IND Application Notes
What is an IND?
An IND, or investigational new drug application, is a submission to the US Food and Drug Administration (FDA) requesting permission to initiate a clinical study of a new drug product in the United States.
From a legal perspective, the IND is a request for exemption from the Act that prohibits from introducing any new drug into interstate commerce without an approved application.
An IND allows you to legally ship an unapproved drug, or import a new drug from a foreign country.
When do I need an IND?
An IND is required anytime you want to conduct a clinical trial of an unapproved drug in the United States.
The term “drug” in this context also applies to an investigational biologic drug product and the exact same regulations for an IND apply equally to an investigational study for a new biologic product.
The Act defines a drug, in part, as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and articles (other than food) intended to affect the structure or any function of the body of man or other animals.”
The Act further defines a new drug, in part, as “any drug the composition of which is such that such drug is not generally recognized as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling.”
An IND would be required to conduct a clinical trial if the drug is:
A new chemical entity.
Not approved for the indication under investigation.
In a new dosage form.
Being administered at a new dosage level.
In combination with another drug and the combination is not approved.
When Don’t I Need an IND?
An IND is not required to conduct a study if the drug:
Is not intended for human subjects, but is intended for in vitro testing or laboratory research animals (nonclinical studies).
Is an approved drug and the study is within its approved indication for use.
The regulations also exempt studies of approved drugs if all of the following criteria are satisfied:
The study will not be reported to the FDA in support of a new indication or other change in labeling or advertising for the product.
The study will not involve a route of administration, dose level, or patient population that increases the risks associated with the use of the drug.
The studies will be conducted in compliance with the Institutional Review Board (IRB) and informed consent regulations.
The studies will not be used to promote unapproved indications.
The IND regulations also provide an exemption for studies that use placebos, as long as the study would not otherwise require submission of an IND.
Finally, an IND is not required for bioequivalence studies in humans to support a generic drug application (ANDA, Abbreviated NDA), if the test and reference product will be dosed at or below the recommended dose and there is no additional risk associated with the conduct of the study.
Pre-IND Meeting
Frequent meetings between the sponsor and the FDA are useful in resolving questions and issues raised during the preparation of an IND.
To promote efficiency, all issues related to the submission of the IND should be included to the extent practical, since the FDA generally expects to grant only one pre-IND meeting.
A pre-IND meeting is considered a type B meeting. It is a “formal” meeting requiring a written request that includes, among other things, a list of specific objectives and outcomes and a list of specific questions, grouped by discipline.
Type B meetings should be scheduled to occur within 60 days of the FDA’s receipt of the written request for the meeting. A briefing document is required at least four weeks before the meeting.
The briefing document should provide summary information relevant to the product and supplementary information that the FDA can use to provide responses to the questions that have been identified by the sponsor for the submission of the IND.
At the conclusion of the meeting, there should be a review of all the issues, responses, and agreements.
An assigned individual from the FDA, typically the project manager, will prepare the minutes of the meeting, and the FDA’s version of the minutes are considered the official version.
In general, they should be available to the sponsor within 30 days after the meeting but are often made available just before the meeting in draft to form the basis for any discussion.
The Content and Format of an IND Application
The content and format of an initial IND is laid out in 21 CFR Part 312 and in numerous guidance documents published by the FDA.
Since the FDA has adopted the common technical document (CTD) format for NDAs, it is also possible and strongly encouraged that sponsors consider submitting the IND in the CTD format.
The FDA is also strongly encouraging companies to submit the CTD document in electronic format.
The initial IND application to the FDA can be for a phase 1 first in human study, or it can be for a later-phase study where clinical studies of the compound have already been conducted in the United States or in another country and some clinical data already exist.
Cover Sheet—Section 312.23(a)(1)
The Form 1571 (Figure 2.1) is a required part of the initial IND and every subsequent submission related to the IND application.
Each IND Amendment, IND Safety Report, IND Annual Report, or general correspondence with the FDA regarding the IND must include a Form 1571.
Each submission to the IND must be consecutively numbered, starting with the initial IND application, which is numbered 0000.
The next submission (response to clinical hold, correspondence, amendment, etc.) should be numbered 0001, with subsequent submissions numbered consecutively in the order of submission.
Table of Contents—Section 312.23(a)(2)
This should be a comprehensive listing of the contents of the IND broken down by section, volume, and page number.
The table of contents (TOC) should include all required sections, appendices, attachments, reports, and other reference material.
Many sponsors begin planning the IND submission by laying out the TOC first.
Introductory Statement and General Investigational Plan—Section 312.23(a)(3)
This section should provide a brief, three- to four-page overview of the investigational drug and the sponsor’s investigational plan for the coming year.
The goal of this section is simply to provide a brief description of the drug and lay out the development plan for the drug.
The introductory statement should begin with a description of the drug and the indication(s) to be studied and include the pharmacologic class of the compound, the name of the drug and all active ingredients, the structural formula of the drug, the dosage form, and the route of administration.
Investigator’s Brochure—Section 312.23(a)(5)
The content and format of the investigator’s brochure (IB) is described in 21 CFR Section 312.23 (a)(5) and in greater detail in the “International Conference on Harmonization (ICH) E6 Good Clinical Practice” guidance document.
The IB is a key document provided to each clinical investigator and the IRB at each of the clinical sites.
The IB presents, in summary form, the key nonclinical (safety), clinical, and CMC (quality) data that support the proposed clinical trial.
The type and extent of information provided in the IB will be dependent on the stage of development of the drug product, but the IB must contain the following information:
A brief summary of the CMC information, including the physical, chemical, and pharmaceutical properties of the drug, and the chemical name and chemical structure, if known. It should also include a description of the formulation and how the drug is supplied, as also the storage and handling requirements.
A summary of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and drug metabolism information generated to support human clinical studies. It should include a tabular summary of each nonclinical study conducted, outlining the methodology used and the results of each study.
If human clinical studies have been conducted with the drug, a summary of information relating to safety and efficacy should be presented, including any information from those studies on the metabolism, pharmacokinetics, pharmacodynamics, dose response, or other pharmacologic activities.
A summary of data and guidance for the investigator in the management of subjects participating in the trial.
An overall discussion of the nonclinical and clinical data presented in the IB and a discussion of the possible risks and adverse reactions associated with the investigational drug product and the specific tests, observations and precautions that may be needed for the clinical trial.
Clinical Protocol—Section 312.23(a)(6)
As with the IB, the content and format of the protocol is described in 21 CFR Section 312.23 and in greater detail in the “ICH E6 Good Clinical Practice” guidance document and will not be 7 presented here. A clinical protocol describes how a particular clinical trial is to be conducted.
The initial IND is required to have a clinical protocol for the initial planned study.
However, the IND regulations specifically allow phase 1 protocols to be less detailed and more flexible than protocols for phase 2 or 3 studies.
The regulations state that phase 1 protocols should be directed primarily at providing an outline of the investigation: an estimate of the number of subjects to be included; a description of safety exclusions; and a description of the dosing plan, including duration, dose, or method to be used in determining dose.
Later-phase protocols should be more detailed than a phase 1 protocol and reflect that stage of development of the drug.
It should contain efficacy parameters, methods, and timing for assessing and analyzing the efficacy parameters and detailed statistical sections, describing the statistical methods to be employed and the timing of any planned interim analysis.
The regulations require any protocol submitted as part of an IND to contain the following elements.
A statement of the objectives and the purpose of the study
The name, address, and qualifications [curriculum vitae (CV)] of each investigator and each subinvestigator participating in the study; the name and address of each clinical site; and the name and address of each IRB responsible for reviewing the proposed study.
The criteria for study subject inclusion and exclusion and an estimate of the number of subjects to be enrolled in the study
A description of the study design, control groups to be used, and methods employed to minimize bias on the part of the subjects, investigators, and analysts
The planned maximum dose, the duration of patient exposure to the drug, and the methods used to determine the doses to be administered
A description of the measurements and observations to be made to achieve the study objectives
A description of the clinical procedures and laboratory tests planned to monitor the effects of the drug in the subjects
CMC Information—Section 312.23(a)(7)
This key section of an IND describes the quality information, comprising the composition, manufacturing process, and control of the drug substance and drug product.
The CMC section must provide sufficient detail and information to demonstrate the identity, quality, purity, and potency of the drug product.
The amount of information needed to accomplish this is based on the phase of the proposed study, the duration of the study, the dosage form of the investigational drug, and the amount of additional information available.
For a phase 1 IND, the CMC 6 information provided for the raw materials, drug substance, and drug product should be sufficiently detailed to allow the FDA to evaluate the safety of the subjects participating in the trial.
A key aspect to assuring the safety of the subjects participating in clinical trials is adherence to current good manufacturing practices (cGMPs).
For phase 2 studies, the sponsor should be able to document the manufacturing process that is controlled at predetermined points and yields products that meet the tentative acceptance criteria.
The regulations require the CMC section of an IND to contain the following sections:
CMC introduction
Information on the drug substance in the form of a summary report containing the following information:
A brief description of the drug substance and evidence to support its chemical structure.
The name and address of the manufacturer.
A brief description of the manufacturing process.
A brief description of the acceptable limits (specifications) and analytical methods used to assure the identity, strength, quality, potency, and purity of the drug substance.
Data to support the stability of the drug substance.
Information on the drug product in the form of a summary report containing the following information:
A list of all components used in the manufacture of the drug product, including components intended to be in the drug product and those that may not appear, but are used in the manufacturing process.
The name and address of the manufacturer of the drug product.
A brief, step-by-step description of the manufacturing and packaging procedures including a process flow diagram. For sterile products, a description of the sterilization process should be included.
A description of the proposed acceptable limits (specifications) for the drug product and the test methods used.
A description of the proposed container closure system and a brief description of the stability study and test methods.
Information on any placebo or comparator product that will be utilized in the proposed clinical study. This should include a brief written description of the composition, manufacture, and control of the placebo.
Copies of all proposed product labels and any other proposed labeling that will be provided to the investigators.
A claim for categorical exclusion from an environmental assessment.
Pharmacology and Toxicology Information—Section 312.23(a)(8)
The decision to proceed to the initial administration of the investigational drug to humans must include the careful conduct and review of the data from nonclinical in vivo and in vitro studies.
These data must provide a good level of confidence that the new drug product is reasonably safe for administration to human subjects at the planned dosage levels.
Generally, the following nonclinical safety studies are required before initiating phase 1 studies, and the results of these studies must be included in the IND:
Safety pharmacology studies (often conducted as part of the toxicity studies).
Single dose and repeat dose toxicity studies (duration of the repeat dose studies should equal or exceed the duration of the human clinical trials).
Genotoxicity studies (in vitro studies evaluating mutations and chromosomal damage).
Reproduction toxicity studies (Nonclinical animal studies conducted to reveal any effects the investigational drug may have on mammalian reproduction).
The pharmacology and toxicology information or safety section of the initial IND should contain the following elements.
A summary report describing the pharmacologic effects and mechanism of action of the drug and information on the absorption, distribution, metabolism, and excretion (ADME) of the drug.
An integrated summary of the toxicologic effects of the drug in animals and in vitro. The summary presents the toxicologic findings from completed animal studies that support the safety of the proposed human investigation.
Full data tabulations for each animal toxicology study supporting the safety of the proposed trial.
Previous Human Experience—Section 312.23(a)(9)
This section should contain an integrated summary report of all previous human studies and experiences with the drug.
The summary should focus on presenting data from previous trials that are relevant to the safety of the proposed investigation (e.g., PK and PD data, the observed AE profile in previous studies or other experiences, and ADME data) and any information from previous trials on the drug’s effectiveness for the proposed investigational use.
Additional Information—Section 312.23(a)(10)
This section is used to present information on special topics.
The following topics should be discussed, if relevant, in this section:
Drug dependence and abuse potential.
Radioactive drugs.
Pediatric studies.
Other information.
Relevant Information—Section 312.23(a)(11)
Any information specifically requested by the FDA that is needed to review the IND application.
Other Important Information about the Submission of an IND
For clinical studies that will be submitted as part of an NDA or BLA, an IND sponsor must collect financial disclosure information from each investigator or subinvestigator who is directly involved in the treatment or evaluation of clinical trial subjects.
Electronic Submissions
Under the recent reauthorized Prescription Drug User Fee Act (PDUFA), the FDA now strongly encourages that all application submissions, including INDs be submitted to the FDA in electronic CTD format.
FDA Review of the IND
When the initial IND submission is made to the FDA, it is logged in the Document Management Room and assigned an IND number.
Once the IND arrives at the review division, it is critically evaluated by several reviewers of chemistry, biopharmaceutics, medical, statistics, microbiology, and pharmacology/toxicology sections, as appropriate.
Once an IND is submitted, the study cannot be initiated until a period of 30 calendar days has passed, or if the FDA has given agreement to start the study before the 30-day period expires.
If there are any major issues relating to the safety of the volunteers or patients in the proposed study, the FDA can institute a clinical hold.
A clinical hold is an order issued by the FDA to the sponsor of an IND to delay or to suspend a clinical investigation.
Maintaining an IND—IND Amendments and Other Required Reports
Clinical development of a new drug will take a number of years and can take as many as 10 or 12 years, all the time requiring an active IND to conduct the necessary clinical studies.
Because of the long development times, the IND is continuously updated with new information and new protocols as the drug moves from one phase of investigation to the next.
The IND regulations discuss two types of amendments, protocol amendments and information amendments, and two types of required reports, safety reports and annual reports.
The IND Safety Report
The sponsor of an IND is responsible for continuously reviewing the safety of the investigational drug(s) under investigation.
IND regulations require each sponsor to review and investigate all safety information obtained about the drug regardless of the source of the information.
The FDA regulations (21 CFR Section 312.32) and the “ICH E6” guidance define an AE as 7 any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the investigational product, whether or not related to the investigational product.
Results in death.
Is life threatening.
Requires inpatient hospitalization or prolongation of an existing hospi tal ization.
Results in persistent or significant disability/incapacity.
Is a congenital anomaly/birth defect.
The IND regulations also require sponsors to notify all investigators and the FDA of certain types of safety events in an IND safety report.
The IND regulations discuss two types of safety reports: a 15-day report and a more urgent 7-day report.
The more urgent safety report, the seven-day report, is required when any unexpected fatal or life-threatening event associated with the use of the drug occurs.
The Protocol Amendment
A protocol amendment is submitted to the FDA when a sponsor wants to initiate a new clinical study that is not described in the existing IND or when the sponsor makes changes to an existing protocol, including adding a new investigator to a trial.
A protocol amendment for a new protocol must include a copy of the new protocol and a brief description of the most clinically significant differences between the new and previous protocols.
A protocol amendment is also required if a sponsor makes significant changes to an existing protocol.
The IND regulations allow a sponsor to immediately implement a change to a protocol if the change is intended to eliminate an immediate hazard to the clinical trial subjects.
A protocol amendment is required when a new investigator or subinvestigator is added to conduct the clinical trial at a new or an existing site.
Information Amendments
Information amendments are used to submit important information to the IND that is not within the scope of a protocol amendment, annual report, or IND safety report.
An information amendment may include new toxicology or pharmacology information, final study reports for completed nonclinical or other technical studies, new CMC information, notice of discontinuation of a clinical study, or any other information important to the IND.
IND Annual Reports
The IND regulations require IND sponsors to submit an annual report that provides the FDA 29 with a brief update on the progress of all investigations included in the IND.
The annual report must contain the following information:
Individual study information
Summary Information
The general investigational plan for the coming year.
A list of the changes along with a copy of the new brochure, if the IB was modified during the year.
Any changes made to the protocol not reported in a protocol amendment, if there is a phase 1 protocol.
A listing of any significant foreign marketing developments with the drug, for example, approval in another country or withdrawal or suspension of marketing approval.
A log of any outstanding business for which the sponsor requests or expects a reply, comment, or meeting with the FDA.
Other Types of INDs
In addition to the IND submitted by the commercial sponsor, there are investigator-sponsored INDs (Section 312.3).
They usually involve a single investigator who is performing a clinical trial and serving as the sponsor as well as the investigator.
Additionally, there are Treatment INDs (Section 312.320), allowing for the use of investigational drugs under expanded access.
These are reserved for investigational products for serious or immediately life-threatening diseases where no satisfactory alternative therapy is available.
Another type of IND is the screening IND (MaPP 6030.4) or exploratory IND.
Promotion and Charging for Investigational Drugs
Promotion of Investigational Drug Products
IND regulations specifically prohibit a sponsor or investigator from promoting or commercializing an investigational drug or stating that an investigational drug is safe or effective for the indication(s) under investigation.
Charging for Investigational Drugs
Charging for an investigational drug product in a clinical trial conducted under an IND is prohibited unless the sponsor has submitted a written request to the FDA, seeking permission to charge for the drug and the FDA has issued a written approval.
To maintain an IND, sponsors must continuously update it with new information, including protocol and information amendments, safety reports (15-day and 7-day),
Here are the definitions:
Clinical Hold: An order issued by the FDA to the sponsor of an IND to delay or suspend a clinical investigation.
IRB (Institutional Review Board): A committee established to review and approve research involving human subjects to ensure their protection.
IND Amendments: Updates to the IND with new information and new protocols as the drug moves from one phase of investigation to the next.
Protocol Amendment: Submitted to the FDA when a sponsor wants to initiate a new clinical study or make changes to an existing protocol, including adding a new investigator to a trial.
Information Amendment: Used to submit important information to the IND that is not within the scope of a protocol amendment, annual report, or IND safety report. May include new toxicology or pharmacology information, final study reports, new CMC information, etc.
IND Safety Report: A report for sponsors to notify all investigators and the FDA of certain types of safety events. Includes 15-day and 7-day reports.
IND Annual Report: A report that IND sponsors submit annually, providing the FDA with an update on the progress of all investigations included in the IND.
CMC (Chemistry, Manufacturing, and Controls): Information comprising the composition, manufacturing process, and control of the drug substance and drug product.
GMP (Good Manufacturing Practice): A system for ensuring that products are consistently produced and controlled according to quality standards.
GCP (Good Clinical Practice): An international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects.
DMF (Drug Master File): Submissions to the Food and Drug Administration (FDA) containing information that is not a requirement, but may be used to support new drug applications (
An IND, or investigational new drug application, is a submission to the US Food and Drug Administration (FDA) requesting permission to initiate a clinical study of a new drug product in the United States. An IND is required anytime you want to conduct a clinical trial of an unapproved drug in the United States. An IND is not required to conduct a study if the drug is not intended for human subjects, but is intended for in vitro testing or laboratory research animals (nonclinical studies).
An IND, or investigational new drug application, is a submission to the US Food and Drug Administration (FDA) requesting permission to initiate a clinical study of a new drug product in the United States.
An IND is required anytime you want to conduct a clinical trial of an unapproved drug in the United States.
An IND is not required to conduct a study if the drug is not intended for human subjects but is intended for in vitro testing or laboratory research animals (nonclinical studies). Also, an IND is not required if the drug is an approved drug and the study is within its approved indication for use. The regulations also exempt studies of approved drugs if all of the following criteria are satisfied:
The study will not be reported to the FDA in support of a new indication or other change in labeling or advertising for the product.
The study will not involve a route of administration, dose level, or patient population that increases the risks associated with the use of the drug.
The studies will be conducted in compliance with the Institutional Review Board (IRB) and informed consent regulations.
The studies will not be used to promote unapproved indications.
Finally, an IND is not required for bioequivalence studies in humans to support a generic drug application (ANDA, Abbreviated NDA), if the test and reference product will be dosed at or below the recommended dose and there is no additional risk associated with the conduct of the study..Indication is not required.