Institutional pressures impede translational research

Controversy over the pain reliever Vioxx has prompted the pharmaceutical industry and medical community to rethink the way drugs make the long journey from petri dish to patient. But it didn't take newspaper headlines to draw attention to the frustrations and difficulties drug developers face. Between 2002 and 2003, the pharmaceutical industry submitted nearly 50% fewer investigational new drug applications than it did just seven years before, while the industry and public institutions together spent two and a half times more money on biomedical research.

"It is clear that many biomedical discoveries have not been transformed into marketable products," FDA officials Lawrence J. Lesko, Ph.D., and Dr. Jack Woodcock wrote in Nature Reviews Drug Discovery (2004;3:763-770).

The predicament has federal agencies, academic institutions, and industry trying to both streamline the drug development process and create more effective drugs. The success of various projects aimed at filling the gaps will affect the radiologist's toolbox and influence advances in detecting molecular biomarkers.

While research in the last two decades has made imaging techniques more powerful than ever, many scientists are ready to up the ante with high-tech tracers and sophisticated detection techniques. Groundbreaking accomplishments have whetted the appetite of radiologists eager to detect disease earlier and to gauge the effectiveness of therapies better.

"In imaging, everybody talks about translational research, but it's important to understand that it's a long process," said Dr. Stanley Baum, former chair and currently a professor of radiology at the University of Pennsylvania.

Delivering the keynote lecture at the 2004 Computer Assisted Radiology and Surgery congress, Baum expressed concern that most investigational medical-pharmaceutical agents require an average of 17 years to move through clinical trials before becoming standard clinical practice.

The cases of MR angiography and CT angiography are exceptions to the usually long road to mainstream acceptance for a new modality, he said. Conceived in the late 1980s and entered into multi-institutional clinical trials by the 1990s, both angiography techniques are replacing the more invasive traditional angiography.

"But for every one of them like that, you have 10 of the others," Baum said.

He quoted a 2003 American Journal of Medicine report stating that only one in four promising technologies resulted in a published randomized trial, and fewer than one in 10 entered clinical use within 20 years of the original basic science publication.

PET, for example, was not approved until after 20 years of clinical refinement, study, and political maneuvering. And inventors of CT colonography, which was developed in 1994, are still tweaking that imaging method, which was intended to replace invasive colonoscopy and persuade more people to undergo colon screening. Advantages such as cost savings and visualization of tissues and organs adjacent to the colon have not ensured virtual colonoscopy's acceptance.

"Many people thought that colonography would be a big winner," Baum said. "Ultimately, it will be better than invasive colonoscopy, but it won't be exactly what we originally thought it was going to be."

This pattern is often repeated in translational research. Iressa, a chemotherapy agent developed by European drug maker AstraZeneca International, is a recent example. Developed to treat non-small cell lung cancer, Iressa was initially billed as a success in early efforts to bring molecular-based medicines into human trials. The agent produced spectacular remissions for a few patients, but it was shown to be effective in only 10% to 15% of patients in clinical trials. Returning to the laboratory, researchers from Dana Farber Cancer Institute and Massachusetts General Hospital discovered that the responding patients possessed a mutation in the gene for epidermal growth factor receptor (EGFR), which was involved in causing the cancer. Developing the ability to visualize biomarkers such as mutant EGFR in the initial diagnosis is a major goal of molecular imaging research.

WORKING TOGETHER

With molecular imaging's potential to make breakthroughs in diagnosing and treating a wide variety of diseases, the National Institutes of Health is lending its clout to steer the field and ensure its success. In issuing its Roadmap in 2002, the NIH acknowledged molecular imaging as key to taking biomedical research to a higher level and interdisciplinary research as crucial to advancing molecular imaging.

"The Roadmap is filling the multidisciplinary gaps," said Dr. C. Norman Coleman, director of radiation oncology sciences at the National Cancer Institute. "The NIH and many of its individual institutes are bringing together people who are not historically together and creating new fields."

Academia is also shifting toward multidisciplinary approaches. Support from the NIH is more likely if a project is multidisciplinary, Baum said. That means more backing for diagnostic imaging efforts that rely on collaboration among radiologists, physicists, biologists, chemists, engineers, and clinicians. NIH funding for radiology departments grew from $65 million in 1995 to more than $242 million in 2002.

Michael Phelps, Ph.D., didn't need the NIH to encourage him in collaborative research. In 1989, Phelps founded the Crump Institute for Molecular Imaging at the University of California, Los Angeles, where he is also chair of molecular and medical pharmacology. Experts in detection technologies, molecular and cell physiology, and structural imaging work together in one department at institute.

"The goal is to avoid traditional disciplines and to focus on solving difficult scientific and clinical problems," Phelps said.

Even with increased collaboration, Phelps and others recognize the need for changes in education and training to fill the gulf between basic scientists and clinicians.

"In our department, we train our young basic scientists about clinical practice, and we train our clinicians to be scientists," he said.

Francesco M. Marincola, founder and editor-in-chief of the Journal of Translational Medicine and director of immunogenetics in the department of transfusion medicine at the NCI, agreed that most clinicians are naive about what it takes to perform good scientific studies.

CURING MICE

Clinicians tend to forget about the precision required for research and the importance of minimizing the number of variables. But physicians often must prioritize their responsibility to a patient who may be too ill to receive a specific dosage prescribed by the protocol or too frail to allow for a biopsy at the required time point.

"On the other hand, researchers who are curing mice need to see what's going on and why it's not working in humans," Marincola said.

While fellowships in translational research are becoming available, reviewing editors at major journals tend to be basic scientists who demand large sample numbers and absolute adherence to the experimental protocols.

"They don't understand what it's like to do clinically related research, so they reject the papers," he said. "Then the studies are published in small journals that nobody reads, which is a shame, because then people do the same studies over and over."

A major frustration for radiologists is the difficulty in recruiting patients for clinical trials. Unlike other medical specialists, radiologists don't have a direct relationship with patients.

"They're not our patients to start with," Baum said. "Patients come from internists, gynecologists, surgeons, and other physicians, who must be willing to promote the clinical trials."

And as with most clinical trials, the challenge of convincing patients to sign up can sometimes prove insurmountable, in part due to the time they must invest. In the case of comparing digital mammography and conventional mammography, for example, participants must be dedicated enough to show up for both exams.

Ensuring greater success in clinical trials, however, will require changes in earlier phases of drug development, Marincola said. Preclinical stages of research largely depend on small-animal models and tissue specimens that don't exactly reflect actual human diseases. Tumors used in mice, for instance, do not represent the genetic heterogeneity found in human cancers.

"It never works, because humans are quite different from animals," he said.

THE LOOKING GLASS

The issue exemplifies the importance of enhancing molecular imaging techniques to generate diagnoses that reveal the offending biomarker and to gauge the efficacy of therapies. Making this a reality will require academic researchers to collaborate with pharmaceutical companies, which have the capacity to screen millions of compounds and find those that bind to biomarkers.

"Merging the goals of molecular imaging probes and drugs together at the beginning of this process is allowing molecules to be produced and screened for both purposes," Phelps wrote in the Proceedings of the National Academy of Sciences (2000;97[16]:9226-9233).

The search for drug compounds and the complicated process of validating biomarkers may be the more painless part of the task.

"Making tracers is more difficult than finding biomarkers," said Dr. Harry Bartelink, chair of radiation therapy at the Netherlands Cancer Institute in Amsterdam.

Much of the challenge comes in tackling the very nature of the human body. With optical imaging, researchers need to develop a probe that emits a signal strong enough to traverse the body. This is hardly an easy task when the signal decreases by 10-fold for every centimeter of tissue, said Dr. Christopher H. Contag, an assistant professor of pediatrics at Stanford University. With a courtesy appointment in the radiology department, Contag is studying luciferases, which emit bioluminescent signals that are detected by a charge-coupled device camera (see related article in this issue).

A frequent obstacle for Contag is hemoglobin. Present throughout the body, hemoglobin absorbs light of 400 to 600 nm, which includes the signals of luciferases, Contag wrote in a paper published in the Annual Review of Biomedical Engineering (2002;4:235-260). Other tissues absorb light according to how much melanin or how many pigmented macromolecules are present. Further diffusion of the light occurs when cell and organelle membranes scatter the light as it leaves the cell.

An advantage with bioluminescence is the low amount of noise.

"Animals and people don't glow in the dark for the most part," Contag said. "There's more noise in PET imaging."

Even so, the costs of developing luciferase reporter genes for humans would be greater than the benefit, he said.

"The greatest benefit to humankind is acceleration to preclinical models," Contag said.

MR is another popular imaging technique, but it's not sufficiently sensitive, according to Simon Cherry, Ph.D., a professor of biomedical engineering at the University of California, Davis. Imaging agents for both MR and optical imaging are large molecules; attached to a drug, usually a small molecule, these probes could interfere with the drug's action.

APPLES TO APPLES

MR and optical imaging, in addition to other imaging modalities, are nevertheless making contributions in the preclinical setting through instruments scaled down for small animals.

"Complementary instrumentation for imaging both animals and patients provides a unique opportunity for substantive translational research," Dr. Ronald G. Blasberg, a professor of neurology and of molecular pharmacology at Memorial Sloan-Kettering Cancer Center, wrote in Molecular Cancer Therapeutics (2003;2:335-343).

Toward that end, Cherry has spent the past decade designing PET scanners for use with small animals. Many large pharmaceutical companies have purchased these devices to aid in drug development efforts.

"With PET you can take a small molecule and switch out a carbon atom for a radioactive carbon atom without affecting the drug's distribution in the body," he said.

But the task is not complete. Unlike optical and MR imaging probes, PET tracers produce a signal even they have not bound to the intended target or anatomical area. And the detectors, which pick up only 5% of the radiation in the animal, need to be much more sensitive, Cherry said.

Phelps, however, is confident that PET scanning has the advantage in gaining approval for use in the clinic.

"PET can work off the fundamentals that have been known for 80 years. That means that not as much info is required, compared to when we didn't have that foundation," he said.

But first, researchers must face a barrage of issues. Contrast agents and other tracers must reach their target by breaking through the cell membrane, exiting blood vessels to enter tissues, and undergoing other complex maneuvers, while avoiding degradation by proteases and neutralization by the immune system. A sufficient amount of an imaging agent must accumulate at the target site but not at other parts of the body to achieve specificity.

Drug developers contend with similar dilemmas, but they don't usually have to address questions posed by the high-tech devices and instruments that make up the other half of molecular imaging research. All imaging modalities need improved performance, either from increases in spatial or temporal resolution, sensitivity, or both, Cherry wrote in a review published in Physics in Medicine and Biology (2004;49:R13-R48). Researchers must also strengthen the ability of imaging devices to quantify molecular imaging studies if these tools are to be used to track disease, he wrote.

Unfortunately, the slow and convoluted process may never improve, Baum said.

"It's not a piece of cake. If you embark on the journey, then you must put in many, many years and be a real proponent. That's the nature of it," he said.