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DRAFT GUIDANCE
 
 
 
  This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 
 
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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 
Pediatric Rare Diseases   
1 
A Collaborative Approach for Drug Development  
2 
Using Gaucher Disease as a Model 
3 
Guidance for Industry1  
4 
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-naive 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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Draft  Not for Implementation 
40  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
41  Instead, guidances describe the Agencys 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/ 
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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 diseases 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-naive 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-naive 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   Male and female pediatric patients, from birth to younger than 18 years with Type I  
subset definition  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-naive 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      ERT drug products:  doses  should be defined.  
regimen, route  of      Substrate reduction therapy  drug products:  doses should be  defined.b   
administration     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     Primary analysis of the primary endpoint:  noninferiority comparison  of each  
including study conduct  individual investigational  drug  product to control, respectively, by means of a 95%  
and analysis   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  Topical anaesthesia should be offered for all venous access procedures with 
pain  and distress   documentation of  usage.  
External independent      External  independent data  safety  monitoring  boards should be used during trials. 
data safety monitoring      Early stopping  of a treatment arm for clinical decline should be considered  
board   
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:e1242e1249. 
283   
284  Farfel-Becker, T, EB Vitner, and AH Futerman, 2011, Animal Models for Gaucher Disease 
285  Research, Dis. Model. Mech, 4:746752. 
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, 107:1947319478. 
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):S4S14. 
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 FDAs 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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