Bulletin of Experimental Treatments for AIDS, July, 1998
Bruce Mirken
The phenomenon isn't limited to AIDS drugs, of course. The airwaves are increasingly filled with commercials for antihistamines, cholesterol reducers and other drugs, a proliferation of ads that has many observers worried. Critics say that ads for prescription medicines can be confusing to consumers, and even misleading. Ads for anti-HIV drugs, critics argue, not only create an unrealistically cheerful picture of life with HIV and with antiretroviral therapy, they oversimplify complex and difficult treatment decisions. The drug companies, on the other hand, reply that they are simply trying to give consumers important and useful information about their products.
Whatever one thinks of the recent ad blitz, all signs are that it is likely to continue. Since--as with all advertising--a well-informed consumer is better able to negotiate the thicket of sometimes conflicting messages, this article will attempt to outline the basic information needed to understand how HIV/AIDS drug ads work, how the U.S. Food and Drug Administration (FDA) regulates them, and their limitations as a source of treatment information.
As recently as the mid-1980s pharmaceutical companies advertised prescription drugs only to the physicians licensed to prescribe them. Although "direct to consumer" (DTC) ads, as they are known, were not formally banned, it was assumed that nonprofessionals lacked the scientific knowledge needed to evaluate claims made for strong and potentially dangerous prescription medicines. Federal regulators were content with the situation, and no one in the pharmaceutical industry was ready to risk alienating FDA by breaking the taboo.
When the first small attempts at DTC advertising finally appeared in 1980, FDA quickly asked for a moratorium while it evaluated the issue, and the companies complied. In 1985 the agency lifted the ban, but continued to make its displeasure with DTC ads clear. In 1988, for example, then-FDA Commissioner Arthur Hull Hayes, MD, was quoted in The New England Journal of Medicine as saying that such advertising was "not in the public interest." As a result, few ads appeared.
Gradually, though, the mood of regulators softened and industry spending on DTC ads increased, rocketing from $12.26 million in 1989 to $313 million in 1995 to nearly $900 million last year. Until mid-1997 the agency never issued any rules specific to DTC ads, but instead simply applied existing regulations governing advertising to health professionals. That finally changed last summer, when the agency issued a "guidance document" that loosened the rules for television advertising, helping to fuel the recent avalanche of commercials. Print ads are still governed by the rules for advertising aimed at doctors, although some changes are now under consideration.
No television ads for HIV/AIDS drugs have yet appeared. The massive outlays required for a television campaign have been reserved for mass-market products like blood pressure medications and allergy relievers. AIDS, for better or for worse, remains a relatively small niche market, with advertising concentrated in the gay press and HIV-focused publications like POZ magazine, although a few ads have appeared in general interest magazines. Some advertisements have also run in publications aimed at the Latino and African-American communities.
Many doctors, AIDS activists and consumer advocates wish these ads would disappear. Robert J. Margolin, MD, an internist at Mt. Zion Hospital and president of the San Francisco Medical Society, calls direct-to-consumer ads "a very bad thing." Ads for AIDS drugs, he says, give a misleading impression to readers who might see them and say, "Wow, look at these guys in this picture. They've got HIV but they're doing great." The impression of HIV disease they give, he argues, is that "you're going to live a perfectly normal life, and if you're not, this [drug] is what's going to make it happen...It's instilling a false sense of expectations in patients."
Margolin, whose practice includes between 75 and 100 patients with HIV, says some have come in asking for drugs that were clearly not appropriate for them because they saw advertisements for the drug.
In a 1996 interview, Project Inform's founding director Martin Delaney called for a complete ban on DTC ads, and 2 years later he says, "I certainly haven't changed my views." About AIDS drug advertising, he complains, "If anything, it's gotten worse." Delaney is particularly disturbed that the ads are "creating the impression that everyone with HIV must be on treatment, which is arguable, to say the least."
Margolin's view seems to be the majority sentiment in the medical profession. In a survey of 454 family physicians published last December in the Journal of Family Practice, 71% of doctors agreed that DTC ads "pressure physicians to use drugs they might not ordinarily use," and 81% considered broadcast ads for prescription drugs "misleading." In 1996--before the recent ad boom--the American Public Health Association passed a resolution calling for much stricter FDA scrutiny of this type of advertising. In February of this year, the California Medical Association's House of Delegates passed a resolution calling for a complete ban. The American Medical Association, though, has not taken any such stand.
The drug companies, not surprisingly, disagree strongly with the critics, arguing that what the ads do--and what they want them to do--is stimulate doctor/patient discussion. "This isn't an over-the-counter medication," notes Joy Schmitt, spokeswoman for Agouron Pharmaceuticals, whose protease inhibitor nelfinavir (Viracept) has been heavily advertised in the gay press. "It's information that creates awareness, that one takes to his or her pharmacist or healthcare provider to get more information."
Jeffrey Trewhitt, spokesman for the Pharmaceutical Research and Manufacturers of America (PhRMA), an industry trade group, adds, "A growing number of patients have told us they want to be involved in their treatment. They want to be empowered. This is a way of educating patients." Delaney has no patience with that argument. "I'm speaking as one who believes big-time in patient empowerment," he says, "but I don't believe marketing departments create patient empowerment." Still, at least a few doctors involved in HIV care think DTC ads can serve a useful function. Mary Romeyn, MD, whose San Francisco practice includes many people with HIV/AIDS as well as a substantial number of geriatric patients, argues that advertising can be a useful counterweight to efforts by managed care organizations to restrict access to high-cost treatments.
"Is it irritating? Yes," Romeyn says. But she argues that advertising can give patients "information the system doesn't want them to know" about costly but potentially effective medicines. "For a patient to have access to state-of-the-art care, it is necessary for them to know that care exists." Ads may not be a perfect way of conveying treatment information, "but it at least begins a conversation, so they can ask."
FDA regulation of prescription drug advertising is based on the idea that ads are effectively an extension of the product's labeling: the FDA-approved package insert that gives detailed explanations of a drug's indications, dosage, side effects and other relevant information. The basic rules are that advertising must be truthful and must include what the agency calls "fair balance," meaning that information about a drug's benefits must be balanced by an equal presentation of its potential harmful effects.
These rules and the more detailed guidelines discussed below apply only to pharmaceutical and biological products licensed by FDA for prescription sale. Ads for nutritional supplements aren't subject to these rules, even though some of them look a lot like prescription drug ads.
FDA spokesman Brad Stone explains that legislation passed by Congress limits the agency's authority over nutritional supplement ads. "Under the Dietary Supplement Health and Education Act of 1994, dietary supplements can be sold with what are called 'structure and function' claims," Stone explains. This means that promotional materials can state that they boost or strengthen the body's structure or functions without having to submit proof to FDA. If the agency believes the claims to be false or misleading, the burden of proof is on FDA, not the company marketing the product.
What dietary supplement makers cannot legally do is "claim that they treat or cure any disease," Stone says. These are considered "drug claims," and are permitted only for licensed prescription medicines.
But sometimes the lines get blurred. Some nutritional products have medical-sounding names, and a few of their ads make claims that push into dubious territory. One widely seen advertisement for a product called Immunocal shows a diver about to spring off a high board under the headline "Dive Into a New Way of Treating HIV." The ad copy says the product "elevates T-helper cells." Several doctors and AIDS advocates we spoke to criticized this ad, believing it made a nutritional product--never evaluated or approved by FDA--look like a licensed pharmaceutical.
Stone and Nancy Ostrove, FDA's acting branch chief for Marketing Practices and Communications, both said that they were unfamiliar with the advertisement and declined to comment on whether or not any regulatory action might be pending, but after hearing the ad's text, Stone called the language "problematic."
John Molson, vice president of Immunotech Research, Immunocal's manufacturer, said he had not spoken to FDA about the ad and explained that it had been placed by one of the company's independent distributors, although Molson had seen it. After BETA explained the concerns that had been expressed, he said, "I'm going to contact the distributor who put that ad out and ask them to take out the word 'treatment.' I'm not a doctor and I'm not as sensitive to these things, but now that I look at it, I agree with you."
Molson provided the protocol for a study of the substance presently being conducted in Canada, but said Immunotech did not anticipate seeking FDA approval as an HIV treatment. "We don't have the financing to do that," he said.
New guidelines issued by FDA in April give more specific guidance than has existed previously regarding what is and isn't an acceptable "structure and function" claim, but the statutory limitations on FDA's authority in this area remain in place.
How does one tell if the product being pitched is in fact an FDA-approved medicine? The simplest way is to look for a mass of fine print which, depending on the layout, might be right next to the body of the ad or might be on the next page. This mass of fine print--often as large as the main ad itself, but in type so tiny you may well need a magnifying glass to read it--is what FDA, without a trace of irony, calls the "brief summary."
All prescription drug ads must contain such a brief summary: a true, accurate listing of all known side effects, warnings and contraindications. Most drug companies meet this requirement by reprinting the relevant sections of the product's labeling. This, after all, is language that FDA has already approved and which it uses as the basis for its scrutiny of a product's marketing. As of August 1997, television commercials can satisfy this rule by providing toll-free numbers and a variety of other means by which viewers can obtain the information.
The problem is that package insert language is complex and highly technical, not at all designed for laypeople. For example, the brief summary accompanying widely published ads for Combivir (Glaxo Wellcome's combined AZT/3TC capsule), tells readers that potential side effects include "lactic acidosis and severe hepatomegaly with steatosis" as well as "myopathy and myositis." Such technical terminology is unfamiliar even to most highly educated people. "How could someone interpret this?" asks an exasperated Margolin. "How could a fellow who hasn't gone through medical training in any way interpret what this is?"
There is presently no FDA requirement that these disclosures be made in lay language, but the agency is "looking at the regulations" in this area, Ostrove says. "Our goal is to have something out by the beginning of next year."
Some companies have, with the FDA's approval and encouragement, created special plain English package inserts designed for patients, and this simpler language can be used to fulfill the "brief summary" requirement in place of the more technical version. Merck created such a patient package insert when it first began marketing indinavir (Crixivan), and has consistently used this plain English disclosure in its advertising. Agouron has done the same thing for nelfinavir (Viracept).
These lay language summaries still present the reader with a mass of small print that may be too much for many to digest, but critics like Margolin regard them as an improvement, since at least the language is reasonably understandable. Most ads for HIV/AIDS drugs, however, still contain "brief summary" disclosures lifted straight from the original, jargon-filled labeling.
Two other key requirements govern the content of advertisements. First, they must contain a "major statement" of side effects and contraindications. The major statement highlights the key warnings associated with a drug and should be fairly prominent in the ad. Second, advertisements must meet a requirement of "fair balance," meaning that, overall, statements about a drug's benefits must be balanced by appropriate disclosure of its risks.
That sounds simple enough, and in practice it sometimes is. For example, FDA felt that a commercial for a popular antihistamine that began airing last summer didn't meet these requirements because certain disclosures appeared on the screen in type that blended in with the background, making it hard to read. The company pulled the ad, put the disclosures in brighter type and solved the problem.
But Ostrove acknowledges that there is no precise way to measure "fair balance," noting, "there's a fair amount of leeway there in terms of interpretation." To a certain degree, the agency must make judgement calls, and some of these are choices about which reasonable people can disagree.
For example, ads for d4T (Zerit) warn that the drug "has been shown to cause tingling or pain in the hands or feet in 13% to 24% of people." Ostrove says FDA preferred that language over the technical term "peripheral neuropathy" because it felt it would be more understandable to most people. But the agency did not require an explanation that this tingling or pain, if it progresses too far, can lead to permanent and potentially crippling nerve damage. The idea was to flag a symptom that patients should look out for and discuss with their doctor, while not causing undue alarm.
The question of how much detail to put into a warning often does not have a clear, simple answer, and FDA assumes that people will think critically when viewing advertising. "We believe that people bring to ads a somewhat healthy skepticism, because that is appropriate," Ostrove says, including an understanding that ads can't contain "all the information a person may need to know when they're taking a drug." But overall, "we think the balance in most of these ads is appropriate."
Notably, FDA does not include an ad's visuals in its evaluation of "fair balance." But advertising professionals readily acknowledge that visuals are often the most important part of an ad, making a first, dramatic impression before the reader even begins to process the text.
Ostrove says that the agency believes that consumers don't view photos and illustrations as actual claims for the product, and thus don't require a balancing statement of drawbacks. But there is no denying that the images used in advertising can be powerful and are chosen with great care to create a positive impression. Ads for diet aids, for example, universally show slim, athletic people rather than obese ones, except perhaps in carefully framed before-and-after scenes. AIDS drug ads are just as consistently filled with happy, healthy-looking individuals--what Delaney calls a "cheery, freshly washed image" that he slams as "so unrepresentative. None of them gives any sign of the reality of taking the drugs."
Perhaps the most dramatic use of visuals in an AIDS drug ad is seen in the 2-page indinavir ad Merck used through most of 1997 and into 1998 (as BETA goes to press it is being replaced by a new version). On the left page, under the headline "In the Battle Against HIV," a mountain climber struggles up a forbidding vertical precipice. Looking to the right one sees the second part of the headline, "There's a Change in Outlook." A second photo, now placed above the headline, shows the same mountain climber standing atop the peak he has been climbing, surveying the valley from which he has just emerged. It is a vivid, dramatic image.
The visuals' job is partly "to motivate people to stop and read the ad," notes Merck spokeswoman Kyra Lindeman, but the images are also tied into the ad's message. "We were trying to show with Crixivan primarily the durability of the effect of the drug and that it is allowing people to live longer. We link it back to the scientific data, which is very strong." The image suggests "moving towards a healthier life," which Lindeman argues is backed up by study data on the drug.
But advertising, she acknowledges, "will never substitute for the discussion between a patient and a physician. Patients and physicians need to have a continuous conversation" about treatment options and strategies. While some argue that the reaching-the-top-of-the-mountain visual might convey an oversimplified view of the benefits of protease inhibitors, she argues that the ads "might interest the patient in getting tested or calling Project Inform's treatment line, which is good."
One of the more controversial protease inhibitor advertisements is one Agouron used extensively last year to market nelfinavir. Facing a full-page photo of one of those happy, smiling young men Delaney complained about is the headline, "Right now I feel great. If I get sick, then I'll start taking the medicine." The ad continues, "If this is what you believe, then here's something new to consider...even if you look good and feel healthy the virus is fighting every day against your immune system--a fight it might someday win."
While the ad never uses the phrase "hit early, hit hard," it certainly comes across as an argument for early treatment. This troubles Donald Abrams, MD, a clinician and researcher at San Francisco General Hospital, something of a skeptic in the debates over "hit early, hit hard" and a strong critic of DTC ads in general. "I'd like to see the data," Abrams says. "I don't think we have any clinical data at this point in time that has really answered this question well enough that it should be amenable to casual advertising in magazines. I think the issues in HIV therapy are so complex that it's hard to distill them down to billboard buzzwords or a little caption on a photo."
Asked about the same ad, Delaney notes dryly, "I don't think they're an unbiased source on that issue. I think it is a very troubling issue, when to start therapy."
Delaney raises another objection to Agouron's ad, one which has cited by other treatment advocates as well. The text of the ad includes the statement, "And in laboratory studies, HIV obtained from 5 patients that became resistant to Viracept was not resistant to other protease inhibitors." Though a disclaimer in parentheses notes that the clinical implications of these lab results have not been established, Delaney and others argue that the ad implies a claim of a lack of cross-resistance between Viracept and other protease inhibitors, a notion that is certainly unproven and which many consider dubious.
Agouron's Joy Schmitt defends the wording about resistance as "a factual statement," one that is "not only accurate, but something that people in the community ask [about]. We felt it responsible to state something we did know about a frequently asked question." As for pushing a "hit early, hit hard" approach, she says, "that's one way to look at it." The advertisements, she adds, "were market tested extensively, and if we'd had a lot of that response we wouldn't have run this." She acknowledges the prevalence in AIDS drug ads of what she calls "the happy pill-taker," noting, "People don't want to see the downside. They want to see a brighter side."
In any case, the controversial ad was replaced earlier this year by one featuring photos of a lion and a pussycat, emphasizing Agouron's claim that the drug is both strong and "easy to live with." Discussions of treatment strategies were dropped, as was the line about resistance. Schmitt says that community input was taken into consideration when the ad was revised, but she is not aware that specific complaints about the reference to resistance caused that language to be dropped.
The fact that the person pictured in the old ad was a white male did draw some flak, she says. "I hear, 'Get more women in your ads. Get more people of color in your ads.'" Indeed, many HIV drug ads now show multiethnic groupings.
FDA generally does not involve itself in the types of sales pitches drug companies make for their products as long as any factual statements match the study data. The statements in the Agouron ad about the results of test tube resistance assays and about HIV being active in the body from the beginning of infection were accurate as far as they went. That some readers may interpret them in ways Delaney or Abrams might consider dubious is not, in FDA's view, something it has authority to regulate.
As noted above, the bottom line in FDA's evaluation of advertisements and other promotional materials is the product's approved labeling. If an ad's claim matches the labeling, it is acceptable. If a statement goes beyond what is in the labeling, the agency is likely to object.
The problem is that the labeling, adopted at the time of a drug's approval and perhaps updated later if the manufacturer comes back seeking licensing for new or expanded uses, often does not reflect the most current scientific knowledge. This isn't unique to HIV/AIDS. For business reasons, pharmaceutical companies sometimes decide not to go through the difficulty and expense of seeking approval for new indications for an already-licensed drug, even though there may be data to support such uses. The label never reflects such "off-label" uses, even though they may be widely accepted. In HIV treatment, information is developing and changing so rapidly that a drug's labeling frequently lags behind the generally accepted standard of care.
What this means for the consumer is that the statements in an advertisement may be factual and may be in accord with the labeling to FDA's complete satisfaction, and yet still not tell people important information they need to know when considering the drug. Perhaps a classic example of this is another campaign that generated controversy in the recent past: Hoffmann La Roche's 1996 and 1997 advertising for the original formulation of saquinavir, called Invirase.
Roche's first ads announced in large headlines that Invirase was "the first HIV protease inhibitor" at a time when this class of drugs was getting reams of favorable press. Later versions called the drug "a protease inhibitor you can live with," and emphasized its generally low rate of side effects. Both versions noted study results showing improved survival and decreased rates of opportunistic infections in patients taking saquinavir plus ddC (Hivid) when compared to those taking either drug alone.
While none of these statements was false, treatment activists argued that Roche's advertisements gave a misleading and even dangerous impression because of what they didn't say: that Invirase, because it was poorly absorbed, was considerably weaker than the other 2 protease inhibitors available by the spring of 1996, and that even then almost no one considered any of the regimens in Roche's study to be adequate. Though there wasn't yet clear data, some feared that people who developed resistance to this relatively weak protease inhibitor would also develop resistance to the stronger ones--perhaps losing the chance to get significant benefit from an entire class of treatments. Project Inform, among others, asked Roche to pull the ads.
The campaign continued. At the time, Laurent Fischer, MD, the company's Medical Director for HIV Products, defended the ads, saying, "I don't think it is misleading...It certainly doesn't say it is superior [to the other protease inhibitors]."
What is striking about this episode is that not only did Roche's ads meet all of FDA's requirements, but if the company had tried to run ads that would have made its critics happier--containing a disclaimer clearly stating that Invirase was weaker than its competitors--FDA would almost certainly have objected. "There is nothing in the regulations that requires comparative information be included in an advertisement," Ostrove explains. If a company wants to include such comparisons, "they have to have head-to-head studies to support those claims." Roche had submitted no such studies when it filed for approval of Invirase, and no comparisons between it and other protease inhibitors were included in the drug's labeling. Thus, by FDA's rules, such comparisons would almost certainly have been barred as false or misleading--even though most treatment activists and physicians would have considered the information not just valuable but essential.
Advertising for prescription medicines, including HIV/AIDS drugs, has become so prevalent that it is nearly impossible to avoid. Indeed, even critics who would prefer to see DTC ads banned don't advise attempting to ignore them completely. Rather, they suggest using them in a very limited way, simply as a starting point for your own research. When looking at drug advertisements, remember:
Still, as Romeyn notes, ads may be a useful conversation starter. Abrams advises that, "If they see something in an advertisement that they think might be relevant to their treatment," patients should "approach their primary care provider and have a conversation. Say, 'Is this something that I might be on, or if not, why not?' Have an open, honest conversation." He hopes that patients will have enough confidence in their doctor that such discussions can be productive and not adversarial. There may be good reasons why a drug that looks terrific in ads may not be right for a given individual.
Abrams, Margolin and Romeyn all emphasize the importance of seeking objective, unbiased sources of information about drugs and treatment decisions. This includes newsletters like BETA, Project Inform's hotline and other community-based sources that don't have a commercial interest in the information they provide. Read other things besides the advertisements, Margolin advises, "There's lots of information out there."
Bruce Mirken is a freelance writer in San Francisco.
980701
BE980705
Copyright © 1998 - Bulletin of Experimental Treatments for AIDS (BETA). Reproduced with permission. BETA is published four times a year by the San Francisco AIDS Foundation. All rights reserved. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. Call 415.487.8060; FAX: 415.487.8069. Mailing Address: P.O. Box 426182, San Francisco, CA 94142-6182. beta@sfaf.org http://www.sfaf.org/beta.html
This information is designed to support, not replace, the relationship that exists between you and your doctor.