Guidance for Industry 
Neglected Tropical Diseases of 
the Developing World: 
Developing Drugs for 
Treatment or Prevention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
	 
 
July 2014 

Clinical/Antimicrobial 
	
   
Guidance for Industry 
Neglected Tropical Diseases of 
the Developing World: 
Developing Drugs for 
Treatment or Prevention 
 
 
Additional copies are available from: 

 
Office of Communications, Division  of Drug Information 

Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
10903 New Hampshire Ave., Bldg. 51, rm. 2201 

Silver Spring, MD   20993-0002 

Tel:  301-796-3400; Fax: 301-847-8714; Email:  druginfo@fda.hhs.gov 

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER)
	 
 
July 2014 

Clinical/Antimicrobial 
	
 
   
TABLE OF CONTENTS	
 
 
I.   INTRODUCTION............................................................................................................. 1
	 
II.   BACKGROUND ............................................................................................................... 3
	 
III.   DEVELOPMENT PROGRAM ....................................................................................... 3
	 
A.		  Nonclinical Development and Chemistry, Manufacturing, and Controls 
 
  Considerations ................................................................................................................................3
	 
1.  Pharmacology/Toxicology Studies ...................................................................................................3
  
2.  Microbiology Considerations and Animal Models of Infection .......................................................5
  
3.  Chemistry, Manufacturing, and Controls .........................................................................................5
  
4.  Resources for Nonclinical Development Considerations .................................................................6
  
B.		  Clinical Development Considerations ...........................................................................................6
	 
C.		  Regulatory Considerations ............................................................................................................9
	 
D.   Other Activities in the Center for Drug Evaluation and Research ..........................................10 
	
APPENDIX 1:  GUIDANCES FOR NONCLINICAL DEVELOPMENT AND 

CHEMISTRY, MANUFACTURING, AND CONTROLS ..................................................... 12	
 
APPENDIX 2: GUIDANCES FOR CLINICAL DEVELOPMENT ..................................... 13	
 
 
  Contains Nonbinding Recommendations 
1
	
Guidance for Industry  
Neglected Tropical Diseases of the Developing World:  
  
Developing Drugs for Treatment or Prevention 

 
 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
 
 
I.  INTRODUCTION  
 
The purpose of this guidance is to assist sponsors in the development of drugs for the treatment 
or prevention of neglected tropical diseases (NTDs) of the developing world.2  Specifically, this 
guidance addresses the Food and Drug Administrations (FDAs) current thinking regarding the 
overall drug development program for the treatment or prevention of NTDs, as defined in section 
524(a)(3) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), including clinical trial 
designs and internal review standards to support approval of drugs.   
 
This guidance is issued in response to section 740 of the Agriculture, Rural Development, Food 
and Drug Administration, and Related Agencies Appropriations Act, 2010 (2010 Appropriations 
Act) (Public Law 111-80), dated October 21, 2009, that directed the FDA to issue guidance 
based on the recommendations of the NTD review group3 regarding drugs being developed for 
the treatment or prevention of NTDs.4  Section 740(b) of the 2010 Appropriations Act defines 
NTDs as the tropical disease[s] described in section 524(a)(3) of the FD&C Act.  A list of the 
NTDs is provided in section 524(a)(3) of the FD&C Act.  
 
This guidance is directed to sponsors who lack general knowledge about drug development 
issues. Pharmaceutical sponsors with experience in drug development will find this guidance to 
                                                 
1 This  guidance has been  prepared by the Office of  Antimicrobial Products  in the Center for Drug  Evaluation and  
Research (CDER) at the Food and Drug Administration.  
 
2 For the purposes of this guidance, all references to drugs  include both human  drugs and therapeutic biological 
products  unless otherwise specified.  
 
3 See section  740(b) of the 2010  Appropriations  Act. 
 
4 Public Law 111-80 can be accessed on the  United States Government Printing Office Web site at  
http://www.gpo.gov/fdsys/pkg/PLAW-111publ80/pdf/PLAW-111publ80.pdf. 
1 
 Contains Nonbinding Recommendations 
be basic, but we acknowledge that sponsors interested in evaluating investigational drugs for 
NTDs may have little experience in working with the FDA on drug development issues.5    
 
Potential sponsors should understand that:  (1) we will review and comment on clinical 
development programs for NTDs under an investigational new drug application (IND) 
submission, regardless of where the clinical development will take place; (2) we can approve a 
drug for treatment of an NTD not endemic in the United States; (3) the regulatory pathways and 
internal review standards for approval of drugs for NTDs are the same as for approval of drugs 
for diseases endemic in the United States; and (4) we are committed to exercising our regulatory 
authorities to facilitate access to therapies that can help reduce morbidity and mortality 
associated with NTDs.  Specifically, FDA regulations give the FDA considerable latitude to 
exercise its scientific judgment to determine the kind and quality of data and information an 
applicant is required to provide . . . to meet the statutory standards [for approval] (21 CFR 
314.105(c)). FDA regulations also specifically require that we consider the severity of disease 
and the absence of alternative satisfactory therapy in weighing whether the benefits of therapy 
outweigh known and potential risks (21 CFR 312.84(a)).  In addition, there may be 
circumstances when one adequate and well-controlled trial, combined with confirmatory 
evidence, provides adequate evidence of efficacy.6   
 
We also note that there is a separate draft guidance that describes the policies and procedures for 
the tropical disease priority review voucher described in section 524(a)(3) of the FD&C Act 
(21 U.S.C. 360n(a)(3)), including the procedures for adding a new disease to the list in section 
524.7  Section 524 allows the FDA to designate as a tropical disease any other infectious disease 
for which there is no significant market in developed nations and that disproportionately affects 
poor and marginalized populations.  
 
Although this guidance focuses on drugs for the treatment of NTDs, in general many of the drug 
development issues for drugs used in the prevention of NTDs are similar to drug development 
issues for drugs used in the treatment of NTDs.  Additional discussion of general clinical trial 
design issues and statistical analyses are addressed in the International Conference on 
Harmonisation (ICH) guidances for industry E9  Statistical Principles for Clinical Trials and E10 
Choice of Control Group and Related Issues in Clinical Trials. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should 
                                                 
5 The following FDA Web site has been  developed to assist academic investigators and inexperienced sponsors in  
submitting an investigational new drug application  (IND): 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati 
ons/InvestigationalNewDrugINDApplication/ucm343349.htm.  
 
6 See section 505(d) of the FD&C Act; see also section III.B., Clinical Development Considerations, of this 
guidance and the guidance for industry  Providing Clinical Evidence of Effectiveness for Human Drug  and 
Biological Products. We update guidances periodically.  To make sure you have the most recent version of a 
guidance, check the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.    
 
7 See the draft guidance for industry Tropical  Disease Priority Review Vouchers.   When  final, this guidance will 
represent the  FDAs current thinking  on this topic. 
2 
 Contains Nonbinding Recommendations 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required. 
 
 
II. 	 BACKGROUND 
 
NTDs are infectious diseases that generally are rare or absent in developed countries, but are 
often widespread in the developing world.  Some of the NTDs, such as tuberculosis, affect 
populations globally, including U.S. populations.  Other NTDs, such as African trypanosomiasis, 
are more geographically confined.  The availability of new safe and effective drugs for NTDs 
could provide public health benefit for overall global health, but because these diseases are found 
primarily in developing countries, existing incentives have been insufficient to encourage 
development of new drug therapies.  By enacting section 524 of the FD&C Act, Congress is 
attempting to stimulate new drug development for NTDs by offering additional incentives for 
obtaining FDA approval of certain NTD drugs.  Under section 524(b)(1), the sponsor of a human 
drug application for a tropical disease product application may be eligible for a voucher that can 
be used to obtain a priority review for any subsequent human drug application submitted under 
section 505(b)(1) of the FD&C Act or section 351 of the Public Health Service Act. 
 
Many NTDs are transmitted by insects or contaminated food and water in parts of the world with 
poor sanitation and hygiene. Effective sanitation, access to clean water supplies, and other 
nonpharmacological interventions (e.g., use of bed nets) help to prevent initial NTD infection 
and help to prevent re-infection following effective treatment.   
 
 
III. 		 DEVELOPMENT PROGRAM 
 
A. 	 Nonclinical Development and Chemistry, Manufacturing, and Controls 
Considerations 
 
1.  	Pharmacology/Toxicology Studies 
 
Nonclinical studies provide an information base to assess whether human clinical trials of an 
investigational drug are reasonably safe to be conducted (21 CFR 312.23(a)(8)).  The types of 
studies that will be needed for each drug under study for an NTD depend on the drugs intended  
use, the proposed clinical trial population (e.g., healthy volunteers versus patients with the 
infection), and proposed treatment regimen.  FDA and ICH guidances addressing nonclinical 
studies for developing drugs are listed in Appendix 1.   
 
Depending on the drug that will be studied under an IND, different approaches can be used to 
provide nonclinical information in support of the proposed use in clinical evaluations under an 
IND.  Some of the possible approaches for nonclinical studies for NTD investigational drugs are 
included in the following list.  
 
3 
 Contains Nonbinding Recommendations 
 	  Nonclinical studies of an FDA-approved drug that was approved for another 
indication:  Depending upon how the drug is proposed to be studied under an IND (e.g., 
dose, duration, route of administration, population of use), additional nonclinical studies 
may not be necessary and reference to the approved product labeling may be adequate.  
Where the manner in which the drug will be studied under an IND is different from its 
FDA-approved use, the information from existing studies should be reviewed in the 
context of the proposed indication for an NTD. Obtaining a right of reference to the 
actual nonclinical studies in the new drug application (NDA) or the IND may be 
necessary. In some cases (e.g., new route of administration for use in an NTD or a longer 
duration of treatment), new nonclinical studies may be needed to support a new IND 
submission. 
 
 	  Nonclinical studies for an investigational drug under an IND for another indication 
(i.e., a drug that is not an FDA-approved drug but some human data are available):   
If the sponsor that holds the IND for the drug under development also wants to develop 
the drug for an NTD, cross-referencing existing information for the investigational drug 
that is being developed for another indication may be a means to provide adequate 
nonclinical information to support IND development for an NTD.  A sponsor intending to 
study an indication for an NTD with a drug that is being developed by another sponsor 
would need to obtain a letter (i.e., right of reference) authorizing the sponsor to rely on 
the nonclinical portions of the original sponsors IND for the same drug.  The review 
division will evaluate the nonclinical studies in the context of the proposed indication for 
the NTD and the clinical dosing regimen to assess their adequacy to support the proposed 
IND development for the NTD and determine whether additional nonclinical studies may 
be needed.  
 
 	  Nonclinical studies of a new investigational drug:  When nonclinical studies have not 
been done (or referencing existing data from nonclinical studies is otherwise not an 
option), nonclinical studies should be conducted to collect data.  In general, studies in 
animals should evaluate: 
 
	   Pharmacology of the drug and its disposition (i.e., mechanism of action, absorption, 
distribution, metabolism, and excretion) 
 
	   Toxicological effects of the drug 
 
  Acute administration (including safety pharmacology) 
  Subacute administration  
  Chronic administration (when appropriate) 
 
	   Reproductive toxicology 
 
	   Genetic toxicity (not needed for biological products) 
 
	   Carcinogenicity potential, for chronically administered drugs (for biological products, 
the sponsor should discuss with the review division) 
4 
 Contains Nonbinding Recommendations 
 
As noted previously, the extent and amount of pharmacology and toxicology information needed 
to initiate a clinical development program under a new IND depends on the indication, proposed 
treatment regimen, and patient population for whom the drug is intended for use.  For example, if 
the total duration of therapy is anticipated to be less than 6 months, animal studies to assess 
toxicity following chronic administration may not be needed.  In most cases, the safety and 
efficacy of a new drug can be assessed in trials enrolling men and nonpregnant women; 
therefore, the submission of reproductive toxicology studies may not be needed for initial clinical 
development.  However, if a drug is targeted for development in pregnant women, a full battery 
of reproductive toxicology studies should be completed, along with some preliminary evidence 
of safety and efficacy, before clinical trials in pregnant women can begin (21 CFR 
312.23(a)(8)(ii)). In general, reproductive toxicology studies should be completed at the time of 
NDA submission. 
 
2.  Microbiology Considerations and Animal Models of Infection 
 
Nonclinical microbiology studies provide information about a drugs mechanism of action and 
its antimicrobial activity that help to inform drug development decisions and the design of 
human clinical trials.  The results from antimicrobial activity studies in animal models of  
infection may be important to select candidate drugs to enter into clinical development and to 
select dosing regimens for clinical trials.  Because animal models of infection do not always 
predict responses in humans, and animal models of infection are not available for certain NTDs, 
results from such studies are not required to initiate an IND and to proceed with human clinical 
trials.  However, developing new animal models or refining existing animal models may assist 
overall drug development in NTDs.  See the draft guidance for industry Microbiological Data 
for Systemic Antibacterial Drug Products  Development, Analysis, and Presentation for 
information on development, analysis, and presentation of microbiology data for IND and NDA 
or biologics license application (BLA) submissions for systemic antibacterial drugs.8  
 
3.  Chemistry, Manufacturing, and Controls 
 
During the review of an NDA or BLA, we assess the quality of the drug manufacturing process 
and establish quality standards to ensure the safety and efficacy of the drug.  This evaluation 
includes inspection of manufacturing facilities within and outside the United States for an NDA 
or BLA for NTDs. 
 
Sufficient chemistry, manufacturing, and controls (CMC) information for the new investigational 
drug and a placebo (if used in the trial) should be provided in an IND submission to allow 
evaluation of drug quality and patient safety in a proposed clinical trial.  A letter of authorization 
to an FDA drug master file9 can also be used to allow the FDA to refer to CMC information in 
                                                 
8  When final, this guidance will represent the FDAs current  thinking on this topic.   
 
9 A drug master file (DMF) is a submission to the FDA that can  be  used to provide confidential detailed  information  
about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of  one or  more 
human drugs.  The information contained in  the DMF can  be used to support an  IND; a DMF is not a substitute for 
an IND.  For more information about DMFs,  see the Guideline for Drug Master Files at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm.   
5 
 Contains Nonbinding Recommendations 
support of an IND or NDA/BLA.  See Appendix 1 for guidances relevant to IND-phase 
development10 and when planning for the NDA.11  
 
If a proposed investigational drug is an unmodified form of a marketed, FDA-approved drug, the 
established and trade names of the drug and the manufacturers name may be sufficient to 
support a new IND submission from a CMC perspective; a reference to the FDA-approved 
product label may be adequate to meet CMC requirements.  
 
For drugs that are already in development under another IND, a letter of authorization to that 
existing IND may be adequate.  
 
For non-FDA-approved, foreign-sourced test or comparator drugs, the type of CMC information 
needed to ensure the quality, safety, and efficacy of drugs used in clinical trials can be discussed 
with the FDA before the submission of an IND (see section III.D., Other Activities in the Center  
for Drug Evaluation and Research).  
 
4.  Resources for Nonclinical Development Considerations  
 
The Biopharmaceutical Product Development Services program provided through the National 
Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH) offers a 
collection of nonclinical services to support the development of high-priority therapeutic 
candidates.12  Access to such resources may help facilitate drug development for NTDs. 
 
B.  Clinical Development Considerations 
 
The demonstration of substantial evidence of safety and  effectiveness of new drugs is required 
for approval for the treatment or prevention of disease.13  Generally, this evidence is derived 
from two adequate and well-controlled phase 3 trials.  However, we may consider data from  
one adequate and well-controlled clinical investigation and confirmatory evidence to constitute 
substantial evidence if we determine that such data and evidence are sufficient to establish 
effectiveness (section 505(d) of the FD&C Act).  For example, a drug already approved for 
another indication may need only one adequate and well-controlled trial for approval for 
treatment of an NTD.14    
 
                                                 
10 See the guidances for industry Content and  Format  of  Investigational New Drug Applications (INDs) for Phase 1 
Studies of  Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived  Products and  INDs for Phase 
2 and Phase 3 Studies   Chemistry, Manufacturing, and  Controls Information. 
 
11 See the ICH guidance for industry  Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical  
Ingredients. 
 
12 Information on the Biopharmaceutical Product Development Services program  at NIH can be found at 
http://www.niaid.nih.gov/labsandresources/resources/dmid/pretheraagents/biopharma/Pages/default.aspx. 
 
13 See section 505 of the FD&C Act. 
 
14 For more information, see the guidance for industry  Providing Clinical Evidence of  Effectiveness for Human  Drug  
and Biological  Products. 
6 
 Contains Nonbinding Recommendations 
Given the geographic distribution of most NTDs, we expect that most of the supporting safety 
and efficacy data for drug development programs for NTDs will be generated from outside the 
United States. FDA regulations permit the acceptance of foreign clinical studies in support of an 
NDA or BLA approval. Under 21 CFR 312.120, if certain conditions are met (including that the 
trial was conducted in accordance with good clinical practice, which necessitates review and 
approval by an independent ethics committee), we will accept as support for an application for 
marketing approval a well-designed and well-conducted foreign clinical trial not conducted 
under an IND.  However, we strongly encourage sponsors who intend to seek FDA approval for 
a drug for NTDs to submit an IND, regardless of where the clinical development occurs, to 
provide an opportunity for the FDA to offer advice on the development program to ensure that it 
will be able to support a future NDA or BLA.  Marketing approval of a new drug based solely on 
foreign clinical data is governed by 21 CFR 314.106.  
 
Phase 1 and phase 2 trials play an important role in characterizing the pharmacokinetics, 
preliminary safety, and early evidence of activity of a drug for the treatment of an NTD.  In 
addition to pharmacokinetic characterization, the clinical pharmacology component of the drug 
development program for an NTD should also employ evaluation of relevant drug interactions, 
effects of renal and/or hepatic impairment on the pharmacokinetics of the drug, and potential 
exposure-response relationships for both safety and efficacy outcomes.  We can provide advice 
and feedback on recommendations for trial designs when submitted as part of an IND.  The 
information from these studies in early clinical  development can help to arrive at optimal dose 
selection(s) for phase 3 trials.  Another advantage of submitting an IND is the advice from the 
FDA on whether the optimal dose selection for the phase 3 trial is applicable and relevant for a 
dose and dosing regimen for the U.S. population. 15     
 
The types of clinical trial designs for demonstration of efficacy of drugs for treatment of NTDs 
of the developing world are listed below (see 21 CFR 314.126(b)(2)(i)  (v)): 
 
 	  Placebo concurrent control.  The test drug is compared with an inactive preparation 
designed to resemble the test drug as much as possible.  A placebo-controlled trial may 
include additional treatment groups, such as an active treatment control or a dose-
comparison control, and usually includes randomization and blinding of patients or 
investigators, or both. Placebo-controlled trials are appropriate in situations where there 
is no approved treatment for an NTD, or where the administration of placebo would not 
raise ethical concerns.  
 
 	  Dose-comparison concurrent control. At least two doses of the drug for which there is 
clinical equipoise (e.g., early phase clinical evaluations demonstrate potential clinical 
activity of two or more different doses) are evaluated in a clinical trial that then shows 
superiority of one dose over the other dose(s).  A dose-comparison trial may include 
additional treatment groups, such as placebo control or active control.  Dose-comparison 
trials usually include randomization and blinding of patients or investigators, or both. 
                                                 
15 To rely solely on foreign clinical data for marketing approval, 21 CFR  314.106(b)  requires, among other things, 
that the data be applicable to the U.S. population and U.S. medical  practice.  Section 314.106(b) further provides 
that FDA will apply this policy in a flexible manner according to the nature of the drug and the data being  
considered.   
7 
 Contains Nonbinding Recommendations 
 
 	  No treatment concurrent control.  Where objective measurements of effectiveness are 
available and placebo effect is negligible, the test drug is compared with no treatment.  
No treatment concurrent control trials usually include randomization. 
 
	   Active treatment concurrent control.  The test drug is compared with known effective 
therapy, for example, when the condition treated is such that administration of placebo or 
no treatment would be contrary to the interest of the patient.  An active treatment trial 
may include additional treatment groups, however, such as a dose-comparison control.  
Active treatment trials usually include randomization and blinding of patients or 
investigators, or both. Active treatment concurrent control can be designed to show 
superiority of a test drug over an active control drug, or to show noninferiority.  
Noninferiority of the test drug and active control drug can mean that both drugs were 
effective or that neither was effective. Therefore, if the intent of the trial is to show 
noninferiority of the test and control drugs, the active control drug should have a well-
characterized and reliable treatment effect over placebo.  
 
	   Historical control.  The results of treatment with the test drug are compared with 
experience historically derived from the adequately documented natural history of the 
disease or condition, or from the results of active treatment, in comparable patients or 
populations.  Because historical control populations usually cannot be as well assessed 
with respect to pertinent variables as can concurrent control populations, historical 
control designs are usually reserved for special circumstances.  Examples include studies 
of diseases with high and predictable mortality (e.g., certain malignancies) and studies in 
which the effect of the drug is self-evident (e.g., general anesthetics). 
 
In general, phase 3 trials should be prospective, randomized to treatment assignment, and have 
treatment groups and investigators blinded to the treatment assignment (double-blinded), unless 
the trial design is a historical control. If there is a compelling reason that trials cannot be double-
blinded, sponsors should discuss with the FDA the efforts to minimize potential biases of single-
blind or open-label trial designs. The number of patients needed for enrollment into clinical 
trials depends on the type of clinical trial design, endpoints, and safety profile.  The results of 
superiority trials usually are straightforward to interpret, when superiority trials are feasible.  For 
the noninferiority trial designs, the noninferiority margin should be justified, ideally, at the point 
of protocol development for a clinical trial.  
 
Adaptive clinical trial designs may be appropriate to consider for clinical trials of some NTDs.  
Clinical trials can be designed with adaptive features that may enhance the efficiency of the trial.  
For example, the adaptive design might result in a shorter overall duration of the trial, a fewer 
number of patients enrolled, or a greater likelihood of showing an effect of the drug if one exists.  
Sponsors who are considering an adaptive design are encouraged to consult the draft guidance 
for industry Adaptive Design Clinical Trials for Drugs and Biologics for review of statistical, 
clinical, and regulatory aspects of this potential approach.16  We also encourage sponsors to 
                                                 
16  When final, this guidance will represent the FDAs current  thinking on this topic.  
8 
 Contains Nonbinding Recommendations 
discuss such clinical trial designs with the FDA before conduct of the trial to provide an 
opportunity for advice on trials with an adaptation.  
 
The size of the preapproval safety database depends on different factors, including the risks and 
benefits of therapy and the conditions under study, and should be discussed with the FDA during 
drug development.  The nonclinical safety studies and reported adverse events in early clinical 
development should also be considered.  The infectious diseases pathogenic characteristic is 
another factor used to determine the size of the preapproval safety database.  For example, a 
smaller safety database might enable an appropriate ascertainment of risk-benefit for infectious 
diseases where the therapy prevents a serious or fatal outcome, compared to larger preapproval 
safety databases for infectious diseases where therapy is intended to provide symptom 
improvement of a less serious condition.  For a drugs use in the prevention of an NTD, a larger 
preapproval safety database may be needed because the drug may be given to healthy people 
who might be exposed to the infectious agent. 
 
Human efficacy studies are ethical and feasible for most NTDs.  Therefore, the rule Approval of 
New Drugs When Human Efficacy Studies Are Not Ethical or Feasible (21 CFR 314.600 for 
NDAs; 21 CFR 601.90 for BLAs) may not be an appropriate regulatory pathway for a new drug 
approval for NTDs. 
 
We encourage sponsors who are planning clinical trials to discuss their planned trials with the 
FDA and to get feedback on their proposed trial designs.  We  have available on the FDA Web 
site a number of guidances that provide valuable information on the design and conduct of 
clinical trials for studying new therapies. A list of guidances pertinent to the clinical evaluation 
of drugs for NTDs is included in Appendix 2. 
 
C.  Regulatory Considerations 
 
There are regulatory paradigms or tools that can be used in the area of drug development for 
NTDs when appropriate. Additional information for sponsors regarding each of these 
procedures can be found on the FDA Web site, referenced below in the appropriate sections.  
 
	   Orphan Product Designation.  The Office of Orphan Product Development (OOPD) 
serves a mission to promote the development of drugs for treatment of rare diseases and 
conditions. Most of the NTDs would be considered orphan diseases among the U.S. 
population. Thus, a drug being developed for an NTD may be considered for designation 
as an orphan product, which has certain benefits for a sponsor.  OOPD supports product 
development for rare diseases through an extramural grants program.  A sponsor can 
submit an application to the OOPD for consideration for orphan designation.17  
 
 	  Expedited Programs for Serious Conditions. The following programs are intended to 
facilitate and expedite development and review of new drugs to address unmet medical 
needs in the treatment of serious or life-threatening conditions: 
                                                 
17 Information about  orphan designation can be found  on the FDA Web site  at  
http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/HowtoapplyforOrphanProductDesi 
gnation/default.htm.   
9 
 Contains Nonbinding Recommendations 
 
  Fast track designation 

  Breakthrough therapy designation 

  Accelerated approval 

  Priority review designation 

 
Sponsors should consult the draft guidance for industry Expedited Programs  for Serious 
ConditionsDrugs and Biologics to determine whether any of these programs may be 
applicable to their development programs.18  That guidance describes the qualifying 
criteria and features (e.g., benefits) of each of the expedited programs.  
 
 	  Tropical Disease Priority Review  Voucher.  The Tropical Disease Priority Review 
program provides for a voucher that is awarded at the time of approval of certain drugs 
that prevent or treat a tropical disease (i.e., NTD) that subsequently can be redeemed for a 
priority review of an application for a drug for any indication submitted at a later time.19  
 
 	  Qualified Infectious Disease Product.  An antibacterial or antifungal drug intended for 
the treatment of serious or life-threatening NTD infections may qualify for designation as 
a qualified infectious disease product (see section 505E(g) of the FD&C Act).  A 
designation as a qualified infectious disease product has certain regulatory incentives, 
including an extension of the drugs exclusivity period. 
 
D.  Other Activities in the Center for Drug Evaluation and Research  
 
The following activities in the Center for Drug Evaluation and Research (CDER) pertain to 
developing drugs for NTDs. 
 
 	  Pre-IND Consultation Program.  Sponsors interested in developing a drug for NTDs in 
developing countries should contact the FDA and discuss their nonclinical and clinical 
development plans with the appropriate review division within the Office of 
Antimicrobial Products.  Our pre-IND program allows sponsors to receive direct 
feedback on their proposed content of an IND submission, including the types of 
nonclinical studies that should accompany the IND, and anticipated clinical trial designs.  
Sponsors have an opportunity to consider our recommendations when planning their 
studies.20  
 
                                                 
18  When final, this guidance will represent the FDAs current  thinking on this topic.   
 
19 See the draft guidance for industry Tropical  Disease Priority Review Vouchers.  
 
20 The Office of  Antimicrobial Products maintains a Pre-IND Consultation Program Web  site at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati 
ons/InvestigationalNewDrugINDApplication/Overview/default.htm.  
10 
  Contains Nonbinding Recommendations 
 	  CDER Review Processes.  The internal review processes for INDs and NDAs or BLAs 
are described on the FDA Web site.  Timelines are provided for FDA application review 
as well as types of communications between sponsors and the FDA.21  
 
                                                 
21 An  overview of the FDA review of  drug  development and approval can be found at the following  Web sites:   
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati 
ons/InvestigationalNewDrugINDApplication/default.htm#FDA%20Guidances%20for%20Investigational%20New% 
20Drugs and  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati 
ons/NewDrugApplicationNDA/default.htm.   
11 
  Contains Nonbinding Recommendations 
APPENDIX 1:  GUIDANCES FOR NONCLINICAL DEVELOPMENT AND 

CHEMISTRY, MANUFACTURING, AND CONTROLS22
 	
 
The following guidances provide relevant information on nonclinical development for sponsors 
interested in developing a drug for an NTD. Sponsors should follow the recommendations in 
these guidances when submitting an IND to begin clinical investigations.  
 
 	  The ICH guidance for industry M3(R2)  Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials and Marketing Authorization for Pharmaceuticals provides an 
overall description of what nonclinical studies generally are needed at any stage of drug 
development and when they are needed.  For biological products, ICH M3(R2) provides 
guidance on the timing of nonclinical studies relative to clinical development.  
 
 	  The ICH guidance for industry Q7A Good Manufacturing Practice Guidance for Active 
Pharmaceutical Ingredients provides guidance for manufacturing under an appropriate 
system for managing quality. 
 
 	  The ICH guidance for industry S6(R1)  Preclinical Safety Evaluation of Biotechnology-
Derived Pharmaceuticals provides an overall description of what nonclinical studies of 
biological products should be considered to support clinical trials.    
 
 	  The draft guidance for industry Microbiological Data for Systemic Antibacterial Drug  
Products  Development, Analysis, and Presentation provides an overview of the 
nonclinical microbiology studies that help to support clinical development.23    
 
 	  The guidance for industry Content and Format of Investigational New Drug Applications 
(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, 
Biotechnology-derived Products describes in general the types of information that should 
accompany an IND submission.  See also the Questions and Answers companion 
document.  
 
 	  The guidance for industry INDs for Phase 2 and Phase 3 Studies  Chemistry, 
Manufacturing, and Controls Information describes the CMC information that should be 
submitted for phase 2 and phase 3 trials conducted under INDs.  
 
                                                 
22 These guidances can be found  on the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
 
23  When final, this guidance will represent the FDAs current  thinking on this topic. 
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  Contains Nonbinding Recommendations 
APPENDIX 2:  GUIDANCES FOR CLINICAL DEVELOPMENT24  
 
The following guidances can be useful in the area of clinical development of drugs for NTDs: 
 
	   The ICH guidance for industry E9 Statistical Principles for Clinical Trials summarizes 
statistical areas for clinical trials.   
 
 	  The ICH guidance for industry E10 Choice of Control Group and Related Issues in 
Clinical Trials highlights some of the important aspects of using an appropriate control 
group. The guidance discusses some of the considerations for the noninferiority trial to 
ensure the appropriate demonstration of efficacy when compared to an active-controlled 
drug. 
 
 	  Effective treatment of some NTDs includes the use of combinations of antimicrobial 
drugs to enhance efficacy or prevent the development of resistant pathogens.  Some  
development programs may include two or more new investigational drugs.  The 
guidance for industry Codevelopment of Two or More New Investigational Drugs for Use 
in Combination covers this area. 
 
 	  Some NTDs have known effective treatment, and clinical trials designed to demonstrate 
noninferiority of an investigational drug to the control drug can be used in this situation.  
The noninferiority clinical trial design poses some unique scientific and regulatory 
challenges, which focus on an ability to describe a reliable treatment effect of the control 
drug. Two guidances in this area include the draft guidance for industry Non-Inferiority 
Clinical Trials25 and the guidance for industry Antibacterial Drug Products: Use of 
Noninferiority Trials to Support Approval. 
 
 	  The principles of good meeting management practices and standardized procedures for 
meetings are outlined in the guidance for industry Formal Meetings Between the FDA 
and Sponsors or Applicants. 
 
 	  The guidance for industry Providing Clinical Evidence of Effectiveness for Human Drug 
and Biological Products provides a general overview of the approach to demonstrating 
effectiveness.   
 
 	  The draft guidance for industry Antibacterial Therapies for Patients With Unmet Medical 
Need for the Treatment of Serious Bacterial Diseases explains the FDAs current 
thinking about possible streamlined development programs and clinical trial designs for 
drugs to treat serious bacterial diseases in patients who have an unmet medical need.26  
 
                                                 
24 These guidances can be found  on the FDA Drugs guidance Web page at  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.   
 
25  When final, this guidance will represent the FDAs current  thinking on this topic. 
 
26  When final, this guidance will represent the FDAs current  thinking on this topic 
13 
  Contains Nonbinding Recommendations 
 	  The draft guidance for industry Expedited Programs for Serious ConditionsDrugs and 
Biologics is a single resource for information on the FDAs policies and procedures for 
fast track designation, breakthrough therapy designation, accelerated approval, and 
priority review designation.27  
                                                 
27  When final, this guidance will represent the FDAs current  thinking on this topic. 
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