07/8/16

Another Empty Promise

I’ve been following the news on the development of a buprenorphine implant for the medication-assisted treatment (MAT) of opioid dependence. An early January 2016 article on The Fix related that a new drug, Probuphine, was scheduled for FDA review on January 12, 2016. Braeburn Pharmaceuticals and Titan Pharmaceuticals jointly developed and brought Probuphine to market. A week later an advisory committee of the FDA recommended approval of the implant by a 12 to 5 vote. The President and CEO of Braeburn Pharmaceuticals was quoted as saying their vision is to “bring change to this underserved population.” But the jury is still out on whether or not that change will ultimately help or harm individuals with opioid use disorders.

Not surprisingly, on May 26, 2016, the FDA announced the approval of Probuphine as the first buprenorphine implant. The main benefit touted seems to be that it provides another way to use buprenorphine. Nora Volkow, director of the National Institute on Drug Abuse was quoted as saying: “This product will expand the treatment alternatives available to people suffering from an opioid use disorder.” FDA Commissioner Robert Califf said: “Today’s approval provides the first-ever implantable option to support patients’ efforts to maintain treatment as part of their overall recovery program.” Is it just me, or do those endorsements seem to be a bit lukewarm?

The first thing to know is that Probuphine was reviewed by the FDA in 2013, and despite recommendations by an advisory committee for approval, it was not approved at that time. The FDA said it needed additional data supporting the efficacy of Probuphine. The executive chairman for Titan Pharmaceuticals said they were “extremely surprised and disappointed” at the action of the FDA. One of the issues then was “human factors testing of the training associated with Probuphine’s insertion and removal.” In other words, 23% of Probuphine patients had implant site adverse events, compared to only 13.5% of the placebo control group. Another concern seems to have been that the Probuphine dose was too low for the kind of patients who were being tested.

Another report on the initial clinical trials indicated that only 8% of patients were opioid-free throughout the treatment, also suggesting the dosage wasn’t adequate. And 25% of the Probuphine-treated patients failed to provide as few as four opioid-negative urine samples over the course of six months. Continued use of illicit substances was not defined as “treatment failure” in the trial, but needing additional buprenorphine beyond preset amounts was. “Overall, 35 percent of the Probuphine patients and 72 percent of the placebo patients in the controlled trials did not complete the six-month treatment course.” Writing for FierceBiotech, John Carroll noted similar concerns—expressed by FDA staffers BEFORE the advisory committee voted to approve Probuphine in 2013.

While the placebo group had even more discouraging results, supporting the conclusion that Probuphine does have an effect on drug use, overall, the response was not what one might hope for, given that the product ensures compliance with medication for six months. It prompts speculation that the dose is simply not high enough. … Potentially, Probuphine could deliver just enough buprenorphine to allow patients to continue to use illicit opioids without experiencing withdrawal when they stop.

A total of 40% to 62% of Probuphine-treated patients needed supplemental buprenorphine; another 11-12% needed supplemental buprenorphine even after receiving a fifth implant. Ironically, one of the voiced advantages for the implant was that the pill and film forms of buprenorphine wouldn’t be accessible to children. The trial was also too small to fully access the safety risks with inserting the implants. Plus there were unanswered questions regarding what happens if addicts never get the implants removed; or how long treatment would continue with the implants; or what happens to patients when they stop treatment. So why did the 2013 advisory committee vote to approve Probuphine with all of these concerns? Carroll provided a link to the full staff review in his article.

The January 12, 2016 FDA report on Probuphine is available here. The trial was revised at the recommendation of the Psychiatric and Drugs Advisory Committee as a treatment for patients stabilized on sublingual buprenorphine at doses of 8 mg or less. The efficacy results demonstrated that the Probuphine-treated patients met the selected margin criteria for non-inferiority. In this study Probuphine was compared to sublingual burprenorphine instead of a placebo. The rationale was that it was inappropriate to expose stable patients to the risk of relapse with a placebo-controlled trial. The non-inferiority margin was the smallest acceptable decrease in effect from that of sublingual buprenorphine. However, the responder rate used in determining the results used a number of assumptions about missing data; and it assumed that using supplemental buprenorphine did not indicate an inadequacy of treatment.

When analyzed under different assumptions, the response rates are lower than reported by the Applicant, and also differ from the expected response rate used to calculate the non-inferiority margin. Therefore, under some sets of assumptions, one might question whether enough of the effect size has been maintained to conclude efficacy of Probuphine. Moreover, because Probuphine ensures compliance, one would expect a clearer demonstration of superiority over sublingual buprenorphine than was demonstrated in this trial.

There were also issues with the data on urine samples. The sampling schedule was less frequent than is customary for efficacy studies. The rationale was that since the population was of stabilized patients, more frequent urine testing could lead to patients dropping out. Only ten samples per patient were to be collected. Nevertheless, 12% in each group missed visits and thus missed giving a urine sample. And 22% (25% in the Probuphine group and 18% in the sublingual buprenorphine group) were missing data from one or more samples because of sampling handling issues.

So even though Probuphine was approved, there doesn’t seem to be an indication that it was clearly superior to sublingual buprenorphine as an opioid maintenance drug. And there are concerns noted within the FDA announcement of its approval. The boxed warning within the medication guide cautions that the insertion and removal of Probuphine can be associated with the risk of implant migration, expulsion and nerve damage. There were additional concerns mentioned by the FDA.

Probuphine implants contain a significant amount of drug that can potentially be expelled or removed, resulting in the potential for accidental exposure or intentional misuse and abuse if the implant comes out of the skin. Patients should be seen during the first week after insertion and a visit schedule of no less than once-monthly is recommended for continued counseling and psychosocial support.

The cost for the implant will be between $1,000 and $1,500 per month, significantly more than the cost of sublingual buprenorphine products. STAT quoted Dr. Carl Sullivan, the director of addiction services as West Virginia University Medicine, as saying: I just don’t see how this is going to help fight the opioid epidemic at all.” Dr. Sarah Wakeman, the medical director for substance use disorders at Massachusetts General Hospital said: “I’d probably still err on the side of prescribing it that way [by tablet or film].”

Some critics don’t think the implant is needed or ready for release. Diana Zuckerman, president of the National Center for Health Research, a nonprofit think tank, said: “We don’t need another product on the market that’s not been tested very well to see how safe it is and how effective it is.” Titan Pharmaceuticals has been trying to get Probuphine approved for over six years, and the voiced concerns about it from abstinence-based recovery go back as far.

In October of 2010, JAMA published an article by Ling et al., “Buprenorphine Implants for Treatment of Opioid Dependence.” Although the study was 24 weeks long, the primary outcome measure was for negative urine samples for illicit opioids during the first 16 weeks of the trial. The rationale for this shortened period was said to because “of the interest in examining early-treatment response in the context of this longer-term treatment.” My question is what were the results of the urine tests for the final 8 weeks, and would they negatively effected the outcome results? The study concluded that: “Among persons with opioid dependence, the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks as assessed by urine samples.”

So it’s not clear that Probuphine has a greater treatment efficacy than sublingual buprenorphine. There are concerns with adverse effects related to the insertion and removal of the implant. There also seems to be a potential for accidental or intentional misuse of the implant, which contains “a significant amount” of a drug that the FDA Advisory Committee report for January 2016 acknowledged is a growing product on the illicit drug market.

Unfortunately, despite these features, buprenorphine sublingual products have been increasingly identified in the illicit drug market, and it is known that they are diverted, abused, and misused. Additionally, they have been implicated in a number of cases of accidental poisonings of small children. Therefore, a depot injection or an implantable product which would be difficult to divert or abuse, and would be less likely to be accidentally ingested by small children, offers potential advantages. In addition, if a depot or implantable product provided a sufficient plasma level of buprenorphine to block the effects of exogenous opioids, the nature of the product would enforce compliance so that patients could not periodically discontinue use to allow the blocking effect to dissipate in order to experience the effects of their opioids of choice.

The clinical trials used to approve Probuphine used sublingual buprenorphine to supplement its dose for some individuals, which neutralizes the rationale of it being less likely for small children to ingest buprenorphine. Adding a benzodiazepine to Probuphine would be a quick work-around for anyone looking to “experience the effects of their opioids of choice.” Trying to remove an implant for the high may seem to be a highly unlikely event. Yet I’ve heard of individuals who would lick or chew fentanyl patches and others who would crush and shoot Suboxone tablets despite the alleged abuse deterrent of it containing naloxone. I even read of one individual who faked a terminal illness to get hospice care for the pain meds.

It won’t take long for stories of removing the implant to get high or sell the drug it contains to emerge. The temptation will be too great for some individuals. Screening for appropriate Probuphine patients will be crucial, but the existing failure to prevent illicit sublingual buprenorphine abuse doesn’t encourage me that will work. And was the question of what happens to patients after implant treatment ever answered? What about people who drop out of treatment after receiving the implant? Probuphine is more likely to become a profitable drug for Titan and Braeburn than it is to bring change to the underserved population of opioid addicts. It seems to be just another empty promise to help the still-suffering addict for financial gain.

05/10/16

Opening the Off-Label Floodgates

On March 8, 2016 the FDA made a settlement agreement with the pharmaceutical company Amarin that allows Amarin to promote its drug Vascepa for off-label use to treat patients with hypertriglycerdemia, persistently high triglycerides. That is, as long as its promotion is truthful and not misleading. Amarin wanted to widen the population for whom they could recommend Vascepa to include other patients with different cardiovascular diseases, but the FDA initially ruled against this. Amarin’s stock price took a nosedive. Concerned with how their investors were reacting, the company fought back by suing the FDA. So what was this breakthrough medication worth taking on the FDA? Fish oil; Vascepa is prescription strength fish oil.

Amarin argued that it had a First Amendment right to market its drug for a broader patient group, “despite the lack of regulatory approval and the lack of evidence of an outcomes benefit for patients.” Justin Karter of Mad in America noted how the FDA settlement strikes at the heart of the drug regulatory system in the U.S. Amarin argued that companies should have the right to market their products consistent with what “a judge would consider to be neither false or misleading.” Be clear on what Amarin was saying. A judge, not the FDA, should rule on whether or not the marketing claims for their product were truthful and not misleading.

Where does a judge get the expertise to discern whether or not a company has made misleading, untruthful medical claims about their product? Pharmaceutical companies have paid millions of dollars for violating off-label promotion of their medications. One example is the blockbuster drug Neurontin, which has cost its parent drug companies millions of dollars in fines for “illegal and fraudulent promotion of unapproved uses.” An internal company email referred to Neurontin as “the ‘snake oil’ of the twentieth century.” This is but one example of the violations from multiple drug companies under the more restrictive FDA guidelines forbidding all off-label marketing.

In August of 2015, a judge in the district court of Manhattan ruled that Amarin could market its drug to the desired broader population. He also ruled the company could claim that Vascepa “may reduce the risk of coronary heart disease.” This was despite the fact that the FDA had called the claim misleading, as there was “supportive but not conclusive research” to that effect. The Amarin ruling, according to attorney Amy Kapczynski, “has the potential to unleash a flood of misleading marketing to physcians.” She believes that at some point, the FDA will have to take the issue to the Supreme Court.

Writing for FDA Law Blog, David Gibbons gave a detailed description of the legal aspects of the case. While Amarin was attempting to gain FDA approval for its off-label promotion of Vespacia, data from several high-profile cardiovascular outcomes trials cast doubt on the clinical benefit of triglyceride lowering. After reviewing the data, the FDA then asked an Advisory Committee to express its opinion on whether or not “Vascepa’s triglyceride lowering effect was sufficient to approve the drug for use in patients with persistently high triglycerides. The Advisory Committee voted 9 to 2 against approval for that indication.” So Amarin sued the FDA.

In a bold move, Amarin filed a civil complaint against FDA claiming that FDA’s threat of prosecution for misbranding Vascepa had a chilling effect on Amarin’s commercial speech that was otherwise protected by the First Amendment. For that reason, Amarin sought declaratory and injunctive relief that would prevent FDA from prosecuting the Company for truthful, non-misleading speech concerning Vascepa, going so far as to detail, in its complaint, certain off-label promotional content regarding Vascepa that the Company proposed to disseminate. Early in the litigation proceedings, Amarin filed a motion for preliminary injunction and the court heard oral arguments on the motion on July 7, 2015, and, on August 7, the court handed down a 71-page opinion in which it granted Amarin’s requests.

Commenting on the FDA settlement agreement in Amrain Pharma v. U.S. Food & Drug Administration for Mad in America, lawyer and mental health advocate Jim Gottstein said he thought that for all practical purposes, the FDA ban against off-label promotion of drug companies was dead. He noted that the ruling in the Amarin case was based upon a 2012 decision in Unites States v. Caronia that reversed a criminal conviction for off-label promotion.

In light of the settlement I think it is fair to ask where things stand with the FDA’s enforcement of its ban against off-label promotion and Department of Justice prosecutions of drug companies for off-label promotion leading to false claims. I think the ban against off-label promotion is dead for all practical purposes. The FDA could try and get a different ruling in another circuit and, if successful, ask the Supreme Court to rule, but since it didn’t ask the Supreme Court to take the case in Caronia, it doesn’t seem likely that it has any intention of trying to overturn Caronia. This will give the drug companies free rein for off-label promotion. Of course, anything that is false or misleading is still grounds for charges, but that is a far harder case to make.

Eric Palmer, writing for FiercePharma, noted that the free speech argument has been closely monitored by the pharmaceutical industry to see just how much leeway they might expect from the FDA in their ability to market for off-label use of their products. Another pharmaceutical company, Pacira, filed suit against the FDA after the August 2015 ruling in favor of Amarin.

Tracy Staton noted on FiercePharma that the FDA agreed to remove its limits on Pacira’s marketing of Exparel, which is now approved for pain treatment at any surgical site. She said that by making a deal with Pacira, the FDA avoided another court ruling on the free-speech issue, as it seeks to adjust its marketing rules. In an attempt to limit any broader application of the Amarin ruling, the FDA has said its Vascepa promotions would not have broken FDA rules in any case. As it did with Amarin, the FDA said regarding its agreement with Pacira: “It’s important to note that this resolution is specific to the parties involved in this matter.”

Parallel to these attempts to weaken the FDA regulations against off-label marketing, there was a January 2016 article published in JAMA Internal Medicine by Eguale et al. that looked at the association between off-label drug use and the risk of adverse drug events (ADEs). Commenting on Medscape, Eguale said to his knowledge, theirs was the first systematic evaluation of the association between off-label use of drugs and the risk for ADEs. They concluded that off-label use of prescription drugs was associated with ADEs. “Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence.”

The study found that the majority of prescriptions (88.2%) were for approved uses. Another 9.5% involved off-label use without strong supportive evidence; and 2.3% were off-label, but had strong evidence supporting its use off-label. The ADE rate was higher for off-label use than for on-label use, “at 19.7 per 10,000 person-months vs 12.5 per 10,000 person-months.” When analysis was done according to the strength of supporting evidence for off-label use, there was an even higher rate (at 21.7 per 10,000 person-months) for use unsupported by strong scientific evidence. “Off-label use indicated by solid scientific evidence had a rate of 13.2 per 10,000 person-months, which was virtually the same as its on-label counterpart.”

The risk for adverse events also rose with the number of prescription drugs used by individual patients. Individuals taking eight or more medications had “a more than fivefold increased risk for ADEs compared to patients who used one or two drugs.”

[P]hysicians and physician organizations should recognize the enormity of the problem and be active participants in the promotion of cautious prescribing of drugs for off-label uses lacking strong scientific evidence.

Within an invited commentary of the study, “Off-Label Drug Use and Adverse Events,” Chester Good and Walid Gellad warned that the FDA and the courts needed to carefully consider the study’s findings as they contemplate any further relaxation of regulations to permit the promotion of drugs beyond their labeled indications. “In light of these concerns, the study of off-label drug use and adverse drug events by Eguale and colleagues … is particularly timely.”

Too bad the Eguale et al. study wasn’t published earlier. Maybe it would have had some influence on the FDA settlement with Amarin. The response of pharmaceutical companies with psychiatric medications to the Amarin settlement is a serious concern. They have already demonstrated a history of flaunting the more restrictive FDA regulations to the tune of billions of dollars in fines.

On March 31, 2016, the nonprofit organization Public Citizen published an updated analysis of all major financial settlements and court judgments between pharmaceutical companies and the federal and state governments. The time period covered by their analysis ran from 1991 through 2015 and included 373 settlements for a total of $35.7 BILLION. Financial penalties have declined sharply since 2013. The most striking decrease occurred with criminal penalties. “For 2012 and 2013 combined, criminal penalties totaled $2.7 billion, but by 2014-2015, the total had fallen to $44 million, a decrease of more than 98%.”

From 1991 through 2015, GlaxoSmithKline and Pfizer reached the most settlements—with 31 each— and paid the most in penalties, $7.9 billion and $3.9 billion respectively. Six additional companies, Johnson & Johnson, Merck, Abbott, Eli Lilly, Teva, Schering-Plough, Novartis, and AstraZeneca paid more than $1 billion in financial penalties. Six of the above eight were listed in the top 14 pharmaceutical companies by global sales in 2014. Thirty-one companies entered repeat settlements. Pfizer (11), Merck (9), GlaxoSmithKline, Novartis, and Bristol-Myers Squibb (8 each) finalized the most federal settlements.

Financial penalties continued to pale in comparison to company profits, with the $35.7 billion in penalties from 1991 through 2015 amounting to only 5% of the $711 billion in net profits made by the 11 largest global drug companies during just 10 of those 25 years (2003-2012). To our knowledge, a parent company has never been excluded from participation in Medicare and Medicaid for illegal activities, which endanger the public health and deplete taxpayer-funded programs. Nor has almost any senior executive been given a jail sentence for leading companies engaged in these illegal activities. Much larger penalties and successful prosecutions of company executives that oversee systemic fraud, including jail sentences if appropriate, are necessary to deter future unlawful behavior. Otherwise, these illegal but profitable activities will continue to be part of companies’ business model.

It seems to this point, risking the fines has just been a potential cost of doing business with medications. With the FDA failing to challenge the decision in Caronia and its recent settlement with Amarin, the floodgates for off-label marketing of medications may have been opened. I hope that Jim Gottstein’s prediction that FDA opposition to off-label marketing is “dead” turns out to be wrong. If he is correct, and the FDA does not actively oppose future off-label marketing of psychiatric medications, we will be flooded with adverse events from their off-label use.

04/8/16

Foxes in the Henhouse

On February 24, 2016, 2015 the FDA announced that Robert Califf MD was confirmed as the new Commissioner of the FDA by an 89 to 4 vote in the Senate. There seems to be opposing opinions regarding his role as the new FDA Commissioner. Presidential candidate Bernie Sanders opposed his appointment because of his extensive ties to the pharmaceutical industry and lack of commitment to lowering drug prices. Writing for Forbes, Matthew Herper said: “Any senators who slow his path to the job he [Califf] deserves should be accused of practicing the basest kind of partisanship.”

Herper said it was no shock that Califf was nominated. His nomination seems to have been the culmination of a leadership transition at the FDA beginning before Califf was appointed as the FDA Deputy Commissioner for Medical Products and Tobacco in January of 2015. Herper said Califf’s departure from Duke University was a clear sign this transition was already in the works. Herper wasn’t alone in seeing this potential nomination and appointment.

Also writing for Forbes, David Kroll commented that Califf’s position as Deputy Commissioner for Medical Products and Tobacco was second in scope to being commissioner of the FDA. Massimo Calabresi, in his article for Time in February of 2015, also suggested Carliff could be the next FDA Commissioner. Then the serving FDA Commissioner, Margaret Hamburg announced she would step down at the end of March 2015. According to Herper, Califf’s name had been in circulation six years ago when Hamburg was nominated. But he was widely seen at the time as having too many links with industry. So instead, the Obama administration went with Hamburg.

Herper acknowledged Califf’s ties with the medical industry, but felt he worked with drug companies “in the best possible way”—convincing them to do large, expensive clinical trials. Not only were these trials profitable for Duke, but they helped prove the effectiveness of major medicines like Plavix, Vytroin, and Zarelto. But he hasn’t been a pushover. “His goal has always seemed to be to make sure that doctors and patients have the best evidence possible for deciding what drugs to give to patients. He has not always been easy on industry.”

Massimo Calabresi gave a more nuanced portrayal of Califf. At Duke, he was the founding director of the Duke Clinical Research Institute, which is considered to be one of the world’s largest academic research organization, with an annual budget of $320 million. Califf himself estimated that 50 to 60% of this annual research funding comes from industry. Calabresi captured the controversy nicely about Carliff when he noted that Carliff sees collaboration between industry, academia and the government as the way of the future: “The greatest progress almost certainly will be made by breaking out of insular knowledge bases and collaborating across the different sectors.”

Carliff went on to say there was a tension that cannot be avoided between the industry and creating the conditions where the industry can thrive. “The FDA’s got to do both.” He thought it would be useful to have someone leading the FDA who understood how companies operate, “because you’re interacting with them all the time.” Calabresi said the tension over Callif’s collaboration with industry gets at the heart of the FDA at a pivotal moment. “While FDA defenders see the collaboration as a threat to its independence, others see close relationships between government, industry and academia as the model for the future.”

Diana Zuckerman, President of the National Center for Health Research, which advocates for FDA regulatory authority, says such ties “should be of great concern.” Dr. Califf is “a very accomplished, smart physician who’s been an important name in the field,” Zuckerman says, but his “interdependent relationships” raise questions about his “objectivity and distance.” She cites several studies suggesting the medical products industry uses such ties to influence the behavior and decision making of doctors and researchers, even when the scientists don’t realize it.

Senator Sanders said he strongly believed “We need a leader at the FDA who is prepared to stand up to the drug companies.” Someone who will strive to substantially lower drug prices, to develop rules to safely import brand-name drugs from Canada “and hold companies accountable who defraud our government.” Carliff’s extensive ties to the pharmaceutical industry did not give him reason to believe he would make “the FDA work for ordinary Americans rather than the CEOs of pharmaceutical companies.”

Whether or not Senator Sanders’ reservations about Robert Carliff come true remain to be seen. But there is a more troubling tie between the pharmaceutical industry and our government to consider. Reporting for The New York Times, Nicholas Kristof said the pharmaceutical industry spent $272,000 in campaign contributions per member of Congress in 2015. And there are more pharma lobbyists than there are members of Congress. One of the key issues at stake is to keep the government from bargaining for lower drug process with Medicare. “That amounts to a $50 billion annual gift to pharmaceutical companies.”

Reporting for STAT News, Sheila Kaplan and Ike Swetliyz said that around 30% of US Senators and 20% of US Representative hold assets in biomedical and health-care companies. Johnson & Johnson, Merck and Pfizer were favored investments for members of the House and the Senate. Some of the most aggressive congressional investors in the biomedical sector served on key committees. The House Energy and Commerce Committee for example, which oversees the FDA and works on issues of importance to the industry such as drug regulation, research funding and taxes on medical devices.

Members of Congress owned more stock in health-related companies last year than in the defense and construction sectors combined, according to the Center for Responsive Politics. Their investments in the sector topped $68 million.

They described legislators who had financial investments and even ownership stakes in companies that Congress was regulating. One Congressman who sits on the Energy and Commerce Committee co-sponsored a bill to repeal taxes on medical devices. If passed, this bill would help two companies in which he has heavily invested. He also proposed that the FDA loosen requirements for drug companies to track the safety and effectiveness of their products once they are on the market. Not only would that provision help many drug companies, it would benefit a biotech company in which he is the largest single stockholder.

Dr. Michael Carome, the director of a nonprofit health advocacy organization, Public Citizen’s Health Research Group, said: “Even if the lawmakers aren’t personally picking and choosing each stock, knowingly holding stocks in pharmaceutical and medical device companies creates obvious financial conflicts of interest.”

Members of Congress are not required to recuse themselves from voting on bills that could effect their personal finances, unless they would be the primary beneficiary of the legislation.

Yet across most of the federal government, employees are required to recuse themselves from working on issues that could influence the value of their investments. Within the Department of Human Services, employees are barred from owning stock in drug companies or other industries that the agency closely regulates. STAT said they called dozens of lawmakers for their story, but none would comment in detail about their investments.

Matthew Herper’s opening comment about partisan politics blocking Califf’s appointment seems to have been baseless. He almost had unanimous support. Whether or not he will be tough on the industry remains to be seen. And with regard to partisanship, it was Democratic Senators who held up his nomination; and three of the four opposing votes were from Democrats. So only 20 to 30 percent of U.S. Member of Congress have a financial stake in biomedical and health-care companies. But it is disturbing that several of those legislators are on committees making regulatory decisions for those companies. And when you consider that the number of pharma lobbyists outnumbers the sitting legislators, it seems we have a situation where the foxes have been invited into the henhouse.

03/18/16

Smoke and Mirrors

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 woke 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.

02/16/16

Nearsighted Drug Development

I was encouraged to hear that ALKS 5461 failed in two late-stage clinical trial studies. This isn’t because I have something against Alkermes, the pharmaceutical company developing the drug. I don’t own stock in a competing company trying to bring their new fast-acting antidepressant drug to market ahead of Alkermes. I do think antidepressants are overprescribed and have potentially harmful side effects for some people, but that’s not why I was happy to hear that ALKS 5461 is in trouble. I just don’t think that putting an antidepressant drug on the market that uses a potentially addictive opioid as its active ingredient is a good idea.

Reporting for Reuters, Amrutha Penumudi said that when news of the failed clinical trails for ALKS 5461 were made public by Alkermes, the company saw its shares fall in value by 42.8%, a $3.88 billion loss for the company. ALKS 5461 is the company’s main product, so the bad news about the clinical trials was a major financial blow. William Tanner, an analyst for Guggenheim Partners was widely quoted by Reuters and others as saying that “We believe trial failures present a major setback in the evolution of the company.” Even if ALKS 5461 succeeds in a third as-yet not completed clinical trial, more studies may be required, according to Ken Cacciatore.

ALKS 5461 is a new molecular entity (NME) that has been fast tracked by the FDA for approval as a treatment of Major Depressive Disorder (MDD) with patients who didn’t respond to standard antidepressant therapies. It is a combination of buprenorphine, a Schedule IV Controlled Substance and samidorphan, a naloxone-like substance. Suboxone, which is a combination of buprenorphine and naloxone, is commonly used as an opioid substitution medication for heroin and prescription opioid addicts. The major difference between ALKS 5461 and Suboxone as far as buprenorphine is concerned is that ALKS 5461 is currently being tested in 2 mg and .5 mg doses, where standard protocols for Suboxone as an opioid substitution drug could reach 16 mg or higher. You will find more information on ALKS 5461 and my concerns about its use to treat depression in: “The Coming Depression Apocalypse,” an article I published here a few months ago.

But it doesn’t seem Alkermes is going to give up the fight. In their press release, Richard Pops, the CEO of Alkermes said:

We are steadfast in our commitment to developing new medicines for serious CNS conditions where there is a clear and compelling need for new treatment options for patients and their families. . . . Major depressive disorder is one of these conditions. We are building a large body of evidence supporting our belief in the clinical utility and the novel mechanism of action of ALKS 5461. We await the results of FORWARD-5 and will determine our next steps along the regulatory path with those results in hand.

In one of the failed trials, Alkermes did post-hoc analyses (reanalysis of the data after the fact) that indicated the 2 mg dose was more effective than a placebo. Given the results of the two failed studies, Alkermes said they plan to increase the number of patients in the ongoing trial and “update” the planned statistical analysis for FORWARD-5, the third efficacy study in the FORWARD program. The updated analysis sounds like it means they plan to use the same analysis process applied to the 2mg dose group for FORWARD-4 after the fact. This is bit like cheating if the researchers went p-hacking or data-dredging in their post-hoc analysis. See “How to Lie About Research” for more information on p-hacking.

Another factor regarding Alkermes and ALKS 5461 that concerns me is how the company describes the drug. In their above-linked press release, Alkermes said that ALKS 5461 acted “as a balanced neuromodulator in the brain;” and was “designed to rebalance brain function that is dysregulated in the state of depression.” This sounds eerily similar to the chemical imbalance theory of depression that even psychiatrists such as Ronald Pies have said was always a kind of urban legend. In an article in Psychiatric Times, he said: “To my knowledge, no professional psychiatric organization has ever publicly promoted a ‘chemical imbalance theory’ of mental illness in general.” Look at Robert Whitaker’s response to that article by Pies and the reams of additional evidence to show how Pies’ claim was clearly wrong.

But there is now another concern with the use of opioids to treat depression. A study by Scherrer et al., published in the Annals of Family Medicine, found that people who used prescription opioids for longer than a month may have an increased risk of developing depression. Scherrer was quoted by Agata Blaszczak-Boxe for Live Science as saying the researchers rigorously controlled for pain, “and we feel strongly that these results are independent of the known contribution of pain to depression.” The longer individuals were taking opioids, the greater was their risk of depression.

Citing a 2014 study by Howe and Sullivan in General Hospital Psychiatry, Scherrer et al. said that research on the efficacy of opioids in treating depression was limited by small sample sizes, short follow-up time and lack of control groups. So they do not support opioids as effective long-term treatments for depression. “This evidence, combined with the finding from the present study, supports the conclusion that opioids may cause short-term improvement in mood, but long-term use is associated with risk of new-onset depression.”

Buprenorphine was not one of the opioids studied, but the findings of the Scherrer et al. study does give me increased concern with the fast-track status the FDA has given ALKS 5461. Recent findings do suggest the risk of new onset of depression increases with a longer duration of opioid use. A replication attempt of Scherrer’s study with buprenorphine seems needed before approving ALKS 5461. The short-term projected improvements could lead to long-term problems with depression. “Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression.”

Hopefully the FDA will have the foresight to weigh all the potential adverse effects with ALKS 5461 before approving it. There is a very real potential for physical dependency to develop with ALKS 5461 given that its active ingredient is a Schedule IV controlled substance. Heroin addicts have told me buprenorphine was more difficult for them to come off of than heroin or methadone. And to top it all off, there seems to be evidence that using opioids longer than 30 days carries a risk of new-onset depression. This is not a very promising profile for a future treatment for depression.

Additionally, the initial statistical analysis done on the first two clinical trials failed to demonstrate that it was more effective than a placebo. Only after a post hoc analysis was there evidence of any statistically significant results. And then it was only with the higher, 2mg, dose. Will that lead to even higher doses of buprenorphine to increase its effectiveness? Read more on the concerns with outcome switching in clinical trials here.

Revising the statistical analysis (outcome switching) of the remaining clinical trial may produce statistically significant results, and if it does, it seems Alkermes intends to argue with the FDA to approve ALKS 5461. On the one hand, I can see where Alkermes would attempt to salvage their “lead product.” But I’m hoping their nearsighted focus on profits and the company’s market value will not blind the FDA to the long-term consequences of using opioids like buprenorphine to treat depression.

02/5/16

Wolves in Sheep’s Clothing

Atypical antipsychotics are now the largest-selling class of drugs in the U.S., accounting for more than $14.6 billion in annual sales by 2010. They are also the class of psychiatric drugs with the most negative side effects—and that’s saying something when you consider the others, namely antidepressants and anti-anxiety meds. Because schizophrenia effects such a small percentage of the population, the initial market for atypical antipsychotics was limited. The path to increased sales led through finding a wider market than just individuals with schizophrenia. So the pharmaceutical companies began to look at the behavioral disorders.

For the most part, these disorders are less serious than schizophrenia, but many are severe nonetheless, including hyper-activity in children and agitation in elderly patients. Marketing atypical anti-psychotic agents to patients with this broader category of disorders held the promise of sales reaching blockbuster levels.

There were two obstacles to this broader promotion. First, the FDA had only approved atypicals for the treatment of severe psychosis—schizophrenia—in adults. Their use for other disorders was then off-label. FDA regulations prohibit pharmaceutical companies from promoting drugs for such additional uses.

The second obstacle was that they didn’t have a very good safety profile. Used for a serious disorder like schizophrenia, the adverse effects of atypicals were understood to be a trade off. “But the risk–benefit calculus is much less favorable when milder conditions are involved.” Despite these impediments, the temptation was too much for the manufacturers to resist and a number of lawsuits over the past few years attest to this. Read “Antipsychotic Medications Are Spelling Legal Trouble for Drugmakers” for more information on this. Robert Field concluded his article with this observation:

In light of the large number of successful enforcement actions and the continued potential for abuses, prosecutors are likely to remain vigilant concerning the marketing of atypical antipsychotic agents. Repeated violations could generate even larger penalties. Publicity over the large settlements has put physicians and the public on notice about the hazards of indiscriminate use of this class of drugs. In the future, regulators, clinicians and patients should view atypical antipsychotics and marketing claims concerning them with caution.

Over time, antipsychotics have “evolved.” Some are now approved as adjunct medication for treating major depression. Many are now are also prescribed for the treatment of bipolar disorder. And then there is off-label market for several behavioral disorders. No longer are they relegated to just the niche market of people diagnosed with schizophrenia.

The FDA-approved uses for antipsychotics now include the treatment of bipolar I disorder, schizophrenia, schizoaffective disorder and as an adjunct treatment for major depression. In addition to their FDA approved uses, several atypicals are used off-label to treat various psychiatric conditions. They have been studied as off-label treatment for the following conditions: ADHD, anxiety, dementia in elderly patients, depression, eating disorders, insomnia, OCD, personality disorder, PTSD, substance use disorders, and Tourette’s syndrome.

Clozapine (Clozaril) was the first atypical developed. Introduced in Europe in 1971, it was voluntarily pulled by its manufacturer when it was shown to cause a condition called agranulocytosis, a dangerous decrease in the number of white blood cells. It was then approved by the FDA in 1989 for the treatment of treatment-resistant schizophrenia. In 2002 the FDA also approved clozapine for reducing the risk of suicidal behavior. However, the FDA also requires it to carry five black box warnings for a series of adverse health effects including cardiovascular and respiratory problems and increased mortality in elderly patients with dementia-related psychosis.

The five main atypical antipsychotics currently used in the US are: Aripiprazole (Abilify), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal) and Ziprasidone (Geodon). There are six newer ones whose off-label use have not been documented or researched as extensively as the preceding five have been. These newer ones are: Asenapine (Saphris), Iloperidone (Fanapt), Lurasidone (Latuda) and Paliperidone (Invega). Two brand new antipsychotics, Rexulti (brexpiprazole) and Vraylar (cariprazine), will be discussed below.

There are also six other atypicals that have not been approved for use in the US. They are: Amisulpride, Blonanserin, Melperone, Sertindole, Sulpride and Zotepine. The following chart lists the FDA-approved indications for atypical antipsychotics.

Atypicals	Bipolar 1	schizophrenia	schizoaffective	Major depression
Aripiprazole	yes	yes		yes
Olanzapine	yes	yes		yes
Quetiapine	yes	yes		yes
Risperidone	yes	yes
Ziprasidone	yes	yes
Asenapine	yes	yes
Iloperidone		yes
Lurasidone	yes	yes
Paliperidone		yes	yes
Clozapine		yes	yes
Brexpiprazole		yes		yes
Cariprazine	yes	yes

Schizophrenia is the primary disorder for which antipsychotics are targeted and bipolar 1 disorder is second. Three of the main antipsychotics have been approved as augmentations for antidepressants, Aripiprazole, Olanzapine and Quetiapine. Interestingly, the medication guides for most of the antipsychotics seem to downplay the drug class they are in. They only refer to themselves as “antipsychotic” within the warning of a potential side effect called neuroleptic malignant syndrome. Coincidentally, that is the only place the other common term for antipsychotic, neuroleptic, is found.

Here is an example of how the warning for the potential side effect of neuroleptic malignant syndrome: was worded for Seroquel (quetiapine): “neuroleptic malignant syndrome (NMS). NMS is a rare but very serious condition that can happen in people who take antipsychotic medicines, including SEROQUEL.” Many of the other antipsychotics have similar wording for the discussion of this side effect. Abilify never refers to itself as an antipsychotic or neuroleptic in its medication guide. Under the discussion of possible side effects with Abilify is the following:

Neuroleptic malignant syndrome (NMS): Tell your healthcare provider right away if you have some or all of the following symptoms: high fever, stiff muscles, confusion, sweating, changes in pulse, heart rate, and blood pressure. These maybe symptoms of a rare and serious condition that can lead to death. Call your healthcare provider right away if you have any of these symptoms.

But you will find a lot of discussion about antidepressants in some of these medication guides. Many of the antipsychotics use language that gives the impression that the drug is an “antidepressant,” not an “antipsychotic.” The medication guides for Abilify (aripiprazole), Seroquel (quetiapine) and Latuda (lurasidone) have an entire section that discusses what someone needs to know about antidepressant medications. Someone not familiar with the various classes of medications who are taking these drugs might think they are taking antidepressant and not an antipsychotic.

The following table summarizes the evidence for off-label use of the five primary atypical antipsychotics currently used in the US are: Aripiprazole, Olanzapine, Quetiapine, Risperidone and Ziprasidone. The strongest evidence of efficacy is noted as “++”, then “+”. “0” means there have been no clinical trials attempted; “-“ represents no efficacy and “+-“ is for mixed results. “FDA” represents FDA approval for the condition. Keep in mind these ratings are based upon the data from the drug companies in their quest to expand the antipsychotic market.

Disorder	Aripiprazole	Olanzapine	Quetiapine	Risperidone	Ziprasidone
Anxiety	0	–	++	–	–
ADHD	0	0	0	+	0
Dementia	++	+	+	++	0
Depression	FDA	FDA	FDA	++	+
OCD	0	+	–	++	–
PTSD	0	+-	+-	++	0
Tourette’s	0	0	0	+	–

Risperidone was the first of the main five antipsychotics brought to market in 1990 by Janssen. In 1996 Eli Lilly brought olanzapine to market in September of 1996 and AstraZeneca brought quetiapine to market in September of 1997. Pfizer brought ziprasidone to market in June of 2002 and Bristol-Myers Squibb had aripiprazole approved in November of 2002. All five are currently off patent. The patent expiration dates for the newer antipsychotics are as follows: Asenapine (Saphris) in 2020, Iloperidone (Fanapt) 2027, Lurasidone (Latuda) 2018. Paliperidone (Invega) lost its exclusivity on October 6, 2014.

Two brand new antipsychotics, Rexulti (brexpiprazole) and Vraylar (cariprazine) were just approved by the FDA in the summer of 2015. Vraylar was approved for the treatment of schizophrenia and bipolar disorder in adults. Rexulti was approved as a treatment for schizophrenia and as an add-on treatment for adults with major depression.

The Rexulti medication guide also has a section describing what you need to know about antidepressants. It has the same warning for the potential side effect of neuroleptic malignant syndrome (NMS) found with Abilify. It also lists major depression as the first disorder it is used to treat; schizophrenia is listed second. So it seems that it is positioning itself to be seen more a treatment for depression than schizophrenia.

To its credit, Vraylar’s medication guide regularly refers to antipsychotics and the side effects of antipsychotics. And I did not find even ONE reference to “antidepressant.” However, its discussion of NMS is subtle, never explicitly saying it could occur from Vraylar. Under warnings and precautions it says:

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

However, truth in advertising isn’t the only concern, at least with Vraylar. Johanna Ryan described a detailed investigation she did of the Vraylar studies registered with ClinicalTrials.gov. Out of the twenty registered studies, seventeen were completed, but still had not shared their results on the government website, a mandatory step in the process. I reviewed all the registered studies for Vraylar on December 4, 2015 and there were still no posted results from the completed clinical trials for Vraylar almost two months after Ryan’s article was posted on davidhealy.org.

She found at least six published papers directly based on these studies; only two were posted on CT.gov. The average number of listed authors was six to eight, with an academic noted as the “lead” author. The rest were drug company employees. Some papers only had employee-authors.

Overwhelmingly they were contract researchers. Some were freestanding clinical trial businesses. Others were busy medical practices with a thriving research business “on the side.” The first recruited subjects largely by TV, newspaper and online advertising which emphasized free treatment. The second combined some advertising with recruitment among their own patients.

The adverse side effects with antidepressants are increasingly evident, as is their well-documented ineffectiveness. But they are more acceptable by our cultural psyche than antipsychotics. Remember Listening to Prozac? Antipsychotics (neuroleptics) are now the “it” class of psychiatric medications. As they expand their market reach to beyond schizophrenia, the term “antipsychotics” has become a liability for sales. “Anti “depression” medication is an easier sell than anti “psychotic.” So it seems there has been an intentional effort by some pharmaceutical companies to blur the lines between the drug classes of antidepressants and antipsychotics.

I think a fitting metaphor for what’s happening is to think of this marketing strategy as an attempt to pass off wolves in sheep’s clothing. But you have to wonder just how bad the adverse effects of antipsychotics (the wolves) are when the less harmful half of the metaphor—the “sheep”—is antidepressants.

01/22/16

Discovering Adverse Drug Events

Okay, you probably don’t wonder about things like how many people to visit the emergency department (ED) of a hospital when they experience serious side effects or have an adverse drug reaction (ADE) from psychiatric medications. But when 26.8 million US adults, approximately 11.5% of the adult population, are using psychiatric medications, it’s a good thing that some people do wonder—and then set out to find an answer to their question. A study published in 2014 estimated that there were over 89,000 ED visits due to ADEs from the use of psychiatric medications from 2009 through 2011. That accounted for 9.6% of all adult ADE ED visits during the same time period. Almost half (49.4%) of the visits involved adult patients aged 19 to 44 years old; 33.3% were between 45 and 64; 17.3% of the ED visits were with adults 65 and older.

Hampton et al. used nationally representative public health data to estimate the numbers and rates of ED visits and hospitalizations for ADEs from psychiatric medications among adults between January 1, 2009 and December 31, 2011. To estimate the use of specific medications, they used publically available data from the National Ambulatory Medical Care Survey. To determine the number of US adults, men and women, between 2009 and 2011, they used National Center for Health statistics estimates, which are based on US census data. They excluded all ED visits resulting from intentional self-harm, documents drug abuse, therapeutic failures, nonadherence or drug withdrawal. They looked at the following classes of drugs: antidepressants, antipsychotics, lithium salts, anxiolytics (anti-anxiety drugs) and stimulants.

The researchers found that 52.8% of the adverse events were negative reactions to the drug. Unintentional therapeutic overdoses accounted for 33.8% of the adverse events and 12.9% were due to allergic reactions. Most of the cases were treated and released or left against medical advice (80.7%). But 19.3% were admitted, observed or transferred to another facility. Around 73 percent of the ADEs involved one implicated medication.

But the percentage of individuals seeking treatment for ADEs who were using multiple concurrent medications was high. Only 34.4% were only using one medication. 34.5% were using 1 to 3 medications. 17.7% were using 4 to 5 medications and 13.4% were using six or more concurrent medications. Polypharmacy of four or more concurrent medications involved 31.1% of the ED visits.

Ten specific medications, either alone or in combination with other medications were involved in 57.5% of the adverse drug—related ED visits. The brand names of the medication are in parenthesis. Surprisingly, Ambien or its generic version, was the number one medication implicated in adverse drug—related ED visits. Among adults 65 and over, Ambien alone was responsible for 21% of ED visits. See the table below.

Data from the Drug Abuse Warning Network have shown that ED visits for zolpidem ADEs increased 220% from 2005 to 2010, and previous studies have indicated that zolpidem use is associated with a substantial risk of falls. While the FDA’s recent efforts to modify recommended dosing regimens hold promise for reducing zolpidem ADEs, clinicians can also reduce zolpidem ADEs by prescribing zolpidem for insomnia, its sole FDA-approved indication, only after considering other treatments such as sleep hygiene education, stimulus control, sleep restriction, relaxation training, and cognitive behavior therapy.

Medications	No of Cases	Estimated # of visits	% of visits
Zolpidem (Ambien)	445	10,212	11.5
Quetiapine (Seroquel)	320	6900	7.7
Alprazolam (Xanax)	241	5616	6.3
Lorazepam (Ativan)	233	5517	6.2
Haloperidol (Haldol)	250	4879	5.5
Clonazepam (Klonopin)	215	4571	5.1
Trazodone (Oleptro)	182	4249	4.8
Citalopram (Celexa)	175	4143	4.6
Lithium	217	4034	4.5
Risperidone (Risperdal)	166	3662	4.1

Antipsychotic medications, such as Seroquel, and lithium salts were implicated in significantly more ED visits relative to the number of outpatient visits at which they were prescribed than other psychiatric medications.” Since over 60% of antipsychotic prescribing has been found to be for off-label uses, it is probable that many of these ED visits were from off-label use. Disturbingly, “well over half of the off-label use of antipsychotics may be based on inadequate evidence.

Concerns about antipsychotics’ risks and their possible overuse have prompted the leaders of the American Psychiatric Association to urge providers to prescribe antipsychotics cautiously and only after exploring the feasibility of using alternate treatments.Avoiding antipsychotics in favor of other options less likely to cause ADEs could be particularly appropriate when considering treatment of major depressive disorder, insomnia, or anxiety disorders because the FDA has not approved the use of any antipsychotic for the first-line treatment of major depressive disorder, the use of any antipsychotic for the treatment of insomnia, or the use of any atypical antipsychotic for the treatment of anxiety disorders.

So adverse drug events with psychiatric medications contribute to a significant amount of the ED traffic in US hospitals. And the majority of them were from the misuse of ten specific medications. But it also seems that these adverse events are under reported—perhaps intentionally.

The FDA has an Adverse Event Reporting System (FAERS) that is the government’s primary safety surveillance system for harm resulting from therapeutic drugs. The Institute for Safe Medicine Practices published a Quarter Watch Report that concluded FAERS suffered from “a flood of low quality reports from drug manufacturers and it has not yet been updated for the changing environment in which drugs are marketed to health professionals and consumers.”

The FAERS system is critically important for two reasons. First, a majority of new FDA safety warnings on FDA approved drugs are generated from these ADE reports. “Despite its limitations, FAERS is the most reliable system for discovering new drug risks that had not been identified in pre-market drug testing.” Second, no other system has comparable international scope. It is sensitive enough to detect rare but catastrophic adverse side effects and the capacity to identify unexpected potential injuries.

The total number of adverse events reported to the FDA over a calendar year ending at the first quarter of 2014 (847,039) was more than double that of 2009 (336,753). Additionally, 96.6% of the case reports were collected and written by drug manufacturers. “Thus, the performance of the drug manufacturers, combined with FDA regulations and compliance activity, determines the quality, coverage and completeness of this safety surveillance system.” While the increased numbers of submitted reports indicate the drug manufacturers are now reporting radically more ADEs than in the past, the overall completeness of the reports was poor.

While drug manufacturers are now reporting adverse drug events in unprecedented numbers from around the world, we judged that the overall completeness of adverse event report was poor. For example, in 36% of cases the age of the patient was not determined; in 44% of cases no event date was indicated. A report was classified as reasonably complete if it contained age, gender, and an event date. While 85% of serious reports sent directly to the FDA were reasonably complete, only 49.4% of the manufacturer serious reports met this basic standard. We also identified thousands of case reports where the adverse event was classified as non-serious and indicated only common health problem such as a cold (n = 1,889), the sniffles (n = 906), or an injection that had been painful (n = 4,331). Manufacturer report quality for serious adverse events varied widely. The weakest performance was seen in four companies that submitted reasonably complete reports in only 15% or fewer cases; not one manufacturer equaled the FDA’s 85% record for complete reports; and only 5/74 (7%) manufacturers reported at least age and gender in 90% or more serious reports.

Some of the problems in the reporting system are that it does a poor job with ADEs from older generic drugs and for events involving newborns and children. For birth defects, the reporting is even more limited. Given the drastic increase in the use of psychiatric medications with children over the past twenty years, this seems to be a serious and dangerous flaw. “Even though 86% of outpatient prescriptions are for generic drugs, according to IMS Health Inc., the major brand name manufacturers provide the overwhelming majority of adverse event reports, even when sales of the brand name drug are extremely small.” And despite major global changes with medications and technology in the past fifteen years, the legally binding FDA guidance document specifying how drug manufacturers are to collect and report ADEs since 2001.

The Institute for Safe Medicine Practices concluded that improving FAERS should be a top priority of the FDA. Modernizing the ADE reporting requirements would provide a low-cost opportunity to improve safety surveillance as well as reduce some of the burden on drug manufacturers and focus resources in a more productive direction. Some changes are straightforward: “We can’t think of a good reason why the quality and completeness of serious adverse event reports collected by drug manufacturers is so much worse than those collected online at the FDA.” The failure to get basic information like the patient’s age in 36% of the cases of adverse events suggests poor quality control and weak collection systems. “And does the system really need thousands of non-serious reports of the sniffles or that an injection was painful?”

Other changes may require substantial discussion and debate. Developing clear and usable protocols for manufacturer-initiated contacts with patients or health professionals may require new report data elements, and specific lists of questions to ask. Improving the quality of patient death reports is non-trivial because patient deaths typically involve multiple contributing factors, and assigning cause may be a subjective medical judgment. But there is no point in manufacturers submitting thousands of reports of deaths in which a possible drug role was never alleged, ascertained, or investigated. In all of these situations, much could be gained from requiring a simple critical question in company-initiated contacts that asked: “Was the drug suspected of contributing to the event?”

But can these simple and reasonable changes ever make it past the vast lobbying efforts of the pharmaceutical industry? Links to other reporting on this FDA study can be found here on Mad in America: “FDA System for Recording Adverse Drug Effects Perilously Deficient.”

08/10/15

Marijuana Peek-a-Boo

On Friday, July 10th, the House of Representatives passed H.R. 6, the 21st Century Cures Act (244-183). The bill is now in the Senate for consideration. There had been an amendment proposed that would have rescheduled marijuana and its derivatives under a new 1-R schedule, which would have facilitated research. Marijuana could then have been rescheduled further, after that research was completed and further reclassification was warranted. The National Institute of Health (NIH) and the Drug Enforcement Agency (DEA) were also directed in the amendment to study the benefits and risks of medical marijuana. But the bipartisan amendment was defeated. The irony is that both critics and supporters of legalizing marijuana put forth the failed amendment.

Reporting for the Washington Post, Aaron Davis said that House Republicans have consistently defended their opposition to marijuana laws, saying there is no evidence that such action would do anything “but destroy the brains of the nation’s adolescents.” But the lack of evidence can be traced to Congressional resistance to fund federal agencies to do objective testing on the effects of marijuana. This “Catch 22” led to the support of the amendment by critics and supporters of legalization.

Maryland Representative Andy Harris, a doctor and outspoken critic of legalization over the past two years, co-sponsored the amendment. Before the House Rules Committee sidelined the amendment, he said: “We need science to clearly determine whether marijuana has medicinal benefits and, if so, what is the best way to gain those benefits.” Harris reportedly doesn’t think that research will find medical benefits, but another Republican, H. Morgan Griffith of Virginia, thinks there are limited circumstances in which marijuana has medical benefits. He said: “This amendment would have answered the question one way or the other. I think it would have shown it is a valuable medical substance, but now we don’t have the evidence.”

The failed effort put advocates for marijuana legislation in the odd position of having to praise Harris, who had become a nemesis of their cause. Michael Collins, the policy manager for the pro-marijuana Drug Policy Alliance, said: “To Mr. Harris’s credit, he thinks there are benefits to researching marijuana, whether you support it or not.” Opponents to legalization of marijuana also see research as a logical step forward. Sue Rusche, head of the National Families in Action, a drug prevention organization, said: “Right now we really don’t know what you’re getting. What we need is research to show us what level of CBD and THC should be given and what’s safe.”

Back in January of 2014, President Obama said it was up to Congress, not his administration, to reschedule marijuana. Steven Nelson, reporting for US News and World Report, said that marijuana advocates said that wasn’t entirely accurate. Representative Earl Blumenauer from Oregon said the law actually permits the current administration to reclassify marijuana. “I don’t dispute that Congress could and should make the change, but it’s also something the administration could do in a matter of days and I hope they will consider it.” Rep. Blumenauer is one of 17 cosponsors of other legislation aimed at reclassifying marijuana, the “Regulate Marijuana Like Alcohol Act.” There has been no action reported on the bill at this point. Govtrack.us said the bill had a 3% chance of getting past committee, and a 1% chance of being enacted. Blumenauer has introduced “The Marijuana Tax Act,” also listed as having a 1% chance of being enacted by Govtrack.us.

Tom Angell, chairman of the group, Marijuana Majority, said it was unfortunate that President Obama “passed the buck” to Congress on marijuana. Dan Riffle, the director of federal policies for the Marijuana Policy Project, said that rescheduling marijuana “is not a ‘job for Congress,’ as the president says.” Riffle said that scheduling decisions are handled by the DEA. In June of 2014, Anna Edney for Bloomberg Business reported that the FDA had been asked by the DEA to review marijuana’s status. This is the third time since 2001. In 2001 and 2006 the FDA recommended that marijuana remain a Schedule 1 Controlled Substance.

Douglas Throckmorton, the Deputy Director for Regulatory Programs at the FDA, acknowledged the FDA was once again conducting an analysis, but could not say when the FDA would complete its analysis or whether it would recommend a change. His testimony before a House subcommittee described the FDA’s role in potentially approving marijuana as a prescription drug. Dr. Throckmorton affirmed the FDA’s belief that its drug approval process was “the best way to ensure that safe and effective new medicines from marijuana are available as soon as possible for the largest numbers of patients.” He added that it was important to apply these scientific standards to the development and assessment of any alleged therapeutic uses of marijuana.

One of the considerations with establishing the safety and efficacy of a drug is a manufacturer’s ability to demonstrate an ability to consistently manufacture a high-quality drug product. This presents a special challenge with botanically derived drugs like marijuana, including the consistency of lot-to-lot potency. Another consideration is the need to identify a method of consistently providing a specific drug dose. Citing a report from the Institute of Medicine (IOM), Throckmorton noted problems associated with getting consistent dosing from smoked products such as marijuana. The IOM recommended that clinical trials involving marijuana be conducted to find a safe, alternative delivery system.

If there is any future for marijuana as a medicine, it lies in its isolated components, the cannabinoids and their synthetic derivatives. Isolated cannabinoids will provide more reliable effects than crude plant mixtures. Therefore, the purpose of clinical trials of smoked marijuana would not be to develop marijuana as a licensed drug but rather to serve as a first step toward the development of nonsmoked rapid-onset cannabinoid delivery systems.

Throckmorton then cited two drugs approved for human use that contain active ingredients that are present or similar to those in botanical marijuana: Marinol and Cesamet.

These products have undergone FDA’s rigorous approval process and have been determined to be safe and effective for their respective indications, and reflect the views of the IOM that the future of marijuana as a potential medicine lies in classical pharmacological drug development. As a result, patients who need medication can have confidence that any approved drug will be safe and effective for its indicated uses.

So here’s what I’m thinking. When the 21st Century Cures Act is reviewed by the Senate, it needs a provision that will add the changes proposed by the Griffth-Harris-Blumenauer-Farr amendment. This would bring future research into medical marijuana under the authority of the FDA. Effective regulations for the safety and efficacy of medical marijuana can be developed. All states, those who have already approved the use of medical marijuana and those in the future who may approve it, would benefit from the standardization of FDA regulation. The existing problems with medical marijuana (see “Let’s Not Get Ahead of Ourselves”) such as biological and chemical contaminants, accurate labeling, overmedication, and consistent dosing in products could be worked out. The at times outrageous claims for exactly what marijuana DOES medically treat can be examined systematically and scientifically.

But I’m also thinking that isn’t what some legalization advocates want, because it will take time; and the momentum towards recreational marijuana legalization could be lost. The best path to legalization is to let the political infighting in Congress and federal agencies like the FDA and the DEA continue to neutralize any federal regulation of medical marijuana while marijuana activists continue their state-by-state battle. If I wanted to develop a strategy for national legalization of marijuana, I’d suggest the following.

The strategy for eventual national legalization of recreational marijuana is to eat the elephant one bite at a time. Keep the battles going state-by-state and keep the federal government out of the fight. Legislatures within the states where medical marijuana is not yet approved should hear about the income and health benefits of legalizing medical marijuana, but not the existing problems where it has been approved. Information on the different kinds of cannabinoids in marijuana and their varying medical benefits—some greater than others—needs to be suppressed. Let them think the medical benefits are all or nothing with marijuana and not contingent upon specific cannabinoids within marijuana. The known health problems from smoking marijuana should be minimized or ridiculed. If I wanted a sound national policy toward medical marijuana, I’d look for the following developments.

The best strategy to slow and perhaps stop the growth of state-by-state legalization of recreational marijuana is to be proactive about the legalization of medical marijuana at the federal level. Quality research that showed the medical benefits of specific cannabinoids, like CBD and THC, the psychoactive cannabinoid in marijuana needs to be done. A more efficient delivery system for medical marijuana than smoking an herbal product of varying potency, with possible biological and chemical contaminants could be developed. The sideshow of existing medical marijuana “treatment” as an excuse to legally medicate (and overmedicate) with THC to get high would stop. Individuals who could benefit from legitimate medicinal marijuana products would get the help they need. And the recreational advocates couldn’t hide behind the medical marijuana movement anymore.

07/29/15

Pharma Goes to Court

Okay, stay with me on this one. I want to talk about some jousting going on in the court system between Pharma and regulatory agencies, like the FDA. Amarin Corporation is suing the FDA, saying that the FDA violated its first amendment rights to free speech. The company argued that it has “a constitutional right to share certain information about its products with doctors.” Lawyers for the company believed this was the first time a manufacturer has sued the agency before the FDA ruled against them. The future “blockbuster” at the center of this fight is an omega-3 fatty acid product derived from fish called Vascepa. That’s right prescription strength fish oil.

As a matter of fact, according to Katie Thomas of The New York Times, Vascepa is the only existing product for Amarin. The FDA approved Vascepa for patients with extremely high levels of triglycerides, which are linked to heart disease. When the company sought to expand the drug’s approved reach to individuals with severe levels of triglycerides, the FDA denied its request. Lawyers for the company claim the company is not trying to market Vascepa to a wider population of patients than it was approved for, which is illegal. Amarin merely wants to make statements about its product that manufacturers of fish-oil supplements make—namely that there is “supportive but not conclusive research” that shows fish oil products like Vascepa may reduce the risk of coronary hear disease.

A lawyer for Amarin pointed out where doctors are already prescribing Vascepa off-label, which is legal for doctors to do once the FDA approves a drug for any purpose. “Those doctors who are already prescribing off-label need more information, not less, about what their treatment options are.” John Sullivan said on Drug and Device Law, that the content of Amarin’s supporting brief was convincing. In addition to the “truthful, non-misleading statements it wants to provide to healthcare workers, it wants to provide the results of its ANCHOR clinical trial and other peer-reviewed articles on the connection between the active ingredient in Vascepa and coronary risk.

But is all this legal dancing around just about the right of a relatively small biopharmaceutical company to make the same claims about its prescription drug that dietary supplement companies can make about their fish oil products?

Toni Clarke, writing for Reuters, noted where drug companies have been increasing their efforts to pressure the FDA to relax its guidelines since a 2012 decision (2-1) from the Second Court of Appeals overturned the conviction of a sales representative for Orphan Medical, who was caught talking to physicians about off-label uses for the narcolepsy drug, Xyrem. The court said truthful and non-misleading off-label “speech” was protected by the First Amendment. “Pharmaceutical companies are citing the Caronia and similar rulings to pressure the FDA to let them talk more freely about off-label use.”

A coalition of pharmaceutical companies known as the Medical Information Working Group has petitioned the FDA to “’adequately justify and appropriately tailor its regulatory regime in light of Caronia and similar rulings.” This coalition includes Pfizer, Sanofi, Novartis AG, Johnson & Johnson, Eli Lily and Co., GlaxoSmithKline, Purdue Pharma, and Bayer Healthcare Pharaceuticals. What’s at stake is the right of manufacturers to attempt to persuade physicians to use their products for unapproved uses. This would be a potentially serious weakening of the FDA’s regulatory authority. Oh, and it could mean billions of dollars in potential sales for Pharma.

The FDA sent a letter to Amarin, essentially saying that it did not have concerns with most of the information Amarin proposed to communicate to doctors. The FDA pointed to existing guidance documents that indicated Amarin could distribute the results of its ANCHOR clinical trial results through peer-reviewed articles. Further, it said Amarin could communicate summaries of those trail results, but not in marketing materials or through sales reps.

Then on June 23, 2015, the FDA filed its brief in response to Amarin’s Motion for Preliminary Injunction. The brief called the lawsuit a frontal assault on the framework for new drug approval, rather than a narrower as-applied constitutional challenge. Lisa Baird, writing for ReedSmith, further noted where the FDA felt that if successful, the Amarin litigation “has the potential to establish precedent that would return the country to the pre-1962 era when companies were not required to prove that their drugs were safe and effective for each of their intended uses.”

At the heart of the matter is the distinction made by the FDA between drugs and dietary supplements. The FDA brief noted that Amarin ignored “the critical reality that drugs present markedly different considerations from dietary supplements.” After citing several legal rulings in support of this claim, the FDA said that Amarin wanted to market Vascepa as a drug intended to treat patients who are already being treated with statins, but continue to be at risk for cardiovascular disease. “Yet, FDA has found on multiple occasions that the heart disease claim did not meet the statutory standard of significant scientific agreement as the claim is based on ‘less persuasive studies.’” The potential harm posed by drugs is presumably much greater than that posed by dietary supplements.

These considerations amply justify a more cautious approach to drug approval and promotion, and the applicable statutory scheme recognizes this necessity. Unlike drugs, there is no statutory requirement of premarket approval for dietary supplements to be distributed. See 21 U.S.C. § 301 et seq. In addition, as a result of Pearson, claims about dietary supplements are held to a much lower standard (credible evidence) than the robust evidentiary requirement for drugs (substantial evidence) or the intermediate standard that FDA applies to reprints. See 21 U.S.C. § 355(d) & (e); Woodcock Decl. ¶¶ 31-32. Unlike for drug claims, qualified health claims “can be made [for dietary supplements and foods] under some circumstances even when the weight of the scientific evidence is against the claim, provided there is some credible evidence supporting it.” Woodcock D ecl. ¶ 33. Indeed, the June 5 Letter advised Amarin that if it “were to repackage and re-label [its] product as a dietary supplement” and ensure that other relevant conditions were met, “FDA would not object to your inclusion on that dietary supplement of the” heart disease claim. June 5 Letter at 10. Plaintiffs thus conflate two separate regulatory regimes and seek to make Amarin subject only to the aspects of each regime that it finds convenient—an approach that is unsupported by law and contrary to logic and sound public health policy.

This is an important and potentially a serious game changer in FDA attempts to protect the public from the growing evidence of the harmful marketing tactics of Pharma. This jousting between Amarin and the FDA is taking place in the context of the recent approval of “The 21st Century Cures Act,” which was unanimously approved by the House Energy and Commerce Committee on May 21, 2015. Toni Clarke reported that language in the bill adds pressure on the FDA to relax its guidelines.

Allen Frances, in his book Saving Normal, published a chart that he called the drug company “hall of shame.” Prepared by Melissa Raven, PhD, it listed the fines and settlements by Pharma companies for off-label promotion, marketing and fraudulent misbranding of 20 well know pharmaceuticals. Most of the companies noted above who are part of the Medical information Working Group were listed there. Here are the companies and their total fines and settlements between 2004 and 2012 recorded in the table in Saving Normal. The fines and settlements combine both civil and criminal cases. Johnson & Johnson ($1.44 billion); GlaxoSmithKline ($3 billion); Abbott ($1.5 billion); Novartis ($422.5 million); Forrest ($313 million); AstraZeneca ($520 million); Pfizer ($2.3 billion); Eli Lily ($1.415 billion); Bristol-Myers Squibb ($515 million); Purdue (almost $635 million). I think it’s clear why Pharma is going after the FDA. The sum total in fines and settlements from the chart was $12.06 billion between 2004 and 2012.

The FDA announced that it plans to hold a public meeting this summer to address drug company concerns with restrictions on what they can say about off-label use of drugs. But as of the beginning of July, I could find no indication of a set date and time for the public meeting. Perhaps the FDA decided to delay scheduling the meeting until there was an indication what would happen with the 21st Century Cures Act. They may also want to see further reaction to its June 23, 2015 brief filed in response to Amarin’s Motion for Preliminary Injunction.

If I wanted to build case law precedents to justify my constitutional right to share certain information about my pharmaceutical products with doctors, I think I’d first try to have the courts rule in favor of a product like pharmaceutical grade fish oil. It’s already sold as a dietary supplement and there are hardly any known side effects. If successful, I’d build on it and the Caronia case by filing additional litigation in an attempt to cut off the FDA regulations against off-label promotion and marketing of pharmaceuticals at the knees.

04/22/15

A Drug in Search of a Disorder

When the DSM-5 was published in May of 2013, binge eating came out of the closet of Appendix B, the section for potential “disorders” needing further study. “Binge Eating Disorder” became a psychiatric diagnosis (Code: 307.51) in its own right. Before that time, binge eating had received a backhanded diagnosis under the rubric of “eating disorder not otherwise specified.” Without official standing as a coded eating disorder, binge eating suffered from diagnostic insecurity and poor self-esteem. It didn’t have an official diagnostic category like anorexia and bulimia or an FDA-approved medication to treat it. But now, less than two years since it became an official psychiatric disorder, that is no longer the case.

The American Psychiatric Association (APA) defined binge eating disorder as: “recurring episodes of eating significantly more food in a short period of time than most people would eat under similar circumstances.” Some episodes would include marked feelings of a loss of control. A binge eater might eat too quickly, even when not hungry. They may feel guilty, embarrassed or disgusted. They may binge eat alone to hide the behavior. “This behavior is associated with marked distress and occurs, on average, at least once per week over three months.” There is a more complete description of the diagnostic symptoms here in “Promoting Amphetamines for Over-Eating.”

On January 30, 2015, the FDA announced that the ADHD drug Vyvanse (lisdexamfetamine dimesylate) was approved to treat binge-eating disorder in adults. It is the first such drug approved to treat this condition. “Vyvanse was reviewed under the FDA’s priority review program.” Expedited reviews can be done to treat a serious condition, especially if it’s seen to provide “a significant improvement” over available therapies. But, “Vyvanse is not approved for, or recommended for, weight loss. Its efficacy for weight loss has not been studied.”

Common side effects from Vyvanse include: dry mouth, insomnia, increased heart rate, jittery feelings, constipation, and anxiety. More serious, but less common side effects include: “psychiatric problems and heart complications, including sudden death in people who have heart problems or heart defects, and stroke and heart attack in adults.” Vyvanse might also cause “psychotic or manic symptoms, such as hallucinations, delusional thinking, or mania, even in individuals without a prior history of psychotic illness.” Oh, and it’s a Schedule II controlled substance with a high potential for abuse. In fact, OxyContin, fentanyl and cocaine are also Schedule II controlled substances. The DEA said these drugs are considered dangerous, “with use potentially leading to severe psychological and physical dependence.”

The FDA Adverse Events Summary for Vyvanse reported the following adverse events out of 14,311 consumers to its FDA Medwatch reports between 2004 and 2012: off-label use; insomnia; DECREASED APPETITE; aggression; headache; anxiety; nausea; DECREASED WEIGHT; irritability; fatigue; SUICIDAL IDEATION; depression; agitation; overdose; feeling abnormal; abnormal behavior.

The New York Times reported that the marketing strategy for Vyanse sheds light on how pharmaceutical companies seek to “influence the treatment and diagnosis of a medical condition” in order to make billions of dollars in sales. Shire, the pharmaceutical company dispensing Vyvanse, seems to have followed a familiar drug industry method of promoting awareness of a disorder before more directly marketing its treatment.

Soon after Shire won FDA approval of its drug to treat Binge Eating Disorder, Monica Seles began to make the rounds of television talk shows such as “Good Morning America” and “The Dr. Oz Show” to relate her personal struggle with binge eating. She was also interviewed by People Magazine. Seles said that one of the reasons she decided to do this campaign was “to raise awareness that binge eating is a real medical condition.” Seles is a paid spokesperson for Shire. She declined to say what she’s getting paid by Shire.

Shire CEO Flemming Ornskov said that about five years ago researchers noticed the similarities between ADHD and binge eating, so they decided to study Vyvanse for the condition. As early as 2011, Shire’s CEO said that the company hoped to generate “multiple billions of dollars” from expanding Vyvnase use into new areas of illness, like schizophrenia, depression and binge-eating. International Business Times reported that Vyvanse made $1.228 billion for Shire in sales for 2013. The company hoped to grow its overall revenue from the $4.91 billion it made in 2013 to $10 billion by 2020 and Vyvanse is a significant part of that projection. Shire’s current patents for Vyvanse don’t expire until 2023. The approval of Vyvanase for BED means that Shire will gain an additional three years of exclusivity with the drug.

In September of 2014 Shire paid $56.5 million to settle claims it violated the False Claims Act related to marketing and promotion practices with some of its various drugs. According to the Justice Department memo detailing the settlement, Shire promoted Adderall XR for “certain uses despite a lack of clinical data to support such claims.” Shire also allegedly promoted Adderall XR to “prevent poor academic performance, loss of employment, criminal behavior, traffic accidents and sexually transmitted disease.” Vyvanse was also mentioned in the lawsuit. Shire sales reps and other agents “made false and misleading claims” about the efficacy and abuseability of Vyvanse. Oh, and it was said to prevent “car accidents, divorce, arrests and unemployment.”

The allegations resolved by the settlement arose from a lawsuit filed by Dr. Gerardo Torres, a former Shire executive, and a separate lawsuit filed by Anita Hsieh, Kara Harris and Ian Clark, former Shire sales representatives. The lawsuits were filed under the False Claims Act’s whistleblower provisions, which permit private parties to sue for false claims on behalf of the government and to share in any recovery. Torres will receive $5.9 million.

In her article for The New York Times, Katie Thomas quoted Dr. Timothy Walsh of Columbia University, as saying: “Once a pharmaceutical company gets permission to advertise for it, it can often become quite widely prescribed, and even tend to be overprescribed, and that’s a worry.”

There were 3 clinical trails in process for additional potential drug treatments for BED: Cymbalta (Eli Lily), Lamictal (GlaxoSmithKline), and Nuvigil. Cosgrove et al. reported that the DSM-5 work group that approved binge eating as a diagnosis included three individuals with financial ties to Eli Lily, three people with relationships to GlaxoSmithKline and one person with a relationship to Shire.

Several articles have noted a variety of concerns with the FDA approval of Vyanse to “treat” Binge Eating Disorder. International Business Times quoted Sandy Walsh of the FDA office of media affairs as saying they had no direct evidence of how Vyvanse worked in BED: “The exact mechanism of action of the drug in reducing the symptoms of BED is … unknown.” Melissa Gerson, the clinical director of an outpatient treatment center specializing in eating disorders, said she would not recommend a drug alone to treat BED. “I can’t imagine how you would see any long-term improvements in the symptoms.”

A Shire website, BingeEatingDisorder.com noted how someone could talk to their doctor about BED. They provided a Doctor Discussion Guide, saying on its link, “Not sure how to start the conversation with your health care provider?” A tip at the bottom of the homepage suggested that the individual could “Print, e-mail, or take a screen shot of this page, and bring it to discuss with your health care provider.” The New York Times reported that some experts were concerned that the content appeared to coach patients on how receive a diagnosis or shop for a new doctor if they weren’t successful.

Some drug safety experts questioned why the FDA fast tracked approval of Vyanase—even foregoing a review by an advisory committee. For decades, amphetamines like Vyanase, have been known to be a widely abused class of drugs when prescribed for obesity. The marketing end run done by Shire to avoid this pitfall was to promote Vyanase for binge eating and acknowledge that about 80% of the people with BED are overweight or obese WHILE COMPLETELY IGNORING the history of amphetamine abuse with weight loss. Don’t forget that weight loss and appetite suppression are already known to be common side effects when taking Vyanase and other amphetamines. And the FDA didn’t see this move or call them on it?

A spokesperson for the FDA said that Vyanase was granted priority approval because there was no other drug treatment available for BED. “And it did not ask an advisory committee to review the issue because Vyanase is already sold as an ADHD drug and its safety profile is well known.” REALLY? Dr. Daniel Carlatt said:

I’m concerned that the FDA’s approval of Vyvanse for binge eating disorder is going to worsen our problems with stimulant abuse. . . . Vyvanse is a derivative of Dexedrine. We’ve seen epidemics of Dexedrine abuse in the past when it was used to help people diet. I predict that the FDA has just opened the gates to another similar epidemic – after all, binge eating disorder is a subjective diagnosis that could be potentially expanded to cover many millions of people.

Revised and updated with information on Shire paying $56.5 milion to resolve civil claims it violated the False Claims Act.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: FDA