IV. What are the sponsor-investigator’s responsibilities as a sponsor?

The SI assumes all responsibilities toward co-investigators that are normally assigned to the sponsor and is responsible for maintaining aneffective IND with respect to the investigations. These responsibilities include:

A. Selection and monitoring of investigators [21 CFR 312.53]

  • Selecting qualified investigators based on training and experience
  • Obtaining a current CV from each investigator
  • Obtaining a signed Form FDA 1572 from each investigator
  • Providing investigators with the information they need to conduct the investigation properly
  • Ensuring the investigation is conducted in accordance with the general investigational plan and protocols contained in the IND
  • Ensuring that the study drug is shipped only to participating investigators
  • Reviewing on-going investigations
  • Informing co-investigators of new observations with regard to the investigational drug and progress of the study
  • Selecting qualified monitors and ensuring proper monitoring of the investigation
  • Assuring compliance of all investigators with the protocol
  • Reviewing and evaluating safety and efficacy data of the investigational drug
  • Discontinuing studies that are deemed to pose an unreasonable and significant risk to subjects
  • Ensuring the FDA and all participating investigators are promptly informed of significant new adverse events (AE) or risks with respect to the drug in safety reports as described below
  • Assuring that all participating investigators return any unused supplies of the investigational drug to the SI, or otherwise provide for disposition of the unused supplies of the drug under 21 CFR 312.59, if the investigation is terminated, suspended, discontinued or completed

B. Reporting Requirements

Once the IND is submitted and becomes effective, the SI must report the following information to the FDA

1. Protocol Amendments

Once the IND is in effect, the SI must submit a new protocol amendment to the FDA for any new or modified protocol not contained in the IND application.

The modification should include the new or modified protocol as well as documentation that the protocol amendment was submitted to the FDA and the date of submission. The study may not begin until the new protocol has been reviewed and approved by the FDA and the IRB.

UI IRB policy

If the SI submits a new protocol to his/her IND application, the IRB expects that the IND holder maintain one IRB application that contains the entirety of the IND application and includes a full history of the initial submission and all amendments that are submitted to the FDA.

Each ancillary study to be conducted at the UI should be submitted in a separate IRB application, include the required IND information relevant to the ancillary study only and reference the IRB ID# of the main IND study in Section I.4.

All amendments must also be submitted to, reviewed and approved by the IRB before implementation.

Protocol amendments are necessary when a sponsor wants to change a previously submitted protocol or add a study procedure not submitted in the original IND.
The following protocol changes must be submitted to the FDA.

  • For Phase 1 studies, any change that significantly affects the safety of subjects
  • For Phase 2 and 3 studies, any change that significantly affects the safety of subjects, the scope of the investigation, or the scientific quality of the study
  • New investigator [21 CFR 312.30(c)]

The addition of a new investigator must be reported to the FDA within 30 days of the investigator being added. Once the investigator is added to the study, the investigational drug may be shipped to the investigator and s/he may begin participating in the study.

There is no set schedule for FDA review of protocol amendments; each review is dependent on the reviewer’s workload. Therefore, the sponsor should contact the FDA project manager assigned to the IND to ascertain the review status of each amendment prior to implementation.

2. Information amendments [21 CFR 312.31]

Any essential information that is not included in a protocol amendment, IND safety report, or annual report must be submitted to the FDA. Examples of essential information include:

  • New toxicology, chemistry, or other technical information
  • Discontinuation of an investigation
  • Information amendments should be submitted as necessary, but not more than every 30 days

When several submissions of new protocols, or protocol changes are anticipated in a short period, the sponsor is encouraged to include these in a single submission.

3. IND safety/adverse events reports [21 CFR 312.32]

Definitions that apply to IND safety reporting requirements

  • Adverse event is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
  • Adverse reaction is any adverse event caused by the drug
  • Suspected adverse reaction is any adverse event for which there is a reasonable possibility that the drug caused the adverse event.
    • Reasonable possibility means there is evidence to suggest a causal relationship between the drug and the adverse event
  • Life-threatening adverse event or life-threatening suspected adverse reaction is an event that places the subject at immediate risk of death.
    • It does not include events that, if they had occurred in a more severe form, might have caused death
  • Serious adverse event or serious suspected adverse reaction is an event that results in:
    • Death
    • Life-threatening adverse event
    • Inpatient hospitalization or prolongation of existing hospitalization,
    • Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
    • Congenital anomaly/birth defect
    • Important medical events that may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed above

FDA regulations require that sponsors make the causality assessment, based on information received from investigators; and indicates that the sponsor should consider both the investigator’s and the sponsor’s assessment when determining if an event is serious.

  • Unexpected adverse event or unexpected suspected adverse reaction is an event that:
    • It is not listed in the investigator brochure (IB) or
    • If it is listed, it includes those events that occur with members of the class of drugs or are anticipated as part of the pharmacological properties of the drug but have not previously been observed with the investigational drug; or
    • If an investigator brochure is not required or available, it is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended

Why are IND safety reports required?

To ensure the timely communication of significant new information about experiences with the investigational drug. Findings that suggest a significant risk would ordinarily result in a safety-related change in the protocol, ICD, IB or the conduct of the study (e.g., result in a protocol amendment).

To whom are they submitted?

  • The FDA division that is responsible for the IND review
  • All participating investigators – this includes
    • All investigators participating in clinical trials under the IND (including US and non-US sites)
    • Investigators conducting a study under their own IND for whom the sponsor provides the drug

How should they be reported?

  • By phone, fax, or e-mail
  • If the IND is in eCTD (electronic common technical document) format, the IND safety report may be submitted in this format

What should be reported and when?

  • Serious and unexpected suspected adverse reaction (SUSAR)
    • Must be reported only if the SI determines there is evidence to suggest a causal relationship between the drug and the adverse event.
    • Must be reported as soon as possible, but in no case later than 15 calendar days after the SI determines that the information qualifies for reporting as indicated below
  • Unexpected fatal or life-threatening suspected adverse reactions
    • Must be reported as soon as possible
    • No later than 7 calendar days after the sponsor's initial receipt of the information
  • Findings from other studies that suggests a significant risk in humans exposed to the drug
    • Whether or not conducted under an IND
    • Whether or not conducted by the SI
    • Includes any findings from epidemiological studies, pooled analysis of multiple studies, or clinical studies
  • Findings from animal or in vitro testing that suggests a significant risk in humans exposed to the drug
    • Whether or not conducted by the SI
    • Includes reports of mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human exposure
  • Increased rate of occurrence of serious suspected adverse reactions
    • A clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure
    • The sponsor should consider a variety of factors (study population, nature and seriousness of the reaction and the magnitude of the observed increase in rate)
  • Additional information that must be included in each IND safety report:
    • All IND safety reports previously submitted to the FDA concerning a similar suspected adverse reaction
    • The significance of the suspected adverse reaction in light of previous, similar reports or any other relevant information

UI IRB policy

The following events are considered reportable per UI policy and must be reported to the IRB via the Reportable Event Form (REF) in HawkIRB.

  • Any serious adverse drug event that the PI determines to be related to the study drug, whether it is unexpected or expected that occurs in a subject enrolled by a UI investigator
  • A serious, unexpected, suspected adverse reaction (SUSAR) occurs in a subject at a non-UI site and the event impacts UI subjects or the conduct of the study at the UI (e.g., results in an amendment to protocol) it meets the reporting requirements of an unanticipated problem involving risks to subjects (UPIRTSO)
  • UI investigators must submit reportable events within 10 working days of the event or the investigator becoming aware of the event. The IRB recommends the SI attach a copy of the report that was sent to the FDA to the REF. An IRB Chair will review the REF and may request additional information.

4. Annual reports [21 CFR 312.33]

The SI must submit an annual progress report to the FDA within 60 days of the anniversary date that the IND went into effect. This is the date the FDA permitted the study to begin and can be found on the FDA IND Acknowledgement Letter. The expected contents of the progress report are included in the hyperlink above.

If the due date of the annual report does not coincide with the date the IRB Continuing Review is due, the SI should describe in the first Continuing Review (CR) application that the annual report is not yet due, but the annual report will be attached at the time of the next Continuing Review. The annual report should be included on the Continuing Review Attachment category of the IRB Continuing Review form at the time of the next Continuing Review (CR). An annual report should be attached to all subsequent CRs.

5. Withdrawal of an IND [21 CFR 312.38]

Sponsor-investigators must inform the FDA of the desire to withdraw an IND. All clinical investigations conducted under the IND must cease, all current investigators must be notified and all of the study drug must be returned to the sponsor or otherwise disposed of at the request of the sponsor per 21 CFR 312.58.

6. Financial disclosure reports [21 CFR 312.57(b)]

Any changes to financial disclosure information must be promptly reported to the FDA during the investigation and for 1 year following completion of the study. This information does not need be reported to the IRB.

7. ClinicalTrials.gov reporting and results [FDAAA801]

The responsible party should update their records within 30 days of a change to the recruitment status, or completion date. Other changes or updates to the record, such as protocol amendments, must be made at least every 12 months.

In general, results of an applicable clinical trial of a drug or biologic that is approved, licensed, or cleared by FDA must be submitted by the sponsor no later than 12 months after the primary completion date.

C. Sponsor recordkeeping [21 CFR 312.57]

The SI is responsible for maintaining the following records.

Accurate records documenting the receipt, shipment, or other disposition of the investigational drug. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment.

Documentation of any financial interests of any of the participating investigators involved in the study (see also 21 CFR 54). The sponsor-investigator is responsible for ensuring all participating investigators provide the SI with sufficient accurate financial information to allow the SI to submit complete and accurate certification or disclosure statements. The SI shall promptly update this information if any relevant changes occur during the course of the investigation and for 1 year following the completion of the study.

D. Sponsor record retention

The FDA requires that the aforementioned records must be maintained: [21CFR 312.57(c)]

  • During time of all research conducted under the IND and for 2 years after the date a marketing application is approved for the drug for the indication for which it is being investigated
  • If no application is to be filed or if the application is not approved for such an indication, the SI is responsible for maintaining the following records until 2 years after the investigation is discontinued and FDA is notified (IRB or other requirements may differ)

E. Inspection of sponsor’s records and reports [21 CFR312.58]

The SI must allow FDA employees access to all records and reports at their request. Drug Enforcement Administration and Department of Justice employees must be given access to records and reports involving controlled substances at their request.