Any comprehensive vision for reducing the burden of cancer includes a large dose of chemoprevention. But a daunting array of hurdles stand between this vision and the reality of getting preventive agents into the hands of the people they might benefit.
Pharmaceutical companies continue to spend billions of dollars bringing to market oncologic drugs that will make only small, incremental improvements in cancer treatment. By contrast, the industry has balked at making major investments in chemoprevention researchthe kind that might lead to agents that would stop cancer in its most formative stages. Among the major obstacles holding drugmakers back is the vast uncertainty surrounding how preventive drugs could be evaluated and approved in a timely manner, and howand to whomthey could be marketed.
At an October 18 forum in Boston, industry and government researchers discussed private sector perspectives on developing targeted cancer prevention drugs. The session was part of the American Association for Cancer Researchs first annual "Frontiers in Cancer Prevention Research" conference.
The forums chairperson, Anna Barker, M.D., founder and CEO of BIO-NOVA Inc., Cincinnati, put forward the questions she said will ultimately determine whether a viable market exists for chemoprevention.
|
Participants had no definitive answers to most of these questions. But they fleshed out the problem by defining its scope, relating examples, and offering some tentative suggestions on how progress could best be made.
Unquestionably, there is a disease burden, with an estimated 1.3 million new U.S. cancer cases and more than a half million deaths in 2002. Cancer costs $180 billion per year, and "reducing the death rate by 20% would save trillions" over the years, said Barker, who recently became a special consultant to National Cancer Institute director Andrew von Eschenbach, M.D.
Although everyone is at risk of cancer, Barker noted that the most promising chemoprevention approaches would initially target populations at elevated risk. Taken together, this group is enormous, encompassing cancer survivors, smokers and former smokers, families with hereditary risks, and people with occupational or environmental exposures to carcinogens.
Although the potential market is huge, Barker said, the way to tap into it is uncharted. "If we try to use the same process as we use for treatment drugs, it wont workits too complex," she said. She then posed a final question: "Are companies going to position themselves at the forefront of chemoprevention?"
Thus far, most drugs used or under evaluation as preventive agents have "backed into the chemoprevention setting" after first being used for another indication, said Homer Pearce, Ph.D., former vice president for cancer research and clinical investigation at Eli Lilly and Co. in Indianapolis, Ind., and currently a Lilly research fellow working on long-range strategic planning for the company.
The drug industry has committed to chemoprevention in several areasosteoporosis, lipid reduction, and transplant rejectionbut not in cancer, Pearce noted. Why? He noted that there are several negative perceptions that pervade the industry: The cancer disease process is too complex and heterogeneous; predictive markers that would identify individuals at risk remain elusive, which makes identifying people who would benefit from chemoprevention akin to looking for a needle in a haystack; the regulatory approval process is uncertain and could become even more lengthy; and conventional wisdom holds that "nobody gets paid to practice prevention." Unless healthy people are known to have a very high risk for a disease, theyor their insurance companiesare unlikely to pay hundreds of dollars per month to prevent that disease.
Another major issue is patent protection. Even for cancer treatment drugs, a large fraction of the standard 20-year patent exclusivity period is commonly used up by clinical trials aimed at U.S. Food and Drug Administration approvala period when the drug is not being sold in the marketplace. For chemoprevention agents, that problem is magnified, since trials to demonstrate preventive benefit typically take much longer than therapeutic trials.
David Parkinson, M.D., global head of translational therapeutic development at Novartis Pharmaceuticals Corp., East Hanover, N.J., and a former director of NCIs Cancer Therapy Evaluation Program, illustrated the problem with the story of ursodiol (Actigall). A Novartis drug that was originally developed to treat gallstones, Actigall was studied in a clinical trial after preclinical studies suggested it had potential for preventing colon polyps and cancer.
|
Because of their responsibilities to shareholders, pharmaceutical companies are wary of a similar fate for other preventive drugs, both newly discovered agents and those developed initially for another use. Drugs that are off-patent for their original indication could conceivably receive additional patent protection if studies showed a new chemo-prevention use, Pearce noted in an interview, but physicians and consumers would still be free to use the cheaper generics off-label.
"Its a challenge to find a business model that makes the investment in these studies appropriate from a shareholders perspective," he said.
Ironically, from a companys vantage point, "the best agents for chemoprevention are the agents we know the most about, and the agents we know most about are those with the least patent protection left," Parkinson added.
A precedent exists in the patent extension granted for drugs when a company starts trials for pediatric use, and Parkinson suggested that a similar extension for cancer prevention drugs might "change the mindset" of the industry. Pearce agreed that pediatric exclusivity, although it extends the patent by only 6 months, has in some cases led companies to seek additional indications for drug approvals. He suggested a ballpark figure of 5 additional years as an incentive that might do the same for prevention drugs.
Gary Kelloff, Ph.D., special adviser in NCIs Division of Cancer Treatment and Diagnosis Biomedical Imaging Program, described one of the rare success stories in cancer chemoprevention marketing: the approval in 1999 of the arthritis drug celecoxib (Celebrex, from G.D. Searle & Co., now part of Pharmacia Corp.) for familial adenomatous polyposis (FAP), a hereditary precursor of colorectal cancer.
The celecoxib story illustrates several factors that help determine whether a company can profitably sell a chemoprevention drug. First, NCI sponsored a trial leading to accelerated FDA approval, which did not require evidence that the drug actually prevents colorectal cancer but simply that it reduces the number of polyps. Second, the target population has a greatly increased risknearly all patients with FAP will develop cancer in their 40s or 50sand thus a compelling motivation to use anything that may reduce that risk. Third, the drug is relatively new, so Pharmacias patent is good until 2013. The confluence of these factors means that the company can sell the drug at a premium. Celebrex is now in clinical trials for other colon polyp syndromes as well as precursors of bladder, esophageal, and skin cancers.
Recognition by the scientific community and FDA that such precancerous conditions could serve as surrogates for cancer incidence would make it possible to perform much quicker and smaller trials than would be required using cancer end points. The FAP trial for celecoxib, for example, had only 83 patients.
Even betterbut still elusiveare biochemical markers that would flag cancer risk even earlier and could be tested in the blood. The ties between blood lipid levels and coronary artery disease, and between the menopausal estrogen falloff, bone mineral density, and osteoporosis made for relatively straightforward approval of preventive agents for those conditions, Pearce noted, but for most cancers, no such direct relationship has been found.
Another difference is the incidence of cancer and how the disease plays out in the population, Pearce said. High cholesterol is rampant, and most untreated postmenopausal women will eventually develop osteoporosis. Thus, huge segments of the population are candidates for drugs to counter these conditions. Cancer, while common as a whole, is a multifarious disease, and in the absence of an inherited syndrome such as FAP, there is usually no way to tell which type of cancer an individual is at highest risk for.
"When we start thinking of preventing the more common malignancies," Pearce said, "without question, the cost of these treatments to patients and providers will have to go down. But the expectation is that people will take the drugs for very long periods of time," similar to the way they now take lipid-lowering drugs. The target markets, at least in the foreseeable future, will not be the general, healthy population but rather people who have been identified as having at least a moderately elevated risk for a particular cancer.
Safetyand the legal liability surrounding safetyis another looming obstacle to marketing chemoprevention drugs, participants at the AACR forum agreed. Because they are targeted at healthy people, the threshold of acceptable risk from taking the drugs would be low, leaving drug companies in a potentially vulnerable position. Parkinson suggested that the federal government would have to take on some of this liability to make chemoprevention attractive to the industry.
"We need a national strategy" for chemoprevention, Barker said. "And NCI has to play a lead role as an honest broker in reducing the risk for the pharmaceutical industry."
Pearce added, "I dont think anyone has a very good appreciation for the full equation: the risks, the benefits, the investment required, the return that could be realized, because its so multifaceted. Theres going to have to be some careful listening and consideration of the possibilities for all the players find a place to play in."
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |