5.3 Expanded Access & Humanitarian Device Exemptions (HDE)

Expanded Access & Humanitarian Device Exemptions (HDE)

Understanding Expanded Access (Compassionate Use)

In clinical research, the standard pathway for accessing an unapproved drug or medical device is enrollment in a controlled clinical trial. However, there are many instances where patients suffer from serious or immediately life-threatening diseases for which no satisfactory alternative FDA-approved treatments exist, and these patients are ineligible to participate in active clinical trials (e.g., due to strict inclusion/exclusion criteria or geographical distance). To address these situations, the FDA established the Expanded Access program (commonly referred to as compassionate use) under 21 CFR Part 312 Subpart I for drugs and biological products, and under comparable pathways for medical devices.

The primary objective of expanded access is to facilitate the availability of investigational products to patients with high unmet clinical needs when the primary goal is patient treatment rather than research.

For the FDA to approve an expanded access request, several general criteria must be met:

1. The patient has a serious or immediately life-threatening disease or condition.
2. There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.
3. The potential patient benefit justifies the potential risks of the treatment, and those risks are not unreasonable in the context of the disease being treated.
4. Providing the investigational drug will not interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval.

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The Three Tiers of Expanded Access for Drugs (21 CFR Part 312 Subpart I)

FDA regulations divide expanded access for investigational drugs into three distinct categories based on the size of the patient population being treated.

1. Individual Patient Expanded Access (21 CFR 312.310)

This pathway is designed for the treatment of a single, individual patient. It requires a request from the patient's licensed physician, who acts as the investigator.

• Non-Emergency Individual Patient Use: The physician submits an individual patient IND to the FDA. The submission must include clinical protocols, investigator qualifications (Form FDA 1572), and a letter of authorization (LOA) from the drug sponsor allowing the FDA to reference their existing IND. Treatment cannot begin until the FDA approves the request and the reviewing IRB approves the protocol.
• Emergency Individual Patient Use (Emergency IND): If the patient's condition is immediately life-threatening and requires urgent intervention before a written submission can be prepared, the FDA can grant emergency authorization over the telephone or electronic communications. The physician must submit a written IND application to the FDA within 5 working days of the initial authorization. Additionally, the investigator must notify the IRB of the emergency use within 5 working days, although full prospective IRB review may be deferred if necessary to save the patient's life.

2. Intermediate-Size Patient Populations (21 CFR 312.315)

This pathway is utilized when a sponsor or physician wants to treat a cohort of patients smaller than a full-scale treatment IND (typically ranging from 10 to 100+ patients). This pathway is appropriate when a drug is not being actively developed for a specific indication but has shown promise, or when patients cannot participate in ongoing trials. The FDA requires that the sponsor demonstrate active efforts to seek marketing approval for the drug.

3. Treatment IND or Treatment Protocol (21 CFR 312.320)

A Treatment IND (or treatment protocol under an existing IND) is used for large-scale expanded access during the final stages of drug development. It is typically initiated during Phase 3 trials or after clinical trials are completed but while the New Drug Application (NDA) is undergoing FDA review.

To obtain a Treatment IND:

• The drug must be under active clinical development for a serious or life-threatening condition.
• There must be sufficient safety and efficacy data (usually from Phase 3 or late Phase 2 trials) to support the use.
• The sponsor must be actively pursuing marketing approval with due diligence.

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Humanitarian Use Devices (HUD) and Humanitarian Device Exemptions (HDE)

To encourage the development of medical devices for patients with rare diseases, Congress established a specialized regulatory pathway under the Safe Medical Devices Act of 1990. This pathway involves two concepts: Humanitarian Use Device (HUD) designation and the Humanitarian Device Exemption (HDE) marketing application under 21 CFR Part 814 Subpart H.

Humanitarian Use Device (HUD) Designation

A Humanitarian Use Device (HUD) is a medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects fewer than 8,000 individuals in the United States per year.

• To obtain HUD designation, the sponsor must submit a request to the FDA's Office of Orphan Products Development (OOPD).
• The sponsor must provide scientific and demographic data proving that the target patient population in the U.S. does not exceed the 8,000-patient annual threshold.

The Humanitarian Device Exemption (HDE) Application

Once a device receives HUD designation, the sponsor must submit a Humanitarian Device Exemption (HDE) application to the FDA to obtain marketing approval. The HDE is a unique marketing application that is exempt from the standard requirement to demonstrate effectiveness.

Under standard Premarket Approval (PMA) regulations, a sponsor must prove through clinical trials that a device is safe and effective. Because the patient population for an HUD is so small, conducting large-scale clinical trials to prove effectiveness is often scientifically and financially impossible.

Therefore, the HDE pathway requires the sponsor to demonstrate only that:

1. The device is safe (it does not pose an unreasonable or significant risk of illness or injury).
2. The probable benefit to health from its use outweighs the risk of injury or illness.
3. There is no comparable legally marketed device (other than another HUD) available to treat or diagnose the disease or condition.

HDE Post-Approval Controls and IRB Role

Although an HDE allows a device to be marketed commercially, it is subject to strict post-approval controls:

• IRB Approval Required for Clinical Use: Even though the FDA has approved the HDE, the device cannot be administered to a patient at a clinical facility until the reviewing IRB has approved its clinical use. The IRB must oversee the use of the device at the institution.
• Profit Restrictions: Historically, HDE holder companies were prohibited from selling the device for an amount that exceeded the costs of research, development, fabrication, and distribution (i.e., they were prohibited from making a profit). However, under the 21st Century Cures Act, HDE holders can sell HUDs for profit if the device is intended for the treatment or diagnosis of a disease that occurs in pediatric patients, or if it meets specific adult orphan disease criteria, provided the number of devices distributed nationwide does not exceed an annual distribution number (ADN) set by the FDA.

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