03/18/16

Smoke and Mirrors

© Ivan Mikhaylov | 123rf.com

© Ivan Mikhaylov | 123rf.com

In this commercial, a guy named Herb said he stopped smoking with the help of Chantix: “The urges weren’t like they used to be and that helped me quit.” In the advertisement, which lasted 81 seconds, there were about twenty seconds worth of dialogue on asking your doctor if Chantix is right for you, telling you that Herb quit smoking with the help of Chantix and support and Herb’s 4 to 6 second testimony quoted above. The remainder of the commercial was a review of the potential side effects, which included: behavior changes, hostility, agitation, depressed mood and suicidal thoughts while taking or after stopping Chantix. Now watch this Saturday Night Live skit that essentially reworks all the same warnings about Chantix.

Soon after its approval in 2006, patients and their doctors began reporting adverse events such as suicidal thinking, aggression, depression and agitation. The drug was given a black box warning by the FDA in 2009 and then updated it in 2011. Refer to the medication guide for Chantix for more information on the possible side effects. But that wasn’t the end of concerns with the drug. In December of 2012, Chantix was linked by the FDA to the risk of a higher rate of heart attacks. A month later, the CEO of Pfizer was kept from testifying in court about the safety profile of Chantix because a plaintiff agreed to a settlement with Pfizer. Then in March of 2013, Pfizer agreed to a $273 million settlement for about 80% of the pending Chantix lawsuits.  In July of 2013, Pfizer said: “The resolution of these cases reflects a desire by the company to focus on the needs of patients and prescribers, and return the conversation to how Chantix can help smokers quit.” For more details on this description of the FDA and Chantix, see the various Chantix articles on FiercePharma from which this information was gleaned.

Pfizer began to win a few battles about Chantix. In September of 2014, a judge would not allow sealed court records of thousands of Pfizer documents related to the settled lawsuits to be opened. Out of court settlements with plaintiffs in cases against drug companies is standard operating procedure if it seems the case could be lost in court because then the related documents could be released into the public record. A standard condition of these kinds of settlements seems to require that all the documents that would have become evidence in a trial sealed.

That same month, the FDA approved changes to the medication guide for Chantix, suggesting that the drug might not be at greater risk of psychiatric problems. Pfizer wanted the black box warning removed. Steve Romano of Pfizer said: “Based on all this new information, a boxed warning is not supported. . . . The bottom line is that the label needs to reflect the most current understanding of the product’s benefits and risks.” Their target was a looming October 2014 FDA advisory panel meeting, where the committee would look at Pfizer’s data from observational studies and a meta-analysis of controlled trials conducted after the original side effects were reported.

FDA reviewers of the Pfizer data pointed out limitations with Pfizer’s meta-analyses and concluded that the observational studies “provided evidence of insufficient quality” to rule out an increased risk of suicide, suicide attempt or psychiatric hospitalization. Recent adverse event reports to the FDA were also said to be consistent with the findings that led to the black boxed warning. They noted how “neuropsychiatric side effects disappeared when patients stopped using Chantix, and/or recurred when therapy resumed.” It suggested that removing a black boxed warning had “limited precedent,” and should await the results from a controlled trial to be released in 2015.

The FDA finally announced its ruling in March of 2015. Not only did it keep the black box warning, it added new cautionary advice about Chantix’s interactions with alcohol. Some patients have reported increased drunkenness, blackouts and unusual or aggressive behavior while drinking. Others have had seizures. In September of 2015 Pfizer released the results of its latest study, in yet another attempt to convince the FDA to revoke the black-box warning. This large-scale by Kotz et al. followed 150,000 smokers over 6 months and found that individuals who took Chantix (known as Champix in Europe) were no more likely to have a heart attack then study participants using nicotine replacement therapy or another drug (Zyban) to facilitate smoking cessation. The study also found they were not at a higher risk of depression or self-harm. Three of the study’s authors reported financial ties to Pfizer independent of the study here.

One of the study’s authors, Aziz Sheikh, said that it was “highly unlikely that (Chantix) has any significant adverse effects on cardiac and mental health.” He though the drug’s black box safety warning “may be unnecessarily limiting access to this effective smoking aid.” Emily Wasserman commented this was exactly the kind of assessment Pfizer was looking for with Chantix. In 2014, Chantix grossed $647 million in worldwide sales; $377 million of which was in the U.S.

What was tellingly silent in this study was no further information on the association of Chantix (varenicline) with violence and aggression. A 2010 study, “Prescription Drugs Associated with Reports of Violence Towards Others” found that acts of violence towards other are associated with a relatively small group of drugs. Varenicline (Chantix or Champix) and antidepressants “were the most strongly and consistently implicated drugs.” Dr. Glenmullen, one of the study’s authors, was also one of the experts who unsuccessfully attempted to have thousands of Pfizer documents related to litigation over Chantix’s potential to trigger depression, suicide and violence made public.  Makes me wonder what was in those documents.

On the RxISK website, you can review an article on Chantix and Violence with a sampling of six selected cases taken from the FDA database on adverse events.  One case involved a 24 year old woman who said she was completely out of control by the third day of taking Chantix. She work her boyfriend up in the middle of the night and started physically beating him. She had suicidal ideation, homicidal ideation and an attempted suicide. Another woman, 28 years old, had a fit of uncontrollable rage after consuming alcohol one evening. She had been taking Chantix for about two weeks. It resulted “in me beating my boyfriend, followed by an attempt to take my own life. An overnight stay in the ER followed.”

Looking like the misdirection practiced by an illusionist, the attention on why Chantix should have its black box warning removed focused on two of the more serious adverse effects—depression and heart attack, but ignored a third—violence and aggression. The potential for violence was also been buried within catch-all categories such as “neuropsychiatric events” or adverse effects on mental health. Indeed, the recent Kotz et al. study admitted that it did not measure neuropsychiatric symptoms that involved aggression. So when the authors said they found no evidence of increased risk of “neuropsychiatric adverse events in smokers using varenicline” we need to recognize that symptoms involving aggression were not measured. They wouldn’t find any evidence for something if they didn’t look for it.

Finally, Paul Christiansen reviewed a recent study published in JAMA that compared the effectiveness of Chantix (varenicline) to the nicotine patch and combination nicotine replacement therapy (C-NRT, a nicotine patch and lozenge). The researchers concluded there were no significant differences in rates of smoking abstinence. “The results raise questions about the relative effectiveness of intense smoking pharmacotherapies.” Christiansen wrote that while the trial suggested there was evidence that varenicline and C-NRT may help lessen craving and withdrawal, there were significant adverse events with varenicline and C-NRT when they were compared to NRT—treatment with a nicotine patch only.

03/11/15

Lair, Liar Pants on Fire

© Wisconsinart | Dreamstime.com

© Wisconsinart | Dreamstime.com

Okay, well perhaps TECHNICALLY Janssen Pharmaceuticals, a division of Johnson and Johnson (J&J) didn’t lie about Risperdal to the public. But thousands of recent lawsuits have charged that there is a troubling side effect in young men who take the medication: gynecomastia. That means it can trigger abnormal breast growth in the males who use the drug.

Mad in America reported that the law firm of Pintas and Mullins (linked above) reported that there were 1,250 pending cases against  J&J (most of which are related to abnormal breast growth) out of which six were selected as “bellwether” trials in 2012. However, Janssen agreed to settle those cases before they went to trial. Janssen also agreed to settle another 80 cases in early 2013. Historically, this has been a regular legal tactic of pharmaceutical companies when they are sued. Peter Breggin has noted how this method and others were used by pharmaceutical companies to neutralize potentially damaging lawsuits against them; and keep the information they contained from becoming public knowledge.

But that doesn’t always work. Pintas and Mullins, Mad in America, Peter Breggin and FiercePharma have reported on past settlements made by Janssen for misleading statements about Risperdal.  In November of 2013 Janssen agreed to pay a $2.2 billion settlement with the federal government for false claims over Risperdal. The company pled guilty to illegally promoting the off-label use of Risperdal with the elderly suffering with dementia or Alzheimer’s in nursing homes. Janssen also settled off-label marketing claims with 36 states and the District of Columbia over Risperdal for $180 million; then with Texas for another $158 million. So I suppose we could say that Janssen was found guilty of lying about Risperdal in these off-label marketing cases.

Recent cases include a lawsuit argued in Philadelphia regarding a 20-year-old man with autism, who took Risperdal to help with irritability caused by his autism. He began taking the drug as an eight-year-old, despite the fact it was only approved for use with adults at that time. FiercePharma reported that the man’s then pediatric neurologist, Jan Mathisen, said sales reps from Janssen had distributed Risperdal samples twenty times between 2002 and 2004, 5 years before the drug was approved for use in autistic children. After a day in court, the autistic man’s mother tearfully said that she was having a difficult time after “Hearing what the pharmaceutical company was doing.”

Janssen claimed that the company’s warnings were complete and proper, and that it did not miss-market the drug. In a statement provided to Blooomberg Business, a Janssen spokesperson claimed that Risperdal “has improved the lives of countless children and adults throughout the world who suffer from debilitating mental illnesses, and it continues to improve patients’ quality of life today.”

Janssen claims that Risperdal’s labels always included warnings of the risk of gynecomastia in adults, and notified doctors that it was not proven safe for use in children. The Pintas and Mullins article said the company claims that the doctor who prescribed Risperdal to the autistic man should be held at fault. In addition,

Janssen is accused not only of illegally marketing Risperdal, but also of paying doctors to speak favorably of the drug. The company paid for gold outings and other flashy incentives to get doctors to prescribe the drug to patients just like the eight-year-old in Alabama. Many of those boys taking Risperdal grew breasts and had to undergo mastectomies.

A former FDA commissioner, David Kessler, testified in Philadelphia that Johnson and Johnson knew as early as 2001 that Risperdal could cause boys to grow breasts—a full five years before the company added the warning about the potential side effect to the drug’s official label. In support of his claim, Kessler pointed to a 2001 study, FUNDED BY J&J that indicated 3.8% of boys using Risperdal in a clinical trial developed breasts. He commented that the study should have been a red flag to the company. According to Bloomberg, the neurologist Mathisen said in his testimony that he would have liked to have known about the study.

A J&J lawyer said that Kessler was a biased witness or “hired gun” because he commonly testified in drug-safety trials since leaving the FDA in 1997 (see articles here and here). She suggested that he was “cutting and pasting” findings from other cases into his conclusions that: 1) officials at Janssen knew Risperdal caused some boys to develop breasts and 2) failed to alert patients, doctors and regulators about it. Kessler disputed her claims saying, “Each case is complex and there is an enormous amount of details associated with them . . . . To say I’ve testified each and every time the same way would be incorrect.” He also indicated where he has testified on behalf of pharmaceutical companies in the past.

As I first wrote this, the trial in Philadelphia was scheduled to take another few weeks. I was rooting for a ruling in favor of the autistic man and his family, which did happen! The Wall Street Journal reported that a Philadelphia jury decided Johnson & Johnson had to pay $2.5 million in damages for failing to warn that Risperdal could cause gynecomastia. The attorney representing the autistic man said: J&J “hid data from the FDA, prescribing doctors and parents. Documents showed they knew there was much higher percentage of children getting gynecomastia than they admitted.”

The settlement is relatively modest, considering what J&J has made from Risperdal. In the seven years between 2003 and 2010, Risperdal grossed more than $24 billion worldwide; 4.5 billion in 2007, the year it went off patent. While there should be enough capital to settle the case without J&J going bankrupt, with the additional 1,200 plus lawsuits, it may be a good time to divest yourself of J&J stock.