IND Maintenance


Sponsor Responsibilities

  • Monitoring progress of all clinical investigations being conducted under the IND

  • Ensuring appropriate cGMPs for preparation of products to humans or animals

  • Maintaining financial disclosure records for applicable clinical trials

  • Notifying the IRB of any change in status of the IND (i.e. clinical hold, transfer to another sponsor, withdrawal, termination, or inactivation)

  • Registering the clinical trial at clinicaltrials.gov within 21 days of enrolling the first subject

  • Maintaining the IND via submission of protocol amendments, information amendments, safety reports, and annual reports to FDA and the IRB, as applicable

Investigator Responsibilities

  • Ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations

  • Protecting the rights, safety, and welfare of subjects under the investigator's care

  • Control of drugs/biologics under investigation

  • Obtaining the informed consent from each human subject to whom the drug/biologic is administered

Amendments

Protocol Amendments (21 CFR 312.30)

IND sponsors are expected to submit protocol amendments for new protocols or changes to existing protocols to FDA before implementing the respective changes. Additionally, new protocols or changes to the existing protocol must be approved by the local Institutional Review Board (IRB) with the responsibility for review and approval of the studies. A cover letter and Form FDA 1571 are required to be included with all amendments.

New Protocol Amendment

  • INDs can include multiple protocols that study the same drug and indication/patient population

  • A new protocol can be added if the proposed study is not covered by a protocol already contained in the IND

  • In addition to a brief description about the new study, the amendment should include the full clinical protocol, informed consent document, 1572s for relevant investigator(s), and Form FDA 3674

  • Per regulation, there is no required 30 day clock with a new protocol amendment

    • Must have IRB approval before beginning/enrolling subjects

    • It is encouraged to check with your FDA project manager before preceding to ensure the Review Team does not have any concerns. It is considered a best practice to wait ~30 days after submission of a new protocol before starting the study.

  • FDA & IRB submissions may occur in any order

  • Best practice to include IRB approval letters to FDA (required by CBER)

Change in Protocol

  • Per 21 CFR 312.30, "once an IND is in effect, a sponsor shall amend it as needed to ensure that the clinical investigations are conducted according to protocols included in the application"

  • Per the regulations, protocol amendments should be submitted to the FDA when:

    • Phase 1 – protocol changes significantly affect safety of subjects

    • Phase 2/3 – changes are made significantly affect safety of subjects, the scope of the investigation, or the scientific quality of the study

    • However, it is considered a best practice to submit all protocol changes to the FDA

  • Keep IND protocols up to date and consistent with IRB protocols

  • In addition to a copy of the revised/updated protocol, a submission of this type should include a brief summary of the differences between revised protocol and previous protocol(s) and rationale for the proposed change

  • There is no required 30 day clock with a change in protocol amendment

    • Must have IRB approval before implementing

    • It is encouraged to check with your FDA project manager before preceding to ensure the Review Team does not have any concerns

  • FDA & IRB submissions may occur in any order

  • Protocol changes may be implemented following submission to FDA and IRB approval

  • EXCEPTION: A protocol change intended to eliminate an apparent immediate hazard to subjects may be implemented immediately - provide subsequent FDA and IRB notification

New Investigator

  • Relevant for multi-center studies

  • An investigator may be added to carry out previously submitted protocol

  • FDA must be notified of the new principal investigator (i.e. a site opening) within 30 days of the investigator being added

  • Sponsor must collect and submit the 1572 and CV of the Investigator from each research site to the FDA

  • Sponsor must also collect the IRB approval letter from each research site prior to shipping investigational drug

  • Best practice to include IRB approval letters with FDA submission

Information Amendments (21 CFR 312.31)

Any amendment for information essential to the IND, which does not fit within the scope of a protocol amendment, IND safety report, or annual report. Information amendments to INDs may include new toxicology, chemistry, or other technical information or a report regarding discontinuance of a clinical or non-clinical investigation.

  • Submitted as necessary but not more than every 30 days, if feasible

  • The amendment should clearly:

    • Identify its contents

      • Chemistry, Manufacturing, and Control

      • Pharmacology/Toxicology

      • Clinical

      • Statistics

      • Clinical Pharmacology

    • State the purpose of amendment

    • Summarize/present data

    • Request for FDA comment, if applicable

Safety Reporting (21 CFR 312.32)

IND application sponsors are required to notify FDA (and all participating investigators) in a written safety report of:

  • Any adverse experience (AE) associated with the use of the drug that is both serious and unexpected

  • Any findings from tests in laboratory animals that suggest a significant risk for human subjects, including reports of mutagenicity, teratogenicity, and carcinogenicity

Serious Adverse Drug Experience - Any adverse drug experience occurring at any dose that results in any of the following outcomes:

  • Death

  • A life-threatening adverse drug experience

  • Inpatient hospitalization or prolongation of existing hospitalization

  • A persistent or significant disability/incapacity

  • Or a congenital anomaly or birth defect

Unexpected Adverse Drug Experience - Any event that is not listed in the current investigator brochure (IB) or in which the specificity or severity of which is not consistent with the IB or package insert;

  • Or, if an IB is not required or available, the specificity or severity of which is not consistent with the risk information described in the general investigational plan or elsewhere in the application

  • Note: “expected” does not include events anticipated based on pharmacological properties (i.e. not theoretical expectedness)

There are two kinds of Safety Report submissions

  • Initial Written Report - IND sponsor must report any adverse reaction or suspected adverse reaction to study treatment that is both serious and unexpected

    • Unexpected serious suspected adverse reactions and observations from animal studies suggesting significant risk to human subjects must be reported to FDA as soon as possible but no later than 15 calendar days following the sponsor's initial receipt of the information

    • Unexpected fatal or life-threatening suspected adverse reactions represent especially important safety information and must be reported to FDA as soon as possible but no later than 7 calendar days following the sponsor's initial receipt of the information

  • Follow-Up to the Written Report - Any relevant additional information obtained by the sponsor during investigation of the AE that pertains to a previously submitted IND safety report must be submitted as a Follow-up IND Safety Report. Such reports should be submitted without delay, as soon as the information is available but no later than 15 calendar days after the sponsor receives the information

Safety Report submission format

  • Narrative or Form FDA 3500A (Mandatory MedWatch)

    • Form FDA 3500A – For clinical trial safety reports, for use by IND reporters, manufacturers, distributors, importers, user facilities personnel

      Do not use: Form FDA 3500 (Voluntary MedWatch), which is used by healthcare professionals, consumers, and patients
    • Narrative format – Use this format if safety report is for animal or epidemiological studies

  • In the report, identify all safety reports previously filed to the IND for similar adverse experiences, and analyze the significance of the adverse experience in light of the previous, similar reports

Annual Reports (21 CFR 312.33)

IND application sponsors are expected to submit brief reports of the progress of the investigations conducted under their respective IND application within 60 days of the anniversary date that the application went into effect.

  • Individual Study Information - A brief summary of the status of each study in progress and each study completed during the previous year. The summary is expected to include the following information for each study:

    • The title of the study (with any appropriate study identifiers such as protocol number), its purpose, a brief statement identifying the patient population, and a statement as to whether the study is completed

    • The total number of subjects initially planned for inclusion in the study; the number entered into the study to date, tabulated by age group, gender, and race; the number of participants who completed the study; and the number who dropped out of the study for any reason

    • A brief description of any available study results. Publications related to the trial can be submitted/referenced

  • Summary Information - Information obtained during the previous year's clinical and nonclinical investigations conducted under the IND application, including:

    • A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system

    • A summary of all IND safety reports submitted during the past year

    • A list of subjects who died during participation in the investigation, with the cause of death for each subject

    • A list of subjects who dropped out during the course of the investigation in association with any adverse experience, whether or not thought to be drug related

    • A brief description of what, if anything, was obtained that is pertinent to an understanding of the drug's actions, including, for example, information about dose response, bioavailability, or relevant information from controlled trials

    • A list of the preclinical studies (including animal studies) completed or in progress during the past year and a summary of the major preclinical findings

    • A summary of any significant manufacturing or microbiological changes made during the past year

  • Update to General Investigational Plan - A description of the general investigational plan for the coming year to replace that submitted 1 year earlier

  • Update to the Investigator's Brochure - If the Investigator's Brochure has been revised, a description of the revision and a copy of the new brochure

  • Significant Protocol Updates - A description of any significant Phase 1 protocol modifications made during the previous year and not previously reported to the IND in a protocol amendment

  • Update on Foreign Marketing Developments - A brief summary of significant foreign marketing developments with the drug during the past year, such as approval of marketing in any country or withdrawal or suspension from marketing in any country

  • Log of Outstanding Business - If desired by the sponsor, a log of any outstanding business with FDA with respect to the IND application for which the sponsor requests or expects a reply, comment, or meeting

IND Annual Report Template

Ending an IND

IND Withdrawal (21 CFR 312.38) initiated by the sponsor

  • An IND application may be withdrawn by the applicant if development of the investigational product has been abandoned for any reason

  • FDA must be notified, and all clinical investigations conducted under the IND must be ended

  • If withdrawn for safety reasons, the IRB and all participating investigators must be notified

Inactive Status (21 CFR 312.45) initiated by sponsor or FDA

  • FDA may inactivate an IND if no subjects are entered into clinical studies for a period of 2 years or more or an investigation remains on clinical hold for ≥1 year

  • A sponsor is not required to submit an annual report while an IND is in inactive status

  • An inactive IND can be reactivated via a protocol amendment

  • INDs inactive for ≥5 years may be terminated by FDA

Termination (21 CFR 312.44) initiated by FDA

  • If an IND is terminated, the sponsor must end all clinical investigations under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug

  • Termination is typically based on safety issues or deficiencies in the IND or in the conduct of the investigation

  • Sponsors usually have a chance to respond (within 30 days)

  • Immediate termination of an IND may occur if at any time FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals

Please visit the FDA web site for more information.