IND Maintenance

Once an IND is in effect, the IND sponsor is responsible for:

• Selecting qualified investigators
• Ongoing monitoring of all studies submitted under the IND
• The validity of the data from all sites conducting research under the IND
• Maintaining adequate records of receipt, shipment, and disposition of the investigational drug
• Ensuring safety reporting to all appropriate parties

Therefore, the IND sponsor must ensure proper reporting of the following:

• Protocol Amendments
• Annual Reports
• Safety Data
• Closing out the IND

Please refer to the FDA guidance regarding reporting to an IND.

IND sponsors are expected to submit protocol amendments for new protocols or significant 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 IRB of Record with the responsibility for review and approval of the studies. The best practice is to include IRB approval letters with FDA submission.

New Protocol to an Existing IND

According to the NIH intramural IRB policy sponsors must submit the protocol to the FDA first if the study will be conducted under an IND. When a new protocol is submitted to an existing IND, a 30-day wait is not required. The NIH IRB will want evidence that the protocol has been submitted to the FDA.

• 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 form, Form FDA 1572 for the relevant investigator(s), and a Form FDA 3674.
• Per regulations, there is no required 30-day clock with a new protocol amendment.
• Each protocol must have IRB approval before beginning/enrolling subjects.
• It is considered a best practice to wait ~30 days after submission of a new protocol before starting the study.

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
• In addition to a copy of the revised/updated protocol, a submission of this type should include a brief summary of the differences between the revised protocol and previous protocol(s), and the rationale for the proposed change
• There is no required 30-day clock with a change in protocol
  • FDA must have received the amendment, if it is a significant amendment.
  • IRB approval must be received before implementing the protocol amendment(s).
  • Depending on the submission, it may be desired to check with your FDA project manager before proceeding to ensure the review team does not have any concerns.
  • If the sponsor wishes to get FDA's explicit opinion or comments on the proposed changes, a request for such comments must be submitted. The request must include the specific questions that FDA's response should address.
• Protocol changes may be implemented following submission to FDA and IRB approval. FDA and IRB submissions of this nature may occur in any order.
• EXCEPTION: A protocol change intended to eliminate an apparent immediate hazard to subjects may be implemented immediately, but the investigator must provide subsequent FDA and IRB notification.

New Investigator

An investigator may be added to carry out a previously submitted protocol. FDA must be notified of the new Principal Investigator within 30 days of the investigator being added. That includes changing NIH PI, or addition a new study site where another investigator serves as a PI.

The sponsor must collect and submit the 1572 and Curriculum Vitae 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.

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 should be submitted as an information amendment. 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.

The amendment should clearly identify its contents: chemistry, manufacturing, and control; pharmacology/toxicology; clinical; statistics; clinical pharmacology. It should also state the purpose of the amendment, summarize/present data, and request for FDA comment, if applicable.

IND application sponsors are required to notify FDA (and all participating investigators) in a written safety report of any adverse event (AE) associated with the use of the drug that is both serious and unexpected, otherwise referred to as a Suspected Unexpected Serious Adverse Reaction (SUSAR). SUSARs 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 SUSARs must be reported to FDA as soon as possible but no later than seven calendar days following the sponsor's initial receipt of the information.

Follow-up reporting: Any relevant additional information obtained by the sponsor that pertains to a previously submitted IND safety report must be submitted as a Follow-up IND Safety Report. Such report 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.

It is both the Investigator's and the sponsor's responsibility to ensure the safety of those on the clinical trial. The Investigator is responsible for tracking AEs during the study and reporting AEs to the sponsor. The sponsor is responsible for submitting SAE and other pertinent AE information to the FDA at the time of the annual report. In addition, the sponsor is responsible for updating the FDA about known risks from the drug, as discovered from literature searches or other means.

An Investigator must immediately report all serious adverse events (SAEs), whether or not considered drug related, to the sponsor and must include an assessment of whether there is a reasonable possibility that the drug caused the event. It is the sponsor's responsibility to determine if the SAE is a SUSAR and needs to be reported by expedited reporting to the FDA. FDA reporting information is here.

IND 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. The anniversary date is not floating, it will remain the same every year.

Example 1: The sponsor submitted an IND application on May 1, 2020 and received FDA receipt on May 3, 2020. The sponsor did not receive any additional FDA comments on the application, and IND went into effect on June 2, 2020. June 2 is considered IND anniversary date. Therefore, the annual report deadline will be August 1 every year.

Example 2: The sponsor submitted an IND application on May 1, 2020 and received FDA receipt on May 3, 2020. The FDA contacted the sponsor with additional questions regarding the application, and after some email exchange with the sponsor, Safe to Proceed letter was issued on May 29, 2020. In this case, May 29 is considered IND anniversary date. Therefore the annual report deadline will be July 28 every year.

The following information should be included in the annual report. The FDA Annual Report guidance can be found here.

• 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:
  1. 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.
  2. 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.
  3. 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:
  1. A narrative or tabular summary showing the most frequent and most serious adverse experiences by body system.
  2. A summary of all IND safety reports submitted during the past year.
  3. A list of subjects who died during participation in the investigation, with the cause of death for each subject. (Note, no personal identifiable information (PII) should be included.)
  4. 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. (Note, no personal identifiable information (PII) should be included.)
  5. 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.
  6. 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.
  7. 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 one 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.

If FDA considers there to be an unreasonable risk to the trial conducted under the IND, the IND will be placed on clinical hold. There are two types of clinical holds:

1. Complete clinical hold: A delay or suspension of all clinical work included in the IND.
2. Partial clinical hold: A delay or suspension of only part of the clinical work included in the IND (e.g., a specific protocol or part of a protocol is not allowed to proceed; however, other protocols or parts of the protocol are allowed to proceed under the IND).

A complete or partial clinical hold involves the FDA

1. requiring additional information and/or data,
2. reviewing the additional information and/or data, and
3. after the review, informing the sponsor that they can proceed.

The FDA may request additional information and/or data from the sponsor but unless the FDA specially notes the IND has been placed on clinical hold, the sponsor does not have to wait for FDA review and authorization to proceed before initiating a new protocol.

A sponsor must submit a complete response to the FDA for the IND to be released from the clinical hold. Per FDA definition, the complete response should have addressed all issues identified in the clinical hold letter.

1. After review of the complete response, the FDA will respond to the sponsor with a letter noting either of the following:
   • The clinical hold is lifted, and clinical work is allowed to proceed under the IND,
   • The complete clinical hold may be reduced to a partial hold, and clinical work is allowed to proceed with specific restrictions, or
   • The sponsor is informed that studies under the IND may still not proceed.
2. In the latter two cases, the FDA's letter will set forth why the clinical hold is being maintained and should be issued to the sponsor within 30 calendar days of the complete response.
3. When FDA lifts the clinical hold, they will notify a sponsor by telephone or other means of rapid communication and send a follow-up letter noting the release of the clinical hold.

Inactive Status

Inactive Status can be initiated by sponsor or FDA. FDA may inactivate an IND if no subjects are entered into clinical studies for a period of two years or more or an investigation remains on clinical hold for ≥one 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, however, INDs inactive for ≥five years may be terminated by FDA. Inactive INDs are unable to be referenced once inactive status goes into effect.

IND Withdrawal

In accordance with 21CFR312.38, a sponsor may withdraw an effective IND without prejudice at any time. The withdrawal can be initiated if a study is complete and the follow-up period has ended, or if development of the investigational product has been abandoned for any reason. FDA must be notified through the IND annual report or as a separate submission, and all clinical investigations conducted under the IND must be halted. If an IND is withdrawn, FDA shall be so notified, all clinical investigations conducted under the IND shall be ended, all current investigators notified, and all stocks of the drug returned to the sponsor or otherwise disposed of at the request of the sponsor in accordance with 312.59. If the IND is withdrawn for safety reasons, the sponsor shall promptly notify the FDA, all participating investigators, and all reviewing IRBs. If the IND is withdrawn due to study completion, include final data and the final published journal article, if applicable. The submission should also make note that all official documents will be disposed of according to federal requirements. Per 21 CFR 312.57(c), the sponsor shall retain records and reports for 2 years after a marketing application is approved for the drug; or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued. The FDA must be notified when the study records are to be disposed.

IND Termination

IND Termination can be 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. The 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.

If a protocol has been halted for futility, safety, or business reasons and has undergone a temporary stop to enrollment, or a permanent stop to the entire study, this information should be immediately communicated to the FDA. The letter to the FDA should include details of the situation, implications to the patients, plans to re-initiate the study, and a gesture to keep the FDA updated with new information via a follow-up correspondence, if applicable. The correspondence should include a summary of the issue, including any relevant data, e.g., a copy of a Data Safety Monitoring Board (DSMB) report.