© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 8, 575-577,
April 18, 2001
© 2001 Oxford University Press
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Chemoprevention: Can Industry and Academia Collaborate?
The advertisements are hard to miss in most medical journals. Full-page color spreads of DNA helixes, robotic humans, and other high-tech images promise an automated medical future. All are from pharmaceutical or biotech companies; all pledge their corporate commitment to build a brave new world of molecular medicine.
As this new molecular world comes into tighter focus, many experts predict that so, too, will the promise of cancer chemoprevention. If true, oncologists would no longer spend their days coping with what we now call cancer. They would have the molecular tools to detect carcinogenesis, the early, multi-step process that leads to cancer, and a pharmacy of tumor-suppressing chemicals that snuff out developing tumors well before they turn invasive and deadly.
Though the promise of chemoprevention far outpaces the science, industry is slowly, but surely, buying into its future, and with good reason. Last October, SkyePharma received approval in the United States to market Solaraze (diclofenac sodium) for the treatment of actinic keratosis, a precursor of squamous cell carcinoma.
Perhaps better publicized, AstraZeneca Pharmaceuticals has approval in the United States to market Nolvadex (tamoxifen citrate) as a chemopreventive agent for women at high risk of breast cancer, and Pharmacia Corp. won U.S. approval in 1999 for the drug Celebrex (celecoxib) to help reduce polyps in people with familial adenomatous polyposis, or FAP, which predisposes to colon cancer.
But, as industry starts to take a more prominent role in cancer chemoprevention, many say they see logistical hurdles on the horizon that should be addressed sooner rather than later. At the top of the list remains the inordinate amount of time, money, and financial risk involved in the development of chemopreventive agents. How can protections be built into the drug-development process to encourage more companies to take the financial plunge into chemoprevention? As all agree, without industry and its powerful resources, future chemopreventives will continue to take an excruciatingly long time to reach the market.
Yet, in granting protections to for-profits, what would this mean for academic scientists, who gave birth to the concept of chemoprevention and have dominated the field for the past 20 years? Would a company’s tight-fisted control of a compound’s research agenda compromise grant opportunities and the free flow of information that are the chief currencies of academic science?
Tall Tasks
At the heart of the matter is that chemoprevention remains a tall task by any measure. Unlike chemotherapy drugs, which are taken briefly and by people with advanced disease, chemopreventive agents will end up in the hands of healthy people who have been deemed at high risk of developing a given cancer, and the acceptable level of risk associated with a chemopreventive is far less than for a potentially life-saving chemotherapy drug.
Determining whether a drug safely prevents a disease takes years of careful observation—time that most companies say they cannot afford. "There is only so much money to go around," said Steven Benner, M.D., vice president for licensing and external development at Bristol-Myers Squibb Co., which has established its own chemoprevention laboratory. "We are balancing it against other treatments for other serious diseases. So, we have to be able to show that there is going to be a financial benefit for the company as well."
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Assuring that a company will benefit financially from a chemopreventive agent is never a safe bet; the field has a history of past clinical surprises and negative results. Many attribute these disappointments to the field’s former heavy reliance on observational epidemiology for its lead compounds.
Dean Brenner, M.D., a scientist at the University of Michigan in Ann Arbor, noted that one way to improve the odds is for the field to place a higher priority on the preclinical development of compounds, particularly understanding their pharmacology and pharmaceutics. Another is to get a better handle on the basic biology of cancer prevention. That is, the field needs to build on current large-scale attempts to define tumors based on their molecular phenotypes, rather than the appearance of biopsies under a microscope, as is now largely the case.
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"All of this is mechanistically driven," said Ernest Hawk, M.D., a scientist at the National Cancer Institute, Bethesda, Md., referring to chemoprevention. "So, every time that you come up with a new insight, it becomes a potential target, as well as a marker for risk and a marker of response."
Michael Friedman, M.D., a senior vice president at Pharmacia Corp. in Peapack, N.J., said establishing surrogate markers for a variety of tumors will be vital to the future success of chemoprevention trials because the markers could dramatically reduce the length of clinical trials.
"Instead of waiting for the development of colon cancer, you can use the appearance of a polyp as a precursor lesion," said Friedman. "I think that has been pretty well accepted as a surrogate of significance. But, if you look at other situations, I’m not sure that we have the same level of conviction about what the surrogate means." Friedman said investigators and regulatory agencies need to sit down and establish clear scientific standards for what constitutes an early cancerous lesion.
As Hawk noted, defining these early cancerous lesions also would allow more scientists to focus on high-risk genetic groups, another strategy to speed chemoprevention studies. Hawk said a recent example is NCI’s collaboration with Searle, now a part of Pharmacia, to study celecoxib in blocking polyp formation in people from families with a history of FAP.
"Once we show that an agent is active in people at high genetic risk, we can take it back into patients at sporadic risk," he said. "Lower risk is going to take more time and people to demonstrate efficacy, if it indeed translates."
Without a surrogate marker or a defined mechanism, industry generally cannot afford to jump into the development process, said BMS’ Benner.
"If you don’t have any surrogates to test, you don’t learn anything while the trial is going on, which means every step takes many years to get through to the phase III process," he said.
Patent Protection
If Bristol-Myers Squibb were at this point willing to conduct a 10-year phase III trial, Benner said its patent protection on the agent would have likely expired, putting Bristol-Myers Squibb at risk of losing out on its already sizable investment.
Benner said he is not sure of the appropriate period of patent protection, but he thinks that the subject needs to be "seriously discussed" to attract a broader segment of industry into cancer chemoprevention.
Some academics, however, wonder whether broader industry protections, such as a longer period of patent protection, might not end up short-circuiting their own research. They point out that industry has one goal, and that is get a promising compound to market as quickly and efficiently as possible. Some contend that companies in the past have pulled the rug out from under academic scientists who want to study issues that do not fit into the companies’ research agendas, often by withholding drugs for the proposed experiments. They warn that such tight industry control could undermine the breadth of science that is traditionally needed to understand a drug adequately.
"Of course, there will be some circumstances, some companies, some products, where there will be a very tight control of the scientific agenda," said Pharmacia’s Friedman. "Investigators might have research that they would like to perform that the particular sponsoring company simply won’t permit to be done. That, of course, could happen."
But Friedman said that the field of chemoprevention needs good ideas, not monopolies. "Industry, like academia, recognizes that nobody has all of the good ideas," he said. "You really want to establish good working relationships so that you can identify good ideas. One way to do that is to work with academicians who have their own ideas, their own research agendas, and, where it is possible, to collaborate."
No matter who controls the research agenda, many predict that it is in the idea department where academic scientists will continue to shine. As Hawk noted, industry excels at following cellular pathways once they already have been laid down, not carving them out.
"Once you have one hypertension drug through, you have a whole proliferation in the field with various pharmacologic approaches that modulate the biology," he said. "But establishing that first paradigm, that first pathway to an approval is really difficult, expensive, and something that they are not really interested to invest in. That’s one place where I think the public, or NCI, has done a good job in trying to establish the paradigms, so that industry can follow up thereafter and have a reasonable chance of success."
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