Drug Approval Process

Most drugs that undergo pre-clinical (animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the agency's rigorous evaluation process, which scrutinizes everything about the drug--from the design of clinical trials to the severity of side effects to the conditions under which the drug is manufactured.

Stages of Drug Development and Review

  • INVESTIGATIONAL NEW DRUG APPLICATION (IND) The FDA first enters the picture when a drug sponsor submits an IND to the agency. Sponsors--companies, research institutions, and other organizations that take responsibility for marketing a drug--must show the FDA results of pre-clinical testing they've done in laboratory animals and what they propose to do for human testing. At this stage, the FDA decides whether it is reasonably safe to move forward with testing the drug on humans.

  • CLINICAL TRIALS Drug studies in humans can begin only after an IND is reviewed by the FDA and a local institutional review board (IRB), a panel of scientists and non-scientists in hospitals and research institutions that oversees clinical research.

    IRBs approve the clinical trial protocols, which describe the type of people who may participate in the clinical trial, the schedule of tests and procedures, the medications and dosages to be studied, the length of the study, the study's objectives, and other details. IRBs make sure the study is acceptable, that participants have given consent and are fully informed of their risks, and that researchers take appropriate steps to protect patients from harm.

    Phase I studies are usually conducted in healthy volunteers. The goal here is to determine what the drug's most frequent side effects are and, often, how the drug is metabolized and excreted. The number of subjects typically ranges from 20 to 80.

    Phase II studies begin if Phase I studies don't reveal unacceptable toxicity. While the emphasis in Phase I is on safety, the emphasis in Phase II is on effectiveness. This phase aims to obtain preliminary data on whether the drug works in people who have a certain disease or condition. For controlled trials, patients receiving the drug are compared with similar patients receiving a different treatment--usually a placebo or a different drug. Safety continues to be evaluated, and short-term side effects are studied. Typically, the number of subjects in Phase II studies ranges from a few dozen to about 300.

    Phase III studies begin if evidence of effectiveness is shown in Phase II. These studies gather more information about safety and effectiveness, studying different populations and different dosages and using the drug in combination with other drugs. The number of subjects usually ranges from several hundred to about 3,000 people.

    Phase IV studies occur after a drug is approved. They may explore such areas as new uses or new populations, long-term effects, and how participants respond to different dosages.


  • NEW DRUG APPLICATION (NDA)* * An application for a product that has already been approved by the FDA (e.g. for a new indication or labeling revision) is called a supplemental NDA (sNDA). An application for a biologic or biotech product is referred to as, for a new product, a Biologic License Application (BLA) and, for an approved product, a Biologic License Supplement (BLS). Biologics are reviewed by the Center for Biologics Evaluation and Research (CBER), a division of the FDA.

    The application (hereafter referred to as an "NDA") is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the United States. An NDA includes all animal and human data and analyses of the data, as well as information about how the drug behaves in the body and how it is manufactured.

    When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be reviewed. FDA can refuse to file an application that is incomplete. For example, some required studies may be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs no later than ten months after the applications were received for standard reviews and six months for priority reviews. Priority reviews are granted by the FDA after an application has been submitted and are intended for products that address unmet medical needs.

    The Tufts Center for the Study of Drug Development in Boston estimates that about 1 in 5 drugs that enter clinical testing ultimately are approved by the FDA. How often the FDA meets with a drug sponsor varies, but the two most common meeting points are at the end of Phase II clinical trials and pre-NDA--right before a new drug application is submitted.

    At the end of Phase II, the FDA and sponsors try to come to an agreement on how the large-scale studies in Phase III should be done. The pre-NDA meeting is for discussing what the FDA expects to see in the application. There is also continuous interaction throughout the review process. A mechanism that some manufacturers use to assist their product development is the Fast Track process. This is a formal mechanism whereby a manufacturer can receive input from the FDA regarding its product development plan. In addition, the manufacturer may submit its new drug or biologic application in sections for the FDA’s review, rather than all at once. Fast Track designation is given by the FDA to the combination of a product and a claim to meet an unmet medical need. A product that receives a Fast Track designation will not necessarily receive a Priority Review once the application is submitted to the FDA.


  • Reviewing Applications

    Though FDA reviewers are involved with a drug's development throughout the IND stage, the official review time is the length of time it takes to review a new drug application and issue an action letter, an official statement informing a drug sponsor of the agency's decision. Once a new drug application is filed, an FDA review team--medical doctors, chemists, statisticians, microbiologists, pharmacologists and other experts--evaluates whether the studies the sponsor submitted show that the drug is safe and effective for its proposed use. No drug is absolutely safe; all drugs have side effects. "Safe" in this sense means that the benefits of the drug appear to outweigh the risks.

    The review team analyzes study results and looks for possible problems with the application, such as weaknesses of the study design or analyses. Reviewers determine whether they agree with the sponsor's results and conclusions, or whether they need any additional information to make a decision. Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evaluations are then considered by team leaders, division directors, and office directors, depending on the type of application. Reviewers receive training that fosters consistency in drug reviews, and good review practices remain a high priority for the agency.

    Sometimes the FDA calls on advisory committees made up of outside experts who help the agency decide on drug applications. Whether an advisory committee is needed depends on many things. "Some considerations would be if it's a drug that has significant questions, if it's the first in its class, or the first for a given indication," says Mark Goldberger, M.D., director of CDER's office that evaluates drugs to treat infectious diseases and immunosuppressive agents. "Generally, FDA takes the advice of advisory committees, but not always," he says. "Their role is just that--to advise."

    FDA Decisions

    If the FDA decides that the benefits of a drug outweigh the risks, the drug will receive approval and can be marketed in the United States. But if there are problems with an NDA, the FDA may decide that a drug is "approvable" or "not approvable."

    A designation of approvable means that the drug can probably be approved, provided that some issues are resolved first. This might involve the sponsor and the FDA coming to a final agreement on what should go on the drug's label, for example. It could also involve more difficult issues, such as the adequacy of information on how people respond to various dosages of the drug.

    A designation of "not approvable" describes deficiencies significant enough that it is not clear that approval can be obtained in the future, at least not without substantial additional data. Common problems include unexpected safety issues that crop up or failure to demonstrate a drug's effectiveness. A sponsor may need to conduct additional studies--perhaps studies of more people, different types of people, or for a longer period of time. Manufacturing issues are also among the reasons that approval may be delayed or denied. Drugs must be manufactured in accordance with standards called good manufacturing practices, and the FDA inspects manufacturing facilities before a drug can be approved. If a facility isn't ready for inspection, approval can be delayed. Any manufacturing deficiencies found would need to be corrected before approval.

    "Sometimes a company may make a certain amount of a drug for clinical trials. Then when they go to scale up, they may lose a supplier or end up with quality control issues that result in a product of different chemistry," says the FDA's Kweder. "Sponsors have to show us that the product that's going to be marketed is the same product that they tested."

    John Jenkins, M.D., director of CDER's Office of New Drugs, says, "It's often a combination of problems that prevent approval." Close communication with the FDA early on in a drug's development reduces the chance that an application will have to go through more than one cycle of review, he says. "But it's no guarantee."

    The FDA outlines the justification for its decision in an action letter to the drug sponsor. When the action is either approvable or not approvable, CDER gives the sponsor a chance to meet with agency officials to discuss the deficiencies. At that point, the sponsor can choose to ask for a hearing or correct any deficiencies and submit new information.

    Accelerated Approval

    Traditional approval requires that clinical benefit be shown before approval can be granted. Accelerated approval is given to some new drugs for serious and life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be approved before measures of effectiveness that would usually be required for approval are available.

    Instead, less traditional measures called "surrogate endpoints" are used to evaluate effectiveness. These are laboratory findings or signs that may not be a direct measurement of how a patient feels, functions, or survives, but are considered likely to predict benefit. For example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of time with anti-retroviral drugs.

    Most drugs to treat HIV have been approved under accelerated approval provisions, with the company required to continue its studies after the drug is on the market to confirm that its effects on virus levels are maintained and that it ultimately benefits the patient. Under accelerated approval rules, if studies don't confirm the initial results, the FDA can withdraw the approval. Because premarket review can't catch all potential problems with a drug, the FDA continues to track approved drugs for adverse events through a postmarketing surveillance program.

    The information contained in "The Drug Approval Process" was compiled from several FDA sources.