Vol. 11 Issue of the Journal of General Internal Medicine
In Pangloss: best of all possible worlds, medical students, residents, and practicing physicians would make prescribing decisions based on being well-informed and properly educated about the benefits, risks, and proper uses of drugs (some information about relative cost would not hurt). At present, we spend approximately $4.48 billion a year educating medical students (Personal Communication, Association of American Medical Colleges [AAMC], August 6, 1996) and an estimated $6.7 billion a year on graduate medical education for a total of $11.18 billion a year (Personal Communication, AAMC, August 23, 1996). Of this amount, only a fraction (surely less than one-tenth or under $1.2 billion dollars a year) goes to teaching the fundamentals of pharmacology or the disease-specific principles of rational prescribing. Moreover, the prescribing practices of most physicians and physicians-in-training are unquestionably influenced by the much larger estimated $12.3 billion a year spent in the United States by the drug industry on advertising and promotion, mostly directed at physicians. This number was calculated based on 22.5% of prescription drug sales being used for marketing (Pharmaceutical R&D: Costs Risks and Rewards, Office of Technology Assessment, 1993) combined with $54.7 billion total U.S. pharmaceutical sales (Scrip, March 12, 1996).
Given that vastly greater amounts of money are spent on advertising and promotion in order to sell specific drugs than on objectively-based educational programs aimed at rational prescribing, the study by Stryer and Bero in this issue makes an important contribution to our knowledge about the content of a major part of this massive drug industry expenditure.
The dangers of commercially driven misinformation being dispensed to prescribing physicians have been described by FDA Commissioner David Kessler, who stated that "enormous potential exists for misleading advertisements to reach the physician and influence prescribing decisions.... Misleading advertisements can result in significant adverse consequences... needless injury or even death may occur because physicians have been persuaded to prescribe products for uses for which they have not been adequately tested or to substitute therapies that may be less safe or less effective than the alternatives." This statement justifies FDA's legal responsibilities for regulating the content of drug promotional materials, and the findings of the present study concerning this issue are cause for serious concern. The authors of the study reviewed materials that drug companies sent to selected practices. Of the materials reviewed, 42% failed to comply with one or more FDA regulations, including 35% which lacked fair balance between the benefits and risks of drugs. This finding is remarkably similar to that in a recent study by Wilkes, Doblin, and Shapiro, who reviewed all full-page pharmaceutical ads in one month's worth of ten highly-regarded medical journals. Those authors found that 40% of the ads did not present fair balance between effectiveness and adverse effects. They also found that 58% of the ads contained images that reviewers felt inappropriately minimized concerns about side effects and adverse drug reactions and that 47% of ads did not appropriately highlight risks and contraindications in special patient populations such as the elderly.
Other major findings in the present study included 17 instances (4% of reviewed materials) of illegal promotion of unapproved uses of approved drugs, 16 involving reprints being handed out. According to the authors, the majority of these reprints discussed only the unapproved use and did not mention any approved use (personal Communication, Dr. Lisa Bero, August, 1996).
Although it is currently illegal for drug companies to promote unapproved uses, legislation introduced in the U.S. Congress as part of the package of FDA-rollback proposals would make this activity legal. Not only would drug companies be allowed to send out reprints which support the safety and effectiveness of unapproved uses-no matter how much out of context-but the increased ability to promote unapproved uses likely would remove incentives for companies to complete the studies necessary to gain FDA approval for unapproved uses. If they could legally, and much more massively than now, promote unapproved uses of drugs, why bother with FDA approval?
A recent example of the dangers of promoting unapproved uses involves Pfizer's distribution of promotional materials and a journal reprint describing the unapproved use of Zoloft (sertraline HCI) for depression after myocardial infarction. In a strongly worded warning letter from FDA Director, Division of Drug Marketing, Advertising and Communication Dr. Minnie Baylor-Henry, RPh, JD to William C. Steere, Chairman of the Board and CEO, Pfizer, Inc, August 1, 1996, the company was charged with promotion of Zoloft for five different unapproved uses. According to the FDA letter, "Pfizer's statements concerning the use of Zoloft to treat depression in cardiac patients raises significant safety concerns. According to its approved product labeling, Zoloft has been associated with cardiovascular adverse reactions, observed during controlled clinical trials, including treatment-emergent palpitations, variations in blood pressure, edema, peripheral ischemia, tachycardia, chest pain, and MI." The letter also pointed out that "Pfizer's targeting of this patient population is also evidenced by its distribution of the reprint...." (Interestingly, the senior author of this paper works for Pfizer.)
Aside from documenting widespread violations of FDA regulations concerning false and misleading claims in drug company promotional materials, Stryer and Bero also have developed a useful rating scale for measuring how much promotional versus educational content there is in these materials. Having defined promotion as "any attempt to influence prescribing decisions that is not based on .the efficacy, adverse effects, contraindication, and cost of drugs" they define education as "any attempt to promote rational prescribing by conveying information about the benefits, risks, and uses of drugs."
For example, typical of the largely promotional, hardly educational mode that the drug industry and its Madison Avenue colleagues thrive in, 80% of the ads made unsupported claims which the authors defined as "claims made in the heading or conclusion . . . not supported by a study result or statistic." Belying the claim that drug promotion serves an educational function was the finding that only 3% of the ads discussed non-drug therapies or alternative drug therapies and that only 0.6% of ads had original data, which the authors defined as "Original evidence to support a claim, rather than a distillation of data ..." (i.e.., the item reports original numbers rather than just a percentage or summary graph). A recent ad by a company which designs drug ads-aimed at the marketing departments of drug companies-vividly portrayed the hippocampus as the "prescription-writing center of the brain" and boasted that "all our communications are focused on making the hippocampus respond favorably to your product." This is done, so the ad stated, with a "unique medical discriminator-an innovative, medically relevant idea that makes your customer see (and remember) how your product is superior and unique." Thus, there is no question that, in the doctor demeaning view of pharmaceutical marketers, brainwashing techniques are as effective when directed at many doctors as they are when pointed to other people.
The success of the annual $12.3 billion in U.S. drug promotional expenditures can be attested to by the poor, often dangerous prescribing practices of American physicians. The fact that 14.4 million prescriptions for fluoroquinolones were filled in U.S. pharmacies in 1995, even though there are few clinical situations in which these drugs should be the first choice, is proof positive of the drug companies' success using massive expenditures to promote fluoroquinolones as first-choice drugs for a large number of infections. So, too, is the extraordinarily successful marketing of calcium channel blocking drugs for the treatment of hypertension. The number of prescriptions for these drugs now exceeds the number of prescriptions for diuretics and beta blockers even though evidence from well-controlled studies shows that diuretics and beta blockers decrease cardiovascular complications and deaths secondary to hypertension, whereas calcium channel blockers not only fail to decrease cardiovascular complications but, according to several studies, actually increase such risks.
Advertising and promotion succeed in unduly and dangerously influencing doctors' prescribing habits in direct proportion to two circumstances: the grossly inadequate education of most medical students, residents, and practicing physicians about rational drug prescribing, and the rampant violation by the drug industry of FDA regulations concerning promotion. The many physicians who do not actually get or stay educated with objective, scientifically valid information about drugs are wonderful targets for the all-too-often false and misleading promotional campaigns of drug companies which, for these undereducated and therefore vulnerable physicians, have a de facto educational impact.
To start to solve the educational part of the problem, much more time and skill are needed in the education of physicians, who must develop a solid, scientifically-derived base of knowledge for prescribing decisions and learn to critically examine, if not ignore, promotional information. Regular reading of peer-reviewed journals in one's specialty, subscribing to the Medical Letter or the new Worst Pills Best Pills News are ways of developing immunity against drug industry promotional schemes. Worst Pills Best Pills News was started in 1995 and is a four-page monthly bulletin discussing newly-approved drugs and newly-discovered adverse drug reactions and interactions along with summaries of petitions filed by Public Citizen's Health Research Group with the FDA for warning labels or bans of prescription drugs. For a free copy of a recent issue write to WPBP News, Dept. IM, 1600 20th Street, NW, Washington, DC 20009.
In addition to educating physicians, however, patient education is also essential. Patient package inserts, which now are provided at the industry's discretion, should be required for all prescription drugs, as is the case in more and more of Europe.
FDA regulation of drug industry promotional activities needs to get onto a much more aggressive plane. The reason why the warning letter to Pfizer got so much attention was that the investigation leading up to it appears to have been well-done and the strong conclusions, including requiring Pfizer to take out corrective ads in all journals in which Zoloft ads ran in the previous 12 months, approaches proper punishment for these potentially dangerous activities. In addition, the FDA does have the authority, which it has rarely utilized, to impose criminal sanctions including large fines and jail for repeat offenders of its advertising laws and regulations.
Other than advertising for cigarettes and alcohol, it is difficult to identify another area of commerce where false and misleading advertising and promotion can do as much damage as it can in the area of pharmaceuticals. FDA Commissioner David Kessler needs a much bigger staff and he needs to apply more force than the FDA is now employing to deal with the "needless injury and death" that he has ascribed to false and misleading advertising.
--Sidney M. Wolfe, M.D., Public Citizen's Health Research Group, Washington, DC.
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