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People eagerly await the latest miracle drugs for everything from high blood pressure to low libido, but many complain about the rising costs of these same drugs.
Similarly, pharmaceutical manufacturers tout their ability to provide treatments for everything from heart disease to hair loss, but many complain about the increasing costs of, and decreasing profits from, drug development.
Both might soon be getting some help from medical imaging.
Evidence is mounting that imaging can help save time and money-without sacrificing quality or integrity-in every aspect of drug development, from preclinical animal studies through every stage of human clinical trials and beyond.
The U.S. Food and Drug Administration already accepts MRI data as a clinical end-point for drugs targeted at multiple sclerosis, and some experts believe it won't be long before the FDA accepts imaging studies as end points in studies of drugs targeted at many other diseases.
The costs to bring a drug to market had risen from an average of $231 million in 1991 to more than $802 million in 2004, researchers at the Tufts Center for the Study of Drug Development (CSDD) in Boston have reported. In addition, Tufts researchers recently reported that market exclusivity for patented drugs has dropped from about 8 years in the 1970s to about 2 years as of 1998.
The extended development time eats up the remaining time on a drug patent-an important factor in each company's ability to recoup its drug development costs.
"Part of the problem is that the time to market is increasing tremendously," said Bradley Patt, PhD, president and CEO of Gamma Medica (Northridge, Calif.), a supplier of small animal imaging systems being used in drug development. "Back in 1982, when insulin was approved, it took only 4 years to go through the entire process. Now it takes from 10 to15 years."
Speeding preclinical trials
The Tufts researchers said that increasing the speed of drug development could save hundreds of millions of dollars, and imaging is stepping up to the plate as a solution right at the outset by increasing the efficiency of preclinical animal studies.
Drug companies currently have some 200 million potential drug compounds, but fewer than one of every 10,000 will eventually emerge as an FDA-approved treatment. Imaging at preclinical stages can quickly reveal which compounds have possibilities, said Timothy McCarthy, PhD, associate director in worldwide clinical technology for Pfizer Global Research and Development.
For example, researchers looking for a drug to treat psychiatric conditions such as depression or schizophrenia need to know first whether a potentially useful compound can get across the blood-brain barrier. If it can't, there's no use developing the compound any further.
"You do not want to spend a lot of money developing a compound into a drug when it cannot go where you intended," said Dr. McCarthy, who is also president of the Society of Non-Invasive Imaging in Drug Development (SNIDD).
For those that can reach their destination, imaging helps to reduce costs of the next step, preclinical studies on absorption, distribution, metabolism and excretion, or ADME studies. These studies are currently conducted by injecting a drug candidate into animals, usually rodents, and then sacrificing a certain number of the animals at each step in the ADME process. The animals are then sectioned, examined and measured with whole body radiography under a microscope to see where the drug ended up, said Hartmuth Kolb, PhD, chief technology officer at CTI Molecular Technologies (Culver City, Calif.).
It's a manually intensive process that requires several groups of animals-six to ten animals per group and seven to ten groups-to avoid random variations in the data, said Dr. Patt. But by attaching nuclear medicine tracers to potential drugs, researchers can follow a prospective therapy through live animals to see ADME characteristics in real time.
"Now you need fewer animal models to see how your drug works," said Hermann Mucke, PhD, author of "Molecular Imaging Comes of Age" (Cambridge Health Associates, Waltham, Mass.), a book on the advantages of molecular imaging and its market perspectives. "You are relieved of using many animals for statistics, so it is quicker, cheaper and, as a side-effect, it also saves animals."
Imaging at this stage indeed results in significant cost savings, said Eric Milne, MD, professor emeritus of radiology and medicine at the University of California at Irvine.
"Preparing a transgenic mouse can cost anywhere from $150 to $3,000," said Dr. Milne, also the chief radiologist for Imaging Diagnostic Systems (Plantation, Fla.). "You do not want to kill that mouse. You would like to follow it day by day while you are treating it, and that is what imaging allows you to do."
Mice can be imaged with the same radioactive tracers, ultrasound, MRI, X-rays or CT used in the clinic, but adapted for the smaller animals. They can also be imaged with bioluminescent or laser imaging systems. IDS is developing a system that permits imaging of bioluminescent molecular imaging tracers combined with laser imaging of the hemoglobin system. The latter provides high-resolution images of mouse anatomy that can be fused with data from the bioluminescent tracer, much like PET/CT and SPECT/CT systems fuse anatomic and functional data.
Advantages of tracer imaging
The tracer method, used in PET, SPECT and bioluminescent imaging, is especially valuable in early stages of drug research, where researchers can directly label a drug to see where it goes. Other tracers can reveal molecular changes brought about by the drug. This is an extremely important capability in light of new cancer therapies, where changes on the molecular level occur long before becoming visible in anatomic imaging.
"As the drug candidate progresses in the development process, you can go from monitoring thekinetics of the drug to monitoring the effects of the drug," said Ward Digby, PhD, director of molecular imaging in advanced research at Siemens Medical Solutions, Hoffman Estates, Ill.
One example is with Gleevec®, (imatinib mesylate), from Novartis Pharmaceuticals in Hanover N.J., an FDA-approved treatment for chronic myeloid leukemia. Because Gleevec affects a pathway in the glucose transport system, the PET imaging agent fluorine-18 fluorodeoxyglucose (FDG) makes an ideal agent for looking at changes to the glucose system, Dr. Digby said, noting that such changes can appear within 8 hours of the drug's administration.
Imaging can also show increased cardiovascular function in response to drug treatment or provide statistical data to help quantify response to neurological agents-for instance, showing increases in dopamine or serotonin uptake.
The pharmaceutical industry is betting big on molecular imaging's potential to improve upon drug discovery and development processes as well as monitoring and guiding drug therapies. A June 2004 overview of the small animal imaging market by Frost and Sullivan reported growing sales of micro-PET and SPECT systems.
The Frost and Sullivan report also stated that optical imaging is gaining popularity. Optical imaging, which uses bioluminescence or fluorescence, works well in small animals, where it has the advantage of not using ionizing radiation.
"This report concluded that there would be 40-percent annual growth in small animal imaging equipment sales this year; that is much faster than any other field in nuclear medicine," said Dr. Patt, who noted that while Gamma Medica used to sell mostly to academic research institutions, sales to biotechnology and pharmaceutical companies have doubled in each of the last two years. The company has also started selling equipment to contract research organizations that perform animal research protocols for biotechnology and pharmaceutical companies.
CTI, which has a division that sells small animal PET imaging systems, is also working with institutional researchers and pharmaceutical companies on the development on new biomarkers to help in clinical and pre-clinical imaging, Dr. Kolb said.
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