US Pharm. 2011;36(12):46-48.
The First Amendment to the United States Constitution states, “Congress shall make no law respecting an establishment of religion, or prohibiting the free exercise thereof; or abridging the freedom of speech, or of the press; or the right of the people peaceably to assemble, and to petition the Government for a redress of grievances.”1 The focus here will be on the “freedom of speech” part of this 1791 addition to our Constitutional rights, with an emphasis on what has come to be known as “commercial speech” (e.g., marketing directed at potential consumers). Ironically, the U.S. Supreme Court first discovered the concept of separate but unequal forms of speech (commercial vs. individual freedoms) in a pharmacy case where the issue was “whether a State may completely suppress the dissemination of concededly truthful information about entirely lawful activity, fearful of that information’s effect upon its disseminators and its recipients.”2
The Commonwealth of Virginia had a statute that prohibited pharmacists from advertising prescription drug prices, providing that those who did would be guilty of being “unprofessional.” The Court held that the answer to this question was a very simple “No.”3 Thus, the statute was found unconstitutional, making it legal for pharmacies to advertise prices for goods and services. While this case has become binding precedent in thousands of others, commercial speech does not enjoy the nearly pure immunity of individual free speech.4
Off-Label Use and Promotion
With this background in mind comes the question: Do drug manufacturers have a right of freedom in commercial speech to market their wares over long-standing FDA prohibitions against promoting medications for so-called “off-label” purposes? An explanation of the terms might be helpful.
When a manufacturer develops a new drug or a new formulation to be administered differently than the original medication, the company must first submit a New Drug Application (NDA) to the FDA. The major question for any NDA is whether the drug is safe and effective for its intended purpose.5 That “intended purpose” is defined by the manufacturer in its NDA by describing what the medication is supposed to do based on a wealth of data from multiple trials and phases of research. Assuming that the NDA is granted, the drug manufacturer will have to label the drug with indications for use, dosages, administration schedules, contraindications, and a long list of other mandated information. In this scenario, if the manufacturer markets the drug for intended purposes with FDA approved labeling—i.e., “on-label” marketing—there is no problem.
However, the FDA does not have any authority to regulate the practice of medicine,6 meaning that prescribers may legally prescribe a drug for purposes not originally intended. Depending on which statistics are used, off-label prescribing occurs between 15% and 50% of the time.7,8 Even federal government reports and medical journal articles have confirmed that an estimated half or more cancer patients receive off-label drugs. This is because physicians and other health care professionals often times will recognize that a drug is useful for conditions not contemplated in the original FDA-approved labeling, usually well before a manufacturer may know about or identify these other uses.
If and when they do determine that an approved drug is safe and effective for unapproved (off-label) purposes, the manufacturers have a well-defined method of submitting additional data supporting this new use. They will seek to have a Supplemental New Drug Application (SNDA) approved by the FDA along with appropriate labeling changes. The major problem with this plan is that there is often a lag time, sometimes of several years, between the determination that a drug is safe and effective for what was an off-label use and the point when the FDA approves the SNDA, thus turning the new purpose into an on-label use. During this interval, manufacturers must be very careful about what the drug representatives who call on prescribers are allowed to say with respect to promoting off-label uses of the drug.
Under the Food, Drug, and Cosmetic Act (FDCA), manufacturers are prohibited from directly marketing a drug for a use other than the FDA-approved indication.9 The Food and Drug Administration Modernization Act of 1997 created a small but significant exception to the prohibition of off-label marketing that allows manufacturers to provide medical practitioners with off-label information but only in response to an unsolicited request.10 The “unsolicited request” has been stretched beyond reasonable interpretations in several cases, resulting in huge fines.
“Misbranding” Violations
In September 2007, Bristol-Myers Squibb (BMS) paid $515 million to federal and state governments in a civil lawsuit brought by the Justice Department.11 Cephalon, the maker of Actiq, was fined $425 million for illegal promotion of the drug in September 2008.12 In 2009, Pfizer agreed to the settlement of criminal allegation of marketing Neurontin for off-label purposes in the amount of $430 million.13 Another Pfizer unit, Pharmacia & Upjohn, pled guilty to accusations that company executives instructed over 100 salespeople to promote Bextra for all kinds of pain relief even though it was only approved for the relief of arthritis and menstrual discomfort. The felony counts resulted in what was the largest criminal fine in U.S. history—$1.19 billion.14 The company also paid fines of an additional $1 billion to settle civil cases for off-label promotion of the drug. That limit was exceeded later the same year by Eli Lilly & Co., the largest U.S. psychiatric drug maker, when it pled guilty and paid $1.42 billion in fines and penalties to settle charges that it had for at least 4 years illegally marketed Zyprexa, a drug approved for the treatment of schizophrenia, as a remedy for dementia in elderly patients. In five company-sponsored clinical trials, 31 people out of 1,184 participants died after taking the drug for dementia—twice the death rate for those taking a placebo.15
Since May 2004, Pfizer, Eli Lilly, BMS, and four other drug companies have paid a total of $7 billion in fines and penalties.16 Every one of these companies has admitted in court that it marketed medicines for unapproved uses. All told, in the last 15 years, drug manufacturers and distributors have paid $8.7 billion to the U.S. government and the states to settle charges brought under the False Claims Act for wrongfully marketing a drug for an off-label use.17 Doing so is deemed to be “misbranding” in violation of the FDCA. These statistics do not include the $950 million that Merck & Co. agreed to pay on November 23, 2011, when the company pled guilty to illegal promotion and governmental deception concerning the safety of Vioxx, which was removed from the market in 2004.18
It should not be that difficult to understand why a consortium of drug manufacturers have mounted a political and judicial campaign to overturn the decades old FDA ban on discussing off-label uses when not specifically asked to do so. There have been numerous cases filed and decided that have questioned this ban on communicating the manufacturers’ knowledge on how to use a product safely, albeit without the FDA’s approval.
One recent case proceeding through a federal court in New York is particularly demonstrative of the problem. Alfred Caronia, a former salesman for the company now known as Jazz Pharmaceuticals, is alleged to have violated the law when he promoted the narcolepsy drug Xyrem to physicians to treat other forms of drowsiness and chronic fatigue.19 He was convicted by a jury in a lower court on a criminal charge of misbranding.20 Paradoxically, the FDA approved Xyrem for “excessive daytime sleepiness” very shortly after what was at the time an off-label promotion.
The chances of reversing his conviction might be very strong given the relatively recent decisions concerning data mining. This is the process whereby third-party companies contract with pharmacy organizations to search their patients’ computer records for prescriber-identifiable data (i.e., practitioners’ prescribing habits) while supposedly removing patient-identifiable information from the collected data to avoid committing any violations of the Health Insurance Portability and Accountability Act (HIPAA).21 The majority opinion in that case was that “speech used in drug marketing is a form of expression protected by the Free Speech Clause of the First Amendment.”22 According to an article published about Mr. Caronia’s legal troubles, “Big drug makers, emboldened by decisions of the high court, have jumped into the Caronia appeal. In a ‘friends of the court’ (amicus) brief, and in other legal actions around the U.S., the industry is challenging the FDA on the rules more forcefully than before.”23 One of those briefs argued that “off-label use is a necessary and common practice,” and that applying the FDA’s off-label rules to Mr. Caronia’s alleged conduct “appears to be constitutionally indefensible.”
The FDA argues that the ban on promoting off-label uses of a drug is grounded in the principle of patient safety. It claims that unless a drug has been proven to be safe and effective for a particular use, it could be dangerous, even lethal, to administer the drug for an off-label purpose.
Analysis
There can be no question that the FDA is following a strict legal, if not moral, imperative in carrying out this duty. The real quandary, however, is whether that mission can be achieved without preventing manufacturers from sharing new knowledge that did not exist during the original NDA process. Although the fines paid by drug companies over the last 15 years may sound staggering, it appears that in drug cases at least, crime does pay. The profits, revenues, and increases in stock prices flourished during the time these fines were being collected from nearly all the pharmaceutical companies. A skeptic might even conclude that the drug companies figure the off-label fines and penalties are just a cost of doing business, and that they will keep on doing what they do until the disciplinary sanctions cost more than the revenue earned from these practices.
It’s a shame that this country cannot find a more realistic solution to a very serious issue. The balance of power will have to change, as will the procedures for amending FDA labeling requirements to eliminate the lag time between an original NDA and an SNDA when the evidence is clear and convincing that new FDA unapproved uses are safe and effective. It will no doubt require a Supreme Court decision to get to this point, and that may not happen for several years.
In the meantime, it is not wrong or illegal for pharmacists to talk to patients or prescribers about off-label uses of drugs as long as there is no pressure from a drug manufacturer to do so. In fact, it could be a therapeutic or economic enhancement if pharmacists engaged in this practice more often. If you read an article in a newspaper or a scholarly journal about a new but unapproved use for a medication, do not hesitate to share that information with prescribers and patients. This could be a golden opportunity to educate yourself and your community about innovative uses of drugs.
REFERENCES
1. Bill of Rights. U.S. Constitution. Cornell University Law School. www.law.cornell.edu/
2. Virginia State Pharmacy Board v. Virginia Citizens Consumer Council, 425 U.S. 748 (1976).
3. Virginia justified its enactment of the regulation on the grounds of maintaining the professionalism of pharmacists, asserting that aggressive price competition among pharmacists would make it difficult for them to provide proper professional services. The author of the majority opinion, Justice Harry A. Blackmun, responded that while regulation of the pharmacy profession was both necessary and within the prerogative of the several states through their police power, the statute promoted consumers’ ignorance, effectively keeping them in the dark about prescription drug prices. Blackmun dismissed this rationale as paternalistic, saying that if consumers had sufficient access to information regarding drug pricing and availability, it would only serve to aid them in their decisions about choosing a prescription drug supplier. Id at 770.
4. Ohralik v. Ohio State Bar Association, 436 U.S. 447 (1978).
5. If a drug formulation is already on the market with an NDA, the reformulation is usually deemed to be a “new drug” and therefore subject to the same scrutiny that was used to approve the original formulation.
6. Joranson DE. Guiding principles of international and federal laws pertaining to medical use and diversion of controlled substances. Pain & Policies Study Group. 1993. www.painpolicy.wisc.edu/
7. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166:1021-1026.
8. Bazzano A, Mangione-Smith R, Schonlau M, et al. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9:81-88.
9. USC 21 §§301-97.
10. 21 USC §360aaa-6.
11. Bristol-Myers Squibb to pay more than $515 million to resolve allegations of illegal drug marketing and pricing. Department of Justice. September 28, 2007.
www.justice.gov/opa/pr/2007/
12. Biopharmaceutical Company, Cephalon, to pay $425 million & enter plea to resolve allegations of off label marketing. Department of Justice. September 29, 2008. www.justice.gov/opa/pr/2008/
13. Evens D. Pfizer broke the law by promoting drugs for unapproved uses. Bloomberg. November 9, 2009. www.bloomberg.com/apps/news?
14. See Note 13, supra.
15. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA. 2005;294:1934-1943.
16. See Note 13, supra.
17. Burton TM. The free speech pill: drug firms see opening to push for end to off-label marketing ban. Wall Street Journal. November 3, 2011. http://online.wsj.com/article/
18. Hobson K. Merck to pay $950 million to settle Vioxx marketing charges. Wall Street Journal. November 23, 2011. http://online.wsj.com/article/
19. A First Amendment showdown in the Second Circuit. Drug Device Law. May 7, 2010. http://druganddevicelaw.
20. See Note 17, supra.
21. Vivian JC. Last words: data mining is legal. US Pharm. 2011;36(8):69-74. www.uspharmacist.com/content/
22. Sorrell v. IMS Health Inc., Slip Op No. 10-779, June 23, 2011. www.supremecourt.gov/opinions/
23. See Note 19, supra.
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