Rare Diseases:  
Early Drug Development 
and the Role  
of Pre-IND Meetings 
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DRAFT GUIDANCE
 
 
This guidance document is being distributed for comment purposes only.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publication in the Federal Register of the notice announcing the availability of the draft 
guidance.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 (CDER) Lucas Kempf at 301-796-1140 or 
(CBER) the Office of Communication, Outreach, and Development at 800-835-4709 or 240-402-
8010.  
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
October 2018 
Rare Diseases 
17022dft.docx 
09/28/18   
Rare Diseases:  
Early Drug Development 
and the Role  
of Pre-IND Meetings  
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
Office of Communication, Outreach, and Development  
Center for Biologics Evaluation and Research 
Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, rm. 3128 
Silver Spring, MD  20993-0002 
Phone: 800-835-4709 or 240-402-8010; Email: ocod@fda.hhs.gov 
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
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) 
 
October 2018 
Rare Diseases 
   
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  REGULATORY AND SCIENTIFIC CONSIDERATIONS ........................................ 2 
A.  Pharmaceutical Quality Considerations ...................................................................................... 2 
B.  Nonclinical Considerations ........................................................................................................... 4 
C.  Clinical Pharmacology Considerations ........................................................................................ 5 
D.  Clinical Considerations ................................................................................................................. 6 
IV.  ADDITIONAL CONSIDERATIONS ............................................................................. 8 
A.  Expedited Programs for Serious Conditions ............................................................................... 8 
B.  Companion Diagnostics ................................................................................................................. 8 
C.  Orphan Drug Product Incentives ................................................................................................. 9 
D.  Pediatric Studies ............................................................................................................................ 9 
E.  Data Standards and Electronic Submissions ............................................................................. 10 
REFERENCES ............................................................................................................................ 11 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Rare Diseases:  
2  Early Drug Development and the Role of Pre-IND Meetings 
3  Guidance for Industry1 
4   
5   
6   
7   
8  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
9  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
10  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
11  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
12  for this guidance as listed on the title page. 
13   
14   
15   
16   
17  I.  INTRODUCTION 
18   
19  The purpose of this guidance is to assist sponsors of drug and biological products for the 
20  treatment of rare diseases in early development and in the planning of and participation in formal 
21  pre-investigational new drug application (pre-IND) meetings with the Food and Drug 
22  Administration (FDA).2  Although also applicable to drug development for common diseases, 
23  this guidance is primarily intended to support and facilitate drug development for the treatment 
24  of rare diseases.  
25   
26  This guidance describes frequently encountered issues to consider in early drug development and 
27  pre-IND meetings including topics related to pharmaceutical quality, nonclinical evaluation, 
28  clinical pharmacology, and clinical development including early phase study designs and 
29  statistical analysis plans.  
30   
31  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
32  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
33  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
34  the word should in Agency guidances means that something is suggested or recommended, but 
35  not required.  
36   
37   
                                                 
1 This guidance has been prepared by the Office of New Drugs in the Center for Drug Evaluation and Research in 
cooperation with Center for Biologics Evaluation and Research at the Food and Drug Administration.  
 
2 The term sponsor as used in this guidance refers to both industry sponsor as well as sponsor-investigator.  The term 
drug as used in this guidance refers to both human drugs and biological products unless otherwise specified. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
38  II.  BACKGROUND 
39   
40  Section 526(a)(2)(A) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) defines a rare 
41  disease as a disease or condition that affects fewer than 200,000 people in the United States.3  
42  Early and careful planning is important for all drug development programs but is particularly 
43  critical for rare disease drug development for a variety of reasons.  The limited number of 
44  patients available for the study population affects the feasibility of certain studies, and there is 
45  typically a lack of drug development precedent.  During drug development, sponsors can request 
46  formal meetings with FDA.  These meetings may be particularly helpful for sponsors of drugs 
47  being developed for rare disease indications.  A pre-IND meeting is often the first regulatory 
48  communication between the sponsor and FDA regarding the development program for an 
49  investigational drug or a new indication for an approved drug.  During pre-IND meetings, 
50  sponsors can discuss with FDA the unique challenges of rare disease drug development and 
51  where regulatory flexibility can be justified.4 
52   
53   
54  III.  REGULATORY AND SCIENTIFIC CONSIDERATIONS 
55   
56  Issues discussed during pre-IND meetings may vary depending on the drug, program 
57  development stage, and targeted disease.  However, sponsors should consider the following 
58  issues (especially when preparing a pre-IND meeting package) to help FDA reviewers 
59  understand the development program and to guide discussion on specific issues.  For standard 
60  pre-IND meeting package elements, see the draft guidance for industry Formal Meetings 
61  Between the FDA and Sponsors or Applicants of PDUFA Products.5 
62   
63  A.  Pharmaceutical Quality Considerations 
64   
65  Regulations in 21 CFR 312.23(a)(7)(i) emphasize sequential CMC submissions to the IND to 
66  support each phase of drug development. These submissions should include information to 
67  ensure acceptable quality (e.g., identity, purity, strength/potency) of the investigational drug for 
68  the intended phase of the drug development.   
69   
                                                 
3 Section 526(a)(2)(B) of the FD&C Act also defines a rare disease 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. 
 
4 For discussion on pre-IND meetings, procedures for requesting meetings, rescheduling and canceling meetings, 
content and timing of meeting package submissions, and the conduct and documentation of meetings, see the draft 
guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants.  See also the guidance for 
industry and review staff Best Practices for Communication Between IND Sponsors and FDA During Drug 
Development and the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of 
PDUFA Products.  When final, this guidance will represent 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/RegulatoryInformation/Guidances/default.htm.  
 
5 When final, this guidance will represent FDAs current thinking on this topic. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
70  Therefore, at the pre-IND meeting for a rare disease drug development program, the sponsor 
71  should clearly summarize the type and amount of CMC information to be submitted in the IND 
72  and justify the appropriateness of the information in supporting the proposed clinical trials (e.g., 
73  number of patients in the proposed trials, trial durations, and a safety risk assessment). 
74   
75  In addition to providing standard meeting background material,6 sponsors should include 
76  additional detailed information to enable meaningful discussion of the specific questions posed 
77  to FDA.  The following topics may be appropriate based upon the questions of interest: 
78   
79    A description of the drug substance, including its physical, chemical, and/or biological 
80  characteristics and its source (e.g., synthetic, animal-derived, plant-derived, 
81  biotechnology-derived) 
82   
83    A description of the drug product including dosage form, formulation, and route of 
84  administration; if a combination product, a description of the components that comprise 
85  the combination product 
86   
87    A description of the manufacturing processes for the drug substance and drug product 
88  and, for a sterile product, a description of the control strategy for assuring the sterility of 
89  the product (e.g., aseptic filling methods and controls and/or terminal sterilization method 
90  and controls) 
91   
92    For biologics, a description of the potency assay and its relationship to the mechanism of 
93  action and, as applicable, a summary of information on viral clearance studies 
94   
95    A description of the testing strategy to characterize the drug, including structural, 
96  physicochemical, impurity/degradant characterization and release testing strategy  
97   
98    A description of any differences (e.g., manufacturing process, impurity profiles) between 
99  the nonclinical batch(es) and the proposed clinical trial batch(es) 
100   
101    A description of the container closure systems used for long-term and in-use storage, the 
102  procedures for shipping and handling, and the stability testing strategy  
103   
104    A description of proposed device delivery systems and delivery procedures, as 
105  applicable, and the plan to evaluate product compatibility/stability in the intended 
106  delivery device 
107   
108    A listing of the manufacturing facilities used to manufacture clinical lots and, if known, 
109  the proposed manufacturing facilities to be used for commercial manufacturing (if 
110  different) and a plan for the transition from the clinical manufacturing to the commercial 
111  manufacturing facilities 
112   
                                                 
6 See the draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA 
Products.  When final, this guidance will represent the FDAs current thinking on this topic.   
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
113  B.  Nonclinical Considerations 
114   
115  Nonclinical studies provide information used to assess whether conducting human clinical trials 
116  with the investigational drug would be reasonably safe.7  The types of studies needed for an 
117  investigational drug depend on the drugs intended use, the proposed clinical trial population 
118  (e.g., healthy volunteers versus patients with the indicated disease, anticipated age group), and 
119  the proposed treatment regimen.  FDA can exercise flexibility in nonclinical programs where the 
120  proposed clinical indications are for treatment of rare diseases, particularly diseases that are 
121  serious and life threatening.8   
122   
123  The ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human 
124  Clinical Trials and Marketing Authorization for Pharmaceuticals provides an overall description 
125  of the nonclinical studies generally needed for all drug development programs.  The ICH 
126  guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived 
127  Pharmaceuticals provides an overall description of the nonclinical studies of biological products 
128  that sponsors should consider to support clinical trials.  In some cases, an abbreviated or deferred 
129  program may be applicable.9  Pharmacology and toxicology testing in an animal model of 
130  disease, when available, may contribute to the overall understanding of the actions of the drug on 
131  disease pathology and on the safety profile, especially when drug toxicity may be more severe in 
132  the presence of disease pathology.10  For recommendations on the substance and scope of 
133  nonclinical studies to support clinical trials for cell and gene therapy products, refer to the FDA 
134  guidance for industry Preclinical Assessment of Investigational Cellular and Gene Therapy 
135  Products.  
136   
137  In pre-IND meetings, sponsors should be prepared to discuss whether the completed nonclinical 
138  studies and the proposed nonclinical study plan for the intended clinical drug formulation are 
139  sufficient to support proof of concept and to inform the safety of the drug before initiating first-
140  in-human studies.  
141   
142  In addition to providing the standard meeting package elements,11 sponsors should include the 
143  following information to support specific nonclinical questions posed to the FDA review 
144  division/office: 
145   
                                                 
7 See 21 CFR 312.23(a)(8). 
 
8 See 21 CFR 312.80. 
 
9 See the ICH guidance for industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. 
 
10 We support the principles of the 3Rs (reduce/refine/replace) for animal use in testing when feasible.  The FDA 
encourages sponsors to consult with review divisions when considering a nonanimal testing method believed to be 
suitable, adequate, validated, and feasible.  The FDA will consider if the alternative method could be assessed for 
equivalency to an animal test method. 
 
11 See the draft guidance for industry Formal Meetings Between FDA and Sponsors or Applicants of PDUFA 
Products.  When final, this guidance will represent the FDAs current thinking on this topic.   
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
146    The rationale for the proposed clinical indication, patient population, and clinical dosing 
147  plan. 
148   
149    A description of and rationale for the proposed nonclinical plan to support the initial 
150  clinical development strategy, including the selection of appropriate animal models and 
151  appropriate species for toxicity evaluation. 
152   
153    A nonclinical plan that supports the initiation of clinical studies by demonstrating the 
154  prospect of direct benefit in any planned pediatric age groups, as applicable.  The plan 
155  should also include the selection of appropriate animal models and appropriate species 
156  for specific pediatric toxicity evaluation, as applicable.  
157   
158    A summary (not full reports) of completed in vitro and in vivo pharmacology, proof of 
159  concept, and toxicology studies. 
160   
161    A summary of relevant published information on the drug or related drugs, when 
162  available, and a summary of safety information for all components of the formulation.  
163   
164    A description of how toxicities identified from nonclinical studies may be addressed in 
165  humans (e.g., modifying the exposure, clinical monitoring, stopping criteria), based on 
166  the drugs toxicological profile and safety margins.  
167   
168  FDA may exercise flexibility in the types and amount of nonclinical data to accept to support 
169  drug development for serious and life-threatening diseases.  In a pre-IND meeting, sponsors can 
170  discuss with FDA the additional nonclinical studies that may be necessary to support clinical 
171  trials (e.g., chronic toxicity, developmental and reproductive toxicity (DART), carcinogenicity 
172  studies) and the timing of those studies, as applicable. 
173   
174  C.  Clinical Pharmacology Considerations 
175   
176  Clinical pharmacology studies provide critical information on a drugs mechanism of action, 
177  pharmacokinetic and pharmacodynamic properties, potential for clinical benefit, safety profile, 
178  and dose- or exposure-response relationship.  These studies also enable therapeutic 
179  individualization based on assessment of the impact of intrinsic factors (e.g., renal and hepatic 
180  function, weight, race, sex, genetics) and extrinsic factors (e.g., concomitant drug use, food 
181  intake) on drug response.   
182   
183  Although studies in healthy subjects may determine which factors influence a drugs disposition 
184  or pharmacodynamic effects, dedicated clinical trials that inform dosing and usage instructions in 
185  the target population with a rare disease may be limited.  Therefore, careful planning of the 
186  clinical pharmacology aspects of the drug development plan for a rare disease is important, 
187  because information from such studies and analyses can inform trial design and serve as 
188  supportive evidence of effectiveness.  Data generated from such studies and analyses can 
189  efficiently optimize conditions for drug use (e.g., dose, schedule, patient selection).   
190   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
191  The FDA can exercise flexibility in determining which clinical pharmacology studies are 
192  essential to inform the safe and effective use of a drug, whether integrated with clinical efficacy 
193  and safety trials or conducted separately in healthy subjects, as well as which clinical 
194  pharmacology studies may be deferred until after a drug is approved.  Sponsors should be 
195  familiar with the expectations for including clinical pharmacology information in a new drug 
196  application.  See the References section for a list of relevant guidance documents that may be 
197  helpful in planning the clinical pharmacology aspects of the drug development program. 
198   
199  In addition to providing the standard meeting package elements12 and a general overview of the 
200  planned human pharmacokinetic evaluation, sponsors should include the following information 
201  to address specific clinical pharmacology questions: 
202   
203    The known or suspected mechanism of action of the drug and its metabolites. 
204   
205    A summary of nonclinical or clinical study results regarding pharmacokinetic and 
206  pharmacodynamic properties of the drug (e.g., in vitro drug metabolism and transport 
207  study results).  The results should include a discussion of the effect of potential predictors 
208  of variability on the drugs pharmacokinetics and pharmacodynamics. 
209   
210    A justification of the dose selection (e.g., dosing range, number of doses, dose interval, 
211  route of administration, pivotal biomarkers) and patient selection strategy (e.g., 
212  enrichment), including an assessment of factors that can contribute to variability in a 
213  patients response to the drug.  Modeling and simulations approaches can be used to 
214  inform the drugs dosing and elements of the trial design.  
215   
216    Detailed synopses of all proposed studies including planned 
217  pharmacokinetic/pharmacodynamic sampling and biomarker assessments that will inform 
218  dosing. 
219   
220    Status of the bioanalytical method validation for all biomarkers.  
221   
222    Plans for conducting population pharmacokinetic, exposure-response modeling and 
223  simulation analyses, particularly for pediatric patients. 
224   
225    Plans for in vitro diagnostic development, including adherence to regulatory requirements 
226  for investigational devices, as applicable. 
227   
228  D.  Clinical Considerations 
229   
230  Sponsors developing drugs for rare diseases face many challenges.  These may include the small 
231  number of disease-affected individuals, lack of understanding of the natural history of the 
232  disorder, lack of precedent for drug development (e.g., established clinical endpoints, validated 
233  biomarkers), phenotypic heterogeneity, and the need to conduct trials in pediatric populations, 
                                                 
12 See the draft guidance for industry Formal Meetings Between FDA and Sponsors or Applicants of PDUFA 
Products.  When final, this guidance will represent the FDAs current thinking on this topic.   
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
234  among others.  Because of the limitations in patient numbers, it is important to maximize the 
235  contribution of each patient in the clinical development program. Participants should be 
236  randomized from the first patient enrolled in a trial (when feasible) to help ensure interpretable 
237  results.   
238   
239  Although FDA has no specified minimum number of patients needed to establish drug safety and 
240  efficacy, the number of patients should be adequate to assess benefit and risk.  While the 
241  approval standard for drugs treating rare diseases is the same as that for drugs treating nonrare 
242  diseases, it is appropriate for FDA to exercise the broadest possible scientific judgment in 
243  applying the evidentiary standard in the rare disease setting.  To that end, FDA will consider:  (1) 
244  benefits and risks of the drug; (2) seriousness of the disease; and (3) if there is an unmet medical 
245  need.  This approach reflects FDAs recognition that patients and physicians are generally 
246  willing to accept greater risks and side effects from treatment of life-threatening and severely 
247  debilitating diseases than they would for other diseases.13 
248   
249  It is important that sponsors be prepared to discuss with FDA in pre-IND meetings the following 
250  topics: 
251   
252    A disease description, including prevalence in adult and pediatric patients (including 
253  populations outside the United States), availability of patients for clinical trials, disease 
254  etiology (including information on genotypic/phenotypic correlation, if the disease is 
255  genetic), clinical manifestations, diagnostic criteria, approved therapies and standard of 
256  care, rate and pattern of progression, prognosis, variability among patients, and the 
257  knowledge gaps in the diseases natural history.   
258   
259    Description and rationale for the following:  proposed clinical trial design(s), efficacy 
260  endpoints, biomarkers trial population, patient selection criteria, choice of control group, 
261  methods used to minimize bias, overview of statistical analysis plan (including the 
262  sample size and power calculation when possible), and statistical analysis methods. 
263     
264    If the trial population is a subgroup of the population with the rare disease, plans for 
265  evaluating the drug in other subgroups to determine whether trial results can be 
266  generalized to the broader disease population. 
267   
268    Anticipated safety issues (based on animal data or pharmacologic properties), plans for 
269  monitoring and mitigating such issues (e.g., immunogenicity testing for therapeutic 
270  protein products, gene, or cellular products) and ways to augment the safety database if 
271  necessary (e.g., using data from drugs in the same class, data from an expanded access 
272  program).  
273   
274    Trial stopping rules and/or criteria for taking the patient off study. 
275   
276    Plans for an independent data monitoring committee (DMC) to identify and respond to 
277  early safety issues.  The guidance for clinical trial sponsors Establishment and Operation 
                                                 
13 See 21 CFR 312.80. 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
278  of Clinical Trial Data Monitoring Committees discusses the roles, responsibilities, and 
279  operating procedures of a DMC and when to use one. 
280   
281    Inclusion of patient perspectives in the drug development plan 
282   
283    Plans to conduct extension studies to evaluate longer term safety and durability of effect. 
284   
285    Considerations related to novel endpoints including the development of clinical outcomes 
286  assessments (e.g., patient reported, observer reported, clinician reported, performance 
287  outcome measures).14 
288   
289    Plans for pediatric studies, as applicable (see section IV.D., Pediatric Studies). 
290   
291  Sponsors may consider the pros and cons of alternative study designs such as platform studies.  
292  Platform studies coordinate with other similar drug development programs for the purpose of 
293  sharing placebo patients and study burden.  
294   
295   
296  IV.  ADDITIONAL CONSIDERATIONS 
297   
298  A.  Expedited Programs for Serious Conditions 
299   
300  A pre-IND meeting is an opportunity for sponsors to consult FDA on how to use the expedited 
301  programs for the development and review of investigational drugs.  These expedited programs 
302  include fast track designation, breakthrough therapy designation, priority review designation, 
303  accelerated approval, and regenerative medicine advanced therapy (RMAT) designation.  The 
304  guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics 
305  provides information on FDAs policies, procedures, and criteria generally applicable to most of 
306  these programs.15  
307   
308  B.  Companion Diagnostics 
309   
310  Sponsors often develop drugs for a specific subtype of patients based on particular genetic or 
311  molecular features.  Drugs in development that are intended to be used in a biomarker-defined 
312  subtype of patients may require a companion diagnostic.  Companion diagnostics are tests that 
313  provide information essential for the safe and effective use of a corresponding drug.  Therefore, 
314  FDA recommends that sponsors discuss drug diagnostic codevelopment early in the drug 
315  development program if the drug is likely to only have a favorable benefit-risk profile in a 
316  biomarker-defined subtype of patients.16  
                                                 
14 See the guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product Development to 
Support Labeling Claims. 
 
15 See also the draft guidance for industry on Expedited Programs for Regenerative Medicine Therapies for Serious 
Conditions for information about the RMAT designation program and the application of other expedited programs to 
regenerative medicine therapies.  When final, this guidance will represent the FDAs current thinking on this topic. 
 
16 See guidance for industry and FDA staff In Vitro Companion Diagnostic Devices. 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
317   
318  C.  Orphan Drug Product Incentives 
319   
320  The Office of Orphan Products Development (OOPD) administers several programs to provide 
321  incentives for the development of products (drugs, biologics, devices, or medical foods) for rare 
322  diseases or conditions.  These programs include Orphan Drug Designation, Rare Pediatric 
323  Disease Designation (administered in conjunction with the Office of Pediatric Therapeutics), 
324  Humanitarian Use Device Designation, Orphan Products Clinical Trials Grants, Orphan Products 
325  Natural History Grants, and Pediatric Device Consortia Grants.  During pre-IND meetings for 
326  rare disease drug development programs, the sponsor often asks whether the drug is eligible for 
327  orphan drug designation for the disease or condition under consideration.  Sponsors can submit a 
328  formal request for orphan drug designation for their drugs at any time before submitting the 
329  marketing application for the drug.  Other questions related to orphan product development 
330  incentives can be discussed at the pre-IND meeting or directly with OOPD.17 
331   
332  D.  Pediatric Studies 
333   
334  For purposes of drug development, pediatric patients are defined as those patients from birth to 
335  17 years of age, including neonates.18  Sponsors should include pediatric patients in studies of 
336  rare diseases as soon as scientifically and ethically appropriate.  Early in drug development, 
337  sponsors should discuss with FDA at what point pediatric patients can be included in an overall 
338  rare disease product development program.  Additionally, sponsors enrolling pediatric patients in 
339  any FDA-regulated clinical study must comply with appropriate regulatory and ethical 
340  requirements, including the additional safeguards for children.  
341   
342  In studies where the risk to children is more than minimal, drug development studies could be 
343  allowed to proceed if the risk is justified by the anticipated benefit to the child and the relation of 
344  the anticipated benefit to the risk is at least as favorable as that presented by available alternative 
345  approaches.19  To justify initial studies of rare diseases in children, the sponsor should provide 
346  data to establish that pediatric patients are likely to benefit from treatment with the 
347  investigational drug (i.e., prospect of direct benefit).  Prospect of direct benefit can come from 
348  adult data, or in some instances, nonclinical animal disease models can also provide proof of 
349  concept that the investigational drug may have a beneficial effect in affected children.  Sponsors 
                                                 
 
17 For information on OOPD and its programs, see the OOPDs web page at 
https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/officeofscienceandhealthcoordinati
on/ucm2018190.htm.  
 
18 See 21 CFR 201.57(c)(9)(iv)(A) (the terms pediatric population(s) and pediatric patient(s) are defined as the 
pediatric age group, from birth to 16 years, including age groups often called neonates, infants, children, and 
adolescents) and the draft guidance for industry Pediatric Study Plans: Content of and Process for Submitting 
Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans.  When final, this guidance will represent 
the FDAs current thinking on this topic.  For 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 seventeenth birthday (i.e., birth through 16 
years of age). 
 
19 21 CFR 50.52. 
  9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
350  can consider consultation with experts trained in ethics for programs that involve pediatric 
351  patients. 
352   
353  The Pediatric Research Equity Act (PREA), as amended and codified in section 505B of the 
354  FD&C Act, requires sponsors of certain new drug applications (NDAs) or biologics license 
355  applications (BLAs) and certain supplements to such applications to submit an assessment of the 
356  safety and effectiveness of the drug in pediatric patients at the time the application is submitted, 
357  unless the requirement has been deferred or waived.20  An initial pediatric study plan (iPSP) is 
358  required to be submitted within 60 days of an end of phase 2 meeting,21 and an agreed-upon iPSP 
359  must be included with submission of an NDA or BLA.  However, for serious and life-threatening 
360  diseases (including rare diseases), FDA encourages sponsors to submit their plans for pediatric 
361  product development as early as feasible before initiating pediatric studies.  Some drugs may be 
362  exempted from requirements under PREA, such as certain drugs that have orphan drug 
363  designation.22  Nevertheless, FDA encourages sponsors to submit pediatric study plans for all 
364  drugs intended for pediatric indications (including drugs exempted from the requirement) to help 
365  facilitate pediatric drug development. 
366   
367  E.  Data Standards and Electronic Submissions 
368   
369  Sponsors should consult FDA guidances for industry regarding time lines and requirements for 
370  providing submissions in electronic format and use of data standards for the submission of 
371  applications for INDs, NDAs, and BLAs.23, 24  Implementation should occur as early as possible 
372  during product development so that data standards are accounted for in the design, conduct, and 
373  analysis of nonclinical studies and clinical trials.25 
374   
                                                 
 
20 Section 505B(a)(1) of the FD&C Act.  Sponsors of applications to which section 505B (often referred to by the 
name of the Act that originally created it, PREA) applies must submit either a pediatric assessment or a report on a 
molecularly targeted pediatric cancer investigation, depending on the application in question. 
 
21 Section 505B(e)(2)(A) of the FD&C Act (21 U.S.C. 355c(e)(2)(A)).  Section 505B(e)(2)(A)(ii)(II) also permits 
submission of an iPSP at such other time as may be agreed upon between [FDA] and the applicant.    
 
22 See section 505B(k) of the FD&C Act (21 U.S.C. 355c(k)). 
 
23 See guidance for industry Providing Regulatory Submissions in Electronic Format  Standardized Study Data.  
 
24 See section 745A(a) of the FD&C Act (21 U.S.C. 379k-1).  See also the guidance for industry Providing 
Regulatory Submissions in Electronic Format  Certain Human Pharmaceutical Product Applications and Related 
Submissions Using the eCTD Specifications. 
 
25 For specifications regarding implementation and submission of nonclinical study and clinical trial data in 
standardized formats, see the Center for Drug Evaluation and Research web page, Study Data Standards for 
Submission to CDER, at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/u
cm248635.htm.  
  10  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
375  REFERENCES1 
376   
377  Formal Meetings 
378  Draft guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of 
379  PDUFA Products2 
380   
381  Guidance for industry and review staff Best Practices for Communication Between IND 
382  Sponsors and FDA During Drug Development 
383   
384  Chemistry, Manufacturing, and Controls  
385  Guidance for FDA reviewers and sponsors Content and Review of Chemistry, Manufacturing, 
386  and Control (CMC) Information for Human Gene Therapy Investigational New Drug 
387  Applications (INDs) 
388   
389  Guidance for FDA reviewers and sponsors Content and Review of Chemistry, Manufacturing, 
390  and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug 
391  Applications (INDs) 
392   
393  Guidance for industry CGMP for Phase 1 Investigational Drugs 
394   
395  Guidance for industry Content and Format of Investigational New Drug Applications (INDs) for 
396  Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, and Biotechnology-
397  Derived Products 
398   
399  Guidance for industry INDs for Phase 2 and Phase 3 Studies  Chemistry, Manufacturing, and 
400  Controls Information 
401   
402  Guidance for industry, investigators, and reviewers Exploratory IND Studies 
403   
404  Nonclinical 
405  Draft guidance for industry Investigational Enzyme Replacement Therapy Products:  Nonclinical 
406  Assessment3 
407   
408  Guidance for industry Preclinical Assessment of Investigational Cellular and Gene Therapy 
409  Products 
410   
411  ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical 
412  Trials and Marketing Authorization for Pharmaceuticals 
413   
                                                 
1 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.  
 
2 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/RegulatoryInformation/Guidances/default.htm.  
 
3 When final, this guidance will represent the FDAs current thinking on this topic. 
  11  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
414  ICH guidance for industry S6(R1) Preclinical Safety Evaluation of Biotechnology-Derived 
415  Pharmaceuticals 
416   
417  Clinical 
418  Critical Path Innovation Meetings (CPIM) web page at 
419  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm395888.htm 
420   
421  Draft guidance for industry Bioanalytical Method Validation4 
422   
423  Draft guidance for industry Clinical Drug Interaction Studies  Study Design, Data Analysis, 
424  and Clinical Implications5 
425   
426  Draft guidance for industry Enrichment Strategies for Clinical Trials to Support Approval of 
427  Human Drugs and Biological Products6 
428   
429  Draft guidance for industry Pharmacokinetics in Patients with Impaired Renal Function  Study 
430  Design, Data Analysis, and Impact on Dosing and Labeling7 
431   
432  Draft guidance for industry Multiple Endpoints in Clinical Trials8 
433   
434  Draft guidance for industry Rare Diseases:  Common Issues in Drug Development9 
435   
436  Draft guidance for industry Reference Product Exclusivity for Biological Products Filed Under 
437  Section 351(a) of the PHS Act10 
438   
439  Guidance for clinical trial sponsors Establishment and Operation of Clinical Trial Data 
440  Monitoring Committees 
441   
442  Guidance for industry and FDA staff In Vitro Companion Diagnostic Devices 
443   
444  Guidance for industry and staff Qualification Process for Drug Development Tools  
445   
446  Guidance for industry Codevelopment of Two or More New Investigational Drugs for Use in 
447  Combination 
448   
                                                 
4 When final, this guidance will represent the FDAs current thinking on this topic. 
 
5 When final, this guidance will represent the FDAs current thinking on this topic. 
 
6 When final, this guidance will represent the FDAs current thinking on this topic. 
 
7 When final, this guidance will represent the FDAs current thinking on this topic. 
 
8 When final, this guidance will represent the FDAs current thinking on this topic. 
 
9 When final, this guidance will represent the FDAs current thinking on this topic. 
 
10 When final, this guidance will represent the FDAs current thinking on this topic. 
  12  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
449  Guidance for industry Considerations for the Design of Early-Phase Clinical Trials of Cellular 
450  and Gene Therapy Products 
451   
452  Guidance for industry Expedited Programs for Serious Conditions  Drugs and Biologics 
453   
454  Guidance for industry Exposure-Response Relationships  Study Design, Data Analysis, and 
455  Regulatory Applications 
456   
457  Guidance for industry Gene Therapy Clinical Trials  Observing Subjects for Delayed Adverse 
458  Events 
459   
460  Guidance for industry Non-Inferiority Clinical Trials to Establish Effectiveness 
461   
462  Guidance for industry Patient-Reported Outcome Measures:  Use in Medical Product 
463  Development to Support Labeling Claims 
464   
465  Guidance for industry Pharmacokinetics in Patients with Impaired Hepatic Function:  Study 
466  Design, Data Analysis, and Impact on Dosing and Labeling 
467   
468  Guidance for industry Population Pharmacokinetics 
469   
470  Guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug and 
471  Biological Products 
472   
473  ICH guidance for industry E8 General Considerations for Clinical Trials 
474   
475  ICH guidance for industry E9 Statistical Principles for Clinical Trials 
476   
477  ICH guidance for industry E10 Choice of Control Group and Related Issues in Clinical Trials 
478   
479  ICH guidance for industry E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
480  Proarrhythmic Potential for Non-Antiarrhythmic Drugs 
481   
482  ICH guidance for industry E16 Biomarkers Related to Drug or Biotechnology Product 
483  Development:  Context, Structure, and Format of Qualification Submissions 
484   
485  Roadmap to Patient-Focused Outcome Measurement in Clinical Trials web page at 
486  https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQ
487  ualificationProgram/UCM370174.pdf 
488   
489  Orphan Product Development 
490  Designating Humanitarian Use Device web page at 
491  https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/DesignatingHu
492  manitarianUseDevicesHUDS/default.htm  
493   
  13  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
494  Designating an Orphan Product:  Drugs and Biological Products web page at 
495  https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/Howtoapplyfor
496  OrphanProductDesignation/default.htm 
497   
498  Office of Orphan Products Development web page at 
499  https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/officeofscience
500  andhealthcoordination/ucm2018190.htm 
501   
502  Orphan Products Clinical Trials Grants Program web page at 
503  https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/WhomtoConta
504  ctaboutOrphanProductDevelopment/default.htm 
505   
506  Orphan Products Natural History Grants Program web page at 
507  https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/OrphanProduct
508  sNaturalHistoryGrantsProgram/default.htm 
509   
510  Pediatric Device Consortia Grant Program web page at 
511  https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/PediatricDevic
512  eConsortiaGrantsProgram/default.htm 
513   
514  Rare Pediatric Disease Priority Review Voucher Program web page at 
515  https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/RarePediatric
516  DiseasePriorityVoucherProgram/default.htm 
517   
518  Pediatric 
519  Draft guidance for industry General Clinical Pharmacology Considerations for Pediatric Studies 
520  for Drugs and Biological Products11 
521   
522  Draft guidance for industry Pediatric Study Plans:  Content of and Process for Submitting Initial 
523  Pediatric Study Plans and Amended Initial Pediatric Study Plans12 
524   
525  Pediatric Device Consortia Grant Program web page at 
526  https://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/PediatricDevic
527  eConsortiaGrantsProgram/default.htm  
528   
529  Data Standards 
530  Guidance for industry Providing Regulatory Submissions in Electronic Format  Standardized 
531  Study Data 
532   
533  Study Data Standards for Submission to CDER web page at 
534  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elect
535  ronicSubmissions/ucm248635.htm 
536   
                                                 
11 When final, this guidance will represent the FDAs current thinking on this topic. 
 
12 When final, this guidance will represent the FDAs current thinking on this topic. 
  14  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
537  Investigational New Drug Applications 
538  Investigational new drug application web navigational tool (with links to guidances for industry, 
539  FDA forms, and online references), available on the Investigator-Initiated Investigational New 
540  Drug (IND) Applications web page at 
541  https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprove
542  d/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm343349.htm 
543   
544  Office of Cellular, Tissue, and Gene Therapies (OCTGT) webinar series (multiple presentations 
545  on regulatory information for sponsors planning to submit an IND to the Center for Biologics 
546  Evaluation and Research for an investigational cell therapy or gene therapy product), available 
547  on the OTAT (Office of Tissues and Advanced Therapies) Learn web page at 
548  https://www.fda.gov/BiologicsBloodVaccines/NewsEvents/ucm232821.htm 
  15