cover letter to fda

• Initial IND submission

IND Template

Video explanation

This initial IND submission template is designed for sponsor-investigators conducting 'simple' clinical studies where commercially marketed drugs are being evaluated.

Maintain all of the headings in this document. If some are not applicable, simply state this under the appropriate headings.

Form FDA 1571 - IND Application

Current version of Form FDA 1571 Form FDA 1571 Instructions

What is the FDA 1571 form?

Form FDA 1571 is used for two purposes: 1) to obtain agreement from the sponsor (or sponsor-investigator) to conduct research according to all appropriate FDA regulations; and 2) to serve as a cover sheet for all submissions to the FDA on behalf of a particular IND.

When is the FDA 1571 necessary?

Form FDA 1571 should be completed for every submission sent to the FDA on behalf of a particular IND.

What information do I need to fill out the Form FDA 1571?

Include the following information on Form FDA 1571:

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.

What is the serial number in box 10?

Each submission to the FDA regarding a particular IND is given a consecutive serial number. The initial submission will be 0000, and all subsequent correspondence will have a new serial number (0001, 0002, etc.)

Form FDA 1572

Frequently Asked Questions – Statement of Investigator (Form FDA 1572)) Current version of Form FDA 1572 Form FDA 1572 Instructions

The intent of the Form FDA 1572 is two-fold. It is a signed agreement from the 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 (or sponsor-investigator) to assure the FDA that all investigators have the experience and background needed to conduct the trial. The sponsor of the study is responsible for ensuring that updated Form FDA 1572 is submitted to the FDA. The site investigator is responsible for updating his/her Form FDA 1572 and providing it to the sponsor in a timely manner so the information can be sent to the FDA.

When is the Form FDA 1572 necessary?

When filing an Initial IND Submission, a completed Form FDA 1572 must be sent from each site.

When adding a new investigator (or new site), or replacing an investigator at an existing site. Note: a Form FDA 1572 must be submitted to the FDA within 30 days of the investigator being added.

When changing any site information: IRB, laboratory, or clinical site.

What information do I need to fill out the Form FDA 1572?

A current CV or statement of qualifications of the investigator listed on the Form FDA 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

Form FDA 3674 - Certification of Compliance

Current version of Form FDA 3674 Adobe Reader may be needed to view this document Form FDA 3674 Instructions

The FDA form 3674 is a document that must accompany all FDA IND initial submissions and submission of new protocols to INDs. It is a signed statement from the sponsor-investigator that they will comply with clinicaltrials.gov requirements concerning their investigation.

BOX A Should be checked if there is not a clinical investigation covered in the IND submission.

BOX B Should be checked if there is a clinical investigation, but the requirements of 42 U.S.C. § 282(j), Section 402(j) of the Public Health Service Act do not apply. This is the case for most Phase I studies.

BOX C Should be checked if there is a clinical investigation and the requirements of 42 U.S.C. § 282(j), Section 402(j) of the Public Health Service Act do apply. By checking this box, the investigator certifies that they will comply with those requirements.

If a clinical trial is funded all or in part through the NIH, it is a federal requirement that the human clinical trial be registered on clinicaltrials.gov .

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 sponsor-investigator to request FDA review of the enclosed information, and briefly describes the proposed research.

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-investigator and (recommended) a designated individual authorized to interact with the FDA on the sponsor-investigator's behalf.

More about the cover letter

Keep cover letter short, ~ 1-2 pages.

For a Drug:

For a Therapeutic Biological Product:

For a Biological Product:

Ensure the date of the cover letter matches the date on the signed copy of Form FDA 1571.

If the sponsor-investigator 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.

Refer to sample cover letter, see below. The text is intended to provide a general example of the flow of a cover letter. It can be changed to fit the particular needs of different studies.

IND Cover Letter Template

Letter of Support / Authorization

If a sponsor-investigator is proposing to evaluate a drug that is the subject of an existing IND (being developed by a commercial sponsor), they can request a letter of cross-reference authorization from the sponsor of that IND. This permits the sponsor-investigator to refer the FDA to the information contained in the commercial sponsor's 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-investigator 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 sponsor-investigator's IND application.

Sections of an IND submission

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.

Refer to FDA's Guidance entitled Investigational New Drug Applications Prepared and Submitted by sponsor-investigators for more information.

Introduction

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: Name Reference number Volume Page number where the information may be found

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.

List any references used in this 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, 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.

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.

Investigator Brochure

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:

• 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.

Proposed Clinical Research

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

• 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.
• 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
• 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.
• 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.

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.

Form FDA 3454

In the interested of collecting this information at the stage of an IND, clinical investigators could 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.

For more information, see FDA's Guidance for Clinical Investigators, Industry, and FDA Staff Financial Disclosure by Clinical Investigators .

Chemistry, Manufacturing and Control Information

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.

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 .

Pharmacology and Toxicology Information

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

Toxicology: integrated summary.

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
• 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.

Previous Human Experience

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.

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.

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.

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.

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.

Relevant Information

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

Submission Formatting

Commercial INDs, where the sponsor intends to conduct clinical research to support a future marketing application, must be submitted electronically in Common Technical Document format (eCTD) through the FDA Electronic Submissions Gateway (ESG) . However, research INDs, where the sponsor intends to conduct clinical research for publishing and general knowledge and does NOT intend to commercialize the product, are not required to be submitted in eCTD format and may be submitted on paper as described below. Additionally, research INDs can be submitted electronically through the ESG in either eCTD or non-eCTD format. Research INDs reviewed by CDER can also be submitted electronically through the CDER NextGen Portal .

General Formatting Guidelines for Paper Submissions

Use 1 ½" left margin to allow for binding space. FDA prefers 12pt font, but smaller fonts will still be accepted. The font should be consistent throughout the entire submission. Use black typeface, with standard blue formatting for hyperlinks if included. Any pictures should be printed in color.

Three copies (original and 2 exact copies) must be sent to the FDA at the appropriate address below:

A "courtesy e-copy" may be sent as well. The e-copy should be an exact copy of the original, in PDF format. If use of multimedia is necessary for the submission (i.e. large detailed images, or videos), then the submission cover letter should indicate the additional information contained on the e-copy. The e-copy is submitted on a CD, DVD, or thumb drive. Make sure that the information is not encrypted, or accompanied by loading software (especially common on thumb drives). Ensure that the e-copy is secured in a pocket page divider and has a label just like the paper submissions. (See below)

The paper submissions should be bound individually in 3-hole punch ACCO-style folders. The original submission should be in a gray folder. The other two copies may be in different colors. Submissions that are inadequately bound will not be reviewed.

A label should be attached to the front of each folder. If more than one volume is needed, indicate the volume number on the folder. The e-copy should have a label.

Headers and Footers

Top Left <Name of Investigation, Initial IND>

Top Right Sponsor: <Name of sponsor-investigator>

Bottom Left <University> Confidential and Proprietary

Bottom Right <Page Number>

• Bioprocessing
• Chromatography
• Drug Delivery
• Formulation Development
• Microbiology
• Spectroscopy

FDA Publishes Guidance for industry: Cover Letter Attachments for Controlled Correspondences and ANDA Submissions

On June 5, 2023, FDA published the guidance for industry titled “Cover Letter Attachments for Controlled Correspondences and ANDA Submissions,” which was published as a draft in December 2021. This guidance is intended to assist prospective applicants, applicants, and holders of abbreviated new drug applications (ANDAs) with optional attachments that can be used when preparing cover letters that accompany controlled correspondence to the Office of Generic Drugs (OGD), as well as original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA.

Cover letters provide an overview of a submission and help FDA ensure that the submission is properly triaged and assigned to the appropriate assessors. In an effort to ensure that submissions are effectively managed by FDA and acted upon within the performance revew goal dates agreed to in the GDUFA III commitment letter, FDA has developed cover letter attachments to accompany, or assist in the preparation of, applicants’ cover letters for the common submissions listed above. These attachments do not replace cover letters.

These cover letter attachments have been designed as a checklist to reflect common types of information applicants are expected to address in their cover letters. The attachments are intended to serve as a useful guide to help applicants prepare their cover letters and to assist FDA in the triage and management of submissions.

FDA published this guidance as part of its GDUFA III commitments and in support of the Drug Competition Action Plan (DCAP), which seeks to foster generic competition and help address the high cost of drugs. Through DCAP, FDA is committed to enhancing the efficiency of the development and approval of ANDAs, with the ultimate goal of more approvals, thereby helping to increase access to high-quality, lower cost generic drugs.

Additional Resources

Controlled Correspondence – Resources for correspondence submitted to FDA by or on behalf of a generic drug manufacturer or related industry requesting information on a specific element of generic drug product development or certain post-approval submission requirements

ANDA Forms and Submission Requirements – Summary tables, application forms, question-based review, and other resources related to ANDA submissions

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Cover Letter Attachments for Controlled Correspondences and Abbreviated New Drug Application Submissions; Draft Guidance for Industry; Availability, 70849-70850 [2021-26893]

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

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27 December 2023

Tips for Writing an Effective FDA 483 Response

Following an FDA inspection, you may be issued an FDA Form 483 listing Inspectional Observations of current issues and/or potentially problematic conditions.

First and foremost, it’s important to take these observations seriously . Although it does not represent the FDA’s final determination on compliance, deciding not to respond to FDA 483 observations within the 15-business day window will almost certainly result in a Warning Letter or further enforcement action.

Many Warning Letters could have been avoided with a proper response to the Form 483. Our aim is to assist you in taking appropriate action to achieve the best possible outcome after receiving a Form 483.

While crafting a strong response is crucial, remember it’s just one part of a larger recovery process.

Grab our free white paper: The Emergency Guide to FDA Warning Letters & FDA 483 , for a comprehensive guide to FDA 483 recovery. 

Before we jump into what makes a response effective and compelling, let’s briefly go over the proper layout.

In this introduction, respectfully thank the FDA for identifying opportunities for continuous improvement and clearly state your obligation to comply with the law through a commitment to action. This should be written by . Restate each observation and include the following for each one: Clearly describe and identify any attachments you provide. The numbers and names referenced in the body should match the list's number and name.  Attachments should be easy to find, read, and understand. For example, if an SOP is attached, reference the specific section(s) in the body that addresses the issue to make it easy for the reviewer. Avoid forcing them to search through reams of documentation to understand your improvements.

Working with this basic outline, below are the essential things to keep in mind before and while crafting your response.

1. Take the time to fully understand each observation.

Before you start crafting your response, make sure you fully grasp each observation the FDA is presenting to you.  During the inspection, ask questions and clarify any points with the FDA investigator and your subject matter experts (SMEs). Pause the discussion if necessary to consult with other SMEs and gather evidence of compliance.

At the closing of each inspection day, take full advantage of the wrap-up to ensure you understand any compliance gaps the investigator finds. This is the best time to get questions answered. We suggest actively confirming your understanding of each gap in detail with the investigator right then and there. Describe it back to them to make sure you understand it the way they understand it.

At the end of the inspection, the inspector will summarize all observations. Again, take this golden opportunity to make sure you clearly understand each one. Present any evidence of corrective actions taken during the inspection, as this may lead to resolving the observation immediately.

2. Investigate each observation and challenge your assumptions.

After the inspection, it’s time to investigate the findings in depth. Every observation documented by the FDA must be taken seriously and addressed accordingly.

Having seen many FDA Form 483s ourselves, it's not uncommon to find frustratingly generic language that can obscure specific concerns. In such cases, we always suggest conducting additional research to fully understand the context of the observations. This will aid in accurately defining the compliance gap and formulating a precise problem statement.

Make sure to write out those problem statements in clear and precise terms. With a problem statement in hand, you can start investigating the root cause(s) and determine the appropriate corrective actions that address that specific problem.  Always document the scope of the investigation in detail, including the root cause analysis tools and techniques used in the investigation (Fishbone, Five Whys, etc.), and the outcome of the investigation. Clearly identify the root cause and the corrective and preventive actions needed for each observation.

In our experience, the FDA is particularly interested in seeing that you're addressing the patient safety implications of all observations. This means comprehensively evaluating the product's safety, identification, strength, purity, and overall quality.  Again, be sure to meticulously document every aspect of your investigation, including the methodologies employed, the results of these investigations, the impact analysis findings, and all actions undertaken in response. Under-documentation is the number one problem we see in inadequate responses.

Beyond making immediate corrections to rectify the specific issue, identify and implement further measures to prevent similar problems in the future. This requires expanding the scope of your investigation to include areas of potential risk that are similar in nature. The goal is to identify systemic issues that might be contributing to the problem.

Adopt a proactive approach and scrutinize other systems for similar deficiencies, considering broader timeframes and other products that utilize the same systems and comparable processes across different quality systems. If you identify systemic root causes, undertake additional corrective actions to address these underlying issues.

Moreover, it’s necessary to assess the need for specific actions on products and batches that are affected by the identified problems. This might involve a thorough examination of other product batches that could be impacted by the same nonconformity. If such actions are deemed necessary, they could impose quality holds on the current inventory, applicable to stock stored onsite and those in the distribution chain.

3. Develop a robust CAPA plan.

Once you've revealed the full extend of each problem, the next step is to document all planned corrective and preventive actions in a formal CAPA plan. We explain how to do that in detail here: Corrective and Preventive Action (CAPA): The Definitive Guide.

The purpose of the CAPA plan is to document your planned actions, monitor progress, and report on the completion of each action. It should also outline feasible solutions that can be implemented within a reasonable timeframe and address the correction of both specific and systemic issues. If you can't complete any actions immediately, provide a detailed explanation of why, together with a mitigation plan and an estimated timeframe for completion.

Implementing CAPAs sometimes requires change controls to revise SOPs, develop new SOPs, and validate or revalidate test methods, processes, and systems. Make sure any required training is identified as part of the change, and that training is completed before implementing the changes. (This is a huge blindspot we've seen in industry.) Also, be prepared to realize that depending on the problem, CAPA actions may take a significant time to fully implement. Developing a mitigation plan will identify actions to be taken to ensure compliance until the permanent solutions are in place. This plan should identify interim controls, such as additional manufacturing controls, process monitoring, in-process testing, or release testing.

A truly robust CAPA plan should also include focused and measurable effectiveness checks to verify that the actions taken have had the intended impact to resolve the identified issues. You may want to consider using outside experts who have not been involved in the investigation for an objective perspective on the results. Talk to us if you're interested in this.

4. Craft your response.

Firms are required to send a preliminary response within 15 working days when responding to the FDA about Form 483. If the Form 483 has many observations, it's permitted to request an extension during these 15 days to prepare a more detailed response.

Your reply must have a well-defined CAPA plan as described above. Address each observation individually and identify any systemic issues. An effective response will comprehensively explain the investigation process, including the root cause analysis tools, the findings, and the specific CAPA actions. It also provides evidence to demonstrate the completion of immediate actions taken to correct issues.

If you need more time to investigate or implement CAPAs, specify a reasonable projected date for completion and communicate it in your response.

It's crucial to track the progress of your CAPA plans. Regular communication with the FDA is necessary until all CAPAs are closed. If there are ongoing actions, provide updates on the work completed so far and realistic timelines for the completion of remaining tasks. If there are delays in pending actions, explain the reasons for these delays and detail the steps taken to mitigate their impact. If there's new information, include and explain this in your communication.

Finally, as actions within the CAPA plan reach completion, provide evidence of these changes to the FDA. This includes updates to documents, details of any training conducted, and other relevant changes made. This ensures that the FDA is fully informed of your compliance efforts and the measures taken to rectify the issues identified in Form 483.

Below are some specific best practices for writing an effective FDA response that are often overlooked.

When responding to an FDA 483, address each observation cited in the letter specifically and respond in a way that is easy to understand and follow. This means avoiding jargon and technical language and instead using clear and concise language. Your response should leave no doubt about what you intend to do to resolve the situation. Just like an SOP, it should also leave no room for (mis)interpretation. Consider breaking your response into sections corresponding to each observation cited to ensure clarity. Within each section, clearly state the observation and then address it in a clear, chronological format that allows you to put your company in the best light possible. Typically, the most effective way to write your response is in narrative form. Start by stating the observation cited in the letter, then provide a detailed response addressing each point raised. Use clear and concise language, and provide supporting evidence to support your claims. By presenting a compelling narrative, you can help to build trust and confidence with the FDA. Support all claims with objective evidence. This means providing hard data, test results, and other evidence to support your claims. Unsupported or poorly explained assertions are useless to the FDA and only raise more doubts about your ability to resolve the problems identified. To ensure that you have the necessary evidence to support your claims, consider thoroughly reviewing your processes and procedures. This can help you identify any gaps in your data collection or analysis and ensure that you have the necessary evidence to support your response. If you decide to dispute an observation in your response, you must be prepared to back it up with enough factual, objective evidence to be convincing. Never ignore an investigator's claims. Even if you believe something may be inaccurate, your response should clearly provide enough explanation to show exactly why you do not concur with the observation. When disputing an observation, always remain professional and respectful. Use clear, concise language, and provide objective evidence to support your claims. You can help build trust and credibility with the FDA by presenting your argument calmly and rationally. Again, when crafting a response, support all claims with objective evidence. This means providing hard data, test results, and other evidence. Unsupported or poorly explained assertions are useless to the FDA and only raise more doubts about your ability to resolve the problems identified. To ensure that you have the necessary evidence to support your claims, consider thoroughly reviewing your processes and procedures. This can help you identify any gaps in your data collection or analysis and ensure that you have the necessary evidence to support your response. Proofread, edit, and re-work your response before submission to ensure it is as complete and compelling as possible. Even one typo or inaccurate statement can reduce the FDA’s confidence in your ability to provide high-quality products to the market and protect the public, increasing the likelihood that a Warning Letter will be issued and potential escalation to enforcement action. To ensure perfection and objectivity, you may choose to seek the help of third-party experts to conduct an independent assessment of the thoroughness and acceptability of the response before submission. This means providing a detailed action plan that clearly outlines the corrective actions you have taken or plan to take in response to each observation. Your plan should include needed to address the issues identified. When outlining corrective actions, it's important to be as specific and detailed as possible. Vague or general statements about "improving processes" or "increasing training" are insufficient. Instead, identify the specific steps you plan to take, such as implementing new procedures, hiring additional staff, or providing more training. Include a timeline for each action, indicating when it will be completed and who is responsible for ensuring its completion. This demonstrates your commitment to taking corrective action and helps to build the FDA's confidence in your ability to address the issues identified. When developing your action plan, be realistic about the available resources and the timelines for completion. Be sure to involve key stakeholders in the process and communicate regularly with the FDA to ensure they know your progress. In addition to demonstrating corrective action, it's important to convey a commitment to compliance with FDA regulations and expectations. This can include implementing new procedures, policies, and training programs to prevent similar issues from occurring in the future. It can also involve changing the company culture or values, ensuring that all employees understand the importance of complying with FDA regulations and are empowered to report any issues or concerns.

4. Follow up with additional remediation and compliance assuredness to prepare for future inspections.

Thoroughly document the entire investigation process as you work to address the observations identified by the FDA. This documentation should include a detailed record of how each observation has been addressed. Compile a complete package for future reference and inspections. The package should include a list of observations, detailed plans and outcomes of the investigations, the root causes identified, the CAPAs implemented, and objective evidence of all actions taken. Keeping this package updated ensures that you are well-prepared for review in any subsequent inspections.

In addition to addressing current observations, we often find that there's deeper remediation work to be done within the Quality System depending on the severity of the issues identified. Often, what starts as a Form 483 response project turns into a formal remediation project afterward.

For example, our remediation model solves a variety of compliance problems while offering ongoing project management and training services each step of the way. Once remediation is complete, we plan, implement, and audit the quality system to ensure regulatory compliance is maintained well into the future.

One of the biggest challenges of remediation is exposing problems that may be completely unknown to you. Even with a capable in-house team, attempting to uncover systemic issues and creating a plan to correct them presents considerable challenges, even for large manufacturers. 

Third party remediation professionals offer a fresh perspective while working diligently to analyze gaps, identify root causes, resolve compliance problems, and communicate your efforts to regulators effectively.

Learn more about our remediation support services .

Once all remediation work is complete, make sure to continuously monitor your quality systems to prevent similar issues from reoccurring. Recurrence of the same issues during future FDA inspections can lead to more severe consequences—usually a Warning Letter.

Keep an eye on the FDA's top-cited observations via its data dashboard . This highlights areas of top concern so you can prioritize your compliance assurance program according to what problems the FDA finds and cites most often

Want to learn more about responding to FDA 483 observations and crafting an effective Corrective and Preventative Action (CAPA) Plan? Grab our free whitepaper: The Emergency Guide to FDA Warning Letters & FDA 483 or contact our team to consult with an expert.

Topics: Process , FDA Form 483 , Quality Standards , Compliance Consulting

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Cover Letter Attachments for Controlled Correspondence and Abbreviated New Drug Application Submissions; Guidance for Industry; Availability

A Notice by the Food and Drug Administration on 06/06/2023

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Notice of availability.

The Food and Drug Administration (FDA or Agency) is announcing the availability of a final guidance for industry entitled “Cover Letter Attachments for Controlled Correspondence and ANDA Submissions.” This guidance is intended to assist prospective applicants, applicants, and holders of abbreviated new drug applications (ANDAs) with optional attachments that can be used when preparing cover letters that accompany controlled correspondence, original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA. This guidance finalizes the draft guidance of the same title issued on December 13, 2021.

The announcement of the guidance is published in the Federal Register on June 6, 2023.

You may submit either electronic or written comments on Agency guidances at any time as follows:

Submit electronic comments in the following way:

• Federal eRulemaking Portal: https://www.regulations.gov . Follow the instructions for submitting comments. Comments submitted electronically, including attachments, to https://www.regulations.gov will be posted to the docket unchanged. Because your comment will be made public, you are solely responsible for ensuring that your comment does not include any confidential information that you or a third party may not wish to be posted, such as medical information, your or anyone else's Social Security number, or confidential business information, such as a manufacturing process. Please note that if you include your name, contact information, or other information that identifies you in the body of your comments, that information will be posted on https://www.regulations.gov .
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Submit written/paper submissions as follows:

• Mail/Hand Delivery/Courier (for written/paper submissions): Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments submitted to the Dockets Management Staff, FDA will post your comment, as well as any attachments, except for information submitted, marked and identified, as confidential, if submitted as detailed in “Instructions.”

Instructions: All submissions received must include the Docket No. FDA-2021-D-0861 for “Cover Letter Attachments for Controlled Correspondence and ANDA Submissions.” Received comments will be placed in the docket and, except for those submitted as “Confidential Submissions,” publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.

• Confidential Submissions—To submit a comment with confidential information that you do not wish to be made publicly available, submit your comments only as a written/paper submission. You should submit two copies total. One copy will include the information you claim to be confidential with a heading or cover note that states “THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.” The Agency will review this copy, including the claimed confidential information, in its consideration of comments. The second copy, which will have the claimed confidential information redacted/blacked out, will be available for public viewing and posted on https://www.regulations.gov . Submit both copies to the Dockets Management Staff. If you do not wish your name and contact information to be made publicly available, you can provide this information on the cover sheet and not in the body of your comments and you must identify this information as “confidential.” Any information marked as “confidential” will not be disclosed Start Printed Page 37070 except in accordance with 21 CFR 10.20 and other applicable disclosure law. For more information about FDA's posting of comments to public dockets, see 80 FR 56469 , September 18, 2015, or access the information at: https://www.govinfo.gov/​content/​pkg/​FR-2015-09-18/​pdf/​2015-23389.pdf .

Docket: For access to the docket to read background documents or the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in the heading of this document, into the “Search” box and follow the prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500.

You may submit comments on any guidance at any time (see 21 CFR 10.115(g)(5) ).

Submit written requests for single copies of this guidance to the Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration, 10001 New Hampshire Ave., Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002. Send one self-addressed adhesive label to assist that office in processing your requests. See the SUPPLEMENTARY INFORMATION section for electronic access to the guidance document.

Jonathan Hughes, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Rm. 1668, Silver Spring, MD 20993-0002, 240-702-3970, [email protected] .

FDA is announcing the availability of a guidance for industry entitled “Cover Letter Attachments for Controlled Correspondence and ANDA Submissions.” This guidance is intended to assist prospective applicants, applicants, and holders of ANDAs with optional attachments that can be used when preparing cover letters that accompany controlled correspondence, original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA.

A cover letter is generally included with controlled correspondence to the Office of Generic Drugs and submissions to an ANDA file. While a cover letter is not required content for an ANDA, the cover letter is a part of the electronic common technical document hierarchy and is included in Module 1 of an ANDA submission.

The cover letter provides an overview of the submission and helps FDA ensure that the submission is properly triaged and assigned to the appropriate assessors. In an effort to ensure that submissions are effectively managed by FDA and acted upon within the performance review goal dates reflected in the Generic Drug User Fee Amendments (GDUFA) Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 commitment letter (GDUFA III Commitment Letter), [ 1 ] FDA has developed cover letter attachments to accompany, not replace, applicants' cover letters for common submissions, including controlled correspondence, original ANDAs, and amendments to ANDAs, as well as supplements to approved ANDAs. These cover letter attachments have been designed as a checklist to reflect common types of information applicants are expected to address in their cover letters. The attachments are intended both to serve as a useful guide to help applicants prepare their cover letters and to assist FDA in the triage and management of submissions.

This guidance finalizes the draft guidance entitled “Cover Letter Attachments for Controlled Correspondence and ANDA Submissions” issued on December 13, 2021 ( 86 FR 70849 ). FDA considered comments received on the draft guidance as the guidance was finalized. Changes from the draft to the final guidance include clarifying that use of the cover letter attachments are voluntary; defining several terms that may have been ambiguous ( e.g., “administrative general correspondence” and “approved citizen petitions”); and adding updated information on labeling carve-outs and requests for reconsideration. In addition, editorial changes were made to improve clarity, such as adding lines to denote where information should be filled in by the applicant and minor reformatting of the attachments in the appendices.

This guidance is being issued consistent with FDA's good guidance practices regulation ( 21 CFR 10.115 ). The guidance represents the current thinking of FDA on “Cover Letter Attachments for Controlled Correspondence and ANDA Submissions.” It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.

While this guidance contains no collection of information, it does refer to previously approved FDA collections of information. Therefore, clearance by the Office of Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) ( 44 U.S.C. 3501-3521 ) is not required for this guidance. The previously approved collections of information are subject to review by OMB under the PRA. The collections of information in 21 CFR part 314 (including subpart C) for to the content and format of ANDAs, including original ANDAs, amendments to ANDAs, and supplements to approved ANDAs, submitted by applicants and approved by FDA have been approved under OMB control number 0910-0001. The collections of information for Form FDA 356h (NDA and ANDA cover letter) have been approved under OMB control number 0910-0338.

Applicants submit to FDA controlled correspondence along with cover letters related to generic drug development and FDA approval. The collections of information for such submissions have been approved under OMB control number 0910-0797. The collections of information in 21 CFR part 11 for electronic records and electronic signatures have been approved under OMB control number 0910-0303. The collections of information in 21 CFR part 211 about the manufacture of the drug have been approved under OMB control number 0910-0139.

Persons with access to the internet may obtain the final guidance at https://www.fda.gov/​drugs/​guidance-compliance-regulatory-information/​guidances-drugs , https://www.fda.gov/​regulatory-information/​search-fda-guidance-documents , or https://www.regulations.gov .

Dated: May 31, 2023.

Lauren K. Roth,

Associate Commissioner for Policy.

1.  Available at: https://www.fda.gov/​media/​153631/​download .

[ FR Doc. 2023-11943 Filed 6-5-23; 8:45 am]

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Writing a Pre-Submission to the FDA

• Thread starter venezia
• Start date Jan 9, 2017
• Jan 9, 2017

Hi all, Anyone have experience with writing a presubmission to FDA? Is there a template or format that I should be following? Thank you in advance!!!!  

chris1price

Re: Presubmission Hi The presubmission process can be used to get advice from FDA on a range of issues associated with 510(k), PMA, IDE, etc and to set up meetings or conference calls with them. The presub is typically used to gain feedback on testing or protocols. However FDA will not analyse any data or give a pass/fail to a result. Use the appropriate format laid out in the guidance document. See the links below: https://www.fda.gov/downloads/Training/CDRHLearn/UCM461721.pdf https://www.fda.gov/downloads/medic...onandguidance/guidancedocuments/ucm311176.pdf If used correctly, they can be very useful. In a previous IVD company, a presubmission was made early in the 510(k) process to ensure we were about to perform appropriate validation testing. Chris  

StevenJaeger

• Jan 11, 2017

Hi Venezia, if you send me a private message I'll be able to provide you with a download link to a redacted version of my startup's pre-sub cover letter and table of contents. This forum is not allowing me to post the link in-line here. Hopefully it will be helpful in giving you a clearer picture of what would be relevant to include in the document. When my company met with the FDA in an in-person meeting to discuss our pre-sub, the FDA commented that ours was one of the best pre-subs they had seen, in terms of thoroughness, etc. So it should be a good guide. If you would like further help in fleshing out what the contents of the document should be, I would be happy to help on a more involved basis.  

RunningMommaCT

• Feb 21, 2017
• Feb 22, 2017

invitro_spain

Involved in discussions.

Hello Venezia, In my opinion, you need to follow the FDA guideline. This guideline describes the documents that you need to submit. For example, a Cover letter. This cover letter must be a formal presentation of your document package. Secondly, you will need to validate the package with e-submitter. The Presubmission process has its own "refuse to accept (RTA)". Anyway, I have submitted two previous pre-submissions and I never had a problem to close the meeting. I think this is all. I hope this information can help Regards  

Ballroom Blitz

Hi I am new to the forum I saw your post would you also be able to PM that redacted pre-sub to me as well, we actually have one for a PMA and I would love to see one that was already successful. Thank you  

• Jun 7, 2017

Hello All, I am also in the process of writing an FDA pre-submission and would very much like to see any redacted copies of other users' pre-submissions. I attempted PM'ing users that had expressed willingness to share but am a new member and as such it seems I do not have the ability to PM. Any feedback would be greatly appreciated  

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CFR - Code of Federal Regulations Title 21

The information on this page is current as of Mar 22, 2024 .

For the most up-to-date version of CFR Title 21, go to the Electronic Code of Federal Regulations (eCFR).

|

[Code of Federal Regulations]

[Title 21, Volume 2]

[CITE: 21CFR131.200]

TITLE 21--FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION SUBCHAPTER B - FOOD FOR HUMAN CONSUMPTION Sec. 131.200 Yogurt. Yogurt is the food produced by culturing one or more of the basic dairy ingredients specified in paragraph (b) of this section and any of the optional dairy ingredients specified in paragraph (c) of this section with a characterizing bacterial culture that contains the lactic acid-producing bacteria, subsp. and The ingredients specified in paragraphs (b) and (c) of this section may be homogenized and must be pasteurized or ultra-pasteurized before the addition of the characterizing bacterial culture. One or more of the other optional ingredients specified in paragraph (d) of this section may also be added. Yogurt contains not less than 3.25 percent milkfat, except as provided for in paragraph (g) of this section, and not less than 8.25 percent milk solids not fat and has a pH of 4.6 or lower measured on the finished product within 24 hours after filling. To extend the shelf life of the food, yogurt may be treated after culturing to inactivate viable microorganisms. Cream, milk, partially skimmed milk, skim milk, or the reconstituted versions of these ingredients may be used alone or in combination. Other safe and suitable milk-derived ingredients may be used to increase the milk solids not fat content of the food above the minimum of 8.25 percent required in paragraph (a) of this section, provided that the ratio of protein to total nonfat solids of the food, and the protein efficiency ratio of all protein present must not be decreased as a result of adding such ingredients. The following safe and suitable ingredients may be used: - (1) - (i) As determined by the method prescribed in section 33.2.26, AOAC Official Method 989.05, Fat in Milk Modified Mojonnier Ether Extraction Method. Calculated by subtracting the milkfat content from the total solids content using the method prescribed in section 33.2.45, AOAC Official Method 990.21, Solids-Not-Fat in Milk by Difference between Total Solids and Fat Contents. As determined by the potentiometric method described in § 114.90(a) of this chapter. As determined by the method described in ISO 7889:2003(E)/IDF 117:2003(E), Yogurt - Enumeration of Characteristic Microorganisms - Colony-Count Technique at 37 deg.C. The name of the food is "yogurt." The name of the food must be accompanied by a declaration indicating the presence of any characterizing flavoring as specified in § 101.22 of this chapter. colony forming units per gram (CFU/g) at the time of manufacture with a reasonable expectation of 10 CFU/g through the manufacturer's assigned shelf life of the product. (1) Yogurt may contain less than 3.25 percent milkfat and at least 2.44 percent milkfat. If the milkfat content is below 2.44 percent, the product is considered a modified food and is covered under § 130.10 of this chapter. Each of the ingredients used in the food must be declared on the label as required by the applicable sections of parts 101 and 130 of this chapter. The standards required in this section are incorporated by reference into this section with the approval of the Director of the Federal Register under 5 U.S.C. 552(a) and 1 CFR part 51. To enforce any edition other than that specified in this section, FDA must publish a document in the Federal Register, and the material must be available to the public. All approved material is available for inspection at the Food and Drug Administration's Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500, and is available from the sources indicated in this paragraph (i). It is also available for inspection at the National Archives and Records Administration (NARA). For information on the availability of this material at NARA, email or go to Note 1 to paragraph (h)(2)(i): [86 FR 31137, June 11, 2021, as amended at 87 FR 76568, Dec. 15, 2022; 88 FR 22910, Apr. 14, 2023] This website has been translated to Spanish from English, and is updated often. It is possible that some links will connect you to content only available in English or some of the words on the page will appear in English until translation has been completed (usually within 24 hours). We appreciate your patience with the translation process. In the case of any discrepancy in meaning, the English version is considered official. Thank you for visiting esp.fda.gov/tabaco. Guardant's blood-based cancer test moves closer to Medicare coverage with FDA approval Medium Text Guardant Health Inc Follow Exact Sciences Corp Follow U.S. Food and Drug Administration Follow Sign up here. Reporting by Sneha S K, Leroy Leo and Sriparna Roy in Bengaluru; Editing by Shounak Dasgupta Our Standards: The Thomson Reuters Trust Principles. , opens new tab HEDGE FLOW Hedge funds grow bearish amid economic slowdown jitters, Goldman says Global hedge funds continued to add bearish equity bets to portfolios in the week to Aug. 1 when fresh data sparked fears the U.S. economy is slowing faster than anticipated, Goldman Sachs said in a note to clients. Skip to main content Skip to FDA Search Skip to in this section menu Skip to footer links The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site. The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. U.S. Food and Drug Administration   Search   Menu Animal & Veterinary Animal Food & Feeds FDA Letter to Stakeholders: Acknowledgment of Expiring FDA-AAFCO MOU August 2, 2024 Dear Stakeholder, I am writing today to offer you a preview of steps FDA intends to take in the transition phase after our longstanding Memorandum of Understanding (MOU) with the Association of American Feed Control Officials (AAFCO) expires on October 1, 2024.  The relationship between FDA and AAFCO is not ending, but it will be evolving. FDA will continue to participate in AAFCO committees and meetings and work closely with AAFCO and states to help ensure the safety of the animal food supply. The expiration of the MOU presents an opportunity for FDA to begin a thorough evaluation of its pre-market animal food review programs, in hopes of adapting to better serve public health and the needs of all stakeholders. To help us understand those needs, FDA intends to issue a Request for Comments (RFC) seeking public input on specific questions to help us determine what’s working, what’s not, and what changes may be needed. FDA has informally begun this process through public listening sessions and stakeholder meetings and believes now is the appropriate time to re-evaluate how FDA conducts its animal food pre-market programs.  In addition, FDA intends to issue two draft guidance documents relevant to the upcoming transition phase – Draft GFI #293: FDA Enforcement Policy for AAFCO-Defined Animal Feed Ingredients and Draft GFI #294: Animal Food Ingredient Consultation (AFIC). FDA intends to create dockets to receive public comments on the RFC and two draft guidances when they are released. At that time, FDA also intends to issue a CVM Update further detailing how the agency plans to handle the upcoming transition and providing detailed information about how stakeholders can provide input. I, and the rest of FDA’s Center for Veterinary Medicine, thank you for your patience and cooperation while this continues to unfold. We hope to have more information to share soon and will look forward to hearing your feedback when the dockets open.  Tracey Forfa, J.D., M.Div. CVM Center Director 456 IMAGES Fda Cover Letter Example Fillable Online fda Letter Pharmaceutical Cover Letter Fda Cover Letter Template Regulatory Cover Letter Fda Ind Cover Letter Template VIDEO C letter signature#viral#trending#trending# Good Vibes Music 🌻 Soothing Acoustic Cover Songs Playlist 2023 ☘️ Healing Songs Why we need to write letter to God and How to write a letter to God COMMENTS Information to include with Cover Letter Create a Cover Letter and Cover Letter Attachment template to include all the information typically included. Reduce chances of leaving out information that will require another submission (i.e ... Cover Letter Attachments for Controlled Correspondences and ANDA Cover Letter Attachments for Controlled Correspondences and ANDA Submissions Guidance for IndustryJune 2023. This guidance is intended to assist prospective applicants, applicants, and holders of ... Cover Letter Attachments for Controlled Correspondence and ANDA Submissions The cover letter attachment provided in Appendix 1 of this guidance is intended for use with controlled correspondence submitted to OGD. The cover letter attachment provided in Appendix. 2 of this ... Federal Register :: Cover Letter Attachments for Controlled The collections of information for Form FDA 356h (NDA and ANDA cover letter) have been approved under OMB control number 0910-0338. Applicants submit to FDA controlled correspondence along with cover letters related to generic drug development and FDA approval. Such submissions have been approved under OMB control number 0910-0797. PDF Cover Letter Attachments for Controlled Correspondences and ANDA 66 cover letter submitted to FDA for the submissions covered in this guidance. 67 68 The attachment provided in Appendix 1 of this guidance is intended for use with controlled 69 correspondence submitted to OGD. The attachment provided in Appendix 2 of this guidance is 70 intended for original ANDA submissions, amendments to original ANDAs, and ... ReGARDD 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 sponsor-investigator to request FDA review of the enclosed information, and briefly describes the proposed research. Items to include in the cover letter: The cover letter should be on ... FDA Publishes Guidance for industry: Cover Letter Attachments for These cover letter attachments have been designed as a checklist to reflect common types of information applicants are expected to address in their cover letters. The attachments are intended to serve as a useful guide to help applicants prepare their cover letters and to assist FDA in the triage and management of submissions. USFDA Guidance: Cover Letter Attachments for Controlled Correspondences The United States Food & Drug Administration published the final guidance "Cover Letter Attachments for Controlled Correspondences and ANDA Submissions" earlier today (June 5, 2023).A controlled correspondence is a communication submitted to FDA by or on behalf of a generic drug manufacturer or related industry requesting information on a specific element of generic drug product development or ... Cover letter attachments for controlled correspondence and ANDA This guidance is intended to assist prospective applicants, applicants, and holders of abbreviated new drug applications (ANDAs) with optional attachments that can be used when preparing cover letters that accompany controlled correspondence, original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA. :: Cover Letter Attachments for Controlled Correspondences and Cover Letter Attachments for Controlled Correspondences and Abbreviated New Drug Application Submissions; Draft Guidance for Industry; Availability, 70849-70850 [2021-26893] USFDA draft guidance on : Cover Letter for Controlled Correspondences On December 10, 2021, the FDA published the draft guidance for industry entitled "Cover Letter Attachments for Controlled Correspondences and ANDA Submissions."This draft guidance is intended to assist prospective applicants, applicants, and holders of abbreviated new drug applications (ANDAs) with optional attachments that can be used when preparing cover letters that accompany controlled ... IND Applications for Clinical Investigations: Regulatory and The Cover Letter is typically addressed to the Director of the Review Division in the Office of New Drugs and signed by the sponsor of the IND application. Form 1571 (PDF - 830KB) This form ... PDF IND Application Cover Letter Form FDA 1571 . Serial #0000 Page 2 of 2 Form FDA 1572 Form FDA 3674 Sincerely, [Sponsor Name], MD Title Institution Phone number Email address . Title: IND Application Cover Letter Author: ISMMS ORS Created Date: Tips for Writing an Effective FDA 483 Response 1. Cover Letter. In this introduction, respectfully thank the FDA for identifying opportunities for continuous improvement and clearly state your obligation to comply with the law through a commitment to action. This should be written by senior management. 2. Body. Restate each observation and include the following for each one: PDF FDA Cover Letter 22MAR2016 Page 2—Mr. Mark Job forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050. Federal Register :: Cover Letter Attachments for Controlled While a cover letter is not required content for an ANDA, the cover letter is a part of the electronic common technical document hierarchy and is included in Module 1 of an ANDA submission. The cover letter provides an overview of the submission and helps FDA ensure that the submission is properly triaged and assigned to the appropriate assessors. PDF FAQs ion?Identify your first eCTD sequence as a general correspondence submission in the cover letter and FDA. orm. State that the application will be submitted in eCTD format from this date forward and then intentionally code the us-regional.xml as the original applica. ion.When transitioning to eCTD, what should the first eCTD sequence be code. Writing a Pre-Submission to the FDA FDA should give you assistance on whether the selected tests are appropriate, however they may not talk about specific endpoints. ... For example, a Cover letter. This cover letter must be a formal presentation of your document package. Secondly, you will need to validate the package with e-submitter. The Presubmission process has its own ... IND Applications for Clinical Treatment: Contents and Format The Cover Letter is used for triaging and routing of an IND application within FDA and is expected to include the following: Submission Identifier: "Expanded Access Submission". Brief ... Cover Letter Attachments for Controlled Correspondences and ... The collections of information for Form FDA 356h (NDA and ANDA cover letter) have been approved under OMB control number 0910-0338. Applicants submit to FDA controlled correspondence along with cover letters related to generic drug development and FDA approval. Such submissions have been approved under OMB control number 0910-0797. CFR To enforce any edition other than that specified in this section, FDA must publish a document in the Federal Register, and the material must be available to the public. All approved material is available for inspection at the Food and Drug Administration's Dockets Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 240-402-7500 ... Guardant's blood-based cancer test moves closer to Medicare coverage According to the FDA's documents, a study showed Guardant's Shield test detected 83% of colorectal cancers. Exact Sciences' stool test Cologuard had a 92.3% sensitivity rate. DMF template The cover letter for an amendment responding to a letter from FDA should specify the date of FDA's letter, the issues raised in that letter, and the DMF holder's responses. Detailed responses ... FDA Must Do More to Protect Kids from Illegal, Flavored Vapes Cuando University Heights Charter School cerró en 2022, su propiedad de 34,000 pies ... COVER LETTER COVER LETTER. TRANSMITTAL (COVER) LETTER REACTIVATION OF A CLOSED DMF. Information to be filled in is in italics. This cover letter is to be used when a DMF holder wishes to reactivate a DMF that ... FDA Letter to Stakeholders: Acknowledgment of Expiring FDA-AAFCO MOU This FDA Letter to Stakeholders signed by CVM Center Director Tracey Forfa gives a preview of steps FDA intends to take in the transition phase after FDA's longstanding Memorandum of ... assignment essay homework paper report resume review speech thesis