Drug reps use friendship, flattery, gifts, and services to establish relationships with physicians that lead to increase use of targeted drugs.¹ Drug reps are trained to assess physicians' personalities and preferences and use this information to manipulate perceptions about both the drug rep and the drugs they sell.¹ Although studies show that physicians do not believe that promotion affects their own personal prescribing,^2-5 promotion has been shown to increase physicians' prescription of targeted drugs, and increases prescription costs.^6-11 A systematic review of 19 studies found that 15 showed a consistent association between interactions with pharmaceutical companies and increased prescribing rates, lower prescribing quality, and/or increased prescribing costs.¹²

Although many physicians rely on sales reps to give them information about drugs, this information is not accurate. Not only do reps not have accurate information about competing therapies, they are not accurate about the drugs they sell either. It has been shown that drug reps downplay or omit adverse events (even serious ones).¹³⁾ Although physicians believe they can extract objective information from information provided by drug reps, studies show that physicians cannot distinguish between correct and incorrect information provided by sales representatives.^14,15 Meeting with drug reps may reduce prescribing quality. A review of 58 studies found that exposure to pharmaceutical-company information did not improve physician prescribing and that exposure to information provided by pharmaceutical companies was associated with higher prescribing frequency, higher costs, or lower prescribing quality.¹⁶

Drug samples are among the most effective marketing tools that companies have. Bringing samples every week or 2 provides reps an opportunity to promote their drugs to physicians. Samples are almost always used only for the most expensive, chronically used drugs.¹ Patients are grateful for samples, and physicians almost always prescribe the same drug that was sampled. That is exactly why samples are so important; samples are meant to give physicians practice in prescribing the targeted drug and to make the targeted drug a routine part of the physician'spractice.

Drug reps may bear food, gifts, or moneymaking opportunities, all of which influence physicians. Gifts do not need to be large to have a powerful effect on human relationships. Meals, pens, and other small gifts create a subconscious obligation to reciprocate. In the physician-drug rep relationship, physicians reciprocate not by returning gifts but through changes in prescribing practices.^1,17 One study found that physicians who received gifts totaling less than $500 a year prescribed more expensive medications ($123) than prescribers who received no gifts ($85).⁶ More expensive gifts had a greater effect in a dose-related fashion.

ProPublica, an investigative reporting organization in the United States, reported on the effect of gifts on prescribing for 150,323 physicians and found that internists, family physicians, cardiologists, psychiatrists, and ophthalmologists who received any gifts from drug or device manufacturers prescribed a higher percentage of branded drugs overall than doctors who received no gifts.¹⁸ Even a few meals increased branded-drug prescribing when compared with doctors who received no payments.

Besides food, sales reps may also offer opportunities to physicians. According to former drug reps we interviewed, tactics include

A rep may invite a physician to give a dinner talk to a small group at an excellent restaurant. The subject of the talk does not matter, because this is a chance for the rep to both honor and pay the speaker, who then responds by prescribing more of the rep's drugs.

In all of these cases, drug reps have found an excuse to give a physician money without it seeming like a bribe. As Michael Oldani, an anthropologist and former drug rep, states, "The essence of pharmaceutical gifting . . . is 'bribes that aren't considered bribes'."¹⁹

Physicians may be asked by drug reps or other pharmaceutical company employees to participate in a "study," usually involving a payment for each patient a physician puts on a targeted drug. This is not a real study but a "seeding" study, meant to increase prescriptions rather than to further science.^20,21

Many studies done after a drug is approved may be primarily for marketing purposes. In Germany, all "postmarketing" studies must be registered; an analysis of studies found that over 3 years, more than a million patients participated in 558 postmarketing studies sponsored by 148 manufacturers of drugs or medical products. Sponsors spent more than €217 million on paying physicians for these studies (most payments were between €1000 and €10,000). There was often a low ratio of patients to physicians. Only 5 of 558-less than 1%-were published. Most studies were case series, sometimes euphemistically called single-arm prospective studies. Without controls, these studies are scientifically worthless. The fact that these were largely uncontrolled, unpublished studies is indirect evidence that these are studies are meant to promote prescriptions, not advance science.²²

Many published studies also bear hallmarks of being primarily designed for marketing purposes; 21% of 194 studies published in 6 general medicine journals showed evidence of being designed for marketing purposes. Raters considered "first, a high level of involvement of the product manufacturer in study design; second, data analysis; third, and reporting of the study; fourth, recruitment of small numbers of patients from numerous study sites for a common disease when they could have been recruited without difficulty from fewer sites; fifth, misleading abstracts that do not report clinically relevant findings; and sixth, conclusions that focus on secondary end-points and surrogate markers."²³

According to industry insiders, some companies send physicians or pharmacologists employed by the company to talk to physicians at their practice sites. This may be a way of getting around regulations regarding drug reps. Because these health professionals are not sales reps, they can address unapproved uses and other subjects that drug reps are not permitted to talk about.

Drug reps may invite physicians to a lunch or dinner talk by an academic physician, or someone who is influential in a community. The speaker is paid by, but not usually an employee of, the sponsoring company, and the talk will cover several marketing messages.²⁴ However, the speaker may not overtly sell the drug. These "thought leaders" or "KOLs" may be used in promotional talks or at continuing education events; they are important for pushing unapproved uses, raising awareness of targeted diseases, and shaping perceptions of a drug's benefits and harms, as well as perceptions about competing drugs.²⁵ KOLs are also important for "disease branding" or "condition branding," in which a specific condition (sometimes one that is invented by the company) is linked with a specific therapy.²⁶ Some companies specialize in identifying KOLs who can help influence their peers.²⁷

Continuing education is often funded by pharmaceutical companies and always contains marketing messages. These messages may be difficult to identify, because marketing messages include exaggerating the prevalence or severity of a specific condition. Sometimes, the targeted drug is not even on the market yet; marketing for a drug can start many years before a drug is approved.²⁶ A "pre-launch" marketing message might emphasize the importance of a specific physiologic process to set the stage for acceptance of a drug that affects that mechanism, or might create a new diagnosis or an unnecessary diagnostic distinction to establish a favorable atmosphere for a new drug.

Companies may sponsor conferences, seminars, or lunches with talks within medical schools, hospitals, clinics, and other practice settings. Companies may sponsor series of talks, suggesting only 1 or 2 speakers as participants. Speakers who are not chosen by the sponsoring company then act as cover for the KOL who carries the marketing messages. Companies also sponsor medical association meetings; again, in exchange for the inclusion of a few KOL speakers. Although the grants provided for talks, seminars, and meetings are described as unrestricted, it is understood that the company gets to choose some speakers. It is also understood that speakers with views that undermine marketing messages from a sponsoring company will not be invited.²⁸

Physicians who take money from pharmaceutical companies for giving talks may not feel compromised because they are saying what they really believe. However, they are chosen because what they are saying aligns with a product's marketing messages, and are supported only as long as they do so.²⁹ A physician who expresses doubts about a product's efficacy, concerns about its risks, or enthusiasm for a competing therapy will not receive further speaking opportunities.²⁴

Several attempts to combat pharmaceutical influence have been made. In July 2018, the Colombian Ministry of Health issued a regulation that creates a public registry of "value transfers" that occur between the pharmaceutical industry and healthcare professionals.³⁰ In the United States, pharmaceutical companies are required to report gifts to physicians in a publicly accessible Federal database called Open Payments.³¹ Some states limit pharmaceutical company payments to physicians; Maine, Vermont, and Minnesota ban gifts to physicians.³²

Some states and medical systems support academic detailing, a form of education in which healthcare providers visit physicians individually, as drug reps do, but academic detailers provide unbiased information about drugs. Academic detailing has been shown to encourage rational prescribing among physicians.³³

Industry-free continuing medical education (CME) is an even more efficient way of providing unbiased information. In 2016, Washington, DC became the first jurisdiction in the United States to provide free, noncommercial, independent, online continuing education to physicians, other healthcare providers, and pharmacists. The DC Center for Rational Prescribing is funded by the DC Department of Health.³⁴