A few decades ago, companies provided their drug to physicians in private practice or academic settings who were then allowed to use it to treat one or more patients without a formal protocol. It was assumed that the company provided the physician information about how to give the drug, what adverse events to look for, and other relevant information. The investigator was also asked to collect data, which the company sometimes collected but often did not. The patients who received the drug under these open-label conditions were reported to the Food and Drug Administration (FDA) in New Drug Applications (NDAs) and other applications, but no formal final study report was prepared or even could have been written. Institutional Review Boards did have to be informed about the patient(s) after Institutional Review Boards came into existence.

Gradually more and more companies either on their own or at the FDA‘s request started to prepare loose protocols for these compassionate studies and to try to collect as much data as possible. Those data were then roughly summarized when the NDA submission was imminent, and this summary was included as a final medical report. This state continued to evolve until today, when formal clinical protocols and case report forms (CRFs) are usually prepared and the data are entered into computers and analyzed and reported more completely than in the past.

The difference between the current and previous approaches to such protocols is enormous. At the current time, this is the standard way of conducting a compassionate use trial. In some situations, regulatory agencies place a limit on the number of patients who may be enrolled in this type of trial, until more
data on safety are established and some indication of benefit is shown. The types of early access or compassionate trials are defined in the following section.

One way of looking at the plethora of guidelines in the United States and European Union with their different intents is to ask what the goal is of each program. Often the different names reflect differences between the European Union and United States or between the Center for Devices and Radiological Health (e.g., expanded access) versus the Center for Drug Evaluation and Research (e.g., early access).

In some cases, a protocol and CRFs are prepared in case a patient is found who wants to be enrolled in the trial but does not meet entry criteria. The company may approach the relevant regulatory agency and obtain permission to enroll that patient under specific terms, and this type of trial, which is on a case-by-case enrollment, is termed a Named Patient Basis in the European Union. One difference between this approach and the others is that this approach is generally used for a few patients only. One term used in the United States is Single Patient IND.

Treatment INDs are another type of compassionate use protocol. A Treatment IND is generally applied for when it is clear to the sponsor and FDA that the product’s NDA is very likely to be approved within a relatively short time. This topic is discussed further later in this chapter.