Initial IND submission

Introductory Statement

Briefly describe the research plan submitted in this IND. This section should be 2-3 pages long. This should include a brief discussion of the disease state to be assessed. The intent of this section is to place the use of the drugs with this indication into perspective for the FDA.
Refer to 21 CFR 312.23(a)(3)

Name of the Drug and All Active Ingredients

Include all known names of the drug: generic and marketed names, chemical name.

Pharmacological Class of the Drug

Include the pharmacological class of the drug.

Structural Formula of the Drug

Both the structural and chemical formulas should be here.

This section may not be applicable to biologics. You could describe the protein or complex of proteins instead (e.g. 341 amino acids with a molecular weight of 150 g/mol)

Formulation of the Dosage Form(s) to be Used

Include a brief description of the formulation and dosage. Describe formulations/dosages of every active component of a combination therapy.

Include placebo information, if applicable.

Route of Administration

Briefly describe the route of administration and the planned exposure (ie duration of study drug administration).

Objectives and Duration of the Proposed Clinical Investigation(s)

If more than one protocol is being submitted under this IND, detail each separately, and clearly indicate that there is more than one planned investigation.

Summary of Previous Human Experience

This is a brief summary of previous human experience with the drug(s), with reference to the relevant literature or other INDs, if pertinent. Also, investigational or marketing experience in other countries may be relevant to the safety of the proposed clinical investigation(s). This topic will be written up in detail in the Previous Human Experience section; however, for many sponsor-investigator INDs that use commercially available drugs, the summary included in the Introduction and Previous Human Experience section are often identical.

If an IND application or other document previously submitted to the FDA is to be referenced, then the sponsor must identify the file/document by:

In order to reference an IND application previously submitted by others (i.e. other sponsor's INDs), such a reference is required to contain a written statement that authorizes the reference and that is signed by the person who submitted the referenced information.

Status of Drug in Other Countries

This section is likely not applicable to a standard sponsor-investigator IND submission. If the drug has been withdrawn from investigation or marketing in any country for any reason related to safety or effectiveness, identification of the country(ies) where the drug was withdrawn and the reasons for the withdrawal are stated here. For a sponsor-investigator IND, you may simply state you are not aware of any withdrawals.

References

List any references used in this section.

As the studies contained in this IND progress from phase 1 to phases 2 and 3, the contents of this section will change. For the purpose of the initial submission, provide information that will be relevant for the first year of investigation. Changes to the plan and additional protocols can be included in future annual reports and amendments.

Rationale

The rationale for the drug and/or research study. Provide enough background information on the topic for the FDA to understand the scientific justification for the investigation.

Indication to be Studied

Identify the indication to be studied in this investigation. Describe sub-sets of a more general study population if needed.

General Approach for Evaluation of Treatment

Provide a high-level description of data to be collected and its use in evaluation of the efficacy of the intervention being studied.

Description of First Year Trial(s)

The FDA understands that study plans may change over time. In this section provide a high-level description of the plan for the first 12 months of clinical investigation.

Number of Subjects to be Evaluated

Provide the planned number of subjects to be enrolled in the first year of IND activity.

Drug Related Risks

Any risks of particular severity or seriousness anticipated on the basis of the toxicological data in animals or prior studies in humans with the drug(s) or related drugs. Include any study procedures that carry risks of more than minimal severity.

References

List any references used in this section.

For sponsor-investigator initiated INDs, there is no requirement to produce an Investigator Brochure if you have a single site study. You may incorporate the following statement:

If an approved drug is being investigated, then it is appropriate to refer to the labeling and provide a URL link to the most current product label. You may find these links useful for finding current product labeling:

• DailyMed
• Drugs@FDA: FDA Approved Drug Products

You may also reference Letters of Authorization in this section.

Multi-Site Investigations

If there will be a multi-center (external site) clinical investigation under a University-based, sponsor-investigator IND application, an Investigator's Brochure should be developed for dissemination to each of the involved study sites and should address the following information:

• A brief description of the active drug substance and the drug product formulation, including the structural formula of the active drug substance, if known.
• A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans.
• A summary of the pharmacokinetics and biological distribution of the drug in animals and, if known, in humans.
• A summary of information relating to the safety and effectiveness of the drug in humans obtained from prior clinical studies. (Reprints of published articles describing such studies may be appended to the Brochure if they are anticipated to be useful.)
• A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug.

Provide a protocol and informed consent document for each planned study.

Study Protocol

The NIH and FDA have developed a protocol template with guidance and example text to assist investigators when applying for an IND.

Refer to 21 CFR 312.23(6) for complete protocol requirements. The general summary of the overall research plan should be followed by the "Executive Summary" section(s) of the protocol template (or some similar brief protocol summary) for each protocol to be included in this IND application. The actual full protocol(s) is/are to be included as an attachment to this application (see last section below describing attachments).

Due to the unpredictable nature of Phase 1 studies, Phase 1 protocols can be flexible and more focused on providing a general outline of the clinical investigation (dosing plan, safety precautions). Additionally, following IND approval, changes to Phase 1 protocols that do not affect the safety of subjects need only be included in IND annual reports, not more frequent amendments.

The main components of a clinical protocol are described in Guidance for Industry – E6 Good Clinical Practice: Consolidated Guidance . Some of the information listed in this guidance document may be contained in other protocol referenced documents, such as the IB.

The NIH-FDA Protocol Template is a highly recommended template that guides investigators through the information that should be included in a protocol.

Informed Consent

Informed consent documents (ICD) do not need to be included in the IND submission, but it is recommended that they be included. If a sponsor does not submit an ICD as part of its IND submission, the review division may request and review the ICD at any time. The request will reference 21 CFR 312.23(a)(11) , which states that if requested by the FDA, the sponsor must submit "any other relevant information needed for review of the application."

Informed consent documents are institution-specific but all forms will address the same required topics. Some guidelines are listed below to assist in drafting an informed consent document:

Informed Consent Checklist

• Required Elements
  • A statement that the study involves research
  • An explanation of the purposes of the research
  • The expected duration of the subject's participation
  • A description of the procedures to be followed
  • Identification of any procedures which are experimental (i.e., not standard of care)
  • A description of any reasonably foreseeable risks or discomforts to the subject (ideally subdivided by frequency and severity)
  • A description of any benefits to the subject or to others which may reasonably be expected from the research
  • A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject
  • A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained
  • For research involving more than minimal risk, an explanation as to whether any compensation, and an explanation as to whether any medical treatments are available, if injury occurs and, if so, what they consist of, or where further information may be obtained
  • An explanation of whom to contact for answers to pertinent questions about research subjects' rights, about the research and in the event of research-related injury.
  • A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits, to which the subject is otherwise entitled
  • Include clinicaltrials.gov language
  • FDA-regulated clinical investigations: Subjects must be informed that the FDA may inspect the records of the study.
• Additional elements
  • A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant), which are currently unforeseeable
  • Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent
  • Any additional costs to the subject that may result from participation in the research
  • The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject
  • Statement that significant new findings developed during the course of the research, which may relate to the subject's willingness to continue participation, will be provided to the subject
  • The approximate number of subjects involved in the study
• For bio-specimen collection consider including the following in the informed consent documents
  • A clear description of the operation of the bio-specimen resource. This description could include details that may be of interest to human research participants, such as whether identifiable information will be maintained by the bio-specimen resource and/or whether research results will be linked to the bio-specimen.
  • The conditions under which samples and data will be released to recipient investigators. Procedures for protecting the privacy of human research participants and confidentiality of data.
  • Specific descriptions of the nature and purpose of the research.
  • Information about the consequences of DNA typing if human genetic research is anticipated.
• Core Elements of HIPAA Authorization
  • Specific and meaningful description of what will be used or disclosed.
  • The name or other specific identification of the person, or class of persons, authorized to make the use or disclosure.
  • The name or other specific identification of the person, or class of persons, to whom the covered entity may make the requested use or disclosure.
  • A description of each purpose of the requested use or disclosure.
  • An expiration date/expiration event that relates to the individual or the purpose of the use or disclosure.
  • Statement regarding the right of the individual to revoke the authorization in writing, and the limits of that right.
  • Statement regarding the right of the individual to refuse to sign authorization
  • Statement regarding ability or inability to condition treatment, payment, enrollment or eligibility for benefits on the authorization
  • Re-disclosure Statement - Information disclosed to others not subject to the Privacy Rule may be re-disclosed by them without the Privacy Rule protections (cannot promise that information will definitely be protected)

Disclaimer:

Informed Consent documents should be written in such a way that they can be understood by the general public. Language should be targeted at a 5th grade reading level. It is advisable to keep the document concise for the benefit of the reader.

If the investigation involves an exception from informed consent requirements, this should be stated and the reasoning explained.

For more detailed information on informed consent regulations, check Guide to Informed Consent - Information Sheet .

Investigator and Facilities Data

Provide the name, address, and a statement of the qualifications (curriculum vitae or other statement of qualifications) of each investigator as well as the name of each sub-investigator (i.e., research fellow, resident) working under the supervision of the investigator. Also needed are the name(s) and address(es) of the research facility(ies) to be used as well as the name and address of each reviewing Institutional Review Board (IRB).

The information needed for this section is provided to the FDA on the Form FDA 1572 along with copies of the sponsor-investigator's CV, medical license, and financial disclosure forms (Form FDA 3454 and Form FDA 3455; see below for additional guidance). While not required, the sponsor-investigator may also provide copies of the CVs, medical or other professional licenses (if applicable), and financial disclosure forms (Form FDA 3454 and Form FDA 3455) for all sub-investigators listed in Box 6 of the Form FDA 1572. If the sponsor-investigator chooses not provide the sub-investigators' information in the application, the applicant MUST maintain copies of this documentation in an IND regulatory binder. Additional guidance on the completion of the FDA forms for this section as well the website where fillable PDF forms can be found are provided below.

The FDA forms, CVs, and licenses may either 1) be placed after the appropriate subheading in this section or 2) placed in the Attachments.

Form FDA 1572

Insert completed Form FDA 1572, or indicate "Signed and dated Form FDA 1572 in Attachments."

Disclosure of Financial Interests

IND sponsors are not required to submit information regarding clinical investigator financial interests or arrangements in IND applications. They are, however, required to collect this information before a clinical investigator participates in a clinical study and clinical investigators are required to disclose financial information to sponsors. The information does not need to be submitted to FDA until a marketing application is submitted containing the results of the covered clinical study.

Chemistry, Manufacturing and Control

If the investigational drug has been marketed, this section may be covered by referring to the product labeling. You may refer back to the URL identified in the Investigator's Brochure section. Alternatively, it might be appropriate to refer to a 'Letter of Authorization' if using a drug provided by a commercial company.

This section describes the composition, manufacture, and control of the drug substance and the drug product according to 21 CFR 312.23(7) . Note: Reference to the current edition of the United States Pharmacopoeia – National Formulary may satisfy relevant requirements in this section.

Drug Substance

• Description of drug; include physical, chemical, or biological characteristics and evidence supporting structure and identity of the active pharmaceutical ingredient(s)
• Name and address of manufacturer of drug product
• Description of the general method of preparation of the drug substance, including a list of the reagents, solvents, and catalysts used. A detailed flow diagram is suggested as the most effective presentation. More information may be needed to assess the safety of biotechnology-derived drugs or drugs extracted from human or animal or plant sources
• The acceptable limits and analytical methods used to ensure the identity, strength, quality, and purity of the drug substance, with a brief description of the test methods used (i.e., Nuclear Magnetic Resonance, Infrared, UV spectra to prove the identity, and High Performance Liquid chromatograms to support the purity level and impurities, etc.). Submission of certificates of analysis is also suggested.
• Information to support stability of the drug substance during storage in the intended container closure and during the toxicological and clinical studies

Drug Product

• List all components used in the manufacture of the investigational drug product, including both those components intended to appear in the drug product and those which may not appear but which are used in the manufacturing process
• Where possible, the quantitative composition of the investigational drug product, including any reasonable variations that may be expected during the investigational stage
• Brief general description of the manufacturing process (in the form of a flow diagram is suggested) and packaging procedure, as well as other relevant tests, as appropriate for the product. Final specifications for the drug product intended to be used in toxicological and clinical studies should be included. For injectable products, sterility and pyrogenicity tests, endotoxin levels and particulate matter should be included. Submitting a copy of the certificate of analysis of the clinical batch is also suggested. Information sufficient to assure the product's stability during the planned clinical studies.
• The acceptable limits and analytical methods used to ensure the identity, strength, quality, and purity of the drug product
• Information to support stability of the drug product during the planned clinical studies

Placebo Product

Note: Delete this section if not applicable

Include a brief general description of the composition, manufacture, and control of any placebo used in the controlled clinical trial.

Labeling

Include copies of the label constructed for the study drug and any associated package.

Note: Labels must contain the phrase: "Caution: New Drug - Limited by Federal law to investigational use".

Environmental Assessment

Insert the statement below, unless there is a reason to believe the distribution and use of the drug could have an environmental impact. The FDA may require an environmental analysis to ensure the study agent does not impose an undue environmental hazard {21 CFR 312.23(7)(e) }. For products already marketed, it may be possible to request and exemption from the requirement to conduct an environmental analysis. Details around the expectation of the FDA for this section should be discussed in the pre-IND meeting held between the sponsor-investigator and the FDA to discuss the IND application.

For more detailed information, take the FDA "Chemistry, Manufacturing, and Controls (CMC) Perspective of the IND" Training Course .

As was true for the Chemistry, Manufacturing and Controls section, you may use an authorization letter(s) or cite the drug label to satisfy this section.

Per 21 CFR 312.23(8) , this section is expected to include information about pharmacological and toxicological (laboratory animals or in vitro) studies on the basis of which the sponsor of the IND application has concluded that it is reasonably safe to conduct the proposed clinical investigations. The kind, duration, and scope of animal and other studies required in the application will depend on the duration and nature of the proposed clinical investigations. For recommendations regarding study types and duration, refer to the FDA Guidance for Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals .

Compliance with Good Laboratory Practice (GLP) is generally expected for pivotal in vitro and in vivo studies submitted in support of an IND application. For each non-clinical laboratory study subject to the GLP regulations, investigators are expected to state in the study report that the study was conducted in compliance with the GLP regulations. If the study was not conducted in compliance with the GLP regulations, investigators should submit a brief statement of the reason for noncompliance. FDA Guidance documents relevant to Pharmacology and Toxicology information are available at the FDA website.

The IND sponsor should also provide a statement describing where the non-clinical investigations were conducted and the location of all records available for inspection.

Pharmacology and Drug Distribution

• Description of the pharmacologic effects and mechanism(s) of actions of the drug in animals
• Information on the absorption, distribution, metabolism, and excretions of the drug

Note: The regulations do not further describe the presentation of these data, in contrast to the more detailed description of how to submit toxicological data. A summary report, without individual animal records or individual study results, usually suffices. In most circumstances, five pages or less should suffice for this summary. If this information is not known, it should simply be so stated.

Pharmacology Summary and Conclusions

Provide high-level summary and general conclusions to be drawn from the pharmacology data.

Toxicology: Integrated Summary

This section should include an integrated summary of the toxicological effects of the drug in animals an in vitro {21 CFR 312.23(8)(ii)(a) }. For this section, refer to discussions in the FDA Pre-IND meeting, where the FDA will clarify guidance and requirements for your submission.

Expected content elements for describing specific toxicology studies for this section typically include:

• Study title
• Study drug formulation/vehicle
• Brief description of the design of the trials
• Dosing
• Systematic presentation of the findings from the animal toxicology and toxicokenetic studies. The format of this part of the summary may be approached from a "systems review" perspective: i.e. CNS, cardiovascular, gastrointestinal, renal, hepatic, genitourinary, hematopoietic and immunologic, and dermal.
• Provide high-level summary and general conclusions of the preceding toxicology findings.
• Identification and qualifications of the individual(s) who evaluated the animal safety data and concluded that it is reasonably safe to begin the proposed human study. This person(s) should sign the summary attesting that the summary accurately reflects the animal toxicology data from the completed studies.
• A statement of where the animal studies were conducted and where the records of the studies are available for inspection, should an inspection occur.
• According to 21 CFR 312.23(8)(iii) , a statement that the study was conducted in compliance with the good laboratory practices (GLP) in 21 CFR 58 , or, if the study was not conducted in compliance with those regulations, a brief statement of the reason for the noncompliance and the sponsor's view on how such noncompliance might affect the interpretations of the findings.

Toxicology: Full Data Tabulation

The sponsor should submit, for each animal toxicology study that is intended to support the safety of the proposed clinical investigation, a full tabulation of data suitable for detailed review. This should consist of line listings of the individual data points, including laboratory data points, for each animal in these trials along with summary tabulations of these data points. To allow interpretation of the line listings, accompanying the line listings should be either: 1) a brief description (i.e., a technical report or abstract including a methods description section) of the study, or 2) a copy of the study protocol and amendments.

A summary of previous human experience with the drug known to the applicant. If the drug(s) is already marketed in the US, then you may be able to simply refer to the product labeling.

There is no specific format for describing previous human experience with an investigational drug in an IND application; however, the FDA website provides helpful points to consider when writing a summary of previous human experience .

If the drug is a combination of drugs previously investigated or marketed, the information should be provided for each active drug component. However, if any component in such combination is subject to an approved marketing application or is otherwise lawfully marketed in the United States, the sponsor is not required to submit published material concerning that active drug component unless such material relates directly to the proposed investigational use (including publications relevant to component- component interaction).

If there is no data on previous human experience for this drug, insert a statement reflecting that under each subheading.

Marketed Experience

Overview any FDA-approved marketed indications for the study drug. Reference to the FDA drug labeling for approved indications should be noted here.

If the drug was withdrawn from the market for any reason related to safety or effectiveness, identify the country(ies) where the drug was withdrawn and the reasons for withdrawal.

Prior Clinical Research Experience

If the drug has been the subject of controlled trials, detailed information on trials that are relevant to an assessment of the drug's effectiveness for the proposed investigational use(s) should also be provided. Any published material that is relevant to the safety of the proposed investigation or to an assessment of the drug's effectiveness for its proposed investigational use should be provided in full. Published material that is less directly relevant may be supplied by a bibliography.

If there has been no previous human experience, the submission should so state.

Clinical Care Experience

Note: Delete this sub-section if not applicable.

It is not uncommon for marketed drugs to be used in clinical care settings to treat patients for indications that do not have an FDA approval. This is often termed "off-label" use. Any published literature on the safety of the drug in that setting, and if available, published practice guidelines of the use of the drug for standard-of-care and the associated safety information could be referenced here. This is particularly relevant if the patient population treated with this off-label use of the drug is similar to the proposed study population for this IND application.

References

List any references used in this section. Complete reprints of select articles may be provided to aid the FDA reviewers, but do not attach more than two to three reprints. Remember that FDA does not have access to all journal articles and so including selected reprints can help facilitate the review of an IND application.

In certain applications, as described below, information on special topics may be needed. Such information shall be submitted in this section as outlined below. Otherwise you may simply state 'not applicable'.

Drug Dependence and Abuse Potential

If the drug is a psychotropic substance or otherwise has abuse potential, a section describing relevant clinical studies and experience and studies in test animals.

If this section is relevant to your investigation, please see Guidance for Industry – Assessment of Abuse Potential of Drugs .

Radioactive Drugs

If the drug is a radioactive drug, sufficient data from animal or human studies should be provided, to allow a reasonable calculation of radiation-absorbed dose to the whole body and critical organs upon administration to a human subject. Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetry calculations.

If this section is relevant to your investigation, please see Medical Imaging and Drug Development .

Pediatric Studies

If the investigational drug will be studied in pediatric setting, plans for assessing pediatric safety and effectiveness should be provided.

If this section is relevant to your investigation, please see Pediatric Product Development .

Other Information

A brief statement of any other information that would aid evaluation of the proposed clinical investigations with respect to their safety or their design and potential as controlled clinical trials to support marketing of the drug.

Selected References

If you are including reprints with your submission, list them in this section.

If requested by FDA, any other relevant information needed for review of the application.