Navigating Expanded Access

Purpose

The purpose of this document is to define criteria for use of FDA’s Expanded Access Program.

FDA Expanded Access Criteria

Expanded Access to Investigational Drugs

FDA regulations (21 CFR 312 Subpart I) define the circumstances under which investigational drugs can be made available to patients with serious diseases or conditions when there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the patient’s disease or condition. To be eligible, 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.

To seek access to an investigational drug, a physician must submit an Investigational New Drug (IND) application or amend an existing IND.

Expanded Access to Investigational Medical Devices

FDA regulations (21 CFR 812.36) define the circumstances under which an investigational device may be used to treat, diagnose, monitor, or prevent the patient’s condition. To be eligible, the FDA must determine:

1. The device is intended to treat or diagnose a serious or immediately life-threatening disease or condition;
2. There is no comparable or satisfactory alternative device or other therapy available to treat or diagnose that stage of the disease or condition in the intended patient population;
3. The device is under investigation in a controlled clinical trial for the same use under an approved IDE, or such clinical trials have been completed; and
4. The sponsor of the investigation is actively pursuing marketing approval/clearance of the investigational device with due diligence.

To seek access to an investigational device, a physician must submit an emergency use/compassionate use of an unapproved medical device request submit a supplement to an existing Investigational Device Exempton (IDE) application.

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Purpose

The purpose of this document is to discuss considerations for establishing institutional oversight, including review, support, and tracking of expanded access requests at academic medical centers.

Institutional Oversight of Expanded Access

While FDA authorization of expanded access is required by federal law, academic medical centers or institutions may wish to establish separate oversight to ensure compliance with federal regulations. Depending on the goal of instutitional oversight, processes or procedures can be established to:

1. Review cases to verify FDA criteria have been met;
2. Track expanded access cases at the institution;
3. Assist with requests to product manufacturers;
4. Assist with contractual agreements;
5. Assist with regulatory applications and obligations;
6. Assist with receipt, storage, and ordering of the investigational product; and/or
7. Train physicians on sponsor and investigator responsibilities.

Importantly, hospitals and health systems may have existing policies on the use of unapproved medications within their facilities and these policies should be considered when establishing institutional support of expanded access cases and/or programs.

Institutional Review

FDA’s Expanded Access Program offers access to investigational medical products for patients with serious or immediately life-threatening conditions when no comparable or satisfactory approved therapies are available. While FDA’s authorization of expanded access is required by federal law, institutions may wish to establish separate oversight by implementing a review and/or approval process for the use of investigational medical products at their centers.

Listed below are some considerations that expanded access committees may wish to consider in their review process. The make-up of the committee may vary based on the purpose and goals of the review. Thus, example commitees are provided.

Purpose of review commitee:

• Verify case meets FDA’s expanded access criteria
• Ensure adequate resources exist to support the treatment/program
• Confirm clinical capabilities for product administration and monitoring exist
• Assess benefit/risk of investigational product use
• Verify necessary approvals have been granted
• Ensure compliance with regulatory and institutional guidelines, as applicable

Examples of review committees and/or members:

• Independent physician(s) with expertise in therapeutic field
• Individual(s) familiar with expanded access
• Regulatory affairs personnel or office
• Investigational pharmacy staff
• Hospital adminstration
• Institutional Review Board (IRB)
• Clinical research oversight personnel or office

If an institution chooses to implement a review of expanded access cases and/or programs, it is advised that a policy be developed that defines the responsibilities, procedures, and timelines of the expanded access review and that this policy be made available to faculty and staff at the institution.

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Purpose

The purpose of this document is to describe processes that should be considered when requesting access to an investigational product being developed and supplied by an entity outside the institution. This entity could be a company, academic center, or service provider. Ultimately, this entity represents the manufacturer of the product and herein is referred to as manufacturer. This document includes information on how to identify an appropriate contact for requesting access, common manufacturer practices, and a list of documents that should be requested/obtained to support the expanded access request.

Processes

Identifying Expanded Access Contacts

To identify the appropriate contact for the Expanded Access request, institutional staff may wish to consider the following resources:

• Project Facilitate: https://www.fda.gov/about-fda/oncology-center-excellence/project-facilitate The Oncology Center of Excellence Project Facilitate call center is a pilot program to assist oncology healthcare providers or regulatory professionals in requesting access to investigational therapies for patients with cancer.
• Expanded Access Navigator: http://navigator.reaganudall.org/ this website provides a roadmap to guide patients, caregivers, and physicians through the expanded access request process. The website includes a drug company directory that includes links to company policies on Expanded Access and provides summary information about timeline for company acknowledgement of an Expanded Access request.
• ClinicalTrials.Gov: https://clinicaltrials.gov/ this website provides a database of privately and publicly funded clinical studies conducted around the world, including Expanded Access programs. It is possible to find existing Expanded Access programs and initiate contact.

Common Manufacturer Practices

The individual responsible for contacting the manufacturer and gaining authorization of the expanded access use should be aware that many manufacturers require a specific form or application to be completed. The physician sponsoring the request should be involved in completing any requested documentation.

Until the manufacturer agrees to the request, it is advised that minimal action be taken on an expanded access request.

In cases where the manufacturer denies the request, the investigational product may not be utilized to treat the patient.

In cases where the manufacturer agrees to the request, additional documentation should be requested to aid in the preparation and submission of regulatory applications. See section 2.3 for a list of documents and their use.

It is common practice manufacturers to request final approved versions of documents for their records. As applicable, final approved documents that incorporate changes made at the request of the manufacturer, IRB, or FDA should be sent to the manufacturer when requested.

Documents to Request

The following documents will aid in the preparation and submission of regulatory applications to oversight committees, including the FDA and IRB, and should be requested from the manufacturer upon authorization to use the requested product under expanded access.

1. Letter of Authorization or Letter of Concurrence: If the physician or institution is sponsor of the expanded access application (i.e., submits the regulatory application to the FDA), a Letter of Authorization (LOA, also called a letter of cross-reference) for drug submissions or a Letter of Concurrence for device submissions should be requested from the manufacturer. This letter will need to be included in the IRB and FDA applications.
2. Investigational Product Information: If available, obtain a copy of the pharmacy manual, Investigator’s Brochure (IB), user manual, instructions for use, or other applicable materials on use of the investigational product. This information should be provided to the treating physician and a copy sent to applicable staff (e.g., investigational pharmacy) and oversight committees (e.g., IRB).
3. Treatment Plan or Protocol Template: Request a treatment plan or protocol template and confirm whether the manufacturer needs to approve the final plan. These documents should be shared with the treating physician and other applicable staff for development of final documents.
4. Informed Consent Template: Request an informed consent template and confirm whether the manufacturer needs to approve the final form. These documents should be shared with the treating physician and other applicable staff for development of final documents.

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Templates

Confidential Disclosure Agreement Single Patient IND Template
Clinical Treatment Plan Agreement Single Patient IND Template

Purpose

The purpose of this document is to describe legal agreements that should be considered when requesting access to an investigational product being developed and supplied by an entity outside the institution. This entity could be a company, academic center, or service provider. Ultimately, this entity represents the manufacturer of the product and herein is referred to as manufacturer.

Legal Agreements

Institutional staff processing expanded access requests should consult with their institutional legal/contracts office to ensure proper agreements are in place for the expanded access use.

1. Confidential Disclosure Agreements

• Institutions may wish to put into place a confidential disclosure agreement (CDA) with the manufacturer to ensure protection of all confidential information, including individually identifiable health information.
• Unless a CDA has been put in place, all communications with the drug manufacturer should be redacted of individually identifiable health information, including the 18 HIPAA identifiers that are considered personally identifiable.

1. Expanded Access Use Agreements

• A clinical trial agreement or clinical treatment plan agreement may be required or recommended by the manufacturer providing the investigational product.
• It can be helpful for legal/contract offices to develop template agreements that are tailored to expanded access and offer these templates in their contractual negotiations.

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Templates

Non-Emergency Individual Patient Expanded Access IND Cover Letter Template
Individual Patient Expanded Access IND Letter of Authorization (LOA) Template
Individual Patient Expanded Access IND Annual Report Template

Other Resources

FDA Example of Wording for Letter of Authorization (LOA) For Individual Patient Expanded Access IND

Templates

IRB Sample Application Pathway for Individual Patient IND submission
Sample Single Patient IND Consent

Other Resources

FDA Guidance for individual patient IRB chair concurrence
Expanded Access to Investigational Drugs for Treatment Use: Questions and Answers

Purpose

To define the minimum required practices for accountability for investigational drugs and biologics.

Drug accountability

Treating physicians who oversee the expanded access use of investigational drugs are considered by the FDA to be investigators. Physicians who submit single-patient INDs and also treat the patient may be considered sponsor-investigators.

Requirements of investigators are detailed in 21 CFR 312.305(c)(4) and include, among other things, maintaining accurate drug disposition records. This process is typically referred to as “Drug Accountability.” As with investigational drugs used in clinical trials, agents used in expanded access require the same degree of drug accountability.

For physicians at sites with an Investigational Drug Service (IDS) or Research Pharmacy (RP), agent management should be delegated to that unit, as it will have staff who are well versed in the handling of investigational products. This is the best practice and should be followed whenever feasible.

For physicians who do not have a Research Pharmacy available, drug accountability can be accomplished by a clinic or institutional pharmacy. The requirements are detailed below and assume that a site does not have an electronic drug accountability system. Manufacturers and institutions may have additional requirements; these are considered a minimum.

Drug information resources

The site should request an Investigator’s Brochure (IB) and Pharmacy Manual from the manufacturer for each investigational agent. The IB will contain relevant clinical and pre-clinical safety and efficacy data about the drug. The Pharmacy Manual should describe storage, handling, preparation, and administration instructions.

required documentation

1. Recordkeeping

   • The physician or pharmacy should create a dedicated physical binder to maintain drug accountability documents. The binder may be tabulated to help organize documents. “Shipment Receipts” and “Drug Accountability Logs” are essential tabs; other potentially relevant tabs may include, “Temperature Logs”, “Pharmacy Manual”, “Expiration Memos”, “Training Logs”, and “Correspondences”.

2. Drug Accountability record forms (darfs)

   • DARFs are logs used to record inventory transactions, including drug receipt, dispensing, and destruction. A dedicated DARF is required for each investigational agent; a DARF should not contain information for multiple drugs or INDs.
   • The header of the DARF should contain the following information and should appear on each page of the DARF:
     • Name of institution
     • The IND number and/or protocol name
     • The name of the sponsor or sponsor-investigator. If industry sponsored, included the name of the local primary investigator.
     • The agent name, strength, dosage form, and container size
   • DARFs should include a running inventory balance; the quantity of drug physically onhand must match the balance indicated on the DARF. Any discrepancies should be immediately resolved.
   • Each entry on a DARF should be dated and signed or initialed by the recorder.

3. Receipt of drug

   • When drug is received from the manufacturer, the physician (or designee) should confirm that the information on the invoice is accurate, and the correct product has been received.
   • The shipment may contain a temperature tracking device that requires inactivation upon shipment receipt. Follow the included instructions for stopping the device and reporting temperature information to the manufacturer or distributer.
   • Shipping receipts and temperature tacking information must be retained. File original versions in the binder.
   • When the shipment is received, promptly record receipt on the DARF. The following information should be recorded:
     • Date of receipt
     • The patient for whom the drug is to be used
     • Quantity received
     • Expiration or retest date(s)
     • Lot number(s) or batch number(s)

4. dispensing

   • Drug should not be dispensed until informed consent is obtained.
   • Follow institutional, local, and federal standards for dispensing drugs. For example, a state board of pharmacy may require physicians to hold a special license in order to dispense to patients directly from a clinic. The board of pharmacy may also specify what information must be included on a prescription label.
   • Each time drug is dispensed or administered, the following information should be recorded on the DARF:
     • Date of dispense
     • Name of the investigator/physician overseeing treatment
     • The patient to whom it was dispensed
     • Prescribed dose
     • Lot/batch dispensed
     • Quantity dispensed
   • The dispensed product or container should have a label that states: “Caution: New Drug—Limited by Federal (or United States) law to investigational use.”
   • Patients should be asked to return any unused medication at their next visit.

5. return

   • Any drug returned by a patient should also be recorded on the drug accountability log. This information should include:
     • Date of return
     • Quantity returned

6. disposal

   • Excess product that the patient returns or remains available at the end of treatment should be disposed of per institutional requirements or returned to the manufacturer.
     • Consult the manufacturer and local institutional guidelines for appropriate disposal.
   • When product is destroyed or returned, the following information should be recorded on the DARF:
     • Date of destruction or return
     • Quantity destroyed or returned
     • Method of destruction or return

Storage

Investigational drugs and biologics should always be kept secure, in a locked room or cabinet, with access provided only to authorized individuals.

Investigational drugs and biologics should always be kept in climate controlled conditions. Consult the manufacturer for the necessary storage conditions. Temperature monitoring may be required.

Investigational drugs and biologics should always be kept separate from other drugs, including other investigational drugs under other protocols.

If a drug shipment experienced a temperature excursion during transit or a excursion was experienced during drug storage, immediately quarantine the drug and notify the manufacturer. Do not use the drug until authorized by the manufacturer.

references

• E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1). Section 4.6: Investigational Product(s)
• Kay SC, Luke DG, Tamer HR. ASHP Guidelines for the Management of Investigational Drug Products. Am J Health Syst Pharm 2018;75:561-73. doi:10.2146/ajhp170812
• Smith AJF, Redic KA. Single-patient expanded access: A primer for pharmacists. Am J Health Syst Pharm 2022;79:2118-27. doi:10.1093/ajhp/zxac242

additional resources

National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP)

The NCI CTEP website provides DARF templates and instructional training videos. NCI templates and documentation standards are not necessary for expanded access but meet the requirements for drug accountability.

CTEP DARF Templates: https://ctep.cancer.gov/forms/

CTEP DARF Training Videos: https://ctep.cancer.gov/branches/pmb/drug_training_videos.htm

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Purpose

To define the special conditions for treating a patient under an expanded access IND, which includes obtaining informed consent, collecting and reporting serious adverse events, and making changes to the expanded access treatment plan.

Institutional Oversight of Expanded Access

Once the manufacturer, FDA, and IRB have signed off on the treatment, the patient must still provide consent for the use of an investigational agent. The process of discussing the investigational treatment and obtaining patient consent is referred to as “informed consent,” and has requirements above and beyond those of a standard procedure consent. These requirements are defined in 21 CFR Part 50 Subpart B, Informed Consent of Human Subjects. Although expanded access treatment is not research, the research standards are used to ensure patient protection.

General Process

For non-emergency treatment, an IRB-approved consent form should be used. This will ensure that the consent document contains all necessary elements. The physician should review the consent document with the patient. Care should be taken to explain the treatment in detail, including the expectation for use of an investigational agent and its risks and uncertainty of the effectiveness of the product.

• If the patient cannot participate in the discussion, a legally authorized representative (LAR) can participate and sign the consent on behalf of the patient.
• If the patient does not read or speak English, additional procedures may be required. You should consult your institution for specific guidance.

The physician should answer any and all questions that the patient has. The patient should be given as much time as desired to think about their participation in the treatment. Once all questions have been answered and the patient has agreed to treatment, the patient (or LAR if applicable) and the physician should both sign the informed consent form in order to document their conversation.

• A copy of the signed form should be provided to the patient.
• A note should be added to the patient’s record that the conversation took place and that an informed consent document was signed.
• The original paper copy of the informed consent form should be kept by the physician per institutional guidelines.

Emergency Treatment

Even in emergency cases, it is important to follow as much of the informed consent process as possible. However, it is understood that some steps (such as the use of an IRB-approved consent form) may not be feasible.

• An informed consent form that includes all the required elements (See Reference Document 6.1) should be used if at all possible, even if it is not approved by the IRB.
• If there is not time to create an appropriate informed consent form (e.g. patient is coding and needs the product immediately), the physician and patient should still have a discussion of the treatment, risks and benefits. This discussion should be documented in such a way that both parties are able to sign to acknowledge the discussion.
• If it is not possible to have this discussion, because the patient is not awake/competent and a legally authorized representative is not available, a second opinion from an independent physician should be documented before treatment can proceed. This should be provided as a letter to the FDA and IRB.

Serious Adverse Events

Physicians are required to monitor patients who receive treatment through expanded access for adverse events. An “adverse event” is any negative health outcome that the patient experiences. In particular, physicians may have reporting requirements related to adverse events that are:

• Suspected to be related to the treatment
• Serious in nature, which means they result in:
  • Death
  • A life threatening experience
  • In patient hospitalization, or prolongation of existing hospitalization
  • Persistent or significant disability or permanent damage
  • Congenital abnormality or birth defect
  • Other important medical events
• Unexpected given the known (or expected) risks of the drug or device, as listed in the informed consent, Investigator’s Brochure, or label

The most critical type of adverse events are those that are suspected, unexpected, and serious. These are referred to as SUSARs (Serious, Unexpected, Suspected Adverse Events).

The most common type of adverse event that requires reporting are those that are serious, whether or not they are related. These are referred to as SAEs (Serious Adverse Events).

Reporting Timelines

Most drug manufacturers require reporting of SAEs within 24 hours of becoming aware of the SAE, whether or not they are related to the treatment. Consult the manufacturer directly for specific reporting requirements. Most institutions require reporting of SAEs that are related to treatment to the IRB in a certain timeframe, usually 14 days. SUSARs are required to be reported to the FDA as part of the IND within 15 calendar days (7 days if fatal). These should also be reported to the IRB per the appropriate institutional timeframe. MedWatch 3500A form should be used to report these events. Non-serious adverse events typically do not require individual reporting, but they should be tracked and recorded in the patient’s medical record. Any related adverse events that have not been individually reported should be included in the FDA annual report and/or IRB continuing review.

Changes to the Treatment Plan

As Expanded Access is considered to be clinical care and not a research protocol, physicians are expected to use their clinical judgement in determining treatment for the patient. However, if significant changes to the patient’s treatment are planned from those that were originally submitted, the physician is required to submit those changes to the FDA as part of the IND. Submission to the FDA can be done by submitting an amendment with a changed protocol (if available), a letter detailing the changes, and a FDA Form 3926 with “Change in Treatment Plan” selected under Item #9.For IRB submission, follow the local institutional process.

End of Treatment

Stopping the patient’s treatment is also a change that requires reporting. The physician is required to submit a summary of treatment, which can take the form of a letter, to the FDA along with an FDA Form 3926 (Item #9 should have “Summary of Expanded Access Use (treatment completed)” selected). In this letter, the physician should also ask the FDA to “withdraw” (close) the IND, which will end their reporting responsibilities. IRB submission is also typically required. Follow the instructions for the local institutional process.

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Templates

Email Template for Physician Training

Other Resources

Duke University Sponsor and Investigator Training Modules
ReGARDD Educational Videos

Purpose

To define the process for educating and training physicians participating in expanded access on the roles and responsibilities of being a sponsor, investigator, or sponsor-investigator.

Reporting Timelines

Most drug manufacturers require reporting of SAEs within 24 hours of becoming aware of the SAE, whether or not they are related to the treatment. Consult the manufacturer directly for specific reporting requirements. Most institutions require reporting of SAEs that are related to treatment to the IRB in a certain timeframe, usually 14 days. SUSARs are required to be reported to the FDA as part of the IND within 15 calendar days (7 days if fatal). These should also be reported to the IRB per the appropriate institutional timeframe. MedWatch 3500A form should be used to report these events. Non-serious adverse events typically do not require individual reporting, but they should be tracked and recorded in the patient’s medical record. Any related adverse events that have not been individually reported should be included in the FDA annual report and/or IRB continuing review.

Changes to the Treatment Plan

As Expanded Access is considered to be clinical care and not a research protocol, physicians are expected to use their clinical judgement in determining treatment for the patient. However, if significant changes to the patient’s treatment are planned from those that were originally submitted, the physician is required to submit those changes to the FDA as part of the IND. Submission to the FDA can be done by submitting an amendment with a changed protocol (if available), a letter detailing the changes, and a FDA Form 3926 with “Change in Treatment Plan” selected under Item #9.For IRB submission, follow the local institutional process.

End of Treatment

Stopping the patient’s treatment is also a change that requires reporting. The physician is required to submit a summary of treatment, which can take the form of a letter, to the FDA along with an FDA Form 3926 (Item #9 should have “Summary of Expanded Access Use (treatment completed)” selected). In this letter, the physician should also ask the FDA to “withdraw” (close) the IND, which will end their reporting responsibilities. IRB submission is also typically required. Follow the instructions for the local institutional process.

Federal Requirements

Expanded Access to Investigational Drugs

1. Sponsor Responsibilities

• Physicians that sponsor an expanded access Investigational New Drug (IND) application are required to fulfill sponsor responsibilities as stated in 21 CFR Part 312, Subpart D—Responsibilities of Sponsor and Investigators. Sponsor responsibilities apply to all expanded access applications whether they are for individual patients or intermediate-size patient populations.

2. Investigator Responsibilities

• Physicians participating as an investigator on an expanded access protocol being run under an IND are required to fulfill investigator responsibilities as stated in 21 CFR Part 312, Subpart D—Responsibilities of Sponsor and Investigators.

3. Sponsor-Investigator Responsibilities

• If the same physician both sponsors an expanded access IND and administers the investigational drug to patients, the physician will be considered a sponsor-investigator. Sponsor-investigators are required to fulfill sponsor and investigator responsibilities as stated in 21 CFR Part 312, Subpart D—Responsibilities of Sponsor and Investigators.

Expanded Access to Investigational Medical Devices

1. Sponsor Responsibilities

• Physicians that sponsor an expanded access Investigational Device Exemption (IDE) (i.e., Treatment IDE) are required to fulfill sponsor responsibilities as stated in 21 CFR Part 812, Subpart C—Responsibilities of Sponsors.
• Sponsor responsibilities apply to all expanded access applications whether they are for individual patients or intermediate-size patient populations.

2. Investigator Responsibilities

• Physicians participating as an investigator on an expanded access protocol being run under an IDE are required to fulfill investigator responsibilities as stated in 21 CFR Part 812, Subpart C—Responsibilities of Investigators.

3. Sponsor-Investigator Responsibilities

• If the same physician both sponsors an expanded access IDE and administers the investigational device to patients, the physician will be considered a sponsor-investigator. Sponsor-investigators are required to fulfill sponsor and investigator responsibilities as stated in 21 CFR Part 812, Subpart C—Responsibilities of Sponsors and 21 CFR Part 812, Subpart C—Responsibilities of Investigators.

Training Resources

It is critical to train physicians on the roles and responsibilities of sponsoring or participating as an investigator on an expanded access application. There are a number of non-research physicians who participate as sponsors or investigators on expanded access programs, and they may be unfamiliar with regulatory requirements. Lack of understanding can result in non-compliance with federal regulations and reporting.

Training should minimally cover the responsibilities required by regulation and can be performed a number of ways:

• Physicians can participate in existing training required of regulatory sponsors at the institution.
• Institutions can develop or use a pre-recorded trainings with a learning assessment such as the IND or IDE Sponsor and Investigator Training Modules created by Duke University and ReGARDD.
• Institutions can perform in person 1:1 training with individual physicians.
• Institutions can email summaries of regulatory responsibilities to physicians and require that the physician review and attest that they understand their requirements.

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Templates

Withdrawal Letter Template

Purpose

Upon completion of treatment, the expanded access request should be withdrawn by closing the submission with the IRB and submitting the summary of expanded access Use and/or withdrawal request to the FDA. To provide resources that assist with closing an expanded access request with the FDA. In closing the IRB application, sponsors should follow local IRB guidance. Included in the templates is an example of a withdrawal request for an individual patient IND.