The U.S. Food and Drug Administration (FDA) is composed of seven Centers responsible for ensuring the safety, efficacy, oversight and security of the nation's human and veterinary drugs, tobacco products, biological products, medical devices, food, cosmetics and products that emit radiation.

Center for Veterinary Medicine History
Center For Drug Evaluation and Research History
Center for Biologics Evaluation and Research History
Center for Devices and Radiological Health History
Center for Food Safety and Applied Nutrition History
National Center for Toxicological Research History
Office of Regulatory Affairs History

FDA's Center for Drug Evaluation and Research (CDER) is the Center responsible for the approval and safety monitoring of drugs, including certain therapeutic biologic products. Through CDER, FDA works closely with the pharmaceutical industry, reducing their regulatory burdens whenever possible, and helping to ensure that safe and effective medicines get to the right people at the right time. To help accomplish this work, FDA devotes a great deal of its resources towards advancing regulatory science and makes sure its decisions are based on sound scientific evidence. CDER regulates drugs but does not regulate the practice of medicine, which is the responsibility of state regulatory agencies.

FDA Regulatory Authority

Congress creates the laws that give FDA its regulatory authority. When a new law involving FDA responsibilities is passed by Congress, FDA interprets the law and creates regulations to implement the law. In the United States, Congress legislates (i.e., passes laws) and agencies (such as FDA) regulate or carry out the intent of the law.

If further clarity is needed for a regulation, FDA may develop an industry guidance document. FDA guidance is not legally binding but is intended to explain the agency's current thinking behind the regulations.

Prescription Drug Development and Approval Process

American consumers benefit from having access to the safest and most advanced pharmaceutical system in the world.

The main consumer watchdog in this system is the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER). The center's best-known job is to evaluate new drugs before they can be sold. The center's evaluation not only prevents quackery, but also provides doctors and patients the information they need to use medicines wisely. CDER ensures that drugs, both brand-name and generic, work correctly and that their health benefits outweigh their known risks.

The prescription drug development process actually begins outside FDA with preclinical research in the laboratory. When various preclinical requirements are met, such as establishing that the compound has limited toxicity, the company developing the drug, which is known as the sponsor, then requests permission from FDA to conduct studies involving human subjects.

Prior to using the drug on humans, the sponsor must submit to and receive approval from FDA for an investigational new drug application (IND). An IND explains why a compound may be a potential candidate to become a new drug.

FDA reviews the IND application for toxicity issues and determines a risk versus benefit ratio. If FDA approves the IND application, the sponsor may then initiate a phase 1 clinical trial. A phase 1 clinical trial involves between 20 and 100 healthy human subjects, and takes place over several months. These studies evaluate safety, biological effects and metabolism.

Following a successful phase 1 clinical trial, testing then progresses to a phase 2 clinical trial. In phase 2 clinical trials, several hundred selected human subjects may be involved. This phase can take several months to years to evaluate the drug's therapeutic effect, dose range and metabolism. During this phase, the goal is to minimize toxicity, maximize therapeutic effect and assess populations of patients who may be beneficially or adversely affected when taking the medication.

Phase 3 is the final clinical trials phase. This phase can include several hundred to approximately 3,000 selected human subjects. Lasting between one to four years, clinical studies during phase 3 evaluate safety, efficacy and dosing.

At various stages during the clinical trial process, FDA involvement is an important element of success. In the past, drug sponsors seeking approval of their prescription drug would have little communication between them and FDA. Today, however, ongoing dialogue between the sponsor and FDA enables a more effective process and can save valuable time and cost in the overall approval process. FDA recommends that sponsors meet with the Agency at the conclusion of phase 2 trials and following phase 3 clinical trials. This collaboration helps to ensure that the development effort stays on track, and that both parties agree on the clinical trial design and that required safety and efficacy information for the drug is appropriately developed.

After clinical studies of a drug are successfully completed, the sponsor may then submit a new drug application (NDA) to CDER. The NDA is almost always electronically submitted to FDA and assigned for review within 72 hours. For therapeutic biologics, a biologic license application (BLA) is completed and submitted in the same manner.

Current law allows FDA to charge drug makers user fees to review NDAs and BLAs. These user fees provide FDA with the necessary resources to review the application in a timely and effective manner. The user fee is submitted by the sponsor with the application.

The NDA documentation is designed to tell the drug's entire story, including results of animal studies, what happened during clinical tests, how the drug is constituted such as its components and composition, how the drug behaves in the body and how it is manufactured, processed and packaged, as well as all quality controls. Additionally, the manufacturer is legally required to create comprehensive written information about the drug. This information will be reviewed by CDER for approval. Approved written information about an FDA-approved drug is called the product label or labeling.

Full reports of the drug's studies are submitted so FDA can evaluate the data. The controlled clinical trials are especially important because they provide the only basis under law to demonstrate safety and effectiveness.

Applications are reviewed by multiple scientific disciplines within CDER and are coordinated by a project manager who serves as review coordinator and the liaison between the sponsor and FDA. This review team is composed of chemists, pharmacologists, physicians, pharmacokineticists, statisticians, microbiologists and others as needed.

When making decisions, FDA tries to inform the public as thoroughly as possible. This is called transparency. One way CDER helps to ensure transparency is through public meetings. Drugs that have new chemical structures never used before in the United States are called new molecular entities (NMEs). Per the law, FDA conducts public meetings prior to the approval of an NME. A public meeting may also be convened if safety concerns develop after approval.

Following the application review, FDA issues an official communication that informs the sponsor of the Agency's decision as to whether or not to approve the drug. An Approval letter allows commercial marketing of the product. A Complete Response letter describes important deficiencies that preclude approval unless corrected.

Pre-approval use and expedited approval methods

Because the usual approval process for prescription drugs can take several years, FDA has established special circumstances by which patients having various degrees of special needs can have access to drugs faster than usual. These circumstances include one method by which the drug is made available prior to approval, known as Single-Patient Treatment IND or more commonly referred to as "Compassionate use" or "Treatment use" and three methods by which the drug is approved faster than it would normally be approved under standard procedures, known as Priority Review, Fast Track and Accelerated Approval.

Compassionate use describes a way to make unapproved drug products available to patients. The intent is to provide treatment of patients, not primarily to evaluate the safety and effectiveness of the drug products. These unapproved drugs are called investigational drugs.

Under compassionate use, a physician may request access to a drug that is under development. The patient is informed that the drug is investigational and not FDA approved. If the patient has exhausted all approved options for a severe and life-threatening disease, they may choose to take a medicine during this investigational phase. The patient is given the opportunity to understand the limitations in knowledge about the risks and benefits of the drug at this stage of development.

The drug's sponsor decides whether to make the investigational drug available to an individual or to many patients through what is called an open protocol. The data from compassionate use are included in the application for FDA review, but since the data are not derived from a well-designed, adequately controlled clinical trial, they are not considered to be pivotal.

Priority Review drugs are drugs that CDER determines to offer a major advance in treatment, or provide a treatment where no adequate therapy exists. The Center seeks to complete review of these drugs within six months of receipt of the drug's NDA, as opposed to the standard target of ten months for review time.

Fast Track drugs are drugs that CDER considers to be able to treat serious diseases and unmet medical needs. Fast Track speeds new drug reviews. For instance, this category of review increases the level of communication CDER allocates to sponsors, is eligible for Accelerated Approval and enables sponsors to use a "rolling review" process such that CDER can review portions of an application before the submission of the full application.

Accelerated Approval applies to drugs or biologics that promise significant benefit over existing therapy for severe or life-threatening illnesses and that fill an unmet medical need. Under accelerated approval, early in the process (sometimes even before the phase 1 trials), a sponsor can inform FDA that it has a compound that is intended to treat or cure a severe and life-threatening disease, and requests an expedited review. If FDA agrees after meeting with the sponsor, the drug will be put on accelerated approval.

Under accelerated approval, FDA approves the product for marketing during or at the end of phase 2 clinical trials. The initial approval is based on a surrogate endpoint. A surrogate endpoint is a laboratory finding or physical sign that may not, in itself, be a direct measurement of how a patient feels, functions or survives but nevertheless is considered likely to predict therapeutic benefit. The sponsor still must show a clinical benefit. If the company cannot complete future studies demonstrating such benefit, FDA can revoke the product's approval and remove the product from the market.

Post-Market Surveillance and Epidemiology

Once a product is approved, the post-marketing phase of a product's lifetime begins. During this phase, products are monitored for adverse events. These events are defined as any unexpected or dangerous reaction to a drug.

Adverse events reports start once a product is on the market. By law, manufacturers are required to report any adverse events that become known to them. Conversely, health care professionals, such as doctors, nurses and pharmacists, as well as consumers are not obligated to report but are encouraged to do so voluntarily. CDER staff involved with post-market surveillance and epidemiology communicate on a regular basis with the CDER staff that originally reviewed and approved the drug to discuss safety issues.

If post-marking surveillance reveals a safety issue, FDA must determine the appropriate action, which can include:

New information added to the product's labeling.
A boxed warning, which is FDA's highest level of warning for a product. These warnings are reserved for more serious adverse events. As the name implies, the warning information is written inside a box to prominently highlight the product's information.
Product withdrawals, which involve the sponsor's removal of a product from the market. These actions may require taking the product off the market permanently.
Medical and safety alerts, which contain important safety information about a product are provided to health professionals, trade and media organizations.
Restricted use, which limits prescribing ability to those in specific medical specialties.
Restricted distribution, which ensures that a product is not available from a local pharmacy. Instead, the product must be obtained directly from the sponsor. Often training and patient-informed consent forms must be submitted prior to being able to receive the medication.
Special safety programs which are known as Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of a drug or biological product outweigh its risks which may include establishing a process to confirm patient adherence to the safety program, referred to as Elements to Assure Safe Use (ETASU).
Medication guides, which are required by FDA to be issued with certain prescribed drugs and biological products when the Agency determines that certain information is necessary to prevent serious adverse effects. Patient decision-making should be formed by information about a known serious side effect with a product, and patient adherence to directions for the use of a product is essential to its effectiveness.

Over-the-Counter Drug Development and Approval Process

Over-the-counter (OTC) drugs are defined as being safe and effective for use by the general public without seeking treatment by a health professional. Six out of every ten medications bought by consumers in the United States are OTC.

Because there are more than 300,000 marketed OTC drug products, FDA reviews and approves the active ingredients and about 80 therapeutic classes of OTC drugs instead of individual products. Each category is defined by an OTC drug monograph which is a kind of "recipe book" that covers acceptable ingredients, doses and formulations.

Using an FDA monograph, companies can manufacture and market an OTC product without the need for FDA pre-approval. Monographs define the safety, effectiveness and labeling of all marketed OTC active ingredients.

Orphan Drug Product Act

The Orphan Drug Act, through the Orphan Drug Designation program, provides orphan status to drugs and biologics. Orphan drugs are intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States, or that affect more than 200,000 persons but companies are not expected to recover the costs of developing and marketing a treatment drug. The Orphan Drug Act was passed by the U.S. Congress to facilitate research and development of such products.

Note Basics of FDA Drug Review And Approval

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