Emergency Use of an Investigational New Drug

Emergency Use of an Investigational New Drug

Emergency Use of a Drug, Biologic or Device

Purpose:

This document provides guidance to physicians who have an emergency needto use an investigational (non-FDA-approved) drug, biologic, or device in themedical care of a patient. This procedure applies solely to drugs, biologics and devices that are not approved by the FDA for any standard clinical use. Unapproved drugs, biologics or devices are considered investigational and normally require IRB approval in order to be used in humans. However, in certain emergency situations where there is insufficient time to obtain prospective IRB approval, there is a provision for the emergency use of the investigational product if various criteria are met (see emergency use criteria below). Physicians are encouraged to contact the PPHS regarding any intent to use an unapproved product for emergency use as soon as the product is being considered.

Emergency use is defined as the use of an investigational drug or biological product in a human subject in a life-threatening or severely debilitatingmedical situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval prior to use [21 CFR 56.102(d)]. The emergency use provision in the FDA regulations [21 CFR 56.104(c)] is an exemption from prior review and approval by the IRB. The exemption, which may not be used unless all of the conditions described in 21 CFR 56.102(d) are met, allows for one emergency use of a test article without prospective IRB review. FDA regulations require that any subsequent use of the investigational product at the institution have prospective IRB review and approval.

Use of FDA Approved products:

As indicated above, this policy applies to the use of investigational products that have not been approved by the FDA.

Use of a marketed product (FDA-approved) in an “off-label” manner (not the approved indication) when the intent is the "practice of medicine" (as opposed to research purposes) does not require review by an Institutional Review Board (IRB). Physicians using a product for an indication not in the approved labeling, have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product's use and effects.

Emergency Use criteria: Please read this guidance thoroughly to determine if these criteria are applicable to your situation.

1.Life-threatening OR severely debilitating situation

Life-threatening situationis defined by the FDA as:

  • Diseases/conditions where the likelihood of death is high unless the course of the disease is interrupted, and with potentially fatal outcome
  • Does not need to be immediately life-threatening or to immediately result in death: Rather, the patient must be in a life-threatening situation requiring intervention before review at a convened IRB meeting is feasible

Severely debilitating situationis defined by the FDA as:

  • Diseases/conditions that cause major irreversible morbidity (e.g. blindness, loss of limb, paralysis, stroke)
  • Requires intervention before review at a convened IRB meeting is feasible
2.No accepted standard treatment is available
  • No accepted standard treatment available is defined by the FDA as “no alternative method of approved or generally recognized therapy is available that provides an equal or greater likelihood of saving the subject’s life.”
3.No existing IRB approved study protocol accessible to the patient
Contact the Sponsor (manufacturer) of the drug/biologic/deviceto determine if there is an approved study that the patient could feasibly enroll in or an existing mechanism under which the product could be provided (e.g. treatment IND). If an approved study exists, or the product can be provided under an existing IND/IDE, the emergency use procedure may not be needed; the product manufacturer or FDA should be able to provide guidance on the next steps involved in the specific scenarios; please contact the PPHS office with additional questions (659-8980).
Check with appropriate department at Mount Sinai (and/or the Mount Sinai Clinical Trials website) to see if an approved study exists for this drug/biologic/device for this indication. If an approved study exists, the emergency use procedure may not be necessary if the study is still enrolling and the patient is eligible.
Check the PPHS website to determine if emergency use of the drug/biologic/device has previously occurred. If the article and indication have been used under emergency use procedures already, a standard application must be submitted to the IRB for prospective review. Call the PPHS office with any questions or issues regarding this requirement (659-8980).
4.Patient is not eligible for approved study
It should be determined if the patient meets entry criteria andif it is feasible to be enrolled in any existing, IRB-approved study. If the patient does qualify and it is feasibly to enroll them, that is the best course of action. If the subject does not meet criteria but enrollment exception is authorized by the sponsor (manufacturer), the study principal investigator should consult the sponsor (manufacturer) and the Protocol Deviations, Exceptions, Violations guidance accessible at
5.Not sufficient time to obtain IRB approval
The IRB considers there to be sufficient time to submit an application in order to obtain IRB review if it is known that the drug/biologic/device is needed 3 working days or more prior to a scheduled meeting of any of the fiveMount Sinai IRBs, and if the meeting will occur before use of the product is necessary (according to the treating physician’s judgment). In most weeks of the year, at least one of the IRBs is scheduled to meet, usually on a Tuesday. The fifth IRB, the executive board, is convened on an ad-hoc basis.
6.Emergency use has not already occurred at Mount Sinai
  • Since FDA regulations intend the emergency use of an unapproved drug/biologic/device without prospective IRB approval as a one-time per-institution event, the physician should consult the PPHS website for the list of products previously used at Mount Sinai via the emergency use mechanism. If the drug, biologic or device is on the list, then a standard application to the IRB needs to be submitted for IRB review for subsequent uses of the product. In the event that there is not sufficient time to obtain IRB approval prior to use, and the other criteria have been met, the physician should proceed with the emergency use application procedures, but should also contact the PPHS, and the Department Chair will need to be further consulted by the PPHS about the situation.

If all of the above conditions are true, the emergency use of an unapproved drug/biologic/device application may be appropriate. The Following steps should be taken:

Read this guidance document thoroughly, then:

  1. Contact the PPHS office regarding the intent to use a test article for emergency use purposes as soon as it is being considered for use.
  2. Contact manufacturer of drug/biologic/device to determine if they will ship the test article under an emergency IND/IDE (submitted by the physician). While 21 CFR 312.10 makes a provision for importing investigational drugs under an IND, FDA cautions against the use of Internet sellers (particularly from foreign countries) for the procurement of medications.
  3. a) DRUGS/BIOLOGICS: Submit an IND application (form 1571 and form 1572) to the FDA [please see appended instructions for completing these forms for emergency use]. If this is an emergent situation, contact the appropriate division of the FDA by telephone (see relevant contact information later in this policy) to see if they will authorize the shipment of the test article in advance of an IND submission. FDA approval for shipment is generally conditioned on the Sponsor [in this case, the physician] making appropriate IND submission as soon as practicable after receiving authorization (within 14 days). Obtain IND number and document contact person at the FDA or make a copy of any/all correspondence with the FDA on this use.

b.) DEVICE: If there is not enough time to even complete the minimum procedure of calling the FDA and submitting an IDE application, a device may be used without FDA approval if there is an immediate need to use the device and there is not time to use existing procedures to get FDA approval for use of the device. The manufacturer or physician must notify the FDA immediately after shipment of the device and again in writing after use.

  1. Complete the Checklist for emergency use and emergency use consent template as applicable (see checklists for Emergency Use of an Unapproved Drug/Biologic or Emergency Use of an Unapproved Device and the Emergency Use Consent Document)
  2. Obtain signature of the Chair of the Department on the emergency use form or provide correspondence from the Department Chair indicating his/her approval.
  3. Take the entire application- the emergency use checklist, emergency use consent document (if applicable), FDA correspondence if any, and letter from the manufacturer (if provided) to the Research Pharmacist (extension 42493) for institutional approval.

FOLLOW-UP Procedures:

  1. Within 14 days of use, the physician- sponsor must submit drug/biologic or device forms to the FDA, if IND paperwork not initially submitted per #4 above and the IND was granted pending receipt of the application. If the forms are not submitted within that time frame, the FDA will cancel the IND and use of the drug will not have been in compliance.
  2. After use, reports to the IRB regarding the outcome of the use must be submitted. Any adverse events must be reported in compliance with the adverse event reporting policy. If there is a positive outcome, or it is foreseeable that this need could potentially arise again for any other patient at Mount Sinai, consideration should be given to submitting a protocol to the IRB for subsequent use.
  3. Follow-up reports to the FDA must be made after the completion of the treatment so that the emergency IND can be closed. A follow-up report to the FDA should include the results of treatment and information concerning the disposition of any unused supplies of the drug. The IND number should be cited at the top of the first page of any communication to the FDA concerning the application.
  4. Any unexpected fatal or life-threatening adverse experience associated with the use of the drug must be reported to the FDA by telephone or fax within 7 calendar days after initial receipt of the information; any adverse experience associated with use of the drug that is both serious and unexpected must be reported to the FDA in writing no later than 15 days after initial receipt of the information
  5. In addition, annual progress reports must be submitted to the FDA.

Additional Information regarding emergency use at Mount Sinai:

  1. The Research Pharmacy is the mechanism for obtaining institutional approval at Mount Sinai for emergency use of test articles (including devices) outside of the jurisdiction of the IRB, regardless of whether you intend to use the pharmacy to dispense the drug/biologic or device. During business hours, the physician should page the research pharmacist at beeper 3680 (241-1300 then 3680#); after hours, packets can be delivered to the inpatient pharmacy at Annenberg B2, Rm 206, x47714.
  2. Data cannot be collected or used for research purposes.
  3. Since an emergency use for a test article for a particular indication is a one-time event at the institution, any subsequent use would require IRB approval. Generally, no provision exists in the federal regulations for the second use of test article at an institution. Therefore, the treating physician- in conjunction with their department-is strongly encouraged to submit an application to the IRB to open a protocol which would allow subsequent use at Mount Sinai. The PPHS office will provide assistance to those unfamiliar with the IRB application process in order to facilitate this service to the institution.

Examples:

Case I: Patient has completed a full course of standard treatment when she is admitted to the hospital in a life-threatening situation and is expected to expire within 24 hours unless she receives medical intervention. She has exhausted treatment options for her condition. Her physician is aware of an investigational new drug, which has not been approved by the FDA. The physician contacts the sponsor(manufacturer), but an existing IND does not cover the use requested. The sponsor (manufacturer) is willing to make the drug available for this use. It is a Tuesday afternoon at 4:45 pm. The next scheduled meeting of the IRB will take place in a week.

Case II: Patient is admitted to the hospital with a condition that will result in blindness, and there is no approved treatment for the condition. The physician is aware of an investigational new drug with a protocol open in Minnesota. It is not feasible to transport the patient there or to participate in the protocol as it is designed. The sponsor (manufacturer) is willing to make the drug available for this use, but cannot do so under the existing IND. The treatment is needed in the next 72 hours. It is a Friday night and the next scheduled meeting of the IRB will take place on Tuesday afternoon.

Case III: Patient has completed a full course of standard treatment when he is admitted to the hospital in a life-threatening situation and is expected to expire within 3 months unless he receives medical intervention. He has exhausted treatment options for his condition. His physician is aware of an investigational device with an active clinical trial being conducted at a different NYC hospital. It is Friday afternoon at 4:45 pm. The next scheduled IRB meeting will take place on Tuesday at 2 pm. The sponsor (manufacturer) has an IDE and protocol and consent forms are available to the Investigator.

Cases I and II would meet the criteria for an emergency use of a test article.

Case III would need to receive prospective IRB review.

Relevant Contact Information:

Mount Sinai:

PPHS office: 88980 (212-659-8980)

Research Pharmacist: 42493 (212-241-2493)

Food and Drug Administration:

Drug: Center for Drug Evaluation and Research (CDER), Division of Drug Information (HFD-240): 301-827-4570

Biologic: Center for Biologics Evaluation and Research (CBER), Office of Communication, Training and Manufacturing Assistance (HFM-40): 301-827-2000

Device: Center for Devices and Radiological Health (CDRH), Program Operations Staff: 301-594-1190

After regular business hours, all calls should be placed to the FDA Office of Emergency Operations (HFA-615): 301-443-1240

Relevant Regulations

Food and Drug Administration (FDA) regulations

  • 21 CFR 312.36 – “Emergency use of an IND” provides for submission of an IND in a situation where there is not time for submission of an IND in accordance with 21 CFR 312.23 or 312.34.
  • 21 CFR 56.102(d) – “IRB Definitions” “Emergency use means the use of a test article on a human subject in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval”
  • 21 CFR 56.102(l) – “Test Article” means any drug, biological product or medical device for human use.
  • 21 CFR 56.104(c) – “Exemptions from IRB requirement” “Emergency use of a test article, provided that such emergency use is reported o the IRB within 5 working days. Any subsequent use of the test article at the institution is subject to IRB review”

Instructions for completing FDA form 1571 for Emergency Use

  1. If you received correspondence from the FDA regarding your application, and that correspondence contained guidance on the completion of this form, follow the instructions in that letter.
  2. The physician/investigator’s name should be shown as the Sponsor of the IND, and the Investigator’s signature at the bottom of page 2.
  3. In some instances, parts of the required Contents of Application (page 2, items 5,7,8 and 9) may be satisfied by obtaining a letter from the supplier of the investigational drug authorizing the FDA to refer, on the Investigator’s behalf, to information already filed by that firm with the FDA. In addition, the Investigator should claim a categorical exclusion under 21 CFR Part 25 from the requirement to prepare an environmental assessment.
  4. To complete the clinical portion of FDA 1571 (Block 12, items 4 and 6), provide a summary of the patient’s record, including, but not limited to, such information as: patient’s past history, hospital discharge with interval note between treatment and discharge, report of any adverse reaction, and post-discharge follow-up. If treatment is expected to last an appreciable time, submit whatever information is available. You may then submit additional information when you have completed treatment, or in the required annual report, whichever is sooner.
  5. Submit three copies of all required documents to the FDA.

Other administrative instructions:

NOTE: The numbers below correspond to the numbered boxes on the Form FDA 1571

The sponsor is the person who takes responsibility for and initiates a clinical investigation A Sponsor-investigator is an individual who both initiates and conducts a clinical investigation and under whose immediate direction the investigational drug is being administered or dispensed. For administrative reasons, only one individual should be designated as sponsor.

If a pharmaceutical company will be supplying the drug, but will not itself be submitting the IND, the company is NOT the Sponsor.

  1. The date of submission is the date that the application is mailed to FDA.
  2. The address is the address to which written correspondence from FDA should be directed. If this address is post office box number, street address must also be provided.
  3. The telephone number is the number where the sponsor is usually available during normal working hours. A telephone number must be provided.
  4. For name(s) of drug, list the generic name(s) and trade name, if available. Also, state the dosage form(s).
  5. If an emergency IND number was previously assigned by FDA, or the Form FDA 1571 is being included with an amendment to the original IND, then that IND number should be entered here; otherwise, the space should be left blank.
  1. For an original IND submission, only the “Initial Investigational New Drug Application (IND)” box should be checked. For subsequent submissions, check ALL the boxes that apply since the submission may contain more than one type of information.
  2. For a Sponsor-investigator IND, items 2,3, and 4 may be briefly addressed in the cover letter or in a summary. Where the investigational drug is obtained from a supplier in a final dosage form, items 5, 7, 8 and 9 may be referenced if authorization is given by the supplier. If the investigational drug is prepared or altered in any way after shipment by the supplier, complete manufacturing (or compounding) and controls information, including information on sterility and pyrogenicity testing for parenteral drugs, must be submitted for that process in Item 7.

Item 7: When claiming a categorical exclusion, the sponsor should include the following statements: “I claim categorical exclusion (under 21 CFR 25.31[e]) for the study(ies) under this IND. To my knowledge, no extraordinary circumstances exist.”

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