======================================================================== HSEM 3010 Spring 2007 Clinical Trials Assignment 3 Due: February 14, 2007 Answer the following for the paper of Omenn, Goodman, et al. on effects of beta carotene and vitamin A on lung cancer and cardiovascular disease [the CARET study] (N. Engl J. Med (1996) v. 334, pp 1150-1155). See also: http://content.nejm.org/cgi/content/full/334/18/1150?ijkey=d8874d4c161a8af4cb0bc7b983175ae5f5643803 and http://content.nejm.org/cgi/content/full/335/14/1065 1. What was the motivation for doing this study [CARET] ? A number of case control studies had indicated that dietary beta carotene is protective for cancer. Plus, the biochemical properties of beta carotene suggest it is an antioxidant and decreases free radicals in the body. This theoretically reduces the chances that chemically induced mutations of DNA which lead to cancer can occur. 2. What is a case-control study, and how does it differ from a clinical trial? A case-control study is a nonrandomized study in which the degree of exposure to a risk factor or protective factor are compared between cases (people who have the disease of interest) and controls (do not have the disease of interest). Most case-control studies are retrospective. Clinical trials are studies in which people are assigned, usual at random, to the exposure factor of interest or to a no-treatment group, and then both groups are followed to see if the disease of interest develops. Case-control studies are not as definitive as randomized clinical trials because of (1) the possibility of bias, particularly recall bias, and (2) the possibility of confounding of the exposure factor with other factors related to the outcome. 3. What was the design of the CARET study? Somewhat complex, because of two previous pilot studies. Essentially it was a two group study in which either men exposed to asbestos or men and women smokers were randomized to received either beta carotene/Vitamin A or placebo. 4. What was the primary endpoint? Time to diagnosis of lung cancer. 5. A total of 18,314 people participated in this study. Why did it have to be so large? What were the eligibility criteria? The expected event rate in either group was low. The expected effect of beta carotene was expected to be modest (relative risk fairly close to 1.0). 6. Summarize the main results in your own words. More people in the beta carotene group were diagnosed with lung cancer. This was true both among smokers and among people exposed to asbestos. The Kaplan- Meier curves for cumulative incidence of lung cancer were diverging, with a distinct advantage for the control group. 7. Do you find this study convincing? Why or why not? Yes. The Kaplan-Meier curves are convincingly divergent and the corresponding p-values are fairly low (p = 0.02 for lung cancer incidence). 8. Why are Kaplan-Meier curves often used to summarize data from clinical trials like this one? (See Fig. 1). Why not just present the numbers of people who were diagnosed with lung cancer sometime during the study in each of the treatment groups? What does the Kaplan-Meier graphical presentation add? K-M curves show the pattern of events across time and they show trends - in this case, for lung cancer incidence, they indicate increasing divergence of the incidence in the two groups. 9. There have been some related clinical trials. You can find them by doing searches in Google, using terms like "beta carotene" "lung cancer", etc. Briefly summarize the relevant results of these, particularly the Physicians Health Study and the ATBC study. The ATBC study (Finland) yielded very similar findings in smokers. The Physicians Health Study indicated no effect of beta carotene. The Women's Health Study also was consistent with no effect of beta carotene. 10. The CARET study and the ATBC study did not agree with previous other studies which were not clinical trials. What are some possible explanations? The other studies were not randomized - most of them were case-control studies. It may be that beta carotene/Vitamin A in vegetables etc. was different from the beta carotene pills. The pills might have contained a contaminant [unlikely]. It may be that beta carotene is correlated with some other factor, not yet identified, which is protective. It may just be bad luck [also unlikely]. 11. These studies all involved people at risk for lung cancer (especially, smokers). Do you think the same kind of effects of carotenoids might be seen in nonsmokers? Do you think the effects are confined only to lung cancer? Why or why not? The lung is subject to several forms of cancer (squamous cell, adenomatous cell, small cell, oat cell, large cell), and it is possible that beta carotene accelerates the development of one or more of these, but not of cancers that are more likely to occur elsewhere in the body. It may be that beta carotene interacts in a bad way with carcinogens in cigarette smoke, and has little or no effect in nonsmokers. 12. Not many women were included in these studies. Why might that have been a serious omission? Women are at risk for different cancers (breast, ovarian, cervical) that men mostly are not. Without enough women in these studies, we cannot know for sure what the effects might be. This is a very serious omission! That may be the reason that a study of beta carotene was launched as part of the Women's Health Study. 13. Do you think it would be ethical now to do another large study of beta carotene to see if it might prevent cancer? In what circumstances? I don't know any clinical trial evidence that beta carotene is beneficial for anything. However the case-control studies suggest otherwise. It might be possible to randomize people to exact extracts of beta carotene from fruits and vegetables. There may be people who are deficient in beta carotene for some reason. In general however, I don't think beta carotene should be given to smokers. 14. What does 'antioxidant' mean? Why do some people think antioxidants are good? Not sure. However I think it means that the substance in question prevents formation of free radicals. Free radicals may react with DNA to start cancer or to defeat DNA-repair mechanisms, or to facilitate the negative side effects of beta carotene. 15. Health food stores sell beta carotene. Do you think they should? Should they include warning labels for smokers? Do they? Do you think the health- food store owners and clerks are aware of the CARET and ATBC studies? Should the Food and Drug Administration regulate the sale of beta carotene? Should the government actively protect you from behavior that might be deemed risky, or just inform you about it, or just not say anything and let you choose to do whatever you want? This is a big question. I don't see that there is definitive epidemiologic evidence for a beneficial effect of beta-carotene supplements. There should be a warning label at least with regard to smoking. In general, the FDA should afford NIH-sponsored clinical trials the same level of respect that they give to drug-company-sponsored trials. I don't think it is clear that they do. 16. Would you take a beta carotene supplement? Why or why not? If you were randomized into a beta carotene clinical trial, would you try to find out whether you were assigned to beta carotene of placebo? What would you do if you knew? I think not, unless I knew that my diet was low in Vitamin A and retinols. I would try to find out. If I were assigned to beta carotene, I would stop taking it. 17. Other comments on any of this? What do animal studies show? 19. Who funded this study? I don't know exactly what was the cost of the study, but it was likely in the $50M - $100M range. Did the results justify that kind of expense? Yes, because millions of people might end up taking beta carotene. 20. Is it likely that this study would have been funded by a drug company? Why or why not? Not likely, because (1) beta carotene is not a patented substance, and (2) a drug company manufacturing a beta carotene drug has nothing to gain from a rigorous scientific explanation. 20. Other comments on any of this? 21. Special Assignment for 5 students (to be selected): Go to a health food store and find out what they say about beta carotene, antioxidants, etc. Is the staff aware of the clinical trial reports? [Try not to be judgemental in talking to them - concentrate on just obtaining information] Write a brief report and present your findings to the class.] The student reports were interesting ...