Does R&D Favor Advanced Cancer?

Economic research suggests patent system deincentivizes investment in therapies for prevention, early-stage disease

Treating cancer is easier in its early stages, before tumors have metastasized or become overly heterogeneous. Yet most cancer drugs are developed for the sickest patients.

MIT healthcare economist Heidi Williams, PhD, and colleagues think market incentives play a key role. Their analyses suggest that firms invest disproportionately in late-stage cancer drugs because they can reach market faster than early-stage and preventive therapies (Am Econ Rev 2015;105:2044–85). Because patents for therapies are filed at the time of discovery rather than first sale, patent exclusivity periods shrink considerably for medicines that take a long time to develop.

To get a drug to market, companies must run clinical trials to show that the intervention prolongs survival without excessive risk. If a drug is tested in people with early-stage cancer, “it's going to take a longer trial to show a benefit,” says Williams, who won a 2015 MacArthur Foundation “genius” grant for her work. “Are firms investing too little in therapies that require long clinical trials?”

To find out, Williams and colleagues turned to the NCI's Physician Data Query Cancer Clinical Trials Registry, which lists the cancer type and disease stage of patients enrolled in trials conducted between 1973 and 2011. They correlated this data with survival over the same period, as recorded in the Surveillance, Epidemiology, and End Results database.

According to the team's analyses, pharmaceutical companies did invest more in drug studies among patients with poorer prospects. For example, 29,602 trials studied drugs in recurrent or metastatic cancers, whereas just 6,083 examined drugs for localized disease, and 523 tested preventive interventions.

If trial length is a key consideration, then research investment patterns should be less skewed when trials use surrogate endpoints, which allow for shorter trials. Indeed, this is what Williams's team found. When they looked at drug trials for certain leukemias and lymphomas, in which early changes in blood or bone marrow can reliably predict patient outcomes, “there was a more equal distribution of research investment” across disease stages, says Williams.

Clinicians and other experts agree that time to market influences decisions about which trials to pursue. However, they think ethics and feasibility considerations are also a major driving force. By the time some cancer patients are diagnosed, “they may be faced with a situation where they don't have a lot of good options,” says Jocelyn Ulrich, MPH, assistant vice president of the trade group Pharmaceutical Research and Manufacturers of America (PhRMA). As a result, patients with late-stage disease are often more willing to enroll in trials, she says.

After a drug shows clear benefit in patients with advanced cancer, some firms will conduct subsequent trials in patients with less aggressive disease. “Once a product is approved for the most urgent setting, patients may be more likely to enroll in studies in earlier stages of disease,” says Emma Van Hook, MS, director of policy and research at PhRMA.

Interestingly, in the economists' analysis, publicly funded trials were less skewed toward advanced disease, compared to privately funded studies, suggesting that the public sector does fund early-stage research and that patients will enroll in these studies when they are conducted, Williams says.

Another reason companies may shy away from early-stage and cancer prevention trials: They fear unrealistic expectations. Many people “want an application that's 100% nontoxic and 100% efficacious,” but no drug meets these requirements, says Powel Brown, MD, PhD, chairman of the Department of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center in Houston.

In 1998, for example, the FDA approved tamoxifen after a large, randomized trial showed that taking it for 5 years slashed breast cancer risk by 49% in older women judged to be at high risk for the disease. “In terms of clinical trials, it was a home run,” Brown says. However, because tamoxifen can cause mild side effects and needs to be taken for such a long time to prevent disease, “hardly anyone took the drug,” says Brown.

Similarly, the arthritis painkiller celecoxib showed effectiveness in preventing new colon polyps in people who had had the growths removed. Side effects'including heart attacks, stroke, and other cardiovascular complications'were rare but occurred slightly more often in the treatment group. Not only did people become unwilling to take the drug to prevent cancer, they also stopped using it for arthritis. That “turned a billion-dollar drug into a loser,” says Brown.

“Companies are exceedingly responsive to past history. They see that drugs developed for prevention lost them money,” he notes. “This is one reason companies are so skittish about conducting prevention trials.”

Yet Brown sees reasons to be optimistic that drug development patterns will evolve. For example, some participants in the I-SPY 2 breast cancer trial could receive experimental drugs before, or in combination with, standard therapy. “This allows brand-new drugs to be tested in early stages where cancers are more likely to be curable,” Brown says. –Esther Landhuis

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.