Year in Review: Troubling New Drug Approvals in 2015

There has been a fairly steady increase in the number of new drugs approved by the Food and Drug Administration (FDA) since 2011, a higher rate than in the previous decade.[1]

Of the 45 new drugs approved by the FDA in 2015,[2] Public Citizen’s Health Research Group has evaluated several and found them unacceptably dangerous or ineffective. This article reviews six such drugs — as well as a newly approved use for a drug already on the market — and is based on Public Citizen’s testimony at FDA advisory committees opposing these approvals.

With so many dangerous and relatively ineffective drugs slipping through the FDA’s lax review process, it may be just a matter of time before we experience a repeat wave of drug safety disasters, as occurred after the FDA approved a record number of drugs in 1996 and 1997. Six of the drugs approved in those two years were removed from the market because they were too dangerous.

Five troubling new drugs

Deoxycholic acid (KYBELLA):
Do Not Use

In April, the FDA approved deoxycholic acid as an injection for the treatment of moderate to severe fat below the chin in adults.[3] Public Citizen testified against approval of the drug because its risks — including nerve damage and difficulty swallowing — outweighed its limited, purely cosmetic benefits in removing chin fat.[4] The testimony also pointed out that the drug likely would be used for purposes other than those approved (off-label use), “thereby endangering nerves in other parts of the body.”

Cangrelor (KENGREAL):
Do Not Use

Cangrelor was approved in June for adults undergoing a heart procedure, known as percutaneous coronary intervention (PCI), to open narrowed or blocked coronary arteries (vessels supplying blood to the heart).[5] These procedures typically involve placement of a stent (a tiny expandable metal mesh tube) to keep the coronary artery open. Public Citizen testified against approval because the drug was studied in an unethical clinical trial that compared cangrelor to a substandard, inadequately administered regimen of the anti-clotting drug clopidogrel (PLAVIX).[6]

To maximize the benefit of clopidogrel, it must be given to patients before undergoing PCI to prevent blood clots from forming in the stent during and after the procedure. But in the trial, a third of the control subjects did not receive clopidogrel until after the procedure began or when it was over.[7] Control subjects therefore did not have adequate levels of clopidogrel in their system while the procedure was underway. This may have resulted in a larger number of clots and heart attacks in these subjects during or immediately after the stent procedure and biased the results of the trial in favor of cangrelor. Cangrelor had been rejected once before by the FDA but was approved the second time, despite no new, properly conducted clinical trials on the drug.[8]

Alirocumab (PRALUENT):
Do Not Use; evolocumab
(REPATHA): Limited Use

Alirocumab was approved in July, and evolocumab in August, to lower LDL (“bad”) cholesterol in patients with cardiovascular disease or genetically high cholesterol levels.[9],[10] Public Citizen testified against the drugs’ approvals in the vast majority of such patients.[11],[12] (We do not, however, oppose the use of evolocumab to treat a tiny population of patients with extremely high LDL due to a genetic condition known as homozygous familial hypercholesterolemia [HoFH].)[13]

Although the drugs significantly reduce LDL levels, neither has yet been proven effective in preventing death or serious cardiovascular events in patients with cardiovascular disease.[14] Two large clinical trials are underway to assess whether the drugs are effective in this regard, but they will not be completed until 2017.[15],[16] In addition, the drugs’ side effects — and, more generally, the long-term effects of reducing LDL to levels as low as those seen in the trials — are as yet largely unknown.[17]

We recommend against using alirocumab, and you should not use evolocumab unless you have HoFH.

Flibanserin (ADDYI):
Do Not Use

Flibanserin was approved in August to treat a condition known as hypoactive sexual desire disorder in premenopausal women.[18] Public Citizen testified against approval of the drug, noting that it caused serious side effects such as abnormally low blood pressure and fainting, which the FDA acknowledged can result in “serious, irreversible or life- threatening injuries.”[19]

In combination with alcohol, flibanserin is even more dangerous, and the FDA noted the difficulty in preventing women from drinking alcohol while taking the drug.[20] In addition, the drug is minimally effective, resulting in an average of one-half to one additional sexually satisfying experience per month.[21] After flibanserin’s approval, Public Citizen issued a press statement predicting that the drug will be removed from the market within a few years.[22]

Lesinurad (ZURAMPIC):
Do Not Use

Lesinurad was approved in December to treat high blood uric acid levels in patients with gout, a common disease that causes bouts of severe joint pain and swelling.[23] Public Citizen testified against approval of the drug because it offers no meaningful benefit but poses serious risks, including acute kidney injury and possible cardiovascular toxicity.[24] The testimony also noted that likely off-label use of the drug would lead to alarming rates of acute kidney failure.[25] In addition, in clinical trials, there were more heart attacks and cardiovascular deaths in the lesinurad-treated subjects than in those who received a placebo.[26]

While such events occurred too few times to draw any definitive conclusions about lesinurad’s cardiovascular harms, the finding was concerning, especially in a drug that offers no meaningful benefit to patients.While such events occurred too few times to draw any definitive conclusions about lesinurad’s cardiovascular harms, the finding was concerning, especially in a drug that offers no meaningful benefit to patients.

A previously approved drug

Fluticasone furoate-vilanterol
(BREO ELLIPTA):
Do Not Use

The combination drug fluticasone furoate-vilanterol was approved in April for the treatment of asthma in adults.[27] It previously had been approved for chronic obstructive pulmonary disease,[28] which Public Citizen opposed.[29] Public Citizen also testified against the drug’s approval for asthma because the drug had not been studied in clinical trials large enough to adequately determine its risks.[30]

Vilanterol is a long-acting beta-agonist, or LABA. Previous studies have shown that LABAs have potentially fatal risks in asthma patients.[31] Patients with asthma should never use LABAs unless taken in combination with an inhaled corticosteroid. All other currently marketed LABAs are being studied in ongoing trials to determine whether these risks persist even in patients on adequate doses of inhaled steroids (such as fluticasone furoate).[32] The trials of fluticasone furoate-vilanterol were far smaller than those ongoing trials,[33] and it is unknown whether the drug carries the same risks as other LABAs. Public Citizen argued that approving the drug now, without requiring a larger trial and before the trials of the other LABAs are complete, would be premature.[34]

References

[1] Food and Drug Administration. Novel new drugs: 2014 summary. January 2015. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugInnovation/UCM430299.pdf. Accessed December 4, 2015.

[2] Food and Drug Administration. New Molecular Entity and New Therapeutic Biological Product Approvals for 2015. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm. Accessed December 4, 2015.

[3] Food and Drug Administration. FDA News Release: FDA approves treatment for fat below the chin. April 29, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm444978.htm. Accessed December 3, 2015.

[4] Public Citizen. Testimony Before the FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee Regarding Deoxycholic Acid Injection. March 9, 2015. http://www.citizen.org/documents/2243.pdf. Accessed December 3, 2015.

[5] Food and Drug Administration. FDA News Release: FDA approves new antiplatelet drug used during heart procedure. June 22, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm452172.htm. Accessed December 3, 2015.

[6] Public Citizen. Testimony before the FDA’s Cardiovascular and Renal Drugs Advisory Committee Regarding the Drug Cangrelor. April 15, 2015. http://www.citizen.org/hrg2254. Accessed December 3, 2015.

[7] Ibid.

[8] Ibid.

[9] Food and Drug Administration. FDA news release: FDA approves Praluent to treat certain patients with high cholesterol. July 24, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm. Accessed December 3, 2015.

[10] Food and Drug Administration. FDA news release: FDA approves Repatha to treat certain patients with high cholesterol. August 27, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm. Accessed December 3, 2015.

[11] Public Citizen. Testimony Before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Regarding Evolocumab. June 10, 2015. http://www.citizen.org/hrg2264. Accessed December 3, 2015.

[12] Public Citizen. Testimony Before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Regarding Alirocumab. June 9, 2015. http://www.citizen.org/hrg2263. Accessed December 3, 2015.

[13] Public Citizen. Testimony Before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Regarding Evolocumab. June 10, 2015. http://www.citizen.org/hrg2264. Accessed December 3, 2015.

[14] Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom? N Engl J Med. 2015;372(16):1564-1565.

[15] Clinicaltrials.gov. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). NCT01764633. https://clinicaltrials.gov/ct2/show/record/NCT01764633. Accessed December 3, 2015.

[16] Clinicaltrials.gov. ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727). NCT01663402.https://clinicaltrials.gov/ct2/show/record/NCT01663402. Accessed December 3, 2015.

[17] Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom? N Engl J Med. 2015;372(16):1564-1565.

[18] Food and Drug Administration. FDA news release: FDA approves first treatment for sexual desire disorder. August 18, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm458734.htm. Accessed December 3, 2015.

[19] Public Citizen. Testimony Before the FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee Regarding Flibanserin. June 4, 2015. http://www.citizen.org/documents/2262.pdf. Accessed December 4, 2015.

[20] Ibid.

[21] Food and Drug Administration. Briefing Materials for June 4, 2015 Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee. NDA 022526 (flibanserin). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM449088.pdf. Accessed December 4, 2015.

[22] Public Citizen. FDA’s big mistake: Expect flibanserin to be pulled from the market in a few years. August 19, 2015. http://www.citizen.org/pressroom/pressroomredirect.cfm?ID=5620. Accessed December 3, 2015.

[23] Food and Drug Administration. FDA News Release: FDA approves Zurampic to treat high blood uric acid levels associated with gout. December 22, 2015. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm478791.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Accessed December 22, 2015

[24] Public Citizen. Testimony Before the FDA’s Arthritis Advisory Committee Regarding Lesinurad. October 23, 2015. http://www.citizen.org/documents/2279-pp.pdf. Accessed December 3, 2015.

[25] Ibid.

[26] Ibid.

[27] Reuters. U.S. FDA approves Glaxo, Theravance's Breo Ellipta asthma drug. May 1, 2015. http://www.reuters.com/article/2015/05/01/us-glaxosmithkline-asthma-idUSKBN0NL2PN20150501. Accessed December 3, 2015.

[28] Food and Drug Administration. FDA News Release: FDA approves Breo Ellipta to treat chronic obstructive pulmonary disease. May 10, 2013. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm351664.htm. Accessed December 4, 2015.

[29] Public Citizen. Testimony on Fluticasone/Vilanterol Combination Therapy to the FDA’s Pulmonary-Allergy Drugs Advisory Committee. April 17, 2013. http://www.citizen.org/hrg2114. Accessed January 20, 2016.

[30] Public Citizen. Testimony Before a Joint Meeting of the FDA’s Pulmonary-Allergy Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Regarding Fluticasone Furoate/Vilanterol (Breo Ellipta) for Asthma. March 19, 2015. http://www.citizen.org/hrg2248. Accessed December 3, 2015.

[31] Food and Drug Administration. Briefing Materials for March 19, 2015 http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM438379.pdf. Accessed December 4, 2015.

[32] Ibid.

[33] Ibid.

[34] Public Citizen. Testimony Before a Joint Meeting of the FDA’s Pulmonary-Allergy Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee Regarding Fluticasone Furoate/Vilanterol (Breo Ellipta) for Asthma. March 19, 2015. http://www.citizen.org/hrg2248. Accessed December 3, 2015.