A clinical trial is a culmination of the several stages of a drug or medical device development program that begins with the discovery of a candidate molecule followed by preclinical toxicology studies in ex vivo, in vitro, and animal models. Once the candidate molecule shows promising results in these stages, the next step involves clinical studies on human subjects. Drug testing in humans is often the most lengthy and expensive phase of the drug development timeline, and therefore requires extensive effort and careful execution to maximize the candidate’s chances of success. In addition to scientific evaluation, clinical studies require approval by the United States Food and Drug Administration (US FDA), the regulatory authority in the United States to administer the experimental drug in humans as well as ship it across state lines. This approval comes in the form of an Investigational New Drug (IND FDA) application that is required to be submitted by sponsors, investigators, or research institutes to the FDA to commence studies on human participants. The following figure shows the various stages of the drug development program (Figure 1) marking IND submission on the timeline. The US Food and Drug Administration (FDA) has established a comprehensive drug development strategy for US FDA. This strategy is designed to ensure that the drugs being developed meet the highest standards of safety and efficacy.The IND is a comprehensive document that contains all the information gained from preclinical and other studies in an organized format. The FDA reviews and makes the decision to support further clinical studies from information in the IND that ultimately forms the basis of marketing approval. INDs can be submitted at any phase during clinical development to protect the safety and rights of subjects (Phase I) and to assure adequate scientific evaluation of the drug’s effectiveness and safety (Phase II and III). The Code of Federal Regulations CFR Title 21. Part 312 Investigational New Drug Application contains information on INDs as well as their content and format and should be reviewed thoroughly by sponsors or investigators prior to submission of an IND application. The IND data requirements are important for the development of new drugs and medical devices. They provide detailed information about the safety and efficacy of a drug or device before it can be approved for use by the public

1. IND Data Requirements and US FDA Submission
Table of Contents
​ Why is an IND required?
​ There are two main types of INDs:
​ Commercial IND:
​ Research IND:
​ Emergency use IND:
​ When do I need to submit an IND?
​ IND content and format
​ Module 1-Regional and administrative information
​ Module 2-Summaries
​ Module 3-Quality
​ Module 4-Nonclinical study reports
​ Module 5-Clinical study report

2. IND Submission Process to the US FDA
A clinical trial is a culmination of the several stages of a drug or medical
device development program that begins with the discovery of a
candidate molecule followed by preclinical toxicology studies in ex vivo, in
vitro, and animal models. Once the candidate molecule shows promising
results in these stages, the next step involves clinical studies on human
subjects. Drug testing in humans is often the most lengthy and expensive
phase of the drug development timeline, and therefore requires extensive
effort and careful execution to maximize the candidate’s chances of
success. In addition to scientific evaluation, clinical studies require
approval by the United States Food and Drug Administration (US FDA),
the regulatory authority in the United States to administer the
experimental drug in humans as well as ship it across state lines. This
approval comes in the form of an Investigational New Drug (IND FDA)
application that is required to be submitted by sponsors, investigators, or
research institutes to the FDA to commence studies on human
participants. The following figure shows the various stages of the drug
development program (Figure 1) marking IND submission on the timeline.
The US Food and Drug Administration (FDA) has established a comprehensive drug
development strategy for US FDA. This strategy is designed to ensure that the drugs
being developed meet the highest standards of safety and efficacy.

3. Figure 1. Schematic representation of drug development stages
Why is an IND required?
The IND is a comprehensive document that contains all the information
gained from preclinical and other studies in an organized format. The
FDA reviews and makes the decision to support further clinical studies
from information in the IND that ultimately forms the basis of marketing
approval. INDs can be submitted at any phase during clinical
development to protect the safety and rights of subjects (Phase I) and to
assure adequate scientific evaluation of the drug’s effectiveness and
safety (Phase II and III). The Code of Federal Regulations CFR Title 21.
Part 312 Investigational New Drug Application contains information on
INDs as well as their content and format and should be reviewed
thoroughly by sponsors or investigators prior to submission of an IND
application.
The IND data requirements are important for the development of new drugs and
medical devices. They provide detailed information about the safety and efficacy of a
drug or device before it can be approved for use by the public

4. There are two main types of INDs:
● Commercial IND:
These are submitted by sponsors with the intent to commercialize the
product at a later stage
● Research IND:
These are submitted by investigators or research institutions that do not
intend to commercialize the product
● Emergency use IND:
Allows FDA to authorize the use of a drug in an emergency for which
there is no comparable treatment and that does not follow the exact
format for the submission of an IND according to 21 CFR Section 312
When do I need to submit an IND?
An IND should be submitted when planning to test a new drug in humans,
when planning to use an approved drug for an indication that has not
been in the approved labeling, when administered at a different dosage
or by a different route of administration, and when administered to a
different population (unless certain exemptions apply).
IND content and format

5. As of 2018, commercial use INDs must be submitted using the electronic
Common Technical Document (eCTD) format for acceptability by the
FDA. The eCTD attempts to harmonize marketing application structure
and format in the US, EU, Japan, and other countries adhering to
International Council for Harmonisation (ICH) guidelines and helps to
save on paper and storage resources for documents.
INDs must contain information from three main areas: animal
pharmacology and toxicology, manufacturing information, and clinical
protocols and investigator information (Figure 2).
Figure 2. Information required for IND application

6. The eCTD format for the IND application contains 5 modules with specific
information in each (Figure 3).
The information that sponsors/investigators must submit in an IND
application based on 21CFR 312.23 can be arranged in the CTD format
as follows and should contain:
Module 1-Regional and administrative information
● Cover letter (FDA 1571)-sponsor details, phase of a clinical trial,
details about clinical trial investigators and monitors, contract
research organization (CRO) details, IRB information
● Table of contents-introductory statement and general
investigational plan, along with information on previous human
experience with the drug, investigational marketing experience,
and withdrawal information (if applicable) and plan for investigation
for one year
● FDA 3674-certification of compliance with requirements
ClinicalTrials.gov data bank
● Labeling-a copy of all labels and labeling to be provided to each
investigator

7. ● General Investigational Plan-contains information about the drug
such as structural formula, pharmacological class, dosage form
and dose, route of administration, and duration of the trial
● Investigator’s brochure-contains information on the drug substance
and formula, a summary of pharmacological and toxicological
effects in animals and humans (if known), a summary of
pharmacokinetics and biological disposition in animals and
humans (if studies), safety and effectiveness in humans from prior
clinical studies, possible risks, side effects, and precautions or
special monitoring as per expected adverse events based on prior
experience with the drug or similar drugs
● Module 2-Summaries
● Quality overall summary-this includes information about the
drug substance such as general information (nomenclature,
structural formula), manufacture, characterization, control of
drug substance, reference standards or materials,
container-closure, and stability. Drug product data must
contain description, pharmaceutical development,
manufacture, control of excipients and drug product,
reference standard or material, container closure, and
stability.
● Nonclinical overview-the aim of this section is to present
data to ensure the safe use of the experimental drug in
humans taking the pharmacological, pharmacokinetic, and
toxicological studies into consideration.
● Pharmacology and pharmacokinetic studies:
include pharmacokinetic, toxicokinetic, and
metabolism studies with the methods used and
analytical methods. Interspecies comparisons of
metabolism and pharmacokinetic parameters (AUC,
Cmax), and limitations for extrapolation of animal data
to humans should be discussed.
● Toxicology studies: onset, severity, and duration of
toxic effects, dose-dependency, reversibility (or
irreversibility), and species and gender differences.
Genotoxicity, carcinogenicity, toxic signs, causes of
death, pathologic findings, pre-and postnatal toxicity,
the safety of the drug during pregnancy and
lactation, and local tolerance. Information Type of
animal species, number of animals, route of
administration and dosages, duration of treatment,
and systemic exposure should be included.

8. ● Nonclinical summary-this includes written and tabulated
summaries for pharmacology, pharmacokinetic, and
toxicology studies
● Pharmacology written summary and tabulated
summary-primary pharmacodynamics studies with other
drugs in the class, secondary pharmacodynamic studies
summarized by organ systems, safety pharmacology
studies, and pharmacodynamic drug interactions. The
tabulated summary should contain information organized
into sections such as test system, method of administration,
dose, species/strain, gender, organ systems evaluated, etc.
● Pharmacokinetics written summary and tabulated
summary-method and validation parameters for the
analytical procedure used for biological samples in the
study, absorption studies (in vitro extents and rate, BA/BE
studies), distribution studies (tissue distribution, protein
binding, and placental transfer studies), metabolism studies
(metabolic pathways, pre-systemic metabolism, P450 in
vitro studies, enzyme induction and inhibition), excretion
studies (route and extent, excretion in milk),
pharmacokinetic drug interactions. The tabulated summary
should include data under the following headings species,
vehicle/formulation, gender, dose, method of administration,
sample, analyte, assay, feeding condition, and sampling
time(s).
● Toxicology written summary and tabulated
summary-single-dose toxicity (species, route),
repeated-dose toxicity (species, route, duration),
genotoxicity (in vitro mammalian and non-mammalian
system, in vivo mammalian system), carcinogenicity studies
(long-term and short-term), reproductive and developmental
toxicity, local tolerance, and other studies (immunogenicity,
antigenicity, dependence, studies on
impurities/metabolites). Tabulated summaries should
include the species/strain, dose, route of administration,
duration, observed maximum non-lethal dose, and any
noteworthy findings.
● Clinical overview includes the product development
rationale (pharmacological class, target indication, current
major therapies, summary of ongoing and planned clinical
studies), biopharmaceutics (bioavailability issues related to
formulations), clinical pharmacology (pharmacokinetics:
comparative PK related to intrinsic and extrinsic factors,
absorption, protein binding, metabolic pathways,

9. pharmacodynamics: mechanism of action and receptor
binding, PK/PD relationships, genetic differences,
immunogenicity, and clinical microbiology), efficacy data
(relevant patient population, study design, endpoint (s),
controls, statistical methods), safety (adverse effects and
monitoring, animal toxicology, overdose reactions), benefits
and risks.
● The clinical summary-This section generally includes a
tabulated summary and comparison of individual studies
related to biopharmaceutics and analytical methods, clinical
pharmacology, clinical efficacy, and clinical safety.
●
● Module 3-Quality
This module contains chemistry, manufacturing, and control data for the
drug substance and drug product.
● Drug substance-general information (name, manufacturer),
nomenclature (CAS no., chemical name), structure (formula and
stereochemistry), general properties (pH/pKa, solubility, melting
point, hygroscopicity, polymorphic form), manufacturer’s name and
address, description of the manufacturing process and controls
(schematic flow diagram of process, raw materials, catalysts,
solvents, pH, critical steps, equipment, and operating conditions),
control of raw materials and solvents, control of critical steps and
intermediates with acceptance criteria process validation and
evaluations, and manufacturing process equipment. Specification
criteria for drug substance, analytical procedures and validation
criteria, batches and batch analyses, and specification, reference
standards and materials, container-closure system description,
and tabular listing of stability protocol and studies
● Drug product description of drug product, dosage, composition,
type of container system, drug substance, excipients, formulation
development, results from in vitro/in vivo comparative studies,
physicochemical and biological properties relevant to performance
(pH, dissolution, particle size, flow properties, rheology, potency,
polymorphism, biological activity, etc.), manufacturing process
development (key validation parameters), container closure
systems microbiologic attributes, compatibility, batch formula,
description of the manufacturing process and controls, process

10. validation, excipient controls, stability data (stress testing,
photostability tests)
● Module 4-Nonclinical study reports
This section involves the organization of nonclinical study reports which
include pharmacology (primary and secondary pharmacodynamics,
safety pharmacology, and pharmacodynamic drug interactions),
pharmacokinetics (analytical methods and validation reports, absorption,
distribution, metabolism, excretion, pharmacokinetic drug interactions),
toxicology (single-dose, repeat dose, genotoxicity, carcinogenicity,
reproductive and developmental toxicity, local tolerance, and other
toxicity studies such as antigenicity, immunogenicity, tolerance,
immunotoxicity, etc.), and literature references.
● Module 5-Clinical study reports
This section involves the organization of clinical study reports which
include biopharmaceutic study reports (bioavailability study, comparative
BA/BE studies, In vitro-in vivo correlations, bioanalytical and analytical
methods), PK study reports (plasma protein binding, hepatic metabolism
and drug interactions, human biomaterial studies), human PK studies
(healthy subject and patient PK and tolerability reports, intrinsic and
extrinsic factor PK reports, population PK report), human PD reports
(healthy subject and patient PK/PD reports), efficacy and safety reports
(controlled and uncontrolled clinical study reports,), reports of
post-marketing experience, case report forms and individual patient
listings, and literature references.

11. IND Submission Process to the US FDA
An IND can be submitted by the sponsor/investigator at any phase of the
clinical trial stage but must be submitted prior to testing the experimental
drug in human participants. Figure 4 shows the steps for submission of
the IND application to the FDA using the eCTD format for electronic
submissions.
Figure 4. Submission process to FDA using the electronic system for
INDs
Following receipt of the eCTD submission to the FDA, the FDA has a
30-day period to respond. The FDA can be in constant communication
during this period to clarify any concerns or doubts about the study. If
there is no response from the FDA during this window, the study can
proceed. Otherwise, the FDA can place the study on partial hold or
clinical hold which can be due to inadequate data in the submitted IND or
safety concerns. It is the responsibility of the sponsor/investigator to
address questions that the FDA has posed and respond to these in a
separate submission to the FDA. The FDA can either lift the clinical hold

12. allowing the clinical investigation to proceed, place the study on partial
hold (with certain restrictions), or continue the hold.
In addition to submitting the initial IND, the sponsor/investigator must
keep the IND current and submit any amendment to the IND such as
protocol amendments, safety reports, and IND annual reports.
Thus, a thorough and clear understanding of the requirements for an IND
especially in the eCTD format that is recommended by the FDA is
necessary to maximize chances for a smooth transition of experimental
drugs to the clinical trial phase. Furthermore, reviewing the FDA
submission process and maintaining contact with the FDA is essential in
updating the IND and protecting patient safety in case of any adverse
events or protocol deviations.
References
● Understanding FDA Regulatory Requirements for Investigational
New Drug Applications for Sponsor-Investigators – PMC (nih.gov)
● M4E(R2): The CTD — Efficacy Guidance for Industry (fda.gov)
● Quality Overall Summary (QOS) in eCTD format
(triphasepharmasolutions.com)
● Investigational New Drug (IND) Application | FDA
● Submit Using eCTD | FDA