eIND: exploratory IND versus emergency IND

eIND may be referred to as either exploratory Investigational New Drug (IND) or emergency Investigational New Drug (IND). An "Exploratory IND" and an "Emergency IND" are both regulatory mechanisms used in the United States by the Food and Drug Administration (FDA) to allow for the use of investigational drugs in certain circumstances. It's important to note that the exploratory IND and emergency IND represent distinct concepts.

Exploratory IND (eIND):

exploratory IND may be called 'Phase 0' clinical trial. Exploratory IND was described in FDA Guidance for Industry, Investigators, and Reviewers "Exploratory IND Studies". The guidance defined the exploratory IND as the following:

Purpose: Used for early-stage clinical trials to explore the preliminary pharmacokinetics and the pharmacodynamics features, not the safety and efficacy of a new drug or treatment. The dose is sub-therapeutic level or micro-dose.

Timing: Typically used in the early stages of drug development, before a drug has been extensively studied in humans and before the phase 1 study

Process: Requires submission of an IND application to the FDA, detailing the proposed clinical trial protocol, preclinical data, and any available safety information. However, less pre-clinical data or animal data is required for the eIND study than for the typical phase 1 study.

Review: The FDA reviews the eIND application and provides feedback before the trial can proceed.

Requirements: Investigators must adhere strictly to the protocol outlined in the IND application, and any deviations must be reported to the FDA.

Emergency IND (eIND):

Emergency Use Investigational New Drug (IND) applications are part of expanded access program (also referred to as compassionate use). expanded access program was described in 21 CRF Part 312 "Subpart I—Expanded Access to Investigational Drugs for Treatment Use". FDA has a designated page to describe the "Expanded Access" process. 

emergency INDs may also be called single-patient INDs, Individual Patient Expanded Access, or Single Patient Expanded Access. They are initiated in urgent scenarios where immediate access to an unapproved drug is necessary, and the clinical circumstances do not permit the time required for a standard IND submission. emergency INDs are primarily utilized in cases of life-threatening conditions where no established treatment options are available.

21 CRF Part 312.310 described the process for expanded access for individual patients, including for emergency use. 

Purpose: Used in emergency situations where there is no alternative treatment available, and the patient's condition is serious or life-threatening.

Timing: Typically used when there is an urgent need to provide access to an investigational drug outside of a clinical trial setting.

Conditions: Reserved for cases where standard treatments have failed, are unavailable, or are not suitable for the patient.

Review: The FDA still needs to review the emergency IND application, but needs to provide feedback / approval in a very short period (hours/days).

Expanded access, compassionate use, and eINDs

Traditionally, drug approvals relied on at least two adequate and well-controlled studies, each convincing on its own, to establish effectiveness. The adequate and well-controlled (A&WC) studies are referring to the randomized, controlled trials (RCTs). However, in some special situations (such as orphan drug development), one adequate and well-controlled study may be sufficient and the evidences from sources other than RCTs may be considered as substantial evidence of effectiveness. 

In FDAs guidance for industry (September, 2023) "Demonstrating Substantial Evidence of Effectiveness With One Adequate and Well-Controlled Clinical Investigation and Confirmatory Evidence", the following seven types of evidences are mentioned as potential substantial evidence of effectiveness.

The one highlighted is 'evidence from expanded access use of an investigational drug'. FDA guidance explained this: 

FDA has a website "Expanded Access" to define the scope of expanded access and provide guidelines how expanded access application can be obtained. There are similar terminologies in 'expanded access', compassionate use', and emergency investigational new drugs (eINDs). These three terms are explained below: 

Expanded Access:

• Expanded access, also known as "expanded access programs" or "compassionate use programs," refers to a regulatory pathway that allows patients with serious or life-threatening conditions to gain access to investigational drugs outside of clinical trials when no other treatment options are available.
• These programs are typically initiated by pharmaceutical companies or drug sponsors and require approval from regulatory agencies such as the FDA in the United States.
• Expanded access may be granted on a single-patient basis or through larger-scale programs, depending on the circumstances and the availability of the investigational drug.
• The primary goal of expanded access is to provide access to promising therapies to patients who may benefit from them, while also collecting additional data on safety and effectiveness outside of the clinical trial setting.

Compassionate Use:

• Compassionate use is often used interchangeably with expanded access, but it specifically refers to the use of investigational drugs for individual patients facing serious or life-threatening conditions who are unable to participate in clinical trials.
• Compassionate use requests are typically made by healthcare providers on behalf of their patients and are evaluated on a case-by-case basis.
• The decision to grant compassionate use access is based on factors such as the patient's medical condition, the potential benefits and risks of the investigational drug, and the availability of alternative treatments.
• Compassionate use is guided by ethical principles of beneficence and nonmaleficence, with the aim of providing relief to suffering patients while minimizing harm.

eINDs (Emergency Investigational New Drug Applications):

• eINDs are a specific type of expanded access mechanism that allows for the emergency use of investigational drugs in situations where there is an urgent medical need and no approved treatment options are available.
• eINDs are typically requested in emergency or life-threatening situations where waiting for traditional regulatory approval processes would not be feasible.
• These applications are submitted to regulatory agencies like the FDA and are subject to expedited review and approval.
• eINDs are governed by strict regulations and guidelines to ensure patient safety and ethical use of investigational drugs in emergency situations.

In summary, while all three mechanisms—expanded access, compassionate use, and eINDs—serve to provide access to investigational drugs outside of clinical trials, they differ in their specific contexts, processes, and regulatory requirements. However, they share the common goal of addressing unmet medical needs and providing hope and relief to patients facing serious or life-threatening conditions.

In clinicaltrials.gov, expanded access is categorized into three types:

Individual Patients: Allows a single patient, with a serious disease or condition who cannot participate in a clinical trial, access to a drug or biological product that has not been approved by the FDA. This category also includes access in an emergency situation.

Intermediate-size Population: Allows more than one patient (but generally fewer patients than through a Treatment IND/Protocol) access to a drug or biological product that has not been approved by the FDA. This type of expanded access is used when multiple patients with the same disease or condition seek access to a specific drug or biological product that has not been approved by the FDA.

Treatment IND/Protocol: Allows a large, widespread population access to a drug or biological product that has not been approved by the FDA. This type of expanded access can only be provided if the product is already being developed for marketing for the same use as the expanded access use.