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Book Review Winter 2005
Powerful Medicines Dr. Avorn, Associate Professor of Medicine at Harvard and the author of Powerful Medicines, knows a lot about drugs. His specialties are pharmacoepidemiology and pharmacoeconomics and he is an attending physician at Brigham and Women's Hospital in Boston. This book covers the current state of the art on prescription drugs: their risks, benefits and costs and how these critical features are measured and evaluated, by the drug companies, the FDA, medical investigators and the drug-consuming public. It couldn't be more topical. Vioxx is mentioned in several sections, only the recent Vioxx recall and the slew of investigations and litigation that promises to follow in its wake (this review is being written as the Congressional hearings are starting) occurred too late for inclusion in this 2004 book. No doubt it will be a major item in a second edition. Make no mistake, though lengthy, this is a treatise well worth the effort. The book starts off with a cautionary tale about the initial enthusiasm by the medical profession for post-menopausal hormone replacement therapy; it was perceived to lower or defer the incidence of heart attacks, Alzheimer's disease and osteoporosis in women as well as block those pesky menopausal symptoms. Millions of women were prescribed Prempro or similar combinations. When the epidemiologic powers that be finally got around to doing a double-blinded, placebo controlled study (at the insistence of the NIH and Women's Health Initiative) in 1998 and 2002, lo and behold, it turned out that estrogen-progesterone treatment actually increased the incidence of coronary disease, strokes and senility, the opposite of what had been marketed to doctors by the manufacturers, based largely on observational studies. The discriminatory value of blinded and controlled studies is emphasized but so is the difficulty of arranging them for drugs already on the market and the small numbers of patients actually required by the FDA for approval of a drug in the first place. The book is divided into five major parts: benefits, risks, costs, information and policy. In part one, the determination of the effectiveness of drugs is emphasized. Dr. Avorn emphasizes that it took nearly twenty years after the enabling legislation in the 1960s (the Kefauver Act) for the FDA to rid the market of such commonly prescribed drugs as Marax or Bellergal or Pavabid, drugs that had been around for years but were ineffective. He explains in some detail the concept and methodology of clinical trials and how they have come to be the gold standard of a drugs effectiveness. The role of probability and chance in these trials are explored and explained well. So too is the political clout exercised by drug companies and especially the vitamin and food supplement industry in order to avoid FDA regulation and hence be treated as "non-drugs." Noteworthy is that even well-controlled new drug evaluations submitted to the FDA need only be measured against a placebo, not the best available current treatment. Part 2, Risks, may well be the heart of the book. Here the author deals with the notion of risk and benefit ratios and other indices of the relative balance of a drug's capacity to help vs. its potential for harm. Although, as mentioned above, the Vioxx recall is not included, the finding of a major clinical study (designed to test the drug's ability to reduce colon polyps) resulted in the finding that the risk of heart attacks and strokes was about double compared to that of the placebo, leading to the recall. No doubt the drug helped many patients with arthritis and probably resulted in fewer gastrointestinal complications for those taking a long-term, rather high dose of the drug. But it was the finding of the cardiovascular risk that led to the recall. Many medical and certainly plaintiff's lawyers claim that earlier studies of which the company, Merck, was well aware should have led to withdrawal of Vioxx from the market years before. Similar fiascos with the fenfluramine and Redux diet drugs and Rezulin for diabetes and phenylpropylamine (PPA) for colds and allergies and diet pills are described in detail. The Bendectin story is an opposite scenario: a potentially valuable and unique drug removed from the market due to bogus lawsuits against the manufacturer. A delicate balancing act between risk and benefit in drug development and marketing is also chronicled for the irritable bowel syndrome (IBS) drug Lotronex. The problem here was the classic confrontation between those helped by the drug for their often severe but non-life threatening disorder versus those severely maimed or possibly killed by a rare complication involving necrosis of the bowel. Here Dr. Avorn describes his experience as an FDA consultant (and his difficulties getting reimbursed for his airfare from Boston to Washington). As for a few other drugs in the past (Accutane, clozapine, even thalidomide) the agency allowed the drug to remain on or re-enter the market under tightly controlled prescribing condition and patient use. The book also reminds us that part of the delicate drug balancing act is that ballet between doctor and patient: changing drugs, reducing or increasing doses, following lab tests (or showing up for them) and side effects assiduously. Moving on, the author then addresses one of the central dilemmas in our current society and the internecine political warfare it has generated between the drug manufacturers and consumer groups, especially the elderly: the high cost of prescription drugs. The author indicts the pharmaceutical industry by critically examining the oft cited excuse of the high cost of drug research and development. In fact most drugs are of the "me-too" category and truly unique drugs with a novel chemical structure or new mode of action are relatively uncommon. Worse, for many of the latter, university and government scientists are responsible for the discovery but it is the drug companies that wind up with the patents. The companies have enhanced this by supporting university and medical school researchers by direct consultation fees to support their products and by paying for and supervising critical clinical trials. Too often the results of negative studies never see the light of publication but even minor advantages of a drug are trumpeted widely with press releases and TV ads and conferences arranged for doctors, usually free dinners or weekend getaways to resorts. Dr. Avorn then addresses one of the more complicated areas of cost-benefit analysis of drugs, to patient and to society in its allocation of healthcare resources. The concept of quality assessment of life-years (QALY) is introduced and analyzed as a measuring rod for determining the value of a given drug treatment. He uses both fictional drugs with certain basic assumptions and real life examples such as the streptokinase vs. TPA clot-busting issue, the former cheaper and slightly less effective, the latter very expensive. Should a decision to use or not use TPA be left to the individual doctor or patient, the hospital formulary committee, the insurer, the government? Is an added life year more valuable at 40 than at 70? What is a life year is only a month? What if a drug treatment requires a large expenditure now (perhaps paid by an HMO) but may well reduce costs in the long run (when the patient may well have moved on to Medicare), as in the analysis of two hemophilia treatments? All of these issues require consideration of ethical and philosophical matters as well as the risk-benefit ratio of drugs and the mission of medicine with regards to the patient and to society. Thorny stuff, well presented. The author's concluding sections deal with information and policy. Here he outlines in some detail the major influences on doctors and pharmacists and how the drug companies influence them. The internet and direct to patient TV advertising have revolutionized the marketing of drugs. As of this writing, the FDA has belatedly removed a Viagra add that promises a restoration of youthful sexual vigor and fails to mention potential side effects. Detail persons, increasingly young attractive women instead of the old-time middle-aged balding drug reps, flood doctor's offices. One learns that newer and more expensive drugs are often not better than older, generics. Between pressures from the industry and demands for the latest drugs from patients the poor doctor is caught between a rock and a hard place. No wonder such unnecessary drugs as Claritin and Nexium are top-sellers. We shall leave Dr. Avorn's recommendations for change and improvement, the final section, to his readers. Suffice to say, he looks to major overhauls in the current system and minor tweaking everywhere. This is a valuable book at a critical time. Let's hope members of Congress, FDA scientists and regulators, drug company executives, health care personnel and the general public get his message. |
