01/31/17

Curiouser and Curiouser with Chantix

© shamian | 123rf.com

In Lewis Carroll’s Alice in Wonderland, Alice famously said: “It would be so nice if something made sense for a change.” Since Carroll wrote this, many people have cited it to refer to one thing or another that puzzles them. I can now add my name to that list, as it does a spot-on job of expressing my thoughts on the recent FDA reversal in removing its black box warning for the smoking cessation drug Chantix.

On December 16, 2016, the FDA issued a drug safety announcement regaring Pfizer’s request that the black box warning be removed from Chantix. The FDA announcement said the decision was consistent with the recommendations of the September 2016 FDA Advisory Committee meeting. Essentially, their rationale was that the benefits of potential smoking cessation outweighed the health risks with Chantix. The conclusion of the committee was that an FDA ordered clinical trial (the EAGLES study) demonstrated “the risk of serious side effects on mood, behavior, or thinking [for Chantix] is lower than previously thought.” These side effects were what led to the black box warning (Given when there are serious or life-threatening risks when using the medication) on Chantix in the first place.

The risk of these mental health side effects is still present, especially in those currently being treated for mental illnesses such as depression, anxiety disorders, or schizophrenia, or who have been treated for mental illnesses in the past. However, most people who had these side effects did not have serious consequences such as hospitalization. The results of the trial confirm that the benefits of stopping smoking outweigh the risks of these medicines.

Notice the FDA is acknowledging the risks are still there and should be noted in the medication guide. However this assertion is debateable when evidence like that on the website RxISK in “Chantix and Violence” is considered. The cases there were originally reported in the FDA database for adverse drug events.

The results of the EAGLES study were published in the journal Lancet here. As Ed Silverman reported for STAT News, this action resulted in renewed efforts by Pfizer to have the black box warning removed. An earlier attempt in 2014 failed when an FDA panel voted to keep the warning intact. The chief medical officer for Pfizer thought removing the warning would more accurately reflect the neuropsychiatric safety profile for Chantix and allow patients and prescribers make informed decisions about treatment options. Despite the rhetoric here, the real reason was money:

The side effects have plagued the drug ever since it was approved a decade ago and endured horrendous publicity about violent or suicidal behavior. As a result, Pfizer spent hundreds of millions of dollars to settle numerous lawsuits and sales for the pill — once pegged to become a blockbuster — have plateaued, sliding from $846 million in 2008 to $671 million in 2015.

Alan Cassels, a pharmaceutical policy researcher at the University of Victoria, British Columbia, pointed out that the FDA action in December 2016 was unprecedented. Most of the drugs removed from the U.S. market over the past 20 years first carried a black box warning. Remember that according to the FDA, those risks ARE STILL PRESENT with Chantix, The EAGLES study concluded those risks are lower than previously reported and the FDA pragmatically agreed the potential benefit from Chantix outweighed the risks.

Not everyone on the FDA Advisory Committee that recommended the removal agreed. Of the 19 panel members, 10 voted to remove the black-box warning. Four wanted to see changes in the wording, while five others recommended the warning remain.

Thomas Moore, a senior scientist with the Institute for Safe Medication Practices, has also voiced concerns with the EAGLES trial itself, used by the FDA to justify removing the Chantix black-box warning. Critical of the study’s design, Moore and the ISMP thought the trial “was greatly underpowered, used a novel, unvalidated measurement scale, required subjective judgements from study investigators, and detected no meaningful differences among eight treatment arms because of a defective design.”

The ISMP letter to the FDA indicated Chantix (varenicline) was suspected to be the primary drug in 17,900 serious injuries from psychiatric adverse events reported to the FDA, 43% of which were done by health professionals. The cases described a series of behaviors ranging from suicidal and homicidal thoughts to delusions, suicidal behavior and bizarre and reckless aggression. These effects were documented in peer-reviewed studies. And Pfizer paid around $300 million in compensation—to over 2,500 varceline victims—for serious injuries that occurred BEFORE the boxed warning was required.

Moore and ISMP were not alone in expressing concern with the EAGLES trial.  Ed Silverman of STAT reported that Sammy Almashat of Public Citizen pointed out how the study had composite outcomes of both serious and milder symptoms, such as irritability and agitation, that normally occur when people are trying to quite smoking. Almashat was concerned with the precedent in this reversal; black box warnings are usually not reversed, especially on such equivocal evidence.

This could set an ominous precedent. If the FDA rescinds, a company can now go to the agency with a substandard post-marketing trial, point to Chantix and demand the same outcome. We’re worried that if the FDA follows through with the recommendation, that this will become a new standard for removing a black box.

The concluding statement from the ISMP letter may be a forewarning of what is to come:

An ambiguous warning can be worse than no warning at all because not only does it render the warning ineffective, it undermines the value of all warnings and the credibility of the FDA. A clear warning does not restrict the access of any patient or physician to this treatment.

“Curiouser and Curiouser,” as Alice would say if she heard about the back-and-forth actions by the FDA. There is more on this topic in another article, “Chantix Tug-of-War.”

09/30/16

Chantix Tug-of-War

© AndreyPopov | stockfresh.com

© AndreyPopov | stockfresh.com

On May 18, 2008, George MacDonald was at Fort Benning Georgia. George and his identical twin brother James had successfully completed Infantry Training and the Airborne Course at Fort Benning. They had also been selected for the U.S. Military Academy Preparatory School. George was a one-time Eagle Scout. He got up from his bunk to do some laundry and slipped a knife into his pocket. He approached the bunk where Rick Bulmer, who he did not know, was sleeping. Then he stabbed and slashed Rick more than 50 times. A month before, MacDonald had been prescribed Chantix by an Army doctor to help him stop smoking.

Nine hours after the killing, Macdonald wrote: “I snapped and didn’t like it … I was stretched and it made me crazy.” The military judge refused to allow an involuntary intoxication defense and quashed a subpoena issued to Pfizer by MacDonald’s lawyer. Within a month of the judge’s decision, the FDA imposed a black box warning on Chantix. “Within weeks of the military trial judge’s decision in 2009 to quash the subpoena, Pfizer began getting hit with civil lawsuits claiming Chantix had caused suicides, suicide attempts or other neuropsychiatric problems.” MacDonald was convicted of premeditated murder in 2009 and sentenced to life without parole.

The U.S. Court of appeals for the Armed Forces overturned MacDonald’s conviction saying the trial judge had erred in not allowing the involuntary intoxication defense. MacDonald agreed to plead guilty to the unpremeditated murder of Rick Bulmer and his sentence was reduced to 45 years. Bulmer’s family was outraged, according to Tom Jackman writing for The Washington Post. “’It’s a mindblower, and we don’t understand it,’ said Bulmer’s mother, Wendy Smith. ‘He cold-bloodedly killed my son. He knew what he was doing and … he should take his punishment.’”

In a 2010 clemency request for his brother, James wrote that he remarked to his brother that life had started to feel like a video game, where he was disconnected from his body. James had also been prescribed Chantix. George agreed he felt the same way. James said, “I remember the two of us waking up at night having really weird dreams, scary dreams.” In 2013, James killed himself by jumping off of a 19-story building. His sister said he never got over his grief over his brother’s ordeal. You can read more about the MacDonald case here, here  and here on McClatchyDC.

George MacDonald is not alone is claiming that his use of Chantix led to violent acts. In the beginning of August 2016, a Maryland man was found not criminally responsible for shooting his wife in the neck because he was “involuntarily intoxicated” from Chantix. A woman who was taking medication for other reasons used Chantix briefly in 2007. She got her daughter off to school and the next thing she remembered was standing in her kitchen in a puddle of blood. Six hours has passed during which she had used a kitchen knife to cut her left arm. Federal prosecutors dropped charges against a man who “who extremely psychotic and disorganized” aboard a United Airlines flight because of a “Chantix-induced psychotic disorder.”

Al Jazeera reported that Chantix has been linked to 544 suicides and 1,869 attempted suicides.  As a result of a report issued by the Institute for Safe Medication Practices that said the organization had “immediate safety concerns” about individuals operating aircraft, trains buses and other vehicles who were using Chantix, the FAA and Defense Department banned Chantix use among pilots and air traffic controllers.

Eventually some 2,700 former Chantix users sued Pfizer in 2011. Pfizer began to settle with the lawyers representing the mass of civil lawsuits at a cost of $299 million through the first quarter of 2013. Pfizer said the settlement would allow the company to focus on the benefits of the drug. This strategy has been the typical way pharmaceutical companies try to settle lawsuits they aren’t sure they can win. It keeps subpoenaed records out of the hands of the public and other individuals who may want to sue them as well. And it prevents the articulation of a coherent argument about the association between a specific drug and an adverse event from being made in the public square. It enables the pharmaceutical continue to assert as Pfizer did in a statement to McClatchy: “There is no reliable scientific evidence that Chantix causes serious neuropsychiatric events.”

Chantix is approved for use in more than 100 countries and has been prescribed to over 20 million patients worldwide, including more than 10 million in the United States.

Then in April of 2016 the results of a study on more than 8,100 people were published in Lancet. The study had been ordered by the FDA because of the ongoing reports of neuropsychiatric adverse events with Pfizer’s Chantix and GlaxoSmithKline’s Zyban. “The study did not show a significant increase in neuropsychiatric adverse events attributable to varenicline or bupropion relative to nicotine patch or placebo.” However, the funding for the study was from Pfizer and GlaxoSmithKline.

Writing for STAT News, Ed Silverman quoted the study authors as saying: “The findings show that it is highly unlikely that (the medicines) contribute to neuropsychiatric adverse events.” The results of the EAGLES study, which the Lancet article was reporting, were processed by Clinical Trials.gov on September 1, 2016, and are available here: Clinical Trials.gov Identifier: NCT01456936.

The results may be a boon for Pfizer, which has struggled for a decade to transform Chantix into a blockbuster product, but instead has encountered negative publicity, expensive litigation, and stalled sales.

Pfizer plans to ask the FDA to remove the black box warning from Chantix. A company spokesperson said: “Available scientific evidence concerning neuropsychiatric events in patients attempting to quit smoking does not support a boxed warning in the Chantix label.” The FDA will review the findings along with additional scientific evidence as they continue to evaluate the issue.

Thomas Moore, a senior scientist with the Institute for Safe Medical Practices, said it would be a mistake to claim the study proves that severe psychiatric side effects don’t occur with Chantix. Because it was a manufacturer-sponsored study done in 140 different centers in 16 countries, Moore suggested it be independently reviewed. Early onset cases of psychosis, aggression and suicidal behaviors have been observed with Chantix by regulators in many countries, “far outnumbering those reported for other smoking treatments.”

With eight different treatment arms, the number of patients in each may not be enough to capture the severe psychiatric side effects for which the drug is known.  The study’s severity assessments were subjective judgments, and the combined endpoint included many psychiatric side effects that Chantix is not suspected of causing.

The criticism by Moore has some legitimacy. Here is a study that found Chantix (varenicline) was no better than NRT (nicotine patch) and C-NRT (nicotine patch and lozenge) with regard to abstinence. “However it is notable that there were significant adverse events of varenicline compared to NRT (e.g. nausea, insomnia, sleepiness) and C-NRT compared to NRT (indigestion, nausea, mouth problems and hiccups).” The website RxISK described several examples of “Chantix and Violence” that were originally reported in the FDA database for adverse drug events.

MacDonald’s case was one of the ones reported on RxISK. There it was reported that George and his twin brother (James) enlisted in the Army were selected for an appointment to the United States Military Academy Preparatory School.  The reported adverse effects experienced by MacDonald included: nightmares, psychosis, homicidal ideation, senseless act, and homicide. The Case report said:

Appellant had been experiencing “new and strange thoughts” including a “person [was] telling me . . . dangerous things that arent [sic] me.” These included violent thoughts of killing someone. On May 18, 2008, one month after the Army doctor prescribed Chantix, Appellant fatally attacked Private (PVT) Bulmer while he was sleeping, stabbing him to death. Prior to this attack, Appellant did not know nor had he ever interacted with PVT Bulmer.

The other cases reported suicidal and homicidal ideation, a suicide attempt, uncontrolled aggression/anger, and senseless violence. What follows are two more of the case reports on RxISK. Thomas Moore sent this information to RxISK.

By the third day of taking Chantix I was completely out of control. I woke my boyfriend up in the middle of the night and started physically beating him. I contemplated suicide about 5 times a day and contemplated homicide about 3 times a day. On Saturday while at home she got into a verbal argument with her mom over a minor issue and reports now that she was ‘totally out of hand’ and she was unable to control her impulses and was yelling and screaming and crying. She acutely became suicidal and also became homicidal threatening her mother with a shotgun. Her mother fled the house and called police. She locked herself in the bathroom and eventually calmed down.

In October of 2014, five nonprofit consumer organizations (Consumer Reports, Institute for Safe Medication Practices, National Center for Health Research, National Physicians Alliance, and Public Citizen) petitioned the FDA to require that the Chantix have boxed warnings clearly describing adverse psychiatric adverse events: suicidal behaviors, aggression/violence, psychosis, and depression. Additional risks with Chantix the petition noted were: sudden blackouts, seizures and impaired vision. I hope and expect they will again protest when Pfizer formally requests that the FDA drop its black box warning for Chantix.

For a previous article about the tug-of-war over problems with Chantix, see “Smoke and Mirrors.”

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.