Navigating Expanded Access

1 Determining Eligibility

Determining whether the patient fits expanded access criteria according to FDA regulations.

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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2 Academic Considerations

Committee and/or processes for tracking expanded access requests via a central data portal.

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.

INSTITUTIONAL SUPPORT

In order to aid expanded access requests in being processed efficiently and consistently, the institution should develop processes for handling expanded access requests and share this information with treating physicians and involved staff. Start by creating an institutional workflow that defines offices, oversight committees, and key contacts involved in processing expanded access requests. List of offices and oversight committees that may be involved:

• Regulatory affairs personnel to assist with FDA regulatory submissions
• Legal or contracts personnel to assist with confidentiality and expanded access use agreements
• Institutional Review Board (IRB) or other independent ethics committee to ensure protection of the rights, safety, and well-being of human subjects
• Clinical research personnel familiar with IRB applications to assist with IRB submissions
• Investigational Pharmacy or related entitity (e.g., Pharmacy and Therapeutics Committee, Investigational Device Review Committee) to asssit with the receipt, storage, dispensing, and return/disposition of the investigational product

Since the the level of support and/or oversight may differ based on the needs of the institution, it is important to define roles and responsibilities of involved offices and personnel. To ensure personnel understand their roles and responsibilities and how offices may interact when processing expanded access requests, it is advised that the institution conduct training with the implementation of any expanded access support programs.

INSTITUTIONAL TRACKING

To ensure the institution or oversight committee is aware of the use of investigational medical products under expanded access, the institution should develop processes for tracking expanded access requests and associated regulatory applications. Centralized tracking is advised since it offers many advantages, including the ability to:

• Quantify requests and track progress (e.g., approved, ongoing, withdrawn);
• Monitor activities for compliance with federal regulations and oversight committees;
• Determine institutional demands and resources needed for support; and
• Obtain information on patients seeking access outside of a clinical trial

Requests (and Institutional Workflow)

Institutions may track expanded access requests due to the critical interfaces required, which may need to be considered in line with institutional guidelines. These include: Interactions between physicians and regulatory bodies

• All expanded access requests must be vetted by the FDA, and in most single-patient cases, the physician will be the sponsor for this submission and will be directly responsible for complying with the regulations for investigational drugs or devices.
• Care activities associated with the administration of an investigational product will in many cases require reimbursement by Medicare or Medicaid.

Interactions between physicians and product manufacturers.

• Expanded access requires direct interactions between the treating physician and the manufacturer of the investigational product. The provision of product at no cost to the patient is occompanied by contractual terms that may obligate the physician or institution to certain levels of data sharing, financial liability, or access to patients.
• Some manufactures provide funding to offset some costs of the administration of an investigational product.

Interactions between clinics and pharmacy/investigational pharmacy

• Like other uses of investigional products, expanded access requires drug or device accountability. As such, it is critical that the institution facilitate interactions between clinical settings and pharmacy to prevent the unauthorized storage and distribution of these products.

It is advised to track the following information for the purposes of this institutional oversight:

• Requesting physicians and specialties
• Products requested
• Number of requests
• Number of patients for whom EA is requested
• Regulatory sponsorship (physician or industry)
• Manufacturer funding if applicable

Institutions can track the work associated with expanded access requests to determine institutional costs associated with supporing requests, as applicable.

Regulatory Applications

Institutions should track regulatory applications sponsored by physicians or their center, including the FDA regulatory application and the institutional review board (IRB) application. It is advised to track the following information and use it to remind the sponsor of annual reporting requirements:

• FDA Center, Review Division, and Project Manager’s Name
• FDA Application Number
• Effective/Approval Date
• IRB of Record
• IRB Application Number
• IRB Approval Date

Tracking Platform

The platform used for tracking depends upon information technology infrastructure at the institution. Regardless of the platform, hosting this information on a platform that has the ability to be shared between personel supporting expanded access requests is suggested.

• Example platforms:
  • Spreadsheet prgrams (e.g., Microsoft Excel)
  • Web based databases (e.g., REDCap)
  • IRB electronic management software
  • Clinical research management sofware

Record Keeping

It is advised that all regulatory applications resulting from expanded access requests be documented according to institutional procedures for FDA regulatory applications. Regulatory sponsors should track all submissions and communication with the FDA, including but not limited to:

• The original submission and any supplements, reports, or amendments
• Acknowledgement letter
• Safe to proceed/approval notification
• Clinical hold/disapproval notification
• Any requests for information
• All phone calls and emails exchanged with the FDA
• Original signed consent forms should be stored in an appropriate and secure area.

Per federal regulations, a sponsor is required to maintain records and reports on the use of the investigational product for a minimum of 2 years after the expanded access use is completed. Institutional record retention policies that pertain to the protection of human subjects may differ and could be dependent on the product or patient treated. Thus, local policies should be consulted and considered in the development of any record keeping procedures that will be applied to expanded access cases.

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3 Manufacturer Approval

Gaining approval from the manufacturer to provide the product or device to treat the patient.

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: https://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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4 Contracts & Agreements

Ensuring that appropriate contracts and/or agreements have been put in place to protect the manufacturer, patient, and institution.

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.
2. 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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CDA Single Patient IND Template

CTPA Single Patient IND Template

5 FDA Submission

Submitting the request to the appropriate FDA division.

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

FDA Example of Wording for Letter of Authorization (LOA) For Individual Patient…

6 IRB Review

Submitting a regulatory application to IRB for approval or chair concurrence for patient protection.

IRB Sample Application Pathway for Individual Patient IND submission

7 Product Handling

Receiving the product or device, storing it under the appropriate conditions, and preparing to document administration to the patient.

More coming soon!

8 Treating the Patient

Taking the appropriate measures to treat the patient and document in the medical record.

More coming soon!

9 Reporting Responsibilities

Understanding the reporting responsibilities of a sponsor and investigator under expanded access.

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.

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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Email Template for Physician Training

Duke University Sponsor and Investigator Training Modules
ReGARDD Educational Videos

10 Withdrawing the Expanded Access Request

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.

More coming soon!