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By Tom Tomlinson, PhD
Why are so much money and effort put into research aimed at curing cancer, and so little devoted to preventing it?
Three professors think they have at least part of the answer, as explained in a recent New York Times article (Why Preventing Cancer Is Not the Priority in Drug Development). They report that between 1971 and 2011, there were 12,000 research trials for drugs to treat patients with later stage cancer and a 90% chance of dying in five years; but only 6,000 for earlier stage patients with a 30% chance of dying. Even more starkly, 17,000 trials enrolled patients with recurrent cancers and low chances of survival, compared to 500 studying cancer prevention, where success would potentially yield much more benefit for more people (Budish, Roin and Williams).
In other words, the most money is being spent in pursuit of the least benefit for the fewest people. Why is this?
At great risk of over-simplifying, their answer is pretty simple: the commercialization lag. This is the time span between obtaining a patent for a new drug, and getting FDA approval to market it. The 20-year patent clock starts ticking when the patent is granted, but a company doesn’t begin to make money until the FDA allows sales. The shorter the commercialization lag, the more time available to amass a profit before your blockbuster goes generic.
So how does this affect cancer drug development? If the measure of success (and FDA approval) is increased cancer survival, success can be determined most quickly in those already likely to die soon. Compared to a group of cancer patients with a 1-year life expectancy, it will take 10 times as long to detect success in a group with an average life expectancy of 10 years. This is why the commercialization lag adversely affects the profitability of research to prevent cancer or to treat it in its early stages, and so discourages such research.
Understandably, the authors of the report then discuss remedies that mitigate the effects of the commercialization lag—e.g., identifying “surrogate endpoints” that can be detected much sooner, are strongly associated with increased survival, and allow for earlier FDA approval.
I’m sure they would admit that there are other factors discouraging early-stage and preventive cancer research. Here are several that occurred to me, some of which have an ethical component.
1. Enrolling early stage patients in a trial of a new, as yet unproven cancer drug could be ethically treacherous, if there is already a standard treatment regimen supported by evidence. The cleanest design would assign some patients to the new drug and others to the standard of care, and this would be especially necessary if the surrogate end point also occurred among patients receiving conventional treatment. But this would mean that the proven treatment was being deliberately withheld from the experimental group, or delayed until the surrogate end point window closed. The interests—even the vital interests—of this group would be sacrificed for the advancement of medical knowledge. Of course, we would require that they give their informed consent to being exposed to that risk. But the quality of such consent would be highly suspect, given that it is so clearly at odds with their self-interest. These are the concerns that underlie the principle of “equipoise”—that the arms of an experiment should be roughly comparable in terms of their potential risks and benefits. (See Declaration of Helsinki, #30.)
This doesn’t mean that it is always ethically impossible to conduct research on early-stage cancer, just that it will probably be ethically more challenging to design such trials.
2. Another challenge is enrolling an adequate number of participants, especially for research on agents to prevent cancer. Studies of potential preventive drugs for cancers that occur later in life and at relatively low population rates will require large numbers to be enrolled for long periods of time to detect a statistically significant effect. If the study agent carries side effects, or burdens of compliance with the research regimen, it may discourage enrollment and encourage later drop outs.
We might address this problem by enrolling people already at high risk for cancer, which will reduce the numbers required to detect an effect. This strategy probably raises no special issues for people whose increased risk is outside their control, like women and men with one of the BRCA genetic variants carrying much higher risk of breast cancer.
But how about a study focusing on preventing lung cancer, which enrolls heavy smokers to more easily achieve scientific feasibility? Its feasibility in part depends on whether the subjects continue to smoke. And the goal of the study—to determine whether the new drug reduces the risk of smoking—may indirectly encourage participants to continue smoking. This would be due to the “therapeutic misconception,” the well-documented belief among many research participants that the experimental intervention offers a much higher likelihood of benefit than the evidence suggests (Lidz et al.).
3. And this example takes me to my last question. Would developing a whole armamentarium of drugs to prevent cancer be an unalloyed good? Of course, it’s almost certain that these drugs will carry their own side-effects and risks, as the pharmaceutical company TV ads constantly remind us; and these risks will be experienced by large numbers of people who never would have gotten cancer in any event. And for this reason, preventing cancer in this way could end up costing much more in total than treating it, as Louise Russell pointed out back at the dawn of time (Russell).
But even setting aside these complications, I would still worry about the effects that ready availability of such drugs would have on other approaches to preventing cancer, like behavior change and environmental clean-up.
If we could all just take our pills as directed, would we in the process be eroding our sense of our personal and political responsibility for the causes of cancer, and if so would that be too high a price? I’m not sure how to answer those questions. I hope you might have some ideas.
Tom Tomlinson, PhD, is Director of the Center for Ethics and Humanities in the Life Sciences and a Professor in the Department of Philosophy at Michigan State University.
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- Budish E, Roin BN, Williams H. 2015. Do Firms Underinvest in Long-Term Research ?Evidence from Cancer Clinical Trials. American Economic Review. 2015; 105(7): 2044–2085. http://dx.doi.org/10.1257/aer.20131176.
- Frakt, Austin. Why Preventing Cancer Is Not the Priority in Drug Development. New York Times. Dec 28 2015. Retrieved from: http://nyti.ms/1me2V7W.
- Gemain, Denicoff, Dimond, et al. Use of the National Cancer Institute Community Cancer Centers Program Screening and Accrual Log to Address Cancer Clinical Trial Accrual. Journal of Oncology Practice. 2014 Mar; 10(2): e73–e80. http://dx.doi.org/10.1200/JOP.2013.001194
- Lidz, Appelbaum, Grisso, Renaud. Therapeutic misconception and the appreciation of risks in clinical trials. Social Science & Medicine. 2004 May; 58(9): 1689-97.
- Murthy, Krumholtz, and Gross. Participation in Cancer Clinical Trials: Race-, Sex-, and Age-Based Disparities. Journal of the American Medical Association. 2004; 291(22): 2720-2726. http://dx.doi.org/10.001/jama.291.22.2720.
- Russell, Louise. Is Prevention Better than Cure? Brookings Institution Press; 1986.