FDA is responsible for assessing the safety, efficacy, and quality of drugs marketed in the United States. As part of this role, it oversees the drug development process and is responsible for approving new drugs for marketing. Patients with serious or immediately life-threatening illnesses and no other FDA-approved therapeutic options may be able to access treatments still in the development process through FDA’s expanded access program. The process by which a drug or biologic is developed and considered for approval for marketing in the United States involves a number of steps that include the clinical testing of the drug’s safety and effectiveness on human volunteers. Before a drug can be tested on humans, it is first tested for toxicity on animals. Following such testing, a manufacturer must submit an investigational new drug application (IND) to FDA in order to test the drug on humans. FDA’s decision of whether or not to allow the human testing to proceed is based, in part, on evidence and analysis regarding the drug’s toxicity in animals and the availability of human volunteers. Additional information about the typical process for human testing and FDA’s review processes is described below and depicted in figure 1. Before a drug or biologic can be tested on humans, it is tested for toxicity on animals. These tests are also used to gather basic information on the safety and efficacy of the drug or biologic. FDA may decide whether or not to allow the investigational drug to be tested on humans, based in part on results of the drug being tested on animals. A manufacturer that wants to test an investigational drug or biologic on humans must first submit an IND to FDA for the agency to review, and FDA must allow the IND to proceed before testing on humans can begin. The IND includes various components, such as the clinical treatment plan, which provides the detailed procedure for how humans will be tested, and Form FDA 1571, which contains a number of administrative elements pertaining to the request. See appendix I for a copy of this form. Clinical trials on humans can only begin after FDA has reviewed and allowed the application to proceed and an IRB has reviewed and approved the clinical treatment plan and reviewed the patient’s informed consent form. After receiving this approval, the manufacturer is considered the sponsor of an existing IND, and clinical trials that involve human volunteers can begin. Once in effect, the sponsor of the existing IND may amend its research plan as needed, such as to expand or otherwise change patient eligibility criteria. Testing under an amended treatment plan may only begin after the changes have been submitted to FDA and approved by an IRB. An investigational drug typically goes through three phases of clinical trials before it is submitted to FDA for marketing approval. According to FDA officials, in some cases when a new drug is being tested for a life- threatening ailment, the drug development process may be expedited by going through only one or two phases of clinical trials before an application is submitted to FDA for marketing approval. At any point during the clinical trials, FDA could issue a clinical hold on the existing IND that would delay the proposed or ongoing clinical trials. When a drug undergoing clinical trials is placed on clinical hold, it cannot be administered to any human volunteers. This includes volunteers already in a clinical trial, and no new volunteers may be recruited to clinical trials. If the drug completes a clinical trial phase and is not on clinical hold, FDA allows it to proceed to the next phase. The three clinical trial phases are detailed below: Phase I: Phase I clinical trials generally test the safety of the drug on about 20 to 80 healthy volunteers. The goal of this phase is to determine the drug’s most frequent side effects and how it is metabolized and excreted. If the drug does not show unacceptable toxicity in the phase I clinical trials, it may move on to phase II. Phase II: Phase II clinical trials assess the drug’s safety and effectiveness on people who have a certain disease or condition and typically are conducted on a few dozen to hundreds of volunteers. During this phase some volunteers receive the drug and others receive a control, such as a placebo. If there is evidence that the drug is effective in the phase II clinical trials, it may move on to phase III. Phase III: Phase III clinical trials generally involve several hundreds to thousands of volunteers and gather more information about the drug’s safety and effectiveness on different patient populations and at different dosages, again while being compared to a control. If phase III clinical trials are successfully completed, the drug may move on to FDA’s review and approval process. When seeking FDA’s approval to market and sell a drug in the United States, the manufacturer submits an application to FDA. Included in these submissions are the data from the safety and efficacy clinical trials for FDA to review. FDA uses the information in the application to either approve or not approve the drug. Based on a study looking at 10 years of data, among the drugs that enter Phase I clinical trials, on average, 9.6 percent were ultimately approved for marketing in the United States. For example, if 100 investigational drugs entered Phase I clinical trials, approximately 63 (63.2%) would advance to Phase II clinical trials, with 19 of those (30.7%) advancing to Phase III clinical trials. Of those 19 drugs, 11 (58.1%) would advance to the new drug application process, and, ultimately, 10 of those (85.3%) would be approved for marketing and sale in the United States. Through FDA’s expanded access program, licensed physicians, on behalf of their patients with serious or immediately life-threatening ailments, who have no other comparable medical options, and who are unable to participate in a clinical trial, can request and possibly access investigational drugs for treatment of the patients, if the patients meet certain eligibility requirements. FDA’s goals for the program are to facilitate the availability of investigational drugs when appropriate, ensure patient safety, and preserve the clinical trial development process. All expanded access requests must be submitted to FDA, and once received take effect within a designated time unless the agency acts to expedite or disallow them from proceeding. The expanded access process also requires the involvement of other entities, including the manufacturer that is developing the drug and must provide access to it, an IRB that must approve the expanded access treatment plan and review the patient’s informed consent form, and a physician who administers the drug. FDA categorizes expanded access requests into two broad categories— protocol requests and IND requests—and the roles and responsibilities of each of these entities within the process can vary depending on the category of the request. An expanded access protocol request aims to provide access to an investigational drug outside of a clinical trial when the sponsor of an existing IND submits a treatment plan for expanded access in an amendment to that existing IND. The manufacturer typically makes these requests and is, therefore, the sponsor of the expanded access request. The manufacturer must submit the expanded access treatment plan using a new Form FDA 1571 notifying FDA that the manufacturer is amending its existing IND to provide the investigational drug to one or more patients outside of the clinical trial. An expanded access protocol may be submitted to provide access to a single patient or to more than one patient. A manufacturer may decide to open an expanded access protocol because it has received requests for a drug that is still in clinical trials— for example, requests for terminal patients with no other options—or because it has a drug that has completed clinical trials and wants to make the drug available to patients who have no other comparable treatment options while waiting for FDA’s new drug approval response. For expanded access protocol requests sponsored by manufacturers, the roles and responsibilities of the various entities involved in the process typically are as follows: The manufacturer: In addition to submitting the request for the expanded access protocol to FDA, the manufacturer, as the sponsor of the request, is responsible for the collection and submission of data to FDA on any adverse events that occurred from administering the drug to patients who received it under the expanded access protocol. These data are included with the manufacturer’s regular adverse event data reporting to FDA under the existing IND. The physician: The patient’s physician administers the investigational drug to the patient and must report any serious adverse events to the manufacturer sponsoring the expanded access protocol. The IRB: A designated IRB must approve the clinical treatment plan that is submitted as part of the expanded access protocol application (similar to its review of the original clinical treatment plan) and review the patient’s informed consent form. FDA generally requires that all IRB reviews be completed by a full IRB—meaning the majority of members of the board participate in the review process—and FDA makes no specific exception for expanded access. An expanded access IND request aims to provide access to an investigational drug outside of a clinical trial and under a new IND. The vast majority of expanded access IND requests are opened to provide access to a single patient. A patient’s physician typically submits these single-patient requests and is, therefore, the sponsor of these requests and must submit to FDA the Individual Patient Expanded Access Application, using Form FDA 3926 or Form FDA 1571. See appendix II and appendix I for copies of these forms. In general, physicians would pursue expanded access IND requests when they learn of a drug being developed and think the benefit of giving their patient expanded access outweighs the risks. For expanded access IND requests sponsored by physicians, the roles and responsibilities of the various entities involved in the process typically are as follows: The physician: The physician first obtains a letter of authorization from the manufacturer that documents it will allow the physician to reference its existing IND information. After receiving this letter, the physician submits an expanded access request to FDA. If FDA allows the request to proceed to treatment, the physician must provide FDA with a written summary of the results at the conclusion of treatment. The manufacturer: The manufacturer decides whether it will allow the patient (or patients) access to the drug.