Number of targeted therapeutics awaiting FDA approval on the rise

Several innovative therapies targeted at the cellular level to treat complex diseases such as cancer are beginning to fill the drug development pipeline.

But they also are likely to remain in the pipeline for a while, given the need for a longer clinical development process dictated by the Food and Drug Administration and by the complexity of the diseases they are intended to treat, according to "Outlook 2009," a report released Jan. 6 by the Tufts Center for the Study of Drug Development at Tufts University in Boston.

After clinical trials are completed, however, the FDA's review and approval process is likely to move more quickly than it has in the past, the report's authors said. The average time for FDA approval declined to 1.1 years in the 2005-07 period studied. The time to approval had ranged up to two years in earlier years.

The upsurge in the number of targeted therapeutics in development has been heralded by many health experts. For example, more than 200 new monoclonal antibodies, or mabs, one type of targeted therapy, are in development worldwide, the report said.

Twenty-two mabs already have been approved by the FDA. Among them are such highly regarded drugs as Herceptin, which was approved in 1998 for treating breast cancer, and Avastin, which was approved in 2004 for treating colorectal cancer.

The success of these drugs, which, because of their targeted nature, tend not to have as many safety issues, has been noted by the large drug firms, said Janice Reichert, PhD, research fellow at the center and author of the report's section on mabs.

"Starting around 2001 and 2002, the focus shifted to mabs," said Reichert, who is also the editor-in-chief of a new peer-reviewed journal called mAbs. "The use of antibodies and other types of protein [large molecule] therapeutics allows pharmaceutical firms to expand their portfolios and to diversify risk," she said. "Small molecules tend to be more promiscuous."

The targeted nature of the drugs doesn't mean they aren't also moneymakers, she noted. Some, such as Rituxan, developed in 1997 to treat non-Hodgkin lymphoma, is a million-dollar seller.

Hopes soared for more cancer drugs to follow the success of Gleevec in 2001. That drug was found effective at treating chronic myeloid leukemia and gastrointestinal stromal tumor. "Frankly, it has been quite inspiring, what has been occurring over the past several years," said Len Lichtenfeld, MD, deputy chief medical officer for the American Cancer Society.

Dr. Lichtenfeld attributes the success of targeted therapies to the core foundation of research produced over the past several decades -- since the war on cancer was declared in 1971. "It's sort of like constructing a large building," he said. "It seems to take forever to do the structural work. But once the building comes out of the ground, the rest seems to be built quickly."

Complex diseases extend process

But success may not be right around the corner, said Ken Kaitin, PhD, director of the Tufts Center for the Study of Drug Development and a professor of medicine at Tufts University. "Many factors are leading to longer clinical times, including a focus on complex diseases and more complicated development design protocols."

As the FDA learns more about adverse events associated with different classes of drugs, the agency is going to require more studies, he said. "There is just a general movement toward more and more being necessary before a drug is approved, because we as the scientific community, the FDA and the industry, know much more about these drugs, their side effects and their mechanisms of action," Kaitin said.

Also, many of the diseases being studied are very complicated. Take Alzheimer's, for example, he said. "There are periods where someone may be very cloudy in terms of their cognitive capacity, and then they'll have a moment when everything seems fine. So it's very difficult to single out what's the drug's effect and what's a natural cycling of disease."

Similar cycling occurs with bipolar disease and schizophrenia, for which drugs also are being developed, he noted.

And the fact that the drugs may be used for long periods of time means that the FDA may require long-term animal studies to demonstrate safety, he added.

The FDA, the National Institutes of Health and many academic centers are working with the pharmaceutical industry to develop better biomarkers and safety markers to try to cut down on the enormous amount of time and investment it takes to bring a product to market -- an attempt that may end up failing, Kaitin said.

The study also predicted that drug firms will conduct more clinical trials outside the United States. Within three years, major sponsors of trials project that up to 65% of FDA-regulated clinical trials will be conducted primarily in Central and Eastern Europe, Latin America, India and Asia. Among the reasons for this shift are ready access to well-trained physicians and large numbers of treatment-naïve patients, according to the report.