When Honesty is a Crime - Medical "Regulation"
A controversy has arisen regarding the pharmaceutical company Amerin’s intention to market the efficacious triglyceride-reducing agent icosapent ethyl, trade name Vascepa, for the lowering of triglycerides in patients with a high risk of cardiovascular events according to the ATP III guidelines who are being treated with a statin and have a post-diet and exercise (residual) serum triglyceride level > 200 and < 500 mg/dL.
The U.S. Food and Drug Administration (FDA) denied Amerin's request for approval not because icosapent ethyl does not work, but because it is not guaranteed to save lives. The medicine works to lower triglycerides, that has been demonstrated. The medicine is safe. However, the FDA demanded that prior to permission of truth marketing, Amerin must show that it will result in a reduction in cardiovascular events.1,2 Icosapent ethyl is an ω-3 fatty acid that contains at least 96% pure icosapent-ethyl, which is the ethyl ester of eicosapentaenoic acid. Icosapent ethyl was approved by the FDA to treat patients with triglyceride levels of > 500 mg/dL on July 26, 2012. The controversy surrounds the FDA’s claimed authority to bring misbranding claims with both criminal and civil penalties against Amerin for truthful off-label marketing, an expression of commercial free speech, of icosapent ethyl. There is the concern of a degradation in the quality of pharmaceutical regulation if we have judges reviewing medical decisions instead of only the FDA. Sharfstein and Charo astutely report that the Federal District Court Judge Paul Engelmayer misinterpreted the FDA’s second proposed disclosure statement for Amerin.1 It was
Vascepa is not approved for the treatment of statin-treated
patients with mixed dyslipidemia and high (> 200 mg/dL and < 500
mg/dL) triglyceride levels. FDA declined to approve this indication
because the available evidence does not establish that reducing triglycerides
with a drug reduces the risk of cardiovascular events among patients already
treated with statins.2
The phrase “the available evidence does not establish,” can be secondary to a paucity of data and the need for a prospective study with enough patients to allow a discovery of a statistically significant change from the therapeutic intervention. Alternatively, it could also mean that there is abundant evidence from multiple randomized controlled trials that failed to show effect. Judge Engelmayer appropriately noted that the potential latter interpretation may be assumed as the sole meaning by some physicians, and the Judge’s presumption is supported by Sharfstein and Charo’s claim that physicians can be confused by advertising.1,2
Although the FDA’s statement did not affirmatively claim there is robust evidence of no reduction in cardiovascular events in the aforementioned group, the Judge’s proposed second disclosure statement for Amerin’s marketing is probably less prone to being misconstrued or confused by physicians than the second proposed disclosure written by the FDA.
Judge Engelmayer proposed the following for Amerin’s second disclosure statement
Vascepa is not FDA-approved for the treatment of statin-treated patients
with mixed dyslipidemia and high (≥ 200 mg/dL and < 500 mg/dL)
triglyceride levels due to current uncertainty regarding the benefit, if any,
of drug-induced changes in lipid/lipoprotein parameters beyond statin-lowered
low-density lipoprotein cholesterol on cardiovascular risk among
statin-treated patients with residually high triglycerides. No prospective
study has been conducted to test and support what, if any, benefit exists.
In addition, the Judge wrote, “the parties are, of course, at liberty to pursue further refinements to this disclosure as this litigation moves forward.”2
The United States of America (USA) was founded with three branches of government: legislative, judicial, and executive, and the intent for there to be checks and balances. This author disagrees that agencies such as the FDA should always be above judicial review. An unregulated FDA that bans truthful advertising about the safety and efficacy of icosapent ethyl by refusing to permit distribution of clinical trial data and truth advertising claims to physicians by only some persons such as pharmaceutical representatives seems unreasonably discriminatory and paternalistic.3
Even though the FDA Advisory Committee found “insufficient evidence to show that triglyceride reduction prevents cardiovascular disease,” such a finding is arguably irrelevant since Amerin only intends to advertise that it reduces triglycerides.1 The clinical decision to prescribe a medication resides with the treating physician and not with the FDA. Furthermore, many FDA-approved drugs are used off-label.4
Amerin’s case should probably not be related to the more than 100 deaths caused by sulfonamide where safety data was lacking because icosapent ethyl was well tolerated in the placebo-controlled study.3 Relating the use of icosapent ethyl to the previous widespread use of thalidomide is unwarranted as Amerin only intends to market icosapent ethyl off-label for those with already receiving statin therapy and triglycerides levels that are > 200 mg/dL and < 500 mg/dL.1-3 Also, the reference to the off-label use of antipsychotic drugs is irrelevant because that marketing lacked the high-quality, level 1b evidence that Amerin has to support its marketing claims.3,5
The idea that the Amerin case opens a slippery slope of low-quality advertising information is not founded because Judge Engelmayer approved only truthful advertising that was also not misleading and was considered safe.3 If the FDA is unable to show that advertisements are false or misleading, then they probably are not harmful and probably should not be considered illegal activity. Judges should not refrain from exercising their constitutionally-given jurisprudence over agencies that interpret the law themselves. One need not assume that Judge Engelmayer’s approval of truthful marketing will lead to another tragedy because of the myriad differences and safeguards that remain for untruthful, misleading, or harmful advertising.2,3 Readers are encouraged to review Judge Engelmayer’s sagacious writing for themselves before assuming the promotion of truthful safety and efficacy information is harmful.2
1. Sharfstein JM, Charo A. The promotion of medical products in the 21st century: Off-label marketing and first amendment concerns. JAMA. 2015:1-2.
2. Amarin Pharma Inc v United States Food & Drug Administration. 1:15-03588-PA (SD NY filed August 7, 2015). http://law.justia.com/cases/federal/district-courts/new-york/nysdce/1:2015cv03588/441887/73/ Accessed September 15, 2015
3. Ballantyne CM, Bays HE, Kastelein JJ, et al. Efficacy and safety of eicosapentaenoic acid ethyl ester (AMR101) therapy in statin-treated patients with persistent high triglycerides (from the ANCHOR study). Am J Cardiol. 2012;110(7):984-992.
4. Brezinski EA, Armstrong AW. Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy. PloS one. 2012;7(4):e33486.
5. Medicine CfEB. http://www.cebm.net/oxford-centre-evidence-based-medicine-levels-evidence-march-2009/. Accessed September 15, 2015.
The good doctors, cardiologists that work for the Amerin company went to court to defend their right to tell the truth and they were given justice by the Honorable Judge Englemayer.
In spite of fear pandering and demands for silencing the cardiologists by a few paternalistic physicians who published a series of letters in NEJM, JAMA, and other top medical journals, telling the truth has continued to provide the public with accurate information about their healthcare.