United States Drug Approval Process

Over 60 years ago, Congress passed the Federal Food, Drug, and Cosmetic Act (FDC) of 1938 in hopes of reforming the drug industry. The action was taken after more than 100 people died from drinking Elixir Sulfanilamide, a form of sulfa medicine that was manufactured and sold in the United States. Prior to the FDC Act of 1938, drugs were only required to meet standards of "strength and purity," as set forth by the Food and Drugs Act of 1906. The FDC act of 1938 required manufacturers to prove the safety of any product that would be marketed over state lines. The FDC act also banned the use of misleading labels on food, drugs, and medical devices. However, any drug on the market prior to 1938 was exempt from the new law.

Twenty-four years later in 1962, Tennessee Senator Estes Kefauver spearheaded an effort to investigate the pharmaceutical industry after a drug (Thalidomide) manufactured in Germany and sold throughout Europe was found to cause severe birth defects in children whose mothers took the drug. The result of the Senator’s effort was the Kefauver-Harris Amendments or the Drug Amendments Act of 1962. This Act required manufacturers to establish the safety and effectiveness of all drugs on the market and made the FDA responsible for regulating the drug industry.

Today, all new prescription drugs must be approved by the U.S. Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) prior to entering the marketplace. The process includes pre-clinical research, clinical studies, and a new drug application (NDA) review. This article outlines the drug development and review process in the United States.

Pre-Clinical Research

New drugs may be developed by a variety of different people or organizations, including independent researchers, university medical centers, government centers, or other organizations. According to the FDA, there are several ways in which new drugs are developed. Some new drug research begins with studies of how the body functions in the broadest terms. From these studies, researchers develop ideas of new ways to treat illnesses and abnormalities. Researchers then begin to search for compounds that will help achieve the desired effect on the body. They may conduct laboratory tests (called assays) by adding compounds to enzymes, cell cultures, or cellular substances grown in the laboratory to determine whether the compounds produce an effect. This process can take a significant amount of time but is often accelerated with the use of computers or other technology. Another way scientists may develop drugs is to study natural compounds made by organisms such as fungi, viruses and molds.

After the researchers have identified a compound that could be effective against a certain illness or disease, they may test the compound in animal studies. This process involves using as few animals as possible, and researchers are careful to make sure that the animals are treated humanely during the studies. Often, more than one species is tested because compounds tend to act differently in different species. The goal of animal testing is to learn how the drug is absorbed by the blood, how the drug is broken down chemically in the body, the toxicity of the drug and its broken down products, and how quickly the drug is excreted from the body. The FDA conducts routine inspections of animal laboratories.

Clinical Studies

After short-term animal studies are completed (and often after some results from long-term animal studies can be obtained), the sponsor of the drug applies for approval from the CDER (Center for Drug Evaluation and Research) to continue testing the safety and effectiveness of the drug in human clinical trials. The sponsor submits an investigational new drug application (IND) to the CDER, which contains the plan for the study. This IND process allows promising drugs to be studied extensively in expanded access protocols. The IND application is carefully reviewed by members of the CDER who specialize in medical, chemistry, pharmacology/toxicity, and statistical fields to determine whether there are any flaws in the initial studies and whether the overall development plan is feasible.

After the IND application is approved by the CDER, human clinical trials usually begin. The purpose of human clinical trials is to determine whether the drug is safe and effective, and also, to give additional treatment alternatives to patients with advanced stages of disease who may have few treatment options. Clinical trials are typically conducted at universities, cancer centers, hospitals, or clinics. Before a clinical trial is conducted, the proposed trial is reviewed by an Institutional Review Board (IRB). An IRB is a separate board of scientists, physicians, and nurses who are not associated with the clinical trial. Once approved by the board, the trial is closely monitored by the IRB and given a formal review each year (or other interval depending on the length of the trial). To make sure that IRBs meet the FDA’s rules for the protection of the rights and welfare of research subjects, the FDA routinely inspects the boards.

There are several types of clinical trials.

Phase I trials usually involve administering the drug to a small number of participants (typically less than 10 people). The purpose of a Phase I trial is to learn how to administer the drug safely. Researchers will closely monitor the participants’ side effects and adjust dosages if need be.

Phase II trials attempt to determine patients’ responses to the drug. Typically 30 to 40 people participate in Phase II trials. If the goal of the drug is to treat cancer for example, participants are closely monitored to see if their tumors shrink during treatment. If a patient’s tumor shrinks, it is responsive to treatment. If at least one-fifth of the participants "respond" to treatment, the drug is considered successful. Researchers of Phase II trials also monitor side effects. If enough patients respond to the drug, the trial moves to Phase III.

Phase III trials enroll a large number of participants (sometimes thousands), and the FDA usually recommends that drug sponsors meet with FDA officials before beginning Phase III trials to help set the standards and expectations for the trials. In a Phase III trial, patients are usually divided into groups: one group (the control group) receives a standard drug or placebo (inactive pill) and the other group receives the new drug. For example, the STAR clinical trial (Study of Tamoxifen and Raloxifene) is a Phase III trial that is enrolling 22,000 post-menopausal women 35 years of age or older who are at increased risk for breast cancer. The STAR Trial will compare the long-term safety of using the drugs tamoxifen (brand name, Nolvadex) and raloxifene (brand name, Evista) to help prevent breast cancer. As with Phase I and Phase II trials, Phase III participants are closely monitored for potentially dangerous side effects from the drug. If side effects become too severe, the trial may be canceled.

Category	# of participants	Purpose
Phase I	less than 10	tests how to administer a new treatment
Phase II	30 - 40	tests patient responses to a new treatments
Phase III	100 - 1000+	compares new treatments to a standard one
Adjuvant	varies	determine if additional treatment will reduce chances of recurrent cancer.

Government Review and Approval

After clinical trials are complete, the drug sponsor submits a new drug application (NDA) for consideration by the CDER (Center For Drug Evaluation and Research). The NDA documents all study results, and the CDER requires samples of the drugs and its labels. Over the past few years, the CDER has significantly accelerated the time it takes to review drug applications. On average, standard drug applications are reviewed in 12 months or less and priority drug applications are reviewed in six months or less.

CDER primary reviewers and supervisory personnel evaluate the NDA. According to the CDER, final review is often based on two questions:

• Do the results of clinical studies provide substantial evidence of the drug’s effectiveness?
• Do the results of clinical studies show that the drug is safe under the proposed labeling (that is, do the benefits of the drug appear to outweigh the risks)?

After the CDER’s evaluation, the office will send an official letter to the drug sponsor that typically states one of the following: 1) the drug is approved for marketing, 2) the drug is approved provided that minor changes are made, 3) the drug is not approved because of significant problems (the sponsor can appeal this latter evaluation, withdraw the application, or resubmit an amended application at a later date). After the drug is approved, marketing, production, and distribution measures begin.

Additional Resources and References

• The U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) provides information on its approval and regulatory processes at http://www.fda.gov/cder/
• The January 1995 FDA consumer report, "Benefit vs. Risk: How CDER Approves New Drugs," is available online at http://www.fda.gov/fdac/special/newdrug/benefits.html. The most recent version of the article is available for PDF download at this web address.
• To learn more about FDA approved drugs used to treat breast cancer, please visit http://www.imaginis.com/breasthealth/bc_drugs.asp

Update: December 17, 2007