The FDA has broad oversight and responsibility for all medical products in the United States. Its legislative basis originated in the Federal Food, Drug, and Cosmetic Act of 1938, which required that new medications be tested for safety before they could be marketed, and these results submitted to the FDA. This act developed after the sulfanilamide elixir disaster of 1937, when over 100 people died from poisoning by diethylene glycol contained in this “medication.” The teratogenic effects of thalidomide became known in Europe in the late 1950s, leading to its removal from the market in 1961. This resulted in the FDA garnering more power. In 1962, the Kefauver-Harris Amendment expanded the FDA’s responsibility and required drug manufacturers to demonstrate that their products were both safe and effective prior to marketing. These amendments raised the standard of evidence significantly for pharmaceutical companies. Due to the stricter nature of the laws, one-third of marketed drugs were eliminated from the market for unsuccessfully demonstrating their efficacy claims [5]. The Kefauver-Harris Amendment also gave the FDA control over advertising for prescription drugs and required that informed consent be obtained from patients participating in clinical trials.

The Food and Drug Administration Modernization Act of 1997 expanded the legislation to include accelerated review of drugs and medical devices, as well as regulation of advertising of unapproved uses (off-label) of approved drugs. Biologic agents, which are medical products derived from living sources, came under the FDA’s control in 1972 and later the Center for Biologics Evaluation and Research (CBER). In 2003, the FDA transferred the jurisdiction of many biologics, including monoclonal antibodies, cytokines, novel proteins, immune modulators, and growth factors, to the Center for Drug Evaluation and Research (CDER), which regulates the approval process for most drugs. CBER maintained jurisdiction over other biologics, such as vaccines, blood products, and gene therapy.

The FDA is led by the Commissioner of Food and Drugs who is appointed by the President of the United States. The Office of the Commissioner (OC) oversees all the agency’s workings and is responsible for implementing the FDA’s mission. There are seven centers within the FDA, each with a different product responsibility. The CDER has oversight for all drugs and most biologic therapeutic products. CDER is responsible for regulating the manufacturing, labeling, and advertising of drug products. Its main objective is to ensure that safe and effective agents are available to improve the health of consumers. The CDER has four functional areas:

New drug development constitutes a major function of the CDER, as it takes approximately 8 years to study and test a new drug before it is approved for use by the public [6].

The Code of Federal Regulations governs the supervision of new drug development by the FDA. The FDA requires three crucial stages for new drug approval: (1) an investigational new drug application (IND), (2) a new drug application (NDA), and (3) post-marketing surveillance (phase IV). Before any trials can take place in humans, an IND is required [7]. The IND is not an application for marketing approval but a request for an exemption from the federal statute that prohibits an unapproved drug from being shipped in interstate commerce. Commercial INDs are applications submitted primarily by companies whose ultimate goal is to obtain marketing approval for a new product. The IND needs to include toxicity data from two animal models and pharmacokinetics and pharmacodynamics. Genotoxicity (DNA mutations) screening is performed, as well as investigations on drug absorption, metabolism, and toxicity of the drug’s metabolites [8]. This process can take up to 3 years, but in most cases, it can be completed in 18 months. With some agents, long-term animal studies may continue in parallel with human clinical trials, particularly if the drug is to be used for chronic or recurrent conditions. A sponsor can also demonstrate that a drug is safe by providing data from previous clinical testing or marketing of the drug in the United States or another country. The FDA encourages meetings with the sponsor at this stage to review plans for further testing. Once the IND application has been approved, the drug sponsor can undertake clinical trials in humans. However, the vast majority of INDs are, in fact, filed for noncommercial research. This includes Investigator INDs for research proposals and Emergency Use INDs and Treatment INDs in cases where no other treatments are available for a condition.

The clinical studies process (phase I–III, described below) typically takes up to 10 years to complete and involves hundreds to thousands of patients at a cost of hundreds of millions of dollars. At its completion, the drug sponsor can submit a new drug application (NDA) to the FDA. Once the division director for that therapeutic area signs an approval action letter, the product can be legally marketed in the United States.

Comprehensive preclinical testing is required but unfortunately does not entirely predict safety of new agents in humans. Systemic allergic reactions can be difficult to predict in preclinical models, as occurred in studies with the anti-CD28 monoclonal antibody TGN1412 [9]. Preclinical studies of immunosuppressive agents are limited to assessing myelosuppression or increased frequency of infections or malignancy in animal models. However, these methods may not detect functional changes in immune function, which needs to be borne in mind when conducting these studies in healthy volunteers and obtaining informed consent at enrollment.

Once the preclinical data collection is completed, the sponsor submits an IND application, as described above. This includes manufacturing information, pharmacological data, and toxicology results. The sponsor nominates principal investigators (PI) who will undertake the clinical trials if the IND is approved. Once the FDA receives the IND, it has 30 days in which to notify the sponsor of concerns that may lead it to place a hold on the process. Otherwise, the IND is effective and clinical studies can begin.

The process of organizing and completing clinical trials is the most time-consuming and expensive element of the FDA approval procedure. Each center that intends to recruit participants is headed by a PI. The PI is responsible for securing and maintaining local institutional review board (IRB) approval and protecting the safety and rights of participants throughout the course of the clinical trial. They must maintain adequate records and submit timely reports relating to study outcomes and adverse events. During the study, the IRB reviews reports of adverse events, as well as reports from the data and safety monitoring committee to decide whether the study may continue based on interim safety reports. In practice, industry-sponsored trials for new agents will often involve contract research organizations (CRO), which assist the investigator in maintaining compliance with the local and federal regulations regarding clinical trials.

The purpose of phase I studies is to establish the safety of a drug and its side effects at various doses in healthy individuals. This process involves obtaining data on the pharmacokinetics, metabolism and excretion, and toxicity by administering the novel agent to healthy human volunteers, starting at subclinical doses. Generally, up to 100 volunteers are recruited over 6–18 months until adequate data are available to design phase II studies. Occasionally phase I studies may involve those with advanced malignancies for whom no other therapies are available. Seventy percent of clinical IND applications advance from phase I to phase II studies [10].

The objective of this enormous task is the gathering of sufficient data to submit an NDA to the FDA for approval to market the treatment. The NDA includes a comprehensive evaluation of the characteristics of the drug including physical composition, manufacturing process, pharmacological effects, toxicology, clinical efficacy, and case report data. The NDA is examined by CDER expert panels in each of the areas of interest and with external advisory committees (FDA Advisory Committees) providing further input. The key questions the FDA has to answer are (1) is this drug effective in treating the condition it purports to treat? and (2) do the results support an acceptable benefit-to-risk ratio? Considerations of cost and health economic analyses are not a part of the FDA pre-marketing approval process.

The FDA’s evaluation may include inspection of the manufacturing facilities and clinical trial sites to verify the details in the submitted application. The FDA is required to provide an interim evaluation within 6 months; and the average time to a final decision is around 24 months. During this period, the FDA is in regular contact with the drug sponsor to ensure that all additional information or data required by the expert panel is provided. The final decision of the CDER panel is either “approval,” “approvable with minor changes,” or “not approvable.” The majority of NDAs are approved, allowing the sponsor to begin manufacturing and distribution. Those considered not approvable can request an appeal hearing or retract the application and reapply with adjustments.

Once a drug becomes FDA approved, it is actually the first time it is utilized and studied in patients who were not eligible for the original trials. This may include the elderly, children, women of childbearing age, and patients with significant comorbidities. Ironically, the elderly, who constitute about 70 % of medication recipients, only make up about 30 % of clinical trial participants. In fact, a recent study demonstrated that only 26 % of UC patients seen in everyday clinical practice would have qualified for pivotal clinical trials for infliximab based on the inclusion criteria [14].

Another feature of the post-marketing phase is that the number of people exposed to the drug expands significantly beyond the confines of clinical studies to general practice. As a consequence, rare side effects, adverse events in particular populations, and long-term complications may only become obvious at this juncture. For example, a greater than expected number of cases of tuberculosis (TB) were recognized when infliximab was first used to treat Crohn’s disease [15]. Since identifying this increased risk of TB, it is now become standard practice to screen for latent TB prior to initiating an anti-TNF. Other examples are the increased risk of fungal infections with anti-TNF and progressive multifocal leukoencephalopathy (PML) with natalizumab.

For all of these reasons, the CDER’s Office of Drug Safety (ODS) monitors the safety profile of a drug after it has been approved for use. Pharmaceutical companies are required to report all adverse events associated with a new drug. In addition, there is a voluntary system of reporting by health-care workers (MedWatch). The ODS is responsible for updating labeling, notifying the public and physicians of new risks, implementing risk management programs, and rarely withdrawing drugs from the market.

Phase IV studies incorporate such post-marketing surveillance and can be requested by the FDA as part of the approval process, as in the case of infliximab’s original license in 2005. The TREAT (Therapy Resource, Evaluation, and Assessment Tool) Registry is an example of an FDA-mandated phase IV trial; and in Europe, the manufacturers of infliximab (Merck) are conducting a post-marketing safety registry for infliximab in collaboration with the European Medicines Agency (EMA). However, once a drug is approved, the FDA cannot enforce this requirement.

The post-marketing surveillance process certainly has its faults, including its dependence on health-care providers and pharmaceutical companies informing the FDA of adverse events. Despite these limitations, 20 % of drugs receive black box warnings after FDA approval, and 4 % of FDA-approved drugs are later withdrawn from the market which demonstrates the positive role of post-marketing surveillance in identifying rare safety signals [16, 17].

The Prescription Drug User Fee Act (PDUFA) was enacted in 1997 and most recently updated and reauthorized in 2012. The Act provides for financial support from pharmaceutical companies to fund the assessment and approval process for new drugs and biologics. The deadlines imposed on the FDA under the Act have led to more expedient approval decisions. However, this process has been criticized by some who feel that the practice may lead to inferior safety monitoring [18], specifically with regard to the discovery of unanticipated post-marketing adverse effects. This area remains of particular relevance to IBD, with case reports of hepatosplenic T-cell lymphoma which appeared after 10 years of antitumor necrosis factor (TNF) use [19]. To offset these concerns, the latest revision of the Act (2012) allowed increased FDA monitoring of adverse events and lengthened the time for FDA review.