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FDA Starts Moving on Critical Path, But Initiative Running Out of Steam
The Critical Path Initiative is an ambitious plan to improve the process of drug discovery and approval. But so far, the U.S. Food and Drug Administration strategy has not gotten funding, and experts are concerned that a lack of money could substantially slow the effort to speed up the drug pipeline.
"There is growing concern that many of the new basic science discoveries made in recent years may not quickly yield more effective, affordable, and safe medical products for patients," Richard Pazdur, M.D., director of the FDA's oncology drugs division, said during a May 2004 House hearing. "This is because the current medical product development path is becoming increasingly challenging, inefficient, and costly."
Two months earlier, an FDA report had concluded that the agency urgently needs a tool kit of new scientific and technical methods—animal or computer-based predictive models, biomarkers for safety and effectiveness, and new clinical evaluation techniques—to improve the predictability and efficiency of drugs along the critical path from laboratory to product.
The Critical Path Initiative is seen as a way for the FDA to step outside its role as a regulatory agency and work with companies to develop that tool kit. The initiative's far-reaching goals are to use new technologies to improve the drug development process by identifying signals of unsafe drugs earlier in testing, targeting patient populations more precisely, streamlining the approval process, and using postmarket data collected in the clinical setting. The March 2004 report included 76 specific scientific opportunities that the agency wants its private and public partners to pursue.
Although the pharmaceutical industry, research groups, and public advocates generally support the initiative's goals, federal funding specifically for the project has not been forthcoming. The White House did not include funding for Critical Path Initiative in its budget proposal until last year. The initiative has its supporters in Congress, but tight budgets have so far kept lawmakers from finding money for the effort. In February, a bipartisan Senate bill was introduced that would establish the Reagan–Udall Institute for Applied Biomedical Research to advance the Critical Path Initiative. The institute would have an annual budget of $20 million.
Building a Better Process
Despite the lack of funding specifically for the initiative so far, the FDA has been able to move forward by partnering with outside groups, such as the University of Arizona. With seed funding from the university, the Critical Path Institute, known informally as C-Path, was created in 2004 with financial support from local governments and private foundations. The institute takes no money from FDA-regulated industries, so it can act as a neutral ground for the government and the industry to work together on nationwide projects.
"For the current investment of $60 billion in science, last year we only had 18 new drugs. We believe a more efficient system that has a better process would be able to improve on that fivefold," said Raymond Woosley, M.D., Ph.D., president of the institute.
Although created at the behest of the FDA, the institute operates independently and has taken on several opportunities identified through the initiative. One example is the Predictive Safety Testing Consortium, a group of 16 drug companies and more than 120 scientists who examine early indicators of drug safety. They meet regularly to share their data and have it validated by the institute's own experts.
"We put in about $400,000 in infrastructure support, but we estimate they do $30 million a year in research to validate biomarkers for preclinical toxicity," Woosley said.
The same scientists had been meeting with the FDA for years, but taken individually their reports were of limited value. In contrast, the institute was able to come in as an impartial middleman to negotiate the terms over which the scientists could begin to talk to each other as well as the agency.
According to an FDA statement, predictive safety tests currently developed by individual companies are not useful to the agency because they have not been validated by an independent party. "Under this consortium, member companies will share the information that will enable them to have their tests validated by C-Path's outside experts and other members of the consortium."
Another project, the Oncology Biomarker Qualification Initiative, was devised as a template for how to develop drugs and diagnostic tests in tandem, said Jeffrey Cossman, M.D., chief scientific officer of the Critical Path Institute.
"Until now they have been developed independently ... without a real strategy," he said. For example, the fact that Herceptin [trastuzumab] and HER-2 testing were developed independently has made it difficult to use them together, despite their innate compatibility.
The biomarker initiative held its first meeting last April, with about 20 diagnostic and drug companies attending. The companies agreed to work together on a project to create diagnostic tests for epidermal growth factor receptor inhibitors in lung cancer. As with the predictive safety tests, these companies can, for the first time, have their testing protocols vetted by the FDA before they enter the approval process. If this project is successful, C-Path plans to extend the approach to other types of biomarkers.
"The diagnostic companies, which were reluctant to work together in the beginning, agreed and have since worked quite closely together to develop ... three different types of tests predicting who is going to respond to [epidermal growth factor receptor] inhibitors. Now the National Cancer Institute is putting together a clinical trial to do a prospective study—not test drugs, but to tests these assays as a type of personalized medicine," Cossman said.
Drop in the Bucket
Despite the lack of funding, the FDA has been able to make some advances in the drug approval process through the initiative, including a few examples where drugs moved forward through alternative approaches to large randomized trials, such as Bayesian analysis or observational studies of off-label use. But lack of funding has slowed such reforms, experts said.
"Progress has been made. I have seen drugs licensed based on new criteria. I wouldn't say that it's not moving forward, but I would say that the rate at which it could move forward could be substantially accelerated," said Robert Peter Gale, M.D., Ph.D., senior vice president of research for Ziopharm Oncology in New York City.
One big problem is that FDA scientists have had difficulty getting approval to attend meetings that were part of the Critical Path Initiative's agenda. Even when these meetings were held in the Washington, D.C., area, the staff members had to take vacation time to attend or could meet only after business hours.
"Scientists in America work on a collaborative basis. If you don't have a travel budget and you can't regularly show up at meetings, then nothing gets done," said Robert Goldberg, Ph.D., vice president of the Center for Medicine in the Public Interest in New York City.
However, some FDA funding may be on its way. The president's fiscal year 2008 budget proposal includes $6.7 million for the initiative, the same amount proposed for 2007. The budget Congress failed to pass for this year cut that down to just under $6 million (much of the government is still running under the budget passed for 2006).
"The FDA previously has asked for $50 million, and that was conservative. ... Six million dollars on a $2 billion [overall FDA] budget is not a reasonable amount to spend on process improvement. Most industries spend 5%–10%, at least, of their budget on process improvement," Woosley said.
Gale agreed that $6 million is a drop in the bucket.
"The estimated cost for each cancer drug licensed is about a half a billion dollars. ... If you think of that as a landmark and you are trying to accelerate cancer drug development, $6 million pays for paper clips," he said.
A bigger budget is justified, given the potential return on investment, Gale said. Take the example of bone marrow transplants for breast cancer patients, a procedure that costs more than $100,000 and was being performed on 3,000–4,000 women a year. With a federal grant of about $2 million—just a fraction of what the nation was spending on the treatment—physicians established a comprehensive registry to track patient outcomes. This is the kind of study that Gale hopes will be conducted regularly through the initiative.
"We were able to determine that these things didn't work, that autotransplants not only weren't helping women with breast cancer, they were harming women with breast cancer," Gale said. The study not only saved millions of dollars that would have been otherwise spent on an ineffective treatment but also prevented much unnecessary suffering.
Even without federal funding for the Critical Path Initiative, the FDA has been undergoing an internal reorganization that will facilitate this effort, according to an agency spokesperson. The recent hiring of a chief operating officer will allow deputy director Janet Woodcock, M.D., who was also recently named chief medical officer, to focus more of her attention on Critical Path Initiative, the spokesperson said. Woodcock was appointed by former FDA Commissioner Mark McClellan, M.D., Ph.D., to study the initiative's creation.
"Her heart is really in the Critical Path," Woosley said.
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