01/31/17

Curiouser and Curiouser with Chantix

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

12/9/16

Channeling Your DXM Personality

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5© ljupco | 123rf.com

June of 2016 was a confusing month for DXM. Alaska became the 11th 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 8th, 10th, and 12th 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

© Maksim Kabakou | 123rf.com

© Maksim Kabakou | 123rf.com

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

© photosebia | stockfresh.com

© photosebia | stockfresh.com

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

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© diego_cervo | stockfresh.com

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

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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 difficult 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

© : J�rg St�ber | 123rf.com

© : J�rg St�ber | 123rf.com

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.

DEAThe 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.”

07/8/16

Another Empty Promise

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© wavebreak_media | stockfresh.com

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

© Christa Eder | 123rf.con

© Christa Eder | 123rf.con

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

© Juan Auni’n | 123rf.com

© Juan Auni’n | 123rf.com

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.