to the existing ERTs. Finally, although
97 	not addressed by this guidance, there is an unmet clinical therapeutic need for pediatric patients
98 	with neurological involvement (Types II and III), because current ERT therapy does not impact
99 	neurologic manifestations of Gaucher disease.
100
101
102 	III. 	NONCLINICAL AND CLINICAL CONSIDERATIONS
103
104 	A. 	Nonclinical Models of Gaucher Disease
105
106 	Animal models of Gaucher disease are available to test preliminarily the effect of new drug
107 	products prior to initiating human studies (Farfel-Becker et al. 2011). However, the Gaucher
108 	disease phenotypes in many disease models have little or no similarity to the human Gaucher
109 	phenotypes. The selection of an animal Gaucher disease model to support pediatric drug
110 	development should be based on the relationship with efficacy endpoints to be evaluated in
111 	pediatric studies, or the need to measure or develop pharmacodynamic (PD) markers of drug
112 	product activity. Because toxicity may result from the sudden release and accumulation of
113 	metabolites resulting from the enzymatic degradation of the accumulated substrate, it may be
114 	appropriate to include toxicity endpoints in the pharmacology studies conducted in animal
115 	models of the disease.
116
117 	For ERTs, the need for juvenile animal toxicology studies should be decided on a case-by-case
118 	basis, depending on the age of the patient population to be treated. Toxicology studies in
119 	juvenile animals of appropriate age should be conducted when considered necessary.
120
121 	Small molecules also should be assessed on a case-by-case basis to determine the need for
122 	juvenile animal toxicity studies. Factors to consider are described in the International Council
123 	for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)
124 	guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical
125 	Trials and Marketing Authorization for Pharmaceuticals.3 It should be noted that the assessment
126 	for small molecules may be more complex than for ERTs, because the on- and off-target effects
3 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
Drugs guidance web page at
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
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127 	of small molecules are less predictable, and the development programs (clinical and nonclinical)
128 	for small molecules differ from ERT development programs.
129
130 	B. 	Endpoint Assessments in Gaucher Disease
131
132 	Previous approval of ERT for Gaucher disease in adult patients has been based upon
133 	demonstrated clinical improvements in hepatosplenomegaly and improvements in biochemical
134 	endpoints (hemoglobin and platelet levels).
135
136 	For drug development programs in pediatric rare diseases, it may be necessary to develop,
137 	validate, and employ age-specific endpoints. The relevant endpoints and outcome measures for
138 	the pediatric population should be identified as early as possible. It is important to include
139 	protocol design features that allow pediatric patients to contribute directly in these measures
140 	when possible (e.g., patient-reported outcome measures). Where relevant, it may also be
141 	reasonable to assess, in the adult drug development program, endpoints that can be potentially
142 	used in pediatric clinical trials.
143
144 	Because the quality of available clinical outcome assessments (COAs) can vary, qualification
145 	and standardization is strongly recommended. Developers are encouraged to discuss the selected
146 	COA for the outcomes of interest with the FDA; involvement of relevant stakeholders, including
147 	patients is encouraged.
148
149 	If for any reason studies cannot be blinded, biases should be addressed. The issue of assay
150 	sensitivity should be considered if the trial uses a noninferiority margin.
151
152 	With specific relevance to Gaucher disease, the following should also be considered when
153 	planning studies:
154
155 	 	Disease-modifying factors (e.g., mutation, residual enzyme activity, age) and epigenetic
156 	factors contribute to different disease presentations. Enrolling pediatric patients who are
157 	as homogenous as possible will increase the probability of detecting a treatment effect.
158 	The need for a study to be conducted in a homogeneous population should not delay the
159 	timely access to a drug product for age subgroups that are inherently harder to study
160 	because of intrinsic heterogeneity.
161
162 	 	Exploratory biomarkers, such as markers of lung and bone disease, and measurement of
163 	bone mineral density or bone marrow disease burden should be assessed.
164
165 	 	Neurological assessments should be included in studies as exploratory endpoints to
166 	inform further studies for neuronopathic manifestations of Type III Gaucher disease.
167 	Inclusion of a pharmacogenomics perspective in the drug development program, to
168 	evaluate and explore the different modifiers of the genotype-phenotype relationship, is
169 	also recommended.
170
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171 	C. 	Long-Term Clinical Aspects
172
173 	Long-term follow-up in a prospective study is necessary to evaluate the long-term safety and
174 	efficacy of treatment on disease manifestations in pediatric patients.
175
176 	Throughout many parts of the world, children with Gaucher disease are often managed at
177 	specialized centers where enrollment into clinical trials can be facilitated. Follow-up of patients
178 	from such centers should be encouraged to evaluate long-term safety and long-term maintenance
179 	dosing.
180
181 	Hematological and/or visceral endpoints have been standardized, and are most commonly
182 	evaluated in the pediatric trials.
183
184 	Improved documentation of other significant measurements (e.g., growth and developmental
185 	changes, bone disease, pulmonary function, and neurological manifestations) should be
186 	implemented to facilitate understanding of the long-term effects of treatment.
187
188 	Patient registries are an adjunctive tool for monitoring efficacy and safety. When registries are
189 	set up individually per drug product, the burden on all stakeholders is increased and comparative
190 	analyses between patient groups or across drug products cannot be easily conducted. The FDA
191 	recommends across-registry agreement on a uniform set of core data elements to be collected by
192 	all existing or future Gaucher disease registries. This may include information on key pediatric
193 	manifestations such as growth rate and bone disease, relationship between treatment and
194 	outcomes, collection of adverse events, etc. All children born to treated mothers should also be
195 	evaluated long term.
196
197 	D. 	The Use of Extrapolation of Efficacy for Pediatric Gaucher Disease
198
199 	Extrapolation of efficacy can be considered when the course of the disease and the expected
200 	response to a drug product would be sufficiently similar in the pediatric and reference population
201 	(i.e., adult or other pediatric age population). In the case of pediatric Gaucher disease, the
202 	impact of the different mechanisms of action and disease-modifying factors (e.g., type of
203 	mutation, residual enzyme activity, age) and epigenetic factors resulting in different
204 	presentations of the disease should be carefully considered. When characteristics of different
205 	patient populations are able to be identified, extrapolation can be considered. The use of
206 	extrapolation of efficacy in pediatric Gaucher disease can avoid unnecessary studies, increase
207 	efficiency, reduce testing burden to patients, and better allocate resources to address relevant
208 	questions. An extrapolation plan could be formulated early during drug development, with the
209 	recognition that the plan may not address all aspects necessary in the development of emerging
210 	drug products across all ages of pediatric patients. Ultimately, additional clinical studies may be
211 	necessary for determination of efficacy across all age groups.
212
213 	Pediatric extrapolation of efficacy from adults to children can be considered for the somatic
214 	manifestations of both Type I and Type III Gaucher disease, such as visceral, hematologic, and
215 	pulmonary disease. In contrast, effects of therapy on specific pediatric manifestations (e.g.,
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216 	growth rate, onset of puberty and progression of pubertal development) are not amenable to
217 	extrapolation.
218
219 	These characteristics should be specifically addressed in pediatric studies. In such studies safety
220 	data should be collected to identify unexpected (age-specific) safety concerns.
221
222 	Existing knowledge generated from adult Gaucher disease programs (such as nonclinical data,
223 	data about related compounds, effect of treatment on specific disease subgroups) can inform
224 	specific aspects of the pediatric program. Data from the adult Gaucher disease programs may
225 	support conclusions of efficacy and safety. Such data could be used in exploring differences in
226 	pharmacokinetic (PK), PK/PD, treatment-induced changes in different disease manifestations,
227 	and clinical response to treatment in the pediatric population. A mechanism-based approach
228 	(e.g., physiologically based PK modeling, mechanistic disease PK/PD) should play a key role for
229 	dose characterization. Whenever new studies in children are deemed necessary, modeling and
230 	simulation should be used to optimize pediatric studies (e.g., design, sample size, starting doses,
231 	timing of sampling, and number of samples) and particularly to inform the dosing rationale.
232
233 	Safety and risk considerations based on the existing knowledge should guide the decision of
234 	whether specific mitigation, such as staggered enrollment based on age group, is necessary.
235 	However, any uncertainties related to the use of existing knowledge should be identified early in
236 	the pediatric drug development and managed prospectively (e.g., potential issues such as
237 	differences in drug product quality/manufacturing, immunogenicity, pharmacokinetics).
238
239
240 	IV. 	PROPOSED MULTI-ARM, MULTI-COMPANY TRIAL FOR PEDIATRIC
241 	GAUCHER DISEASE
242
243 	The proposal in this guidance covers the principal features necessary to demonstrate efficacy and
244 	safety in treatment-naïve pediatric patients with Gaucher disease Type I. It also applies to the
245 	systemic non-neurological manifestations in Type III Gaucher disease. The proposal provides a
246 	strategy for designing a multi-arm, multi-company drug development program. It includes a
247 	description of the main inclusion criteria, relevant age groups, suggested efficacy endpoints, and
248 	study duration. Although such a program can be very challenging, the aim of the strategic plan
249 	is not only to facilitate agreement on individual applications, but also to address the feasibility of
250 	developing multiple drug products for a rare disease in a time-efficient manner.
251
252 	While recognizing the inherent limitations and challenges in conducting simultaneous drug
253 	development programs in pediatric Gaucher disease, this guidance proposes a multi-arm, multi
254 	company, as presented in Table 1. If this approach is to be undertaken, each individual new drug
255 	product should demonstrate both safety and efficacy.
256
257 	This approach may allow for a reduction in the total number of children to be enrolled, as
258 	compared to conducting separate controlled trials, because a single control arm can be used to
259 	assess the effects of more than one drug product. The proposal applies only to systemic (i.e.,
260 	non-neurological) manifestations of Gaucher disease in treatment-naïve patients with Type I and
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261 	Type III phenotypes, across all the pediatric ages. It is not intended for the neurological
262 	manifestations of Gaucher disease for which there are no approved drug products at this time.
263
264 	Table 1. Proposed Double-Blind, Controlled, Randomized, Multi-Center, Multi-Arm,
265 	Multi-Company Noninferiority or Superiority ERT Trial for Non-Neurological
266 	Manifestations of Gaucher Disease
Study Identifier(s) 	Strategic Collaborative Pediatric Approach for Gaucher Disease
Study design features 	 	Double-blind, controlled, randomized, multi-center, multi-arm, multi-company
noninferiority or superiority trial to evaluate the efficacy and safety of “product
A,” “product B,” “product C,” etc., compared to a single ERT drug product in
pediatric patients with Gaucher disease Type I and Type III.
 	Equal allocation to each arm: e.g., 1:1:1:1; an unequal 2:1 allocation (new drug
product:ERT drug product) may be considered.
 	Randomization should ensure that at any point in time, patients can be randomized
to control as well as a new active drug product
 	Centralized randomization stratified for type and age group
 	Centralized assessment (laboratory and radiographic) may be considered.
Main objective(s) 	To evaluate noninferiority or superiority of new drug product(s) to an approved ERT
treatment.
Study population and
subset definition
Male and female pediatric patients, from birth to younger than 18 years with Type I
and Type III phenotypes with non-neurological manifestations of Gaucher disease.a
Number of study 	 	The calculated sample size should be sufficient to detect noninferiority in the
patients by pediatric 	proposed primary endpoint with at least 80% power and a type I error rate of 0.025
subset (e.g., age, sex, 	for each investigational drug product in the trial. Superiority trials are also
severity or stage) 	acceptable. The noninferiority margin should be carefully chosen and
prespecified. This is particularly crucial because the assay sensitivity of the trial
cannot be assessed in the usual way due to lack of a placebo control group.
Consulting regulatory bodies for scientific advice about this issue before study
start is therefore highly recommended.
 	The sample size is determined by the predefined noninferiority margin and the
assumed variability of the primary endpoint. The most precise information available
at the time of study planning should be thoroughly considered and be supported by
data and/or literature references.
Main inclusion criteria 	 	Clinical diagnosis of Gaucher disease, with documented deficiency of acid beta
glucosidase activity by enzyme assay.
 	Gaucher Type I and Type III with non-neurological manifestations.
 	Genotyping for Gaucher disease.
 	Treatment-naïve patients.
 	Birth to younger than 18 years of age.a
267 	continued
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268 	Table 1, continued
Study Identifier(s) 	Strategic Collaborative Pediatric Approach for Gaucher Disease
Main exclusion criteria 	 	Clinical symptoms predominantly indicative of neurological disease (i.e., Type II
disease; Type III patients with neurological manifestations can be enrolled as long
as the efficacy measures somatic disease).
Study duration for 	 	Two years of treatment for the analysis of the primary endpoint.
patients 	 	Long-term monitoring of primary and secondary endpoints and safety in an
extension study. This extension should cover at least 3 years; however, at least 5
years is recommended.
Dosage, treatment
regimen, route of
administration
 	ERT drug products: doses should be defined.
 	Substrate reduction therapy drug products: doses should be defined. b
 	Other therapies: doses should be defined.
Control(s) 	 	Active control group — ERT administered at the approved dose. The dose should
be adjusted by weight at least every 6 months, in line with growth, as reflective of
current standard of care.
 	An add-on placebo-controlled design can be considered when evaluating study
drugs with different mechanisms of action.
Endpoint(s) with 	The relevant endpoints should be chosen based on the mechanisms of action of the
time(s) of assessment 	selected drug products. Such selection should also take into consideration the
heterogeneity of the pediatric Gaucher population. Consider the following
suggestions:
 	Change in hemoglobin relative to baseline, stratified by background hematinic
usage.
 	Growth rate as measured by Z-score; bone age, height change, weight and body
mass index at baseline and subsequent time points (e.g., every 6 months and yearly
thereafter).
 	Age at pubertal onset (Tanner Stage II) and Tanner staging at baseline and at least
every 6 months between Tanner Stage I and Stage IV for the duration of the trial.
 	Platelet count at baseline and at least every 6 months.
 	Liver and spleen size as multiples of normal (measured with magnetic resonance
imaging) at baseline and subsequent time points.
 	Bone manifestations; including pain intensity and duration and fractures, at least
every 6 months.
 	Pulmonary function, measured at baseline and appropriate time intervals (e.g.,
every 6 months).
 	Safety and tolerability, including infusion-related reactions.
 	Antibody levels (including neutralizing antibodies) for each ERT drug product —
the specific schedule should be discussed with the regulatory agencies. Assays
should be validated at the time of trial initiation.
269 	continued
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270 	Table 1, continued
Study Identifier(s) 	Strategic Collaborative Pediatric Approach for Gaucher Disease
Statistical plan
including study conduct
and analysis
 	Primary analysis of the primary endpoint: noninferiority comparison of each
individual investigational drug product to control, respectively, by means of a 95%
confidence interval method, in both the per-protocol and intent-to-treat
population. c
 	After data freeze, the main analysis of the multi-company study should be
performed by therapy-blinded, independent statisticians. It is recommended that
the long-term monitoring results be analyzed in the same way.
 	All statistical analyses should be prespecified in detail in a statistical analysis plan.
 	The potential impact of missing values should be addressed with sensitivity
analyses. Various approaches should be performed and their results should be
compared and critically discussed, in particular with respect to the noninferiority
design of the trial. d
Measures to minimize
pain and distress
Topical anaesthesia should be offered for all venous access procedures with
documentation of usage.
External independent
data safety monitoring
board
 	External independent data safety monitoring boards should be used during trials.
 	Early stopping of a treatment arm for clinical decline should be considered
271 	a Although pediatric age is defined per FDA regulation from birth to 16 years (21 CFR 201.57(c)(9)(iv)(A)), studying patients up to 18 years of
272 	age is appropriate because other definitions of pediatric age used in clinical practice apply to children up to 18 years.
273 	b For a substrate reduction therapy or “other therapies” trial, a placebo, add-on design may be more appropriate. The FDA should be consulted.
274 	c See the guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness.
275 	d See the ICH guidance for industry E9 Statistical Principles for Clinical Trials for detailed recommendations.
276
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277 	GENERAL REFERENCES AND GUIDELINES
278
279 	Literature
280
281 	Dunne, J, WJ Rodriguez, MD Murphy, et al., 2011, Extrapolation of Adult Data and Other Data
282 	in Pediatric Drug-Development Programs, Pediatrics, 128:e1242–e1249.
283
284 	Farfel-Becker, T, EB Vitner, and AH Futerman, 2011, Animal Models for Gaucher Disease
285 	Research, Dis. Model. Mech, 4:746–752.
286
287 	Futerman, AH and A Zimran, editors, 2007, Gaucher Disease (Hardback), CRC Press.
288
289 	Mistry, P, J Liu, M Yang, et al., 2010, Glucocerebrosidase Gene-Deficient Mouse Recapitulates
290 	Gaucher Disease Displaying Cellular and Molecular Dysregulation Beyond the Macrophage,
291 	PNAS, 107:19473–19478.
292
293 	Pastores, GM, NJ Weinreb, H Aerts, et al., 2004, Therapeutic Goals in the Treatment of Gaucher
294 	Disease, Semin Hematol, 41(Suppl 5):S4–S14.
295
296 	Guidances for Industry
297
298 	Draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies
299 	for Drugs and Biological Products4
300
301 	Guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness
302
303 	Guidance for industry Patient-Reported Outcome Measures: Use in Medical Product
304 	Development to Support Labeling Claims
305
306 	Guidance for industry Scientific Considerations in Demonstrating Biosimilarity to a Reference
307 	Product
308
309 	ICH guidance for industry E9 Statistical Principles for Clinical Trials
310
311 	EMA Documents5
312
313 	Concept Paper on Extrapolation of Efficacy and Safety in Medicine Development
314
315 	Guideline on the Choice of the Non-Inferiority Margin
316
317 	Guideline on Clinical Trials in Small Populations
318
4 When final, this guidance will represent the FDA’s current thinking on this topic.
5 EMA documents can be found on the Search the Document Library web page at
http://www.ema.europa.eu/ema/index.jsp?curl=pages/document_library/landing/document_library_search.jsp.
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319 	Guideline on Missing Data in Confirmatory Clinical Trials
320
321 	Patient Registries Workshop, 28 October 2016
322
323 	Preliminary Meeting Report: Workshop on Methodological Aspects of Clinical Trials for
324 	Efficacy Evaluation in Small Populations
325
326 	Press Release: Orphan Drug and Paediatric Clinical Trials — EMEA Workshop on
327 	Methodological Aspects of Clinical Trials for Efficacy Evaluation in Small Populations
328
329 	Points to Consider on Switching Between Superiority and Non-Inferiority
330
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