FDA Approves Neurotoxic Flu Drug For Infants Less Than One

FDA Approves Neurotoxic Flu Drug For Infants Less Than One

Whereas the flu is self-limiting, the FDA’s capacity for bad decisions is not…

The recent decision by the FDA to approve the use of the antiviral drug Tamiflu for treating influenza in infants as young as two weeks old, belies an underlying trajectory within our regulatory agencies towards sheer insanity.

Tamiflu, known generically as oseltamivir, has already drawn international concern over its link with suicide deaths in children given the drug after its approval in 1999. In fact, in 2004, the Japanese pharmaceutical company Chugai added “abnormal behavior” as a possible side effect inside Tamiflu’s package.  The FDA also acknowledged in its April, 2012 “Pediatric Postmarket Adverse Event Review” of Tamiflu that “abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions” are possible side effects.[i]

Recent animal research on Tamiflu has found that the infant brain absorbs the drug more readily than the adult brain,[ii]  [iii]lending a possible explanation for why neuropsychiatric side effects have been observed disproportionately in younger patients.

The very mechanism of Tamiflu’s anti-influenza action may hold the key to its well-known neurotoxicity. Known as a neuromindase inhibitor, the drug inhibits the key enzyme within the flu virus that enables it to enter through the membrane of the host cell.  So fundamental is this enzyme that viruses are named after this antigenic characteristic. For instance,  the “N” in H1N1 flu virus is named for type 1 viral neuromindase.

Mammals, however, also have neurimindase enzymes, known as ‘sialidase homologs,’ with four variations identified within the human genome so far; NEU1,NEU2,NEU3 and NUE4.  These enzymes are important for neurological health. For example, the enzyme encoded by NEU3, is indispensable for the modulation of the ganglioside content of the lipid bilayer, which is found predominantly in the nervous system and constitutes 6% of all phospholipids in the brain.

It is therefore likely that neurimindase-targeted drugs like Tamiflu are simply not selective enough to inhibit only the enzymes associated with influenza viral infectivity. They likely also cross-react with those off-target neurimindase enzymes associated with proper neurological function within the host. This “cross reactivity” with self-structures may also explain why the offspring of pregnant women given Tamiflu have significantly elevated risk of birth defects (10.6%) relative to background rates (2-3%), according to a 2009 safety review by the European Medicines Agency.

Beyond the recognition of Tamiflu’s intrinsic toxicity, there are two additional problems with the use Tamiflu in infants:

  1. Infants do not yet have a sufficiently developed blood-brain barrier capable of keeping the chemical out of their rapidly developing brains
  2. Their detoxification systems are not sufficiently developed to remove the chemical rapidly enough to prevent harm

The FDA’s decision to include infants under one as treatable with Tamiflu is all the more disturbing when you consider that a 2010 study published in The Pediatric Infectious Disease Journal found that of 157 evaluable infants (mean age 6.3 months) treated for influenza with Tamiflu, complications due to the medication were found in the majority (54%) of the treated group.

According to the study

Complications were recorded in 84 patients (54%), the most serious of which were meningitis in 1 infant (1%), pneumonia in 9 (6%), and otitis media in 2 (1%).

Are meningitis, pneumonia and otitis media (ear infection) acceptable risks for treating influenza? Apparently for the FDA, it is.

How about death? Is that an acceptable risk of Tamiflu treatment for flu, a self-limiting disease?

In 2011, the International Journal of Vaccine Risk and Safety in Medicine published an article titled, “Oseltamivir and early deterioration leading to death: a proportional mortality study for 2009A/H1N1 influenza,” described 119 reports of Tamiflu-induced death. According to the study:  “of 119 deaths after Tamiflu was prescribed, 38 deteriorated within 12 hours (28 within 6 hours).”

The study concluded:

These data suggest Tamiflu use could induce sudden deterioration leading to death especially within 12 hours of prescription. These findings are consistent with sudden deaths observed in a series of animal toxicity studies, several reported case series and the results of prospective cohort studies. From “the precautionary principle” the potential harm of Tamiflu should be taken into account and further detailed studies should be conducted.

So, how did the FDA justify its decision to consider Tamiflu safe in infants under one year? Did it use controlled, randomized, placebo-controlled trials to ascertain safety?  Of course not. Testing drugs on infants is unethical, and no parent in their right mind would enroll their newborn in such a trial. Lacking definitive evidence of safety, the FDA’s expanded approval in children younger than one year was based on extrapolation of data from previous results in adults and older children.[iv]  This, of course, is inappropriate as it denies the aforementioned differences in the susceptibility to drug toxicity and neurotoxicity between infants and older individuals.  It also avoids proper consideration of the studies in the biomedical literature indicating its potential for severe, if not life-threatening toxicity to infants, children and adults alike.

Another concern, not addressed in the FDA announcement, is that as of Dec. 15th, 2010, the World Health Organization has acknowledged that, based on over 300 tested worldwide samples of the 2009 pandemic H1N1 flu, resistance to Tamiflu is growing.[v]  Therefore, treating an infant with Tamiflu-resistant influenza would not only do nothing to combat the infection, but would poison that child and further disable their natural immune response.

The clear winner in the FDA’s decision will be the bottom line of Roche, the manufacturer of this patented chemical.  How much longer can the FDA continue to expect those subject to its regulatory decisions to maintain the illusion that it is interested in the public welfare?

We must remember that infants do not get sick from the flu as a result of Tamiflu deficiency, or flu vaccine deficiency for that matter.  They do get sick from the immune-disrupting effects of synthetic chemicals completely foreign to human physiology (such as Tamiflu), and lack of vital hormone modulating compounds that result from adequate sunlight exposure (vitamin D3), and good nutrition.

For additional information on this topic view our research on natural anti-influenza agents.


Hemophilia B Treatment Refixia Passes Key EU Regulatory Hurdle

Hemophilia B Treatment Refixia Nears European Union Approval
Novo Nordisk’s hemophilia B treatment Refixia has cleared a major hurdle toward European Union approval.

An arm of the European Medicines Agency (EMA) known as the Committee for Medicinal Products for Human Use (CHMP) has recommended approving Refixin for preventing and treating patients 12 years and older with hemophilia B, or congenital factor IX deficiency. The European Commission will make the final decision on approval.

The EU designated Refixia (nonacog beta pegol, N9-GP) an orphan drug on May 15, 2009. The EMA said in a press release that the new recommendation covers Refixia as a powder and solvent for injection. The doses it covers include 500 IU, 1000 IU and 2000 IU.

Nonacog beta pegol, the active ingredient in Refixia, is a recombinant coagulation factor IX. It replaces the missing factor IX in patients with hemophilia B, helping the blood to clot and providing temporary bleeding control.

CHMP’s Refixia recommendation was based on the results of a Phase 3 clinical trial that enrolled 115 children and adults with moderately severe to severe hemophilia B.

Novo Nordisk reported in January 2016 that trial investigators found Refixia effective in preventing and treating bleeding episodes, and controlling bleeding in surgery. The treatment was well-tolerated, with no safety problems, the investigators said.

Refixia’s half-life was five times longer than that of other factor IX products, the trial results showed.  Participants achieved a higher level of factor IX in their blood than with other products, even with less frequent doses of Refixia. A drug’s half-life is the amount of time it takes for its effectiveness to drop in half.

The trial also found that 40 IU/kg of Refixia once per week kept patients’ factor IX levels above 15 percent, and reduced their median annualized bleeding rate (ABR) to 1.0. In addition, the treatment showed potential in preventing joint bleeding, and in improving patients’ quality of life.

“We are excited about the positive opinion obtained for Refixia, Mads Krogsgaard Thomsen, executive vice president and chief scientific officer of Novo Nordisk, said in a press release. It represents a significant milestone in our efforts to expand the treatment options for patients with haemophilia. We believe Refixia with its strong clinical profile provides hemophilia B patients better protection against bleeds, even into damaged joints, and an overall improved quality of life.”


Sandoz biosimilar etanercept recommended by FDA advisory committee for approval to treat multiple inflammatory diseases

Sandoz, a Novartis division and leader in biosimilars, announced today that the US Food and Drug Administration (FDA) Arthritis Advisory Committee recommended approval of its proposed biosimilar etanercept. The committee voted unanimously (20-0), in support of biosimilar etanercept for all five indications of the reference product, including rheumatoid arthritis (RA), plaque psoriasis (PsO), psoriatic psoriasis (PsA), ankylosing spondylitis (AS) and polyarticular juvenile idiopathic arthritis (JIA).

 “We are encouraged by today’s favorable advisory committee recommendation for our proposed biosimilar etanercept,” said Mark McCamish, M.D., Ph.D., Head of Global Biopharmaceutical Development, Sandoz. “As a global market leader in biosimilars, we are pleased to move one step closer toward our goal of expanding patient access with our proposed biosimilar etanercept, and look forward to continuing to work with the FDA as they complete their review of our application.”

 The recommendation was provided after the presentation of data from a global development program including analytical, pre-clinical and clinical studies of the Sandoz biosimilar etanercept, which demonstrated biosimilarity to the reference product. Clinical studies included four comparative pharmacokinetic (PK) studies in 216 healthy volunteers** and a confirmatory efficacy and safety similarity study in 531 patients with chronic plaque psoriasis.

 The FDA frequently seeks the advice of its advisory committees as it reviews and decides whether to approve applications, although the agency does not always follow their recommendations.

 In December 2015, the European Medicines Agency (EMA) accepted Sandoz Marketing Authorization Application (MAA) for its biosimilar to Amgen’s EU-licensed Enbrel®, which seeks approval for the same indications as the reference product.

 Sandoz is committed to providing patient access to high-quality, life-enhancing biosimilars. It is the pioneer and global market leader and currently markets three biosimilars worldwide. Sandoz has a leading pipeline with several biosimilars in late stage development, including assets in immunology and oncology. As part of the Novartis Group, Sandoz is well-positioned to lead the biosimilars industry based on its experience and capabilities in development, manufacturing and commercialization.


About GP2015

GP2015, the Sandoz proposed biosimilar of Enbrel®, has been studied in a global development program, which included a comprehensive comparison of GP2015 and Enbrel® at the analytical, non-clinical, and clinical levels, including data from four pharmacokinetic (PK) studies (GP15-101, GP15-102, GP15-103 and GP15-104**) involving a total of 216 healthy volunteers, as well as data from a confirmatory efficacy and safety study of 531 patients with moderate-to-severe chronic plaque psoriasis (PsO) (GP15-302). The development program also included five non-clinical studies. The proposed indications for GP2015 are identical to the indications for Enbrel® in rheumatoid arthritis (RA), PsO, psoriatic psoriasis (PsA), ankylosing spondylitis (AS) and polyarticular juvenile idiopathic arthritis (JIA).

Sleep-Wake Disorder Drug Hetlioz Gets Nod in Europe

The European Medicines Agency (EMA) has recommended marketing authorization for tasimelteon (Hetlioz), a melatonin-receptor agonist, for the treatment of adults with a chronic circadian rhythm condition called non–24-hour sleep-wake disorder (non-24).

Tasimelteon would represent the first European Union (EU) treatment for non-24, the agency said in a press release.

The drug was approved early last year by the US Food and Drug Administration (FDA), also the first FDA approval of a treatment for the disorder.

Non-24 is a rare condition that occurs almost exclusively in blind people. Because they don’t perceive light, these patients fall asleep and wake up at different times compared with the general population, often in a pattern that is closer to a 25-hour clock.

As a result, they have problems adjusting to the standard timetable of everyday life, often being awake or asleep at unusual times. Many experience excessive daytime sleepiness, which affects their quality of life and ability to follow a normal daily schedule.

Melatonin, produced by the pineal gland during hours of darkness, plays a key role in coordinating the body’s sleep cycle by acting on receptors in the brain.

The effectiveness of tasimelteon was demonstrated in two clinical trials. These studies showed that treatment resulted in significant improvement compared with placebo, both in increasing night-time sleep and decreasing daytime sleep duration.

The most common adverse effects include headache, drowsiness, and nightmares or unusual dreams.

Orphan Drug
In 2011, tasimelteon received an orphan designation in Europe. This designation and the associated incentives, such as scientific advice, are among the most important instruments to encourage the development of medicines for patients with rare diseases, said the press release.

The opinion adopted by the Committee for Medicinal Products for Human Use (CHMP) at its meeting this month is an intermediary step on Hetlioz’s path to patient access. This opinion will now be sent to the European Commission for the adoption of a decision on EU-wide marketing authorization.

Once marketing authorization is granted, each Member State will decide on price and reimbursement, considering the potential role/use of this medicine in the context of the national health system of that country.

The marketing authorization applicant for Hetlioz is Vanda Pharmaceuticals Limited, United Kingdom. In the United States, the drug is manufactured by Vanda Pharmaceuticals Inc, Washington, DC.

According to the FDA, up to 100,000 Americans have non-24 and can’t perceive enough light to establish a normal night sleep schedule. If prescribed tasimelteon, they should take this drug at the same time every night before bedtime and limit activities after taking it.

CardioBreak: Bad Marriages, HF Prevention?

Early-stage data with plasma-derived alpha-1 antitrypsin suggests a single injection in ST-elevation MI dampened inflammation and reduced heart failure incidence over 12 weeks.

A bad marriage can be bad for the heart, especially for women, a study of middle age and older adults showed.

The first women’s heart health organization, Sister to Sister: The Women’s Heart Health Foundation, is calling it quits after 15 years; Cedars-Sinai takes over the group’s patient education materials.

Diversity in clinical trials is poor, according to a snapshot from the FDA.

For men, European regulators determined that there’s no consistent evidence for elevatedcardiovascular risk with testosterone medicines. An FDA advisory committee was more convinced that the risk was real, as MedPage Today reported in September.

The European Medicines Agency did, though, recommend taking measures to reduce risk of heart attack and bradycardia in patients taking ivabradine for angina (the drug is approved there as Corlentor/Procoralan). See MedPage Today coverage of its flop in the SIGNIFY trial.

The PreSERVE-AMI trial wasn’t a total bust, despite missing a primary endpoint with autologous stem cells in acute MI, according to some researchers.

More negative data on digoxin in atrial fibrillation emerged from Kaiser Permanente databases.

The Aorfix endovascular stent for abdominal aortic aneurysm repair did well in its pivotal trial.

The first large-scale study of inferior vena cava filters — the PRESERVE trial — is underway in response to an FDA warning about risk of migration and breakage. The collaboration among seven IVC filter manufacturers and two professional societies will start enrolling patients in the spring.

The Cardiovascular Safety of Diabetes Drugs — Insights from the Rosiglitazone Experience.

The management of type 2 diabetes has been challenged by uncertainty about possible cardiovascular effects related to treatment intensity and choice of drug. Although the Food and Drug Administration (FDA) considers a decrease in glycated hemoglobin an approvable end point, very intensive glycemic control is associated with increased cardiovascular and all-cause mortality.1 The safety of specific drugs for type 2 diabetes — particularly the thiazolidinediones — has also been questioned. After rosiglitazone had been approved in the United States in 1999 and in Europe in 2000, a highly publicized meta-analysis in 2007 reported a 43% increase in myocardial infarction (P=0.03) and a 64% increase in death from cardiovascular causes (P=0.06).2 This report and subsequent FDA advisory committee reviews led to a boxed warning of myocardial ischemia in 2007 and highly restricted access to rosiglitazone in 2010. In 2010, the FDA placed a full clinical hold on the Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial (ClinicalTrials.gov number, NCT00879970), a large cardiovascular-outcome trial designed to evaluate the benefit of rosiglitazone and pioglitazone as compared with placebo (superiority hypothesis) and the safety of rosiglitazone as compared with pioglitazone (noninferiority hypothesis). In part owing to the rosiglitazone experience, the FDA issued an updated Guidance for Industry in 2008 requiring that preapproval and postapproval studies for all new antidiabetic drugs rule out excess cardiovascular risk, defined as an upper bound of the two-sided 95% confidence interval for major adverse cardiovascular events (MACE) of less than 1.80 and less than 1.30, respectively.3 Regardless of the presence or absence of preclinical or clinical signals of cardiovascular risk, the guidance has been applied broadly to all new diabetes drugs, creating substantial challenges in the drug development and approval process.

On June 5 and 6, 2013, the FDA held a joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (on which we serve) and the Drug Safety and Risk Management Advisory Committee to further evaluate the cardiovascular safety of rosiglitazone. When rosiglitazone was approved in Europe, the European Medicines Agency raised concern about the cardiovascular risks of the thiazolidinedione class, including fluid retention, heart failure, and increased levels of low-density lipoprotein cholesterol. This concern led to a postmarketing requirement that cardiovascular-outcome trials be conducted for both pioglitazone and rosiglitazone, and these were reviewed at subsequent FDA meetings. Although the results of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) study (NCT00379769) did not suggest an increased risk of MACE,4issues with trial design and data integrity led the FDA to require the sponsor to perform an independent readjudication of the data. This extensive exercise, performed by the Duke Clinical Research Institute, had a minimal effect on the overall point estimates and confidence intervals for MACE, which remained at less than 1.30. The result was consistent with the FDA guidance and provided reassurance that rosiglitazone was not associated with excess cardiovascular risk.

Two groups of authors (Scirica et al. and White et al.) now report in the Journal the results of large, placebo-controlled, cardiovascular-outcome trials, these involving saxagliptin and alogliptin, members of the incretin drug class. Neither of these drugs had shown increased cardiovascular risk in its development program. Both trials were designed to first rule out excess cardiovascular risk by means of noninferiority testing; if that was shown, superiority testing followed, on the assumption that better glycemic control might yield cardiovascular benefit. Both trials clearly met the FDA 2008 guidance for cardiovascular safety, but neither showed a reduction in cardiovascular events. Saxagliptin was associated with an unexpected increased risk of hospitalization for heart failure and a high frequency of hypoglycemia. Neither trial showed any increased risk of pancreatic adverse events, including cancer.

Before rosiglitazone, the cardiovascular safety of diabetes drugs had not been well studied. The initial concern with rosiglitazone arose from observational and case–control epidemiologic studies that generated a legitimate signal of possible cardiovascular harm, but every study had substantial methodologic shortcomings, including multiplicity, which meant that a statistically positive finding might be a false positive result.5 Meta-analyses were also performed with preapproval studies that had been designed to show a positive glycemic effect as the primary end point. These studies enrolled patients at low cardiovascular risk, were short in duration, used both placebo and active controls, and did not prospectively adjudicate cardiovascular safety events. In such situations, comparison of a new drug with an active agent is challenged by the uncertain cardiovascular risk of the active comparator. In contrast, a placebo-controlled design may lead to imbalances in background therapy (as was the case with saxagliptin) that could influence the cardiovascular outcomes. Meta-analyses of these premarketing trials from phase 3 development programs were therefore relatively insensitive in assessing cardiovascular risk, making dedicated postmarketing cardiovascular-outcome trials such as the RECORD study necessary to substantiate any risk signals. But the design of the RECORD study had substantial limitations that precluded a complete assessment of the cardiovascular safety of rosiglitazone.

In 2010, the FDA took a cautious stance and limited exposure to rosiglitazone, given the numerous alternative therapies that were available. But this position did not acknowledge the uncertainty of cardiovascular risk associated with other diabetes drugs on the market, and the FDA decision may have had unintended consequences. The intense publicity about the ischemic cardiac risk of rosiglitazone may have diverted attention from the better-established risk of heart failure that is common to the drug class. Restricted access led patients to switch from rosiglitazone to other diabetes drugs of unproven cardiovascular safety. Patients who had a myocardial infarction while taking rosiglitazone may have concluded that the drug was the cause, adversely affecting their perceptions of their doctor, drug companies, and the FDA. And placing a hold on the TIDE trial, although arguably justifiable, prevented any further clarification of the cardiovascular risks or benefits of the thiazolidinedione drug class. The rosiglitazone experience also raises the question of how to define a regulatory standard for withdrawing drugs from the market. New drug approvals are based on “substantial evidence” of drug safety and efficacy. But there is little guidance on what constitutes substantial evidence of harm that is sufficient to justify market withdrawal or the imposition of severe market restrictions.

What have we learned from the rosiglitazone experience? Clearly, the presumed cardiovascular risks of rosiglitazone led to a major change in FDA policy regarding the approval of all new diabetes drugs. From a cardiovascular perspective, rosiglitazone, saxagliptin, and alogliptin appear to be relatively safe. It is disappointing, however, that neither intensive glycemic control nor the use of specific diabetes medications is associated with any suggestion of cardiovascular benefit. Thus the evidence does not support the use of glycated hemoglobin as a valid surrogate for assessing either the cardiovascular risks or the cardiovascular benefits of diabetes therapy.

Patients with type 2 diabetes and their physicians currently have numerous treatment options, and additional drugs are in development. Perhaps the recent experience with rosiglitazone will allow the FDA to become more targeted in its adjudication of the cardiovascular safety of new diabetes drugs, focusing the considerable resources needed to rule out a cardiovascular concern only on drugs with clinical or preclinical justification for that expenditure. New therapies targeting glycemic control may have cardiovascular benefit, but this has yet to be shown. The optimal approach to the reduction of cardiovascular risk in diabetes should focus on aggressive management of the standard cardiovascular risk factors rather than on intensive glycemic control.

Source: NEJM


r�a>�,� �b� n> At 2.5 years, the rate of repeat revascularization was less frequent in the immediate– and staged–preventive PCI groups combined, as compared with the group receiving no preventive PCI (11% and 33%, respectively), and there was a nonsignificant decrease in the rate of cardiac death (5% and 12%, respectively). These studies were limited by a lack of statistical power and a reliance on repeat revascularization as an outcome, which, as indicated above, may be subject to bias. However, the results of these studies are consistent with those of our study.


Current guidelines on the management of STEMI recommend infarct-artery-only PCI in patients with multivessel disease, owing to a lack of evidence with respect to the value of preventive PCI.2-5 This uncertainty has led to variations in practice, with some cardiologists performing immediate preventive PCI in spite of the guidelines, some delaying preventive PCI until recovery from the acute episode, and others limiting the procedure to patients with recurrent symptoms or evidence of ischemia. The results of this trial help resolve the uncertainty by making clear that preventive PCI is a better strategy than restricting a further intervention to those patients with refractory angina or a subsequent myocardial infarction. However, our findings do not address the question of immediate versus delayed (staged) preventive PCI, which would need to be clarified in a separate trial.

Several questions remain. First, are the benefits of preventive PCI applicable to patients with non-STEMI?21 Such patients tend to be difficult to study because, unlike those with STEMI (in whom the infarct artery is invariably identifiable), there is often uncertainty over which artery is the culprit. Second, do the benefits extend to coronary-artery stenoses of less than 50%? There is uncertainty over the level of stenosis at which the risks of PCI outweigh the benefits. Third, would a physiological measure of blood flow, such as fractional flow reserve,22,23 offer an advantage over angiographic visual assessment in guiding preventive PCI? Further research is needed to answer these questions.

In conclusion, in this randomized trial, we found that in patients undergoing emergency infarct-artery PCI for acute STEMI, preventive PCI of stenoses in noninfarct arteries reduced the risk of subsequent adverse cardiovascular events, as compared with PCI limited to the infarct artery.


Source: NEJM




When EMA and FDA decisions conflict: differences in patients or in regulation?.

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 US 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 United States 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 US) 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 UK 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.

Source: BMJ

Drug licensed for advanced rare skin cancer.

Cancer experts have welcomed a move that makes a drug for patients with advanced skin cancer available in the UK.
Regulators have licensed Erivedge (vismodegib) for people with severe basal skin carcinoma.
Currently, treatment is limited to surgery or radiotherapy.
Cancer Research UK, whose scientists discovered the mechanisms the drug uses, said the decision was “great news for patients”.
Basal cell carcinoma is the most common form of skin cancer in the UK and is often found on the head and neck.
Around 700 people a year in the UK are diagnosed with an advanced form of the cancer – a small number, but cancer experts say the lack of treatment options currently available is what makes this change significant.
Many will have already had surgery and radiotherapy, and it is often considered inappropriate for them to have further procedures
Continue reading the main story
“Start Quote
“This drug is a major advance for the treatment of this disease” ”
Dr Harpal KumarCancer Reseach UK
Erivedge, made by Roche, had to be licensed by the European Medicines Agency before it could be made available in the UK.
The drug, which patients take once a day, costs around £6,000 per month.
Clinicians who want to give it to their patients will have to apply to the Cancer Drugs Fund in England.
In Scotland, Wales and Northern Ireland, doctors would have to ask their local health provider to fund the drug.
Hedgehog pathway
The drug works by blocking a process in the body that has gone awry.
The hedgehog pathway is a chemical process that is normally only active in the early stages of life and which becomes less so in adulthood.
The reactivation of this process is responsible for cell growth in more than 90% of basal cell carcinoma cases.
Dr Harpal Kumar, chief executive of Cancer Research UK, said: “We are proud to have played a key role in the early development of this drug and we’re delighted that it has passed this regulatory hurdle and is approved for use in the UK.
“This drug is a major advance for the treatment of this disease, providing advanced basal cell carcinoma patients with a new treatment option.
“This is great news for patients.”
Source: Cancer experts have welcomed a move that makes a drug for patients with advanced skin cancer available in the UK.
Regulators have licensed Erivedge (vismodegib) for people with severe basal skin carcinoma.
Currently, treatment is limited to surgery or radiotherapy.
Cancer Research UK, whose scientists discovered the mechanisms the drug uses, said the decision was “great news for patients”.
Basal cell carcinoma is the most common form of skin cancer in the UK and is often found on the head and neck.
Around 700 people a year in the UK are diagnosed with an advanced form of the cancer – a small number, but cancer experts say the lack of treatment options currently available is what makes this change significant.
Many will have already had surgery and radiotherapy, and it is often considered inappropriate for them to have further procedures
Continue reading the main story
“Start Quote
“This drug is a major advance for the treatment of this disease” ”
Dr Harpal KumarCancer Reseach UK
Erivedge, made by Roche, had to be licensed by the European Medicines Agency before it could be made available in the UK.
The drug, which patients take once a day, costs around £6,000 per month.
Clinicians who want to give it to their patients will have to apply to the Cancer Drugs Fund in England.
In Scotland, Wales and Northern Ireland, doctors would have to ask their local health provider to fund the drug.
Hedgehog pathway
The drug works by blocking a process in the body that has gone awry.
The hedgehog pathway is a chemical process that is normally only active in the early stages of life and which becomes less so in adulthood.
The reactivation of this process is responsible for cell growth in more than 90% of basal cell carcinoma cases.
Dr Harpal Kumar, chief executive of Cancer Research UK, said: “We are proud to have played a key role in the early development of this drug and we’re delighted that it has passed this regulatory hurdle and is approved for use in the UK.
“This drug is a major advance for the treatment of this disease, providing advanced basal cell carcinoma patients with a new treatment option.
“This is great news for patients.”
Source: BBC


Novartis receives positive CHMP opinion for Ilaris® in active Systemic Juvenile Idiopathic Arthritis, a serious form of childhood arthritis.

  • The CHMP has endorsed the use of Ilaris® in patients aged 2 years and older who suffer from Systemic Juvenile Idiopathic Arthritis (SJIA)
  • In Phase III studies, 84% of Ilaris-treated SJIA patients achieved significant improvement of systemic and arthritic symptoms (pediatric ACR30) after a single subcutaneous dose[1]
  • Ilaris is the first interleukin-1 beta inhibitor to receive such an opinion for the treatment of SJIA and, once approved, will be the only treatment that is given as a monthly subcutaneous injection.


Basel, July 26, 2013 – Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the use of Ilaris® (canakinumab) in the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients aged 2 years and older. SJIA is a rare and disabling form of childhood arthritis with limited treatment options[2]. The condition is characterized by spiking fever, rash and arthritis that can affect children as young as 2 years old and can continue into adulthood[2],[3].


This opinion was based on two Phase III trials in SJIA patients, aged 2-19, which showed significant improvement in the majority of Ilaris-treated patients[1]. Study 1 showed that 84% of patients treated with one subcutaneous dose of Ilaris achieved the primary endpoint of the adapted pediatric American College of Rheumatology 30 (ACR30), compared to 10% achievement of ACR30 for placebo at Day 15[1]. In the open-label part of Study 2, 92 of 128 patients attempted “corticosteroid tapering”. Of those 92 patients, 62% were able to substantially reduce their use of corticosteroids, and 46% completely discontinued corticosteroids[1]. In the controlled portion of Study 2, there was a 64% relative reduction in the risk of flare for patients in the Ilaris group as compared to those in the placebo group (hazard ratio of 0.36; 95% CI: 0.17 to 0.75)[1].


CHMP recommended Ilaris for the treatment of active SJIA in patients aged 2 years and older who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. CHMP stated that Ilaris can be given as monotherapy or in combination with methotrexate.


“If approved, Ilaris would provide a new treatment option for patients whose choice of therapy has, to date, been very limited,” said Timothy Wright, MD, Global Head of Development, Novartis Pharmaceuticals. “This positive opinion by the CHMP is an important step towards the approval of Ilaris for SJIA in the EU.”


The European Commission generally follows the recommendations of the CHMP and usually delivers its final decision within three months of the CHMP recommendation.


The incidence of SJIA in Europe is thought to be around 0.4-0.8 per 100 000[3], with a prevalence estimated at 1-10 in 30,000 children[4]. Although the disease can be life-threatening, treatment options are limited. Corticosteroids are often used to treat symptoms and pain despite their long term use being associated with potentially serious adverse effects, including Cushing syndrome, growth suppression and osteoporosis[1].


Ilaris is being investigated in a number of inflammatory diseases where interleukin-1 (IL-1) beta is a key component of disease pathogenesis. These include rare autoinflammatory conditions for which approved treatments do not exist, including, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), colchicine-resistant Familial Mediterranean Fever (FMF) and Hyper IgD Syndrome (HIDS). Ilaris is considered an investigational agent for these conditions at this point in time. As such, the role that Ilaris could play in treating these conditions and potential benefit to patients is still being determined.


About the Pivotal Phase III Studies

Study 1, a 4-week, randomized, double-blind, placebo-controlled study, involved 84 patients between the ages of 2 and 19 years with active SJIA[1],[2]. Patients were treated with either a single subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) (n=43) or placebo (n=41)[1]. The primary endpoint was the proportion of patients achieving the adapted pediatric American College of Rheumatology (ACR) 30 response criteria and resolution of fever from baseline at Day 15[1]. This means that patients had at least a 30% improvement in systemic and arthritic symptoms versus baseline. The study met its primary endpoint.


Study 2, a two-part study, had an open-label, single-arm active treatment in Part I followed by a randomized, double-blind, placebo-controlled, event-driven withdrawal design in Part II[1]. A total of 177 patients between the ages of 2 and 19 years with active SJIA were enrolled in the study[1]. Some of these patients had previously participated in the Study 1. In Part I, patients received a subcutaneous dose of Ilaris (4 mg/kg, up to 300 mg) every 4 weeks[1]. The primary endpoint of Part I was to assess whether treatment with Ilaris allowed successful tapering of corticosteroids in at least 25% of SJIA patients who entered the study using a corticosteroid.


In Part II of the study, patients were randomized to either continue receiving Ilaris, or to receive placebo every 4 weeks (“placebo-after-Ilaris group”), until a pre-specified number (37) of flare-events (“flares”) had occurred[1]. The primary endpoint of Part II was to demonstrate that the time to flare was longer with Ilaris than with placebo.


The primary endpoints for Study 1 and Study 2 were all met.


About Ilaris

Ilaris is a selective, fully human, monoclonal antibody that inhibits IL-1 beta, which is an important part of the body’s immune system defenses[1]. Excessive production of IL-1 beta plays a prominent role in certain inflammatory diseases[5]. Ilaris works by neutralizing IL-1 beta for a sustained period of time, therefore inhibiting inflammation[1].


Ilaris is approved for the treatment of SJIA in the US and for the symptomatic treatment of refractory acute gouty arthritis in the EU. Ilaris is also approved in more than 60 countries, including in the EU, US, Switzerland and Japan for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), a rare, lifelong, genetic disorder with debilitating symptoms. The approved indication may vary depending upon the individual country.


[1] Ruperto N, Brunner H, Constantin T, et al. Baseline characteristics of patients with active Systemic JIA successfully discontinuing corticosteroid while receiving canakinumab: secondary analysis from a pivotal phase 3 trial. Abstract presented at European League Against Rheumatism, Madrid 12-15 June, 2013.
[2] Woo P. Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome. Nat Clin Pract Rheumatol 2006; 2(1):28-34.
[3] Ramanan AV, Grom AA. Does systemic-onset juvenile idiopathic arthritis belong under juvenile idiopathic arthritis? Rheumatology (Oxford) 2005; 44(11):1350-3.
[4] ORPHANET – http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=85414.Accessed 12th June 2013.
[5] Martinon F, Petrilli V. Gout-associated uric acid crystals activate the NALP3 inflammasome.Nature 2006; 440(9): 237-241.


Source: Novartis Newsletter


Diabetes treatments and cancer risk: the importance of considering aspects of drug exposure.


Investigations of the association between diabetes, diabetes treatments, and cancer risk have raised several epidemiological challenges. In particular, a patient’s exposure to glucose-lowering drugs needs to be represented accurately to allow unbiased assessment of the link between the treatments and cancer risk. Many studies have used a simple binary contrast (exposure to a specific drug vs no exposure), which has potentially serious drawbacks. In addition, methods used to determine the duration and cumulative dose of drug exposure differ widely between studies. In this Review, we discuss representation of drug exposure in pharmacoepidemiological investigations of the connection between diabetes drugs and cancer risk. We identify principles that might improve future research (particularly in observational studies), and consider issues related to reverse causation and detection bias.


Diabetes mellitus is a major public health challenge in many countries. WHO estimates that 350 million people have diabetes worldwide.1 Investigators of epidemiological studies have identified associations between diabetes and an increased risk of some cancers. Evidence for these associations has been summarised in reviews and meta-analyses of cancer of the breast,2endometrium,3 prostate,45 liver,67 pancreas,89 bladder,10 colon and rectum,11—14 and kidney,15 and of non-Hodgkin lymphoma.16 In all these types of cancer, except cancer of the prostate, diabetes is linked to increased risk. Many possible explanations for these associations have been reviewed.17—20

Three mechanisms exist that might (alone or in combination) explain the link between diabetes and cancer: risk factors common to both disorders (eg, obesity or physical inactivity), direct causal effects of metabolic derangements in diabetes on cancer development, and the effect of diabetes treatments. We acknowledge the importance of lifestyle interventions (smoking cessation, increased physical activity, a healthy diet, and maintaining a healthy weight) in reducing cancer risk; however, this Review is limited to methodological challenges in studying the effects of diabetes drugs.


Investigation of the association between treatment of diabetes and risk of cancer is complex, and substantial scope exists for false-positive and false-negative conclusions to be made about causality. Accurate representation of exposure is one key dimension of high-quality studies in this specialty, and is arguably as important as other features of study design such as avoidance of other forms of bias, adequate sample size, appropriate adjustment for confounders, and the use of validated data sources. The use of validated data sources is arguably of particular importance in this article; we discussed how drug exposure can be represented in analysis, but the source data used to construct that representation should be of the highest possible quality. One example of a data source that has been subjected to extensive validation is the General Practice Research Database.67 This resource has an international reputation for the study of drug safety,67 and has been used in several studies of diabetes drugs and cancer risk.52—54 Two reports6869 have described the validity of cancer outcomes recorded in the General Practice Research Database and contributors suggest that validation could improve data quality.

Our examination of a small and opportunistic sample of studies about diabetes treatments and cancer risk suggests that a wide range of approaches have been used to represent exposure to glucose-lowering drugs. Although we recognise that all investigations are inevitably subject to resource constraints, we suggest that future studies observe three principles for the representation of exposure. First, investigators should carefully consider the restricted validity and value of simple binary representations (ever-or-never). Where such representations are unavoidable, investigators should apply of some form of sensitivity analysis (as Monami and colleagues32 used), if feasible. Second, construction of measures that represent total exposure (ie, dose—duration products), analogous to the pack year used in tobacco studies, offers potential benefits and could be explored. Third, the concept of continuity of exposure (ie, continuous versus interrupted treatment) has received relatively little attention. Representation of this concept in an analysis will be challenging, both to obtain the necessary detailed prescription data and in developing appropriate analysis techniques (eg, multistate models). However, continuity of treatment is, arguably, a meaningful component of the total exposure experience, and representation should be considered if possible. Finally, adherence to drug regimens is not likely to be complete, is difficult to assess, and could result in differential misclassification bias and underestimation of the real effect of a drug.

Source: Lancet