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April 27th, 2005, 02:12 PM
<TABLE ><TR><TD><FONT size=2>http://www.redflagsdaily.com/<BR><BR>?The Truth About the Drug Companies? A Book Review <BR><BR>by Red Flags Columnist, David Crowe <BR><BR>Marcia Angell<BR>Random House<BR>2004 <BR><BR>The title of this book, The Truth About the Drug Companies, contradicts its message. One of author Marcia Angell?s main points is that the truth is most definitely not out there. Enough is known, however, to provide a shocking tale of how drug companies manipulate America?s drug approval and patent system to keep competitors out and prices obscenely high. <BR><BR>Angell does not provide the more important story of how the rush to increase consumption of new and high-priced drugs is maiming and killing Americans every day of the year. But as she shows, drug companies are incredibly secretive, especially when it comes to their financial situation. And since making money is the almost the sole purpose of the modern pharmaceutical industry, the secrecy is virtually total. <BR><BR>Angell is a true insider, a medical doctor who spent more than 20 years with TheNew England Journal of Medicine, including a stint as editor-in-chief. Obviously by the time she left, she was more than a little jaded. In 2000, she wrote an editorial entitled ?Is Academic Medicine for Sale?? in response to a scientific paper in which the authors? conflicts of interest were so lengthy they could only be posted on the website. One reader wisecracked in response to her question, ?No, the current owner is very happy with it.? <BR><BR>In her book, Angell charges that drug companies are lying when they say they are creative and innovative. Their game is to wangle a patent on critical research from U.S. government laboratories (paid for by American taxpayers) or to purchase it from cash-starved startups. Regardless of the quality of the drugs ? even if they are far more expensive and no better than existing drugs ? the pharmaceutical companies will pour money into marketing to maximize sales. Angell describes how drug companies extend their exclusive marketing rights and use dishonest techniques to influence governments, consumers and, especially, doctors. <BR><BR>Engines of Research?<BR>Drug companies, led by their lobbying association PhrRMA, explain the high cost of drugs by the high cost of research. The rest of the world, they wail, is paying lower prices because the American consumer is subsidizing research. Angell shows just how false this is (although she is forced to admit that hard numbers are impossible to come by because of the financial secrecy). Part of the game is to move marketing expenses into the category of research. In 2002, for example, she estimates that the 10 top American drug companies spent 14 percent of their $217 billion in sales on R&D, 31 percent on marketing and sales, and kept 17 percent as profit. <BR><BR>The new drugs produced are generally not innovative. Between 1998 and 2002, some 415 new drugs were approved by the U.S. Food and Drug Administration (FDA), but the number of innovative drugs was small and showing a downward trend, from 16 in 1998 and 19 in 1999 to 9 in 2000 and 7 in both 2001 and 2002. <BR><BR>More profitable, by far, are the ?me too? drugs, those in the same class as an existing blockbuster. Patenting a variant of an existing class can capture and expand the market for that drug, especially when any minor improvement can be used to market its advantages to doctors and consumers. The basic game plan is: get it patented; get it approved for as many uses as possible (or failing that ?educate? doctors on off-label uses); and extend the patent and FDA exclusive marketing time as long as possible. Then, when the drug reaches the end of its patented life and nobody can rustle up any more extensions, have a ?me three? chemical in the back pocket. The company will drop ?me two? like a hot potato and market ?me three,? which just has to be different enough to gain a patent. <BR><BR>Angell describes how Prozac, now off-patent, was re-packaged by Eli-Lilly in a weekly dosage, approved by a compliant FDA, for ?premenstrual dysphoric disorder,? renamed Sarafem and put on the market in a pink and lavender pill for a much higher cost than generic Prozac (fluoxetine). Similarly, Schering-Plough replaced the now off-patent Claritin by its active metabolite, called it Clarinex and began acting as if Claritin had never existed. <BR><BR>Government: For Pharma, By Pharma <BR>The pharmaceutical industry is taking advantage of many drug company-friendly changes in the U.S. legal and regulatory regime since the 1980s ? changes that did not happen by accident. The new ?efficiency? means drugs are approved quicker and are under exclusive licence longer. <BR><BR>Angell describes how U.S. Supreme Court decisions in 1980 and 1982 made it easier to obtain patents on chemicals and patents on obvious uses of them, and made it harder to get patents overturned. The old-fashioned standard that patents have to be for something useful and non-obvious has been discarded. <BR><BR>New legislation helped, too. The 1980 Bayh-Dole act allowed the patenting of discoveries funded by the National Institutes of Health. Before this, such discoveries were in the public domain. <BR><BR>In 1984, the Hatch-Waxman Drug Price Competition and Patent Term Restoration Act was passed. It removed the requirement that generic drugs had to pass clinical trials before approval, but more than compensated the patent drug companies for this loss. Up to five years could be added to a patent based on delays coming to a market (because the patent life starts before clinical trials can begin). If a generic drug company is sued, FDA approval must be held up for 30 months no matter how spurious the lawsuit. <BR><BR>An additional exclusivity tool is the FDA exclusive marketing period. Although this is relatively short ? three years for changes in previously approved drugs (e.g., for a new condition), five years if the drug is a novel chemical and seven years for an orphan drug ? it has the advantage of a clock that does not start until marketing approval is obtained. The patent clock is ticking, by contrast, all through the approval process. The consequence is that the average exclusivity period of a drug had been extended from eight years in 1980 to 14 years by 2000. <BR><BR>Patent drug companies use this bag of tricks very carefully to stretch out their monopoly on blockbuster drugs as long as possible. However, this is a double-edged sword. Fourteen years, in the grand scheme of things, is still a relatively short time. The drug companies? high-cost marketing machine needs a regular fix from patented drugs; the profits from generic compounds are simply inadequate. Drug companies have become addicts, Angell says, facing financial withdrawal based on their inability to fill the pipeline with novel, patentable products. <BR><BR>What about Safety?<BR>Angell?s book is not overly concerned about safety. An egregious example is her use of the drug AZT to illustrate not how a dangerous drug was approved, but how a patent drug company (Glaxo Wellcome) expropriated government research in order to make literally billions of dollars in profit since the drug was approved for AIDS in 1987. Angell calls this drug ?effective? (rather than ?safe and effective?), suggesting she is aware of safety issues but has chosen not to discuss them. <BR><BR>A review of the literature shows this drug definitely has safety problems: ?the estimated probability of developing lymphoma ? by 36 months (was) 46.4%? (Pluda, 1990); ?Blood transfusion is often necessary in patients with AIDS, especially in those receiving AZT, a drug which produces severe anemia in a proportion of recipients.? (Costello, 1998); ?in adult mice, lifetime AZT administration induces vaginal tumors at a 10-20% incidence ?. In newborn monkeys and mice, AZT was incorporated into DNA of many fetal tissues ? AZT appears to be a moderately-strong transplacental carcinogen? (Olivero, 1997); ?In HIV-infected pregnant women treated with two RTI (nucleoside analogs, of which AZT was the most common) with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies.? (Lorenzi, 1998); ?our data indicates a strong correlation between treatment with AZT and the development of a decrease in left ventricular performance in children with HIV infection.? (Domanski, 1995). Finally, the winner for making the best out of a bad thing: ?Zidovudine was generally well tolerated in this high-risk population (pre-term infants) ? (from Table II: 32%-Anemia grade >=2; 11%-Neutropenia; 13%-Thrombocytopenia; 45%-Received transfusion; 26%-Received erythropoetin; 11%-HIV infection; 8%-Died)?Slightly more than half of the subjects had anemia severe enough to require a transfusion? (Capparelli, 2003) <BR><BR>It?s not really clear from the literature whether Angell is justified in calling this drug effective either: ?Adjusted for baseline CD4 (immune cell counts) and age, (hemophiliacs) who had started on zidovudine (AZT) had increased risks, especially for AIDS (4.46 times greater risk) and death (2.37 times)? (Goedert, 1994); ?The Concorde trial showed no difference in the survival rates for symptom-free HIV-positive individuals between those given immediate and those given deferred zidovudine, and Chaisson et al found previous use of zidovudine to be a negative indicator, with an increase in the risk ratio for death or disease progression of 1.7? (Scott, 1996); ?(AZT may) unmask silent opportunistic infections? (Kelleher, 1997); ?(in these clinical trials) it was often difficult to distinguish adverse events possibly associated with administration of Retrovir from underlying signs of HIV disease or intercurrent illnesses? (PDR, 1996); ?Overall, zidovudine treatment was associated with only a small reduction in circulating levels of plasma RNA? (Sperling, 1996); ?in individuals with fewer than 400 CD4 cells per cubic mm, those treated with AZT for longer than 16 months had the same levels of plasma (HIV) RNA as a similar group of patients who never received antiretroviral therapy.? (Winters, 1993); and ?The comparison of the two studies (one European, one French) ? is interesting. Despite the wider and earlier use of zidovudine (AZT) monotherapy in the French study, morbidity or mortality was similar to that in the ECS (European Collaborative Study)? (Blanche, 1997) <BR><BR>There have even been a number of challenges to the ability of the drug to become activated (meaning that, unless the theoretical science behind the drug is totally off base, the drug cannot be effective). Without triphosphorylation, this drug cannot block the creation of DNA, and therefore cannot protect against a retrovirus: ?from the evidence published since 1991, it has become apparent that no such phosphorylation takes place and thus AZT cannot possess an anti-HIV effect? (Papadopulos-Eleopulos, 1999) <BR><BR>Discussing statins, of which there are many ?me too? competitors, Angell does mention that Baycol was removed from the market because of a deadly side effect, although she doesn?t mention that other statins have the same problem albeit perhaps not as severe. She also says that Crestor might be dangerous due to its approval at a higher dose. But paradoxically she says, ?Crestor is now promoted as the strongest statin, but that may be because the dose approved by the FDA was relatively high. A larger dose of one of the other stations might be just as good.? <BR><BR>Perhaps the problem for Angell is that to discuss safety calls into question whether the high prices for modern drugs are entirely a bad thing if it means that people are less likely to take them. There are many stories about poor or elderly people on fixed incomes who are forced to ?trade off drugs against home heating or food.? We are supposed to feel sorry for those who sacrifice one for the other. But are those who pay the heating bill, get groceries and fail to buy their prescriptions really suffering? <BR><BR>Further, for Angell to take safety really seriously would be to admit that for all her years in influential positions at one of the world?s top medical journals, she only watched the safety problem grow worse. But she is essentially admitting that she was powerless to stop the publication of science that was designed to make pharmaceutical companies and their stable of compliant doctors richer, so what?s the problem with admitting that publication of many of those papers contributed to the death of thousands. <BR><BR>Panning the Placebo<BR>One of the problems of modern medicine is the corruption of the clinical trial. Angell has nothing good to say about the placebo, once considered a critical component of clinical trials. Some people argue that a placebo is unethical, that denying someone a ?proven? therapy is wrong, although these same people see nothing wrong with giving trial participants an unproven therapy instead of the proven therapy. Angell?s complaint is different. She complains that comparing a new drug to a placebo doesn?t prove that it is better than current accepted therapy. <BR><BR>Two papers published in 2000 by FDA scientists Robert Temple and Susan Ellenberg provide a strong argument that the placebo is an essential element in clinical trials. One problem they raise is the choice of an unsuitable trial population. Let?s imagine a drug, the currently accepted therapy, that could reduce to almost zero the risk of heart attacks in a population. (Of course, it would likely compensate by raising the risk of cancer, but let?s ignore that for now.) So the type of trial supported by Angell would compare this drug against a new drug. If the result was zero heart attacks, then she would accept a conclusion that the new drug is just as effective. <BR><BR>If a placebo arm was included and five percent of these people had heart attacks, the conclusion would be justified. But what if the heart attack risk in the placebo arm was also zero? This would indicate that a population had erroneously been chosen for the trial that was not at an appreciable risk for heart attacks. This is only one reason why a placebo arm is critical in every clinical trial. <BR><BR>Late in the book, Angell admits that ?if there is really doubt about whether a standard treatment is effective, the FDA should require that clinical trials of new treatments have three comparison groups ? new drug, old drug and placebo.? But are there any standard treatments for which there aren?t questions about effectiveness? <BR><BR>Even disregarding corruption due to financial conflicts, there are many reasons why no drug should ever be accepted as ?proven effective.? Drugs are only ever tested on limited populations. Interactions with drugs that were not invented at the time of the original trial are possible (and consumption of these newer drugs may be allowed by the protocol of new trials where the older drug is being used as the standard comparison therapy). Standards of proof change over time, and it is quite possible that the clinical trials of older drugs would not be accepted as evidence of effectiveness today because of weaknesses in the protocol. <BR><BR>Recommendation: Buy this Book<BR>My recommendation is to buy this well-written and attractive book for its detailed description of how drug companies manipulate the marketplace for drugs. Although the issue of safety is not adequately addressed, it is not difficult to see how the methods used to manipulate the market will result in more and more dangerous drugs making it onto prescriptions. <BR><BR>Perhaps the underlying problem is the touching faith of the modern world, especially America, in what is new and technologically advanced, regardless of whether it is needed or whether there are safer or more effective old-fashioned alternatives. There is no question that some of the finest chemists in the world work in drug research. But does the world really need new chemicals when so many health problems are caused by pollution of our environment, our diet and our sedentary lifestyle? Even the high price of drugs may increase our perception of their worth because of our belief in a reliable association (some would say obsession) between money and value. <BR><BR>References<BR>(Angell, 2000) <BR> Angell M. Editorial: Is Academic Medicine for Sale? N Engl J Med. 2000 May 18; 342(20): 1516-8. <BR> <BR>(Angell, 2004) <BR> Angell M. The truth about the drug companies: How they deceive us and what to do about it. Random House. 2004 Aug. <BR> <BR>(Blanche, 1997) <BR> Blanche S et al. Morbidity and mortality in European children vertically infected by HIV-1. The French Pediatric HIV Infection Study Group and European Collaborative Study. J Acquir Immune Defic Syndr. 1997 Apr 15; 14(5): 442-50. <BR> <BR>(Costello, 1988) <BR> Costello C. Haematological abnormalities in human immunodeficiency virus (HIV) disease. J Clin Pathol. 1988 Jul; 41(7): 711-5. <BR> <BR>(Domanski, 1995) <BR> Domanski MJ et al. Effect of zidovudine and didanosine treatment on heart function in children infected with human immunodeficiency virus. J Pediatr. 1995 Jul; 127(1): 137-46. <BR> <BR>(Ellenberg, 2000) <BR> Ellenberg SS et al. Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments; Part 2: Practical Issues and Specific Cases. Ann Intern Med. 2000 Sep 19; 133(6): 455-63. <BR> <BR>(Goedert, 1994) <BR> Goedert JJ et al. Risks of immunodeficiency, AIDS, and death related to purity of factor VIII concentrate. Lancet. 1994 Sep 17; 344(8925): 791-2. <BR> <BR>(Kelleher, 1997) <BR> Kelleher AD et al. Immunological effects of antiretroviral and immune therapies for HIV. AIDS. 1997; 11(Suppl A): S149-155. <BR> <BR>(Lorenzi, 1998) <BR> Lorenzi P et al. Antiretroviral therapies in pregnancy: maternal fetal and neonatal effects. AIDS. 1998; 12: F241-247. <BR> <BR>(Olivero, 1997) <BR> Olivero OA et al. Transplacental effects of 3?-Azido-2?,3?-dideoxythymidine (AZT): tumorigenicity in mice and genotoxicity in mice and monkeys. J Natl Cancer Inst. 1997 Nov 5; 89(21): 1602-8. <BR> <BR>(Papadopulos-Eleopulos, 1999) <BR> Papadopulos-Eleopulos E et al. A Critical Analysis of the Pharmacology of AZT and its Use in AIDS. Current Medical Research &amp; Opinion. 1999; 15: S1-45. <BR> <BR>(PDR, 1996) <BR> (PDR, 1996) Retrovir. PDR. 1996. <BR> <BR>(Pluda, 1990) <BR> Pluda JM et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med. 1990 Aug 15; 113(4): 276-82. <BR> <BR>(Scott, 1996) <BR> Scott WF. The Delta Trial. Lancet. 1996; 348(9036): 1238. <BR> <BR>(Sperling, 1996) <BR> Sperling RS et al. Maternal viral load, zidovudine treatment and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. N Engl J Med. 1996 Nov 28; 335(22): 1621-9. <BR> <BR>(Temple, 2000) <BR> Temple R et al. Placebo-Controlled Trials and Active-Control Trials in the Evaluation of New Treatments; Part 1: Ethical and Scientific Issues. Ann Intern Med. 2000 Sep 19; 133(6): 455-63. <BR> <BR>(Winters, 1993) <BR> Winters MA et al. Biological variation and quality control of plasma Human Immunodeficiency Virus type 1 RNA quantitation by reverse transcriptase Polymerase Chain Reaction. J Clin Microbiol. 1993; 31(11): 2960-6. <BR> <BR></FONT></TD></TR></TABLE>