Speeding anticancer drug development 15 January 2002 by Apoorva Mandavilli, BioMedNet News The US takes awkward first steps toward deregulating cancer drug development, though small biotechs and big pharma don't agree on how. And what does toxicity testing mean for the terminally ill? Eager to disentangle the knotty regulatory process of cancer drug development, leading US cancer researchers are meeting today at the National Academy of Sciences. Organized by the academy's Institute of Medicine, "Shortening the Timeline for New Cancer Treatments" is the first in a series of four meetings scheduled to take place all year. The project may be off to a rocky start, however. Just days before the meeting, at least two speakers were unaware they were to be present. But others anticipated the event with enthusiasm and resolve. "It's time to alter the type and nature of regulatory requirements to get molecules into trials," said Edward Sausville, associate director of the US National Cancer Institute's Developmental Therapeutics Program. The US Food and Drug Administration (FDA) recently has come under fire for unnecessarily delaying the requirements for drug approval. But the FDA may not to be blame, says Sausville. "If you compare with historical data, [the drug approval process] has actually gotten a lot better," he said. "The FDA doesn't operate in a vacuum. My feeling is that within the constraints of the law, they're being diligent to bring those drugs forward." Rather than the time required for approval, it's the framework itself that needs restructuring, he suggests. "The essential question we have to address is whether or not the current model of [toxicity testing] works," he said. Before beginning clinical trials of new cancer drugs, US pharmaceutical firms carry out exhaustive toxicology tests on animals such as dogs and monkeys. The results, obtained with great cost and effort, are used to set the maximum tolerated dose of a drug and predict long-term effects on humans. Testing toxicity in animals helps predict the starting dose and acute toxicity, but "that's basically all the animal data is good for," said Richard Schilsky, associate dean for clinical research at the University of Chicago, another scheduled speaker. Once the clinical trial begins, data from human patients are much more important, Schilsky says. Is the animal data then useful to predict long-term effects? Ninety days is long-term for a mouse, but a human patient may need to take a drug for 40 years. Given such discrepancies, Schilsky added, its "appropriate to question" whether the animal toxicity data is necessary at all. One alternative to extensive toxicological testing is to rely exclusively on rodent models, suggests Sausville. In the UK, for example, most trials are performed under CTX (clinical trial exemption) or DDX (doctors and dentists exemption). The CTX criteria are very similar to FDA requirements for drug testing, explains Sally Burtles, director of drug development for the not-for-profit Cancer Research Campaign (CRC). But investigator-led trials can use the DDX criteria to begin rodent-only testing for short-term toxicity and the starting dose for a trial. Such trials are usually designed primarily for patients, Burtles says. "If they're worrying about long-term toxicity, we're doing a fantastic job," she said. "It means [the patients] are alive." Once the CRC has finished a successful trial in an academic setting, a pharmaceutical company should be able to begin large phase III trials. "The [initial] trials don't need to be redone since they're of the same quality," Burtles said. But often, large companies go back and repeat toxicity tests on dogs and monkeys, she says. "I don't know how the companies think, to be honest," she said. "But the argument that we'd like to make is if you've got the data and the patients, then why do you need to go back and test it in dogs and monkeys?" If speed is of the essence, she adds, it makes sense not to invest in long-term toxicology tests. As genome sequencing, databases of genes in cancer cells, and identification of functional targets becomes more sophisticated, Sausville says, the community also needs to prioritize which targets will be useful. "We have a very target-rich set of playing fields in relation to cancer drug discovery," he said. But while "everyone's darling is STI-571, obviously ... the unfortunate reality is that in solid tumors, it's very unusual to be able to tie the biological behavior of neoplasm to a single target." Microarrays have also made it possible to generate profiles of tumor cell expression. For example, Louis Staudt of the NCI and his colleagues recently determined that large B-cell lymphoma is, in fact, two separate diseases that respond differently to current treatments. Information that in one subtype the NF-kappa B pathway is activated "is exciting because there are drugs that can affect this pathway," he said. Given such advances, it's crucial that scientists learn to deal with a combination of targets, Sausville adds. The real problem lies in translating leads into real drugs, he added. The incentives of small biotechs are not aligned with those of big pharma: The biotechs excel at innovation, while the pharmas are shy of taking risks - and the vast majority of drug candidates are lost because of adverse reactions, Sausville says. Meanwhile, adds Schilsky, pharmaceutical companies are driven by the need for FDA approval. Their initial strategy may not target the disease for which a drug is most useful. While drug companies usually test drugs of a specific disease, over the last few decades, 13 "cooperative groups" of cancer researchers have performed clinical trials to explore different treatment schedules, the benefits of adjuvant therapy and combination chemotherapy, and the use of candidate drugs in different diseases. Sponsored by the NCI, the groups have approximately 1,000 member institutions and nearly 10,000 researchers. They enroll 28,000 patients each year. While the groups provide an existing infrastructure for clinical trials, they are "woefully underfunded," said Schilsky, who is chair of the Cancer and Leukemia Group B. The groups' collective annual budget of $150 million, used to perform 100 randomized clinical trials, is "what pharma spends on one clinical trial," he noted. The budget also leads directly to a major criticism of the groups - their trials are slow. But the snail's pace is inevitable because the oncologists, physicians, investigators, data managers, and nurses who staff the groups are all volunteers, Schilsky explains. The researchers also rarely have access to a drug in the early stages and must wait till later in the drug's development to begin testing, he says. Scientists at the meeting plan to emphasize several other practical barriers to hastening the process of drug development. For example, because of the lure of genomics and proteomics, relatively few people are willing to study animal biology and other techniques required for drug development. Also, a bias toward the life sciences at the US National Institutes of Health means that chemists, who are crucial for drug discovery, are relatively underfunded. The agenda is ambitious and the speakers have a myriad of regulatory and scientific hurdles to discuss. "My hope is that the [decision makers] are fairly open-minded to these things," said Schilsky. "I guess we'll just have to wait and see." JAMA, 5/1/02 Cancersource.com JAMA,5/02 Ann Oncol, 3/02 New York Times, May 29, 2002 Efficacy, Safety & Cost of New Drugs Maryann Napoli Center for Medical Consumers 8/02 Dosages Too High More Public Review of Cancer Drug Studies Abstract #6068 ASCO, 2004 Abstract # 6001 ASCO, 22004 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.