The FDA must determine that:

1. The patient or patients to be treated have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition;
    
2. The potential patient benefit justifies the potential risks of the treatment use and those potential risks are not unreasonable in the context of the disease or condition to be treated; and
   
   
3. Providing the investigational drug for the requested use will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the expanded access use or otherwise compromise the potential development of the expanded access use.

Toolkit documents directly relevant to these submission types are HRP-023, HRP-027, HRP-322, HRP-324, and HRP-325.  There are no checklists associated with Expanded Access submissions.

RDC approval is required for non-emergency single-patient expanded access requests, as well as intermediate or wide-spread treatment uses.   As the VA RDC is using a designated review process, final approval should be provided at the outset, without the need for endorsement first (in other words, these should not need to go to the VA twice).  For reports of an emergency use of a VA patient, RDC approval is NOT required but a letter of acknowledgement from the VA Chief of Staff is required.

Follow-on submissions for sIND and emergency use applications do not require VA review or approval.

An emergency use allows access to an investigational drug (including a biologic) for use by a single patient in an emergency situation (i.e., a situation that requires a patient to be treated before a written submission can be made). See HRP-322 for more information.

This submission type allows a patient to be treated without IRB approval, provided that there is insufficient time to obtain such approval. However, the IRB typically requires that Chair Concurrence be provided prior to the use. If the latter is not feasible, the use must be reported within five days of the use. For the purposes of obtaining concurrence of emergency uses, the chair or designee must be an MD. If concurrence is requested ahead of the use, study teams should be encouraged to request this by submitting an ARROW application. However, if they feel there is insufficient time to complete and submit an application in ARROW ahead of the use, the chair concurrence process can be handled via email.

Obtaining Chair Concurrence via email:

This process is initiated when the treating team emails the IRB analyst with a request for emergency use.  The treating team should be instructed to provide the following information either via email or in ARROW:

• Description of how the use meets the criteria outlined above in the “Criteria for Emergency Use”, including whether any other reasonable alternative treatments are available;
• Summary of the patient’s diagnosis and treatment history; and
• Date and/or timing of the proposed use;
• Description of the informed consent process, including when and from whom consent will be obtained; and
• Attach the following as appropriate:
  • Draft consent document
  • For drugs or biologics only, documentation of approval of the use from the FDA (or include in the email the date when the request was submitted to the FDA).
  • For devices only, a concurrence letter from an independent physician that states that use of device is warranted and no other reasonable alternative treatments are/were available.

This information should be forwarded to the Chair who can provide concurrence via email.  The study team should be instructed to follow-up with a submission in ARROW within 5 business days of the use.  A copy of the chair concurrence email should be included on the Supplemental Information Page.

Obtaining Chair Concurrence via ARROW

If the request for chair concurrence is submitted in ARROW (versus email) ahead of the use this can be sent for chair concurrence per the process below and this notification would also satisfy the 5-day report requirement (I.e. a second notification in ARROW after the use would not be required).  If concurrence is obtained via ARROW ahead of the use, the staff reviewer should determine whether or not FDA approval of the eUse IND has been uploaded in ARROW.

• If approval documentation from the FDA is uploaded, no further action is necessary after obtaining chair concurrence. The process is complete.
• If FDA approval documentation is not available, the concurrence letter sent to the study team should be edited to include the following:
  • The use may not occur until the FDA has granted approval of the eIND.  Documentation of this approval must be submitted via a change of protocol within 5 business days of treatment.

Pre-review should focus on:

• Confirming the process for emergency use was followed, including obtaining chair concurrence (or explanation as to why this was not necessary);
• Reviewing the consent document prior to use, when feasible
• Confirming that the use was reported to the IRB within 5 working days

Once the use has been reported in ARROW and pre-review has been completed:

• Complete HRP-401 (select FDA only)
• Use the “Send to IRM Member” activity to send the submission to the Chair, selecting “designated reviewer” as the reviewer type and “5-day report of an emergency use” and the review type. 
• The Chair will complete the IRB Member review activity form and submit back to the Analyst.
• When ready to approve, complete HRP-402 as follows:
  • Select “Expedited Review” and “Other” as the category. 
  • In the text box that appears document the decision: 
    • This submission represents the 5-day report of an emergency use
  • Select Continuing Review required as this is an FDA regulated submission.
    • Select “expedited approval of new protocols” as the Agenda Item Type.
  • Prepare and Send Correspondence
    • Select “Chair Acknowledgement of EUse 5 day report” as the letter template.
  • Submission moves to the Approved state.
  • CRs/COPs must still be submitted but can be reviewed by the Chair/designated reviewer using HRP-402.

Any questions related to whether criteria as outlined in HRP-322 have been met should be outlined in 401 Notes.

See HRP-324 for more information. Non-emergent single patient INDs (sINDs) can be processed in two ways:

• Chair concurrence in lieu of convened board review
• Convened board review

Which process is used depends on whether the study team requested a waiver from convened board review from the FDA. Documentation of this request must be uploaded in ARROW.  Note that no response from the FDA is required; documentation of the request is met by the study team selecting box 10b in FDA form 3926 .  If this documentation has been provided, the following process should be used:

• Staff conducts pre-review, confirming that documentation of the waiver has been requested from the FDA and is uploaded in ARROW.
• Complete HRP-401 (select FDA only)
• Use the "Send to IRB Member" activity to send the submission to the Chair, selecting "designated reviewer" as the reviewer type and "single-patient expanded access with FDA waiver" as the review type.
• The Chair will complete the IRB Member review activity form and submit back to the Analyst.
• When ready to approve, complete HRP-402 as follows:
  • Select “Expedited Review” and “Other” as the category.
  • In the text box that appears document the decision:
    • The IRB Chair reviewed this submission and concurs with the use. The decision to concur is in lieu of review and approval at a convened IRB meeting at which a majority of the members are present per the request for a waiver under 21 CFR § 56.105 of the requirements in § 56.108(c).
  • Select Continuing Review required as this is an FDA regulated submission.
  • Select “expedited approval of new protocols” as the Agenda Item Type.
• Prepare and Send Correspondence
  • Select “Expanded Access with FDA Waiver” as the letter template.
• Submission moves to the Approved state.
• CRs/COPs must still be submitted but can be reviewed by the Chair/designated reviewer using HRP-402.

If a waiver from the FDA has not been requested, the submission must be assigned for full board review: 

• Complete HRP-401 (select FDA only)
• Post-meeting, prepare and send correspondence
  • Select the "ER Approved" as the letter template.

See HRP-325 for more information. Non-emergent compassionate use of an unapproved device for a single subject follow the same procedures as for non-emergent expanded access to a drug (sIND) with a waiver from convened board review (I.e. compassionate use of a device does not require convened board review).

• Staff conducts pre-review and Ccompletes HRP-401 (select FDA only).
• Use the “Send to IRB Member” activity to send the submission to the Chair, selecting “designated reviewer” as the reviewer type and “compassionate use of a device” as the type of review. 
• The Chair will complete the IRB Member review activity form and submit back to the Analyst.
  • When ready to approve, complete HRP-402 as follows:
    • Select “Expedited Review” and “Other” as the category. 
    • In the text box that appears document the decision: 
      • This submission represents the compassionate use of a device. The  FDA does not consider the compassionate use of an unapproved device to be a clinical investigation and FDA does not require compliance with 21 CFR §50 and 21 CFR §56. The IRB Chair concurs with this use.
  • Select Continuing Review NOT required since Part 56 does not apply.
    • Select “expedited approval of new protocols” as the Agenda Item Type.
  • Prepare and Send Correspondence
    • Select “Chair Concurrence of Compassionate Use” as the letter template.
• Submission moves to the Approved state.
• CRs/COPs must still be submitted but can be reviewed by the Chair/designated reviewer using HRP-402.

Pre-review considerations:

Documentation of FDA approval of the compassionate use is NOT required prior to IRB acknowledgement, although the treating team should confirm that the use will not proceed until they have received FDA approval.

Focus the review of an expanded access request for an individual patient on assessing the risks and benefits for the patient involved. The information reviewed by the IRB must be adequate to assess whether risks to the patient have been minimized and that such risks are reasonable in relation to anticipated benefits. FDA regulations under 21 CFR § 56.111 outline the criteria for IRB review of research. In the context of an individual patient expanded access request, the FDA does not expect that a protocol will be necessary to provide the IRB with sufficient information to determine if those criteria are satisfied. Rather, a thorough patient history and treatment plan, included in the Form FDA 3926 or in another document, can be sufficient to provide the information necessary for an IRB assessment. Such information should include:

• The proposed daily dose, route, and frequency of administration, duration of planned treatment, criteria for discontinuation of treatment, and planned dose modifications for adverse events;
• The planned monitoring for adverse events, response to treatment, and changes in clinical status, as well as proposed modifications to the treatment plan to mitigate risks to patients as appropriate;
• The key details of the patient’s history, including diagnosis and a summary of prior therapy (including response to such therapy), as well as information regarding a patient’s relevant clinical characteristics (such as comorbid conditions and concomitant medications) that are necessary to assess the potential for increased risks of the drug; and
• A summary of known risks of the drug.

The following are also important components of an IRB’s review of an expanded access request for an individual patient:

• Assess the qualifications of the physician submitting the individual patient expanded access request.
• When the request is for a pediatric patient, confirm that adequate provisions are included for soliciting age-appropriate assent from children and permission from a parent or guardian, as required under 21 CFR § 50.55.
• Confirm that the informed consent document contains the information required under 21 CFR § 50.25. [For compassionate uses of a device, the FDA does not require the consent process to follow the informed consent requirements at 21 CFR §50.]

Intermediate-Size Populations

FDA may permit an investigational drug to be used for treatment of a patient population smaller than that typical of a treatment IND or treatment protocol.  In cases where FDA has received a significant number of requests for individual patient expanded access for the same use, a sponsor may be asked to consolidate expanded access under this category.  

In addition to the criteria for all expanded access listed at the beginning of this section, the FDA must also determine that there is enough evidence that the drug is safe at the proposed dose and duration and there is at least preliminary evidence of effectiveness of the drug as a therapeutic option in the patient population.  For more information about FDA requirements, please see 21 CFR § 312.315.

Large Patient Populations

Expanded access protocols for large patient populations are also referred to as treatment IND or treatment protocols and are usually sponsored by a pharmaceutical company.  This category is used for widespread treatment use of an investigational drug.  In addition to the criteria listed at the beginning of this section for all expanded access, FDA must also determine that the drug is being investigated in a controlled trial under an IND to support a marketing application for the expanded access or all clinical trials of the drug have been completed, the sponsor is actively pursuing marketing for approval of the expanded access and there is sufficient data supporting safety and effectiveness of the drug for the expanded access.

Procedures for IRB submission of expanded access protocols for intermediate–size or large populations

Intermediate size and large patient population expanded access protocols are handled the same as any other clinical trial and require full IRB review and approval under FDA regulations.  In cases where the sponsor provided protocol does not address local implementation (e.g., local identification, inclusion of any vulnerable populations consent procedures, etc.) a Site Supplement should be requested.

Emergency uses or single patient expanded access submissions (non-emergency) submitted by a UW physician but for which the use will occur at Meriter – UnityPoint Health Hospital will be processed in the same way as other emergency/single patient expanded access submissions with the following two exceptions:

• During pre-review, assign Meriter IRB administrator, Liz Michaels , as an external auditor, using the “Assign External Viewer” activity.
• These will be reviewed by the UW IRB Member/Meriter representative, who will serve as the chair designee for these cases. This is currently Steve Cattapan. When pre-review is complete, use the “Send to IRB Member” activity to assign the submission to Dr. Cattapan.

Email communications about these uses should be sent to both Dr. Cattapan (steven.cattapan@uwmf.wisc.edu) and Liz Michaels (liz.michaels@unitypoint.org).