cover letter for fda submission

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>

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Writing the perfect cover letter: A look at the FDA’s forthcoming guidance on submitting RWE studies

In May 2019, the U.S. Food and Drug Administration (FDA) released a draft guidance that encourages sponsors and applicants to include a uniform cover letter to identify real-world evidence (RWE) submitted as part of a regulatory submission. The templated document builds on the Framework for FDA’s Real-World Evidence Program .

It is yet another milestone in the developing infrastructure surrounding regulatory-grade evidence.

Thanks to the template, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) will track RWE submissions. The process also represents a broad learning opportunity for all stakeholders in RWE as it will ensure transparency and consistent documentation of key study components.

Tracking enabled by consistent submissions should help answer key empirical questions surrounding RWE. When and where can health care databases provide robust estimates of treatment safety and efficacy? When ought the FDA rely on such evidence for regulatory decision-making?

The FDA’s Dr. Jacqueline Corrigan-Curay said of using RWE in decision-making, “These studies are really complex, and the shift relies on how we build the infrastructure that makes it all possible. It’s an ongoing conversation, and we’re here to engage.”

In response to the FDA’s invitation to engage, industry has weighed in. Two of the top 15 pharmas, a biotech, three trade groups, two individuals, and Aetion shared their comments on the positioning of the cover letter, the terms it includes, and the data sources, technology, and process used to generate and submit real-world evidence studies.

These recommendations are likely to shape the FDA’s guidance; we summarize them here to help our readers prepare for the process:

The positioning of the cover letter:

Expand the guidance to address alignment on submissions that include RWE between CDER, CBER, and the Center for Devices and Radiological Health (CDRH) for medical devices and combination product submissions containing RWE; and,
Change the positioning from an example to a recommended format to enable the FDA to consistently track RWE submissions. ‍

The terms in the cover letter:

Be precise and consistent with terms including RWD, RWE, the type of study design (e.g., randomized pragmatic trial, single arm trial with external control arm, and non-randomized study), and the type of data/data set; and,
Add definitions for natural history studies, product and/or disease registry data, and data quality and context. ‍

Data sources and technology used to generate RWE:

Distinguish among specific types of RWD in order to track and analyze submissions by data type. Consistent interpretation of data types, from EHRs to emerging sources of clinical data, will inform a regulatory framework; and,
Use validated RWE software platforms to enable transparency, reproducibility, and scientific validity in methods and results. ‍

The process for the cover letter:

Provide information to the sponsor on whether the FDA agrees or disagrees with the sponsor’s classification of RWD/E and how the RWE was used to inform the regulatory decision;
Consider how the Agency’s tracking can generate publicly available information. The Breakthrough Therapy program provides a model with metrics such as therapeutic area, average review time, and speed of approval. Other relevant metrics for RWE include the submission volume and context, the study design, the data type, and the number of approvals where RWE was supportive evidence vs. the basis of the approval;
Develop best practices to inform the program (i.e., process and content via Manuals of Policies and Procedures) and other regulators (e.g., the EMA, the PMDA) to enable early harmonization; and,
Use the aggregated information provided by tracking the cover letters to prioritize resourcing and assessment support by subject matter experts. ‍

The FDA’s encouragement of RWE submissions represents a learning opportunity for the field in designing and executing studies, particularly if the FDA releases complete response letters or provides data from tracking the letters that reveals both successful and unsuccessful approaches. As Amgen’s Dr. Cathy Critchlow stated, “certainly we can learn from the successes, but we also need to make sure we’re learning from the failures .”

Department of Health and Human Services
National Institutes of Health

Regulatory Toolbox

Initial ind application.

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

Current version of Form FDA 1571

Form FDA 1571 Instructions

The purpose of the Form FDA 1571 is to:

obtain agreement from the sponsor (or sponsor-investigator) to conduct research according to all appropriate FDA regulations; and
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.

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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 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.
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

Current version of Form FDA 3674

Form FDA 3674 Instructions

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 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:

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

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.

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

"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.

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

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

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

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 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

NOTE: PDF documents require the free Adobe Reader .

This page last updated on 05/08/2023

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Dec 11, 2021

USFDA draft guidance on : Cover Letter for Controlled Correspondences & ANDA Submissions

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 correspondence to the Office of Generic Drugs, as well as original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA.

These attachments do not replace the recommendations for the content of cover letters provided in other FDA guidances.

The cover letter attachments provided in this guidance have been developed by the disciplines that receive and respond to controlled correspondence and that assess ANDAs (including amendments and supplements). By publishing this guidance, FDA hopes to:

Provide greater clarity on the content and format of cover letters that accompany controlled correspondence, original ANDAs, amendments to ANDAs, and supplements to approved ANDAs submitted to FDA

Improve the overall efficiency of the ANDA submissions process by ensuring these submissions are properly triaged and effectively managed by FDA and acted upon within the performance review goal dates set by GDUFA

FDA is issuing this guidance as part of our Drug Competition Action Plan (DCAP), which seeks to foster generic competition and help address the high cost of drugs.

Under DCAP, FDA 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.

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FDA 510(k) Submission: A Step-By-Step Guide On How To Prepare Yours

Feeling a little lost as you start to compile your first 510(k) submission?

You’re not alone.

There is all this information out there to try and help you, but it can be overwhelming trying to sift through. As you likely already know, the majority of 510(k) submissions are rejected the first time. Maybe you’ve already had yours kicked back to you once or twice.

This step-by-step guide to preparing your 510(k) submission aims to put the requirements in easy-to-understand terms and includes some helpful, actionable and practical tips you can begin to implement immediately. The goal of this guide is to provide you step-by-step guidance through each part of the FDA 510(k) submission process and help improve your time to market.

To start, here’s a list of all the sections required in a 510(k) submission:

Throughout the guide you’ll notice we’ve grouped certain sections of the 510(k) submission together. These sections are typically related and tend to be focused on similar topics. It’s also easier to bite off smaller chunks than to try and tackle it all at once.

You can jump to any of these groups by clicking on the links below:

Group 1 – Cover Sheet Forms

Section 1.0 – Medical Device User Fee Cover Sheet (Form FDA 3601)

Section 2.0 – CDRH Premarket Review Submission Cover Sheet

Group 2 – Public Information About Your Device

Section 3.0 – 510(k) Cover Letter

Section 4.0 – Indications for Use Statement

Section 5.0 – 510(k) Summary

Group 3 – Templated Sections

Section 6.0 – Truthful and Accuracy Statement

Section 7.0 – Class III Summary and Certification

Section 8.0 – Financial Certification or Disclosure Statement

Section 9.0 – Declarations of Conformity and Summary Reports

Group 4 – Comparing Your Device vs. Predicate(s)

Section 10.0 – Executive Summary

Section 11.0 – Device Description

Section 12.0 – Substantial Equivalence Discussion

Group 5 – Ensuring Patient Safety

Section 13.0 – Proposed Labeling

Section 14.0 – Sterilization and Shelf Life

Section 15.0 – Biocompatibility

Group 6 – Software and Electrically Powered Components

Section 16.0 – Software

Section 17.0 – Electromagnetic Compatibility and Electrical Safety

Group 7 – Performance Testing

Section 18.0 Performance Testing – Bench

Section 19.0 Performance Testing – Animal

Section 20.0 Performance Testing – Clinical

Without further ado, let’s jump into the first group.

510(k) Submission Group 1 – Cover sheet forms

There are going to be several sections of your 510(k) submission that are going to revolve around forms or templates that you get directly from the FDA. The first two sections of your 510(k) submission consist entirely of FDA forms for you to complete.

Section 1.0 is the Medical Device User Fee Cover Sheet (FDA Form 3601) and Section 2.0 is the CDRH Premarket Review Submission Cover Sheet (FDA Form 3514).

Seems pretty straightforward right? There are a couple of things that you’ll need to keep in mind.

First and foremost – make sure you’re using the current revision of the form. If you’re preparing several 510(k) submissions, you’re going to want to save yourself time and download a copy of the form. Just make sure that before you go to use it, that it’s still current.

Second – make sure you’re using Internet Explorer and have the latest version of Adobe Acrobat. The Medical Device User Fee Cover Sheet is now actually only available online. You will need to register with the FDA to be able to view it.

In all reality, it’s just a receipt of payment. It has basic information and type of submission. All you need to do is include a copy of it as section 1.0 in your submission.

The CDRH Premarket Review Submission Cover Sheet is a little more involved. It’s about 5 pages long and contains nine sections. The first few sections (sections A – D) are straightforward. It’s basic information about the type of submission, reason for submission, and applicant.

It can start to get a little more complicated after that. When you get to Sections E and F, take a few moments to read and re-read the form. Section E is asking about the PREDICATE device. Section F is asking about your device.

The big problem? The two sections run together. There is a black line separating them, but there’s no white space to help you out. It’s not uncommon for people to put the predicate device name in section F instead of their product name.

And finally, a reminder to check that the indications for use statement on the form matches the indications for use statement used in the rest of the submission. This is one of the biggest reasons FDA rejects 510(k) submissions .

Go ahead and create a folder on your computer to start organizing everything now. Take those forms and put them in folders labeled section 1.0 and section 2.0. It’s also a good idea to go ahead and create the cover sheets for those sections now too.

Get organized now (you’ll be glad you did later) and then let’s move on to the next sections.]

510(k) Submission Group 2 – Public information about your device

Section 3.0 is exactly what it sounds like: a cover letter with some basic administration information, the basis for the submission, and a table supplying information on the design and use of the device. It should be kept fairly straightforward and to the point.

Do be sure your cover letter includes all of the following:

Type of 510(k) submission, Abbreviated or Traditional
Your device type in plain terms, i.e., by its common name
510(k) submitter
At least one contact person, by name, title, and phone number
Your preference for continued confidentiality (21 CFR 807.95)
Your recommended classification regulation
Class (i.e., whether it is unclassified or a class I, II, or III device)
Review panel
FDA product code
Any FDA document numbers associated with prior formal correspondence with FDA (e.g., IDE, pre-IDE, 510(k), PMA, request for designation (RFD)) related to your device.

Section 4.0 – Indications for Use statement ( FDA Form 3881 ) and Section 5.0 – 510(k) Summary are what you will find if you go searching the 510(k) database. That means the summary document you created will be out there for everyone to see.

Per CFR 21 Part 807.95(d) ,

FDA will make a 510(k) summary of the safety and effectiveness data available to the public within 30 days of the issuance of a determination that the device is substantially equivalent to another device.

Things can start to get a little trickier in Section 4.0 – Indications for Use Statement. Once again, the format is addressed by Form FDA 3381. The tricky part is in the actual content of your indications for use statement.

This is a key component of your submission. You have to prove substantial equivalence of the indications for use between your device and the predicate device. You’re going to be tempted to get more specific than the predicate device.

You might be thinking about ways you can better market your device if you can claim it’s intended for use in a specific way. You might even be thinking that you can do less testing if you get more specific. Unfortunately, it doesn’t exactly work that way. The level of specificity needs to match between your device and the predicate device.

If you get more specific, you may raise questions on safety and efficacy of the new device and need to conduct additional testing. Or you may get told by the FDA to change your indications for use…or even to pick a new predicate device. Either way, it can mean a longer time to market.

The whole goal of this section is to be a summary of the rest of your submission and includes information from the cover letter as well as a summary of the substantial equivalence comparison and of the testing that was performed.

Remember : FDA makes this summary public within 30 days of the decision. So, you’re also walking a fine line not to include too many details and still meet FDA’s minimum requirement.

510(k) Submission Group 3 – Templated sections

Now that we’ve gotten all of the introductory pieces out of the way, there are four templated sections to get through before getting into all the details of your proposed medical device.

These sections are going to be fairly straightforward.

Section 6.0 – Truthful and Accuracy Statement is exactly what it sounds like. It’s a statement that certifies that all of the information included is truthful and accurate and that nothing has been omitted. To make it even easier for you, the FDA has provided you with the exact content of the statement .

Don’t forget the lessons you learned in Group 1, the following sections contain forms, and the same guidelines still apply.

Section 7.0 – Class III Summary and Certification might be just as easy to complete as section 6.0 was, if your device is class II. If you have a class II device, which is going to be most of the 510(k) submissions, the section is going to consist of a single sentence: “ This device is not a class III device .”

If your device type is a class III, but does not require a PMA, you’ve got a bit more work to do for this section. Once again, the FDA has provided you with a statement to start the section. After that, you’ll need to provide a summary of the types and causes of safety/effectiveness problems and the data to back it up.

Section 8.0 – Financial Certification or Disclosure Statement is another section that might contain a single sentence. If you didn’t perform any clinical studies as part of testing the device, you can simply include a single sentence: “No clinical studies were performed to test this device.” And once again, if you did perform clinical studies, the FDA has very kindly provided the forms for you to use.

You might notice that this section is titled Financial Certification or Disclosure Statement. That’s because there are two different forms that you might need to use.

The Financial Certification is used if you did not pay the clinical investigators enough money that it might impact the results. In plain language, this means that outside of paying for the costs of the study, there was no equity interest or payment of another kind (such as a grant) given to the clinical investigators.

The Disclosure Statement is used if you did pay the clinical investigators. Part of that form includes submitting the details of how you mitigated any bias.

If you noticed, we didn’t just tell you to leave sections 7.0 and 8.0 blank if they didn’t apply. We told you to include a statement about why these sections are not applicable. It's important to remember that your submission looks like an incomplete submission without them. And you’re going to either get rejected or get asked to supply them.

510(k) Submission Group 4 – Comparing your device vs. predicate(s)

At this point, you’ve made it halfway through your 510(k) submission. Give yourself a pat on the back and take a few deep breaths.

The last half of the 510(k) submission is going to go one of two ways – easy or hard.

Have you kept up with design controls documentation, risk management documentation, and establishing a quality management system ? If not, then the last half of the submission could be rather difficult and time consuming. But, if you have a QMS and have been documenting your design controls and risk management as you go, it’s going to be a whole lot easier.

The second half of the 510(k) submission starts with an Executive Summary describing your medical device, comparing it to the predicate device, and summarizing all of the testing you’ve done.

Though there is some overlap between this and the 510k summary from section 5.0, the Executive Summary is not released on the internet after substantial equivalence determination has been made. That means you can include a more detailed summary on what testing has been performed.

After the Executive Summary, each section is going to be a lot more detailed.

Section 11.0 – Device Description is not just the brief description you’ve been using over and over again.

Remember all those design controls you have been documenting? We’re going to be pulling up the design history file and design controls contents and printing out copies from here on out. From your design outputs , grab the detailed drawings (complete with dimensions and tolerances) for each device, accessory, and component.

Does any part of your device come into patient contact? You’ll want to list those components and include the material specifications. If there are any applicable device-specific guidance documents, make sure of any of the requirements in the device description.

The device description section gets the FDA reviewer intimately familiar with your device. It sets the stage for Section 12.0 – Substantial Equivalence Discussion.

The basis for the 510(k) submission is to show that your new device is safe and effective, because it’s a lot like another device that’s already been reviewed and cleared by FDA.

Go step by step through the devices and show how the indications for use, technology, and performance are the same or equivalent. Seeing as the Executive Summary included a table comparison (from Section 10.0), I’d recommend starting there.

Create an easy-to-read table that specifically calls out indications for use, technology, and performance. Please don’t include ridiculously long paragraphs of details in the table —keep it short and to the point and make it easy for your FDA reviewer to find the information they need.

510(k) Submission Group 5 – Ensuring patient safety

I started out Group 4 telling you that documenting design controls and risk management will make your life a lot easier. This is absolutely going to be the case from here on out.

Section 13.0 – Proposed Labeling is going to be pulled straight from your design outputs. Grab a copy of your device label, but don’t stop there. Labeling includes your device label, your instructions for use (IFU), package insert, and any patient labeling. While this should be your final version, it’s a good idea to expect some changes to come during the review and approval process.

Also note that the FDA considers information on your website about your product as labeling too. (While we are on the subject of websites, remember that you are not allowed to market your device prior to receiving 510(k) clearance.)

In the next few sections, we’re going to start getting into the testing required for your 510(k) submission. As we start to go into more details on what’s required, keep a couple of things in mind.

First and foremost, if a section isn’t applicable to your device, don’t just skip it. You need to include the section and a brief explanation stating why it’s not applicable.

Second, when presenting test results, include both the protocol and the report. The FDA wants to see the results of the testing. Without reports, there’s no proof that your device is safe and effective.

The first section on testing is Section 14.0 – Sterilization and Shelf Life.

If your device is non-sterile, very clearly state that. Don’t assume that because your labeling said non-sterile, you can just ignore it here.

Also included in this section is the shelf-life testing, which will include both shelf life and sterilization. If your device is sterile, part of proving the shelf life of the device is proving that the device is sterile at the end of the shelf life and that the device still performs as expected.

It’s important to note that shelf-life testing is not always applicable. There are some instances where the product has a very low chance of time degrading the performance.

Do realize that if you plan to make a shelf-life claim, you will be expected to support this with applicable product testing to demonstrate performance over the stated shelf life. This often includes accelerated age testing.

After sterilization and shelf life comes biocompatibility. If you’ve got anything that’s in direct or indirect patient contact, this section is important. In the FDA Refuse to Accept (RTA) checklist , it very clearly states that you need to include the protocol and reports.

There is only one exception —and that’s if your device is identical (in both material and manufacturing) to the predicate device. Essentially, you need to include biocompatibility testing, because unless you are the legal manufacturer of the predicate device, the chance of you knowing the exact manufacturing processes is pretty slim.

510(k) Submission Group 6 – Software and electrically powered components

Section 17.0 – Electromagnetic Compatibility and Electrical Safety

There are going to be quite a few of you who are going to completely skip over this Group.

If your device doesn’t have any software or electrical components, fee

l free to skip the Group, just make sure you don’t skip the sections entirely in the 510(k) submission.

You still need to include them as part of the submission, but the entire contents will consist of one sentence: “ My medical device does not have software/electrical components, this section is not applicable. ” For the rest of you, these sections are going to be very important.

If your medical device has software/firmware, then you’ve likely heard the term “level of concern.”

Section 16.0 – Software is going to start off with the level of concern and your rationale behind it.

The rest of the section might feel a little like its own 510(k) submission. In fact, it even has its own special guidance document: Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices .

In general, you’re going to talk about the requirements, specifications, risks, and verification and validation activities. The higher the level of concern, the more documentation you’ll need to include.

If you’re looking for more help and guidance on this, you’re in luck. IEC 62304 is recognized by the FDA and provides an excellent framework for the entire medical device software lifecycle and incorporates a risk-based approach throughout.

The contents of Section 17.0 – Electromagnetic Compatibility and Electrical Safety will depend on whether or not your device has any electrically powered components, regardless of whether those components are in patient contact or not, you’re going to need to evaluate its electromagnetic compatibility (EMC).

In layman's terms, you’re looking at whether your device interferes with other devices (either deliberately or accidentally) or can be interfered by other devices. It’s like proving your device is an island.

The good news is that there’s a recognized standard for the EMC testing, IEC 60601-1-2 Medical Electrical Equipment — Part 1: General Requirements for Safety; Electromagnetic Compatibility -- Requirements and Tests (Second Edition, 2001).

The other part of Section 17.0 depends on whether the electrically powered components are in patient contact. If they are, you need to prove the device is safe for the patient. Once again IEC has come to the rescue with the standard, IEC 60601-1 Medical Electrical Equipment - Part 1: General requirements for safety, and don’t forget about Amendment 1 (1991) and Amendment 2 (1995).

510(k) Submission Group 7 – Performance testing

Section 18.0 – Performance Testing – Bench

Section 19.0 – Performance Testing – Animal

Section 20.0 – Performance Testing – Clinical

You’re in the home stretch when it comes to preparing your 510(k) submission – the performance testing sections.

The next three sections are going to be variations on the same theme, the testing you did to support the performance characteristics.

Part of proving substantial equivalence is comparing the performance characteristics of your device to the predicate device. These sections are where you include all of the proof for the comparison you did in Section 12.0.

It’s important to keep in mind that not all of these sections are mandatory, just like all of the other sections in the submission so far. For example, just because there is a section titled Performance Testing – Clinical, does not mean that you have to do clinical testing for the submission.

No matter which section you’re working on, there are some general things to keep in mind:

Each section should have a description of the protocol, a summary of what the results are, how you analyzed it, and what the conclusion is.
The protocol needs to spell out what the goal of the test is (objective), the number of devices (sample size), how you’re going to do the testing (test method), what thing you’re testing (study endpoint), and what the results should look like (pass/fail criteria).
The results should be very clearly and concisely stated.
Do not stick raw test data in the middle of the report. If you feel it is necessary to include raw test data as part of your submission, put it in an appendix.

Hopefully you were following the design control requirements laid out in 21 CFR Part 820.30 and compiling these sections is going to be nothing more than printing out your design verification and validation test protocols and reports.

First up is the bench testing, Section 18.0 – Performance Testing – Bench.

Depending on your role in your organization, this may have been what you spent the bulk of your time focusing on. There’s even a good chance that at least some of the bench performance testing was done in-house – maybe even by you.

This section will likely contain the majority of your design verification and validation testing.

Section 19 - Performance Testing - Animal and Section 20.0 - Performance Testing - Clinical might not be applicable to your 510(k) submission. You are not obligated to do animal and clinical testing. If you do need to perform animal testing, the FDA branch responsible for reviewing your 510(k) submission is available to provide guidance.

One great option for getting feedback is the pre-submission process (Q-Sub). Another way to determine what animal testing is required is to follow any applicable guidance documents.

As for clinical testing, the FDA will always consider alternatives to clinical studies when the proposed alternatives are supported by an adequate scientific rationale. If you determine clinical testing is necessary, make sure you are following the applicable regulations, The first of which is to determine if your study is significant or non-significant risk.

If your study is determined to be significant risk, you’ll need to conduct the study under the IDE regulations in 21 CFR Part 812. If not, there are abbreviated requirements in 21 CFR Part 812.2(b).

Regardless of the risk level, if you are sponsoring

a clinical trial, you must comply with the regulations governing institutional review boards (21 CFR Part 56) and informed consent (21 CFR Part 50).

The very last thing you should do before you submit your 510(k) is grab the RTA checklist. Go through the RTA checklist and write down the page numbers where everything can be found. If you notice anything is missing, this gives you the chance to add it. It will also make it a little easier for your reviewer.

Preparing 510(k) submissions the easy way with Greenlight Guru

Congratulations! You’ve made it through compiling your entire 510(k) submission! As you can tell by now, this is no easy feat. Successful 510(k) submissions require planning ahead, injecting quality into your work, and educating yourself sooner will prepare your teams early so you can go into submissions with confidence.

So, shouldn't your QMS make you feel confident, too? And what about collecting and managing clinical data in a compliant system? That's why we here at Greenlight Guru built a Quality Management System and an Electronic Data Capture (EDC) Software specifically for the MedTech Industry. That means you get to automatically generate all the critical documentation you need as well as capture and manage clinical data for submission.

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Jesseca Lyons

Jesseca Lyons is a Senior Medical Device Guru at Greenlight Guru and a Mechanical Engineer by trade who loves working with cross functional teams, including both engineering and non-engineering disciplines. She’s spent most of her career gathering and defining requirements for new product design and development in the...

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Drug Master File (DMF) Templates

The following templates recommend elements to include in certain DMF submissions:

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* For Type III and Type IV DMFs, new item represents a new item in the DMF, such as a rubber stopper, cap, and so forth.

FDA Confirms Its Cover Letter Attachments for Generic Submissions Are Voluntary

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510k Cover Letter and FDA Form 3514 – How to Webinar

In this webinar, you will learn how to complete a 510k Cover Letter and you will receive a 510k cover letter template. Your cart is empty

Why you should register for the 510k Cover Letter Webinar?

A 510k Cover Letter needs to include the administrative information that is needed to properly identify you, your company, the 510k submission type, applicable regulations, product classification, the review panel, the device product code, and any previous submissions related to this 510k submission. The 510k Cover Letter also includes a statement that your submission includes a paper copy and an eCopy. There are also specific questions that the reviewer needs to be answered about your product in order to identify specific specialists that may need to be involved, such as:

Is the device provided sterile?
Does the device contain a drug?
Does the device use software?
Does the submission include clinical information?
Is the device implanted?

In addition to the 510k Cover Letter, there is also a submission cover sheet that must be prepared (i.e., FDA Form 3514). The submission cover sheet includes details that are used to create a database entry for you, your company, and your product submission. The submission cover sheet is also used for pre-submission requests, De Novo applications, and other types of device submissions. During this presentation, I will review each section of FDA Form 3514 and explain when each section applies and how to complete it.

Does the Webinar Still Matter for the FDA eSTAR?

The FDA eSTAR incorporates all of the elements of FDA Form 3514, and you no longer have to fill in that form. However, the instructions for Form 3514 may be helpful. The 510k course we updated for the eSTAR shows how to fill in each section of the the eSTAR from beginning to end. The eSTAR has a section near the beginning where you need to attach a cover letter. The cover letter template we use in this webinar has only changed with regard to the eCopy statement.

Download button for 510k Cover Letter 1024x152 510k Cover Letter and FDA Form 3514 How to Webinar

What’s Included in the 510k Cover Letter Webinar?

a recording of the webinar you can replay anytime
my updated 510k Cover Letter Template
a copy of FDA Form 3514
a template I created for a supplement to FDA Form 3514
the native slide deck for this webinar

There are 22 slides in this presentation, and the presentation is 20 minutes in duration. This presentation is a recorded presentation, but p lease submit questions to me by email at [email protected] .

510k Cover Letter Webinar ($29)

510k Cover Letter Screen Capture 150x150 510k Cover Letter and FDA Form 3514 How to Webinar

Additional Resources for 510k submissions

If you would like additional training on 510k submissions or you would like to access Medical Device Academy’s templates, you can purchase all of our templates and 510k webinars on our 510k course webpage .

About Your Instructor

Rob 150x150 510k Cover Letter and FDA Form 3514 How to Webinar

Rob Packard is a regulatory consultant with ~25 years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Rob was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certifications. From 2009 to 2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Rob’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone at 802.281.4381 or by email . You can also follow him on Google+ , LinkedIn , or Twitter .

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IMAGES

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Form FDA 1571 - IND Application

What is the FDA 1571 form?

When is the FDA 1571 necessary?

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

What is the serial number in box 10?

Form FDA 1572

When is the Form FDA 1572 necessary?

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

Form FDA 3674 - Certification of Compliance

Cover Letter

Letter of Support / Authorization

Sections of an IND submission

Introduction

Name of the Drug and All Active Ingredients

Pharmacological Class of the Drug

Structural Formula of the Drug

Formulation of the Dosage Form(s) to be Used

Route of Administration

Objectives and Duration of the Proposed Clinical Investigation(s)

Summary of Previous Human Experience

Status of Drug in Other Countries

General Investigational Plan

Indication to be Studied

General Approach for Evaluation of Treatment

Description of First Year Trial(s)

Number of Subjects to be Evaluated

Drug Related Risks

Investigator Brochure

Multi-Site Investigations

Proposed Clinical Research

Study Protocol

Informed Consent

Informed Consent Checklist

Disclaimer:

Investigator and Facilities Data

Disclosure of Financial Interests

Form FDA 3454

Chemistry, Manufacturing and Control Information

Drug Substance

Drug Product

Placebo Product

Environmental Assessment

Pharmacology and Toxicology Information

Pharmacology and Drug Distribution

Pharmacology Summary and Conclusions

Toxicology: Full Data Tabulation

Previous Human Experience

Marketed Experience

Prior Clinical Research Experience

Clinical Care Experience

Additional Information

Drug Dependence and Abuse Potential

Radioactive Drugs

Pediatric Studies

Other Information

Selected References

Relevant Information

Submission Formatting

General Formatting Guidelines for Paper Submissions

Headers and Footers

The Federal Register

Writing the perfect cover letter: A look at the FDA’s forthcoming guidance on submitting RWE studies

RELATED ARTICLES

Regulatory Toolbox

Form FDA 1571

Form FDA 1572

Form FDA 3674 - Certification of Compliance

Cover Letter

Letter of Support / Authorization

Sections of the Initial IND

Introduction

General Investigational Plan

Investigator Brochure

Proposed Clinical Research

Chemistry, Manufacturing, and Control Information

Drug Substance

Drug Product

Placebo Product

Environmental Assessment

Pharmacology and Toxicology Information