When EMA and FDA Decisions Conflict: Differences in Patients or in Regulation?

The following text, reprinted here with permission of the British Medical Journal (BMJ), originally appeared as one of Dr. Sidney Wolfe’s regular columns in the BMJ.

Are Americans more resistant to the risks and more likely to benefit from certain drugs than Europeans or, on the contrary, is the European Medicines Agency (EMA) more resistant than the U.S. Food and Drug Administration (FDA) to the drug industry’s desire to get approval for drugs with unique risks but without compensating benefits?

This question arises because the FDA has recently approved two diet drugs, heralded by the agency as “the first drugs for long-term weight management that FDA has approved in 13 years”[1] but rejected by the EMA. In both cases FDA advisory committees earlier rejected approval but later supported the FDA’s and the companies’ desire for approval. Similarly, the FDA has also failed to ban the diabetes drug rosiglitazone (AVANDIA), banned three years ago by the EMA.[2]

In June 2012, the FDA approved lorcaserin (marketed in the U.S. as BELVIQ). The weight loss drugs dexfenfluramine and fenfluramine were banned in 1997 because of many post-approval cases of heart valve damage, attributed to adverse effects on the 2B serotonin heart receptor.[3] Lorcaserin has minimal 2B serotonin receptor activity, but the FDA approved the drug despite a 16% increase in heart valve damage in randomized trials, not statistically significant but with an upper confidence interval of 67%.[4] The reduction in weight loss, beyond that of placebo, was 3% to 3.7%.[5] The chairman of the FDA advisory committee reviewing the drug stated, “There’s probably not sufficient data at this time to rule out a clinically meaningful increase in the risk for valvular heart disease.” The cardiologist Sanjay Kaul, a committee member who voted against approval, said, “Given the totality of evidence, the potential benefits of lorcaserin do not, in my opinion, outweigh the potential risks when used long term in a population of overweight and obese individuals.”[6]

Despite its approval of the drug, the FDA required the company to do post-marketing randomized trials to better evaluate cardiovascular risk, including heart valve damage.[7]

Before the EMA had formally rejected the application for lorcaserin, but after withdrawal of the marketing application by the drug’s sponsor, Arena, the EMA stated that “at the time of the withdrawal the CHMP [the EMA’s Committee for Medicinal Products for Human Use] . . . was of the provisional opinion that BELVIQ could not have been approved for weight control in obese and overweight patients” because “the benefits of BELVIQ did not outweigh its risks.” The committee’s safety concerns included “the potential risk of psychiatric disorders (such as depression) and valvulopathy.”[8]

Shortly after it approved lorcaserin, the FDA approved a combination of phentermine and topiramate (now marketed as QSYMIA in the U.S.) despite concerns about its cardiovascular risk. In studies the proportion of patients with pulse increases exceeding 10 beats per minute, a risk factor for cardiovascular disease,[9] was significantly higher in the high dose QSYMIA group than in the placebo group.[10] In patients in the mid-dose QSYMIA group, the incidence of arrhythmia related adverse events was 4.2%, compared with 1.8% in the placebo group.[11] Metabolic acidosis — significantly higher in patients taking QSYMIA — can be a risk factor for cardiac arrhythmias.[12] Metabolic acidosis resulted in increased nephrolithiasis: 22 cases in the QSYMIA groups, five in the placebo group.[13] Cognitive related adverse events, including memory impairment and reduced concentration or attention, occurred in 1.7% of placebo patients and 5.6% of mid-dose QSYMIA patients.[14]

An FDA analysis of serious adverse cardiovascular outcomes in randomized clinical trials of QSYMIA found six events in 743 patients taking QSYMIA but none in 227 placebo patients. These events included myocardial infarction or acute coronary syndrome in four patients.[15] However, patients in the mid-dose QSYMIA groups in the randomized trials lost 6.7% more weight than patients in the placebo groups.[16]

When QSYMIA was approved in July 2012, the FDA hailed it as another treatment option but decided that a study was needed to clarify the risks of major adverse cardiac events such as heart attack and stroke — but only after it was on the market. The FDA also required training of prescribers and certification of pharmacies and a patient leaflet giving important safety information.[17]

The EMA rejected QSYMIA for the second time in February 2013, noting that “the main studies showed clinically relevant weight loss following treatment with QSIVA [the European name for QSYMIA]” but that it had “concerns about the medicine’s long-term effects on the heart and blood vessels” and “about the long-term psychiatric effects (depression and anxiety were reported in the studies) and cognitive effects (such as problems with memory and attention).”[18] It concluded that “the benefits of QSIVA did not outweigh its risks and recommended that it be refused marketing authorisation.”[18]

Thus, two more diet drugs, following in the footsteps of the now banned phenylpropanolamine, dexfenfluramine, sibutramine and others, were found by the EMA to be too dangerous to be used for weight loss but are considered by the FDA to be “safe enough” for Americans.

This safe diet drug delusion recalls the editorial by the U.K. endocrinologist Gareth Williams after sibutramine was removed from the European market by the EMA but was, unfortunately, still available for many more months in the US until it was banned. He wrote, “The fate of sibutramine reminds us how little antiobesity drugs have had to offer — at best, a reduction of a few per cent in the total burden of excess weight carried until death. With energy homoeostasis so deeply enmeshed in physiology, it has always seemed unlikely that a magic bullet could ever switch off food intake without hitting something vital.”[19]

This is not to say that the EMA is perfect but rather that its recent record on drugs such as these puts the FDA to shame. It is not the resistance of Americans to the risks of these drugs but the intermittently dangerous malleability of the FDA that is the problem in the cases discussed here.

References

[1] Food and Drug Administration. Medications target long-term weight control. Jul 2012. www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM312391.pdf.

[2] Cohen D. European regulatory body recommends suspension of rosiglitazone. BMJ 2010;341:c5291.

[3] FDA. FDA approves Belviq to treat some overweight or obese adults [press release]. 27 Jun 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm.

[4] FDA. NDA 22529: lorcaserin hydrochloride tablets, 10 mg [FDA briefing document for 10 May 2012 advisory committee meeting]. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303198.pdf: 57.

[5] FDA. NDA 22529: lorcaserin hydrochloride tablets, 10 mg [FDA briefing document for 10 May 2012 advisory committee meeting]. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303198.pdf: 76.

[6] FDA Center for Drug Evaluation and Research. Endocrinologic and Metabolic Drugs Advisory Committee meeting Thursday, May 10, 2012. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM309522.pdf: 328, 354.

[7] FDA Center for Drug Evaluation and Research. Application number 022529Orig1s000: approval letter. www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022529Orig1s000Approv.pdf: 6.

[8] European Medicines Agency. Withdrawal of the marketing authorisation application for Belviq (lorcaserin). 30 May 2013. www.ema.europa.eu/docs/en_GB/document_library/Medicine_QA/2013/05/WC500143811.pdf.

[9] Palatini P. Elevated heart rate: a “new “cardiovascular risk factor? Prog Cardiovasc Dis 2009;52:1-5.

[10] FDA. Clinical briefing document: Endocrinologic and Metabolic Drugs Advisory Committee meeting February 22, 2012. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM292315.pdf: 94.

[11] Colman E. 15 July 2010, Advisory Committee meeting for phentermine/topiramate (Qnexa) [briefing memo]. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218824.pdf: 6.

[12] Colman E. 15 July 2010, Advisory Committee meeting for phentermine/topiramate (Qnexa) [briefing memo]. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218824.pdf: 5.

[13] Colman E. 15 July 2010, Advisory Committee meeting for phentermine/topiramate (Qnexa) [briefing memo]. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218824.pdf: 5.

[14] Colman E. 15 July 2010, Advisory Committee meeting for phentermine/topiramate (Qnexa) [briefing memo]. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218824.pdf: 4.

[15] FDA. Clinical briefing document: Endocrinologic and Metabolic Drugs Advisory Committee meeting February 22, 2012. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM292315.pdf: 58, 71.

[16] Colman E. 15 July 2010, Advisory Committee meeting for phentermine/topiramate (Qnexa) [briefing memo]. www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM218824.pdf: 2.

[17] FDA. FDA approves weight-management drug Qsymia. 17 Jul 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm.

[18] EMA. Refusal of the marketing authorisation for Qsiva (phentermine/topiramate): outcome of re-examination. 21 Feb 2013. www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002350/WC500139215.pdf.

[19] Williams G. Withdrawal of sibutramine in Europe. BMJ 2010;340:c824.