Regulatory Toolbox

The initial IND submission to the FDA will provide the reviewers with the information necessary to conduct a thorough evaluation of the safety of the investigation, and its scientific merit. The submission is divided into several sections. The summaries listed in this page will provide detailed instructions to prepare a complete IND submission.

Form FDA 1571

The purpose of the Form FDA 1571 is to:

1. obtain agreement from the sponsor (or sponsor-investigator) to conduct research according to all appropriate FDA regulations; and
2. serve as a cover sheet for all submissions to the FDA on behalf of a particular IND.

Form FDA 1571 should be completed for every submission sent to the FDA on behalf of a particular IND and should include the below:

• Contact information and mailing address of the Sponsor (or Sponsor Investigator)
• IND number, if it has been issued
• Serial number (see below)
• The name(s) of the drug/biologic and the indication being studied
• The contents of the submission
• Name and title of the individuals responsible for monitoring the study and reviewing safety data.

Form FDA 1572

The intent of the 1572 form is two-fold. It is a signed agreement from the Investigator (i.e., Principal Investigator) that he/she will conduct the research in compliance with FDA regulations. Additionally, it collects all the clinical site and investigator information needed by the sponsor to assure the FDA that all investigators have the experience and background needed to conduct the trial. The site investigator is responsible for updating his/her 1572 form and providing it to the sponsor in a timely manner so the information can be sent to the FDA. (Although it is not a requirement for the updated 1572 to be submitted to the FDA, it is the responsibility of the sponsor to provide updated information to the FDA; therefore the 1572 is often submitted to the FDA rather than providing information in another format.)

The Form FDA 1572 is necessary to include in an initial IND submission and must be filled out when adding a new principal investigator at each site.

• Please note that a 1572 must be submitted to the FDA within 30 days of the investigator being added and when changing any site information, i.e., IRB, laboratory, or clinical site.

Additional information to be provided:

• A current CV or statement of qualifications of the principal investigator listed on the 1572. It does not need to be signed.
• Name and address of the location where the clinical investigation will be conducted, the clinical laboratories that will be used, and the IRB reviewing the study.
• Names of the sub-investigators at the site
  • To note, it is not a requirement to fill out a new 1572 when there is a Sub-Investigator change as long as this information is sent in a timely manner to the sponsor. However, the 1572 is often used for updates to have all information in an organized place.

  Form FDA 3674 - Certification of Compliance

  The Form FDA 3674 is a document that must accompany the initial submission, and when submitting a new protocol to IND. It is a signed statement from the sponsor that they will comply with clinicaltrials.gov requirements concerning their investigation.

  It is a requirement for NIH trials to be registered on clinicaltrials.gov. OPS is responsible for registering studies on clinicaltrials.gov and the study team is responsible for updating this information when primary endpoints are met. Please see FDAAA 801 Requirements at clinicaltrials.gov for more information.

  Cover Letter

  The cover letter is the first piece of information that the FDA sees upon receipt of an Initial IND submission. It expresses the intent of the investigator to request FDA review of the enclosed information, and briefly describes the proposed research. It is the responsibility of the sponsor to compose the cover letter.

  Items to include in the cover letter:

  • The cover letter should be on departmental letterhead
  • Title the cover letter: "Initial Investigational New Drug Application"
  • Brief explanation of the investigation (i.e., use the study title)
  • Disease or condition being studied
  • Name, formulation, and proposed dose of drug product.
  • Contact information (phone, email, address) of the Sponsor and (recommended) a designated individual authorized to interact with the FDA on the Sponsors behalf.
  • Ensure the date of the cover letter matches the date on the signed copy of Form FDA 1571.
  • If the sponsor and FDA have already had a Pre-IND meeting, then this should be noted in the letter, and reference the PIND number and date of meeting.

  The cover letter can be short, ~ 1-2 pages, and should be addressed to either the appropriate CDER/CBER Division Director with a copy sent to the Division's Chief of Project Management staff or to the appropriate office contact within CDER/CBER. This should also be the mailing address for the entire submission:

  • For a Drug:
    Food and Drug Administration
    Center for Drug Evaluation and Research
    Central Document Room
    5901-B Ammendale Rd.
    Beltsville, Md. 20705-1266
  • For a Therapeutic Biological Product:
    Food and Drug Administration
    Center for Drug Evaluation and Research
    Therapeutic Biological Products Document Room
    5901-B Ammendale Road
    Beltsville, MD 20705-1266
  • For a Biological Product:
    U.S. Food and Drug Administration
    Center for Biologics Evaluation and Research
    Document Control Center
    10903 New Hampshire Avenue
    Silver Spring, MD 20993-0002

  Letter of Support / Authorization

  If a sponsor is proposing to evaluate a drug that is the subject of an existing IND, they can request a letter of cross-reference authorization from the sponsor of that existing IND. This permits the sponsor to refer the FDA to the information contained in the referenced IND, and maintain the confidentiality of their proprietary information. The FDA can use the original IND material, along with their own internal reviews of that material to assist in their review process. Additionally, an IND for a drug that has been approved by the FDA for commercial use, may require more information than what is provided in the package insert. Again, the sponsor may request a letter of cross-reference authorization from the commercial sponsor. Commercial sponsors should provide the IND, NDA, or BLA file name, reference number, volume, and page numbers where the FDA can find the information relevant to the referencing IND application. In general, INDs that are withdrawn or inactive cannot be cross-referenced.

  Sections of the Initial IND

  The initial IND submission to the FDA is broken down into several distinct sections. Each section addresses a topic necessary for FDA review. The links below will provide a detailed description of each section and provide guidance on what information should be included in the IND submission.

  The Investigator-Initiated Investigational New Drug (IND) Applications website has all the information to get from start to finish with an application to the FDA.

  Introduction

  The introduction should briefly describe the research plan submitted in this IND, including a 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. This section should include the product’s active ingredients, pharmacological class, structural formula and dosage form, and route of administration. The study objectives and proposed timeline should be stated. Additionally, include the status of the drug in other countries, i.e., if the product has been withdrawn from investigator or marketing for any reason related to safety or effectiveness.

  This section will include a brief summary of previous human experience with the drug, 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. This topic will be written up in further detail in the “Previous Human Experience” section.

  General Investigational Plan

  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, information that will be relevant for the first year of investigation should be included. Changes to the plan and additional protocols can be included in future annual reports and amendments. This should include:

  • The rationale for the drug and/or research study and enough background information on the topic for the FDA to understand the scientific justification for the investigation.
  • Identification of the indication to be studied in this investigation, including sub-sets of a more general study population if needed.
  • A high-level description of data to be collected and its use in evaluation of the efficacy of the intervention being studied.
  • A high-level description of the plan for the first 12 months of clinical investigation. The FDA understands that study plans may change over time.
  • The planned number of subjects to be enrolled in the first year of IND activity.
  • 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. Any study procedures that carry risks of more than minimal severity should be included.

  Investigator Brochure

  For single site INDs where an NIH Institute or Center (IC) is the Sponsor and an employee of the IC is the investigator, it is generally acceptable to ask for a waiver for the Investigator Brochure, much like a sponsor-investigator study. The following statement may be incorporated into the application:

  "As this is a single site study with the investigator initiating the study and being employed by the sponsoring entity, we believe that an investigator’s brochure is not required per 21 CFR 312.55(a)."

  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. Links that may be helpful are:

  • DailyMed
  • Drugs@FDA: FDA Approved Drug Products

  Letters of Authorization may also be referenced in this section.

  If there will be a multi-center (external site) clinical investigation, 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.

  Proposed Clinical Research

  This section should contain the full study protocol document and informed consent document for each planned study.

  Informed consent documents should be written in such a way that they can be understood by the general public. Language should be targeted at an elementary grade reading level. It is advisable to keep the document concise for the benefit of the reader. A statement should be included here that informed consent will be obtained by all study participants in accordance with 21 CFR Part 50, Protection of Human Subjects. If the investigation involves an exception from informed consent requirements, this should be stated in this section and the reasoning should be explained.

  Chemistry, Manufacturing, and Control Information

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

  Drug Substance

  This section should include:

  • Description of drug; included should be the 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

  This section should include:

  • A list of 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. There should be 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

  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.

  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. For products already marketed, it may be possible to request and exemption from the requirement to conduct an environmental analysis.

  "We request a claim for categorical exclusion for this proposed clinical trial as provided for in 21 CFR Part 312.31(e) in that the drug shipped under this notice is intended to be used in clinical trials in which the amount of waste expected to enter the environment may reasonably be expected to be non-toxic."

  Pharmacology and Toxicology Information

  As was true for the Chemistry, Manufacturing and Controls section, an authorization letter may be used or a reference to the drug label to satisfy this section. This section is expected to include information about pharmacological and toxicological (laboratory animals or in vitro) studies on the basis that it is reasonably safe to conduct the proposed clinical investigation. The type, duration, and scope of these studies required in the application will depend on the duration and nature of the proposed clinical investigations.

  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, there should be a brief statement of the reason for noncompliance.

  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

  This section should include a description of the pharmacologic effects and mechanism of actions of the drug in animals, and 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

  A high-level summary and general conclusions to be drawn from the pharmacology data should be included in this section.

  Toxicology: Integrated Summary

  This section should include an integrated summary of the toxicological effects of the drug in pre-clinical studies. Expected content elements for describing specific toxicology studies for this section typically include:

  • Study title
  • Study drug formulation and dosing
  • Brief description of the design of the trials
  • 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.
  • A 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.

  Previous Human Experience

  A summary of previous human experience with the drug known to the applicant should be included in this section. If the drug(s) is already marketed in the US, then it may be possible 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. 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, a statement should be inserted reflecting this under each subheading.

  Marketed Experience

  This section should provide an overview of the FDA-approved indications for the study drug if it is a commercial product. 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, identification of the country(ies) where the drug was withdrawn and the reasons for withdrawal should be included.

  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 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

  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

  References used should be listed in this section. Complete reprints of select articles may be provided to aid the FDA reviewers, limited to two to three reprints. FDA does not have access to all journal articles and so including selected reprints can help facilitate the review of an IND application.

  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.

  In the interest of collecting this information at the initial stage of an IND, clinical investigators may also complete a Form FDA 3454 if they have no financial interests or arrangements to disclose, or Form FDA 3455 to disclose the nature of their interests and arrangements.

  Additional Information

  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 should be included.

  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 should be included in this section.