How new drugs reach the market safely

July 1, 1999

Pharmaceutical Representative

The FDA's drug approval process.

For patients who are coping with AIDS or cancer, drug research and development and the FDA drug approval process can't move fast enough.

However, it takes between 12 to 15 years for a drug to move from a lab petri dish to a plastic orange bottle sitting in someone's medicine cabinet, according to Jeff Trewhitt, spokesperson for the Pharmaceutical Research and Manufacturers of America, Washington. Approximately six years of that development time are spent in clinical trials, undergoing Food and Drug Administration drug approval.

Last year, the FDA approved 90 medicines, including 30 new molecular entities. How were these new drugs approved - and why does their approval take so long?

Drug approval process

In general, a drug undergoes pre-clinical testing in animals and then is reviewed in three stages of human clinical trials - Phase I, II and III - before it gains FDA marketing approval. Drug safety is monitored throughout all phases of the FDA drug approval process.

According to the FDA's Center for Drug Evaluation and Research Handbook, a drug sponsor - a pharmaceutical company, for example - that wants to market a new drug must first submit an Investigational New Drug application for review. A sponsor must receive approval of its IND application during the pre-clinical development stage in order to advance to the next stage of drug development, known as clinical trials or human trials.

During pre-clinical development, the sponsor must show that the drug is reasonably safe for initial use in humans and that the compound exhibits pharmacological activity that justifies commercial development. Three broad areas of data are examined during the IND review process:


• Animal pharmacology and toxicology studies provide data for assessing whether the product is safe for initial testing in humans.


• Manufacturing data regarding the drug's composition, stability and the controls used in manufacturing ensure that the company can adequately produce consistent batches of the product.


• Proposed protocols for the clinical studies are examined by a medical officer to assess whether humans could be exposed to unnecessary risks during testing. The medical officer also decides if the study design will provide relevant data about the safety and efficacy of the drug.

The CDER has 30 days to review the IND application. If the medical officer places no clinical holds on the application, the drug proceeds to human clinical trials.

Phase I tests are designed to determine the safety, tolerance, metabolism, absorption, elimination, preferred route of administration, safe dosage range and perhaps the efficacy of the new drug in humans. In this phase, the drug is given to approximately 100 to 200 healthy people who volunteer to participate in a clinical trial for about one year. CDER can stop a trial, also known as "imposing a clinical hold," at Phase I to protect patients for safety reasons or because a sponsor didn't accurately disclose risks.

In Phase II of a clinical trial, researchers try to obtain preliminary data on the effectiveness of the drug for a particular indication or indications in patients with the disease or condition. Phase II testing lasts approximately two years, according to Jeff Trewhitt of PhRMA. Researchers may learn more about common short-term side effects and risks associated with the drug in Phase II testing.

In Phase III, researchers conduct large scale clinical trials that involve 1,000 to 3,000 patients stationed at research centers across the nation to determine a drug's safety and efficacy, identify adverse reactions and determine optimum dosage schedules. Phase III lasts approximately three to four years, according to Trewhitt.

Throughout the entire drug approval process, CDER uses project teams to perform drug reviews. Team members use their expertise in various stages of drug review:


•Â Pharmacologists and toxicologists evaluate the short-term and long-term effects of drugs in lab animals with continued animal testing.


•Â Biopharmaceutists evaluate the rate and extent to which a drug's active ingredient is made available to the body.


•Â Clinical pharmacologists evaluate the body's response to the drug dose.


•Â Chemists monitor the drug's manufacturing and packaging to preserve the purity, potency and stability of the drug.


•Â Statisticians evaluate the designs and results of each study.


• Microbiologists evaluate the effect of anti-infective drugs on germs. Medicines like antibiotics differ from other drugs because they affect the germs, not the patient. Another set of microbiologists monitor manufacturing processes to test for sterility.

Approval and post-marketing

After Phase III clinical trials are complete, the drug sponsor files a New Drug Application that summarizes the test procedures and results. The NDA is, more or less, an application for permission to market the drug.

Before NDA approval is granted, CDER reviews samples and manufacturing controls from the pharmaceutical plant site. CDER also checks the data that goes behind each component of the drug's labeling. Drug labeling requirements are defined in the Code of Federal Regulations.

Most of the NDA review process involves CDER's re-analysis of the drug data that the sponsor collected in all testing stages and presented in the NDA. If an NDA shows deficiencies along the way, CDER's review team immediately notifies the drug sponsor with a request for more information and clarification.

Once a drug gets NDA approval, the Food and Drug Administration continues post-marketing surveillance of the drug. This is Phase IV of the drug approval process. The FDA monitors reports of adverse drug reactions, which are typically submitted by physicians, patients and the drug's sponsor, via its Adverse Event Reporting System. In recent years, the reporting of adverse drug reactions has been faster due to the FDA's electronic initiative to get this important surveillance component on the Internet, according to Bronwyn Collier, the FDA's assistant director for regulatory affairs.

Fast track: accelerated approval

A few drugs have taken a faster route to secure FDA approval, thanks to the agency's "accelerated approval track," according to Anthony DeCicco, chief project management officer at the FDA.

"It's both a development and approval program, and it happens under two stipulations," DeCicco said. "For life-threatening illnesses, a surrogate endpoint is accepted in lieu of morbidity or mortality."

A surrogate endpoint is a laboratory finding or physical sign that may not be a direct measurement of how a patient feels, functions or survives, but is still considered likely to predict therapeutic benefit for the patient. "In the case of HIV, we measure CD4 counts and antigen levels, which are indicative of viral load," DeCicco said.

The FDA also grants accelerated approval to drugs for life-threatening illnesses when it determines that safe use of a product depends on restricting its distribution or use, as in the case of thalidomide, DeCicco said.

Thalidomide is a drug that caused nearly 10,000 children to be born with deformed arms and sometimes deformed legs because their mothers took the sedative during their pregnancies. Now researchers think thalidomide has applications for treating patients with diseases such as leprosy, AIDS, lupus and rheumatoid arthritis. The FDA knows, however, that it must communicate the potential risks of thalidomide to consumers and doctors thoroughly, so the same mistake isn't made again.

Two other "fast track" approval processes have been used, quite often with AIDS medicines: the "parallel track" and "treatment IND."

The parallel track was designed in the early 1990s for patients with AIDS or AIDS-related illnesses whose conditions prevented them from participating in controlled clinical trials. Under this policy, these patients can receive investigational drugs shown in preliminary studies to be promising. (They receive the drugs "in parallel" with testing.)

The treatment IND track makes investigational new drugs available to desperately ill patients as early in the drug development process as possible, usually during Phase III studies. The FDA allows a drug to be used to treat a desperately ill patient if the drug shows early evidence of efficacy and if no other comparable drug exists to treat that certain stage of the disease.

Treatment INDs are only given to patients who do not qualify for regular human clinical trials. Treatment INDs allow the drug sponsor to learn more about a drug's safety and efficacy.

Of the three "fast track" approval processes, DeCicco said the accelerated approval track is most commonly used.

The cost of research and development

According to PhRMA, it costs, on average, $500 million to develop and achieve FDA approval for one new drug. "But that $500 million is just an average," Trewhitt said. "Some companies spend $200 million. It cost Merck $1 billion to develop Crixivan, one of the big protease inhibitors for AIDS that was approved in the 1990s."

Only one in every 5,000 compounds screened eventually becomes an approved drug, according to PhRMA. And on average, only three out of 10 approved drugs recover average research and development costs. Companies must rely on these highly successful products to fund research and development in the future. PR