10/17/17

Tell It Like It Is

Recently I saw one of the ubiquitous “ask your doctor if … is right for you” commercials for Rexulti. The slick 90-second ad tells you that when Rexulti is added to your antidepressant, it has been shown to reduce symptoms of depression. The smiley faces used by the actors illustrate how: “Even when you’re taking an antidepressant, you may still be struggling with depression.” You learn that 2 out of 3 people taking an antidepressant may experience unresolved symptoms of depression; and that antidepressants can cause unusual changes in behavior, worsening depression and thought of suicide, especially in those 24 and younger. But you never learn that Rexulti is not an antidepressant.

The commercial never claims Rexulti is an antidepressant, but it clearly leads its viewers in that direction. Counter intuitively, in order to make the case for using Rexulti, it not-so-subtly tells you that antidepressants alone aren’t always effective, since 67% of people taking them have “unresolved symptoms” of depression. But then you learn Rexulti has been shown to reduce symptoms of depression when it is added to an antidepressant. The message is that Rexulti is effective relieving symptoms of depression. But let’s deconstruct what the commercial is telling you even further.

In the mix of the marketing rhetoric, you hear a litany of possible adverse medication side effects. The initial side effects are found with antidepressants: there could be unusual changes in behavior, worsening depression, even thoughts of suicide. “Antidepressants can increase these in those 24 and younger.” This information is legitimately about the side effects from antidepressant medications. See “Antidepressant Misuse Disorder” and “Antidepressants: Their Ineffectiveness and Risks” on this website.

Actually, Rexulti is an atypical antipsychotic or neuroleptic; in the same drug class as Abilify, Zyprexa, Seroquel and Risperdal. The other described side effects and warnings in the commercial are commonly found with atypical antipsychotics. See “Adverse Effects of Antipsychotic Medications” by Muench and Hamer for further information.

Looking further, the commercial said: “Elderly dementia patients taking Rexulti have an increased risk of death or stroke.” Antipsychotics were being used to control behavior problems in elderly patients with dementia. Then research demonstrated there was an increased risk of death in the elderly patients given antipsychotics. So the FDA issued a black box warning to that effect. There was also evidence that antidepressants increased the risk of stroke with elderly patients, thus the Rexulti warning. See “Seniors and Antipsychotics” and “Stroke Risk in Elderly Treated with Antipsychotics” for more information on this.

“Uncontrollable muscle movements” in the commercial is likely referring to tardive dyskinesia, a serious and potentially permanent neurological side effect from antipsychotics. The risks for developing metabolic syndrome (high blood pressure, high blood sugar, excess body fat at the waist, and abnormal cholesterol levels) are mentioned as well. Tardive dyskinesia and metabolic syndrome are widely acknowledged as potential adverse effects from antipsychotics, but not antidepressants. Try “Blind Spots with Antipsychotics,” Part 1 and Part 2 for a discussion on metabolic syndrome and other side effects from antipsychotics. Stiff muscles, confusion, and high fever are symptoms of “a possible life threatening condition” known as Neuroleptic Malignant Syndrome (See “Neuroleptic Malignant Syndrome”).

So you wouldn’t know Rexulti was an atypical antipsychotic or neuroleptic drug from listening to the commercial unless you knew the above were typical side effects with that class of drug. And you may not even discover this from reading the required Medication Guide, unless you knew what to look for. The FDA’s highlights of prescribing information for Rexulti, all 38 pages worth, does have a more complete discussion of the warnings and precautions as well as the adverse reactions. And Rexulti is referred to there as an atypical antipsychotic. However, in the shorter, two page medication guide, that is made available to individuals filling a prescription for Rexulti, there is no explicit reference to it being an atypical antipsychotic or neuroleptic.

The Rexulti Medication Guide does describe tardive dyskinesia, “problems with your metabolism” and Neuroleptic Malignant Syndrome as possible side effects, which are all potential side effects from antipsychotic or neuroleptic medications. But the only place in the medication guide that the word “antipsychotics” is used is in the section “What should I tell my healthcare provider before taking Rexulti?” There, the medication guide advised that if you become pregnant while taking Rexulti, you should “talk to your healthcare provider” about registering with the National Pregnancy Registry for Atypical Antipsychotics. The only place in the Rexulti medication guide the word “neuroleptic” in mentioned is when it notes how Neuroleptic Malignant Syndrome is a possible side effect.

This rhetorical sleight-of-hand is also present in the medication guides for three other antipsychotics approved by the FDA as adjunct medications for depression. Aripiprazole (Abilify), Olanzapine (Zyprexa) and Quetiapine (Seroquel) all use the same descriptive technique of avoiding reference to the drugs as antipsychotics or neuroleptics in their medication guides. And several have an extended discussion of information on antidepressants. Again, someone not familiar with the medications might think they are taking an antidepressant rather than an antipsychotic medication.

The rational for this would appear to be because the initial market for antipsychotics, treating schizophrenia, is limited. Atypical antipsychotics are now the largest-selling class of drugs in the U.S. with more than $14.6 billion in annual sales for 2014. They also are the class of psychiatric drugs with the most side effects. See “Wolves in Sheep’s Clothing” and “Abilify in Denial” for more on these observations.

Another piece of information about Rexulti in contrast to the other antipsychotics approved as adjunct medications for depression is that it is the only one still on patent. Rexulti patents don’t expire until February of 2027 Abilify, Zyprexa, and Seroquel have all been approved as generics. So Otsuka Pharmaceutical Company Ltd. has the potential for much greater profits from Resulti over the next ten years than the generic pharmaceutical companies have for the off-patent atypical antipsychotics.

There seems to be a general trend when discussing psychiatric medications to avoid any reference to them as atypical antipsychotics or neuroleptics. You can even see this in the FDA press release for the approval of Rexulti in July of 2015. This means a consumer looking for information on the potential adverse effects from an atypical antipsychotic may have some difficulty finding and then understanding what the risk is for them to take the drug.

For clarity’s sake, I think the FDA should require all consumer medication guides to clearly identify the drug class for approved psychiatric medications. They should also direct a patient to where they can find a more complete discussion of the potential adverse effects of the medication than what is contained within the brief summary of the medication guide. Confusing discussions of depression, its symptoms and the side effects from antidepressants included in antipsychotic medication guides should be clarified or removed entirely by the FDA. Additionally, there should be a truth in advertising requirement that tells it like it is for all psychiatric drug advertisements. An antipsychotic by any other name is still an antipsychotic and the commercials should say so.

08/8/17

Kratom: Part of the Problem or a Solution?

In August of 2016 the DEA announced that it would temporarily classify kratom as a Schedule I substance. The public outcry against this plan influenced the DEA to reverse itself and delay scheduling kratom in October of 2016. The DEA announcement said before taking further action, it would solicit public comments and review the FDA’s “scientific and medical evaluation” of the proposed scheduling of kratom. Once the DEA has received and considered the information, it would decide how to proceed. But while we await the DEA’s decision, kratom is being sold in vending machines.

Advocates for kratom were overjoyed with the DEA’s decision. Chris Ingraham reported for The Washington Post that researchers welcomed the decision to delay scheduling kratom, but were concerned that the future of their research was still up in the air. After its October 2016 announcement, the DEA set a period for public comments on the potential scheduling of kratom until December 1^st of 2016. As of August 6^th, 2017, there has not been a public announcement about its decision or its review of the FDA report on kratom.

Since the DEA delayed a decision on kratom, it is still unregulated and will remain available for anyone to use without a prescription. And research into the risks and benefits of kratom can continue unhindered by a temporary Schedule I classification.

Andrew Kruegel of Columbia University is working to develop new painkillers from compounds contained in kratom. He commented: “I am encouraged that they will now be having more serious input on this important policy decision.” While the DEA announcement might be good news for now, studies with the methodology of rigorous, controlled trials typical of FDA evaluations don’t exist for kratom. So will the DEA wait for the months or years it could take to complete rigorous kratom studies before deciding whether or not to schedule it?

According to the American Kratom Association (here) and PinneyAssociates (here), Jack Henningfield did an “8-factor analysis” with kratom, which is the legal framework used by the FDA to assess the abuse potential of substances. Henningfield concluded that kratom had a low toxicity level; and that scheduling it as a controlled substance was not warranted.

It’s important to understand that although kratom has some mild effects similar to opioids, its chemical make-up is different, and it appears overall much safer, with apparently relatively small effects on respiration. In fact, kratom’s analgesic effects and impact on energy, combined with its favorable safety profile supports continued access by consumers to appropriately regulated kratom products while research on its uses continues.

STAT News identified another person doing research with kratom, Edward Boyer, who is currently at UMass Memorial Medical Center and Boston Children’s Hospital. Boyer has been interested in kratom since 2006. Even then there was a Catch-22 of sorts when trying to get government funding for kratom. “The National Institute on Drug Abuse didn’t want to fund kratom projects, saying it was a complementary and alternative medicine, while the National Center for Complementary and Integrative Medicine didn’t want to fund them because it was a drug of abuse.”

In 2008, Boyer and two colleagues filed a patent to use kratom or its chemical compounds as a new treatment method for opioid withdrawal, one of the ways it is currently used informally and non-medically. Two large freezer bags of kratom he obtained still sit in a cabinet of the UMass Memorial Medical Center’s toxicology office. Boyer said the bureaucratic nightmare of running the FDA gauntlet to do a clinical trial stopped them cold.

Andrew Kruegel’s research has had some promising initial results. His team was able to demonstrate that the main components of kratom primarily stimulated the painkilling response, while having minimal effects on the proteins that caused other side effects. But these findings need to be repeated in mice and then humans, “before they could claim that they have used kratom to create an opioid-like painkiller without as many risky side effects.” But there is a problem obtaining kratom of the quality needed for his research and the red tape involved in the process of obtaining it. “There is nowhere to buy the plant unless I am going to go to Indonesia and contact plantation owners.”

In the mean time, you can order kratom on the Internet from several vendors. And if you live near the East Coast Super Subs shop in Tucson Arizona, you can buy it out of a vending machine. Eric Boodman reported for STAT News that the vending machine there attracted five customers in an hour. The servers at the sub shop said it gets even busier around opening and closing time. Using cash or a credit card, a customer can buy as little as 10 grams for $5, or up to 120 grams for $50.

The almost-scheduling of kratom seems to have been good advertising for the herbal product. Drew Pickett, the owner of a second kratom vending machine company, Arizona Kratom, said many people discovered kratom because of the bad publicity. “People were like, ‘Wow, if the government doesn’t want me to have it, I want to try it.’” He estimated the aborted ban triggered a 400% boost in his sales.

One person said kratom helped him stop using heroin six years ago. Last year he relapsed, and was back using heroin for several months before he used kratom to wean himself off heroin for the second time. He found the Tucson Kratom vending machine when the kratom he used to get from head shops became too pricey. Now he wants to wean off of kratom as well. “I start with a lot of it initially … and then I taper down. I’ve been doing it very gradually and probably in the next two or three months, I’ll be done with it.”

But things aren’t all sunshine and happiness with the kratom vending machine. Dr. Mazda Shirazi, the medical director of the Arizona Poison and Drug information Center first heard about the machine when a patient of his began to show signs of liver toxicity from using kratom from the machine on a daily basis. He’s worried about the lack of regulation with kratom, meaning you can’t be sure of the purity of what you are buying. He’s also concerned that using kratom to wean off of opioids will give some addicts false hope. “I think it actually prolongs the addiction cycle and puts the patient in a dangerous situation, whereas by getting help they might be better off.”

Susan Ash, the founder of the American Kratom Association, saw the vending machine as a sign of how pervasive the opioid epidemic has become. “Maybe a person who is going to walk into that sandwich store and has never heard of kratom — maybe that will be their first day off of opiates.” She liked the idea of people not having to wait a day or longer for their kratom to arrive in the mail. But she worried the vending machine made kratom available to children under 18. “There’s not enough research to know how the substance affects developing brains.”

And there’s the rub: there simply isn’t enough reliable, replicated research with kratom to make an informed decision on how to use it or whether to schedule kratom. Henningfield’s study is suggestive of a good safety profile for kratom, but can’t be regarded as conclusive since it was funded by the American Kratom Association. In contrast to Henningfield’s safety assessment of kratom, others have said there is a real probability of becoming addicted with kratom.

The National Institute on Drug Abuse (NIDA) noted how two compounds in kratom, mitragynine and 7-hydroxymitragynine, interact with opioid receptors in the brain, and produce the same effects of sedation, pleasure and decreased pain as opioids. There are symptoms of withdrawal when an individual stops using kratom and some users have reported becoming addicted to kratom. Adverse health effects from kratom use include: sensitivity to sunburn, nausea, sweating, loss of appetite, and sometimes psychotic symptoms. Chronic use of kratom has been linked with liver problems, as noted above. Kratom by itself hasn’t been linked with deaths, but if mixed with other substances, it has been part of a fatal drug cocktail. See “Krypton Can Kill You” and “The Secret of Kratom” for more on this.

While it isn’t a federally controlled substance at this time, six U.S. states and three cities have listed kratom as a Schedule I substance. Globally, several countries have either regulated or banned kratom. In Europe, kratom is a controlled substance in Denmark, Latvia, Lithuania, Poland, Romania, Sweden and the UK. It is a controlled narcotic in Australia and New Zealand. Possession of kratom is illegal in Thailand and its use is prohibited in Malaysia. Canada has made it illegal to market it for human consumption.

What is clear is the need for reliable, replicated research with kratom. Edward Boyer said: “Is it an effective treatment for opioid withdrawal, or is it another pathway to addiction? I don’t think anybody has a defined concept of where it actually lies on that continuum.” Nevertheless, it seems there is growing anecdotal evidence of some level of dependence or addiction with kratom. If the DEA delays its decision to regulate kratom much longer, it might become part of the problem instead of a solution to the opioid epidemic.

07/18/17

Opana Cold Turkey

On June 8, 2017, the FDA did something it had never done before. It formally requested that a pharmaceutical company voluntary remove its opioid pain medication from the market. The company was Endo Pharmaceuticals and the opioid was Opana ER. “Should the company choose not to remove the product, the agency intends to take steps to formally require its removal by withdrawing approval.” Way to go FDA.

The FDA decision was based on a review of post marketing data, which showed a drastic shift in the route of Opana ER abuse after the drug was reformulated in 2012. This review demonstrated that instead of crushing and snorting Opanas, individuals abusing the drug were now dissolving and injecting it. The FDA’s decision follows a March 2017 FDA advisory committee meeting where a group of independent experts voted 18-8 that “the benefits of reformulated Opana ER no longer outweigh its risks.” The newly appointed FDA Commissioner, Scott Gottlieb said:

We are facing an opioid epidemic – a public health crisis, and we must take all necessary steps to reduce the scope of opioid misuse and abuse. . . . We will continue to take regulatory steps when we see situations where an opioid product’s risks outweigh its benefits, not only for its intended patient population but also in regard to its potential for misuse and abuse.

The NPR program, All Things Considered, interviewed Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research about the decision on June 9^th. She said the decision was made due to the risks of abusing the product. An outbreak of HIV and hepatitis C, as well as cases of a serious blood disorder (thrombotic microangiopathy), were associated with individuals injecting the reformulated Opana ER. The request to remove Opana ER from the market is not an outright ban. When asked what the response from Endo Pharmaceutials has been, Dr. Woodcock said the company is evaluating the request.

Well, FDA does not have the authority for drugs to immediately remove them from the market. Generally we ask companies to voluntarily pull their drug off the market. If they are not willing to do that, we will issue a notice of a hearing, and we have to go through a judicial type of process.

Another NPR report on April 1, of 2016 said that the reformulation in 2012 effectively stopped people from snorting Opana, which had been the preferred method of abuse. “But the change also led a significant number of people to abuse the drug by injection.” Endo said the company’s decision to reformulate Opana was “a well-intentioned attempt to prevent abuse.” But there seems to have been an additional motivation for the action. According to NPR, “interviews with experts, court filings, documents from the FDA, as well as Endo’s own statements, suggest the company’s decision to reformulate Opana was also motivated in large part by financial interests.”

Soon after its release in 2006, there were reports of abuse and overdose deaths with Opana from around the country. But the painkiller was a major moneymaker for the company. It accounted for 14% of Endo’s total revenue; $384 million in net sales in 2011. In late 2011 the FDA approved Endo’s reformulated version of Opana and Endo began replacing the old version of Opana in pharmacies. That August, Endo filed a petition with the FDA (available in the NPR article), arguing that it removed the crushable version of Opana because it was a safety hazard. It also asked that the FDA refuse or withdraw the approval of generic versions of Opana because they were not crush-resistant.

In 2012 Endo filed a lawsuit to compel the FDA to speed up its review of their petition, predicting a spike of misuse and abuse if generic, crush-resistant versions of Opana went to market. It also estimated that if a generic version went to market, “annualized net sales will decrease by an amount up to $135 million.”

This was nothing new. In 2010 Purdue Pharmaceuticals reformulated OxyContin to make it crush resistant. And the FDA determined the reformulated version was much safer and that the benefits of the original no longer outweighed the risks. The agency blocked generic versions of OxyContin, which made Purdue billions. Dr. Anna Lembke, an assistant professor of psychiatry at Stanford University Medical Center said: “We see this again and again in the pharmaceutical industry. . . . They come up with some new fancy formulation of basically the same old drug … and then that way they have a new drug that they can charge a lot of money for.”

But on May 10, 2013, the FDA decided Endo’s tamper-resistant formula didn’t actually prevent drug abuse better than earlier versions of Opana without the abuse-deterrent feature. That day the price of Endo shares dropped more than 5 percent. The FDA said the reformulated version could be compromised when it was subjected to “cutting, grinding and chewing.” It could be “readily prepared for injection.” The agency also warned the preliminary data suggested the possibility “that a higher percentage of reformulated Opana ER abuse is via injection than was the case with the original formulation.”

The FDA said Endo could not refer to Opana ER as “abuse deterrent.” Writing for FiercePharma, Emily Wasserman quoted Douglas Throckmorton, a deputy director for the FDA’s Center for Drug Evaluation and Research, as saying: “We think the public health would not be served if a company can market itself as ‘abuse deterrent,’ if the scientific evidence did not support that claim.” The problems with Opana seemed to put the FDA on alert that abuse-deterrent technology may not be all that effective. An FDA spokesperson, Sarah Peddicord said: “The FDA is very concerned about potential unintended consequences of abuse-deterrent opioids (and purportedly abuse-deterrent opioids) and it is something we are actively looking at.”

FDA is requiring all sponsors of opioids with approved abuse-deterrent labeling to conduct long-term epidemiological studies to assess their effectiveness in reducing abuse in the real world. . . . Abuse-deterrent does not mean abuse-proof.

So while the June 8^th request by the FDA may be unprecedented, it seems to have been coming for a few years. Then a week after the FDA request, Scott Gottlieb ordered a review of all opioid pain relievers with abuse-deterrent formulas to see if they actually help prevent abuse and addiction. In a statement released on June 13^th, Gottlieb said there would be a public meeting to discuss whether they have the right information to determine if the abuse-deterrent products “are having their intended impact on limiting abuse and helping to curb the epidemic.”

The FDA, he said, recognizes there is a gap in their understanding of whether these products have a real-world, meaningful effect on opioid misuse and abuse. At the July 10-11 meeting, the FDA will engage external thought leaders to discuss how to better “evaluate the impact of these products in the real world.” There is a link in the statement to an issues paper that outlines some of the existing regulatory and public health challenges they face.

Opioid formulations with properties designed to deter abuse are not abuse-proof or addiction-proof. These drugs can still be abused, particularly orally, and their use can still lead to new addiction. Nonetheless, these new formulations may hold promise as one part of a broad effort to reduce the rates of misuse and abuse. One thing is clear: we need better scientific information to understand how to optimize our assessment of abuse deterrent formulations; and I look forward to a productive discussion on how to best tackle this challenge.

Sidney Wolfe, the founder of and senior advisor to Public Citizen’s Health Research Group supported the FDA request for Endo to remove Opana ER from the market. He also said the FDA had enough information before its approval in late 2011 to “reject the drug as possibly more dangerous than its older … version.” He was a member of the FDA’s Drug Safety and Risk Management Advisory Committee at the time, but for some reason, the approval decision was not presented to the Committee. Had the Committee advised rejecting the drug, and the FDA followed the Committee’s advice in 2011, the adverse effects leading the current request could have been avoided.

In addition to FDA’s serious mistake in approving the OPR version, Endo’s defiant response yesterday that they would not necessarily take this more dangerous form of the drug off the market is reckless. In proportion to how many people will use and, in many cases abuse the drug, causing deaths, hospitalizations and other preventable between yesterday’s FDA decision and the ultimate, but certain forced removal of the drug, Endo will be exposed to many product liability lawsuits from those damaged or their surviving families.

Endo suffered some significant financial withdrawal symptoms after the FDA request. The company’s shares were down more than 12% afterwards, according to Fortune. A financial analyst for RBS Capital Markets referred to Opana ER as a “declining asset” with sales expected to fall to $97 million in 2019 from an estimated $134 million in 2017. But Endo seems to have counted the potential future cost if it challenged the FDA recommendation and fought to keep Opana ER on the market. On July 6, 2017, Endo International announced it would voluntarily withdraw Opana ER from the market.

Ed Silverman reported for STAT News that Endo executives “blinked” by saying they were reconsidering their initial statement that they would review the FDA request and evaluate “the full range of potential options.” Silverman noted Opana ER hadn’t been a huge seller for Endo. And it seems the FDA request would impact sales even further. It only generated around $159 million in revenue in 2016. Through the first quarter of 2017, sales were $35.7 million, down from almost $44.7 million in the first quarter of 2016. Given the adverse impact on public health, and the potential for future product liability lawsuits, Endo did the right thing in deciding to go “cold turkey” with Opana.

01/31/17

Curiouser and Curiouser with Chantix

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

12/9/16

Channeling Your DXM Personality

5© ljupco | 123rf.com

June of 2016 was a confusing month for DXM. Alaska became the 11^th state to limit the sale of products containing dextromethorphan (DXM) to individuals 18 and older. Representative Charisse Millett of Anchorage thanked her colleagues for passing a bill that will protect Alaska teens. On the other hand, there was a study published in the journal, Substance Abuse Treatment Prevention, and Policy by Spangler, Loyd and Skor that same month which said DXM was a safe, effective cough suppressant, available without a prescription since 1958. The article reported how the annual prevalence of DXM abuse has sharply decreased since 2010. So why would so many states be restricting the sale of a “safe, effective cough suppressant”?

Adding to the issue, there is H.R. 3250, The DXM Abuse Prevention Act, which was sent to both the House and Senate for consideration on April 27, 2016. H.R. 3250 seeks to prevent the abuse of DXM and would restrict its sale to individuals 18 and over. Civil penalties for retailers violating H.R. 3250 would range from a warning for a first offense up to $5,000 for four or more violations. If implemented, the federal law would take precedence over any existing state legislation.

The pro-drug website Erowid noted that while DXM is still unscheduled in the US, and legal to buy, possess and ingest without a prescription, it is becoming increasingly difficult to purchase. “Some pharmacies and mega-stores like WalMart have instituted voluntary procedures to reduce the sale of DXM-containing products to minors.” Erowid listed and commented on the legal status of DXM in 25 different states and was soliciting more information on its status in other states.

In 2007 the DEA requested that the FDA evaluate whether dextromethorphan should be scheduled as a controlled substance. Three years later the FDA held an Advisory Committee meeting on the matter. After hearing presentations on DXM and its abuse potential, the committee voted 15 to 9 against scheduling DXM. An Erowid assessment of the presenters was they did not believe that scheduling was warranted, but were concerned about abuse.

The DXM article by Spangler, Loyd and Skor said that to address reports of abuse, the Consumer Healthcare Products Association (CHPA) initiated a plan to raise awareness of the behavior and “address prevention by focusing on the factors that impact teen behavior.” All three authors were employees of the CHPA, “which represents manufacturers of over-the-counter medicines and dietary supplements.” And funding for the research, collection of the data, analysis, interpretation, plan implementation, and writing of the manuscript was provided by CHPA member companies. They concluded:

It is noteworthy that the annual prevalence of over-the-counter cough medicine abuse has sharply decreased since 2010. While a true cause-and-effect relationship cannot be assured, the Consumer Healthcare Products Association and its member companies believe that the increased awareness of the issue since the 2010 Food and Drug Administration Advisory Committee meeting, and the subsequent implementation of a well-delivered and targeted abuse mitigation plan that addressed the levers influencing teen decisions is contributing to the observed reduction in abuse. During the period of 2010–2015, reported abuse of dextromethorphan by 8^th, 10^th, and 12^th graders decreased 35 %. The authors believe this reduction supports the view of the Consumer Healthcare Products Association at the outset of the abuse mitigation plan effort and today: Controlled substance scheduling or prescription requirements would result in a reduction in the legitimate use of this medicine that has benefits that far outweigh its risks. Instead, there are more targeted, more effective, and less disruptive interventions to address dextromethorphan abuse.

Writing for The Fix, John Lavitt reported that one in 30 adolescents use DXM to get high because it is cheap and accessible. In 2014 there were six DXM-related deaths, according to the American Association of Poison Control Centers. Non-medical use of DXM leads to around 6,000 ER visits per year. Adolescents account for almost 50% of those visits. The effects range from mild stimulation to euphoria and hallucinations. There can be an out-of-body dissociative state, complete dissociation with unresponsiveness and even overdose.

Medline Plus lists some of the many products that contain DXM, including NyQuil, DayQuil, TheraFlu, Tylenol Cold, Dimetapp DM, Robitussin DM, Triaminic DM, and Alka-Seltzer Plus Cold and Cough. Some of the symptoms of a DXM overdose listed included: breathing problems, bluish-colored fingernails and lips, blurred vision, coma, Convulsions, drowsiness, hallucinations, heart palpitations, nausea and vomiting, rapid heart beat.

Now here is some DXM history from Erowid. It was approved by the FDA in 1958. In the early 1960s, there were reports that beat poets like Allen Ginsberg and Peter Orlovsky and the author Jack Kerouac were using DXM in the form of Romilar tablets. Incidentally, Romilar was introduced as a replacement for codeine cough remedies in an attempt to cut down on abuse. In 1973, Romilar DXM tablets were removed from the market after an increase in recreational use was noted. DXM continued to be available as a syrup, with the thinking that consuming large quantities of syrup would be deterrent for recreational use. OTC DXM tablets have been back on the market now for number of years. In the late 1980s DXM use was prominent among the punk subculture.

By the way, codeine cough syrup is main ingredient in the concoction “Sizzurp” that sent rapper Lil Wayne to the hospital with multiple seizures. He even wrote a song about his love for Sizzurp, “Me and My Drank.” Then there’s Justin Beiber and his street-racing-DUI-Sizzrup arrest. Teens and others without ready access to a codeine prescription cough formula can substitute OTC DXM formulas in their Sizzurp knockoff. Add some Jolly Ranchers to make the concoction more drinkable.

So while DXM may be safe and effective when used as recommended, it was being used as a recreational high almost from the time it came onto the market as a substitute for codeine. It has ebbed and flowed in its consideration for classification as a controlled substance. Currently it isn’t one. However, it does seem likely to face restricted sales to anyone under the age of 18. Eleven states have already passed legislation to that effect, and larger chains like WalMart, Walgreens, Target, Rite-Aid and others now require ID and limit sales to two DXM-containing products. And there is pending federal legislation that has a 38% of passing that would make it illegal to sell DXM products to minors. The last word on DXM is from Erowid.

Recreational DXM use continues. A number of deaths have been documented due to the recreational use of DXM although a majority of these have been the result of products (such as Coricidin Cough and Cold) that combine DXM with other substances that become dangerous in high doses.

So if you decide to try and contact your inner beat poet, or channel your punk rock personality through DXM, be careful.

12/2/16

Pharma and Advertising

The FDA recently held public hearings on the off-label advertising of approved medications and medical devices on November 9 and 10, 2016. “FDA is engaged in a comprehensive review of its regulations and policies governing firms’ communications about unapproved uses of approved/cleared medical products, and the input from this meeting will inform FDA’s policy development in this area.” There were specific questions asked at the hearing, but the FDA was also interested in “any other pertinent information participants would like to share.” If you weren’t able to be in Maryland for the hearing, electronic or written comments will be accepted until January 9, 2017. A videotape of the hearing will be available for one year afterwards.

Your initial reaction may be one of “Boring!” That is unless you are aware of the crossroads we are approaching with regard to the off-label advertising of medications and medical devices. On March 8, 2016, the FDA made a settlement agreement with the pharmaceutical company Amarin that allows the company to promote its drug Vascepa for off-label use. What is this important breakthrough medication? Vascepa is prescription strength fish oil. This action was the outcome of a struggle between Amarin and the FDA going back several years.

Amarin wanted to widen the population for whom they could recommend Vascepa to include patients with different cardiovascular diseases—patients other than what Vascepa was initially approved to treat. But the FDA ruled against their request. Amarin’s stock price took a nosedive. Concerned with how their investors were reacting, the company fought back by suing the FDA. Then in August of 2015, a judge ruled that Amarin could market its drug to the 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.

Amarin successfully 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 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 by a pharmaceutical company for their product were truthful and not misleading.

Amarin argued that this system is unconstitutional, and that companies should instead be allowed to market their products in any way that a judge would consider to be neither false nor misleading.

Commenting on the FDA settlement agreement in Amrain Pharma v. U.S. Food & Drug Administration, 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.

So if this is the supposed future for off-label drug advertising unless there is some radical change by Congress, let’s now take a look at the past—what has been taking place under the existing FDA rules. In his book Saving Normal, Allen Frances 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.

Here is a sampling of the companies and their total fines and settlements between 2004 and 2012 recorded in the Saving Normal chart. The fines and settlements listed below 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 in fines and settlements between 2004 and 2012.

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. It seems these fines were simply the cost of doing business.

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.

Since the U.S. approved direct-to-consumer advertising of prescription drugs in 1997, there has been a dramatic increase in spending on pharmaceuticals. A New England Journal of Medicine study by Donohue, Cevasco and Rosenthal in 2007 found that spending on pharmaceutical promotions increased from $11.4 billion in 1996 to $29.9 billion in 2005. This was a 330% increase. Promotion to physicians was still the primary marketing strategy, but spending on direct-to-consumer advertising increased both in absolute terms and as a percentage of pharmaceutical sales.

Becker and Midoun recently published an article that investigated the effects of direct-to-consumer advertising (DTCA) on patient prescription requests in the Journal of Clinical Psychiatry. Of the 989 articles they initially identified, they read full-text reviews of 69 articles, but only found four that met their inclusion criteria for investigating the consequences of these ads on prescription rates and treatment quality. They conclusion was: “Findings suggest that DTCA requests are typically accommodated, promote higher prescribing volume, and have competing effects on treatment quality.” They called for methodlogically stronger studies to increase the confidence in their conclusions.

Reporting for Mad in America on the study, Justin Karter noted where the U.S. is only one of three countries globally that allows DTCA. He said the pharmaceutical industry spent $3.83 billion on DTCA in 2013 and $4.53 billion in 2014. He also noted that the American Medical Association (here) and the American Society of Health-System Pharmacists (ASHP) (here) have called for a ban on DTCA. The AMA Board Chair, Patrice Harris, commented that physicians were concerned with the negative impact of DTCA and the role marketing costs play in fueling escalating drug prices. “Direct-to-consumer advertising also inflates demand for new and more expensive drugs, even when these drugs may not be appropriate.” The ASHP approved a new policy at their 2016 meeting that would advocated for Congress to ban DTCA for prescription drugs and medication-containing devices.

Pharmaceutical companies have whittled away at existing FDA regulations that restrict direct-to-consumer advertising. And they seem to be poised to begin an era of DTCA that will massively overshadow what has already taken place under the existing rules. Healthcare organizations representing physicians and pharmacists in the U.S. have publically voiced their opposition to DTCA. Individuals and organizations have an opportunity to voice their concern for this practice, which is implicated in the rising cost of healthcare and medications. Congress also has an opportunity to enact new legislation that would eliminate this predatory marketing practice. But it will have to overcome the horde of lobbyists—more than there are members of Congress—and the $272,000 in campaign donations Pharma spent per member of Congress in 2015.

10/11/16

Stacking the Deck with Clinical Trials

In September of 2007 the “Food and Drug Administration Amendments Act of 2007” became law. This law requires that findings from human testing of drugs and medical devices be made publically available on the NIH website, ClinicalTrials.gov. But it seems that both drug companies and most research institutions—including leading universities and hospitals—routinely violate the law. An investigation by STAT News found that at least 95 percent of all disclosed research results were posted late or not at all.

Drug companies have long been castigated by lawmakers and advocacy groups for a lack of openness on research, and the investigation shows just how far individual firms have gone to skirt the disclosure law. But while the industry generally performed poorly, major medical schools, teaching hospitals, and nonprofit groups did worse overall — many of them far worse.

Four of the top ten recipients of federal medical research funding from the NIH were among the worst offenders. These four were: Stanford, the University of California, San Diego, the University of Pennsylvania, and the University of Pittsburgh. Researchers, university administrators and hospital executives interviewed by STAT News said they were not intentionally breaking the law. They were just too busy and lacked administrative funding to complete the required data entry on ClinicalTrials.gov. NIH estimated it takes, on average, around 40 hours to submit trials results.

Six organizations — Memorial Sloan Kettering, the University of Kansas, JDRF (formerly the Juvenile Diabetes Research Foundation), the University of Pittsburgh, the University of Cincinnati, and New York University — broke the law on 100 percent of their studies — reporting results late or not at all.

The Director of NIH, Francis Collins, said the findings were “very troubling.” He said pointing to the time demands on posting data to ClinicalTrials.gov was not an acceptable excuse for noncompliance. Beginning in the spring of 2016, after further refinement of the ClinicalTrials.gov rules, Collins said NIH and FDA will have “a firmer basis for taking enforcement actions.” The FDA is empowered to levy fines of up to $10,000 a day per trial for late reporting to ClinicalTrials.gov.

In theory, it could have collected $25 billion from drug companies since 2008 — enough to underwrite the agency’s annual budget five times over. But neither FDA nor NIH, the biggest single source of medical research funds in the United States, has ever penalized an institution or researcher for failing to post data.

When the “Food and Drug Administration Amendments Act of 2007” became law, Senator Charles Grassley said: “Mandatory posting of clinical trial information would help prevent companies from withholding clinically important information about their products. . . . To do less would deny the American people safer drugs when they reach into their medicine cabinets.” But the failure of drug companies and others to post clinical trial results, coupled with the failure of the FDA to hold them accountable via fines when they don’t, means the American people are being denied the ability to see for themselves if the drugs they take are safe and effective. Kathy Hudson, a deputy director for NIH, said: “If no one ever knows about the knowledge gained from a study, then we have not been true to our word.”

The scarcity of clinical trial results posted to ClinicalTrails.gov is not the only issue with clinical trials and the NIH website. Drug companies and research facilities are also not prospectively registering clinical trials as they should. Scott, Rucklidge and Mulder found that “less than 15% of psychiatry trials were prospectively registered with no changes in POMs [primary outcome measures].” You can see Julia Rucklidge’s discussion of the study here. Also see “Clinical Trial Sleight-of-Hand” on this website.

Writing for Health Care Renewal, Bernard Carroll said there was a disconnection between the FDA’s drug approval process and what gets published in the medical journals. “Pharmaceutical corporations exploit this gap through adulterated, self-serving analyses, and the FDA sits on its hands.” He suggested that independent analyses of clinical trials be instituted, “because we cannot trust the corporate analyses.”

When corporations are involved, there is no point in prolonging the myth of noble and dispassionate clinical scientists searching for truth in clinical trials. It’s over. We would do better to stop pretending that corporate articles in medical journals are anything but marketing messages disguised with the fig leafs of co-opted academic authors and of so-called peer review.

Carroll proposed that Congress mandate the FDA to analyze all clinical trials data strictly according to the registered protocols and analysis plans. This should apply to new drugs as well as approved drugs being tested for new indications. And it should be applied to publications reporting new trials of approved drugs. “Corporations and investigators should be prohibited from publishing their own in-house statistical analyses unless verified by FDA oversight.” (emphasis in the original) Carroll quoted Eric Topol in a recent BMJ editorial as saying: “The disparity between what appears in peer reviewed journals and what has been filed with regulatory agencies is long standing and unacceptable.”

He gave three reasons for prohibiting in-house corporate analyses of clinical trials data. First, the inherent conflict of interest is too great to be ignored. Carroll described Forest Laboratories and citalopram as an example in his article to illustrate this point. Second, when corporate statisticians are encouraged to play around with the statistical analysis of the trial data (i.e., p-hacking), “they are no longer testing the defined study question with fidelity to the methods specified in the IND protocol.” Third, the FDA should monitor the publication of clinical trial reports in medical journals. The FDA inspects production facilities for evidence of physical adulteration, why not verify that what gets published in journals matches what they presented to the FDA for drug approval? “The harms of adulterated analyses can be just as serious as the harms of adulterated products.”

Pharmaceutical corporations are betting on huge profits with drug development. And allowing them to play fast and loose with clinical trial registration and the analysis of the trial data is akin to stacking the deck in their favor. It’s time to require pharmaceutical companies to stop trying to rig the clinical trial process in their favor.

09/13/16

E-Cigarettes Are Just Unhealthy

The pros and cons of e-cigarettes have been trading studies and expert opinions back-and-forth for a number of years. In “Nicotine without smoke: tobacco harm reduction,” The Royal College of Physicians sees e-cigarettes as “an ideal tobacco harm reduction product.” While acknowledging that e-cigarettes are not currently made to medical standards and are probably more hazardous than nicotine replacement therapy (NRT), the report said it was unlikely that the health risks from long-term vapor inhalation would exceed 5% of the harm from smoking tobacco. The report also downplayed concerns that e-cigarettes will increase tobacco smoking and act as a gateway to smoking in younger people. But this strong endorsement is not the last word on the saga of e-cigarettes.

Writing for AfterParty Magazine, Tracy Chabala pointed to a study published in the New England Medical Journal raising the danger of inhaling formaldehyde at concentration levels higher than that of nicotine. If that doesn’t good healthy, you’re correct. Formaldehyde is a known cancer-causing agent, and “How formaldehyde-releasing agents behave in the respiratory tract is unknown.” The study authors calculated the risk from e-cigarettes to be 5 to 15 times as high as the risk of long-term smoking. What’s more, “formaldehyde-releasing agents may deposit more efficiently in the respiratory tract than gaseous formaldehyde, and so they could carry a higher slope factor for cancer.”

In her article,“Can Your E-Cigarette Give You Cancer?,” Tracy Chabala noted there were several strong opinions on the study. A lawyer for the American Vaping Association said the study used the vaping device “in a manner that no one does.” He likened it to leaving a steak on the grill all day—“many cancer-causing substances might be formed but no one would eat such charred works.” I’m not sure I buy his analogy, that vaping with an e-cigarette is like having a good steak on the grill. But his point seems to be that one limit of the study was that the researchers based their findings on a method of using their devise that no one actually does when vaping.

What the study actually reported was that they used an e-cigarette with a “tank system” and a variable-voltage battery. The aerosolized liquid was collected in an NMR spectroscopy tube over five minutes with each puff of their device taking 3 to 4 seconds. They did not find any formaldehyde-releasing agents at the low voltage setting. However, they did detect agents at the high voltage setting. The lawyer for the American Vaping Association seems to have overplayed his analogy. A biologist from the American Cancer Society said he was reasonably convinced that all the formaldehyde released during the test tube studies would likely break down into formaldehyde in the e-smoker’s lungs. I think I’m going with the opinion of the biologist on this one.

The President of The Cancer Action Network, an advocacy group of the American Cancer Society, urged the federal government to consider the new findings and finalize its proposal to regulate all tobacco products, including e-cigarettes. The findings were just another example of how little is known about these products or the varying levels of exposure to toxic chemicals that can result from using any of the hundreds of different types of e-cigarette devices. He said federal regulation was imperative to help address the health risks of e-cigarettes and others who are exposed to e-cigarette vapor. “Furthermore, until the FDA finalizes its proposal to regulate e-cigarettes and other tobacco products, the industry’s unfettered ability to market these products to kids remains a threat to public health.”

In May of 2016, David Nather reported for STAT News that the FDA issued a set of rules regulating e-cigarettes for the first time, despite strong resistance from the industry. All states would now be required to ban the sale of e-cigarettes to anyone under the age of 18. All devices that went on sale after February 15, 2007 would be subject to FDA review unless the manufacturers can prove their products are ”substantially equivalent” to products being sold or that there is another reason they should be exempt. Dr. Robert Cardiff, the FDA commissioner said: “Today’s rule is a milestone in consumer protection. It marks a new chapter in our efforts to do everything we can under the law to protect Americans from the dangers of tobacco products.”

Manufacturers would have between a year and two years to prepare their applications, depending on whether they are submitting to the reviews or arguing they should be exempt. Then they would have another year to win approval from the FDA. The rule would not ban flavored tobacco products, including e-cigarettes. But the FDA is working on a rule that would restrict cigar companies from using flavors in their marketing just as cigarette makers can’t include flavors in their sales pitches.

The president of the American Vaping Association said it was a big win for American cigarette companies and a giant loss for small businesses. He predicted that in two or three years, “nearly every vape shop in the country will be closed.” I’m not sure that would be such a bad thing. It seems that the rhetoric pitting Big Tobacco against little vape shops has ignored the real concern over the potential health hazards of vaping instead of smoking tobacco products.

While acknowledging there are anecdotal reports that some people have used e-cigarettes to stop smoking, Mitch Zeller of the FDA said the agency needed more data on how e-cigarettes are being used, including how many people who use e-cigarettes never used tobacco products before. “I hope everyone can agree that kids should not initiate on e-cigarettes simply because of the harm that can come from nicotine.”

Lobbyists for the cigar and e-cigarette industries pushed Congress to create bills that would either exempt them from the new rules or grandfather in products already on the market. Representative Tom Cole of Oklahoma, the chairman of the House subcommittee funding health programs, added a measure to the FDA’s funding bill for next year that would get rid of the February 2007 effective date. Cole said his legislation “provides the same framework for new tobacco products without needlessly subjecting small businesses to unnecessary regulations and without treating law abiding adults like naïve children.”

Mitch Zeller noted that Cole’s measure would eliminate all reviews of e-cigarette products that came on the market after 2007 (the vast majority of them) and clear the way for future products that are similar in design. The proposal “would have an enormously adverse impact on public health and the ability of FDA to do its job.” Beginning on August 8, 2016, the FDA will start regulating e-cigarettes, all cigars, waterpipes (hookahs), tobacco, pipe tobacco, and nicotine gels.

So this leads us to the newest published study of e-cigarettes in the journal Environmental Science & Technology by Sieiman et al., “Emissions from Electronic Cigarettes.” Their study found that all electronic cigarettes emit harmful chemicals. Levels of those toxic compounds are affected by factors in the use of e-cigarettes such as temperature, and the type and age of the device.

A news release from Berkley Lab said the study found that the thermal decomposition of propylene glycol and glycerin leads to the emissions of toxic chemicals such as acrolien and formaldehyde. Propylene glycol and glycerin are found in most e-liquids, the substance vaporized in e-cigarettes. There were 31 different toxic chemicals found at significant levels in e-cigarette vapor. Hugo Destailats, one of the researchers said that while it may be true emissions are much lower from e-cigarettes than conventional ones, that’s only true for certain users, for example, long time smokers who cannot quit. “Regular cigarettes are super unhealthy. E-cigarettes are just unhealthy.”

One of their findings indicated there was a big difference in emissions between the first and last puffs. They found that vapor temperature rose quickly in the first 5 to 10 minutes until it reached a steady state temperature around the twentieth puff. Emission levels between the first few puffs and the steady state increased by a factor of ten of more. Factors affecting the levels included the device used, the battery voltage and the emitted compound.

In order to test effects due to the device aging, the researchers used a single device over nine consecutive 5-puff cycles without cleaning it. Emissions for formaldehyde, acetaldehyde, and acrolein, which are all irritants or carcinogens, increased. “In some cases we saw formaldehyde levels increase 60 percent between cycles 1 and 9.”

This effect is consistent with the buildup of polymerization byproducts on or near the coil leading to accumulation of the sort of residues that are often referred to in the blogosphere as ‘coil gunk’ or ‘caramelization.’ Heating these residues would provide a secondary source of volatile aldehydes.

Looking at the effect of voltage on emissions, the researchers found that as the voltage increased, both the amount of e-liquid consumed per puff and the vapor temperature were higher. Destailats pointed out this did not mean e-cigarettes were safer to use at lower temperatures. “We found there are emissions of toxic chemicals at any temperature at which you use the device. . . . And the higher the temperature, the more emissions.”

This won’t be the last word in the e-cigarette saga. The back-and-forth conflict is just getting started. You should also keep in mind there is another aspect to the e-cigarette conflict. E-cigarettes are modified or “hacked” to smoke marijuana—dry herb, hash oil or THC liquids. They’re called, ironically, e-joints. See “E-Cigarettes and E-Joints” or do your own Google search.

08/23/16

Clinical Trial Sleight-of-Hand

7501727 - a rabbit in a hat and a magic wand against white background

In 2005 a researcher named John Ioannidis published a seminal paper on publication bias in medical research, “Why Most Published Research Findings are False.” When Julia Belluz interviewed Ioannidis for Vox ten years later, she reported that as much as 30% of the most influential medical research papers turn out to be wrong or exaggerated. She said an estimated $200 billion, the equivalent of 85% of the global spending on research, is wasted on poorly designed and redundant studies. Ioannidis indicated that preclinical research on drug targets received a lot of attention since then. “There are papers showing that, if you look at a large number of these studies, only about 10 to 25 percent of them could be reproduced by other investigators.”

Ioannidis noted even with randomized control trials, there is empirical evidence indicating only a modest percentage can be replicated. Among those trails that are published, about half of the initial outcomes of the study are actually reported. In the published trials, 50% or more of the results are inappropriately interpreted, or given a spin that favors the sponsor of the research. “If you multiply these levels of loss or distortion, even for randomized trials, it’s only a modest fraction of the evidence that is going to be credible.”

One of the changes that Ioannidis’s 2005 paper seemed to produce was the introduction of mandatory clinical trial registration guidelines by the International Committee of Medical Journal Editors (ICMJE). Member journals were supposed to require prospective registration of trials before patient enrollment as a condition of publication. The purpose is that registering clinical trial ahead of time publically describes the methodology that should be followed during the trial. If the published report of the trial afterwards differed from its clinical trial registration, you have evidence that the researchers massaged or spun their research data when it didn’t meet the originally proposed outcome measures. In other words, they didn’t play by the rules they said ahead of time they were going to do in their research if they didn’t “win.”

Julia Rucklidge and two others looked at whether five psychiatric journals (American Journal of Psychiatry, Archives of General Psychiatry/JAMA Psychiatry, Biological Psychiatry, Journal of the American Academy of Child and Adolescent Psychiatry, and the Journal of Clinical Psychiatry) were indeed actually following the guidelines that said they would follow. They found that less than 15% of psychiatry trials were prospectively registered with no changes in their primary outcome measures (POMs). Most trials were either not prospectively registered, had either their POMs or timeframes changed sometime after registration, or they had their participant numbers changed.

In an article for Mad in America, Rucklidge said they submitted their research for review and publication in various journals, including two of the five they investigated. Six medical or psychiatric journals rejected it—they refused to publish Rucklidge et al.’s findings. PLoS One, a peer-reviewed open access journal did accept and publish their findings. She said while the researchers in their study could have changed their outcome measures or failed to preregister their trials for benign reasons, “History suggests that when left unchecked, researchers have been known to change their data.”

For example, an initial clinical trial for an antidepressant could be projected to last for 24 weeks. The 24-week time frame would be one of the initial primary outcome measures—will the antidepressant be more effective than a placebo after 24 weeks. After gathering all the data, the researchers find that the antidepressant was not more effective than placebo at 24 weeks. But let’s say it was more effective than placebo at 18 weeks. What gets reported is the results after 18 weeks; the 24 week original timeframe may disappear altogether when the research results are published.

People glorify their positive results and minimize or neglect reporting on negative results. . . . At worst, our findings mean that the trials published over the last decade cannot be fully trusted. And given that health decisions and funding are based on these published findings, we should be very concerned.

Looking ahead, Rucklidge had several suggestions for improving the situation with clinical trials.

1) Member journals of the ICMJE should have a dedicated person checking trial registries, trials should simply not be published if they haven’t been prospectively registered as determined by the ICMJE or the journals should state clearly and transparently reasons why studies might be published without adhering to ICMJE guidelines.2) If authors do change POMs or participant numbers or retrospectively register their trials, the reasons should be clearly outlined in the methods section of the publication.3) To further improve transparency, authors could upload the full clinical trial protocol, including all amendments, to the registry website and provide the raw data from a clinical trial in a format accessible to the research community.4) Greater effort needs to be made to ensure authors are aware of the importance of prospectively registering trials, by improving guidelines for submission (3) and when applying for ethical approval.5) Finally, reviewers should not make decisions about the acceptability of a study for publication based on whether the findings are positive or negative as this may be implicitly encouraging authors to be selective in reporting results.

Rucklidge also mentioned another study by Mathieu, Chan and Ravaud that looked at whether clinical trial registrations were actually looked at by peer-reviewers. The Mathieu et al. survey found that only one-third of the peer reviewers looked at registered trial information and then reported any discrepancies to journal editors. “When discrepancies were identified, most respondents (88.8%) mentioned them in their review comments, and 19.8% advised editors not to accept the manuscript.” The respondents who did not look at the trial registry information said that main reasons they failed to do so was because of the difficulty or inconvenience in accessing the registry record.

One suggested improvement by Mathieu, Chan and Ravaud was for journals to provide peer reviewers with the clinical trial registration number and a direct Web link to the registry record; or provide the registered information with the manuscript to be reviewed.

The actions of researchers who fail to accurately and completely register their clinical trials, alter POMs, change participant numbers, or make other adjustments to their research methodology and analysis without clearly noting the changes is akin to the sleight-of-hand practiced by illusionists. And sometimes the effect is radical enough to make an ineffective drug trial seem to a new miracle cure.

07/29/16

Be Careful of Where You’re Going

On July 9, 2015 eight Senators sent a letter to the Department of Health and Human Services (HHS), Office of National Drug Control Policy (ONDCP), and the Drug Enforcement Administration (DEA) asking for information on their efforts to facilitate scientific research into the benefits of medical marijuana. The Senators asked for answers to a series of questions, stating that relevant federal agencies had to play a leadership role in coordinating and facilitating research into medical marijuana. This began a process culminating in the administrators of the three agencies sending a detailed reply to their questions in an April 4, 2016 response … 26 pages long. And so speculation began that the DEA would decide whether or not to change the controlled substance status of marijuana “in the first half of 2016.”

This was part of the inquiry made by the Senators’ letter, in noting the need to remove “extraneous regulatory barriers for researchers who wish to perform scientific studies on the sue of marijuana for various diseases.” They pointed to the need of the federal government to make a concerted effort to understand how marijuana works and what the appropriate doses and methods of treatment are, “like any prescribed medicine.” Within Appendix C of the HHS, ONDCP, DEA response, was the following graphic and text delineating the process to schedule or re-schedule any drug.

The Controlled Substance Act requires eight factors as part of its scientific review: 1) the actual or relative potential for abuse; 2) the scientific evidence of its pharmacological effect; 3) the state of current scientific knowledge regarding the substance; 4) the history and current pattern of abuse; 5) the scope, duration and significance of abuse; 6) the risk to the public health; 7) the psychic or physiological dependence liability; and 8) the immediate precursor of a substance already controlled.

Writing for the Huffington Post in April 2016, Matt Ferner noted the FDA completed its review of the medical evidence of the safety and effectiveness of marijuana, and forwarded it to the DEA. But the FDA recommendations are still not public. In the Washington Post, Christopher Ingraham interviewed John Hudak of the Brookings Institution, who said the small amount of researchers currently working with marijuana is not due to the government turning down applications to do the research. Rather, it is a function of the application process itself. “People just aren’t applying because of all the headaches involved. . . . It’s a huge disincentive for the academic community.”

The bureaucratic hurdles also mean that colleges and universities are often hesitant to fund marijuana research for fear of running afoul of complex federal regulations. One ongoing study on the use of marijuana to treat veterans with PTSD has been struggling to get off the ground for more than five years, for instance.

There was an unconfirmed rumor by an “anonymous” DEA attorney that the DEA planned to reschedule marijuana as a Schedule II controlled substance and make medical marijuana legal with a doctor’s prescription in all 50 states. This is simply not true. Rescheduling would merely make it easier to get permission to do research with marijuana, not make it legal for doctors in all 50 states to prescribe marijuana. If that were the case, why can’t doctors prescribe cocaine legally? It is a Schedule II Controlled Subtance. Writing for The Fix, McCarton Ackerman noted the skepticism about the validity of the source.

In response to the rumors, DEA staff coordinator Russ Baer would not confirm the rumored rescheduling by August 1st in an interview with aNewDomain. Baer pointed out the complexity of what is referred to as “medical marijuana.” While THC and CBD are the two main cannabinoids, there are an estimated 480 compounds in cannabis. “What is under-reported right now is how complex the marijuana plant is.”

Baer said the DEA wants to remove the roadblocks to further research into the effectiveness of medical marijuana. However, he said the DEA doesn’t support decisions made on anecdotal evidence.

We want there to be research on marijuana and its component parts, there needs to be (more) studies about both the benefits and the adverse effects about marijuana. . . . We want to know more about cannabis— we need rigorous scientific research — the DEA stands behind the scientific process.

He added that safe medical cannabis requires rigorous peer-reviewed studies. He singled out current research into the benefits of cannabinol (CBD). “We are told by NIDA, also, that there are medical studies out there also preliminarily indicate CBD is beneficial.” But the opioid crisis has captured most of the DEA’s attention. “Marijuana is important, but our efforts are mainly focused on the nation’s growing opioid crisis. . . . We’re focusing on fentanyl, fentanyl compounds and on preventing the deaths caused by opioid addiction.”

A June 24th article by Kate O’Keeffe for the Wall Street Journal said Baer didn’t expect an answer by June 30th, but the agency was in the final stages of deciding whether to reschedule marijuana. He added that a decision is expected sometime soon.

On July 13, 2016 Dr. Douglas Throckmorton of the FDA appeared before the Judiciary Subcommittee on Crime and Terrorism. In his written statement to the committee, he reiterated its standing 2006 recommendation that marijuana remain as a Schedule I controlled substance because of a high potential for abuse; no currently-accepted medical use; and that it lacks accepted safety for use under medical supervision. However, “DEA is currently in the process of evaluating a number of other Citizen Petitions regarding the scheduling of marijuana.”

He noted there are three drugs approved for human use that contain active ingredients present in or similar to those in botanical marijuana: Marinol Capsules, Syndros and Cesamet Capsules. These products have undergone the FDA’s approval process and have been determined to be safe and effective for their respective indications. The future of medical marijuana lies in “classical drug development.”

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 pointed to three Fast Track designations for Savitex (April 2014), Epidiolex (June 2014) and a CBD formulation of Insys Therapeutics to treat Dravet syndrome (February 2015). All three are drugs derived from marijuana. He said the FDA is working with researchers who are conducting studies on the development of potential new drugs derived from marijuana.

FDA encourages and supports medical research into the safety and effectiveness of marijuana products through adequate and well-controlled clinical trials conducted under an IND [Investigational New Drug] and consistent with DEA requirements for research on Schedule I substances. FDA has provided scientific advice to representatives from several states considering support for medical research of marijuana and its derivatives, including CBD, to help ensure that their research is rigorous and appropriate.

Another date floated on the rumor pond for a DEA decision on rescheduling marijuana was August 1st, which is fast approaching. Will there be an answer? Who knows? According to Russ Baer, the DEA is not bound to give its answer within some artificially determined timeframe. So I suggest those anxious for an announcement by the DEA (senators and marijuana activists alike) apply a mash up of a famous Yogi-ism here: “Marijuana ain’t re-scheduled till it’s rescheduled.” Perhaps the DEA is just trying to be careful in its decision making process about the rescheduling. Yogi Berra has some further words of wisdom to apply there: “You’ve got to be very careful if you don’t know where you are going, because you might not get there.”

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag Archives: FDA