Grant system good at ruling out bad things?

Grant System Leads Cancer Researchers to Play It Safe, by Gina Kolata, The New York Times, June 27, 2009. [Page 1][Page 2][Page 3][FriendFeed entry].

Excerpts from Page 1:

Yet the fight against cancer is going slower than most had hoped, with only small changes in the death rate in the almost 40 years since it [the "war on cancer" initiated by President Nixon in 1971] began.

One major impediment, scientists agree, is the grant system itself. It has become a sort of jobs program, a way to keep research laboratories going year after year with the understanding that the focus will be on small projects unlikely to take significant steps toward curing cancer.

.....

Even top federal cancer officials say the system needs to be changed.

“We have a system that works over all pretty well, and is very good at ruling out bad things — we don’t fund bad research,” said Dr. Raynard S. Kington, acting director of the National Institutes of Health, which includes the cancer institute. “But given that, we also recognize that the system probably provides disincentives to funding really transformative research.”

Excerpt from Page 2:

“They said I don’t have preliminary results,” she said. “Of course I don’t. I need the grant money to get them.”

Excerpt from Page 3:

Some experienced scientists have found a way to offset the problem somewhat. They do chancy experiments by siphoning money from their grants.

Comment: The focus of the article is on the grant funding system for cancer research in the USA. The author, a well-known science journalist, is pessimistic about the success that the current funding system has had in yielding research outputs that have led to any substantial decrease in cancer mortality rates. However, other than briefly mentioning overall cancer mortality rates, she does not attempt to analyze current approaches to cancer control.

In Canada, age-standardized mortality rates, for all cancers and all age groups, have decreased from 248/100,000 in 1984 to 212/100,000 in 2004 (about 15%) for males. In contrast, the corresponding mortality rates for Canadian females were 152/100,000 in 1984 and 147/100,000 in 2004 (a decrease of only about 3%). A detailed analysis is beyond the scope of this brief commentary, but a major reason is that age-standardized mortality rates for respiratory cancers have been higher in males and have been decreasing, while they have been lower in females, and have been increasing.

It has been estimated that, in the USA, "reductions in lung cancer, resulting from reductions in tobacco smoking over the last half century, account for about 40% of the decrease in overall male cancer death rates" (Tobacco Control 2006; 15: 345-347; doi:10.1136/tc.2006.017749). Strong evidence that tobacco smoking and lung cancer rates are related has been available for more than 50 years, since the research work of Richard Doll and Austin Bradford Hill.

We now know a great deal about success stories and best practices for effective, evidence-based tobacco control programs. (See, for example, Success stories and lessons learnt, Tobacco Free Initiative (TFI), World Health Organization).

So, does research play a crucial role in cancer control? Of course it does.

Can it take a very long time for research outputs to have a substantial impact on cancer control? Unfortunately, it can.

Do we have good ways to identify, in advance, areas of transformative research? Unfortunately, no. It can even take a long time to demonstrate that certain research has, indeed, been transformative.

So, what to do? My answer: investment in research is much like investment of venture capital. Only a very small minority of investments yield a big payoff, but one can predict much more easily which investments are likely do badly than which ones are likely to do well.

Article in The Scientist

How to win the war against cancer by Frank L Douglas and Robert E Litan, The Scientist, November 5, 2008 [free registration is required]. Excerpt:

We now know from many areas of science -- including cancer research -- that collaborative research by investigators with different but complementary areas of expertise are more likely to crack difficult problems than "lone rangers" who work in isolation. With more cooperation and less competition in cancer research, the war against cancer is much more likely to be won.

Over the past month, this short opinion article has attracted a number of comments from readers. An example: "Competition vs. collaboration" by an anonymous poster, November 10, 2008. Excerpt:

Therefore big bucks should be spent by the NIH on big projects, but these projects should have a purely supportive role (core facilities, tissue banks, high-throughput assay systems, result databases) and the people involved should be paid enough to make up for decreased career opportunities, which working in such supportive roles would entail. Enticing people to collaborate just because there is money in collaborating is going to just result in a lot of people flocking around the trough and pretending they have some common goal, while in fact they will be doing disparate things under a makeshift common banner.

Another example of a comment: "Doubtful strategy" by Rainer Zahlten, November 7, 2008. Excerpt:

This "new" strategy is bound to fail. Why? Because enforced cooperation for the sake of obtaining research grants is counterproductive to a physiologic matching of research interests, including a viable chemistry between participating scientists.

Thanks to Lisa Willemse, who noticed this article.

Translational research for medical interventions

Tracking the lag between promise and payoff by Janet D. Stemwedel, Adventures in Ethics and Science, October 2, 2008. This blog post isn't about cancer stem cells, but is of interest because it's focus is on translational research for medical interventions. Excerpts:

One of the reasons non-scientists see science as at all valuable is that scientific research may result in useful medical treatments. And one of the aspects of science that seems elusive to non-scientists is just how long it can take scientific research to bring those useful medical treatments about.

.....

The time interval between the first report on preparation, isolation, or synthesis (or the earliest patent) and the highly cited articles reporting successful clinical interventions -- between the report of findings with clinical potential and the determination via clinical trials that that promise is realized in a treatment -- is the "translational lag". (There is, of course, another lag that's harder to quantify this way -- that between the initial findings in the research lab and the publication of those findings.)

Contopoulos-Ioannidis et al. found that the median translational lag for the highly cited article[s] in their study was 24 years. That's a long time.

The blog post is based on this article: Life Cycle of Translational Research for Medical Interventions, by Despina G. Contopoulos-Ioannidis, George A. Alexiou, Theodore C. Gouvias, John P. A. Ioannidis, Science 2008(Sep 5); 321(5894): 1298-9 [PubMed Citation]. The article isn't freely accessible, and has no abstract. The brief Summary:

From the initial discovery of a medical intervention to a highly cited article is a long road, and even this is not the end of the journey.

An excerpt from the final section of the full text:

The following are some recommendations for improving the system, based on our analyses:
• Discovery of new substances and interventions remains essential, but proper credit and incentives should be given to accelerate the testing of these applications in high-quality, unbiased clinical research and the replication of claims for effectiveness.
• Multidisciplinary collaboration with focused targets and involving both basic and clinical sciences should be encouraged.
• Proof of effectiveness for new interventions requires large, robust randomized clinical trials.
• Translational efforts for common diseases should focus more on novel agents and new cutting-edge technologies; for these ailments, it is unlikely that genuine major benefits from interventions already known for a long time have gone unnoticed.

Comments: Of the 32 interventions highlighted in this study, only two were cancer-related:

1) Levamisole (with Fluorouracil): Colon cancer

• Date of highly cited study: 1990
• Date of first description of intervention: 1966
• Report of first human use: 1977

2) Tamoxifen: Breast cancer prevention

• Date of highly cited study: 1998
• Date of first description of intervention: 1964
• Report of first human use: 1971

For cancer stem cells, what might be an important first intervention to be described? Proof that the eradication of cancer stem cells from a patient's tumor is therapeutic?

Perhaps a clinical demonstration that cancer stem cells can be used as a prognostic indicator of disease progression wouldn't be regarded as a "therapeutic intervention", but it's a key challenge for those doing research on cancer stem cells. See, for example, a review by Eric Lagasse, Gene Ther 2008(Jan); 15(2): 136-42 [PubMed Abstract]. Excerpt from the full text (not freely accessible):

[Remaining challenges] include the clinical demonstration that cancer stem cells can be used as a prognostic indicator of disease progression and proof that the eradication of cancer stem cells from a patient's tumor is therapeutic.