Alexander Browne HSEM 3010 Spring 2007 Clinical Trials Assignment 3 1. Observational epidemiological comparisons had shown a cancer-reducing effect from eating fruits and vegetables. It was hypothesized that it was the beta carotene and vitamin A in fruits and vegetables that provided the benefit. The CARET study was therefore carried out in order to see if beta carotene and vitamin A really did prove beneficial for (lung) cancer patients. 2. A case-control study looks at people that already have a certain condition (such as a disease) and compares them to people who don't in order to find some differences between the two populations. They are much cheaper and easier than a randomized clinical trial, especially for diseases that rarely occur and would therefore require a huge population and many years for a clinical trial. 3. Two study groups (smokers and former smokers, workers exposed to asbestos) were each randomized into two groups that were given either a beta carotene and vitamin A supplement or the placebo. 4. The primary end points were new cases of lung cancer and death. 5. The population had to be large in order for lung cancer to occur enough times without the study taking too long. The eligibility criteria were male workers exposed to asbestos 15 years before randomization who were 45–69 years old (45–72 for the pilot study). For smokers, it was men and women 50–69 years old with at least 20 pack-years of smoking who had smoked within the previous 25 years. 6. It was found that beta carotene and vitamin A do not protect against lung cancer in heavy smokers and those exposed to asbestos, as was expected. In fact, these supplements led to an increased cancer risk. 7. I think the study is convincing. The results, even though the study was stopped early, appear definitive. Details such as compliance and homogenous nature of the result also makes it convincing. 8. The results were fairly definitive that taking the supplements led to an increased cancer risk. This was opposite of the perceived wisdom, so everyone wanted to get the results out to the medical community and to the public as quickly as possible. 9. The Kaplan-Meier curve can account for things such as a long enrollment period, patients who drop out of the study, and different sizes in the treatment groups (e.g., the CARET pilot study was not 1:1 active-placebo). If we only looked at the number of cancer cases, we would be able to account for these factors. 10. The ATBC study shared the results of CARET: beta carotene led to a increased lung cancer risk for smokers. The Physician’s Health Study showed no effect, positive or negative, for beta carotene in a population of smokers, former smokers, and non-smokers. Studying infrequent events such as death from cancer using randomized clinical trials or other controlled prospective studies requires that large populations be tracked for lengthy periods to observe disease development. In the case of lung cancer this could involve 20 to 40 years, longer than the careers of most epidemiologists. 11. Randomized clinical trials remove as much bias as is possible from the study. Because of this, the results are the most reliable. 12. It is possible that non-smokers might not be effected by carotenoids in the same way. The study reported no significant difference in new cancers besides lung cancer between the active treatment and the control, so it appears that the carotenoid effect only occurs with lung cancer.. 13. It is possible that carotenoids affect women differently—perhaps they even have a cancer preventing effect. Without a study with more women, we can not know for sure. 14. I think it would only be ethical if there was some new evidence that pointed to beta carotene. In this case it might be ethical to carry out a trial in order to better understand this new effect. With the current evidence, it appears that the studies that have been done have given mostly the same results—against beta carotene—so it is not ethical to do the same study again. 15. Antioxidants are simply chemicals that reduce the rate of oxidation reactions. In biology, they reduce oxidation damage to cells and prevent the formation of disease-causing free radicals, thereby preventing disease according to some people. 16. There might be other legitimate reasons to take a beta carotene supplement, so I don't think it should be arbitrarily banned. However, I do think that all dietary supplements should be regulated by the FDA and their health claims should be evaluated like for drugs. I don't think the government should always intervene in every risky aspect of your life. The high shared costs of, for example, treating lung cancer, however, means that since your actions do not effect only you, the government has an obligation to change yours behaviors with more force than through just warning about risky activities—without becoming too much of a nanny state, if possible. 17. I would not take a beta carotene supplement, but my diet is high in fruits and vegetables that contain a lot of beta carotene already. If I were a (former) smoker, I would definitely not take the supplement. Knowing the results of this study, if I were smoker I might try to figure out which treatment group I was in. In other cases, I hope I would try to not figure it out so that I would not introduce my bias into the study, but of course this is easy to say hypothetically but probably harder to do in real life. 18. The National Cancer Institute funded the CARET study. Lung cancer is a major cause of death in the US, so a study like this that leads to fewer cases of lung cancer saves many lives and a lot of money spent on treatment, no to mention that the results in this case even save the money that would have been spent on beta carotene supplements. 19. I don't think a drug company would be interested in funding a study like this, since it is not looking at a disease that would be directly treated by a drug. The study was very expensive, but the drug company would get little out of it (unless maybe they produced beta carotene as well). 20. It would interesting to see the results of the same study if it could somehow be carried out with foods with high amounts of beta carotene and vitamin A instead of isolated supplements.