Rare Diseases: Considerations 
for the Development of Drugs 
and Biological Products 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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)  
 
December 2023 
Rare Diseases 
   
Rare Diseases: Considerations 
for the Development of Drugs 
and Biological Products 
Guidance for Industry 
 
Additional copies are available from:  
 
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Center for Drug Evaluation and Research 
Food and Drug Administration 
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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)  
 
December 2023 
Rare Diseases 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CONSIDERATIONS FOR NATURAL HISTORY STUDIES .................................... 3 
IV.  NONCLINICAL STUDIES.............................................................................................. 4 
V. CONSIDERATIONS IN CLINICAL DEVELOPMENT, EFFECTIVENESS, AND 
SAFETY ..................................................................................................................................... 8 
A.  Clinical Pharmacology Considerations, Dose Selection, and Use of Biomarkers .................... 8 
1. Clinical Pharmacology Considerations and Dose Selection ........................................................... 8 
2. Identification and Use of Biomarkers .............................................................................................. 8 
B.  Clinical Investigation Design ...................................................................................................... 10 
1. Controls ......................................................................................................................................... 10 
2. Randomization and Blinding .......................................................................................................... 11 
3. Innovative Designs ......................................................................................................................... 12 
C.  Evidence of Effectiveness and Efficacy Endpoints .................................................................... 12 
D.  Safety Evaluation ......................................................................................................................... 16 
E.  Additional Considerations Related to Clinical Development for Rare Disease Drugs .......... 17 
VI.  PHARMACEUTICAL QUALITY CONSIDERATIONS .......................................... 20 
VII.  ADDITIONAL CONSIDERATIONS ........................................................................... 21 
A  Participation of Patients, Caregivers, and Advocates .............................................................. 21 
B.  Expedited Programs .................................................................................................................... 22 
C.  Pediatric Considerations ............................................................................................................. 22 
VIII.  INTERACTIONS WITH FDA ...................................................................................... 23 
REFERENCES ............................................................................................................................ 25 
 
   Contains Nonbinding Recommendations 
1  Rare Diseases: Considerations for the Development of 
2  Drugs and Biological Products 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
9  this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can 
10  use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To 
11  discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title 
12  page.   
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  The purpose of this guidance is to assist sponsors of drugs2 for the treatment of rare diseases in 
20  conducting efficient and successful drug development programs. The statutory requirements for 
21  marketing approval for drugs to treat rare and common diseases are the same and issues 
22  discussed in this guidance are encountered in other drug development programs. These issues are 
23  frequently more difficult to address in the context of a rare disease for which there is often 
24  limited medical and scientific knowledge, poorly understood natural history data, sample size 
25  constraints, and lack of drug development experience. 
26   
27  This guidance does not contain discussion of the general issues of statistical analysis. Those 
28  topics are addressed in other documents, including ICH guidances for industry E9 Statistical 
29  Principles for Clinical Trials3 (September 1998) and E10 Choice of Control Group and Related 
 
1 This guidance has been prepared by the Office of New Drugs and the Office of Translational Sciences 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 The term drug, as used in this guidance, refers to both human drugs and biological products unless otherwise 
specified. 
 
3 Clinical trial has the same meaning as the term clinical investigation as the latter is defined in FDA regulations 
(see 21 CFR 312.3(b)). 
1  Contains Nonbinding Recommendations 
30  Issues in Clinical Trials (May 2001), respectively.4 Additional FDA guidances cover other 
31  specific topics that may be of specialized interest.5,6,7,8 
32   
33  In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
34  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
35  as recommendations, unless specific regulatory or statutory requirements are cited. The use of 
36  the word should in Agency guidances means that something is suggested or recommended, but 
37  not required. 
38   
39   
40  II.  BACKGROUND 
41   
42  Section 526(a)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) defines a rare 
43  disease or condition, in part, as a disease or condition that affects less than 200,000 persons in 
44  the United States.9 Most rare diseases, however, affect far fewer people. The sponsor of an 
45  orphan drug (a drug intended for use in a rare disease or condition10)  may be eligible for orphan-
46  drug designation and certain financial incentives intended to help make developing drugs for 
47  small numbers of patients financially viable;11 however, the Orphan Drug Act does not create a 
48  statutory standard for the approval of orphan drugs that is different from the standard for 
49  approval of drugs for common diseases or conditions. 
50   
 
4 We update guidances periodically. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
5 See the ICH guidance for industry E8(R1) General Considerations for Clinical Studies (April 2022). 
 
6 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics (November 2019). 
 
7 See the draft guidance for industry Considerations for the Design and Conduct of Externally Controlled Trials for 
Drug and Biological Products (February 2023). 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. Also see the guidance for industry 
Considerations for the Use of Real-World Data and Real-World Evidence To Support Regulatory Decision-Making 
for Drug and Biological Products (August 2023). 
 
8 See the guidance for industry E9(R1) Statistical Principles for Clinical Trials: Addendum: Estimands and 
Sensitivity Analysis in Clinical Trials (May 2021). 
 
9 In addition, section 526(a)(2)(B) of the FD&C Act also defines a rare disease or condition as any disease or 
condition that affects more than 200,000 in the United States and for which there is no reasonable expectation that 
the cost of developing and making available in the United States a drug for such disease or condition will be 
recovered from sales in the United States of such drug. 
 
10 See 21 CFR 316.3(b)(10).  
 
11 Incentives associated with orphan-drug designation include a tax credit for 25 percent of qualified clinical trial 
costs, exemption from fees under the Prescription Drug User Fee Act, and potential eligibility for a 7-year period of 
market exclusivity. See Public Law 97-414 (1983), as amended.  
 
2  Contains Nonbinding Recommendations 
51  Approval of any drug  for either a rare disease or a common disease or condition  must be 
52  based on substantial evidence of the drugs effectiveness for its intended use and sufficient 
53  information to conclude that the drug is safe for use under the conditions prescribed, 
54  recommended, or suggested in the proposed labeling.12 Sponsors should demonstrate evidence of 
55  effectiveness in an identified population from adequate and well-controlled13 clinical 
56  investigations.14 FDA regulations provide flexibility in how the regulatory standard may be met. 
57  FDA exercise[s] its scientific judgment in determining the kind and quantity of data a sponsor 
58  is required to provide for individual drug development programs.15 This flexibility extends from 
59  the early stages of development to the design of adequate and well-controlled clinical 
60  investigations required to demonstrate effectiveness to support marketing approval and to 
61  establish safety data needed for the intended use. 
62   
63  Many rare diseases are serious conditions with no approved treatments, leaving substantial 
64  unmet medical need for patients. FDA recognizes that rare diseases are highly diverse with 
65  varying prevalence, rates of progression, and degrees of heterogeneity that can affect both 
66  clinical manifestations and disease courses even within a condition. Further complexity is added 
67  depending on what is known about a diseases natural history and pathophysiology. As such, no 
68  one program can be designed exactly like another. FDA is committed to helping sponsors create 
69  successful drug development programs that address the particular challenges posed by each 
70  disease and encourages sponsors to engage early with the Agency to discuss their drug 
71  development program.  
72   
73   
74  III.  CONSIDERATIONS FOR NATURAL HISTORY STUDIES 
75   
76  All drug development programs benefit from a firm scientific foundation, including an 
77  understanding of disease natural history. The natural history of rare diseases is often poorly 
78  understood, and the need for prospectively designed, protocol-driven natural history studies 
79  initiated in the earliest drug development planning stages cannot be overemphasized. Although 
80  FDA does not require natural history studies, we advise sponsors to evaluate early the depth and 
81  quality of existing natural history knowledge to determine whether it is sufficient to inform their 
82  drug development programs.  
83   
84  For details about natural history studies, refer to the draft guidance for industry Rare Diseases: 
85  Natural History Studies for Drug Development (March 2019).16 
86   
 
12 See section 505(d) of the FD&C Act (21 U.S.C. 355(d)). 
 
13 See 21 CFR 314.126.  
 
14 See 21 CFR 314.126.  
 
15 21 CFR 314.105(c).  
 
16 When final, this guidance will represent the FDAs current thinking on this topic. 
 
3  Contains Nonbinding Recommendations 
87   
88  IV.  NONCLINICAL STUDIES 
89   
90  Nonclinical studies are a mandated part of drug development.17 The goal of the nonclinical 
91  program, which consists of in vitro and/or in vivo studies, is to provide evidence that the drug is 
92  reasonably safe to conduct the proposed clinical investigations.18 Nonclinical studies can also 
93  contribute to a better understanding of the drugs mechanism of action, metabolism, 
94  pharmacokinetics, pharmacodynamics, and possible efficacy. The data generated from 
95  nonclinical studies are important to the design of early-phase clinical investigations, particularly 
96  for selecting the starting clinical dose, dose escalation plan, dosing regimen, and route of 
97  administration. The nonclinical data may help guide the selection of patient eligibility criteria 
98  and will often determine important safety monitoring procedures based on the observed 
99  toxicological profile. 
100   
101  Internationally accepted guidelines discuss the general design of nonclinical safety studies and 
102  the timing of such studies relative to the conduct of a clinical development program.19 Factors 
103  that FDA evaluates when determining areas of nonclinical flexibility include the 
104  pharmacological and chemical characteristics of the drug, the design and objectives of the 
105  proposed clinical investigations, the severity of the targeted disease (including the rate of 
106  progression to death or irreversible morbidity), adequacy of other available therapies, and the 
107  anticipated risks to humans based on the accumulated nonclinical toxicology and human data. 
108  When determining the relevance of existing data, a sponsor can consider factors such as drug 
109  product constituents, dosage form, route of administration, dose levels, and dosing regimen plan.  
110   
111  The sponsor should design the pivotal toxicology studies considering the biology of the disease, 
112  expected pharmacology of the drug, existing proof-of-concept (POC) data, proposed population 
113  to be studied (e.g., adult versus pediatric), and proposed clinical investigation design(s) for the 
114  clinical indication sought. Generally, healthy animals are the test system used in traditional 
115  toxicology testing and, in most circumstances, would be the test system used to support initiation 
116  of clinical investigations.20 When an animal model of the disease is available, pharmacology and 
117  safety studies may contribute to understanding the actions of the drug on disease 
118  pathophysiology, inform safety in the context of that disease, and guide plans for measuring 
119  biological effects in patients. Combined POC and safety studies in animal models of human 
 
17 See 21 CFR 312.23(a)(8).  
 
18 21 CFR 312.23(a)(8).  
 
19 See the ICH guidances for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials 
and Marketing Authorization for Pharmaceuticals (January 2010) (ICH M3(R2)); S6(R1) Preclinical Safety 
Evaluation of Biotechnology-Derived Pharmaceuticals (June 2011) (ICH S6(R1)); and S9 Nonclinical Evaluation 
for Anticancer Pharmaceuticals (March 2010) (ICH S9).  
 
20 We support the principles of the 3Rs (replace/reduce/refine) for animal use in testing when feasible. FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible. FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
 
4  Contains Nonbinding Recommendations 
120  disease have been used in limited situations such as enzyme replacement therapy. Toxicology 
121  testing in an animal model of disease may contribute to the nonclinical support for clinical 
122  investigations but usually will not substitute for toxicology testing in healthy animals. However, 
123  safety evaluation in an animal model may be particularly valuable when drug toxicity is 
124  predicted to be more severe in the presence of disease pathophysiology. 
125   
126  It can also be appropriate to conduct the pivotal toxicology studies in juvenile animals when the 
127  indicated population is pediatric and/or the weight of evidence suggests a cause for concern for 
128  adverse developmental effects not otherwise evaluated by studies conducted to assess 
129  developmental and reproductive toxicity, or the data from adult animals (and adult humans, if 
130  appropriate) are inadequate.21 
131   
132  When clinical investigations are to be conducted in pediatric participants, POC data are required 
133  to establish a prospect of direct benefit to the pediatric population.22 Robust animal model results 
134  may support the possibility of clinical benefit and the potential for a favorable benefit-risk 
135  assessment to support testing in children. However, for many rare diseases, an animal disease 
136  model may not exist or may not exhibit some of the clinically important manifestations of the 
137  disease. Sponsors should thoroughly understand the biological relevance and limitations of the 
138  animal model of disease if it is used in nonclinical studies. Data from relevant ex vivo or in vitro 
139  models, such as tissue explants or cell cultures from participant-derived samples, can also be 
140  used to support the POC in some instances (e.g., correction of an mRNA or protein expression or 
141  subcellular trafficking defect that is known to have a causal relationship to the disease).  
142   
143  FDA has determined that it is appropriate to exercise the broadest flexibility in applying the 
144  statutory standards, while preserving appropriate standards of safety and effectiveness, for 
145  products that are being developed to treat severely debilitating or life-threatening (SDLT) rare 
146  diseases.23 For products being developed for SDLT rare disease indications, clinical 
147  investigations can often proceed with modifications to the typical nonclinical development 
148  programs described in guidance.24 The degree of flexibility afforded to such programs may 
149  depend on a variety of factors, such as the adequacy of current treatment options, the mechanism 
150  of the drug, the safety findings from the available data, and the expected rate of progression to 
151  mortality or irreversible morbidity.  
152   
153  For SDLT rare disease indications, certain types of nonclinical data  primary pharmacology 
154  (including POC data); secondary pharmacology; safety pharmacology; in vitro absorption, 
155  distribution, metabolism, and excretion; and genetic toxicology data  is generally expected at 
156  the time of investigational new drug application (IND) submission, as appropriate, as outlined in 
 
21 See the ICH guidance for industry S11 Nonclinical Safety Testing in Support of Development of Pediatric 
Pharmaceuticals (May 2021). 
 
22 See 21 CFR 50.52, 50.53, and 50.55(c)(2).  
 
23 See 21 CFR 312, subpart E. 
 
24 See ICH M3(R2), ICH S6(R1), and ICH S9. 
 
5  Contains Nonbinding Recommendations 
157  relevant regulations and guidance.25 The IND application should also include results from good 
158  laboratory practicecompliant general toxicology studies of sufficient duration to support the 
159  proposed first-in-human clinical protocol.26 The in vivo safety pharmacology assessments can 
160  generally be integrated into the general toxicology studies. 
161   
162  Modifications to the typical nonclinical development paradigm may be appropriate for SDLT 
163  rare disease indications in the following areas: 
164   
165    Repeat-Dose General Toxicology Study Duration and Timing of Submission: 
166   
167    If the clinical investigation entry criteria define a phenotype that is anticipated to 

168  progress rapidly to mortality within approximately 1 year (i.e., similar prognosis as 
169  for advanced cancer), 1-month general toxicology studies will be adequate to evaluate 
170  support for early clinical development. The study reports from the completed 
171  subchronic general toxicology studies (typically of 3 months duration) should be 
172  submitted before initiating pivotal clinical investigations (those intended to provide 
173  substantial evidence of clinical effectiveness) and would generally be adequate to 
174  support marketing. 
175   
176    If the clinical investigation entry criteria define a phenotype that would be expected 

177  to have a slower rate of progression to death or is characterized by major debilitating 
178  irreversible morbidity, then the 3-month general toxicology studies should be 
179  submitted to support clinical investigations of greater than 1 months duration. 
180  Chronic toxicity studies, when warranted (see ICH M3(R2) or ICH S6(R1) as 
181  appropriate), should be ongoing at the time of submission of clinical investigation 
182  protocols of more than 3 months duration. Study reports from the chronic toxicity 
183  studies can generally be submitted with the marketing application but should be 
184  submitted earlier if warranted. In cases where the shorter duration studies identify 
185  safety signals needing further characterization, the chronic toxicity studies should be 
186  completed before initiating the pivotal clinical investigation(s). 
187   
188    Species Selection: 
189   
190    Sponsors should conduct nonclinical evaluations in pharmacologically relevant 

191  species. It may be appropriate to conduct the general toxicology studies in a single 
192  species, for example, if there is only one relevant species and the potential for off-
193  target toxicity is low. In some cases, initiation of clinical investigations can be 
194  supported by POC studies of appropriate duration in animal disease models, with 
195  incorporation of adequate toxicological assessments into the POC study. For such 
196  modified POC studies, FDA encourages sponsors to discuss the adequacy of the study 
 
25 See 21 CFR 312.23. See also ICH M3(R2), ICH S6(R1), and ICH S9. Additionally, see the ICH guidances for 
industry S7A Safety Pharmacology Studies for Human Pharmaceuticals (July 2001), S7B Nonclinical Evaluation of 
the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals 
(October 2005), and E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential  Questions and Answers (August 2022). 
 
26 See 21 CFR 312.23(a)(8) and ICH M3(R2), ICH S6(R1), and ICH S9. 
6  Contains Nonbinding Recommendations 
197  design (e.g., number of animals used and plans for tissue collection and evaluation, 
198  good laboratory practice status) with the review division before initiating the study. 
199   
200    Developmental and Reproductive Toxicity Assessment: 
201   
202    An assessment of toxicity to embryofetal development can generally be submitted 

203  with the marketing application;27 however, it may be appropriate to defer submission 
204  to after approval, depending on factors such as the indication and patient population. 
205  In some instances, embryofetal developmental data may be requested earlier if there 
206  is a cause for concern that needs to be better characterized. The need for fertility and 
207  prenatal and postnatal development studies should be determined based on the patient 
208  population and existing data concerning identified hazards to these endpoints. If these 
209  studies are needed, the data would generally be submitted with the marketing 
210  application or in the postmarket period, as appropriate. 
211   
212    Carcinogenicity Assessment: 
213   
214    If the conduct of carcinogenicity studies is warranted, these data should generally be 

215  submitted with the marketing application. In certain circumstances, submission of 
216  these data may be deferred to after approval. The timing of carcinogenicity studies 
217  should be discussed with the review division as early as possible in the drug 
218  development program.28  
219   
220  The suitability of any or all of the above flexibilities to any given development program needs to 
221  be determined on a case-by-case basis. Therefore, FDA strongly encourages the sponsor to 
222  discuss the proposed approach with the review division to obtain concurrence with the sponsors 
223  proposed nonclinical development program.29 
224   
225   
 
27 This is predicated on an expectation that effective pregnancy prevention measures will be employed by persons of 
childbearing potential enrolled in the clinical trials. See ICH M3(R2). 
 
28 See ICH S6(R1), and the ICH guidances for industry S1A The Need for Long-term Rodent Carcinogenicity Studies 
of Pharmaceuticals (March 1996) and S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals 
(November 2022). 
 
29 For recommendations on the substance and scope of nonclinical information needed to support clinical trials for 
cell therapy and gene therapy products, see the guidance for industry Preclinical Assessment of Investigational 
Cellular and Gene Therapy Products (November 2013).  
 
7  Contains Nonbinding Recommendations 
226  V.  CONSIDERATIONS IN CLINICAL DEVELOPMENT, EFFECTIVENESS, AND 
227  SAFETY 
228   
229  A.  Clinical Pharmacology Considerations, Dose Selection, and Use of 
230  Biomarkers 
231   
232  The following should be considered about clinical pharmacology, dose selection, and use of 
233  biomarkers in rare disease drug development. 
234   
235  1.  Clinical Pharmacology Considerations and Dose Selection 
236   
237  FDA expects that routine clinical pharmacology assessments typically undertaken during drug 
238  development will be performed in rare disease drug development programs.30 The need for 
239  specific clinical pharmacology assessments may depend on factors such as what is known about 
240  the drugs disposition, drug interaction potential with any concomitant medications, 
241  comorbidities, the anticipated safety profile of the drug, and the potential impacts of organ 
242  impairment on a drugs pharmacokinetics.   
243   
244  In general, sponsors should evaluate the effects of more than one dosage on response using 
245  pharmacodynamic or other sensitive clinical measures of efficacy and safety to inform dosing. 
246  Use of more than one dosage provides a range of exposures that can be used to determine which 
247  dosage should be carried forward into registrational clinical investigations and which dosage is 
248  appropriate for the general population upon approval. Biospecimens for analysis of 
249  pharmacokinetics and/or pharmacodynamics should be obtained from all clinical investigation 
250  participants to aid in evaluation of exposure-response relationships and selection of the most 
251  appropriate dosage. Sponsors developing drugs for rare diseases should provide a comprehensive 
252  plan for clinical pharmacology assessments to FDA early in drug development and discuss the 
253  plan with the review division. Further information on dose selection is under subsection E., 
254  Additional Considerations Related to Clinical Development for Rare Disease Drugs.   
255   
256  2.  Identification and Use of Biomarkers 
257   
258  Sponsors are encouraged to evaluate biomarkers that are relevant to the disease process and drug 
259  response throughout the course of drug development for rare diseases. When appropriate and 
260  feasible, sponsors should develop a plan for obtaining specimens from clinical investigation 
261  participants to evaluate the effects of the drug in relevant tissues. When biomarkers are used to 
262  support critical decisions, such as for patient monitoring, dose selection, or supporting efficacy 
 
30 See the guidances for industry Pharmacokinetics in Patients with Impaired Hepatic Function: Study Design, Data 
Analysis, and Impact on Dosing and Labeling (May 2003), Population Pharmacokinetics (February 2022), In Vitro 
Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020), 
Clinical Drug Interaction Studies  Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions 
(January 2020). See also the draft guidance for industry Pharmacokinetics in Patients with Impaired Renal Function 
- Study Design, Data Analysis, and Impact on Dosing (September 2020). When final, this guidance will represent 
the FDAs current thinking on this topic. 
 
8  Contains Nonbinding Recommendations 
263  and safety, adequate information should be provided to support the biomarker and validation of 
264  the assay method.31 Early consultation with the appropriate review division is encouraged. 
265   
266  The following should also be considered for use of biomarkers in rare disease drug development:  
267   
268    Identifying new biomarkers or modifying the use of existing biomarkers that may 
269  indicate effects on different steps in the pathophysiologic processes. 
270   
271    Predictive biomarkers may have critical roles in POC and dose-selection clinical 

272  investigations or in identification of characteristics of patients with greater potential 
273  to respond to therapy. Biomarkers that promptly indicate drug response might be used 
274  in a patient-specific manner to individualize the dosage or regimen. 
275   
276    Identifying early biomarkers of disease or effects of interventions and biomarkers that 
277  could be used in adaptive and enrichment designs for greater efficiency.32 
278   
279    For example, values of a laboratory measurement expected to be sensitive to a drugs 

280  effect could be used to screen potential responders for inclusion in efficacy clinical 
281  investigations. Sponsors may also be able to identify clinical or genomic 
282  characteristics that predict response using these biomarkers.  
283   
284  The analytical validity of the assay(s) used for biomarker quantitation should be evaluated before 
285  the phase 3 clinical investigation.33 In addition, standardized methods for sample collection, 
286  storage, shipment, and preparation should be used.  
287   
288  The guidance for industry and FDA staff Qualification Process for Drug Development Tools 
289  (November 2020) includes important information about the features of biomarkers used as 
290  endpoints.34 For information about biomarker development within a specific drug development 
291  program, the sponsor should discuss with the appropriate review division.35  
292   
 
31 See the draft guidance for industry and FDA staff Biomarker Qualification: Evidentiary Framework (December 
2018). When final, this guidance will represent the FDAs current thinking on this topic. 
 
32 See the guidances for industry Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness 
of Human Drugs and Biological Products (March 2019) and Adaptive Designs for Clinical Trials of Drugs and 
Biologics.  
 
33 See the guidance for industry Bioanalytical Method Validation (May 2018).  
 
34 There is no statutory requirement that biomarkers be qualified through this process.  
 
35 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products (September 2023). When final, this guidance will represent the FDAs current thinking on this topic.  
 
9  Contains Nonbinding Recommendations 
293  B.  Clinical Investigation Design 
294   
295  In rare disease drug development, given the limited number of patients, it is crucial to optimize 
296  all aspects of clinical investigation design and standardize the collection and management of data 
297  to ensure quality and interpretability. In general, increased measurement variability and 
298  inconsistency reduce data interpretability and confidence in the results. Standardized operating 
299  procedures, quality assurance, and quality control are essential. This is especially important when 
300  the clinical investigation is being conducted at multiple sites.  
301   
302  The purpose of conducting clinical investigations of a drug product is to distinguish the effect of 
303  a drug on the target condition from other influences, such as spontaneous change in the course of 
304  the disease, placebo effect, or biased observation.36 Adequate and well-controlled clinical 
305  investigations provide the primary basis for determining whether there is substantial evidence to 
306  support the claims of effectiveness, and sponsors should discuss with FDA their anticipated 
307  approach to demonstrating substantial evidence of effectiveness early in the development 
308  process.37 FDAs regulation at 21 CFR 314.126(b) describes characteristics of an adequate and 
309  well-controlled clinical investigation.38  
310   
311  Recommendations for the design of clinical investigations below reflect best practices for 
312  conducting rare disease clinical studies designed to demonstrate whether a drug is effective in a 
313  patient population. However, in certain rare disease development programs, such as cell and gene 
314  therapies, there may be situations where it would be reasonable to explore flexibility in clinical 
315  investigation design.39 Important factors would include if there is a well-defined, predictable 
316  natural history and if the therapeutic product has a large treatment effect on an objective and 
317  reliably measured biomarker or clinical endpoint. In these situations, flexibility in design should 
318  be considered on a case-by-case basis in discussion with the review division. 
319   
320  Considerations that are particularly relevant to rare disease drug development are addressed 
321  below. 
322   
323  1.  Controls 
324   
325  A critical element of an adequate and well-controlled study is the use of an appropriate control to 
326  enable reliable and unbiased, to the degree possible, efficacy assessments. Typically, use of a 
327  randomized concurrent control group (e.g., placebo, no treatment, active treatment) is 
328  recommended to distinguish changes occurring because of the drug from those changes 
329  occurring because of other factors, such as natural disease progression. 
 
36 See 21 CFR 314.126(a). 
 
37 See section 505(d) of the FD&C Act (21 U.S.C. 355(d)); 21 CFR 314.126(a). 
 
38 See also the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products (December 2019). When final, this guidance will represent the FDAs current thinking on this 
topic. 
 
39 See the guidance for industry Human Gene Therapy for Rare Diseases (January 2020). 
 
10  Contains Nonbinding Recommendations 
330   
331  For serious rare diseases with unmet medical need, interest is frequently expressed in using an 
332  external control. In clinical investigations with external controls, outcomes in participants 
333  receiving the test treatment according to a protocol are compared with outcomes in a group of 
334  people external to the clinical investigation who had not received the same treatment.40 However, 
335  the lack of blinding and inability to eliminate systematic differences between treatment groups, 
336  given the nonrandomized nature of the comparison, are limitations to the use of an external 
337  control group. For example, in the case of a historical external control, there may be systematic 
338  differences between the nonconcurrent treatment groups attributable to changes in standard of 
339  care or diagnostic approaches over time. 
340   
341  Given the limitations, external control designs are usually reserved for specific circumstances, 
342  such as clinical investigations where the drug effect can be demonstrated in diseases with well-
343  understood and characterized natural history, high and predictable mortality or progressive and 
344  predictable morbidity, and clinical investigations in which the drug effect is large and self-
345  evident.41,42 The suitability of an externally controlled clinical investigation design warrants a 
346  case-by-case assessment, and early discussion with the relevant review division is recommended.  
347   
348  2.  Randomization and Blinding  
349   
350  Randomization in combination with blinding is a powerful clinical investigation design feature to 
351  mitigate bias as it aims to balance both known and unknown factors that may affect the outcome. 
352  Randomized, double-blind, controlled clinical investigations are an efficient and effective way to 
353  generate data on clinically meaningful outcomes to demonstrate substantial evidence of 
354  effectiveness.43 Thus, randomized, double-blind, controlled clinical investigations are generally 
355  the preferred approach.  
356   
357  Randomization of all enrolled clinical investigation participants, including those in the earliest 
358  phases of clinical development, helps ensure that each participants contribution is interpretable, 
359  avoiding potentially misleading findings from open-label, single-arm, externally controlled 
360  clinical investigations. Stratification of randomization by important prognostic factors such as 
361  age or disease severity may be considered to improve comparability of treatment groups. FDA 
362  also recommends that sponsors consider adjustment for prognostic factors as covariates in 
363  statistical analyses to improve precision and power.44  
 
40 See the draft guidance for industry Considerations for the Design and Conduct of Externally Controlled Trials for 
Drug and Biological Products. 
 
41 See the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products. 
 
42 See the draft guidance for industry Considerations for the Design and Conduct of Externally Controlled Trials for 
Drug and Biological Products. 
 
43 See ICH E9. 
 
44 See the guidance for industry Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological 
Products (May 2023). 
 
11  Contains Nonbinding Recommendations 
364   
365  Sponsors should explore and address concerns about clinical investigation design (such as 
366  control arms and randomization) with patients, caregivers, and clinical investigators early in 
367  planning stages to avoid undermining clinical investigation recruitment and retention. Sponsors 
368  can sometimes address patient and family concerns by using modified clinical investigation 
369  designs, when appropriate, to demonstrate effectiveness and identify important safety signals. 
370  These designs retain the advantages of placebo-controlled clinical investigations and include 
371  features that minimize placebo exposure and enhance access to experimental therapies (e.g., dose 
372  response, delayed start, randomized withdrawal, crossover, adaptive designs with interim 
373  analysis, unequal randomization ratio).45 
374   
375  3.  Innovative Designs 
376   
377  It is important that plans to use innovative clinical investigation designs be discussed in advance 
378  with the review division, ideally at the pre-investigational new drug application (pre-IND) 
379  meeting.46 Examples of innovative or nontraditional approaches in rare diseases include 
380  Bayesian methods, n-of-1 clinical investigations, randomized delayed-start designs, crossover 
381  designs, and master protocols (where a common placebo arm is shared among different drug 
382  arms).47  
383   
384  For example, sponsors may be able to use Bayesian methods to maximize the use of information 
385  gleaned from early-phase studies or natural history studies. Bayesian methods also may inform 
386  pediatric clinical investigations through incorporation of adult clinical data. 
387   
388  The design of clinical investigations may allow early evidence to be used later in a clinical 
389  investigation, which may be especially helpful when there are limited numbers of participants to 
390  study, as is the case in rare diseases.48 If an adaptive clinical investigation design is under 
391  consideration, a detailed statistical analysis plan including the key features of the clinical 
392  investigation design and preplanned analyses (including interim analyses) should be discussed 
393  with the review division before clinical investigation initiation.  
394   
395  C.  Evidence of Effectiveness and Efficacy Endpoints 
396   
397  The overall goals of drug development programs are to demonstrate the effectiveness of a drug in 
398  treating or preventing a disease or condition, to assess the magnitude and frequency of that 
399  effect, and to assess the risks of the drug, thereby enabling a benefit-risk assessment and 
400  appropriate labeling.  
 
45 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics. 
 
46 See the guidance for industry Interacting with the FDA on Complex Innovative Trial Designs for Drugs and 
Biological Products (December 2020). 
 
47 See the guidance for industry Master Protocols: Efficient Clinical Trial Design Strategies to Expedite 
Development of Oncology Drugs and Biologics (March 2022). 
 
48 See the guidance for industry Adaptive Designs for Clinical Trials of Drugs and Biologics. 
 
12  Contains Nonbinding Recommendations 
401   
402  One of the statutory requirements for drug marketing approval is substantial evidence that the 
403  drug will have its claimed effect.49 This requirement is the same for all drugs regardless of 
404  whether they are for common or rare diseases. Adequate and well-controlled investigations of a 
405  drug are able to distinguish the effect of a drug from other influences, such as spontaneous 
406  change in the course of the disease, placebo effect, or biased observation.50  
407   
408  In addition to clinical investigation design considerations discussed above, the selection of 
409  appropriate endpoints is critical for a clinical investigation. An endpoint is a precisely defined 
410  variable intended to reflect an outcome of interest that is statistically analyzed to address a 
411  particular research question.51 A precise definition of an endpoint typically specifies the type of 
412  assessments made, the timing of those assessments, the assessments used, and possibly other 
413  details, as applicable, such as how multiple assessments within an individual are to be combined. 
414  For many rare diseases, well-characterized efficacy endpoints appropriate for the disease are not 
415  available. The frequency of assessments and patients (and caregivers) involvement in the 
416  selection, development, or modification of existing clinical outcome assessment measures and 
417  available instruments can improve the chances of success for the development program.52  
418    
419  Endpoint selection for a clinical investigation involves understanding the following:  
420   
421    The range and course of clinical manifestations associated with the disease. Sponsors can 
422  often obtain this knowledge, along with possible differences among patient subtypes, 
423  from a natural history study of the disease.53 
424   
425    The clinical characteristics of the specific target population, which may be a subset of the 
426  total population with a disease. 
427   
428    The aspects of the disease that are meaningful to the patient and caregivers and that could 
429  be assessed to evaluate the drugs effectiveness at each of the different stages of disease 
430  and levels of disease severity.54  
431   
 
49 See section 505(d) of the FD&C Act (21 U.S.C. 355(d)). For a biological product to be licensed under section 351 
of the Public Health Service Act, a sponsor must demonstrate, among other things, that its product is safe, pure, and 
potent. Potency has long been interpreted to include effectiveness (21 CFR 600.3(s)). 
 
50 See 21 CFR 314.126(a). 
 
51 See the FDA-NIH-BEST (Biomarkers, Endpoints, and other Tools) Resource for a definition of endpoint, 
available at https://www.ncbi.nlm.nih.gov/books/NBK338448/. 
 
52 See the CDER Patient-Focused Drug Development web page, available at 
https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-development.  
 
53 For further discussion, see the draft guidance for industry Rare Diseases: Natural History Studies for Drug 
Development.  
 
54 See the guidance for industry, Food and Drug Administration staff, and other stakeholders Patient-Focused Drug 
Development: Methods to Identify What Is Important to Patients (February 2022).   
13  Contains Nonbinding Recommendations 
432    In small sample sizes, it is important to distinguish outcomes from different participants 
433  as much as possible. Dichotomous endpoints (e.g., dichotomizing a continuous 
434  measurement) can result in loss of information and should be avoided whenever possible. 
435   
436  Sponsors should select endpoints considering the objectives of each clinical investigation in the 
437  context of the overall clinical development program. Endpoint selection, especially 
438  considerations related to novel endpoints (that could be clinical outcomes or biomarkers as 
439  surrogate endpoints), is an important aspect of rare disease drug development. Sponsors are 
440  encouraged to engage early with the Agency to discuss endpoint development. Clinical 
441  investigations within a drug development program generally build upon the knowledge gained in 
442  early studies to guide the design and endpoint selection for later stages of development. 
443  Exploratory evidence from earlier phase clinical investigations may help inform the choice of 
444  dose and timing of endpoints.  
445   
446  Different endpoints are often appropriate for the evolving objectives of successive clinical 
447  investigations. Although the earliest clinical investigations will usually focus on safety 
448  assessments, they also can be useful in evaluating a drugs pharmacokinetics and assessing 
449  pharmacodynamic effects. Ideally, sponsors should conduct early- and mid-phase investigations 
450  (e.g., phase 2 clinical investigations, dedicated pharmacokinetic/pharmacodynamic studies) to 
451  guide selection of dose and frequency and can rely on pharmacodynamic or intermediate clinical 
452  effects, which may be assessed earlier than more definitive endpoints.55 Additionally data from 
453  initial rare disease drug development in animal models may help to identify biomarkers to be 
454  used as candidate surrogate endpoints. Leveraging data from natural history or registry-based 
455  studies of rare diseases may also help to identify clinically relevant endpoints as well as to 
456  examine the relationship between disease severity/progression and the biomarker changes (e.g., 
457  to provide initial support for a surrogate endpoint). In general, late-phase clinical investigations 
458  are designed to provide clear determinations of efficacy and further evaluation of safety. FDA 
459  acknowledges that in rare disease drug development, the size of the population may prevent 
460  traditional early-, mid-, and late-phase clinical investigations. Other types of studies conducted 
461  early in drug development, including natural history or registry-based studies and use of animal 
462  models, can provide important information for later stages. FDA encourages sponsors to engage 
463  early with the Agency to discuss their drug development program to ensure learnings from 
464  earlier phases can be carried forward and adapted throughout a drug development program.  
465    
466  Sponsors should also consider the characteristics of an endpoint for the full range of participants, 
467  including all ages, affected races, ethnicities, and sexes to be enrolled into a clinical 
468  investigation. For rare diseases, practical considerations may warrant inclusion of a broad range 
469  of disease stages (e.g., severity of manifestations, development of manifestations secondary to 
470  long-standing primary disease manifestations) or phenotypes. The validity, sensitivity, reliability, 
471  or interpretability of an endpoint may be different for patients with mild, early-stage, or slowly 
472  progressive forms of a disease compared to patients with severe, late-stage, or rapidly 
 
55 See the guidance for industry Population Pharmacokinetics (February 2022). 
 
14  Contains Nonbinding Recommendations 
473  progressive forms of the same disease.56 These differences in characteristics of rare disease 
474  conditions can have effects on aspects of clinical investigation design (e.g., power) and endpoint 
475  interpretation. For considerations related to the patient population and enrollment criteria for a 
476  particular study endpoint in a rare disease drug development program, sponsors should 
477  communicate with the relevant review division.    
478   
479  Sponsors should consider approaches to clinical investigation design and assessment procedures 
480  that may improve the evidence supporting the rationale that an assessment is fit for purpose and 
481  the standardization/interpretability of assessment tools.57 For example, qualitative interviews 
482  with clinicians can improve the quality of clinician-reported outcome measures, and detailed 
483  descriptions of procedures and training for performing assessments may improve accuracy and 
484  intra-reader and inter-reader reliability. It is possible for sponsors to assess the adequacy or 
485  success of blinding at the end of a clinical investigation.58 Effective blinding of treatments can 
486  reduce concern about bias in the subjective aspects of an assessment (e.g., participant 
487  motivation), as can conduct of endpoint evaluation by raters not involved in other aspects of the 
488  clinical investigation (e.g., radiologists, exercise testers). Another consideration is that rare 
489  disease clinical development programs are often multinational, and sponsors should consider the 
490  effects of language, culture, and customs on the interpretability and relevance of outcome 
491  assessments.  
492   
493  Sponsors considering the development of novel clinical outcome assessments should identify and 
494  characterize these assessments early in their drug development programs. FDA advises sponsors 
495  to consider using or modifying existing measures for the disease under study because evaluating 
496  novel measures is time consuming, with potential unexpected outcomes, and evaluations initiated 
497  late in the process could delay drug development. FDA acknowledges that sometimes use of an 
498  existing endpoint measure is not feasible. Therefore, creation of a novel clinical outcome 
499  assessment may be necessary. At meetings with FDA, sponsors should discuss the availability 
500  and modification of existing clinical outcome assessments; such discussions should take place as 
501  early as possible in the drug development program. Furthermore, it is important to consider that 
502  the appropriateness of a clinical endpoint or clinical outcome assessment is context dependent, 
503  and endpoints that might be appropriate for some patients with a rare disease may not be 
504  appropriate for all patients with that rare disease, for patients with other rare diseases, or for 
505  patients with common diseases.  
506   
507  The following should also be considered for endpoint selection in rare disease clinical 
508  investigations:  
509   
 
56 See the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products.   
 
57 See the draft guidance for industry, Food and Drug Administration staff, and other stakeholders Patient Focused 
Drug Development: Selecting, Developing, or Modifying Fit-for Purpose Clinical Outcome Assessments (June 
2022). When final, this guidance will represent the FDAs current thinking on this topic. 
 
58 See the guidance for industry Placebos and Blinding in Randomized Controlled Cancer Clinical Trials for Drug 
and Biological Products (August 2019). 
 
15  Contains Nonbinding Recommendations 
510    Selecting the appropriate endpoint (and timing of endpoint assessment) in a specific drug 
511  development program, such as a clinical endpoint that directly measures patient benefit or 
512  a surrogate endpoint that is not a direct measure of clinical benefit. In cases where using 
513  clinical endpoints is not feasible because changes in symptoms and disease status occur 
514  too slowly to be measured in a clinical investigation of reasonable duration, surrogate 
515  endpoints may be considered.59  
516   
517    Estimating the magnitude of effect that may provide clinically meaningful benefit. 
518   
519  Additionally, FDA recognizes that for diseases that are very rare or have very slow and variable 
520  progression over years, the use of clinical endpoints may be challenging. In these situations, 
521  several strategies may be considered, such as using data from natural history or registry-based 
522  studies, to identify clinically relevant changes that are most prominent and most rapidly 
523  progressive that could serve as the basis for a clinical endpoint. Another strategy is to consider 
524  early development work on biomarkers as surrogate endpoints that may support approval (either 
525  for traditional or accelerated approval). Initial evaluation of the literature to identify such 
526  biomarkers, early work on translational animal models, and leveraging data from natural history 
527  cohorts before initiation of clinical development is essential. An early focus on developing a 
528  broad package of information, including genetic, in vitro, animal model, clinical data in patients 
529  with the disease, and eventually clinical pharmacodynamic (PD) data from early clinical 
530  investigations with the drug, can contribute to substantiate the use of the proposed biomarker as a 
531  surrogate. Sponsors are encouraged to request initial discussions with FDA (e.g., pre-IND) when 
532  they have a well-developed strategy and initial information on a proposed surrogate endpoint in 
533  drug development programs.60  
534   
535  D.  Safety Evaluation  
536   
537  Evaluating whether a drug is safe involves weighing whether the benefits of the drug outweigh 
538  its risks under the conditions of use defined in labeling. Ultimately, what is a feasible and 
539  sufficient safety assessment is a matter of scientific and regulatory judgment based on the 
540  particular challenges posed by each drug and disease, including patients tolerance and 
541  acceptance of risk in the setting of unmet medical need and the benefit offered by the drug.61 A 
542  higher degree of uncertainty is common in drug development programs for rare diseases, where 
543  the prevalence of disease, and consequent limitations of study size, can limit the precision of 
544  safety and efficacy characterizations.62 FDA recognizes that when a drug is developed to treat 
 
59 See the draft guidance for industry Demonstrating Substantial Evidence of Effectiveness for Human Drug and 
Biological Products. 
 
60 See SOPP 8101.1: Regulatory Meetings with Sponsors and Applicants for Drugs and Biological Products (March 
2023) for information on types of FDA meetings.  
 
61 See the guidance for industry Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket 
and Postapproval Clinical Investigations (February 2016). 
 
62 See the guidance for industry Benefit-Risk Assessment for New Drug and Biological Products (October 2023).  
 
16  Contains Nonbinding Recommendations 
545  serious diseases for which there are few or no approved therapies, greater uncertainty or greater 
546  risks may be acceptable provided that the substantial evidence standard has been met. 
547   
548  Regulations do not specify the needed evidence of safety, except that the evidence must include 
549  adequate tests by all methods reasonably applicable.63 The ICH guidance for industry E1A The 
550  Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term 
551  Treatment of Non-Life-Threatening Conditions (March 1995) (ICH E1A) describes expected 
552  exposure for chronically used drugs for non-life-threatening conditions, but these expectations do 
553  not apply to the many rare diseases that are life threatening. Although ICH E1A does not 
554  mention rare diseases, the guidance states that a smaller number of patients may be acceptable 
555  when the intended treatment population is small.  
556   
557  E.  Additional Considerations Related to Clinical Development for Rare Disease 
558  Drugs 
559   
560  Evidence-based decisions about what is feasible in terms of rare disease drug clinical 
561  investigation enrollment depend on accurately estimated disease prevalence.64 Many rare 
562  diseases are genetic in origin and characterized by more than one phenotypic subtype (e.g., 
563  infantile, juvenile, adult). Prevalence estimates should include all phenotypic subtypes of a 
564  disease anticipated to respond to the investigational drug. Sponsors should determine prevalence 
565  estimates for countries in which clinical investigation sites are being considered. If prevalence 
566  estimates are anticipated to vary across countries, sponsors should evaluate the potential 
567  differences in prevalence estimates. Sponsors should provide the individual sources of current 
568  published prevalence estimates, rather than calculated averages, because published prevalence 
569  estimates can vary widely depending on clinical investigation details (e.g., case definition), 
570  country or region, and advances in diagnostics and treatment over time. To facilitate discussion 
571  with the review division about a feasible clinical investigation population enrollment goal, 
572  submissions should include complete citations and, if possible, a copy of each reference 
573  pertaining to the prevalence estimate.  
574   
575  FDA encourages sponsors to discuss their overall plans for maximizing the quantity and quality 
576  of safety and efficacy data in early drug development meetings with FDA. This may include 
577  approaches such as the following:  
 
63 See the guidance for industry Premarketing Risk Assessment (March 2005). 
 
64 The term prevalence is used here in the context of a database for clinical development program, not in the context 
of orphan-drug designation. Information about prevalence in orphan-drug designation can be found on the FDAs 
Designating an Orphan Product: Drugs and Biological Products web page, available at 
https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDes
ignation/default.htm. 
 
17  Contains Nonbinding Recommendations 
578   
579    Decentralized clinical investigations: Decentralized clinical investigations may enhance 
580  convenience for clinical investigation participants by enabling remote participation. 
581  Decentralized clinical investigations reduce the burden on caregivers and facilitate 
582  research on rare diseases and diseases affecting populations with limited mobility or 
583  access to traditional clinical investigation sites. This may help improve clinical 
584  investigation participant engagement, recruitment, enrollment, and retention of a 
585  meaningfully diverse clinical population.65 
586   
587    Natural history: Knowledge about a diseases natural history can inform many important 
588  aspects of clinical investigations, including planning for disease-specific challenges to 
589  patient accrual and retention to increase the size of the dataset. Robust natural history 
590  data can also help distinguish drug-related adverse events from underlying disease 
591  manifestations.66 
592   
593    Clinical investigation eligibility: For rare diseases, it is especially important that inclusion 
594  and exclusion criteria do not unnecessarily constrain patient eligibility not only for 
595  patient accrual but also for an adequate representation of the safety in the intended 
596  treatment population. However, when appropriate, sponsors should consider enrichment 
597  strategies to decrease heterogeneity (nondrug-related variability) and to enhance the 
598  ability of the clinical investigation to identify safety risks of the drug and demonstrate a 
599  potential treatment effect.67 Many rare diseases severely affect children, and for diseases 
600  that affect both children and adults, sponsors should explore early inclusion of pediatric 
601  participants in clinical studies and discuss their plans for pediatric enrollment with FDA 
602  during early stages of drug development, including pre-IND meetings.68,69 
603   
604    Dose selection: Data-driven dose selection is important to avoid participant 
605  discontinuations because of unnecessary toxicity (dose too high) or lack of efficacy (dose 
606  too low), especially when only one registration clinical investigation is feasible. Consider 
607  using data from animal models of disease for different doses, a range of exposure 
608  response, intrapatient dose escalation studies, or quantitative modeling approaches (e.g., 
609  physiologically based pharmacokinetic or pharmacokinetic/pharmacodynamic modeling) 
610  to facilitate dose selection. 
611   
 
65 See the draft guidance for industry, investigators, and other stakeholders Decentralized Clinical Trials for Drugs, 
Biological Products, and Devices (May 2023). When final, this guidance will represent the FDAs current thinking 
on this topic.  
 
66 See the draft guidance for industry Rare Diseases: Natural History Studies for Drug Development. 
 
67 See the guidance for industry Enrichment Strategies for Clinical Trials to Support Determination of Effectiveness 
of Human Drugs and Biological Products.  
 
68 See 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations.  
 
69 See the draft guidance for industry Rare Diseases: Early Drug Development and the Role of Pre-IND Meetings 
(October 2018). When final, this guidance will represent the FDAs current thinking on this topic.  
18  Contains Nonbinding Recommendations 
612    Comparator arm: Sponsors should use a concurrent comparator arm design (e.g., placebo, 
613  no treatment, standard of care, active drug, multiple doses), employing randomization 
614  and blinding/masking whenever ethically and practicably feasible, to facilitate 
615  interpretation of results, including adverse event causality, especially with respect to the 
616  incidence and severity of adverse events that could be a manifestation of the disease 
617  under study.  
618   
619    Clinical investigation conduct and data quality: Sponsors should ensure appropriate 
620  clinical investigation conduct and high data quality. This should include steps to prevent 
621  missing data, as even a small amount of missing data can impact the reliability of results. 
622  Sponsors should also maintain confidentiality of interim results while the clinical 
623  investigation is ongoing.  
624   
625    Auxiliary cohorts: Depending on details of the clinical development program, the 
626  following approaches may augment the safety and efficacy database if the sponsor 
627  rigorously collects and analyzes the data:  
628   
629    A clinical investigation protocol with a safety cohort running parallel to the efficacy 

630  clinical investigation: This cohort would include patients with the disease who 
631  investigators think might benefit from the investigational drug but who do not meet 
632  all the registration clinical investigation eligibility criteria. Such patients can be 
633  enrolled in the clinical investigation, avoiding the need for a separate clinical 
634  investigation and protocol. However, these patients are not randomized and are 
635  excluded from the efficacy analysis. The ability to reliably evaluate outcomes from 
636  nonrandomized data sources can be limited. 
637   
638    Patients receiving drugs under expanded access:70 Systematic collection of expanded 

639  access safety data might identify important premarketing signals that might otherwise 
640  not be observed until the drug is used in the more diverse practice setting. Plans for 
641  the use of these cohorts in a drug development program should be discussed early in 
642  the development process with the review division.  
643   
644    Relevant data from other sources, such as clinical investigations using the drug for 

645  other indications or studies of similar drugs.71  
646   
 
70 See the draft guidance for industry Expanded Access to Investigational Drugs for Treatment Use  Questions and 
Answers (November 2022). When final, this guidance will represent the FDAs current thinking on this topic. 
 
71 New drug applications must include a description and analysis of any other data or information relevant to an 
evaluation of the safety and effectiveness of the drug product obtained or otherwise received by the applicant from 
any source, foreign or domestic, including information derived from clinical investigations, including controlled and 
uncontrolled studies of uses of the drug other than those proposed in the NDA, commercial marketing experience, 
reports in the scientific literature, and unpublished scientific papers (21 CFR 314.50(d)(5)(iv)). If an applicant 
relies on FDAs finding of safety or effectiveness for another drug or uses information to which it does not have a 
right of reference to fulfill a requirement for approval or licensure, FDA will not be able to consider the marketing 
application as a stand-alone application.  
 
19  Contains Nonbinding Recommendations 
647  Sponsors should maintain communication with FDA throughout the development program to 
648  discuss potential required studies to collect additional efficacy data, such as postmarketing 
649  studies, and risk mitigation strategies. This can help avoid preventable delays in approving a safe 
650  and effective drug for patients with unmet medical need.72 For additional information, refer to 
651  section VIII., Interactions With FDA.  
652   
653   
654  VI.  PHARMACEUTICAL QUALITY CONSIDERATIONS 
655   
656  Drug manufacturing should undergo development concurrently with clinical development. 
657  Review divisions encourage sponsors to discuss pharmaceutical quality development plans in 
658  early-phase meetings (such as at pre-IND meetings73) and throughout drug development to 
659  decrease the potential for developmental or approval delays related to drug manufacturing.  
660   
661  FDA recommends that the sponsor carefully assess any planned changes to the drug substance or 
662  drug product manufacturing process, analytical methods, or drug product formulation at any 
663  phase of development to determine if the changes could affect the safety or efficacy of the drug. 
664  These assessments may include analytical studies, nonclinical studies, and clinical investigations. 
665  These assessments should be conducted with each change and could inform whether bridging 
666  studies will be needed. Sponsors should design adequate testing procedures early and implement 
667  them in a timely manner to mitigate delays. To allow time to evaluate the potential effect of 
668  manufacturing changes on drug safety and effectiveness and to minimize possible delays in 
669  development, manufacturing changes should be made as early as feasible, and sponsors should 
670  use quality risk management.74,75  
671   
672  FDA may exercise some flexibility on the type and extent of manufacturing information that is 
673  expected at the time of submission and approval for certain components (e.g., stability data 
674  updates, process validation strategies, inspection planning, manufacturing scale-up). FDA can 
675  explore the level of flexibility on a case-by-case basis after considering factors such as (1) 
676  product characteristics, (2) seriousness of the condition and medical need, (3) manufacturing 
677  processes, (4) the robustness of the pharmaceutical quality system, and (5) the strength of the 
678  sponsors risk-based quality assessment.  
679   
 
72 See the guidances for industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment 
(March 2005) and REMS: FDAs Application of Statutory Factors in Determining When a REMS Is Necessary 
(April 2019).  
 
73 See the draft guidance for industry Rare Diseases: Early Drug Development and the Role of Pre-IND Meetings. 
 
74 See FDAs Emerging Technology Program web page, available at https://www.fda.gov/about-fda/center-drug-
evaluation-and-research-cder/emerging-technology-program, and the CBER Advanced Technologies Team (CATT) 
web page, available at https://www.fda.gov/vaccines-blood-biologics/industry-biologics/cber-advanced-
technologies-team-catt. 
 
75 See the draft guidance for industry Manufacturing Changes and Comparability for Human Cellular and Gene 
Therapy Products (July 2023). When final, this guidance will represent the FDAs current thinking on this topic. 
20  Contains Nonbinding Recommendations 
680  The need for larger amounts of the drug during the product development process may lead to the 
681  need to modify manufacturing procedures and purification methods. FDA also recognizes that 
682  transfer of manufacturing responsibilities may occur after initial nonclinical studies and/or 
683  clinical investigations (e.g., from a single investigator to a company, from a small company to a 
684  large company), which may be a more common scenario for drugs for rare diseases. Any of these 
685  changes (even changes expected to be minor) might result in unanticipated changes to drug 
686  characteristics (e.g., drug impurities, physical-chemical characteristics of proteins, cell 
687  phenotype of cellular products). If significant differences are identified in drug characteristics 
688  after a manufacturing change compared with drug batches (or biological product lots) used in 
689  earlier nonclinical studies or clinical investigations, then additional nonclinical studies and 
690  clinical investigations may be needed because these differences can raise concerns that the 
691  knowledge gained from the earlier studies will not apply to further use of the drug. Some 
692  examples of the many ways a change in drug characteristics may affect drug development 
693  include the following:  
694   
695    The type, number, and level of impurities in a drug used in clinical investigations and for 
696  commercial distribution should be comparable to the drug batches used in toxicology 
697  studies. Changes might raise concerns that the drug used in later clinical investigations 
698  has unknown toxicological characteristics. Additional toxicology studies may be needed 
699  to evaluate the newly produced drug, delaying the clinical development program.  
700   
701    Changes in critical quality attributes of the planned commercial drug after the clinical 
702  investigations might raise concerns that the safety and effectiveness findings of the 
703  clinical investigations do not apply to the newly manufactured drug. These concerns 
704  could warrant additional studies (nonclinical, clinical, or both) to address the concern 
705  before marketing approval.  
706   
707  Given the wide variety of drugs, some of which are complex, FDA advises sponsors to consult 
708  relevant guidances for industry (see sections III through V for a list of selected guidances).  
709   
710   
711  VII.  ADDITIONAL CONSIDERATIONS 
712   
713  A  Participation of Patients, Caregivers, and Advocates 
714   
715  FDA encourages involvement of patients, their caregivers, and advocates in rare disease drug 
716  development.76 Patient input can provide important information about patients experiences, 
717  perspectives, needs, and priorities that can be incorporated throughout the drug development 
718  process. This engagement can take many forms, such as providing solicited consultation on 
719  scientific issues (e.g., clinically meaningful treatment effects), working with industry sponsors as 
720  they design and conduct clinical investigations, and contributing to patient-focused drug 
 
76 FDA can provide support for patients, caregivers, and advocates through interactions with FDA staff and offices 
(e.g., CDERs Professional Affairs and Stakeholder Engagement team, CDERs Patient Focused Drug Development, 
the Center for Biologics Evaluation and Research (CBER) Patient Engagement Program, and the Office of 
Commissioners Patient Affairs Staff). 
 
21  Contains Nonbinding Recommendations 
721  development initiatives.77 For drugs in development, FDA is subject to strict confidentiality 
722  requirements and may not be able to discuss with the public specific information about a drug 
723  development program.78 In these situations, FDA encourages direct sponsor-patient 
724  communication, when feasible, to facilitate the incorporation of patient perspectives and 
725  experiences into the drug development process.  
726   
727  B.  Expedited Programs 
728   
729  Many rare diseases are serious or life-threatening disorders with unmet medical needs. 
730  Therefore, drugs treating these diseases may qualify for one or more expedited programs. FDA 
731  encourages sponsors to consider these programs, which include fast-track designation, 
732  breakthrough therapy designation, and accelerated approval. For details on eligibility and 
733  applications for expedited program designation, sponsors should consult the guidances for 
734  industry Expedited Programs for Serious Conditions  Drugs and Biologics (May 2014) and 
735  Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (February 
736  2019).  
737   
738  C.  Pediatric Considerations 
739   
740  According to estimates, about half of the people affected by rare diseases are children. Therefore, 
741  conducting studies to evaluate drugs in pediatric patients is critical for determining the safety and 
742  efficacy of medications for many rare diseases.79,80 When preparing development plans, the 
743  sponsor should consider whether the rare disease affects children and adults or only children. The 
744  degree of overlap between pathophysiology and similarity of clinical outcomes is an important 
745  consideration in pediatric development when a disease is seen across the life span. In general, 
746  sponsors should include pediatric patients with rare diseases in premarketing clinical studies to 
747  develop data on the full range of people with the disease.  
748   
749  FDA strongly encourages sponsors to study the drug in all relevant pediatric populations, birth to 
750  younger than 17 years of age, so that the drug can be properly and completely labeled for 
751  pediatric use. As part of these pediatric studies, FDA encourages sponsors to develop pediatric 
 
77 See the draft guidance for industry and other stakeholders Developing and Submitting Proposed Draft Guidance 
Relating to Patient Experience Data (December 2018). When final, this guidance will represent the FDAs current 
thinking on this topic. For more information, see the web page Learn About FDA Patient Engagement, available at 
https://www.fda.gov/ForPatients/PatientEngagement/default.htm#PFDD_2.  
 
78 For example, see 21 CFR 314.430.  
 
79 21 CFR 201.57(c)(9)(iv)(A) defines pediatric population(s) and pediatric patient(s) as the pediatric age 
group, from birth to 16 years, including age groups often called neonates, infants, children, and adolescents.  
 
80 For the purposes of pediatric drug development, FDA interprets birth to 16 years in 21 CFR 201.57(c)(9)(iv)(A) 
to mean from birth to before the 17th birthday (i.e., birth through 16 years of age).  
 
22  Contains Nonbinding Recommendations 
752  formulations of the drug to enable accurate dosing, down to the youngest children affected by the 
753  rare disease.81  
754   
755  For studies in which both pediatric and adult participants are included, the sponsor should 
756  consider the relevance and comparability of endpoints to both groups, including whether results 
757  from both groups can be combined in a single statistical analysis. Importantly, there are 
758  additional safeguards for pediatric participants enrolled in clinical studies beyond those provided 
759  for adult participants.82 These additional safeguards could limit the use of some procedures in 
760  children that would be acceptable for adults. Careful planning for a drug being developed to treat 
761  a rare disease in children is important to maximize the efficiency and increase the likelihood of 
762  success of the drugs clinical development program. Such planning should include discussions 
763  with FDA early in drug development about the epidemiology of the rare disease and plans for 
764  inclusion of pediatric participants in clinical studies.83, 
765   
766   
767  VIII.  INTERACTIONS WITH FDA 
768   
769  FDA offers sponsors numerous opportunities for interaction. When developing an investigational 
770  drug for a rare disease, FDA encourages sponsors to meet with the relevant drug review division 
771  supporting development of that particular drug early in the development program.84 FDAs early 
772  feedback to sponsors may result in more efficient drug development. At the sponsors request, 
773  FDA will, if possible, provide advice on specific matters relating to an IND, including advice on 
774  the adequacy of data to support an investigational plan, the design of a clinical investigation, and 
775  whether proposed investigations are likely to produce the data and information needed to meet 
776  requirements for a marketing application.85 FDA provides formal advice through milestone 
777  meetings (e.g., pre-IND meeting, end of phase 2 meeting).  
778   
779  In addition, CDERs Critical Path Innovation Meetings (CPIM) program provides a nonbinding 
780  and informal forum for investigators from industry, academia, patient advocacy groups, and 
781  government to obtain general advice on methodologies or technologies and to discuss topics of 
 
81 See the draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies of 
Drugs, Including Biological Products (September 2022). When final, this guidance will represent the FDAs current 
thinking on this topic. 
 
82 See 21 CFR part 50, subpart D.  
 
83 See the draft guidance for industry Pediatric Drug Development: Regulatory ConsiderationComplying With the 
Pediatric Research Equity Act and Qualifying for Pediatric Exclusivity Under the Best Pharmaceuticals for 
Children Act (May 2023) and the draft guidance for industry, sponsors, and IRBs Ethical Considerations for 
Clinical Investigations of Medical Products Involving Children (September 2022). When final, these guidances will 
represent the FDAs current thinking on this topic. 
 
84 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products. 
 
85 See the guidance for industry and review staff Best Practices for Communication Between IND Sponsors and 
FDA During Drug Development (December 2017).  
 
23  Contains Nonbinding Recommendations 
782  interest independent of a specific drug development program.86 In CPIMs, FDA staff members 
783  may provide general advice on how a technology or methodology might be used to enhance drug 
784  development. CBER participates in CPIM meetings when crosscutting issues arise that involve 
785  both centers. CPIM discussions are nonregulatory and nonbinding on both FDA and CPIM 
786  requesters. 
787   
788  In addition, the INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs 
789  (INTERACT) meetings are intended for novel questions and unique challenges in early 
790  development (i.e., prior to filing of an IND). The advice provided by the FDA staff to a potential 
791  sponsor during an INTERACT meeting may help streamline development by, for example, 
792  helping sponsors avoid unnecessary preclinical studies.87  
793   
794  Additional information about rare disease drug development programs can also be found at 
795  CDERs Accelerating Rare disease Cures (ARC) Program website,88 CDERs Rare Diseases 
796  Team website,89 and CBERs Rare Disease Program website.90 The Office of Orphan Products 
797  Development can be contacted for matters related to orphan product designation. 
798   
 
86 See the guidance for industry Critical Path Innovation Meetings (April 2015). 
 
87 See SOPP 8101.1: Regulatory Meetings with Sponsor and Applicants for Drugs and Biological Products. 
 
88 Available at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/accelerating-rare-disease-
cures-arc-program. 
 
89 Available at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/rare-diseases-team. 
 
90 Available at https://www.fda.gov/vaccines-blood-biologics/cber-rare-disease-program. 
24  Contains Nonbinding Recommendations 
REFERENCES 
 
CDER Patient-Focused Drug Development 
https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-
development 
 
FDA, Accelerating Rare disease Cures (ARC) Program, March 2023 
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/accelerating-rare-
disease-cures-arc-program 
 
FDA, Clinical Outcome Assessment (COA) Qualification Program, November 2021 
https://www.fda.gov/drugs/drug-development-tool-ddt-qualification-programs/clinical-outcome-
assessment-coa-qualification-program 
 
FDA, Medical Products for Rare Diseases and Conditions, May 2022 
https://www.fda.gov/industry/developing-products-rare-diseases-conditions 
 
FDA, Externally Led Patient-Focused Drug Development Meetings, July 2022 
https://www.fda.gov/industry/prescription-drug-user-fee-amendments/externally-led-patient-
focused-drug-development-meetings 
 
FDA CDER & NIH NCATS Regulatory Fitness in Rare Disease Clinical Trials Workshop, May 
2022 
https://www.fda.gov/drugs/news-events-human-drugs/fda-cder-nih-ncats-regulatory-fitness-rare-
disease-clinical-trials-workshop-05162022 
 
FDA Drug Development Resources for the Rare Disease Community and More, May 2022 
https://www.fda.gov/media/158424/download 
 
FDA, Food and Drug Administration Safety and Innovation Act (FDASIA) Section 1137: Patient 
Participation in Medical Product Discussions Report on Stakeholder Views, January 2016 
https://www.fda.gov/media/96077/download 
 
FDA, Framework for FDAs Real-World Evidence Program, December 2018 
https://www.fda.gov/media/120060/download 
 
FDA, Model-Informed Drug Development Paired Meeting Program, October 2022 
https://www.fda.gov/drugs/development-resources/model-informed-drug-development-paired-
meeting-program 
 
FDA, OTP INTERACT Meeting, June 2023 
https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/otp-interact-
meeting 
 
FDA, Rare Diseases Team 
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/rare-diseases-team 
25  Contains Nonbinding Recommendations 
 
FDA, SOPP 8101.1: Regulatory Meetings with Sponsors and Applicants for Drugs and 
Biological Products, March 2023 
https://www.fda.gov/media/84040/download  
26