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Opinion: Reasons for the R&D Crisis

Response to an opinion in The Scientist charting current pitfalls in translational research

By | September 23, 2013

FLICKR, _TAWCANMasoud Manjili’s recent opinion that translational research is “in crisis” is accurate, timely, and on target. Although all are in favor of innovation, few welcome change—“a radically new approach,” as Manjili has called for. But if the new approach promises a better outcome, especially for patients with solid cancers, it would be supported by the public and private sectors. However, such an approach would have to be based on a comprehensive analysis, the identification of substantive and sizable roadblocks to innovation, and a persuasive plan to overcome the obstructions.

In his 1962 book The Structure of Scientific Revolutions, Thomas Kuhn explained that in times of crisis, the most significant roadblock to innovation is inertia—the persistence of an establishmentarian opinion. This has been true throughout the history of science, and remains so today. Following Manjili’s lead, we limit our comments to cancer research and development (R&D).

Manjili pointed out preclinical and clinical problems that are well known among scientists, but those were simply tactics. The key question at hand remains unaddressed: What are the factors that drive scientists—who know better—to perform inadequate research that predictably lead to outcome dead-ends? Based on our experiences in academia and pharma, the primary reason for the failure of productivity stem from regulations, particularly those based on simplistic, one-size-fits-all disease paradigms and regulatory guidance. Approved antibiotics cure infections, and marketed antihypertensives lower the blood pressure, but do approved anticancer agents, in general, slow the progression of solid cancer?

Preclinical science is aimed at preventing local invasion and metastasis, and progress in the field has been nothing short of spectacular. But innovation is more than spectacular science; it also concerns the profitable commercialization of safer and more effective products. Investment in pharma R&D is based on expectations, both clinical and financial. Anticancer R&D is not profitable today, and the business outlook, dismal. Often, the first question addressed to academic scientists submitting a research proposal is: What are the chances of clinical benefit? On the other hand, the first question posed to pharma scientists is: Is there a clear regulatory pathway? This helps explain the dichotomy in anticancer R&D: academic investigators focus on the mechanisms of invasion and metastasis, while pharma researchers are locked in to the tumor-shrinkage paradigm. The former suffer from a lack of funds, while the latter are well-funded. But both camps are losing.

Based on recent performance, we can safely predict that it is unlikely that even a small fraction of the some 950 cancer drugs in development will demonstrate meaningful benefit (especially those for solid cancers, which are notoriously difficult to treat). Clinical R&D programs that are aimed at tumor shrinkage have no bearing on the causes of progression—namely, local invasion and metastasis. Solid cancer drives morbidity and mortality by local invasion and metastasis, not by tumor size. However, if candidate drugs do not cause tumor shrinkage in rats, they are not advanced to the clinic. The problem is that those candidates that cause tumor shrinkage in rats and people most often do not stop progression of the disease. Indeed, the tumor shrinkage paradigm has yet to be validated as an accurate predictor of clinical benefit.

Accordingly, a simpler, better, and radical approach would involve strategies to prevent or delay invasion and metastasis. The transmission of relevant science to the clinic and regulators is our best bet for generating better outcomes, and thereby generating support and fostering partnerships between academia and industry. Certainly, the productivity crisis in cancer R&D merits a reconsideration of strategy. Science is necessary but not sufficient in and of itself to drive innovation. Continuing to operate under an outmoded regulatory paradigm is unlikely to produce different results.

Jan Brábek is a professor of cell biology at Charles University in Prague, and Michael Fernandes is founder and partner at the Chapel Hill, N.C.-based think tank Medbase.

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Avatar of: James V. Kohl

James V. Kohl

Posts: 110

September 23, 2013

Excerpt: "In his 1962 book The Structure of Scientific Revolutions, Thomas Kuhn explained that in times of crisis, the most significant roadblock to innovation is inertia—the persistence of an establishmentarian opinion."

My comment: For example, On August 14, 2013, comments from the ISHE yahoo group moderator changed from his oft-repeated regurgitation of scientifically unsupported opinion: “Random mutations are the substrates upon which directional natural selection acts.” The change was to “mutations are A substrate upon which natural selection acts.” Attempts to address the change in his claims were not posted to the group because I clearly show in my published works and in more recent presentations that adaptive evolution is nutrient-dependent and pheromone-controlled. (The moderator thinks that my claims are redundant. They are not as redundant as claims for mutation-driven evolution, yet no one will tell me how natural selection acts on mutations or answer the question: Is there a model for that?)

On September 13, 2013 a refutation of mutation-driven evolution was published: An experimental test on the probability of extinction of new genetic variants. Since then, I have not seen anyone address the biological facts that refute mutations theory by showing that mutant alleles are not fixed in the DNA of the C. elegans' organized genome. If mutations are not fixed in the genome, mutations are not the substrate or a substrate on which natural selection acts.  Are they?

So goes the battles of cancer research, and perhaps all biologically based reseach. Unless the negative aspects of mutations can be compared to an accurate model of nutrient-dependent pheromone-controlled adaptive evolution via the conserved molecular mechanisms of species from microbes to man, we seem destined to look only at how bad things happen. We're not likely to look at how the good things that happen are maintained in the genome via limited nutrient stress, limited social stress, and moderate physical activity, all of which act on the conserved molecular mechanisms of species from microbes to man.

September 23, 2013

I have nothing but hope for the needed conversation about how to get the regulators, and many of the researchers, out of the simplistic box that attempts to find linear mechanisms behind our illnesses. We are not linear organisms; we are complex, and even more, we can adapt with a novelty that is completely invisible to the researcher stuck in linear thinking.

The best way I have seen out of this is similar to the research looking at preventing local invasion and metastasis: look for ways to help our defenses. We all have defenses that help us cope with challenges and there are ways to optimize them. A secondary GI defense is gastroenteritis and it is best honored by oral rehydration, which keeps the fluid levels up despite GI losses. Saving more lives in ten years than penicillin did in 40 makes this combination of salt, sugar and water into a drug, but a drug with absolutely no regulatory track since you can mix it up in your kitchen. Same with xylitol, which prevents tooth decay by interfering with the adherence of Strep. mutans, the bacteria that mostly makes the acid that eats through the enamel to cause a cavity;  the summation of 40 years of clinical studies is that 5 oral exposures of xylitol a day prevents about 80% of tooth decay. And xylitol has the same action of S. mutans cousin S. pneumoniae, which lives primarily in the nose and causes thousands of deaths from related infections. Spraying a small amount of xylitol into the nose should reduce these deaths. But like oral rehydration xylitol is not controlled and so is without a regulatory pathway; and since you can buy it at your market if there were a pathway the lack of control would make it unprofitable.

So how can we help change the regulations to include these promising innovations?

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