The Food and Drug Administration (FDA), under the authority of the Federal Food, Drug, and Cosmetic Act (FFDCA), regulates the sale of drugs and biological products, such as vaccines, in the United States. Under the act, a manufacturer may not market a prescription drug without an approved new drug application (NDA) or a vaccine without an approved biologics license application (BLA). However, under limited circumstances—some of which this report addresses—there are certain mechanisms under which the FDA may expand access to a drug or biologic outside the standard regulatory framework. Two such mechanisms are expanded access to investigational drugs , commonly referred to as compassionate use , and emergency use authorization . Compassionate Use . One type of compassionate use request may come from a person with a terminal diagnosis who has tried all appropriate FDA-approved drugs. Perhaps a promising drug is being tested in a clinical trial closed to new patients or for which the patient does not qualify. In that case, a physician may ask FDA for permission to get the investigational new drug for the patient outside of the clinical trial. Before approaching FDA, the patient or physician must already have contacted the sponsor of the investigational drug, usually its manufacturer, to ask for the drug, and the manufacturer must have agreed to provide the drug pending FDA authorization. In 2014, FDA received 1,882 such requests and approved all but 9. What that 99.5% rate does not reveal is how many people took the first step—requesting access from manufacturers—and how many of those requests companies denied. Companies do not release those numbers. An article in BioCentury related a conversation with bioethicist Arthur Caplan, whom it described as consulting with many companies about expanded access, writing that Caplan "says it is likely that only a small fraction of the refusals make it into the media." Also not revealed by the over 99% FDA approval rate is how many patients and doctors did not pursue expanded access because the FDA process was too involved or lengthy. Emergency Use Authorization. Emergency use authorization (EUA) follows another path. When one of the Secretaries of Defense, Health and Human Services, or Homeland Security declares a military, domestic, or public health emergency or potential for such an emergency, FDA, following procedures authorized by law, may issue EUAs for unapproved products. Two circumstances have contributed to a recent increase in public and congressional discussion of expanded access to investigational drugs. The first is patients and interested groups who are asking state legislatures to pass right-to-try laws, which aim to bypass FDA authorization. These advocates are using the power of social media to influence manufacturers' decisions to provide investigational drugs. Second is the demand for unapproved medical products to fight Ebola virus disease. Members of Congress ask about FDA authorities and practices such as compassionate use, which can apply to one or a few patients, and emergency use authority, which expands access to investigational drugs to protect the public against national security or public health threats. Both mechanisms involve people with an immediate life-threatening condition, no standard therapy, and a possible "nothing-to-lose" attitude who are willing to try a drug that may not work or may even hasten an already imminent death. This report discusses the underlying philosophy behind how FDA, concerned with safety and effectiveness, weighs risks and benefits when deciding whether to allow access to a medical product, either through normal approval channels or outside them; FDA policies on compassionate use and emergency use authority; obstacles—perceived as the result of FDA or manufacturer decisions—to individuals' expanded access to investigational drugs, and some possible remedies; and how expanded access to compassionate use and emergency use authority might form part of a broader approach to ensuring safe, effective, and available drugs. In general, a manufacturer may not sell a drug or vaccine in the United States until FDA has reviewed and approved its marketing application. That application (a new drug application [NDA] or a biologics license application [BLA]) includes data from clinical trials as evidence of the product's safety and effectiveness for its stated purpose(s). After laboratory and animal studies have identified a potential drug or vaccine, a sponsor may submit an investigational new drug (IND) application to FDA. With FDA permission, the sponsor may then start the first of three major phases of clinical—human—trials. ( Figure 1 illustrates the general path of a pharmaceutical product.) Once the IND application is approved, researchers test in a small number of human volunteers the safety they had previously demonstrated in animals. These trials, called Phase I clinical trials, attempt "to determine dosing, document how a drug is metabolized and excreted, and identify acute side effects." If a sponsor considers the product still worthy of investment based on the results of Phase I trial, it continues with Phase II and Phase III trials. Those trials look for evidence of the product's efficacy —whether it works under controlled conditions—and evidence of how well it works when conditions are less controlled, such as effectiveness in larger groups of individuals with the particular characteristic, condition, or disease of interest. The sponsor presents analyses of the clinical trials in its marketing application—NDA or BLA—as evidence of the product's safety and effectiveness. The application also includes information on the manufacturing facilities and processes, reporting mechanisms, and labeling information. When the FDA approves a drug or licenses a vaccine, it usually leaves prescribing decisions to licensed clinicians. If the risks associated with a drug outweigh the expected benefit to the population with the condition it is meant to treat, FDA typically keeps the product off the market. Sometimes, though, FDA may approve a drug subject to certain restrictions or requirements. One mechanism is a risk evaluation and mitigation strategy (REMS), which may limit who may prescribe the drug and which pharmacies may dispense it. A REMS may require patient registries or clinical laboratory tests at the time of dispensing (e.g., for liver function or pregnancy). Once FDA has approved a drug (with or without a REMS), it places several ongoing requirements on the manufacturer. These include periodic facility registration and inspection requirements, along with manufacturer reporting requirements regarding any adverse events that may be related to the drug's use. FDA may also require studies to resolve specific questions about the drug's safety or effectiveness; such studies may require a large number of people to take the drug, or a long time to observe infrequent problems. A manufacturer may distribute a drug or vaccine in the United States only if FDA has approved its NDA or BLA, or if its use is in a clinical trial under an FDA-approved IND. Under standard procedures, individuals outside of the sponsor-run clinical trials do not have access to the investigational new drug. The FFDCA, however, permits FDA in certain circumstances to allow access to an unapproved drug or to an approved drug for an unapproved use. This report focuses on two main categories of expanded access: individual investigational new drug applications (commonly referred to as compassionate use) and emergency use authorizations . The primary route for an individual to obtain an investigational drug is to enroll in a clinical trial testing that new drug. However, an individual may be excluded from the clinical trial because its enrollment is limited to patients with particular characteristics (e.g., in a particular stage of a disease, with or without certain other conditions, or in a specified age range), or because the trial has reached its target enrollment number. Through FDA's expanded access procedure, a person, acting through a licensed physician, may request access to an investigational drug—through either a new IND or a revised protocol to an existing IND—if a licensed physician determines the patient has "no comparable or satisfactory alternative therapy available to diagnose, monitor, or treat" the serious disease or condition; and "the probable risk to the person from the investigational drug or investigational device is not greater than the probable risk from the disease or condition"; and the Secretary determines "that there is sufficient evidence of safety and effectiveness to support the use of the investigational drug" for this person; and "that provision of the investigational drug … will not interfere with the initiation, conduct, or completion of clinical investigations to support marketing approval"; and "the sponsor, or clinical investigator, of the investigational drug ... submits" "to the Secretary a clinical protocol consistent with the provisions of" FFDCA Section 505(i) and related regulations. In addition to the individual IND or protocol, regulations describe other categories of expanded use of investigational drugs: individual patient IND or protocol, including for emergency use; intermediate-size patient populations, with one IND or protocol that consolidates several individual access requests; treatment IND or treatment protocol for "widespread treatment use" when a drug is farther along the clinical trial and marketing application process. FDA makes most expanded use IND and protocol decisions on an individual-case basis. Consistent with the IND process under which the expanded use mechanism falls, the requesting physician is considered the investigator. The investigator is responsible for complying with informed consent and institutional review board (IRB) review of the expanded use. The manufacturer is responsible for required safety reports to FDA. FDA may permit a manufacturer to charge a patient for the investigational drug, but "only [for] the direct costs of making its investigational drug available" (i.e., not for development costs or profit). The widespread use of expanded access is limited by an important factor: whether the manufacturer agrees to provide the drug, which—because it is not FDA-approved—cannot be obtained otherwise. The FDA does not have the authority to compel a manufacturer to participate. Since 2004, and with the most recent amended reauthorization in 2013, the Commissioner of Food and Drugs (FDA commissioner), as delegated by the HHS Secretary, may issue an emergency use authorization (EUA) to allow temporary use of medical products that FDA has not approved or licensed, or unapproved uses for approved or licensed products.