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The preponderance of "me too" drugs has created a highly competitive marketplace for prescription drugs. Pharmaceutical companies are waging aggressive campaigns to change prescribers' habits and to distinguish their products from competing ones, even when the products are virtually indistinguishable. This is occurring in many therapeutic classes -- antiulcer products, angiotensin-converting-enzyme inhibitors, calcium-channel blockers, selective serotonin-reuptake-inhibitor antidepressants, and nonsteroidal antiinflammatory drugs, to name a few.
Victory in these therapeutic-class wars can mean millions of dollars for a drug company. But for patients and providers it can mean misleading promotions,2,3 conflicts of interest,4,5,6 increased costs for health care,7 and ultimately, inappropriate prescribing8.
Crowded Therapeutic Classes
Pharmaceutical companies do not usually set out to produce a "me too" drug. However, this is frequently the result of the process of drug development. Often, the FDA receives a spate of Investigational New Drug applications at about the same time for products in the same therapeutic class because several companies develop similar drugs concurrently. Another, more common scenario is that several companies set out to develop new entries in a class in which one drug is already a lucrative breakthrough product. Such was the case, for example, with the H-receptor antagonists (Tagamet [cimetidine]) and the serotonin-reuptake-inhibitor antidepressants (Prozac [fluoxetine]). A company may hope that its "me too" product will be an improvement over the current members of a class, but often those hopes are not borne out in clinical trials. Even when a drug fails to offer a clear advantage over existing therapies, a company may nevertheless conclude that it would be profitable to bring it to market.
The economics of the prescription-drug marketplace make this feasible. There are a large number of companies in the marketplace, each with a relatively small share of the market. Merck and Co., the largest pharmaceutical company, controls only 6.2 percent of the U.S. sales market9. However, since total sales for U.S. pharmaceutical companies in the United States exceed $58 billion per year, even a small share can mean large revenues. More important, sales in the top 18 therapeutic categories each exceeded $1 billion in 1993,10 so that even if a "me too" drug has a small market share in a single category, it can generate tens of millions of dollars in sales.
An additional incentive for introducing a similar product is that companies can sometimes charge more for a new drug, even in an already crowded class. Traditional economics might suggest the contrary -- that a late entry would have to be priced below its competitors to win a market share. Sometimes this is the case. However, companies also rely on the widely held notion -- not always true -- that what is newer is better and is therefore worth more. Aggressive advertising campaigns and lack of information among prescribing physicians about comparative costs can facilitate the higher pricing of "me too" drugs.
Another factor that encourages the marketing of "me too" drugs is that on the basis of clinical trials a drug can be approved for a single indication, but the sponsor may recognize that other products in the class are widely prescribed for different (unlabeled) indications, with a lucrative market. Thus, a company can complete a New Drug application quickly by testing the drug for one indication and then increase market share on the basis of its association with other products in the class. For example, a company may undertake studies to demonstrate that a new angiotensin-converting-enzyme inhibitor is effective in treating hypertension. But the company may anticipate that the drug will also be prescribed for congestive heart failure, because physicians will assume that angiotensin-converting-enzyme inhibitors, which have a common effect on hypertension, will have the same therapeutic effects in heart failure.
We discuss here three techniques used by drug companies to promote "me too" drugs that are of particular concern to the FDA: "seeding" trials, unsubstantiated claims of superiority over competing products, and "switch" campaigns. In general, the FDA does not have the authority to require the approval of advertising and promotional materials and activities before they are introduced. In most cases, the agency can take action only after the fact, when false or misleading claims are made. When the FDA determines that a manufacturer has made false or misleading claims, it typically sends the company a letter requesting that the claims be corrected. Usually companies comply. When there are recurrent violations or more serious initial violations, the FDA may issue a "warning letter" or begin judicial enforcement through an injunction, a seizure, or criminal prosecution. If warranted, the FDA may request that a manufacturer send a correction notice to prescribers and other parties who may have been influenced by the false or misleading claims. We describe violations that were resolved at the earliest stage, as well as those that required more serious action.
Seeding Trials
Some company-sponsored trials of approved drugs appear to serve little or no scientific purpose. Because they are, in fact, thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company, they are often referred to as "seeding trials." Features that distinguish such trials from scientifically rigorous studies include the use of a design that does not support the stated research goals, the recruitment of investigators not because they are experts or leading researchers but because they are frequent prescribers of competing products in the same therapeutic class, disproportionately high payments given to "investigators" for their work (although the only work may be to write prescriptions for the drug), sponsorship of the studies by the company's sales and marketing division rather than its research department, minimal requirements for data, and the collection of data that are of little or no value to the company. Typically, these trials involve introducing a new drug in a crowded therapeutic class. The success of such a new product may depend on undoing physicians' comfortable habits of prescribing a competing, more established product.
One example of a seeding trial involved a large project associated with the launch of a new antihypertensive agent, a latecomer to its therapeutic class. The stated objectives of the study were to assess the efficacy and tolerability of this agent in controlling mild-to-moderate hypertension. The sponsor used its sales force to recruit 2500 office-based "investigators" who were frequent prescribers of drugs in the therapeutic class in question. Each investigator was to enroll 12 patients (for a total enrollment of 30,000) and was offered reimbursement of $85 per patient enrolled, or $1,050 per physician.
The "study" was not capable of achieving even the modest objectives stated. There was no control group, and the study was not blinded. There was thus no possibility that it would generate useful data on efficacy and little likelihood that it would produce data on safety other than the potential for detecting a rare adverse event. The study aroused other types of concern. At the investigators' conference and in the accompanying materials, the sponsor discussed unapproved uses of the product and distinguished it from competing members of the class on the basis of unsubstantiated, and thus misleading, claims. FDA officials informed the sponsor that no data from this trial could be used to promote the product.
In another case, a manufacturer was starting a seeding trial to encourage the use of its product for an unapproved indication. The manufacturer mailed more than 12,000 letters of solicitation to office-based physicians, inviting them to participate in the trial of an anticonvulsant drug to treat panic disorder, an unapproved use of the product. From this group, the manufacturer hoped to recruit 500 investigators, each of whom would enroll five patients in the trial. The investigators were to be paid $500 for their participation, which involved completing a one-page case report for each patient.
The FDA determined that this study violated the Food, Drug, and Cosmetic Act in that it was a thinly disguised promotion of an unapproved use11. The manufacturer agreed to discontinue the study.
In their internal operations, certain manufacturers conducting seeding trials of this type do not even pretend that the trials are anything but marketing endeavors. The FDA received a copy of a memorandum sent from the marketing division of one sponsor to its sales representatives about yet another seeding trial, this one of an antihypertensive drug. The memo read in part:
Make no mistake about it: The [name of drug] study is the single most important sales initiative for 1993. Phase I provides 2500 physicians with the opportunity to observe in their patients . . . blood pressure control . . . provided by [name of drug]. . . . If at least 20,000 of the 25,000 patients involved in the study remain on [name of drug], it could mean up to a $10,000,000 boost in sales. In Phase II, this figure could double.
False and Misleading Claims
A second technique in these therapeutic-class wars is to use promotional materials that make unsubstantiated claims of superiority over competing products. The antiulcer products that are also used to treat gastroesophageal reflux disease constitute a lucrative, highly competitive therapeutic category in which sponsors have sometimes seized on unproved and relatively unimportant differences to distinguish their products from competing ones. The distinctions claimed frequently concern relative safety. The FDA took action against a sponsor that engaged in a prolonged and extensive effort to disparage the relative safety of a competing product. The sponsor misrepresented the risk of drug interactions associated with its product relative to the risk with the competing product by making selective use of negative clinical reports and omitting certain important drug interactions associated with its own product. The sponsor also mischaracterized the data to suggest that a competitor's product was associated with negative hemodynamic effects, when those effects had not been documented at therapeutic doses.
In some cases, sponsors have relied on pharmacokinetic distinctions that have unknown clinical relevance, or none. The FDA acted against the sponsor of a newly approved angiotensin-converting-enzyme inhibitor that claimed its product was superior to those of competitors by alleging that its product was the only true once-a-day angiotensin-converting-enzyme inhibitor. This claim not only had no data to support it, but also perversely relied on the absence of data; the sponsor had never studied a twice-daily dosing regimen. In addition, the new product had not been shown to be more effective in achieving 24-hour control of blood pressure than any other long-acting angiotensin-converting-enzyme inhibitor.
Another problem we have encountered is that of advertisements targeting particular populations without substantiating adequately that one product is superior to another. An example is the attempt by some manufacturers of antiulcer medications to promote their products as having superior efficacy in smokers. Warning letters have been sent to the makers of two such products for this reason.
Finally, promotional materials making claims of cost effectiveness and comparative effectiveness have become more and more common. In response to the shift toward managed care and health care reform, manufacturers are increasingly directing their promotional campaigns toward large purchasers of drugs. Increasingly, the focus of these campaigns is cost effectiveness. Although traditionally the FDA has not been involved in cost-effectiveness issues, its responsibility for monitoring prescription-drug advertising has required it to evaluate cost-effectiveness studies that are used to support advertising claims.
Despite the growing interest in cost comparisons, there is still no consensus on how to conduct cost-effectiveness studies12,13. What is clear, however, is that cost comparisons must be based on sound clinical data regarding comparative efficacy. The FDA has challenged advertised claims of cost effectiveness that are based on unsubstantiated assumptions about comparative efficacy. In the past year, for example, the agency has objected to an unsubstantiated claim by the manufacturer of an antiepileptic drug that the drug's higher cost was justified by its superior clinical efficacy. Prescribing decisions based on inadequate data on comparative efficacy and cost effectiveness could result in increased, rather than decreased, costs for health care.
Switch Campaigns
Pharmaceutical companies, as well as third-party providers of health care and their agents, are increasingly trying to cause patients to be switched from their originally prescribed medications to "me too" drugs marketed by the companies. These attempts are sometimes referred to as "switch campaigns." When done appropriately, switching can improve the quality of care, lower costs, or both. For example, switching from a brand-name product to a less expensive, bioequivalent generic product can reduce the patient's expense and overall expenditures for health care, without affecting the quality of care.
Other types of switching efforts, however, have potential implications for treatment and cost that merit careful consideration. These include efforts to switch patients to another dosage form of the same product or to another product in the same therapeutic class. Sometimes these campaigns involve payments to pharmacists who convince physicians to change their prescribing patterns14. Earlier this year, a group of attorneys general of several states reached settlements with two major pharmaceutical firms with regard to their payments to pharmacists15,16.
Switch campaigns are typically premised on claims of superior or equivalent therapeutic outcome, lower cost, or both. Recently, there have been a number of examples in which the therapeutic implications of a proposed switch have not been thoroughly considered, the claims on which the suggested switch is based have proved to be misleading, or both.
In one case, the FDA has taken regulatory action against a pharmaceutical manufacturer for a promotional campaign intended to switch patients from one form of an oral hypoglycemic agent to a newer form of the same molecular entity, with a more bioavailable dosage. The promotional material claimed that the newer form offered better overall treatment of diabetic patients than the older form. The manufacturer also claimed that the switch entailed a modest cost savings for the patient.
The manufacturer asked retail pharmacists who received prescriptions for the older form of the drug to contact the prescribing physicians and request that they change their prescriptions to the newer form. In addition, pharmacists were encouraged to identify patients taking the drug in the older form, to send them information about the new form with a coupon they could redeem with a prescription for the new form, and to urge the patients to contact their physicians and ask to be switched. The pharmacists would receive a payment for each prescription thus switched.
FDA officials determined that this sponsor's claim was misleading in several respects. First, there was no substantiation for the statement that the newer form of the drug offered superior overall benefit. Second, the campaign failed to reveal that there was no exact dosage relation between the newer and older forms of the drug. Therefore, a switch would require retitration and might expose a patient to the risk of a period of poor blood glucose control, as well as to added costs associated with blood glucose monitoring during retitration. Finally, the claim that the newer form of the drug offered patients a cost savings was incomplete, if not overtly misleading. The manufacturer did not mention that the newer form had patent exclusivity beyond the year 2000, whereas the older form would lose its patent exclusivity sooner. Therefore, the slight cost savings associated with the newer form would most likely be offset by a substantially increased cost in the future, because patients would not be able to have their prescriptions transferred as readily to a lower-cost generic version of the older form.
At the FDA we are increasingly concerned with switch campaigns that involve substitutions of a different therapy. Such switches are commonly seen in the case of providers of mail-order drugs who contract with pharmaceutical manufacturers to feature their products at a lower price17. The mail-order pharmacists then ask physicians who prescribe competing drugs to switch to the featured products. From a therapeutic perspective, it is not always clear that such switches are in patients' best interests, because a switch may be based on little more than an unsubstantiated assumption of comparable effectiveness.
Conclusions
The hallmark of the FDA's drug-approval process has been an insistence on adequate and well-controlled trials to support New Drug applications. Inappropriate promotional efforts for "me too" drugs -- whether they take the form of seeding trials, switch campaigns, or false and misleading claims -- should not be permitted to undermine these high standards, for these standards provide physicians and patients with the assurance that decisions about prescriptions will be based on high-quality data.
Source Information
From the Food and Drug Administration, Department of Health and Human Services, Rockville, Md.
Address reprint requests to Ms. Rose at the FDA, Division of Drug Marketing, Advertising, and Communications, HFD-240, 5600 Fishers Ln., Rockville, MD 20857.
References
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Related Letters:
Drug Promotion
Hoberman D., Puma J. L., Cohen S. N., Mossinghoff G. J., Stryer D. B., Bero L. A., Kalish R. S., Kessler D. A., Rose J. L., Temple R. J., Schapiro R., Griffin J. P., Stern R. S.
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Full Text
N Engl J Med 1995;
332:1031-1033, Apr 13, 1995.
Correspondence
This article has been cited by other articles:
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