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.