A Brief History of Expanded Access (Pt. 1) 1960 – 2009

1960s — Kefauver Harris Amendment

Following the thalidomide scandal during the late 1950s and the early 1960s, the Kefauver Harris Amendment of 1962 established a drug approval process (still used today) to ensure both safety and effectiveness during development.  Compassionate Use programs in the United States (which are now referred to as Early Access Programmes, Expanded Access Programs, or Named Patient Programs) began informally at the same time as a result of concerns that the new drug approval process would hinder timely and equitable access to possibly life-saving medication.

1970s — Cancer patients advocate for access to investigational new drugs

In 1976, the U.S. Food and Drug Administration (FDA) introduced the Group C Cancer Investigational New Drug Program, which provided more access to certain investigational cancer drugs distributed by the National Cancer Institute. The Group C program was set up as a means for oncologists to use certain investigational cancer drugs to treat patients outside of Clinical Trials. The program currently provides access to drugs in phase 3 of development that have shown evidence of relative and reproducible efficacy in a specific tumor type. The FDA published its first official Expanded Access policy in 1979 in response to the growing demand for experimental cancer drugs.

The 1980s — The AIDS crisis prompts formal compassionate use pathways

The real impetus for the creation of Expanded Access and Compassionate Use pathways was the emergence of the AIDS crisis in the 1980s and with that patient advocates placed a great deal of pressure on the FDA. In response, the FDA took several significant steps to make experimental drugs, intended to treat life-threatening diseases, more widely available to severely ill patients. The agency also sped up the review and approval of the applications for these drugs.

During this period, patients started to organize themselves, which led to the formation of the first patient advocacy groups (PAGs). The AIDS patient community essentially created a blueprint for other patient advocacy organizations to become more vocal in demanding access to pre-approval drugs. These events have had a major and lasting impact on issues around access to investigational drugs.

1987 — The investigational New Drug (IND) application allows patients to obtain investigational drugs outside of Clinical Trials.

In response to patient demands, the FDA added a new regulation to the Code of Federal Regulations (CFR), which formally allowed patients to obtain access to investigational drugs outside of Clinical Trials. The new regulation divided investigational new drugs into three categories:

• Investigator IND – submitted by a physician conducting his or her own investigation of a drug.
• Emergency IND – allowing the FDA to authorize the use of experimental drugs in time-sensitive, emergency situations.
• Treatment IND – submitted for experimental drugs that showed particular promise for serious or life-threatening conditions.

These treatment-use mechanisms were designed to make promising products available as early in the drug evaluation process as possible.

1988 — The “Fast-Track” program facilitates expedited drug development

The FDA created an additional “fast-track” pathway that expedited access to drugs for life-threatening conditions by allowing drug developers to not conduct or defer Phase 3 Clinical Trials.

1992 — “Accelerated-Approval” regulations revise endpoints

The FDA began its “accelerated-approval pathway,” which allowed access based on reasonably likely patient benefits. It eased the requirements of the Clinical Trial process by eliminating clinical endpoints (e.g. hospitalization) in favor of surrogate endpoints (e.g. laboratory values) that could be obtained more quickly.

1994 — France successfully implements a Compassionate Use Framework

The Temporary Authorisation for Use (ATU) process has been in operation in France since 1994. Today it is regarded as one of the better-structured pre-approval frameworks. For promising therapies in areas of high unmet medical need, the ATU process provides a path to obtaining early market access, which leads to patients receiving necessary treatment for life-threatening diseases. It allows the exceptional use of medicinal products without marketing authorization and outside of a Clinical Trial.

2000 — Patients push for changes to the Expanded Access framework

In the 2000s, more so in the U.S. than in Europe, individual patients and advocacy groups brought cases before the courts in an attempt to make governments pass legislation that would compel companies to provide access. The stories of patients such as Josh Hardy and Abigail Burroughs rose to prominence in the public consciousness in part due to social media. The first ever global anti-cancer Expanded Access program (imatinib) was launched in this same year.

2001 — Abigail Alliance for Better Access to Developmental Drugs versus von Eschenbach

Many followed with great interest the lawsuit, Abigail Alliance for Better Access to Developmental Drugs versus von Eschenbach. The Abigail Alliance, a group that advocates for access to investigational drugs for people who are terminally ill, sued to make access a legal right. This led the FDA to realize that patients were increasingly demanding more access to investigational drugs, earlier and faster.

In 2001 within the European Union (EU) the basic notion of a Compassionate Use Program was for the first time established by Directive 2001/83/EC. This formed the legal basis for providing access outside of Clinical Trials. EU member states’ National Compassionate Use Programs, making medicinal products available either on a named patient basis or to cohorts of patients, are governed by the individual country’s legislation.

2004 — The European Union finalizes the Compassionate Use Framework

A few years later, in 2004, the exact regulatory framework that defined the term “Compassionate Use”, was created and finalized by the European Legislature under Article 83 of Regulation (EC) no. 726/2004.

This made medicinal products that were undergoing clinical trials or were within the marketing authorization process, available to a selected group of patients in the EU. Prior to that, France and Italy were the only European countries with Compassionate Use Programs incorporated into national law.

2007 – Access to investigational new drugs goes to court

The Abigail Alliance eventually lost their case in the U.S. Court of Appeals and the U.S. Supreme Court declined to hear their appeal in 2008. This upheld the previous court decision that found terminally ill patients did not have a constitutional right to unapproved drugs. The Abigail Alliance was of the opinion that the FDA was a barrier to access and attempted to address this at the federal level.

2009 – Revision of Expanded Access regulations

In response to such legal efforts and the public calling for changes to its policies, the FDA revised the U.S. Code of Federal Regulations, Part 312 by adding Subpart I. The new Expanded Access regulations ensured broad and equitable patient access to investigational drugs for treatment use. It provided safeguards, and submission requirements and established the criteria that needed to be met.

This led to the creation of three categories of access:

• Single Patient IND – for treatment of an individual patient; also used for emergency indications.
• Intermediate Sized Patient Population IND – for treatment of more than one patient but a group smaller than that treated by a Treatment IND or Protocol.
• Treatment IND or Protocol – typically for treatment of a large patient population.

The FDA also issued its Final Rule, with the goal of releasing new EA regulations. This included a description of safeguards, submission requirements, as well as certain criteria that needed to be met.

END OF Part 1. To read Part 2 click here.