Frequently asked questions about the FDA and drug safety, with links to resources for consumers and further reading.

+ When the FDA approves a drug, does that mean I can count on it being "safe and effective"?

When the FDA approves a drug, it means that it has determined that the benefits of the drug will outweigh the risks when it is released into the general population. During a drug's testing, up to 3,000 people will take the drug in the final stage of clinical trials. But if a serious side effect occurs in one out of 10,000 people, for example, the manufacturer and the FDA most likely will not find out until it is out on the market and hundreds of thousands, or millions, of people have taken it.

"I think Americans need to recognize that every time they put a pill in their mouth, especially a new pill that they've never taken before, it's an experiment," says Dr. Raymond Woosley of the University of Arizona, who was a top candidate to become FDA commissioner last year. "When a drug goes on the market, only about 3,000 patients have ever been given that drug. We will never know all the toxicity that can occur, especially the one in 10,000 or the one in 20,000 that can be seriously harmed. Our detection of that will only happen after the drug is on the market and exposed to huge numbers of patients."

+ What part of the FDA is responsible for drug safety?

The FDA's Center for Drug Evaluation and Research (CDER) oversees drug safety and regulation. With a staff of approximately 1,800, it reviews drug applications submitted by drug companies, monitors drugs once they are out on the market, and keeps the public informed with updates. Steven Galson is the acting director of the CDER. Paul Seligman is the acting director of CDER's Office of Drug Safety.

Read FRONTLINE's interviews with Paul Seligman and Steven Galson.

+ Where does the FDA gets its funding for drug safety?

As stipulated in the Prescription Drug User Fee Act, CDER collects fees from drug manufacturers to help fund the drug approval process. The amount of the fee is set by law and adjusted yearly with regard to inflation. According to a March 2003 financial report for the Fiscal Year 2002, the FDA collected fees totaling $143.3 million. CDER's total operating cost for reviewing drugs in FY 2002 was $209.8 million.

+ What is an "adverse event"? How common are they?

The FDA defines an "adverse event" (commonly known as a "side effect") as "any undesirable experience associated with the use of a medical product in a patient." An adverse event should be reported if it results in death, disability, hospitalization, is life-threatening, causes a congenital anomaly, or requires treatment to prevent permanent damage. According to Paul Seligman, director of the Office of Drug Safety in the CDER, the FDA receives 278,000 reports of adverse events a year, of which 30,000 are considered serious. Every year, there are approximately 100,000 deaths due to drug-related adverse events.

+ How does the FDA find out about adverse events?

Doctors and health care professionals generally report adverse events to drug companies, which are then required by law to relay serious reports to the FDA within 15 days. For the first three years after a drug is approved, the drug manufacturer must also report all of its adverse event information to the FDA quarterly, and after three years, these reports must be submitted annually.

The FDA also has a voluntary system, called Medwatch, for reporting adverse events directly to its Office of Drug Safety. Consumers and health care professionals are encouraged to submit reports to this system, and the FDA receives approximately 1,000 such reports a day, handled by a staff of about 50. The reports are typically redirected to evaluators with the proper expertise, and they may follow up by contacting the person who sent the report for more information.

Since these reports of adverse events are voluntary, it is difficult for the FDA to make an accurate count of how many injuries or deaths are associated with any particular drug. (Finding these numbers requires a Freedom of Information Act request for the adverse event records related to the specific drug.) The FDA estimates that only between 1 and 10 percent of all adverse events are reported.

+ What does the FDA do when it learns about a drug's adverse effects?

The FDA handles each case differently according to the severity of the side effects and the importance of the drug relative to the condition it treats, taking into account whether there are other treatments available on the market. It might engage in "risk management" steps, such as changing the labeling to include a "black box" warning, and/or advising health care professionals with a "Dear Doctor" letter indicating the additional risks found to be associated with the drug. These issues are discussed with the manufacturer, and an advisory committee might be convened to gain an outside opinion on what to do next.

+ How does the FDA decide to pull a drug from the market?

When it is clear that the risks outweigh the benefits of a drug, and earlier warnings have not done enough to limit the danger to the public, a drug company may voluntarily withdraw a drug or heed the FDA's request that it withdraw the drug from the market. The FDA can also use its authority under the law to enforce a mandatory recall of the drug. More than a dozen drugs have been withdrawn since 1997.

+ What role does the FDA play in the drug development and approval process?

The drug manufacturer is responsible for testing a new drug for safety and effectiveness, which involves conducting pre-clinical research that includes animal testing and then three phases of clinical trials on humans. This information is packaged in a "new drug application" (NDA) and submitted to the FDA, which determines if the application is fileable for review.

A fileable NDA is then subject to CDER review, in which FDA scientists (including doctors, statisticians, microbiologists, pharmacologists, and chemists) review the evidence submitted by the drug company and evaluate both the efficacy and safety of the drug and whether its benefits outweigh any risks. If the CDER wants more information, it may consult with the drug company and it may seek the opinions of outside experts by convening an advisory committee. Finally, after reviewing the label information and the quality of the manufacturer's facility, the application is sent to "NDA action," where the division director reviews the CDER evaluation and makes a final decision.

See an interactive diagram of the drug development process and an interactive chart showing the FDA's NDA review process on the CDER Web site.

+ What's an advisory committee?

Using the 1972 Federal Advisory Committee Act as its guideline, the FDA convenes an advisory committee made up of outside experts in order to gain an external, independent opinion on a drug's risks and benefits in any stage of its life, be it in clinical trials or after it's on the market. These meetings are usually open to the public, and testimony is encouraged from various perspectives, including those of both drug companies and consumer advocates. FDA staff chooses committee members from a pool of candidates that includes specialists, nurses, academics, members of government agencies, and patient groups. An advisory committee decision is not a mandate, but the FDA takes it into serious consideration when making its final decision about a drug.

See CDER's information on advisory committees.

+ How do I know if the drug I'm taking is the safest and most effective of its kind on the market?

The FDA does not require drug manufacturers to prove that new drugs are safer or more effective than existing drugs that treat the same conditions, nor that a drug will actually help patients live better or longer. For instance, as FRONTLINE producer Andrew Liebman explains, "some drugs might do a good job at lowering blood pressure -- but not do a good job preventing the strokes, heart attacks, diabetes, and premature death that are the concern in people who have high blood pressure. Those ultimate measures of success are called 'outcomes,' and most drugs do not get approved on the basis of leading to good outcomes, but rather, on the basis of so-called 'surrogate measurements' like blood pressure."

The FDA does not conduct comparative testing of drugs on its own, and manufacturers rarely conduct these types of comparisons voluntarily, unless it's to show that a drug will fare better in the market than a rival. As Dr. Raymond Woosley notes, "That's not really a comparative trial; that's a marketing trial. A true comparative trial will take a group of medications that are potential choices and really compare them fairly to see which does give you the best outcome at the best cost."

The pharmaceutical industry maintains that introducing drugs that are no more safe and effective than existing drugs for the same condition is justified because they offer more options to patients who do not respond to existing therapies. But critics argue that these so-called "me too" drugs draw the market away from more proven therapies and detract from the manufacturer's research and development of truly innovative new drugs.

"There is little the FDA can do," says Liebman, "when a pharmaceutical company puts a new drug on the market that they know is inferior to other products already for sale -- so long as the new drug has some effectiveness compared to getting nothing (that is, a placebo) and so long as the new drug doesn't pose any serious hazards."

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posted november 13, 2003

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