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Drug development: the lottery that you pay for.

Last year, Roche, the giant Swiss pharmaceutical company, prematurely terminated a large-scale clinical trial of dalcetrapib, a drug that increases HDL-cholesterol levels by inhibiting cholesterol ester transfer protein. In the study, published recently in the New England Journal of Medicine, 15,871 patients who had suffered a recent acute coronary event were randomly assigned to receive dalcetrapib or placebo. The primary efficacy endpoint was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. As expected, dalcetrapib increased HDL-cholesterol levels compared with the placebo. However, in a preplanned interim analysis conducted after a median follow-up period of 31 months, the incidence of the primary endpoint was nonsignificantly higher by 4% in the dalcetrapib group than in the placebo group. At that time, the data management committee concluded that there was virtually no chance of finding at least a 15% reduction in the primary endpoint, and it recommended early termination of the trial.

The stock price of Roche plummeted after the announcement of the trial's termination, and the market capitalization of the company fell by $5 billion. Although it is not clear how much Roche spent in researching and developing dalcetrapib, it was likely many hundreds of millions of dollars. Pfizer experienced a similar disaster in 2006, after it had spent $800 million developing torcetrapib, another cholesterol ester transfer protein inhibitor. Like dalcetrapib, torcetrapib raised HDL-cholesterol levels in patients who were at high risk for cardiovascular disease. However, the drug also resulted in significant increases in cardiovascular events and all-cause mortality.

One lesson which can be learned from these events is that putting a foreign chemical in the body for the purpose of modifying a laboratory risk factor is not necessarily beneficial or safe. While low HDL-cholesterol levels are associated with an increased risk of cardiovascular disease, it is not clear whether this association is causal. Even if it is, the potential adverse effects of interfering with cholesterol ester transfer protein (and who knows what other biochemical pathways?) might outweigh the beneficial effect of increasing HDL-cholesterol levels. We already know that HDL-cholesterol levels can be increased with aerobic exercise and nutritional supplements such as niacin and possibly magnesium, L-carnitine, and vitamin C. We also know that each of these interventions has shown promise for preventing or treating cardiovascular disease. So, if we want to raise HDL-cholesterol levels, it would seem more logical to use "natural" methods, rather than introducing some foreign chemical that the human body has never before seen.

The other lesson that can be learned from the cholesterol-ester-transfer-protein-inhibitor experience is that drug companies are willing to spend enormous amounts of money in exchange for the possibility of making much more enormous amounts of money, in the event that the drug actually shows benefit and the FDA grants the company a monopoly over a particular biochemical pathway. In that respect, the drug approval process is one big lottery: the drug companies keep playing the game until they "hit it big." The problem is that they "hit it big" with our money. That is because FDA approval means that insurance companies pay for the drug no matter how expensive it is, which leads to higher insurance premiums. For the uninsured, the FDA-granted monopoly leads to higher out-of-pocket expenses. Neither the drug companies nor the FDA seem to care that more effective, safer, and less expensive natural remedies may be available for the same conditions for which expensive lottery games are being played. The drug-approval lottery is a rigged game, because only large companies that own patents on chemicals have the financial resources and the financial incentive to play it. Every year this game goes on, and every year we spend more money on health care while becoming less healthy as a nation.

There are at least two ways that we can improve on the current drug-lottery model. First, we should reform the rules and regulations so that it is no longer so expensive to have a drug approved by the FDA. Current FDA regulations for drug approval arose from the Kefauver Harris Amendment to the Federal Food, Drug, and Cosmetic Act, which was passed by Congress in 1962 in response to the thalidomide disaster. In the early 1960s, thousands of children in Europe were born with serious birth defects after their mothers took thalidomide for morning sickness during pregnancy. Prior to the passage of the Kefauver Harris Amendment, drug companies had been required to provide evidence that a new drug was safe before it could be approved by the FDA. The Kefauver Harris Amendment added the requirement that drugs also be proved effective. Using the thalidomide disaster to add an efficacy clause was disingenuous, because the existing Food, Drug, and Cosmetic Act was already strong enough to prevent thalidomide from being approved in the US on safety grounds (which is why the birth defects occurred in Europe but not in the US). Removing the proof-of-efficacy requirement from the drug approval process would not compromise patient safety, but it would eliminate the main excuse that drug companies have for charging such high prices.

Second, we should stop the FDA from prohibiting the dissemination of truthful scientific information about natural remedies. Under current rules, it is illegal for a manufacturer to state, for example, that vitamin A eyedrops work as well as Restasis for the sicca (dry eye) syndrome, that niacinamide is an effective treatment for osteoarthritis, or that coenzyme Q1 0 is beneficial for patients with heart failure. The FDA has a long history of declaring natural substances to be "unapproved drugs" and removing them from the market, on the grounds that the manufacturer made an unapproved health claim. Allowing doctors and patients to have ready access to truthful scientific information would level the playing field between drugs and natural remedies. This would result in fewer drug side effects and would force pharmaceutical companies to compete more on price.

Alan R. Gaby, MD
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Author:Gaby, Alan R.
Publication:Townsend Letter
Article Type:Editorial
Geographic Code:1USA
Date:Jun 1, 2013
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