Troubling New Drug Approvals in 2012

Following a decade-long downturn in the number of new drugs it approved each year, the Food and Drug Administration (FDA) in the past three years has approved an increasing number of new drugs, with 21 approved in 2010, 30 in 2011 and 39 in 2012 — the highest number since 1996.

Innovative and life-saving new drugs for which risks do not outweigh benefits are vital tools in preventing or slowing the progression of disease. However, as in previous years, the new drug approvals in 2012 included many that were neither innovative nor effective but that were known to have serious safety concerns, even before approval. Below is an overview of the most concerning new drugs of 2012, as well as newly approved versions of or uses for existing drugs, all of which were opposed by Public Citizen.

Ineffective and/or dangerous new drugs approved in 2012: Do Not Use

Florbetapir F-18 (approved April 2012)

Florbetapir F-18 (AMYVID) is a radioactive tracer developed to detect early signs of Alzheimer’s disease (AD) through an advanced brain-imaging technique known as a positron emission tomography (PET) scan. Unfortunately, the tracer has been consistently shown to lack accuracy in quantifying a particular biological marker of AD in the brain: Researchers comparing the images the tracer produces to autopsy results have noted large discrepancies. Also, interpreting the images is difficult, with a high rate of variation between different radiologists’ interpretations. Finally, a false AD diagnosis can lead to needless therapy with dangerous and ineffective medications, such as donepezil 23 milligram (ARICEPT 23), as well as heightened anxiety for patients and their families. For these reasons, Public Citizen opposes florbetapir F-18 until more definitive evidence of its accuracy is available.

Mirabegron (approved June 2012)

Mirabegron (MYRBETRIQ) is a new drug developed to treat overactive bladder, a condition characterized by urinary urgency or incontinence. In the pre-approval clinical trial, the drug yielded only a marginal benefit in terms of reduced incontinence episodes and increased urinary volume, and it seemed to cause a number of adverse effects, including an increase in blood pressure, allergic reaction, urinary infection and possible liver toxicity. In a letter to the FDA, Public Citizen noted that the extremely limited clinical benefit of the drug, particularly in the context of a vaguely defined and non-life-threatening disease, did not justify the serious risks and urged the FDA to deny approval.

Lorcaserin (approved June 2012) and phentermine-topiramate (approved July 2012)

Lorcaserin (BELVIQ) and phentermine-topiramate (QSYMIA) are the latest in a series of obesity-related drugs posing serious health threats, as Public Citizen noted in testimonies and press statements opposing both approvals. Several earlier diet drugs we have opposed have been withdrawn from the market due to increased cardiovascular risk: Sibutramine (MERIDIA) was pulled due to evidence of an increased risk of heart attacks and strokes, fenfluramine (PONDIMIN) and dexfenfluramine (REDUX) because of heart-valve problems, and ephedrine because of heart attacks and strokes.

Public Citizen noted that the latest diet drugs present some of the same risks, as lorcaserin also seemed to cause heart-valve damage (as with REDUX), while phentermine-topiramate caused increased heart rate — a strong predictor of future heart attack (as caused by ephedrine) — in addition to numerous other troubling side effects in the pre-approval clinical trials.

The day before lorcaserin was approved, the Annals of Internal Medicine published online a recommendation from the U.S. Preventive Services Task Force (USPSTF) against using diet drugs. Referring to currently marketed diet drugs, the USPSTF concluded that because of safety problems and a lack of data showing that people can keep weight off after discontinuing diet medications, it could not recommend that anyone use diet drugs.

Lomitapide (approved December 2012) and mipomersen (approved January 2013)

Two drugs that came up for approval in October prompted Public Citizen opposition. Lomitapide (JUXTAPID) and mipomersen (KYNAMRO) both were developed to treat a very rare, fatal genetic condition, homozygous familial hypercholesterolemia (HoFH), which causes very high blood cholesterol levels.

The pivotal studies supporting approval for both drugs were unethical and withheld an effective, standard and life-prolonging treatment — LDL apheresis — from patients with HoFH, Public Citizen said in its testimony opposing approval to the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. Both drugs also caused significant liver damage in a large number of patients in the trials, and mipomersen also may be carcinogenic.

Given that there are only approximately 300 HoFH patients in the U.S. (many of whom will not be able to afford the hundreds of thousands of dollars per year in drug costs), Public Citizen noted that the drugs would almost certainly be prescribed “off-label” for patients with high, but not as dangerous, cholesterol levels, in whom the risks of these two new drugs would almost certainly outweigh any benefits and for whom effective treatments already exist.

Bedaquiline (approved December 2012)

In December, Public Citizen sent a letter to the FDA strongly opposing the accelerated approval of a new drug for tuberculosis (TB) called bedaquiline (SIRTURO). Patients taking the drug in addition to standard TB treatment during a small, phase 2 (premarket) clinical trial were five times more likely to die than those who took a placebo with standard TB treatment.

Public Citizen also urged the FDA to consider if future (larger) phase 3 trials would be ethical. The fact that bedaquiline is part of an entirely new class of drugs means that an increased level of scrutiny should be required for its approval. But by the time of approval, the FDA had not yet answered concerns related to unexplained increases in toxicity and death in patients getting the drug — a common question in new drug classes — even though the agency admitted that the drug could be the culprit.

Inhaled loxapine (approved December 2012)

An inhaled form of loxapine (ADUSAVE), a drug already approved in capsule form for the long-term treatment of schizophrenia, was approved for treatment of acute agitation in patients with schizophrenia and bipolar disease. Public Citizen wrote a letter to the FDA opposing approval because the drug has been shown to cause significant, life-threatening lung toxicity (particularly in patients with asthma and chronic obstructive pulmonary disease) and fails to provide any significant benefits in comparison to currently available, FDA-approved alternative drugs.

Two drugs fail to expand their existing markets

Rilonacept for the treatment of gout (rejected in July 2012)

Rilonacept (ARCALYST) was approved by the FDA in 2008 for treating a group of rare, serious genetic disorders called cryopyrin-associated periodic syndromes, which cause widespread inflammation in the body. In 2012, the manufacturer sought additional approval to also market the drug to prevent acute flares of gout in adult gout patients. However, in testimony to an FDA advisory committee in May, Public Citizen noted that the drug provides only trivial clinical benefits but exposes patients to a known risk of serious infections and possibly to a slightly increased risk of malignancies and adverse cardiac events. Additionally, other, safer treatments to prevent gout flares are already on the market. The advisory committee unanimously recommended rejecting the drug for the treatment of gout, prompting the FDA to turn down the manufacturer’s application.

Rivaroxaban for treatment of heart attacks (rejected in July 2012)

Rivaroxaban (XARELTO) was approved in 2011, first for preventing blood clots in patients undergoing knee or hip surgery and then for treating the heart arrhythmia atrial fibrillation. The drugmaker sought additional approval for the treatment of Acute Coronary Syndrome (ACS, which includes heart attacks and unstable angina), which would have greatly expanded the use of the drug.

As a member of the FDA advisory committee reviewing the proposed new indication for this drug for ACS, Worst Pills, Best Pills News Editor Dr. Sidney Wolfe opposed approval due to concerns about increased bleeding risks, incomplete data, and because the comparison group for rivaroxaban had not been adequately treated with other drugs. An overall concern of the advisory committee was that the approval of this risky drug for treating ACS would mean that the standard for treatment would now be expanded beyond the current two drugs, aspirin and an antiplatelet drug. The advisory committee voted against approval, and the FDA concurred.

Expedited approvals, orphan drugs and ‘me-too’ medicines

One major reason for the dramatic increase in new drug approvals in 2012 was the FDA’s expedited approval pathway, which allows certain drugs to be approved with shorter, smaller and/or fewer clinical trials, as well as quicker FDA review based on short-term laboratory values (e.g., lowering blood cholesterol levels) rather than long-term clinical outcomes (e.g., decreased death or improved disease). At least 10 of the 39 new drugs in 2012 were approved through this pathway.

According to the FDA, only drugs that treat “serious diseases” and that “fill an unmet medical need” can qualify for expedited approval. However, as Public Citizen pointed out in the case of bedaquiline, these vague criteria can be misused to justify the premature approval of potentially dangerous drugs.

Medications for rare diseases, or orphan drugs, were also common among last year’s drug approvals. The strong, positive Wall Street reaction to the approval of these drugs, such as lomitapide, indicates that off-label prescribing is almost certain to occur due to the lack of a sufficient market in the small patient population for whom the drugs are intended.

Finally, several new drugs approved in 2012 were not truly innovative, but rather very minor structural variants of existing drugs. These so-called “me-too medicines” often fail to provide significant benefits over the older drugs in a given class, and less is known about their risks. One example from the past year is avanafil (STENDRA) for the treatment of erectile dysfunction, which is a structural variant of sildenafil (VIAGRA).

What to expect in 2013

The trend of increased new drug approvals seen over the past three years is expected to continue in 2013. It remains to be seen whether this year’s approved drugs will be even more dangerous than many of their highly worrisome 2012 counterparts.

The last period that saw such a sizeable volume of new drug approvals, with a similarly high number of accelerated approvals, perhaps represents a cautionary tale of what to expect going forward. An unusually large proportion of the record number of new drugs approved in 1996 (53) and 1997 (39) were later banned because of serious safety problems.