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HOW BIG PHARMA’S OFF-LABEL MARKETING LEADS TO MASS TORT CLAIMS:
THE LEGAL AND ETHICAL DIMENSIONS OF OFF-LABEL
PROMOTION AND THE WAR AGAINST DEFECTIVE DRUGS AND MEDICAL DEVICES

TABLE OF CONTENTS

I. Introduction
II. Off-Label Prescription and Promotion: A Background
III. History of FDA’s Policy Decisions
IV. The Approval Process for New Drugs

A. Exceptions for Drugs
B. Marketing of Drugs
C. Pre-Market Clearance Process of Medical Devices..
D. Exceptions to Class III Devices
E. Marketing Approval

V. Potential Claims for Violations of Off-Label Promotional Use

A. Fraud on FDA
B. Fraudulent Misrepresentation
C. Failure to Warn
i. Overpromotion as a Defense To Failure-to-Warn
D. False Claims Act
E. RICO
F. Negligence Per Se Violations of the FDCA

VI. General Defenses to Off-Label Promotions Claims

A. The Learned Intermediary Doctrine

VII. Arguments Surrounding Off-Label Promotion

A. Freedom of Speech vs. Incentive for Profit
B. Safety, Efficacy, and Mistrust
C. Proof of Mistrust and Enforcement of Violations

VIII. Landmark Cases Lead the FDA Towards Easing Off-Label Promotion
Restrictions:
A. Washington Legal Foundation, the FDCMA, and Good Reprint
Packages Guideline

a. U.S. v. Caronia
B. United States v. Harkonen
C. Where We Are Today

1. Introduction

The legal and ethical dimensions discussed in this article will focus on the risks and liabilities among three relationships: the manufacturer-doctor relationship; the doctor-patient relationship; and one relationship that is somewhat disconnected, the manufacturer-patient relationship. The point of disconnection in the manufacturer-patient relationship may be understood on a visual basis when all of the players are viewed on a continuum, with the manufacturer on one end, the patient on the opposite end, and the doctor— who is directly involved with both—in the middle.

The two main sources of strain within these relationships originates from the Food and Drug Administration (FDA) and the right of free speech that is asserted by pharmaceutical companies when they are promoting their off-label products. Notably, Big Pharma has won an important battle regarding its right to market off-label products by leveraging our precious right to freedom of speech.  It also should be noted that the underlying motivation of promoting off-label drugs and medical devices points less towards safety, efficacy, and availability, and more towards profits.

Ultimately, this article makes the recommendation that the FDA re-introduce a similar version of its prior prerequisites to manufacturers who promote off-label drugs and medical devices: the FDA should be required to review all off-label materials intended to be submitted to prescribing physicians on a pre-approval or trial basis. Past FDA policies had the effect of a general rule that off-label materials sent to physicians was a violation.  In fact, this requirement was strongly imposed upon them. However, successful court battles by manufacturers asserting freedom of speech claims turned the tables in their favor. Today, the exception is now the general rule, as manufacturers may send materials on off-label products with significantly less restrictions. This is the “new normal.” Significantly, record-setting criminal fines of more than $1 billion for violations and the increase in mass tort Multidistrict Litigation (“MDL”) throughout the country.  Clearly, the FDA’s current position is demonstrative of a failed effort to fight fraudulent promotion of unsafe products.

A new approach could allow the Agency , as well as unsuspected patients who have not been warned of the serious and fatal complications often associated with off-labels, to win an important battle in the war against defective drugs and medical devices, and take advantage of the lost opportunities by the FDA to provide needed practical guidance.


II. Off-Label Prescription and Promotion: A Background

Before drugs and devices are approved by the FDA for general use, they undergo through clinical trials (also called “research studies”) to determine how well they comport with safety and efficacy.1 Specifically, the trials must prove that the drug: (1) works to treat a particular medical condition; (2) works the way in which it is expected; and; (3) is safe when used as instructed. 2

Originally, the FDA focused solely on safety; however, after realizing that even snake oil could be safe, the agency added efficacy to its threshold of approval.3 Following approval for safety and efficacy, the FDA works with the drug or device manufacturer to develop the “label.”4This “label” does not refer to the “label” on the side of a prescription bottle or medical device package5 . Rather, it is a report that provides information about the drug or device, such as the conditions it is approved to treat (“indications”) and dosage amounts.6

Drugs and medical devices may be used for purposes that are not approved, provided they are approved for some type of treatment.7 Those that are administered contrary to the FDA- approved label are called “off-label.”8 Types of off-label drug prescription include administering a drug for a different disease or a different manner of ingestion.9 However, unbeknownst to many patients, physicians do not have strict legal limitations when prescribing off-label. In fact, doctors may prescribe FDA-approved drugs and medical devices in any manner they believe is medically suitable, and may do so without FDA oversight.10 This is because the FDA lacks the authority to oversee doctors in this manner. In particular, the Federal Food, Drug and Cosmetic Act (FDCA) states, “Nothing in this Act shall be construed to limit or interfere with the authority of a healthcare practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate healthcare practitioner-patient relationship.”11 In essence, off-label use “is an accepted and necessary corollary of the FDA’s mission to regulate in this area without directly interfering with the practice of medicine.”12 This policy, which originates from the 1938 Food, Drug, and Cosmetic Act and is known as the “practice-of-medicine exception,” says that “once a drug is approved for marketing, FDA does not generally regulate how, and for what uses, physicians prescribe that drug . . . [and a] physician may prescribe a drug for uses or in treatment regimens or patient populations that are not listed in the FDA-approved labeling.”13

Off-label prescriptions are commonly pursued for non-experimental purposes, and the medical community is rife with examples that demonstrate their highly effective uses.14 Arguably, the most notable off-label use of a prescription drug could be that of Pyrimethamine, Famciclovir, and Ganciclovir, which are used for the treatment of AIDS, a condition which is treated with nearly 100% off-label prescriptions.15 This is a significant statistic that must be underscored. If an average of 40% of all prescriptions are off-label, it is not a great leap of logic to suggest that 40% of all revenues and profits come from off-label prescription. This figure cannot be ignored by corporate executives reviewing cash flow and profit-and-loss statements, especially when designing strategic approaches to market the medications they have developed.

What may be more eye-opening is that doctors generally do not need to disclose that the drug or medical device has been prescribed for an off-label purpose during an informed consent discussion with the patient.16 Typically, a doctor is bound to discuss the potential complications associated with a drug or device.17 Yet, that is not necessarily the case with off-labels. There are two approaches states apply to the question of whether a doctor should provide the patient with information about the potential side effects, complications, benefits, and history.18 The majority rule is the “reasonable patient standard,” which allows a jury to determine “whether a reasonable patient would have regarded the information as important.”19 Notably, expert testimony is not required here because there is no such thing as an expert-reasonable-patient; it is an illusory figure.20 On the other hand, the minority approach applies an “actual patient standard,” which is a subjective approach that gives more weight to the true patient.21

Notwithstanding, pharmaceutical companies have a history of rigid restrictions when promoting off-label drugs and medical devices. For example, marketing drugs for unapproved purposes is forbidden in that it prohibits doctors and patients from making unbiased and informed decisions.22 This is based upon the FDA’s charge of regulatory oversight of protecting the general public from profit-focused pharmaceutical companies.23 If a non-FDA-approved use of a drug is included on a label, it is deemed “misbranded” and the manufacturer faces potential criminal and civil penalties.24 It is also a violation to release an “adulterated” product, one that is categorically problematic with respect to the product’s degree or level of toxicity, cleanliness, or sterility, how well it conforms to its label in terms of composition of ingredients and strength, and any issues with manufacturing quality control.25 Notably, a medical device may be deemed both adulterated and misbranded if promoted for a used not approved or cleared by the FDA.26

 

  • 1American Cancer Society, http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/chemotherapy/off-label- drug-use (last visited January 3, 2016). Go Back
  • 2Id. Go Back
  • 3Significant Dates in U.S. Food and Drug Law History, U.S. Food and Drug Administration,
    http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ ucm128305.htm (last visited January 3, 2016). In 1962, the Kefauver-Harris Drug Amendments were enacted to ensure drug efficacy, and is the first instance in which manufacturers had to demonstrate the effectiveness of their drugs and medical devices prior to promotion. Go Back
  • 4 Steven R. Salbu, Off-Label Use, Prescription, and Marketing of FDA-Approved Drugs: An Assessment of Legislative and Regulatory Policy, 51 Fla. L. Rev. 181, 186 (1999). Go Back
  • 5Id. Go Back
  • 6Id. This information is then made available to medical professionals through publication in the Physician’s Reference Desk. Id. Go Back
  • 7Id., at 189. Go Back
  • 8Id. Go Back
  • 9Id. An example of off-label medical device prescription could be the implantation of a device for a purpose other than the reasons it was approved. Id. Other examples of general off-label use include treatment of a different “patient population, or providing a drug combination other than as indicated in the label.” Wash. Legal Found. v. Friedman, 13 F. Supp. 2d 51, 55
    (D.D.C. 1998). Go Back
  • 10Donald C. Arbitblit, Wendy Fleishman, The Risky Business Of Off-Label Use, Assoc. of Trial Lawyers of America, 41 – MAR Trial 46, citing 21 U.S.C. §§ 301-00(2000); see 78 CONG. REC. 3, 2728-29 (1934) (statement of Sen. Copeland). Go Back
  • 11 See Federal Food, Drug and Cosmetic Act, ch. 675, 52 Stat. 1040 (1938) (codified at 21 U.S.C. § 396 (1997).Go Back
  • 12 Buckman Co. v. Plaintiff’s Legal Comm., 531 U.S. 341, 350 (2001).Go Back
  • 13 Promotion of Unapproved Drugs and Medical Devices, Hearing Before the Senate Committee on Labor and Human Resources. 104th Cong. (1996) (statement of William B. Schultz, Deputy Commissioner for Policy, Food and Drug Administration, Dept. of Health and Human Services). Go Back
  • 14 Manufacturer Liability for Off-Label Uses of Medical Devices, L.A. Law, April 2008, at 18. Go Back
  • 15 Richard C. Ausness, “There’s Danger Here, Cherie!”: Liability for the Promotion and Marketing of Drugs and Medical Devices for Off-Label Uses, 73 Brook. L. Rev. 1253, 1254-1255 (2008). Cancer treatment is another common example, as 8 out of 10 doctors prescribed off-label medications to cancer patients. Id., at 193. Other studies indicate that chemotherapy drugs are prescribed for off-label use approximately 50% of the time. Id., at 194. Go Back
  • 16 Arthur Shorr, Hospital Negligence: Legal and Administrative Issues, Use of Off-Label Drugs and Medical Devices § 5:17, Ch.
    5Patient Rights. Go Back
  • 17 Id. Go Back
  • 18 Id. Go Back
  • 19 Id. Go Back
  • 20 Id. Go Back
  • 21 Id. Go Back
  • 22 Katherine A. Helm, Protecting Public Health from Outside the Physician’s Office: A Century of FDA Regulation from Drug
    Safety Labeling to Off-Label Drug Promotion, 18 Fordham Intell. Prop. Media & Ent. L.J. 117 (2007) 121-22. Go Back
  • 23 Id. Go Back
  • 24 Risky Business, pp. 47-48; See also (FD&C Act § 502(f); 21 U.S.C. § 352(f); 21 CFR 201.100(c)(1)). Go Back
  • 25 21 U.S. Code § 351. Go Back
  • 26 U.S. Dept. of Health and Human Services, Food and Drug Administration, Office of the Commissioner, Office of Policy, Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved new Uses of Approved Drugs and Approved or Cleared Medical Devices, 2009, hereinafter ‘Good Reprint Practices.Go Back

 


III. History of FDA’s Policy Decisions

The FDA’s policy is reflective of the background of the 1938 Federal Food, Drug, and Cosmetic Act (FDCA) and its amended 1997 Food and Drug Administration Modernization Act (FDAMA). The FDA initially focused on safety, then added the element of efficacy in 1962.27 The agency’s oversight authority is expressed in the Code, with the mandate that new uses for drugs outside of their scope of approval are to be tested and cleared by the FDA28 .The FDAMA provided strict limitations on the distribution of off-label use of drugs and medical devices, which included the following:

  • The drug manufacturer must provide the FDA with an application for new-drug use;
  • Any dissemination of data must not be abridged, false, misleading, or pose a significant health risk;
  • All information containing clinical research must be based upon the manufacturer’s work;
  • The drug manufacturer must provide the FDA with any data it will provide to doctors, and include prominent disclaimers clearly stating the drug’s non-FDA approved status regarding any off- Label prescription.29

Based on this construction, the FDA’s policies and restrictions arguably forbid drug manufacturers from distributing off-label uses. The FDAMA’s strict limitations on off-label marketing found in § 401 expired in 2006. New guidance was announced on January 13, 2009, when the FDA released the Good Reprint Practice Guidelines that offered the FDA’s “current thinking” on how manufacturers may disseminate off-label uses of drugs and devices to physicians.30 Interestingly, these guidelines are non-binding and have no force of law. Thus, the guidelines without the standard note-and-comment format found in enacted legislation and promulgated regulations do not serve as a reliable source of direction for manufacturers. Also, when a manufacturer pursues off-label drug promotion within its guidelines, it need not provide a supplemental new drug application. Finally, the manufacturer is not required to apply to the FDA for approval of off-label promotional materials prior to introducing the content to prescribing physicians, as this restriction is no longer in effect.

Given this background of toothless guidelines, it begs the following question: why do restrictions upon manufacturers for distribution of off-label drug and medical device prescriptions exist? The answer is twofold. First, they cannot be trusted to comply with federal or state guidelines regarding off-label marketing because they generate enormous sales from off-label revenue streams.31 Second, drug manufacturers have historically been motivated to support the medical community in pursuing reimbursement for such uses.32 The initial problem with reimbursement is that off-label use is not reimbursable by private insurance companies, such as Cigna, United HealthCare, or public health care programs like Medicare and Medicaid.33

 

  • 27 Significant Dates in U.S. Food and Drug Law History, U.S. Food and Drug Administration, http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ ucm128305.htm (last visited January 3, 2016). Go Back
  • 28 21 U.S.C.A. § 355. This process starts with the manufacturer submitting a New Drug Application (“NDA”). Once approved, the manufacturer proceeds through the first phase of the NDA process, which typically entails animal testing and corresponding
    toxicity research. Ausness, supra note 19, at 1256. This is followed by clinical trials on humans. 21 C.F.R. § 314.50 (2007). Upon completion of these two phases, the manufacturer submits the updated NDA to the FDA that details “the drug’s ingredients,
    detailed chemical information, detailed biological information, summaries of clinical testing results, a summary of the risks and benefits of the drug, an environmental impact statement, marketing history, and proposed labeling.” Id.Go Back
  • 29 21 U.S.C. § 360aaa(b) (2000).Go Back
  • 30 Good Reprint Practices, supra note 27.Go Back
  • 31 Ausness, supra note 19, at 1253.Go Back
  • 32 id. Go Back
  • 33 id. Go Back

 


IV. The Approval Process for New Drugs

Pursuant to the FDCA, a “new drug” must be approved by the FDA prior to being introduced into commerce.34 This starts with the manufacturer submitting a New Drug Application (“NDA”).35 Once approved, the manufacturer proceeds through the first phase of the NDA process, which typically entails animal testing and corresponding toxicity research—followed by clinical trials on humans.36 Upon completion of these two phases, the manufacturer submits the updated NDA to the FDA that details “the drug’s ingredients, detailed chemical information, detailed biological information, summaries of clinical testing results, a summary of the risks and benefits of the drug, an environmental impact statement, marketing history, and proposed labeling.”37

Provided the drug obtains approval by the FDA, the labeling information follows. “The FDA requires that a drug’s label include information necessary for safe and effective use, warnings, precautions, clinical pharmacology, indications, contraindications, and information about adverse reactions.”38 FDA-approved drug labels, geared for physician and medical staff use, is provided in the Physician’s Desk Reference and enclosed within the medication’s packaging.39

A. Exceptions for Drugs

In the event that an individual is presented with a life threatening situation, there is an emergency use exemption available that permits the prescription of an Investigational New Drug (IND).40 This exemption is defined as “the use of an investigational drug or biological product with a human subject in a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval.”41 The IRB has the authority to approve, disapprove, and modify research on IND’s.42

B. Marketing of Drugs:  The Gateway That Leads to Mass Torts

The FDA’s Office of Prescription Drug Promotion oversees the marketing of prescription drugs, including television, radio, print, and online advertising, as well as materials provided to physicians and patients by pharmaceutical sales representatives.43 Company marketing materials are to be provided to the Office contemporaneous with its original dissemination of publication.44   

C. Pre-Market Clearance Process of Medical Devices

One avenue that a manufacturer may pursue in order to get a medical device on the market is by pursuing a 510(k) clearance.45 This pre-market submission to the FDA is a demonstration by the manufacturer that a device is minimally as safe and effective – or substantially equivalent – to a device that is legally marketed, which is not subject to pre-market approval.46 Companies wishing to obtain clearance of medical devices must refer to the Medical Device Amendments of 1976 (”MDA”), which divides devices into three classes in order to properly regulate them.47

Class I is for devices that must abide by the FDA’s “general controls” guidelines.48 Class II is for devices in which “the general controls by themselves are insufficient to provide reasonable assurance of the safety and effectiveness of the device.”49 Class III is for devices that: (1) lack sufficient data to determine whether the general controls and special controls provide reasonable assurance of safety and efficacy; and (2) are for life sustaining-based, impairment-based, or have unreasonable risk of illness or injury.50

Class III devices also have strict guidelines. The device maker must complete the following:

  • A Pre-market Approval Application prior to introducing it into interstate commerce.
  • A complete detail of safety and effectiveness of the device.
  • A complete detail of what components, properties, and how the device operates.
  • A complete detail of manufacturing facilities, controls, methods, processing, packaging and implanting procedures, where necessary.
  • Any additional information discussing safety and efficacy evaluations that should be known or that should reasonably be known.
  • Proposed labeling for the device.51

D. Exceptions to Class III Devices

There are three general exceptions to pre-market approval: (1) in the event the device was marketed before the MDA was passed and contemporaneously, there was no requirement for pre-market approval;52 (2) if a “substantially equivalent” predecessor device existed prior to the MDA,53 and; (3) when human testing on the device is involved under an “Investigational Device Exemption.”54

E. Marketing Approval

Another avenue a manufacturer may pursue to legally market a medical device within the United States is to submit a Pre-market Notification (PMN) under § 510(k) of the FDCA55. Here, the manufacturer must notify the FDA within 90 days of any intent to promote the device56. This allows accurate identification and classification of new, first-time introduction of devices that are entering the marketplace, as well as those being reintroduced with major modifications such that safety and efficacy are affected.57

 

  • 34 21 U.S.C. § 355. Go Back
  • 35 Id. Go Back
  • 36 Ausness, supra note 19, at 1256. Go Back
  • 37 21 C.F.R. § 314.50 (2007). Go Back
  • 38 See Ausness, supra note 19, at 1257. Go Back
  • 39 Gregory Conko, Hidden Truth: The Perils and Protection of Off-Label Drug and Medical Device Promotion, 21 Health Matrix 149, 162 (2011). Go Back
  • 40 21 CFR 56.102(d). Go Back
  • 41 Id. The acronym IRB stands for Institutional Review Board, which is an FDA comprised committee that oversees biomedical research in order to assure that the safety, welfare and rights of human test subjects are protected. Food and Drug Administration, Emergency Use of an Investigational Drug or Biologic, http://www.fda.gov/RegulatoryInformation/Guidances/ucm126491.htm (last visited January 3, 2016). Go Back
  • 42 Id. Go Back
  • 43 Amy Toscano, Food and Drug Administration, Office of Prescription Drug Promotion, Regulation of Prescription Drug Promotion, 2013, http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM361326.pdf (last visited January 3, 2016). The Office receives its regulatory authority from 21 CFR 314.81(b)(3) Go Back
  • 44 Id. Go Back
  • 45 21 CFR § 807.92(a)(3). Go Back
  • 46 Id. Go Back
  • 47 Id. Go Back
  • 48 Id. Go Back
  • 49 Id. Go Back
  • 50 Id. Go Back
  • 51 21. S.C.A. § 360c. Go Back
  • 52 21 U.S.C. § 360e(b)(1)(A). Go Back
  • 53 21 U.S.C. § 360e(b)(1)(B). Go Back
  • 54 21 U.S.C. § 360(g). Go Back
  • 55 21 U.S.C § 360e. Go Back
  • 56 Id. Go Back
  • 57Off-Label Use of Medical Devices, 125 Am. Jur. Trials 1 (Originally published in 2012).Go Back

 


V. Potential Claims for Violations of Off-Label Promotional Use

There are many claims that apply to violations of the FDA’s off-label marketing guidelines. These claims have generated many mass tort cases, and can implicate federal and state laws that impose civil and criminal violations.

A. Fraud on FDA

When a manufacturer makes a material misstatement to the FDA that results in a pre-market approval, and the drug or device subsequently injures an individual, a “fraud on the FDA” claim may arise 58. According to a fraud on the FDA claim, “but for” the fraudulent marketing of a product a person’s injuries would not have occurred, and the manufacturer is thus liable regardless of whether the product was defective 59. This is traditionally a federal claim, and the FDA’s policy is that such claims remain under its exclusive authority, thus preempting state laws and civil litigants 60. Circuit Courts, however, had been split over whether such claims were preempted by the FDA until Buckman Co. v. Plaintiff’s Legal Committee 61. There, the plaintiff’s asserted that manufacturer AcroMed Corporation and its consultant, Buckman Company misled the FDA by obtaining clearance for fixation implant devices (“screws”) as “substantially equivalent” devices to be used in leg and arm bone surgeries62. In reality, the manufacturers in Buckman intended to market the screws primarily as spinal implant or fusion devices63. In effect, the manufacturers evaded the lengthy and expensive pre-market approval process.

B. Fraudulent Misrepresentation

Patients have also pursued claims against manufacturers for fraudulent misrepresentation. This cause of action requires six elements be proven by a clear and convincing standard: (1) a representation; (2) which is material to the transaction at hand; (3) made falsely, with knowledge of its falsity or recklessness as to whether it is true or false; (4) with the intent of misleading another into relying on it; (5) justifiable reliance on the misrepresentation; and (6) the resulting injury was proximately caused by the reliance 64. The anti-depressant medication Zoloft is illustrative of such a claim, and Miller v. Pfizer Inc. (Roerig Division)65 demonstrated the difficulty of establishing the elements of reliance and causation with such assertions. Here, the plaintiff’s defective marketing action was based upon the assertion that the manufacturer had “gone to great lengths to reassure doctors that the violence and suicide problems that they ha[d] heard about, mainly with its chief competitor Prozac, would not occur with Zoloft, and to assuage patient’s concerns over the initial adverse effects which are frequently harbingers of tragedy.”66 Evidence supporting this claim came from a Pfizer employee who “advised the representatives to communicate information about Zoloft to high-prescribing physicians and told them not to discuss suicide unless a physician asked about it.”67 If someone did inquire about the suicide risks, they were instructed to reassure them of Zoloft’s safety by stating that the drug had a low risk of suicide.68

Unfortunately for the plaintiffs, establishing the elements of reliance and causation proved to be the Achilles heel in their action. The United States District Court in Kansas granted Zoloft a partial summary judgement, and on two of the four claims held that (1) the prescribing physician did not rely on supposed material misstatements by Zoloft, and (2) the plaintiffs did not show medical causation.69

C. Failure To Warn

Manufacturers of drugs and devices have a duty to provide adequate warnings regarding inherent dangers associated with the normal use of their products that are outside the scope of knowledge of an ordinary user 70. In Knowlton v. Deseret Medical, Inc. 71, a plaintiff went into heart surgery in which a device composed of a catheter-and-needle combination was used 72. The special catheter, called an Intracath, was used off-label to transfer Nitroprusside (Nipride) to the patient’s heart73. However, the drug leaked from the catheter, made contact with the patient-victim’s chest and abdominal walls, and resulted in “extensive and intensive chemical burns 74. The trial court found in favor of the plaintiff regarding the manufacturer’s failure to warn claim, and the First Circuit Court of Appeals affirmed 76. Specifically, the trial court held that FDA approval for the device was for venipunctures, which is when a needle goes into a vein 77. Yet, evidence showed that the manufacturer of Intracath knew that its product was being used as an off-label vehicle to transport drugs during heart surgery 78. Moreover, corporate insiders admitted their knowledge of the high risk involved in such procedures because the product’s tubing could be sliced or otherwise compromised under these surgical conditions 79. The court also held that a reasonably prudent cardiovascular surgeon would have been unaware of the inherent danger involved in such a procedure, thus recognizing the valid failure-to-warn claim.80

i. Overpromotion As A Defense To Failure-to-Warn

It is possible for a plaintiff to still maintain a failure-to-warn claim in the event the drug or device maker “diluted the effect of the warning” 81. A common example is that of a pharmaceutical sales representative making inaccurate statements about FDA-approved warnings within the product’s label. In this instance, anyone with a financial or beneficiary tie with the pharmaceutical company would be equally as liable. However, courts are split on the viability of such a claim when the physician understands that the representative’s comments are contrary to the label’s warnings 82 Love v. Wolf 83.

In Love v. Wolf, a doctor prescribed chloromycetin, an antibiotic frequently used for off-label purposes 84. The prescription was refilled several times by the patient, who was provided the medication to treat a gum infection and subsequently suffered severe a plastic anemia 84. This is a condition in which the bone marrow fails to generate enough red blood cells. Meanwhile, “Letters were dispatched intended to reach all physicians in the United States stating these warnings in great detail 85. The warning letters to doctors were considered “over promotion,” and that prevented use of the defense from the learned intermediary doctrine 86, an exception to the duty to warn that many courts have recognized in situations where the product is recommended or prescribed to the consumer by a learned third party, such as a physician. This is discussed in detail below in Section VI-A.

D. False Claims Act

The False Claims Act offers an additional source for fraud-based claims. Courts have defined such claims as “a demand for money or for some transfer of public property 87. The purpose of the Act is to reduce “fraudulent claims” by applying liability to those who defraud the government 88 one of these violations. Under the Act, liability arises when an individual “knowingly presents, or causes to be presented, to the United States Government a false of fraudulent claim for payment or approval”; when the person “knowingly makes, uses, or causes to be made or used, a false record or statement to get a false or fraudulent claim paid or approved by the Government;” or; when a person “conspires to commit” one of these violations 89. Liability could include damages between $5,000 and $10,000 for each false claim provided to the government 90. Under the Act, “knowingly” is defined as any individual who “(1) has actual knowledge of the information; (2) acts in deliberate ignorance of the truth or falsity of the information; or (3) acts in reckless disregard of the truth or falsity of the information 91. Thus, innocent mistakes and negligence could act as a defense.

In United States v. Krizer 92, the U.S. filed a civil suit against a doctor and his wife for falsely billing Medicare and Medicaid patients, in which the billing mechanism included numeric codes that corresponded to certain procedures and their respective billable times 93 with medical personnel. The doctor asserted that his “bundled” approach was comprised of one-on-one time with the patient combined with time reviewing files and consultation with medical personnel 94. Conversely, the government asserted that a strict “face-to-face” approach was the correct application of the parameters of the program 95. The D.C. Circuit held that the code was ambiguous and that the doctor took a reasonable interpretive approach 96. However, the doctor lost on one of the claims, as the court held that he fell within the third aspect of the “knowingly” standard of the False Claims Act, as the statute was designed to prevent the “ostrich-with-the-head-in-the-sand.” This was evident in light of the fact that he allowed his wife to make inaccurate assumptions of time with the patient per corresponding numeric code 97.

E.RICO

RICO, the Racketeer Influenced and Corrupt Organizations Act98treble damages, was passed in 1970 to stop legitimate companies from being forced to deal with organized crime syndicates. The Act allows for claims based upon fraudulent promotional schemes in the marketing of drugs and medical devices, and the elements of a RICO claim include: (1) any person who invests funds from racketeering activities (2) in an enterprise (3) through a pattern (4) of racketeering activity. Clear and convincing proof of these elements can subject a defendant to civil penalties with treble damages 99.

F. Negligence Per Se Violations of the FDCA

Generally, a negligence per se action in common law is appropriate when a plaintiff demonstrates that “(1) a duty, recognized by law, requiring the defendant to conform to a certain standard of conduct; (2) a breach of that duty; (3) a causal connection between the defendant’s conduct and the resulting injury; and (4) actual loss or damage 100. Interestingly, plaintiffs pursuing this claim likely take the stance that the drug and device manufacturers who violated FDA or FDCA rules are liable under state negligence per se laws for damages proximately caused by such infractions 101 dangers are not evident.. The problems for claimants here have been two-fold: either the jurisdictions do not recognize the claim or causation has been difficult to prove.

 

  • 58 Buckman, at 341.Go Back
  • 59 See Ausness, supra note 19, at 1286.Go Back
  • 60 Marcia Boumil, FDA Approval of Drugs and Devices: Preemption of State Laws for “Parallel” Tort Claims, 18 J. Health Care L. & Pol’y 1, 31 (2015).Go Back
  • 61 Id., at 38.Go Back
  • 62 Buckman at 341.Go Back
  • 63 Id., at 346.Go Back
  • 64 18 U.S.C. § 1962.Go Back
  • 65 Miller v. Pfizer Inc. (Roerig Div.), 196 F. Supp. 2d 1095, 1119 (D. Kan. 2002) aff’d sub nom. Miller v. Pfizer, Inc., 356 F.3d 1326 (10th Cir. 2004).Go Back
  • 66 Id.Go Back
  • 67 Miller v. Pfizer Inc. (Roerig Div.), 196 F. Supp. 2d 1095, 1100 (D. Kan. 2002), footnote 7.Go Back
  • 68 Id.Go Back
  • 69 Id., at 1130.Go Back
  • 70 See Ausness, supra note 19, at 1310.Go Back
  • 71 Knowlton v. Deseret Med., Inc., 930 F.2d 116, 118 (1st Cir. 1991).Go Back
  • 72 Id.Go Back
  • 73 Id.Go Back
  • 74 Id.Go Back
  • 75 Id., at 124.Go Back
  • 76 Id.Go Back
  • 77 Id., at 119.Go Back
  • 78 Id.Go Back
  • 79 Id., at 116.Go Back
  • 80 See Ausness, supra note 19, at 1316.Go Back
  • 81 Id.Go Back
  • 82 Love v. Wolf, 226 Cal. App. 2d 378, 384, 38 Cal. Rptr. 183, 186 (Ct. App. 1964).
    Go Back
  • 83 Id.Go Back
  • 84 Id.Go Back
  • 85 Id., at 395.Go Back
  • 86 Id.Go Back
  • 87United States v. Tieger, 234 F.2d 589, 591 (3d Cir. 1956), Cited by United States v. McNinch, 356 U.S. 595, 599, 78 S. Ct. 950, 952, 2 L. Ed. 2d 1001 (U.S. 1958) and “an individual who makes a material misrepresentation to avoid paying money owed the Government.” Cullins v. Astra, Inc., 2010 WL 625279 (S.D.Fla. Feb. 17, 2010) quoting S. Rep. No. 99–345, at 18; 1986
    U.S.C.C.A.N. 5266, 5283.Go Back
  • 88 See Ausness, supra note 19, at 1275.Go Back
  • 89 31 U.S.C.A. § 3729.Go Back
  • 90 Id. Significantly, any attorney involving in such litigation should be prepared to deal with the “knowingly” aspect of culpability.Go Back
  • 91 Id.Go Back
  • 92 United States v. Krizek, 111 F.3d 934, 936 (D.C. Cir. 1997).Go Back
  • 93 Id.Go Back
  • 94 Id.Go Back
  • 95 Id.Go Back
  • 96 Id., at 937.Go Back
  • 97 Id., at 942-643Go Back
  • 98 18 U.S.C.A. § 1961 to 1968.Go Back
  • 99 Id. It is important to understand the differences in application of RICO and the FDCA: RICO applies to untruthful off-label marketing, whereas truthful off-label promotions falls under the FDCA.Go Back
  • 100 O’Guin v. Bingham Cnty., 142 Idaho 49, 52, 122 P.3d 308, 311 (2005).Go Back
  • 101 See Ausness, supra note 19, at 1300.Go Back
  • 102 See Ausness, supra note 19, at 1314.Go Back
  • 103Id.Go Back
  • 104Id.Go Back
  • 105Id.Go Back

 


VI. General Defenses to Off-Label Promotions Claims

There are several defenses to off-label marketing violations. Freedom of speech has proved to be a powerful defense, which will be detailed later in this article. Other defenses for negligence-based claims include assumption of the risk, contributory negligence, and comparative negligence. Typically, those are not as well-documented. On the other hand, the most commonly used defense appears to be the learned intermediary doctrine.

A. The Learned Intermediary Doctrine

As mentioned earlier, manufacturers have a general obligation to warn patients about the inherent dangers of their products in the event such dangers are not evident. 102  Hence, they are required to provide an adequate warning. However, the “learned intermediary doctrine” acts as an exception to the rule by allowing a warning from the patient’s prescribing doctor.  It is a successful proxy for the warning as long as the doctor did in fact provide an adequate enough warning 103.  So, while the manufacturer is typically responsible for warnings lacking adequacy to the patient, a patient’s physician can preclude an inadequate warning claim by giving acceptable warnings directly to the patient 104. Thus, the claim will fail if the physician—who is acting as a learned intermediary—was cognizant of the inherent dangers, because the physician’s duty to warn eliminates the “but for” argument regarding the patient’s injury.105

 

 


VII. Arguments Surrounding Off-Label Promotion

There are a number of reasons people advocate for off-label promotion. Among the more popular are that the FDA’s approval and clearance process: (1) is too slow and cumbersome; (2) delays the availability of potentially life-saving medical advances to those in need; and (3) precludes the exchange of relevant treatments and complications of drugs and medical devices. The typical response to these arguments focuses on the manufacturers’ continuous violations of FDA protocols for selling, marketing, and distributing drugs and devices, especially for off-label uses. The violations suggest that manufacturers simply cannot be trusted, as the pursuit for profits outweighs the ramifications of failing to comply with FDA policies of safety, efficacy, and regulations effectuating policy.

A. Freedom of Speech vs. Incentive for Profit

On one hand, physicians do not have restrictions on prescribing drugs and devices for off-label purposes 106. Yet, for years, manufacturers generally have been barred by the FDA from promoting their products for off-label uses because of a fundamental mistrust by FDA against manufacturers. However, the FDA’s approach has changed. Pursuant to the Good Reprint Practices Guidelines, it now permits a manufacturer to distribute reprints of non-solicited, peer-reviewed medical journal articles detailing these off-label prescriptions. Here, such unsolicited distribution of materials falls under the FDA’s definition of “education” 107.

Significantly, doctors lacking a financial conflict of interests are not barred from communicating the uses and benefits of off-label drugs and medical devices to their patients and the public. This creates the dilemma of one prescribing doctor with financial ties to a company introducing the same truthful data about off-label successes as a non-paid physician. The disturbing effect is that the first could face criminal and civil charges, while the second could be celebrated as a leader in the medical field.108

B. Safety, Efficacy, and Mistrust

There are three policy reasons for the FDA’s strict limitations on off-label marketing: “protecting public health through its certification of drug and medical device safety, preserving the integrity of the drug and device approval process, and ensuring that physicians and patients do not receive inaccurate or biased information that may influence prescribing decisions 109. The core aspect of the argument favoring manufacturer limitations is that off-label use already generates a significant stream of revenue—and in some cases the primary source of sales—such that without the limitations there would be little motivation to seek FDA approval 110.  And the logic is simple: why endure a lengthy and expensive approval process for a particular purpose when a manufacturer can realize the same results (i.e., hundreds of millions of dollars in sales and profits) without going through the headache and delay? Reflection on the alleged mindset of Big Pharma should help one easily arrive at the answer.  Simply put, it does not take much reflection upon the billions in settlement fees for breaches of duty and fraudulent actions to lend credibility to the the FDA’s argument that profits can interfere with the public’s interests of safety and effectiveness.

C. Proof of Mistrust and Enforcement of Violations

In 2013, sales from the biggest pharmaceutical manufacturers churned an astronomical $501.8 billion in sales, based upon annual reports. By the same token, over the years, they have also tallied some impressive penalties and fines for tortious conduct in off-label promotion, both criminal and civil. Consider the following more notable examples:

Johnson & Johnson:

After generating $1.45 billion in sales from Risperdal in 2012, the company was fined $2.2 billion. There were close to 240,000 violations, mostly for not detailing the drug’s risks and deceptively marketing the drug as being safer and better than its competition.111

Pfizer:

With sales of well over $5 billion in 2012 from Lyrica, Zyvox, and Bextra, the company was fined $2.3 billion.112 The company’s Pharmacia & Upjohn subsidiary offered a guilty plea following a felony criminal violation for misbranding Bextra with intent to defraud or mislead. This included the biggest criminal fine to date of $1.195 billion 113. Coupling the $105 million criminal resolution with another $1 billion for illegal drug promotion, as well as the false claims, the total comes to a staggering $2.3 billion 114. The company’s conduct concerning Bextra was the most egregious of the violations. In late 2001, the FDA “approved small dosages of Bextra for treating the symptoms of a limited number of conditions 115. Yet, following this approval the company marketed and sold Bextra throughout the U.S. touting it as an effective morphine-sparing analgesic after knee surgery. The drug was not approved for post-surgery pain and was pulled from the market in 2005.116 The company also continued to fund “medical education programs that were used to promote Bextra for off-label uses…and sponsoring articles that promoted off- label uses.117

GlaxoSmithKline:

With over $11 billion in sales in 2012 for drugs including Advair, Flovent, and Paxil, the company was fined $3 billion. The reasons for the hefty penalty included failing to report safety information to the FDA (a criminal fine), promoting drugs for off-label/non-covered uses, paying kickbacks to physicians, and making false and misleading statements.118

Some of the other major fines and settlements include Abbot ($1.6 billion), Eli Lilly ($1.415 billion), Merck & Co. ($950 million), and Amgen ($762.1 million).

For some of these pharmaceutical giants, the enormous profits are a drop in the bucket relative to the fines imposed. And this is somewhat recent history. The FDA may be quick to remind the public of the risk of “snake oil salesmen peddling approved products for off-label uses with unproven, exaggerated, or fraudulent health claims,” and how “eliminating the ban would open the floodgates for such objectionable conduct 119.

 

  • 107 Good Reprint Practices.Go Back
  • 108 Conko, supra note 43, at 150.Go Back
  • 109 Id., at 151.Go Back
  • 110 Id.Go Back
  • 111 Katie Thomas, J.&J. Fined $1.2 Billion in Drug Case, New York Times, April 11, 2012. (last visited January 22, 2016).Go Back
  • 112 Press Release, U.S. Dept. of Justice, Justice Department Announces largest Health Care Fraud Settlement in its History – Pfizer to Pay $2.3 Billion for Fraudulent Marketing (Sept. 2, 2009), available at http://www.justice.gov/opa/pr/justice- department-announces-largest-health-care-fraud-settlement-its-history (last visited January 3, 2015).Go Back
  • 113 Id.Go Back
  • 114 Id.Go Back
  • 115 In re Bextra & Celebrex Mktg. Sales Practices & Prod. Liab. Litig., No. 05-CV-01699 CRB, 2012 WL 3154957, at *1 (N.D. Cal. Aug. 2, 2012).Go Back
  • 116 Id.Go Back
  • 117 Id.Go Back
  • 118 Katie Thomas & Michael S. Schmidt, Glaxo Agrees to Pay $3 Billion in Fraud Settlement, The New York Times, July 2, 2012 (last visited January 22, 2016).Go Back
  • 119 Conko, supra note 43, at 151.Go Back

 


VIII. Landmark Cases Lead the FDA towards Easing Off-Label Promotion Restrictions

A. Washington Legal Foundation, the FDCMA, and Good Reprint Packages Guideline

During the 1990’s, the Washington Legal Foundation (WLF) alleged that the FDA’s policy based upon the Food and Drug Administration Modernization Act of 1997 regarding off-label promotion via sponsored article reprints was a violation of the First Amendment 120. In particular, one important dispute involved the FDA’s stance on circulation of “independent medical and scientific publications concerning the off-label uses of their products,” and ”manufacturer support for Continuing Medical Education (CME) programs for doctors that focus on off-label use 121. The D.C. District Court analyzed this under the four-prong Central Hudson Test to determine whether commercial free speech restrictions are in violation of the First Amendment 122. That standard directs the court to determine whether: (1) the particular speech is not misleading or unlawful 123; if the speech comports with this benchmark, it is within the scope of the First Amendment and the court can proceed to determine; (2) if there is a substantial government interest in regulating the speech; (3) if the regulation advances the government’s substantial interest; and finally (4) if the regulation is more extensive than necessary to serve or advance the State’s interests 124.

The first question regarding the lawful and truthful activity was satisfied because off-label prescription by doctors is legal, and circulation of data by manufacturers was not a misleading activity 125. This threshold question was affirmatively answered and allowed for the analysis to continue, where the court determined that a substantial government interest in regulating this speech existed, and the FDA’s regulation of the speech furthered that interest 126. However, the final question regarding whether the regulation was too extensive to further the government’s interest was found against the FDA: “They fell short of satisfying the final part of the Central Hudson Test, however, because the policies restricted considerably more speech than necessary to encourage manufacturers to achieve this objective 127. As a result, the District Court found in favor of the plaintiffs and granted their request for an injunction 128.

But the story does not end there. During the litigation process, the Court obtained guidance from the Food and Drug Administration Modernization Act of 1997 (FDAMA), which allowed for the circulation of “enduring materials” 129. These were defined as unedited copies of peer-reviewed medical journal articles and studies that included certain stipulations, such as a disclaimer that off- label usage was not approved 130. The decision’s effect was later rendered meaningless for guidance, as the FDA took a different position. The Court of Appeals dismissed the FDA’s appeal and vacated the district court’s decisions and injunctions to the extent that they ruled the FDAMA and the CME Guidance unconstitutional 131. Thus, an opportunity for direction lost.

In January 13, 2009, the FDA released the Good Reprint Practice Guidelines that eased limitations of off-label promotion. However, there were issues with it. First, the guidelines would have no force of law and could not act as a true source of guidance for manufacturers 132. Second, providing a supplemental new drug application when a manufacturer pursues off-label promotion was not required 133. Third, the manufacturer need not provide its marketing materials to the agency before circulation 134.

a. U.S. v. Caronia 135

This case shows the conflict between free speech and “misbranding,” which is the promotion of a drug or device outside of its approved indications. In this case, a pharmaceutical sales representative was promoting off-label usage of Xyrem, a drug approved in 2002, to treat narcolepsy patients with weak muscles and daytime sleepiness 136. Due to heightened safety issues with the drug, a “black box” warning was required by the FDA, and only one pharmacy in the United States could carry the drug 137. In 2005, the government initiated a sting operation against the manufacturer. Its sales representative, Caronia, was recorded discussing Xyrem for off-label purposes with a government informant posing as a physician 138. Caronia argued that the criminal misbranding-related charges violated his First Amendment right to free speech 139. The district court was not persuaded, and denied his motion to dismiss the charges 140.

On appeal, the Second Circuit vacated the criminal sanctions under the guise that the FDCA “and its accompanying regulations do not expressly prohibit or criminalize off- label promotion 141. As to whether government prosecution under the FDCA was constitutional, the Court first determined that Caronia was being prosecuted for speech 142. However, the government failed in its argument regarding restricting manufacturers marketing activities under a strictly scrutinized application of the Central Hudson Test.

Accordingly, even if speech can be used as evidence of a drug’s intended use, we decline to adopt the government’s construction of the FDCA’s misbranding provisions to prohibit manufacturer promotion alone as it would unconstitutionally restrict free speech. We construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA-approved prescription drugs. Our conclusion is limited to FDA-approved drugs for which off- label use is not prohibited, and we do not hold, of course, that the FDA cannot regulate the marketing of prescription drugs. We conclude simply that the government cannot prosecute pharmaceutical manufacturers and their representatives under the FDCA for speech promoting the lawful, off-label use of an FDA-approved drug 143.

B. United States v. Harkonen144

In 1990, a California-based drug company named InterMune received FDA approval for the medication Actimmune which treats childhood immune disorder and childhood osteoporosis 145. However, about 12 years after its approval, the former CEO of the company, Dr. W. Scott. Harknonen, began promoting the drug for other uses. On August 28, 2002, he issued a press release that stated, “Actimmune also demonstrated a strong positive trend in increased survival in the overall patient population.” The statement was made under the premise that it constituted a scientific debate with First Amendment protections 146. However, Harkonen was aware that the drug lacked therapeutic value by failing to reduce disease progression while it was not approved for that purpose 147. There was a significant inference made by the district court regarding Harknonen’s charge of intent to fraud, when it detailed how “the release states in its third paragraph InterMune expected that the results of the GIPF–001 study would ‘lead to peak sales in the range of $400–$500 million per year” 148. Harkonen was subsequently hit with a wire fraud charge for making allegedly false statements in his news release, which was affirmed by the Ninth Circuit 149. The free speech argument became moot, as the “First Amendment did not protect defendant’s fraudulent press release” 150. The case does, however, demonstrate the abusive possibilities available if the door opens too wide for off-label promotion.

C. Where We Are Today

There is a clear rift between opponents and advocates regarding the free-flow of information for off-label use between the manufacturer and the doctor. The arguments are evident by a review of the positions of those who support and those who reject the FDA’s new principles. On one hand, allowing more flexible off-label promotion “could weaken FDA’s overall influence in promoting efficacy and safety practices 151. This comes at the expense of safety to society, as government oversight has diminished in an area fraught with profit-minded executives who are willing to introduce inaccurate information to vulnerable populations. The Caronia decision finally brings a degree of clarification on how the Constitution affects the FDA’s ability to enforce its stance on off-label promotion by manufacturers 152. In fact, prior to the conclusion of the case, the FDA’s recent guidance on circulating printed materials to physicians was released.

 

  • 120 Washington Legal Found. v. Friedman, 13 F. Supp. 2d 51 (D.D.C. 1998).Go Back
  • 121 Washington Legal Found. v. Henney, 202 F.3d 331, 333 (D.C. Cir. 2000).Go Back
  • 122 Id., at 334.Go Back
  • 123 Id.Go Back
  • 124 Id.Go Back
  • 125 Id., at 334.Go Back
  • 126 Id.Go Back
  • 127 Id., at 334.Go Back
  • 128 Washington Legal Found. v. Friedman, 13 F. Supp. 2d 51 (D.D.C. 1998) amended, 36 F. Supp. 2d 16 (D.D.C. 1999) appeal dismissed, judgment vacated in part sub nom. Washington Legal Found. v. Henney, 202 F.3d 331 (D.C. Cir. 2000) and amended,
    36F. Supp. 2d 418 (D.D.C. 1999) and appeal dismissed, judgment vacated in part sub nom. Washington Legal Found. v. Henney,
    202F.3d 331 (D.C. Cir. 2000).Go Back
  • 129 Id., at 333.Go Back
  • 130 Id.Go Back
  • 131 Id., at 336.Go Back
  • 132 Good Reprint Practices, supra note 27.Go Back
  • 133 Id.Go Back
  • 134 Id.Go Back
  • 135 United States v. Caronia, 703 F.3d 149, 156 (2d Cir. 2012).Go Back
  • 136 Id.Go Back
  • 137 Id., at 155.Go Back
  • 138 Id., at 156.Go Back
  • 139 Id., at 158.Go Back
  • 140 Id., at 159. The court imposed one year of probation, 100 hours of community service, and a $25 special assessment. Id.Go Back
  • 141 Id., at 160.Go Back
  • 142 Id., at 162.Go Back
  • 143 Id., at 168 – 69.Go Back
  • 144 United States v. Harkonen, No. C 08-00164 MHP, 2010 WL 2985257, at *1 (N.D. Cal. July 27, 2010).Go Back
  • 145 Id.Go Back
  • 146 Id., at 9.Go Back
  • 147 Id., at 8.Go Back
  • 148 Id., at 13.Go Back
  • 149 United States v. Harkonen, 510 F. App’x 633, 638 (9th Cir.) cert. denied, 134 S. Ct. 824, 187 L. Ed. 2d 685 (2013).Go Back
  • 150 Id., at 1.Go Back
  • 151 Mariestela Buhay, Off-Label Drug Promotion Is Lost in Translation: A Prescription for A Public Health Approach to Regulating the Pharmaceutical Industry’s Right to Market and Sell Its Products, 13 J. Health Care L. & Pol’y 459, 487 (2010).Go Back
  • 152 Id., at 483 (stating that “Caronia could make it more difficult for drug and device manufacturers to prevail on a First Amendment defense in promotion of off-label cases, and for good reason.”).Go Back

 


IX. Arguments Supporting and Against the Good Practice Guidelines

A. Supporters of the FDA’s Guidance

Beyond the free speech argument, support stems primarily from the interest in the exchange of data between manufacturers and the patient-consumers 153. According to advocates, the FDA has been an obstacle in the efficient flow of information, and the easing of off-label promotional limitations lowers the governmental barrier 154. Thus, modern medical technological advances on drugs and devices can be shown to prescribing doctors, which allows for up-to-date treatment options for patients without FDA interference through claims of misbranding 155.

B. Dissenters to the FDA’s Guidance

The leading argument against the FDA’s Guidance is that it no longer requires manufacturers to apply for new drug approval when circulated materials mention off-label uses—the requirement once mandated by the now expired § 401 of the FDAMA156. It is not a big leap to suggest that without such a process, there is a disincentive to obtain approval for new uses for a drug or device.

Another argument is that “off-label prescribing of drugs that have not been proven safe or effective for prescribed use drives up the cost of health care and exposes patients to unnecessary risks 157.

Finally, there is an argument that the new Guidance offers the potential for manipulation of data from the manufacturer to the doctor and finally to the consumer. Circulation of off-label uses may not ensure the right balance of safety and efficacy. Pushing the information into the hands of large groups of patients could have aggravating effects, as nearly all drugs have complications, many of them serious and even lethal 158.

C. Ironic Pitfalls of Opening the Gates to “Accurate Information”

It is debatable whether drug and device manufacturers are circulating factually accurate and trustworthy peer-reviewed medical journal entries based upon scientifically-based data, pursuant to the new FDA Guidance 159. This creative approach to evading the FDA’s weakened oversight comes from manufacturers giving attribution to credible sources for the materials they circulate, only to later discover that a predominant source originated from unacknowledged authors. Further, the effects of unsafe off-label promotion based upon misleading information should not be forgotten. One merely need to examine the “fen-phen” debacle. That case involved the use of fenfluramine, dexenfluramine, and phentermine, which were FDA approved as appetite suppressants 160. Unfortunately, many patients experienced heart valve damage after prolonged use: the extended use and interaction of the medications was contrary to the approved label 161.  It turns out that “safety of dexenfluramine beyond 1 year of use had not been established by clinical trials” 162. To take this one step further, informed consent from the physician could be absent 163. This begs the question, amid publication and distribution of inaccurate and unreliable data, is there really such a thing as “informed” consent for off-label products?

 

  • 153Off-Label Drug Promotion Is Lost in Translation at 489.Go Back
  • 154 IdGo Back
  • 155 Id.Go Back
  • 156 Id., at 490.Go Back
  • 157 Margaret Z. Johns, Informed Consent: Requiring Doctors to Disclose Off-Label Prescriptions and Conflicts of Interest, 58 Hastings L.J. 967, 1008 (2007).Go Back
  • 158 Id., at 490-491.Go Back
  • 159 Joseph S. Ross et al., Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents from Rofecoxib Litigation, 299 JAMA 1800, 1806-10 (2008) (announcing that several industry-sponsored publications related to a medication were authored independently by Merck & Co., Inc. before crediting authorship to medically affiliated practitioners or academics).Go Back
  • 160 73 Am. Jur. Trials 485 (Originally published in 1999).Go Back
  • 161 Food and Drug Administration, Questions and Answers About Withdrawal of Fenfluramine (Pondimin) and Dexfenfluramine (Redux).Go Back
  • 162 Id. See Also 12 Causes of Action 2d 1 (Originally published in 1999).Go Back
  • 163 James M. Beck & Elizabeth D. Azari, FDA, Off-Label Use, and Informed Consent: Debunking Myths and Misconceptions, 55 Food & Drug L.J 7, 91 (1998) (“No appellate cases have held that a physician’s failure to disclose that a drug therapy was prescribed off-label violated informed consent.”).Go Back

 


X. Conclusion

Big Pharma is making money hand over fist. In fact, “profits of the top ten drug companies on the Fortune 500 list in 2002 were greater than the combined profits for the other 490 businesses” 164. Drug and device manufacturers are businesses, and the economics of the pharmaceutical industry centers on profits along with healthcare for society. Understandably, manufacturers are unlikely to test off-label uses of their products unless the FDA orders them to do so, due to the added expense that cuts into their profits 165. What’s more, it is not helpful that federal health care programs often do not reimburse health care providers for off-label therapies—effectively eliminating the opportunity to use medication for those who could benefit the most from these treatments.

An authoritative review of off-label materials being sent to prescribing physicians, combined with evidenced-based substantiation of those uses is desperately needed 166. Several of the decisions examined in this article provide a framework for the type of federal regulation that is required for off-label medications. There is much more that can be done. Under the current FDA Good Reprint Practices era, Big Pharma has set record-breaking violations surpassing $1 billion accompanied by hundreds of thousands of individual violations and corresponding health complications. Unless the FDA looks to now be a profit center for the federal government, a more collaborative approach to guidance that allows substantiated statements could save lives and prevent more record-breaking violations. And help put an end to this other drug war.

 

  • 164 Margret Z. Johns, Informed Consent: Requiring Doctors to Disclose Off-Label Prescriptions and Conflicts of Interest, 58 Hasting L.J. 967, 973 (2007).Go Back
  • 165 See Ausness, supra note 19, at 1319.Go Back
  • 166 The State Bar of Texas Advertising Review Committee of the State Bar of Texas provides an excellent roadmap. See Rule 7.07(b): “a lawyer shall file with the [Committee], no later than the first dissemination of an advertisement in the public media, a copy of each of the lawyer’s advertisements in the public media.” TX ST RPC Rule 7.07(b), Filling Requirements for Public Advertisements and Written, Recorded, Electronic, or Other Digital S. Under Rule 7.07(d), “[a] lawyer who desires to secure an advance advisory opinion, referred to as a request for pre-approval . . . may submit to the [Committee], not less than thirty (30) days prior to the date of first dissemination, the material” to be sent to physicians. TX ST RPC Rule 7.07(d). And Under 7.07(f) “[i]f requested by the Advertising Review Committee, a lawyer shall promptly submit information to substantiate statements or representations made or implied in any advertisement in the public media and/or written solicitation communication.” TX ST RPC Rule 7.07(f).Go Back

 


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