- Neeraj G Patel, medical student1,
- Ayman Mohammad, medical student2,
- Joseph S Ross, professor of medicine and public health345,
- Reshma Ramachandran, assistant professor in medicine34
1Yale School of Medicine, New Haven, CT, USA
2Icahn School of Medicine at Mount Sinai, New York, NY, USA
3Section of General Internal Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
4Yale Collaboration for Regulatory Rigor, Integrity, and Transparency, Yale School of Medicine, New Haven, CT, USA
5Department of Health Policy and Management, Yale School of Public Health, New Haven, CT, USA
- Correspondence to: R Ramachandran reshma.ramachandran{at}yale.edu
In 2012, the US Congress gave the Food and Drug Administration authority to grant “breakthrough therapy” designation to expedite development and regulatory review of new drugs. The designation is used for potential treatments for serious conditions when preliminary evidence suggests they may perform substantially better than available alternatives on “clinically significant endpoints.” Preliminary evidence can include surrogate marker endpoints reasonably likely to predict clinical benefit, such as imaging changes and biomarkers. The programme has been successful in at least one way: an analysis of FDA approved drugs from 2015 to 2022 found that breakthrough designation was associated with a two year reduction in clinical development time.1 However, these therapies are approved on the basis of less rigorous evidence, often a single pivotal clinical trial instead of two, and trials that are smaller and weaker in design.2
Manufacturers had requested around 1400 breakthrough designations for candidate drugs as of October 2023, 537 of which were granted (292 drugs later received FDA approval).3 The numbers have far exceeded initial expectations that one to two drugs would qualify annually.4 The breakthrough designation has received criticism for unintended consequences—including that the title “breakthrough” has led to press releases, news articles, and product labels that have led patients and physicians to overestimate the efficacy of designated therapies.2567
Separately, over the past two decades, the rise in direct-to-consumer pharmaceutical advertising in the United States (one of only two higher income countries that allows it, alongside New Zealand), has continued unabated, eclipsing $6bn annually. Such advertising has generated concerns about overstating the efficacy of new drugs.8910 Critics have warned that the advertisements have low informational quality and are associated with increased prescribing of costly drugs that are not necessarily clinically superior to less expensive alternatives.8111213 We consider how the growth of television advertising, together with the breakthrough designation, has created confusion for patients and what can be done to counter it.
Controversial rise of consumer advertising
Nearly half a century ago, in Virginia State Pharmacy Board v Virginia Citizens Consumer Council, the US Supreme Court overturned a state statute that prohibited pharmacists from advertising the price of prescription drugs. In his dissent, Justice William Rehnquist warned of unintended consequences of the decision, writing that newspapers might one day run advertisements such as, “Can’t shake the flu? Get a prescription for Tetracycline from your doctor today,” and prescription drug advertisements might be shown on television during family viewing time.14
The warning probably seemed outlandish at the time. Prescription drug advertising had been uncommon since 1969 when FDA guidance had placed restrictions on such advertising, including requirements that it presents a “fair balance” of risk and benefit information, as well as a “brief summary” mentioning all risks included in the drug label.15 But in 1999, the FDA issued guidance clarifying that broadcast adverts do not have to list all drug risks—they can instead include “major risks” and direct viewers elsewhere, such as to a web page, for a more complete description. One study found that while industry spending on direct-to-consumer prescription drug advertising still lags behind spending on marketing directed at medical professionals, it increased from $1.3bn on 79 000 advertisements in 1997 to $6bn on 4.6 million advertisements in 2016, with over half of that spending on television advertising.16 Spending has remained roughly $6bn annually in recent years.1117
Previous research has linked direct-to-consumer advertising with increases in patient requests for prescription drugs and population rates of prescribing.18 One study of advertising spending following the introduction of the Medicare Part D programme (which provides pharmaceutical insurance coverage for seniors and disabled adults in the US), estimated that a 10% increase in advertising views was associated with a 4% increase in drug spending.19
Proponents of direct-to-consumer advertising have argued that it can educate patients about treatments, empower them to take a more active role in their healthcare, and increase appropriate prescribing and medication adherence. However, growing research suggests that it is associated with increases in clinically inappropriate prescribing and inflated healthcare costs by focusing promotion on more expensive treatments of limited comparative clinical value. One explanation for this might be that innovative, highly effective treatments are likely to get prescribed without advertising. Other research has questioned the quality of information in such advertising (box 1).
Arguments over effects of direct-to-consumer drug advertising
Effects on inappropriate prescribing
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Proponents have argued direct-to-consumer (DTC) advertising increases awareness of conditions and treatments that are underdiagnosed and underused. Some research has found links between such advertising and improved medication adherence, particularly for cholesterol lowering drugs2021
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Critics have argued it has led to increased prescribing of newer brand name drugs, including when it may be clinically inappropriate.22 A 2005 randomised controlled trial found that antidepressant prescribing rates for patients presenting with adjustment order (for which antidepressant use was unsupported by clinical data) were 55.1% (95% CI 20.3% to 69.3%) for patients who requested a branded medicine motivated by a television advertisement compared with 9.8% (3.3% to 21.4%) for patients who made no such request23
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Pharmaceutical marketing may be associated with increased reporting of adverse drug reactions for certain therapeutic areas.24 Two high profile examples that have generated concern about patient wellbeing are advertising campaigns for the non-steroidal anti-inflammatory drug Vioxx (rofecoxib) before its withdrawal because of safety concerns,25 and advertising’s contribution to overuse of opioids such as oxycodone (OxyContin)26
Effects on patient education and patient-prescriber relationship
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Proponents have argued DTC advertising can educate patients about treatments, empowering them to take a more active role in healthcare decisions. Data have been limited, and surveys have yielded mixed results27
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In a 2000-01 survey of patients who had recently discussed DTC advertising during a visit, 24% of respondents reported an improved relationship as a result; however, respondents who requested a drug that they did not receive were more likely to report a worsened relationship28
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Surveys suggest that prescriber attitudes on the effects of DTC advertising on the patient-prescriber relationship are more negative29
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A growing body of literature has questioned the educational value of such advertisements, highlighting inadequate descriptions of risk, distorted portrayals of benefit, and misleading promotional aspects, including off-label promotion789
Effects on drug spending
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Critics of DTC advertising fear that it has inflated drug spending because companies focus advertising budgets on newer branded drugs14
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DTC advertising has also been tied to anticompetitive marketing strategies through product hopping, in which manufacturers encourage patients to switch to drug products with longer patent periods30
Breakthrough designation: a misleading name?
Since breakthrough designation is granted before pivotal trials have been conducted, products eventually approved with this designation are not necessarily associated with substantial clinical benefit over existing alternatives and may fall short of a “breakthrough.” One review of breakthrough approvals from 2007 to 2017 found that only about 60% of the drugs were rated by at least one of four health technology assessment agencies in other countries to have moderate or greater therapeutic value than available alternatives.31 Results of another study suggested that clinical trials supporting approval of breakthrough designated drugs were of lower quality than those not designated as breakthrough.2
A 2015 study found that participants given short factual descriptions of a recently approved drug were significantly more likely to rate the drug as “very” or “completely” effective if the description stated that the FDA called the drug a “breakthrough.”3 Participants who were given the “breakthrough” information were also significantly more likely to believe the evidence supporting the drug was “strong” or “extremely strong.” All FDA press releases announcing approval of drugs with breakthrough designation, at that time, had used the term breakthrough. A 2016 survey of physicians showed that 52% of respondents incorrectly believed that “strong evidence (eg, randomised trials evaluating clinical outcomes) was required to receive FDA breakthrough designation, and in a hypothetical scenario asking which of two drugs they would choose to treat a condition, 94% of respondents chose the drug that was described as receiving “breakthrough” designation over the drug that was not, even though its description met the definition of breakthrough.4 These findings were largely replicated in a similar study in 2022.29
Television advertising of “breakthrough” drugs
The use of the term “breakthrough” within advertising may overshadow the underlying evidence around efficacy for drugs granted the designation. Moreover, since early data suggest these drugs may represent advances, sponsors may be emboldened to make strong advertising claims even when clinical data have not shown substantial therapeutic improvement over existing alternatives. We used an online database to obtain 57 unique television adverts for drugs with FDA breakthrough designation from 2012 to 2021,3233 assessing their informational quality and language.
Our examples were not collected systematically or intended to be representative so can only give a snapshot of advertising behaviour. In this sample, five adverts (9%), representing two of the 17 advertised drugs (12%), used the word “breakthrough” [Keytruda (pembrolizumab) and Dupixent (dupilumab)]. Even if they did not use the term “breakthrough,” adverts often appealed to the concept of hope, the product’s newness, and the product’s uniqueness (table 1). While use of these appeals is not necessarily inherently misleading, they were often paired with misleading portrayals of benefit that, when taken together, depict these products as groundbreaking advances when evidence supporting such an assessment is often lacking.
We assessed the value of the 17 drugs for the advertised indications in Prescrire International, a peer reviewed bulletin which rates the therapeutic value of new drugs based on harm-benefit balance versus existing treatments.34 Four of the indications were not rated by Prescrire. Of the 13 included, five were rated to “offer an advantage” (has some value but does not fundamentally change current therapeutic practice) and none was rated to be an important or major therapeutic advance. This may explain why few of the adverts used the term breakthrough. However, the claims made in the adverts were sometimes incongruent with the available evidence, potentially misleading patients about drug benefit (table 2)
Although 44 adverts (for 10 drugs) quantitatively described benefits, only 38 included control group statistics. Other advertisements emphasised product benefit while minimising the comparator statistic or used relative risks without providing any context on size of risk. FDA guidance produced after the period of our study advises that consumers may find relative frequency data challenging to understand and encourages use of relevant context to improve consumers’ understanding. It also recommends that advertisements with quantitative efficacy or risk information about a drug include quantitative information for the relevant control group.36 No advertisements in our sample quantified risks associated with a product.
Ethical quandaries and regulatory opportunities
We have highlighted examples of overpromotion in direct-to-consumer pharmaceutical advertising of breakthrough designated drugs. Further research is needed to determine whether this is more common for breakthrough designated drugs than for other drugs. Overstatement of drug benefit in direct-to-consumer advertising, paired with use of the word “breakthrough” in press releases and media reports, may skew patients’ impressions of risk-benefit profiles and undermine their ability to make healthcare decisions adequately informed by unbiased information.
Assessment of the permissibility of such advertising is complicated because the definition of breakthrough is subjective. Advertising that overemphasises benefits of such products may be characterised as an acceptable expression of free speech that consumers should critically assess, just as they do for any other advertisement. However, unlike other commonly advertised items such as cars, prescription drugs have complicated risk-benefit profiles and powerful health effects, making the consequences of misleading promotion more serious.
To improve informational quality in direct-to-consumer advertising of breakthrough designated drugs, policy makers and regulators could implement additional content restrictions on consumer marketing. This might entail the FDA directing its Office of Prescription Drug Promotion to regulate the use of words such as “breakthrough” in addition to issuing guidance to manufacturers that assertions of “breakthrough designation” should be accompanied by descriptions of what the programme means. The FDA could study whether products with special regulatory designations are more likely to violate advertising standards and, if so, give them priority for assessment for issuing warning notices to broadcasters. Another option is to change the name of the programme to something that more clearly captures its meaning and is less likely to mislead, such as early potential programme.37
Since the FDA does not approve all advertisements before they air, and often reviews advertisements only after they have been broadcast,38 another option is to prioritise adverts for drugs with breakthrough designation for predistribution review or move to reviewing all advertisements before public dissemination. This could help reduce the prevalence of advertisements with misleading and confusing information.39 Such a policy would require increased funding, especially considering that issuing of warning letters has fallen in recent years.40 Policy makers could discourage drug advertising by eliminating federal tax deductions that manufacturers receive for advertising expenses. A more drastic approach would entail banning direct-to-consumer advertising for prescription drugs, as the American Medical Association has previously suggested.41
Aggressive lobbying by the pharmaceutical industry has helped blunt previous efforts at reform. However, recent legislative proposals aimed at regulating advertising content and tax revenue,4243 as well as congressional action on prescription drug pricing and the accelerated approval pathway, suggest renewed interest and political feasibility. In the meantime, policy makers and regulators should consider more proactive oversight of consumer advertising to ensure that patients are not misled by advertising of drugs approved with breakthrough therapy designation.
Key messages
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FDA’s breakthrough therapy designation is inaptly named and could lead physicians and patients to overestimate the benefit and strength of evidence of approved drugs
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Television adverts of these drugs sometimes use the word breakthrough and often emphasise uniqueness and high comparative value in misleading ways
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Regulators and policy makers should consider stronger content restrictions and more proactive regulation of direct-to-consumer pharmaceutical advertising
Footnotes
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Contributors and sources: NGP is a medical student whose research focuses on improving regulations concerning the approval, affordability, and marketing of pharmaceutical products. AM is interested in translational research, drug development, and FDA regulatory policy. JSR has expertise in regulatory science research. RR has a research and policy focus on the regulation of and access to health technologies. NGP wrote the first draft of this article. NGP and AM contributed to data collection. All authors contributed to the conceptualisation, edited drafts, and approved the final version.
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Competing interests: We have read and understood BMJ policy on declaration of interests and have the following interests to declare: RR receives research support through Yale University from Arnold Ventures as well as the Stavros Niarchos Foundation. She was a consultant for the ReAct-Action on Antibiotic Resistance Strategic Policy Program at Johns Hopkins Bloomberg School of Public Health funded by the Swedish International Development and Cooperation Agency (Sida). JSR receives research support through Yale University from Johnson and Johnson to develop methods of clinical trial data sharing, from the Medical Device Innovation Consortium as part of the National Evaluation System for Health Technology (NEST), from the FDA for the Yale-Mayo Clinic Center for Excellence in Regulatory Science and Innovation (CERSI) programme (U01FD005938), from the Agency for Healthcare Research and Quality (R01HS022882), from the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH) (R01HS025164, R01HL144644), and from Arnold Ventures. He was an expert witness in a qui tam suit alleging violations of the False Claims Act and Anti-Kickback Statute against Biogen that was settled September 2022.
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Provenance and peer review: Not commissioned; externally peer reviewed.