The development and marketing of drugs for the prevention or treatment of diseases can present opportunities for contributions by scientists, medical professionals, and other people in the healthcare industry. In the vast majority of instances, they do so with the best of intentions and the purest of motives. However, they may also be challenged by temptations to circumvent the controls that have been put in place by the regulatory agencies that we discussed in the previous module of this course. Breaking or “stretching” the rules can sometimes be rationalized based on humanitarian goals, such as the possibility of allowing broader and cheaper access to medicines for disadvantaged patients. At the other end of the spectrum, however, is the all-too-human desire for personal gain- either in wealth or status- that can sometimes be fulfilled by pursuing methods that compromise accepted legal or ethical standards. Regardless of the motivation, these abuses can result in threats to public health and welfare. In this module, we will examine some of the categories of violations that may be committed and how the law deals with them.
Promotion of Pharmaceutical Products
For most people, the drug development process is a black box that only enters into their sphere of consciousness at the stage known as Marketing. It is at this point that drug companies promote the use of their drug to the customers, the physicians who prescribe it and the patients who use it.
In the late 1950’s, the pharmaceutical industry was confronted with an attack led by the late Senator Estes Kefauver, Chairman of the Senate’s Antitrust and Monopoly Subcommittee. He accused the industry of the following abuses[i] :
(1) Patents sustained predatory prices and excessive margins;
(2) Costs and prices were extravagantly increased by large expenditures in marketing; and
(3) Most of the industry’s new products were no more effective than established drugs already on the market.
As a result of this campaign, public perception of the industry was transformed, as ”the image of life-saving ‘researchers in white coats’ was now contested by the one of greedy ‘reps in cars’”. [ii] The US Food and Drug Administration (FDA) responded by developing legislation and non-binding guidance that were intended to regulate the pharmaceutical industry’s promotional activities. This activity is now managed by the Office of Prescription Drug Promotion, or OPDP.
The OPDP and the Bad Ad Program
The OPDP is composed of two divisions: the Division of Professional Promotion and the Division of Direct-to-Consumer Promotion[iii]. The mission of the office is: “To protect the public health by ensuring that prescription drug information is truthful, balanced, and accurately communicated. This is accomplished through a comprehensive surveillance, enforcement and education program and by fostering better communication of labeling and promotional information to both healthcare professionals and consumers.”[iv]
OPDP reviewers ensure that the information in prescription drug advertising and promotional labeling is not false or misleading. This office works with the pharmaceutical industry and within the FDA by providing advice, education, and guidance. It may preview and provide comments on materials that are voluntarily submitted to them by sponsors, but this is not always required. After promotional materials have been published, OPDP will monitor them and enforce the relevant regulations. This monitoring may be done at its own discretion or in response to complaints by consumers. In addition, FDA has established a “Bad Ad” program, administered by OPDP, “to help raise awareness among healthcare providers about misleading prescription drug promotion and provide them with an easy way to report this activity to the agency.”[v]
Why Drug Makers May Break the Rules
A drug maker has only a relatively narrow time-frame during which it may recoup the expenses that it has put into developing its product and to generate profits. The primary limitation is the period of “patent exclusivity” during which a drug may only be sold under the approved brand name and only by the original manufacturer and patent holder. After this period is over, competitors may obtain approval to manufacture and to sell “generic” versions of the drug. While the original manufacturer may also obtain approval to market a generic version of the drug, competition assures that this is almost always going to be at a significantly reduced price with a much smaller profit margin. Patent protection is awarded for approximately 20 years. However, this period typically encompasses many years of pre-approval clinical testing and development. The length of this testing will vary depending on the number and durations of required trials which will, in turn, depend on the types of indications and populations for which the drug is intended to be used. In addition, the company must generally devote several years to optimizing the commercial manufacturing process and packaging. Thus, the period of effective patent protection after the drug is approved for marketing is actually closer to between seven and twelve years. This reduced window of opportunity for commercial profit provides one of the rationalizations that may tempt pharmaceutical companies to circumvent the regulations that impact the marketing of their products.
Types of Promotion
There are two general ways in which drugs are promoted: (1) advertising; and (2) promotional labeling. The FDA is authorized to oversee both of these methods by virtue of the Federal Food, Drug, and Cosmetic Act and other legislation.
Traditionally, drug companies have advertised prescription drugs only to doctors and pharmacists, typically through ads in professional journals. They may also publicize their products through oral communications between sales representatives and medical practitioners and through presentations at professional congresses. Although “Direct to Consumer”, or DTC, advertising had never been prohibited by federal law, companies did not generally promote drugs directly to the general public until the mid-1980s. We will say more about DTC advertising and its impacts later on in this course.
The other major marketing tool, promotional labeling, may take the forms of sales aids, brochures, mailings, and a wide variety of items that are imprinted with the name of the drug. The next time you go to your doctor’s office, look for a “Lipitor” clock or a “Nexium” coffee mug as common examples of these promotional devices.
Regulation of Drug Promotion
The guidelines governing promotional activities for prescription drugs are contained in the Federal Food, Drug and Cosmetic Act (FD&CA) with detailed rules defined in Title 21 of the Code of Federal Regulations Parts 201[vi] (Drug Labeling) and 202[vii] (Prescription Drug Advertising). These rules require that promotional materials:[viii]
o Are not false or misleading with regard to effectiveness, side effects, or contraindications. If the information were to be relied upon, it should not pose a significant public health risk;
o Reflect a fair balance between effectiveness vs. side effects and contraindications;
o Are consistent with the approved product labeling or package insert;
o Only include claims that are substantiated by adequate and well-controlled clinical studies. Claims of superiority over other treatments must be supported by data from head-to-head trials;
o Do not promote uses not contained in the product labeling, also known as “off-label use”; and
o Do not omit or minimize risks associated with the proper use of the drug. This includes overstating safety claims and dismissing warnings that appear on the label.
There are also constraints on the types of proprietary names that may be used, prohibiting the use of:
o a proprietary name that could lead to confusion with the proprietary name of a different drug or ingredient; or
o a “fanciful proprietary name for the drug or any ingredient in such a manner as to imply that the drug or ingredient has some unique effectiveness or composition, when, in fact, the drug or ingredient is a common substance, the limitations of which are readily recognized when the drug or ingredient is listed by its established name” viii. Thus, an ad for an analgesic that has aspirin as its active ingredient must not call itself “Zeropain” or claim that it contains a “super pain-relieving compound”.
While most offences relate to advertising drugs that are already on the market, OPDP also considers most pre-approval promotion of a new drug to be a violation unless there is no mention of safety, efficacy, or how to use the product.
How the Law in Enforced
The OPDP is empowered to enforce these regulations and impose penalties that are commensurate with the seriousness of the abuse. Tools that may be used in enforcement include the following:
- Notices of violation and advisory action letters: these serve to document formal notifications from the FDA that a violation has been identified. There are 3 main types of these notices[ix]:
o Untitled letter: an initial notification that FDA is aware of a violation of federal law that may allow the offender to come into compliance without further FDA action;
o FDA form 483: lists deficiencies found during an inspection of a pharmaceutical manufacturing facility;
o Warning letter: notifies the offender that action may be taken if the violation is not promptly and adequately corrected. These are issued to encourage voluntarily compliance and to establish that the offender has received prior notice of the violation. A warning letter may be issued if corrective action has not been taken to address issues identified in an untitled letter or a form 483.
- Consent decree or injunction: If the violations are brought the attention of the firm by way of a warning letter and they are not adequately resolved, FDA and the federal Department of Justice may file a formal complaint against the offending organization. The defendant in these cases will frequently agree to settle the matter through an FDA Consent Decree, also known as an injunction. Failure to comply with a Consent Decree may be considered grounds for contempt.[x]
- Criminal charges: violations of the FD&CA are civil offenses. However, repeated, intentional, and fraudulent violations can also be subject to criminal prosecution[xi].
Examples of Prohibited Types of Promotion
Off-label use
The term “label” in this context does not refer only to the physical label that is found on the vial, bottle, or box in which the drug is stored, but, more generally, to a specifically formatted summary of information about the drug that contains[xii]
- indications and usage;
- dosage and administration;
- a summary of safety and efficacy data;
- “black box” warnings that emphasize certain risks;
- contraindications;
- the most clinically significant known adverse drug reactions and how to treat and report them;
- drug interactions;
- use in specific populations;
- counseling information that should be shared with the patient.
Most of this material can be found in the drug’s package insert, which is a leaflet that is provided to practitioners and patients along with both prescription and over-the-counter medications. Information about the drug that is provided in the package insert, the container label, or any other literature that is provided by the manufacturer must be consistent with and limited to what has been authorized by FDA. Any deviation from this restriction is referred to as “off-label”.
In addition to the Food, Drug and Cosmetic Act, the government also enforces the prohibition against off-label promotion by bringing cases under the Anti-Kickback Statute[xiii], and the False Claims Act[xiv]. The prohibition against off-label promotion is intended to protect patients against the use of drugs in ways that have not been shown to be safe and effective. However, it is legal for doctors to prescribe the off-label use of approved drugs for indications that have not been approved by FDA. Drug companies may learn of new uses for their product from anecdotal evidence that may be provided by doctors or patients who use it off-label. They are, however, prohibited from sharing this information unless they have conducted controlled clinical investigations and have submitted the resulting data to FDA for review to secure approval for an expanded label. The costs- in time and money- of these activities may render this effort prohibitively expensive to make what may be only a minor change to their label. Thus, it can be attractive for drug companies to increase sales by promoting the drug for an unapproved use without doing the required investigations. Even if a manufacturer does not engage directly in off-label promotion, personal conversations, social media and similar informal methods of communication by sales representatives may lead to the dissemination of subjective data whose reliability has not been verified. Regardless of the intentions of the party who is sharing the information, this would be a violation of the rules. Thus, regulatory authorities have been faced with the need to amend their criteria for enforcement or even revise the laws to better suit the realities of today’s world[xv]. As another example, a common and often problematic practice has been for sales personnel to distribute to physicians medical literature that suggest that a drug may be useful in a certain unapproved scenario. In response, FDA issued a guideline[xvi] in 2009 that described clearly-defined circumstances under which manufacturers may distribute reprints of medical journal articles that describe off-label use of prescription drugs in response to unsolicited requests for information[xvii].
The agency has also found novel ways to clarify its interpretations of the regulations to make enforcement more straightforward. In one example, FDA has recently directed that claims of safety or efficacy that are not approved in the label will be considered a violation of the prohibition against “misbranding” if they are not supported by “scientifically appropriate and statistically sound” evidence[xviii]. In another illustration, FDA requires that a drug maker provide directions for the use of a drug for an intended indication. Since these directions would not have been approved in the case of off-label use, FDA may choose to pursue enforcement for the lack of adequate directions rather than for the absence of scientifically substantiated claims.[xix] There continue to be, however, many examples of regulatory actions that are based on unsubstantiated claims. Let’s take a look at a few of these.
One of the most common examples of unacceptable promotion is making claims about the attributes of a drug that are exaggerated or patently untrue- a practice commonly referred to as “false advertising”. Some examples of advertising claims that were based on non-existent or discredited clinical data are:
- the use of marijuana derivatives to treat or cure cancer[xx]
- orally administered pills or capsules to replace sunscreen[xxi]
- vitamin E supplements to provide alleged cardiovascular benefits[xxii]
- label claim that an algae supplement was “clinically proven” to boost memory[xxiii]
Omission or Minimization of Risks
Risks that are known to be associated with the use of a drug are required to be listed in the label and package insert, but drug manufacturers sometimes attempt to downplay the frequency or severity of these side effects when describing their product. The following is a list[xxiv] of some of the drugs whose sponsors received FDA warning letters in 2009/2010 for misleading advertising, including inadequate presentation of risks:
- Cymbalta (Eli Lilly):In a print ad showing a patient suffering from fibromyalgia-associated pain, information on risks- including an increased likelihood of suicidal thoughts- appeared on an adjacent page between unrelated advertisements.
- Kaletra (Abbott Laboratories):In a DVD testimonial for this AIDS drug by former basketball star Earvin “Magic” Johnson, there was no mention of life-threatening risks like pancreatitis, new-onset diabetes, and spontaneous skin hemorrhages.
- Treximet (GlaxoSmithKline):in internet ads for this migraine medication, risks only appeared in quickly scrolling text below the banner. These included heart attack, stroke, and gastrointestinal bleeding.
- Depakote ER (Abbott Laboratories):pharmacy flashcards promoting the drug for bipolar disorder did not prominently discuss known side effects, such as potentially fatal liver damage, pancreatitis, and brain and spinal cord birth defects.
[i] The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States
Marc-André Gagnon , Joel Lexchin http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0050001
[ii] Froud J, Johal S, Leaver A, Williams K (2006) Financialization and strategy: narrative and numbers. London and New York: Routledge
[iii] www.pharmaspective.com/2011/09/goodbye-ddmac-hello-opdp.html
[iv] https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm090142.htm
[v] https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/DrugMarketingAdvertisingandCommunications/ucm209384.htm
[vi] https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=201
[vii] https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=202
[viii] https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=202.1
[ix] https://fdaimports.com/fda_requirements/fda_enforcement/warning_untitled_letters_483s.php
[x] https://fdaatty.com/fda-consent-decree/
[xi] www.ehcca.com/presentations/pharmacongress12/fahey_pc1_2.pdf
[xii] https://www.medscape.com/viewarticle/566885_2
[xiii] 42 U.S.C. § 1320a-7b
[xiv] 31 U.S.C. §§ 3729, et seq.
[xv] www.bioworld.com/content/label-use-fine-line-between-illegal-promotion-and-useful-information
[xvi] https://www.fda.gov/regulatory-information/search-fda-guidance-documents/good-reprint-practices-distribution-medical-journal-articles-and-medical-or-scientific-reference
[xvii] pharmaceuticalcommerce.com/legal-regulatory/regulatory-focus-on-off-label-promotion-is-rising/
[xviii]FDA, Medical Products Communications That Are Consistent With the FDA-Required Labeling – Questions and Answers, Draft Guidance, at 8
(Jan. 2017).
[xix] https://www.fdli.org/2017/10/compounding-off-label-promotion-debate-fda-regulate-promotion-unapproved-drugs/
[xx] “FDA warns companies marketing unproven products, derived from marijuana, that claim to treat or cure cancer”, https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm583295.htm
[xxi] “Sunscreen Pills Are Dangerous Nonsense, According to the FDA”, fortune.com/2018/05/23/fda-sunscreen-pills-skin-cancer/
[xxii] https://www.law360.com/lifesciences/articles/1044969/9th-circ-revives-vitamin-e-labeling-row-over-heart-claims?nl_pk=539311f1-32f7-4a77-a8554ed78f7a795b&utm_ source=newsletter&utm_medium=email&utm_campaign=lifesciences
[xxiii] “CVS Deal Would Make Memory Of Supplement Class Action”, https://www.law360.com/articles/809099?scroll=1
[xxiv] https://www.forbes.com/2010/02/02/drug-advertising-lipitor-lifestyle-health-pharmaceuticals-safety_slide/#5844272cb246