11/14/17

Pharma’s Not Getting the Message

© Ioulia Bolchakova | 123rf.com

In response to rapidly increasing prescription drug prices and congressional inability or unwillingness to intervene, individual states are attempting to address the issue. While Californians approved a ballot initiative for recreational marijuana in November of 2016, state voters also turned down one aimed at curbing the high cost of prescription drugs. The California Drug Price Relief Act, or Proposition 61, sought to limit the state’s health programs from paying more than the U.S. Department of Veterans Affairs (VA), which receives the steepest discounts in the country, according to Reuters. Pharma companies lobbying against Proposition 61 spent $100 million to defeat it.

Proposition 61’s opponents, led by global drugmakers such as Pfizer Inc and Amgen Inc, spent around $106 million. They argued that it would benefit only 12 percent of Californians, while putting the other 88 percent, and veterans across the country, at risk of higher drug costs.

The defeat of the measure: “reaffirms the power of the biomedical lobby,” according to Brian Abrahams, a Senior Biotechnology Analyst at CIBC World Markets. Stuart Schweitzer, a professor of health policy and management at the University of California, said the measure would have only had a modest impact on state drug costs. Nevertheless, “They wanted to draw a line in the sand.”  A similar proposition will be on Ohio’s 2017 November ballot.

U.S. New and World Report said New York State approved rules in April of 2017 that will put pressure on pharmaceutical companies if they want to continue doing business in the state. If Pharma companies don’t agree to voluntarily rebate or return money to the state if prescription medication spending is projected to exceed the sum of medical inflation plus 5 percent, New York State could initiate a series of reviews using scientific studies and other information to evaluate whether specific medications are overpriced. “Drug makers generally object to such reviews and often dispute their results.” The NY State Medicaid Director said the law created an incentive for pharmaceutical companies to collaborate and give the state rebates.

New York is not the only state taking action. Vermont lawmakers passed legislation requiring justification for price increases that are driving up spending in state programs like Medicaid. In March of 2017 Maryland lawmakers passed legislation, still not signed by the governor, directing Medicaid to notify the state attorney general when off-patent or generic drugs have “an excessive price increase.” The new law also sets financial penalties if the pharmaceutical company can’t justify the price hike. Louisiana officials are looking into whether a rarely used federal law could be used to “sidestep patents and allow government programs to get lower-cost generic versions of pricey hepatitis C treatments.”

In August of 2017, JAMA gave greater details about the New York legislation in: “Value-Based Pricing and State Reform of Prescription Drug Costs.” Hwang et al. said if the rate of drug spending growth exceeded the 10-year average inflation plus 5% in 2017-2018 or 4% in 2018-2019, the state department of health would be authorized to identify and refer high-cost drugs to a drug utilization review board to determine a target rebate amount. The provisions are likely to trigger a review this year. The board may consider the effectiveness of the drug, its therapeutic alternatives, and the seriousness and prevalence of the disease in formulating its recommendation for a value-based price.

If the state and manufacturer fail to agree on a rebate that is at least 75% of the difference between the drug’s current price and value-based price, the state may waive provisions that currently require managed care plans to cover medically necessary drugs in certain protected classes, including antidepressants, antiretrovirals, and hermatologic drugs. Furthermore, if total drug expenditures continue to increase faster than inflation despite these new rebates, the state may implement more aggressive actions to promote use of clinical alternatives, including directing managed care plans to remove drugs from their formularies that lack new rebate agreements.

The pharmaceutical industry is taking steps to prepare to do battle against these and other steps taken to rein in drug prices. The pharmaceutical lobby, PhRMA (Pharmaceutical Research and Manufacturers of America), is increasing membership dues by 50 percent to raise an additional $100 million PER YEAR to fund its ongoing fight over drug prices.  “PhRMA has consistently ranked among the biggest lobbying spenders in Washington over the past few years.” By August of 2016, it had already spent $11.8 million that year, making it the fourth-largest lobbying group in Washington DC. TV advertising in 2017 was to target how “new drugs could add years to patients’ lives, as well as the years of complex research needed to develop a drug.”

The Intercept reported that newspapers in the Washington D.C. area were getting swamped in April of 2017 with ads warning of the dire consequences of proposals to lower drug prices. The groups placing the ads had no obvious connections to pharmaceutical companies. The ads appeared in the Washington Post, Washington Times, Roll Call, The Hill and Politico just as legislators were taking up proposals to lower drug prices. As it turned out, the organizations had undisclosed financial ties to PhRMA.

A bill proposed by Senator Al Franken would reverse a 2003 law prohibiting Medicare from using its collective bargaining power to negotiate lower drug prices. Legislators who wrote the 2003 bill worked closely with PhRMA lobbyists while drafting the legislation. The bill’s sponsor later became the president of PhRMA.  Franken and others introduced the “Improving Access to Affordable Prescription Drugs Act” on March 29, 2017. Here is a five-page summary of the bill. A companion bill to “Improving Access to Affordable Prescription Drugs Act” was introduced in the House on the same day.

Some of its provisions would include several current problems with prescription drug costs. It would close the coverage gap in Medicare Part D coverage (known as the donut hole) in 2018, two years earlier than under current law. Tax credits given to pharmaceutical companies for their direct-to-consumer (DTC) advertisements would be eliminated. (WE WERE GIVING PHARMA COMPANIES TAX CREDITS WHEN THEY TRY TO GET US TO BUY THEIR DRUGS?) It would allow individuals, wholesalers and licensed U.S. pharmacies to import prescription drugs manufactured at FDA-inspected facilities from licensed Canadian sellers.

Significantly, Section 201 would allow the Secretary of Health and Human Services to negotiate with drug companies to lower prescription drug prices. It directs the Secretary to “prioritize negotiations on specialty and other high-priced drugs.” Under existing law, unlike Medicaid and the VA, Medicare is not allowed to leverage its purchasing power to negotiate lower drug prices.

STAT News reported that the Thursday before the November 2017 election, Andy Slavitt, the acting administrator for Medicare and Medicaid Services, said the rising costs for prescription drugs “will put unsustainable pressure on the Medicare program, and action is going to be necessary to address them.” He was addressing the BioPharma Congress, an industry conference. He said: “Drug costs have become the health policy issue Americans are most anxious to see us act on, and we have a responsibility to them to explore all the options available us to make their medications more affordable.” He told those at the conference that we could have both innovation and affordability. “These two goals shouldn’t be in opposition.”

In every-forward looking industry outside of health care, we see that competition actually fuels innovation, and affordability improves alongside the development of new technologies. . . . There are plenty of policy options and certainly a number of ways innovators like you can choose to respond – from disputing the math and fighting it, to looking for win-wins.

So far, it seems Pharma is ignoring the message. They are still trying to convince the American public and U.S. lawmakers that innovation in drug development will dry up if price caps are enacted.

The debate over the cost of drug development has been going on since the late 1950s, believe it or not. An often-quoted 2003 study, “The Price of Innovation,” which was published in the Journal of Health Economics, estimated it cost $802 million in 2000 dollars to bring a new drug to market. PhRMA’s 2014 profile found that estimate low and said it actually costs $1.2 billion to develop a new drug. However, “Demythologizing the High Costs of Pharmaceutical Research,” in the journal BioSocieties, suggested the true research and development costs were a median of about $43.4 million per new drug. That is about 5.4% of “The Price of Innovation’s” cost projection and 3.6% of the PhRMA estimate. See “Pharma and Its Golden Hoard” for a further discussion of what a new drug costs.

08/8/17

Kratom: Part of the Problem or a Solution?

© Nanthawan Suwanthong | 123rf.com

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 1st of 2016. As of August 6th, 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.

03/14/17

Fentanyl: Fraud and Fatality

© Alexi Novikov

In December of 2016, several former pharmaceutical executives and managers of Insys Therapeutics were arrested on charges they participated in a nationwide conspiracy to bribe medical practitioners to prescribe one of the company’s fentanyl products, Subsys. The medication is approved for treating cancer patients suffering intense episodes of breakthrough pain. “In exchange for bribes and kickbacks, the practitioners wrote large numbers of prescriptions for the patients, most of whom were not diagnosed with cancer.” The indictment also alleges that these same former Insys executives conspired to “mislead and defraud” health insurance companies who were reluctant to approve payment for Subsys when it was prescribed for non-cancer patients.

The Special Agent in Charge of the Boston Field Division of the FBI said top executive of Insys Therapeutics, Inc. allegedly paid kickbacks and committed fraud in selling the highly addictive opioid. “The indictment also alleges that the conspiracy to bribe practioners and to defraud insurers generated substantial profits for the defendants, their company, and for the co-conspirator practioners.” The investigative team included multiple federal agencies, including: FBI, FDA Office of Criminal Investigations; Health and Human Services (HHS), U.S. Postal Service, the Department of Labor, and the Department of Veterans Affairs.

Reporting for STAT News on the indictments, David Armstrong said a Florida doctor was invited to Insys headquarters near Phoenix, where sales officials took him out for a night on the town. In a text message to a sales rep, one of the company’s regional sales managers said: “He had to have had one of the best nights of his life.”  The next week the doctor wrote 17 prescriptions for Subsys, when he usually wrote three. “He also received $260,050 in payments over three years for participating in the Insys speaking program — something federal officials allege was nothing more than a mechanism for bribing doctors.”

Subsys was launched in March 2012 into a crowded field of competitors, which included other brand-name medications and several generics. The drug was approved only for cancer patients with intense flares of pain — a narrow market — and only about 2,000 doctors in the country prescribed fentanyl products. The drug is also expensive, costing thousands of dollars a month.

Prosecutors allege the company overcame these challenges with a speaker program, where “educating” doctors on the use of the drug was actually a way to bride them. A former chief executive of Insys wrote to sales managers that they needed to make it clear to sales reps how having one of their top targets as a speaker “can pay big dividends for them.” Doctors didn’t need to be good speakers; they just needed to “write a lot of” Subsys prescriptions. The indictment did not identify any of the parishioners by name who allegedly received and kickbacks.

To sweeten the pot, the Insys employees allegedly scheduled speaking events at establishments owned by doctors, or their families and friends. The events allegedly had little do with education: They were often held at high-priced restaurants and attendees were frequently just friends of the doctor hired as the speaker, the indictment alleges. Fake names were used on sign-in sheets, and some events had no attendees at all, according to prosecutors.

The cancer market for Subsys was considered to be “small potatoes” by one of the indicted former Insys executives. While the alleged bribes led doctors to prescribe more prescriptions for Subsys, insurance companies were reluctant to pay when the drug was prescribed for non-cancer patients. So a system was created to deceive insurers into paying for off-label uses of the drug, which is incidentally, quite expensive. A call center was created at Insys to handle insurance reimbursement approvals for doctors prescribing Subsys.

Employees in this unit are alleged to have contacted insurers, giving the appearance they were calling from the doctor’s office.  Along with the supposedly deceptive medical information given to the insurers, they reportedly said patients had difficulty swallowing, which meant Subsys, as a nasal spray, had a distinct advantage over similar products that were in pill form. “Employees of the unit were rewarded with lucrative financial bonuses if the entire unit met a weekly target of reimbursement approvals.”

The Subsys fiasco is not the only fentanyl-related contribution to the opioid problem in the U.S. Two years ago the DEA issued a nationwide alert on fentanyl as a threat to health and public safety. State and local labs reported 3,344 fentanyl submissions in 2014, an increase from 942 in 2013. “In addition, the DEA has identified 15 other fentanyl-related compounds.” Warnings were issued to law enforcement about guarding against fentanyl absorption through the skin or accidental inhalation of airborne powder, as it is 30 to 50 times more potent than heroin. Ingesting as small as .20 mg to 2mg of fentanyl can be lethal. The following image, taken from the 2016 National Drug Threat Assessment (NDTA), illustrates the size of 2mg of fentanyl compared to a penny.

 

Globally, fentanyl abuse has increased in Russia, Ukraine, Sweden and Denmark. Mexican authorities have seized fentanyl labs run by the drug cartels. Intelligence indicated the precursor chemicals for fentanyl have come from companies in Mexico, Germany, Japan and China.

According to the 2016 NDTA, licit fentanyl is only diverted on a small scale. Illicit fentanyl, typically manufactured in China or possibly Mexico, is smuggled into the U.S. across the border with Mexico. Traffickers usually obtain fentanyl and mix it with heroin on their own. This happens at a variety of locations, including homes and even hotel rooms.

In August 2015, the DEA Manchester, New Hampshire DO, along with the Salem, New Hampshire Police Department, conducted an enforcement operation at a fentanyl mill in a hotel in New Hampshire. The traffickers used a hotel room kitchenette for mixing heroin and fentanyl together. Upon entry by law enforcement officers, the traffickers attempted to dispose of the drugs down the sink, spilling the highly lethal drugs all over the room.

Traffickers in the U.S. are also using fentanyl powder and a pill press to create counterfeit pills of oxycodone and other drugs. Officials in New Jersey and Tennessee seized pills that appeared to be oxycodone. But laboratory analysis indicated they were fentanyl or acetyl fentanyl. In May of 2015, Orange County Police Officers in California seized what appeared to be black tar heroin. “Upon laboratory analysis, the substance was revealed to be fentanyl and showed no traces of heroin or any other drug.”

In another article for STAT News, David Armstrong described the China connection with fentanyl. Raw fentanyl and the machinery necessary for assembly-line production of the drug are coming from Chinese suppliers. “The fentanyl pills are often disguised as other painkillers because those drugs fetch a higher price on the street, even though they are less potent, according to police.” A Southern California fentanyl lab had a dozen different packages shipped to mail centers and residences. A box labeled as a “Hole Puncher” was in fact a quarter-ton pill press. “The Southern California lab was just one of four dismantled by law enforcement in the United States and Canada in March [of 2016].”

In British Columbia, police raided a lab at a custom car business that was allegedly shipping 100,000 fentanyl pills a month to Calgary, Alberta. Federal agents shut down a Seattle lab set up in the bedroom of a home in a residential neighborhood. Police near Syracuse New York raided a similar residential lab, where they were warned by the people there not to touch the fentanyl without gloves because of its potency. “The emergence of decentralized drug labs using materials obtained from China — and often ordered over the Internet — makes it more difficult to combat the illicit use of the drug.” See “Buyer Beware Drugs” for more on this topic.

In January of 2017 the acting administrator of the DEA met with Chinese officials to address the synthetic drug crisis in the U.S. He said: “These meetings underscore our improving relationship and cooperative efforts as we work to stem the flow of dangerous synthetic opioids and related chemicals.  I appreciate the good work they are doing in China to help us address our opioid epidemic.” The DEA maintains an office in Beijing and hopes to expand its presence in China. Hopefully, if the China connection with fentanyl is turned off, the future outlook from the 2016 NDTA will not be as bleak.

Fentanyl will remain an extremely dangerous public safety threat while the current production of non-pharmaceutical fentanyl continues. Fentanyl poses not only a threat to users, but also to law enforcement personnel and postal service employees as minute amounts of the drug are lethal and can be inadvertently inhaled or absorbed through the skin. Although many drug users avoid fentanyl, still others actively seek it out for its strong and intense high. In 2015 traffickers expanded the historical fentanyl markets as evidenced by a massive surge in the production of counterfeit tablets containing the drug, and manipulating it to appear as black tar heroin. The fentanyl market will continue to expand in the future as new fentanyl products attract additional users.

In February 2017, Time reported that China announced that carfentanyl (carfentanil) and three related synthetic opioids would be added to its list of controlled substances effective March 1, 2017. The DEA called China’s action a potential “game changer.” Russell Baer, a DEA special agent said: “It’s a substantial step in the fight against opioids here in the United States. . . We’re persuaded it will have a definite impact.” In October, the Associated Press identified 12 Chinese companies the offered carfentanyl for export. That same month China began evaluating whether to add it and three other fentanyls to its list of controlled substances. “Usually, the process can take nine months. This time, it took just four.”

02/3/17

“Political” Science?

© Luis Molinero Martinez | 123rf.com

A 2014 study by a well known researcher from Columbia University indicated that “Sexual minorities living in communities with high levels of anti-gay prejudice experienced a higher hazard of mortality than those living in low-prejudice communities.” The press release for the study said it was the first study to look at the consequences of anti-gay prejudice for mortality. The study’s lead author, Mark Hatzenbuehler, said: “The results of this study suggest a broadening of the consequences of prejudice to include premature death.” The authors thought their study’s results highlighted the importance of examining structural forms of stigma and prejudice as social determinants of health and longevity among minority populations. A significant and potentially important finding—except it may not be true.

The original study, “Structural Stigma and All-Cause Mortality in Sexual Minority Populations” by Hatzenbuehler et al. was published in the February 2014 issue of Social Science & Medicine. Another researcher, Mark Regnerus, set out to replicate the Hatzenbuehler et al. study, but was not able to do so. Regenerus included a more refined imputation strategy in his replication, but still failed to find any significant results. “No data imputation approach yielded parameters that supported the original study’s conclusions.” Regenerus said:

Ten different approaches to multiple imputation of missing data yielded none in which the effect of structural stigma on the mortality of sexual minorities was statistically significant. Minimally, the original study’s structural stigma variable (and hence its key result) is so sensitive to subjective measurement decisions as to be rendered unreliable.

Writing for the National Review, Maggie Gallagher said that Regenerus’s failure to replicate the Hatzenbuehler et al. study amounted to a repudiation of that study. She also thought the study was faked. “When social justice displaces truth as the core value of academics, bad things happen to science.” She implied Hatzenbuehler might have slipped a bogus study into a major social-science journal, “confident that nobody would want to review and contest its findings, which so please the overwhelmingly liberal academy.”

Gallagher then referred to Mark Regenerus as an emerging scientific hero; a “modern-day Galileo standing up to the new theology of the Left.” But I think she misses the point. Both Hatzenbuehler and Regenerus are doing exactly what they are supposed to do in science: publishing their results and attempting to replicate the research of others. Henry Bauer, a professor of Chemistry & Scientific Studies at Virginia Polytechnic Institute and State University, describes how the “knowledge filter” in science can help uncover the real failures and confirm the true successes.

Bauer asks what would happen if most scientists rounded off or fudged their findings. What if they thought more about who wanted results and less about what an experiment actually showed? “To understand why science may be reliable or unreliable, you have to recognize that science is done by human beings, and that how they interact with one another is absolutely crucial.” He then went on to describe how frontier science leads to publication in the primary literature.

If those [findings] seem interesting enough to others, they’ll be used and thereby tested and perhaps modified or extended – or found to be untrue. Whatever survives as useful knowledge gets cited in other articles and eventually in review articles and monographs, the secondary literature, which is considerably more consensual and reliable than the primary literature.

Regenerus’s findings themselves have to be replicated; by more than one additional study before Gallagher’s assessment that Regenerus repudiated Hatzenbuehler et al. is confirmed. Concluding the study was faked or bogus based just upon his findings is irresponsible and goes beyond what Regenerus himself said.

Regenerus said the findings of the Hatzenbuehler et al. study seemed to be very sensitive to subjective decisions made about the imputation of missing data, “decisions to which readers are not privy.” He also thought the structural stigma variable itself was questionable, “Hence the original study’s claims that such stigma stably accounts for 12 years of diminished life span among sexual minorities seems unfounded, since it is entirely mitigated in multiple attempts to replicate the imputed stigma variable.” He thought his study highlighted the importance of cooperation and transparency in science.

The unavailability of the original study’s syntax and the insufficient description of multiple imputation procedures leave unclear the reasons for the failed replication. It does, however, suggest that the results are far more contingent and tenuous than the original authors conveyed. This should not be read as a commentary on missing data or on the broader field of the study of social stigma on physical and emotional health outcomes, but rather as a call to greater transparency in science (Ioannidis, 2005). While the original study is not unique in its lack of details about multiple imputation procedures, future efforts ought to include supplementary material (online) enabling scholars elsewhere to evaluate and replicate studies’ central findings (Rezvan et al., 2015). This would enhance the educational content of studies as well as improve disciplinary rigor across research domains.

Regenerus is not a scientific hero and Hatzenbuehler is not a research villain. But two other individuals identified by Gallagher in her article may fit within those categories.

Michael LaCour co-authored a paper along with Donald Green that was published in the prestigious journal Science in December of 2014. The original article abstract said: “LaCour and Green demonstrate that simply a 20-minute conversation with a gay canvasser produced a large and sustained shift in attitudes toward same-sex marriage for Los Angeles County residents.” Green is a highly respected political science professor now at Columbia. LaCour was a political science grad student at UCLA.

Back in September of 2013, Michael LaCour met with David Broockman at the annual meeting of the American Political Science Association and showed him some of the early results of his study. Writing for NYMag.com, Jesse Singal noted how Broockman was “blown away” by some of the results LaCour shared with him. LaCour also told him he was looking to get Donald Green as a coauthor on the paper. Coincidentally, Green happened to be Broockman’s undergraduate advisor when they were both at Yale.

Singal pointed out that LaCour’s results were so noteworthy because they contradicted every established belief about political persuasion. “The sheer magnitude of effect LaCour had found in his study simply doesn’t happen — piles of previous research had shown that.” In early 2015, Broockman decided to replicate LaCour’s findings. The first clue there was something wrong was when he realized the estimated cost for a replication would be a cool million dollars. Where would a grad student like LaCour get the money or funding for a study like that? That first anomaly eventually led to: “Irregularities in LaCour (2014),” a 27 page report he coauthored with Josh Kalla and Yale University political scientist, Peter Arnow.

“Irregularities” is diplomatic phrasing; what the trio found was that there’s no evidence LaCour ever actually collaborated with uSamp, the survey firm he claimed to have worked with to produce his data, and that he most likely didn’t commission any surveys whatsoever. Instead, he took a preexisting dataset, pawned it off as his own, and faked the persuasion “effects” of the canvassing. It’s the sort of brazen data fraud you just don’t see that often, especially in a journal like Science.

Green quickly emailed the journal and asked for a retraction, which he received. When contacted about comments that he had failed in his supervisory role for the study, Green said that assessment was entirely fair: “I am deeply embarrassed that I did not suspect and discover the fabrication of the survey data and grateful to the team of researchers who brought it to my attention.”

LaCour had a job offer as an incoming assistant professor at Princeton rescinded. He also reportedly lied about several items on his curriculum vitae, including grants and a teaching award. You can review a post mortem of the LaCour controversy by Neuroskeptic for Discover Magazine here. Neuroskeptic thought LaCour’s objections to Broockman et al. were weak. He also thought Lacour’s objections to the findings of Broockman et al. failed to refute their central criticism.

Cases of seeming scientific fraud, like that of LaCour, draw attention to themselves when they are discovered. Writing for STAT News, Ivan Orlansky and Adam Marcus described a survey by researchers in the Netherlands of working scientists. They were asked to score 60 research misbehaviors according to their impressions of how often the misbehaviors occur, their preventability, the impact on truth (validity), and the impact of trust between scientists.  The respondents were more concerned with sloppy science than scientific fraud. Fraud, when it occurred, has a significant impact on truth and public trust. But those cases are rare; and detected cases are even rarer. They concluded:

Our ranking results seem to suggest that selective reporting, selective citing, and flaws in quality assurance and mentoring are the major evils of modern research. A picture emerges not of concern about wholesale fraud but of profound concerns that many scientists may be cutting corners and engage in sloppy science, possibly with a view to get more positive and more spectacular results that will be easier to publish in a high-impact journal and will attract many citations. In the fostering of responsible conduct of research, we recommend to develop interventions that actively discourage the high-ranking misbehaviors from our study.

So it would seem that problems with the Hatzenbuehler et al. study are not fraud, but could be due to smaller more pervasive issues in its research, such as a shoddy methodology. The LaCour case catches more attention and generates mistrust because of its apparent fraud. Orlansky and Marcus are right. Although not as flashy as fraudulent research, the smaller, less outrageous research sins are a greater threat to scientific credibility. Gallagher may have let her own ideology influence how she emphasized these two cases, but she was unquestionably right in her concluding remarks:  “Science is not right-wing or left-wing. But to work, it needs scientists fearlessly committed to truth over their preferred outcomes.”

01/24/17

Herding Pharma “Cats”

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The Chinese government released a report in September of 2016 by the State Food and Drug Administration (SFDA) that found fraudulent clinical trial practices on a massive scale. The SFDA concluded that over 80% of clinical trial data was fabricated. The scandal was the result of a “breach of duty by supervision departments and malpractice by pharmaceutical companies, intermediary agents and medical staff.” More than 80% of the applications for the mass production of new medications have been cancelled, with warnings by the SFDA that further evidence of malpractice might still emerge.

Radio Free Asia also reported the SFDA indicated much of the clinical trail data was incomplete at best. But it also failed to meet basic analysis requirements or was untraceable. “Some companies were suspected of deliberately hiding or deleting records of adverse effects, and tampering with data that did not meet expectations.” Apparently, this came as no surprise to industry insiders. “Clinical data fabrication was an open secret even before the inspection.”

Many of the new drugs were combinations of existing ones. Clinical trial outcomes were written beforehand, and their data presented so it agreed with the fabricated outcomes. A doctor at a top Chinese hospital said the problem lay with the failure to implement regulations governing clinical trial data. “Guangdong-based rights activist Mai Ke said there is an all-pervasive culture of fakery across all products made in the country.” Reporting for Pharmafile, Ben Hargreaves said:

The root of the issue is then not regulation, with regulation for clinical trials running on similar lines to Western practises, but in the lack of adherence to them. China’s generic drug industry has struggled with quality problems and therefore there is a temptation for companies to manipulate data to meet standards. The report found that many of the new drugs were found to be a combination of existing drugs, with clinical trials outcomes written beforehand and the data tweaked to fit in with the desire outcomes.

Sadly, clinical trial problems are not unique to China. An editorial published in the British journal The Lancet Psychiatry described multiple issues beginning with how subjects are recruited, moving on to determining what the control group should be, and ultimately defining meaningful outcome measures. Sometimes, trial recruits receive “care” they didn’t agree to. “Researchers and ethics review boards need to examine the ethical arguments and practical procedures from other areas of medicine where consent is problematic.” If such trials are done, regular and rigorous monitoring is essential. Patient safety and autonomy needs to be a priority.

In his discussion of the editorial, Justin Carter elaborated on one of the problems with recruiting subjects. An individual was recruited into a study on three antipsychotics while under a forced commitment order from a judge. “The psychiatrist who recruited him was in charge of the study and was his treatment provider and was also empowered to report on the patient’s progress to the judge.” The individual died by suicide during the drug trial.

The work of Irving Kirsch and others has shown the problem with inert placebos (sugar pills). The side effects from medication make it easy for participants to guess which study group they are in.

And when the trial is over and the data in, do the outcome measures really provide something meaningful for people’s lives? If the ultimate goal is for people to fell better and resume their prior level of functioning, should outcome measures by primarily patient self-reports, clinical assessment, or differences shown by imaging or the as-yet-to-be-clearly-identified biomarkers?

Given the problems running and interpreting psychiatry trials, it is essential to learn how even the most successfully tested interventions work in real clinics with the broad patient population. Implementation, uptake, and effectiveness in real-life settings must be analysed, and delivery of new innovations modified accordingly. Future research should be thought of not as a plain linear process from innovation to trial to implementation, but as a virtuous circle where research feeds into the clinic and vice versa.

Another issue pointed to by Carter was the validity and reliability of the diagnosis or classification system used to determine who to include and who to exclude from the trials. The DSM system, now in its fifth edition (DSM-5), is the current “bible” for assessing and diagnosing problems the psychiatric medications in clinical trials are supposed to “treat” in the U.S. Yet there have been questions about the reliability and validity of the DSM dating from an argument raised by Robert Spitzer and others in the 1970s that ushered in changes still embedded in the DSM-5. Rachel Cooper gave a brief history of the reliability questions with the DSM in “How Reliable is the DSM-5?” You can also refer to “Psychiatry Has No Clothes,” “Where There’s Smoke …”, and  “The Quest for Psychiatric Dragons,” Parts 1 and 2.

A few weeks before the release of the DSM-5, Thomas Insel, then the NIMH Director, announced the NIMH would be “reorienting” its research away from DSM categories. The agency’s new approach is called the Research Domain Criteria (RDoC) project. For now, RDoC is a research framework and not a clinical tool. But NIMH has high hopes for it: “RDoC is nothing less than a plan to transform clinical practice by bringing a new generation of research to inform how we diagnose and treat mental disorders.” While Tom Insel has moved on to work for Alphabet (Google), RDoC is alive and well within NIMH. You can keep up with news about RDoC on the “Science News About RDoC.”

The Science Update for February 16, 2106 noted the March 2016 issue of the journal Psychophysiology would be devoted to the RDoC initiative. Dr. Bruce Cuthbert said the special issue was a unique opportunity for researchers to engage with one another and reflect on work being done in various laboratories throughout the country. He thought it was encouraging to see many investigators already engaged in the kind of work RDoC advocates. “What this shows is that while the RDoC acronym may be new, the principles behind RDoC are certainly not new to psychiatric research.”

If the principles behind RDoC are not new to psychiatric research, how can it bring “a new generation of research to inform how we diagnose and treat mental disorders” in order to transform clinical practice? It sounds a lot like using the same deck of cards to just play a new card game. RDoC may not be the transformative framework it’s touted to become.

Added to these issues is the failure of pharmaceutical companies to publically report the results of clinical trials, as they are required by law to do. New reporting rules will take effect on January 18, 2017. But advocates for transparency in clinical research have cautioned the success of the new rules will depend upon the willingness and vigor of government enforcement of those rules. The failure to enforce the existing rules, which went into effect in 2008, led to widespread noncompliance with reporting requirements. If the FDA had fined the violators, they could have collected an estimated $25 billion.

Reporting for STAT News, Charles Piller said studies have indicated only a small fraction of trials will comply with the law. Yet there are no current plans to increase enforcement staffing at the FDA and NIH. That’s a big problem, according to Ben Goldacre, an advocate for full disclosure in clinical research. Francis Collins, the NIH director said they are serious about this and will withhold funds, if needed. “It’s hard to herd cats, but you can move their food, or take their food away.”

The legislation that created ClinicalTrials.gov emerged from numerous cases of drug manufacturers withholding negative trial results, making drugs look more effective and less harmful. Efforts to market the antidepressant Paxil for teenagers more than a decade ago stimulated the push for better reporting. A recent analysis in the journal BMJ found that GlaxoSmithKline, Paxil’s manufacturer, failed to disclose 2001 data showing the drug to be no more effective than a placebo, and was linked to increased suicide attempts by teens.

Writing for Time, Alexandra Sifferlin reported on a new study that suggested many of the medical reviewers for the FDA go to work for the drug companies they oversaw while working for the government. One of the study’s authors said: “I don’t think there is overt collusion going on, but if you know in the back of your mind that a major career opportunity after the FDA is going to work on the other side of the table, I worry it can make you less likely to put your foot down.”

Returning to the Francis Collins metaphor, it seems that the willingness to try and herd Pharma cats is dependent on whether or not you are afraid they will scratch you in the attempt.

11/1/16

Ketamine Desperation

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© Novic | stockfresh.com

Jeff wants to smile again and know what happiness is like again. He wants to not feel the urge to kill himself again. He has been hospitalized in psychiatric facilities and has taken a variety of antidepressants and mood stabilizers for his bipolar disorder, but nothing worked. He remained employed as a football analyst until the sky fell in on him and he lost his job. “He was suicidal; so overwhelmed with despair, that he couldn’t even leave his house.” He finally found a treatment option at the Ketamine Clinics of Los Angeles. And so goes one of many testimonies of ketamine’s potential as a rapid treatment for depression.

Steven Mandel MD, the President and founder of the Ketamine Clinics of Los Angeles, is an anesthesiologist who uses ketamine to treat patients who are depressed and suicidal. The standard protocol is to give low dose IV infusions of ketamine. It worked for Jeff. He said, “It’s been remarkable.” His wife looked at him and saw the smile on his face and had the biggest smile herself in response. Jeff thought it was immoral to withhold ketamine from the general public. You can watch a four-minute video on Jeff and Dr. Mandel’s treatment here.

Over the last ten to fifteen years, ketamine has been getting a significant amount of research and media attention as a fast-acting treatment for depression. Reporting for The Washington Post, Sara Solovitch quoted Dennis Hartman as saying: “My life will always be divided into the time before that first infusion and the time after.” But the relief is temporary. “Clinical trials at NIMH have found that relapse usually occurs about a week after a single infusion.”  And it can cause intense hallucinations or a kind of lucid dreaming or dissociative state where some patients lose track of time.

NIMH studies suggest the psychedelic experience with ketamine may play a small but significant role in the drug’s efficacy. Steven Levine, a psychiatrist who has treated 500 patients with ketamine said:

With depression, people often feel very isolated and disconnected. Ketamine seems to leave something indelible behind. People use remarkably similar language to describe their experience: “a sense of connection to other people,” “a greater sense of connection to the universe.”

Hartman travels back-and-forth to an anesthesiologist in New York City for his bimonthly infusions of ketamine. He doesn’t consider himself permanently cured, “but now it’s something I can manage.” In 2012 he helped to found an organization called the Ketamine Advocacy Network, a group that screens ketamine clinics, advocates for insurance coverage and spreads the word on the effectiveness of ketamine to treat depression. The problem is the treatment is not FDA approved. And in higher doses, ketamine is known as the club drug, “Special K.” See previous articles, “Ketamine to the Rescue?” and “Falling Down the K-Hole.”

The promise of ketamine as a fast-acting alternative to other antidepressant medications had led to a growth industry for ketamine clinics around the U.S. and multiple pharmaceutical companies doing their own research into developing ketamine derivatives without the side effects. Ketamine is known to interact with the NMDA receptor involved in learning and memory. So scientists assumed the same receptor was responsible for the anti-depressive action of ketamine. STAT News reported this led to more than a dozen companies trying to develop drugs that target the NMDA receptor. “But these drugs haven’t worked as well as ketamine.” AstraZeneca pulled out of developing its own highly touted ketamine derivative, lanicemine in 2013 when it failed to show long-term benefits.

Iadarola et al. published a 2015 article in the journal Therapeutic Advances in Chronic Diseases that reviewed the growing literature on ketamine efficacy as an antidepressant treatment. They confirmed the temporary effects from ketamine; the effects waned after several days in most patients. The authors suggested that after achieving the antidepressant response from ketamine, the effects could be maintained with intermittent doses of ketamine as described above with Dennis Hartman. Pharmaceutical companies aren’t really interested in moving forward with ketamine infusion since the drug has been long off patent and they can’t make a billion dollar profit on a drug that is off patent. So they seek to develop biosimilars to ketamine.

The latest pharma compound to target the NMDA receptor is esketamine, which Janssen Pharmaceuticals, a division of Johnson & Johnson, is developing as an intranasal spray. Johnson & Johnson announced on August 16, 2016 that the FDA granted esketamine a Breakthrough Therapy Designation. This is the second time esketamine has received a Breakthrough Therapy Designation. The first was in November of 2013. The Breakthrough Therapy Designation is to expedite drug development when a drug demonstrates the potential to be a substantial improvement over available therapies for serious or life-threatening conditions.

But the real excitement may still be ahead. The STAT article cited above reported on a new research study published in the May 26th 2016 issue of the journal Nature that demonstrated a derivative of ketamine could achieve the same benefit, but without the side effects. The study was done on mice, so it has a ways to go in drug development before it can compete with esketamine. Dr. Todd Gould, who led the Nature study, suggested the ineffectiveness of previous studies that targeted the NMDA receptor were because they were looking in the wrong place. His research team showed that the effectiveness of ketamine as an antidepressant doesn’t come from the NMDA receptors—at least not in mice.

In the body, ketamine turns into a molecule called hydroxynorketamine — or HNK — and that molecule is actually what treats the depression. Gould’s team also found that HNK does not interact with the NMDA receptor, and it doesn’t have some of the side effects that ketamine does.

Gould said they have a game plan to move forward with the clinical development of HNK. He and his coauthors have filed a patent application for certain uses of HNK. Outside researchers thought the study was well-done science, but they aren’t convinced it’s time to give up on the NMDA receptor. Their drugs targeting the NMDA receptor are further along in drug development. And they are not convinced they are beating a dead horse just yet. STAT reported that Dr. John Krystal, a psychiatrist and neuroscientist who consults for companies developing NMDA-target drugs said: “In my view, it is quite premature to move away from the hypothesis that NMDA receptor antagonists have antidepressant activity based on this single study.” True, but to you rush to bring your ketamine-like drug to market first?

There will still be the same adverse effects as with ketamine, won’t there? And the temporary nature of the mood elevation is still there, isn’t it? The lack of long-term effects led to the AstraZeneca decision to stop development with lanicemine. And esketamine is “an investigational antidepressant medication, for the indication of major depressive disorder with imminent risk for suicide.” That sounds like a short-term use designation.

Uli Hacksell, chief executive of Cerecor, a Baltimore company that has a Phase 2 drug candidate directed at the NMDA pathway, also took issue with the claim that such drugs might be going after the wrong target, and he said that the paper will have no implications for his company’s development plans. “We think that the clinical data we get with our molecule will speak for themselves,” he said.

One outside researcher, Dr. Francis Collins, the director of the National Institutes of Health (NIH), was quite supportive of Gould’s research. In his NIH Director’s blog, Collins described the background work leading up to the Gould study. He then said:

 HNK appears to come without the side effects of ketamine. After receiving HNK, mice didn’t show changes in their physical activity, coordination, or sensory perception, as is normally seen after a dose of ketamine. HNK also doesn’t appear to have the same potential for abuse either. When given the option, mice will choose to self-administer ketamine, but not HNK.

The new evidence confirms that HNK doesn’t block NMDA receptors like ketamine does. While there’s more to discover about how HNK works, the evidence reveals an important role for AMPA receptors, another type of glutamate receptor in the brain.

Long-term ketamine users can have irreversible urinary tract and bladder problems. Erowid, a pro-drug website, conducted an online survey that indicated there was a clear correlation between total lifetime use of ketamine and the likelihood of reporting bladder/urinary problems. Now these are health problems that occur with higher doses of ketamine than those used to treat depression. Lower doses over the long-term may not have the same adverse effects. However, these known health concerns should not be overlooked in the rush to bring a new fast-acting antidepressant to market. Ketamine (and its derivatives) to the rescue of depression may not turn out to be the super cure some think it is.

10/11/16

Stacking the Deck with Clinical Trials

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© 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.

09/30/16

Chantix Tug-of-War

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© AndreyPopov | stockfresh.com

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

09/20/16

Appalling Silence on ECT

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© rangizzz | 123rf.com

Kenny was put on antidepressants at the age of 14 because he was struggling in a difficult family situation. His symptoms became worse. The psychiatrist added another drug with again worsening symptoms. At one point, he was taking six different psychiatric drugs. Kenny was eventually told his depression was “treatment resistant” and needed electroshock therapy.  “The risks were downplayed.” He was given 30 rounds of ECT and went from a high school honor student to having to be retaught how to tie his shoes. Wait, there’s more!

Kenny lost all memories of childhood and all memories of high school. He says it’s an identity crisis. He suffered severe headaches for a year and a half after the shocks and had to see a cardiologist because ECT left him with heart arrhythmia. Testing by a neurologist, done six months after the shocks, showed a loss of 50 IQ points compared to his high school IQ. Kenny still suffers from night terrors about the shocks.

Dr. Langemann’s article on “Shock Therapy” for the Huffington Post also referred to a biomedical engineer who said the “brief pulse” of ECT is actually a series of several hundred pulses, and not a single pulse. These pulses overstimulate brain cells, causing rapid random firing, intentionally causing a Grand Mal seizure. “The current causes overheating inside the brain and the electric field can tear holes in the cells (which causes the cells to die).” She noted that a conservative estimate is that 100,000 patients per year receive ECT.

Incredibly, ECT has never been through the standard clinical trial process to prove its safety or efficacy. Although the FDA has had the authority to regulate medical devices since 1976, it disregarded ECT machines because they’ve been in widespread use since the 1950s, according to STAT News in “Psychiatric Shock Therapy.” The FDA placed ECT machines in the class III (high risk) category where they have remained since that time. But in December of 2015, the FDA made public a draft document proposing to reclassify ECT machines as a class II (low risk) device. Before the public comment period ended in late March of 2016, the FDA had received 2,040 comments on its draft rule. The agency has not set a timetable for issuing its final ruling.

While the proposed regulations would indicate that ECT was “safe and effective” and only moderately risky for adults, it would only be approved for adults with severe depression who haven’t responded to medication or other therapies. It would remain classified as a high risk  (class III) for psychiatric conditions other than major depression and for children and adolescents. There would be new requirements as well. Doctors would have to warn patients of the side effects of ECT, which include confusion and memory loss; and that long-term safety for ECT is not proven.

Psychiatrists warn that that these new regulations could lead to insurers not covering ECT and doctors not recommending it for younger patients and those with conditions like schizophrenia, bipolar disorder and catatonia. (They say it like that’s a bad thing) Charles Kellner, a professor of psychiatry at the Icahn School of Medicine said, “Its use for these indications is widespread, even ubiquitous, and to deny the extensive evidence in support of that is indefensible.” Supporters say ECT has come a long way since it was portrayed in “One Flew Over the Cuckoo’s Nest.” Patients get anesthesia and sedatives to minimize pain and muscle spasms, so they are less likely to hurt themselves during the ECT seizure. “Ultra-brief pulse therapy delivers a fraction of the electricity used in the past.” However, as noted above, this claim is disputed. See “The Frankenstein Monster of ECT” and “Is ECT Brain Disabling?” on this website.

Writing for GlobalResearch, Dr. Gary Kohls described ECT “therapy” sessions as: “sub-lethal electrocutions of the brain that reliably produces seizures and coma.” He noted that the perceived improvement with ECT is often because of the frequent short-term and long-term memory loss that occurs with shock treatment. “The patient may no longer remember the traumatizing interpersonal/sexual/social/ psychological/spiritual conflicts that previously made them feel sad, nervous, depressed, anxious or hopeless.” He lamented that studies show physicians reach for their prescription pad within minutes of most clinic encounters. “Time is money.”

Dr. Kohls then quoted excerpts from the testimony of Leonard Roy Frank before the Mental Health Committee of the New York State Assembly in 2001. Mr. Frank was a psychiatric survivor and activist who personally experienced 35 ECT procedures and 50 insulin coma treatments. The transcript of his testimony can be read here in its entirety. He said:

This was the most painful and humiliating experience of my life. My memory for the three preceding years was gone. The wipeout in my mind was like a path cut across a heavily chalked blackboard with a wet eraser. Afterwards I didn’t know that John F. Kennedy was president although he had been elected three years earlier. There were also big chunks of memory loss for events and periods spanning my entire life; my high school and college education was effectively destroyed. I felt that every part of me was less than what it had been.

Frank then elaborated on some of the adverse effects from ECT. With regard to memory loss, he indicated that the APA downplays memory loss, saying most patients actually report improved memory; and only a minority of patients report problems with memory loss. He said the vast majority of individuals he has talked to reported moderate-to-severe amnesia going back two years and more from the time they received ECT.  His own experience was noted above.

Quoting the 2001 APA Task Report on ECT, Frank noted where a reasonable ECT-related mortality rate was suggested to be 1 per 10,000 patients. However, some studies show the ECT death rate is about one in 200. This rate may not still be accurate, as an increasing number of the elderly are being electro shocked. “Statistics based on California’s mandated ECT reporting system indicate that upwards of 50 percent of all ECT patients are 60 years of age and older.”

Frank described what he referred to as “the myth of informed consent.” While outright force is seldom used, “genuine informed consent is never obtained” because ECT specialists minimize the procedure’s nature and effects to candidates and their families; and because of the implicit coercion that can be brought to play. There is a lack of accountability with psychiatry. It was a “Teflon” profession, meaning what little criticism there is doesn’t stick. “Psychiatrists routinely carry out brutal acts of inhumanity and no one calls them on it — not the courts, not the government, not the people.”

Electroshock could never have become a major psychiatric procedure without the active collusion and silent acquiescence of tens of thousands of psychiatrists. Many of them know better; all of them should know better. The active and passive cooperation of the media has also played an essential role in expanding the use of electroshock. Amidst a barrage of propaganda from the psychiatric profession, the media passes on the claims of ECT proponents almost without challenge. The occasional critical articles are one-shot affairs, with no follow-up, which the public quickly forgets. With so much controversy surrounding this procedure, one would think that some investigative reporters would key on to the story. But it’s happened only rarely up to now. And the silence continues to drown out the voices of those who need to be heard. I’m reminded of Martin Luther King’s 1963 “Letter from Birmingham City Jail,” in which he wrote: “We shall have to repent in this generation not merely for the vitriolic words and actions of the bad people, but for the appalling silence of the good people.”

Psychiatrist Peter Breggin has advocated against ECT for decades. You can watch an 11-minute video he did called, “Electroshock is Brain Trauma.” He indicated the 100,000 per year estimate for ECT was based on data he gathered in 1979 for his book critical of shock treatment. He said today every large city has several places that do shock treatment. “It’s extremely remunerative.”

Dr. Lagemann indicated that standard treatment is 9 to 12 shocks, at a cost of $2,000 to $2,500 each. When you do the math, you come up with a minimum income of $1.8 billion (9 x 100,000 x $2,000 = $1.8 billion). About half the cost is covered by Medicare. Mr. Frank indicated that in 2001, psychiatrists specializing in shock treatment earned $300,000-$500,000 a year compared to other psychiatrists whose mean annual income was $150,000.

What’s wrong with shock treatment? How does it work? It’s not as mysterious as the advocates make out. Shock works by passing an electric current through one or both frontal lobes of the brain, producing an electrical lobotomy.  The electricity also passes through the memory centers of the temporal lobe, causing additional devastation. Finally, the current passes throughout the brain and that, along with the severe seizures that result, causes widespread brain dysfunction and damage. Some patients initially become euphoric from the damage, whereupon the shock doctor notes approvingly, “mood elevated.” All patients eventually become apathetic and indifferent, and unable to resist, whereupon the doctor notes with finality about the outcome, “no longer complaining.”

Dr. Breggin said the only reason that modern shock doctors don’t talk about ECT as damaging the brain is because he publicized and documented how it was in his book, Electroshock: Its Brain-Disabling Effects. He noted that when ECT treatment is done, it results in a period of coma. “How could a blow to the brain with electricity so severe it causes a coma, and you’re not harmed by it?” Very often the EEG brain waves flat line—that’s temporary brain death. The person wakes up completely disoriented. The longer the treatment continues, the more past memory the person loses.

The STAT News article noted where a woman who had 66 ECT treatments between 1996 and 2010 to treat depression left such holes in her memory that she couldn’t recall her wedding day or the birth of her children. Her 28-year marriage ended, ““because I couldn’t remember that relationship, and without those memories, I had no emotional connection.”

Dr. Breggin created a free website about shock treatment: ECT Resources Center.  Among its documents is a simple introductory statement and brochure for widespread distribution. There are also PDFs of more than 100 scientific articles on issues with ECT. He urged people to do everything they can to stop someone they know getting ECT, because they will never be the same afterward.

As of September 1st, there has not been an announcement of what the FDA plans to do with ECT. But when the FDA announced it was soliciting comments of the proposed regulatory changes, the American Psychiatric Association created a form letter for psychiatrists to “take the lead in expressing their views” regarding the role of ECT in clinical practice and treating major depressive disorder. See “Time is Now to Support the ECT Reclassification Effort.” The letter asserted that ECT was an important treatment option for some people with severe mental health conditions. “Your proposed reclassification will greatly improve access to safe, effective treatment for individuals with serious and persistent psychiatric disorders.” You can download and read a copy of the form letter in the above link. I wonder how many of the 2,040 comments were APA form letters from psychiatrists?

06/7/16

Buyer Beware Drugs

© Yurly Kirsanov | 123rf.com

© Yurly Kirsanov | 123rf.com

At the end of March in 2016, detectives with the Onondaga County Sheriff’s Office executed a search warrant at a split level home in quiet suburban neighborhood about 8 miles north of Syracuse, New York. They discovered a fentanyl processing operation where six people were mixing and packaging fentanyl for street-level sales. Detectives found an estimated 5,866 doses of fentanyl, 2 ounces of A-PVP (flakka), a loaded 12-gauge shotgun, a replica sub machine gun, drug paraphernalia and $3,571. The total street value of the drugs was $60,000.

The individuals arrested were considerate enough to warn the arresting officers not to touch the fentanyl without gloves. The drug is potent enough to be absorbed through the skin if you touch it without gloves. I guess they were concerned about a possible felony murder charge on top of the drug charges. Although the source of the drug was not known at the time of the drug bust, it typically comes from international sources in Mexico and increasingly from China.

A similar arrest took place near Los Angeles, where four men were operating a pill lab in Baldwin Park. Police found several pill presses and large quantities of variously colored powders, among them acetyl-fentanyl and methamphetamine. DEA Agent David Dowling said: “Fentanyl and its analogues pose a serious public health risk. Even small doses absorbed through the skin or accidentally inhaled can be fatal.” They were getting their drug supply from China. The Southern California lab was just one of four by law enforcement in the U.S. and Canada in March of 2016.

David Armstrong reported for STAT News on both of the above incidents as well as a lab in a custom car business in British Columbia that was shipping 100,000 fentanyl pills monthly to nearby Calgary, Alberta. Police reported that the equipment used to press the pills had come from China. Recently a quarter-ton pill press was intercepted before it was transported to a suburban Los Angeles drug lab. It had been labeled as a “Hole Puncher.”

In an affidavit, DEA agent Lindsey Bellomy said that based on wire transfers and other evidence, she “strongly believes” the Southern California group acquired its fentanyl from China. The affidavit lists a dozen deliveries from China to members of the group in January and February.

The China connection is allowing local drug dealers in North America to mass produce fentanyl in pill form, in some cases producing tablets that look identical to an oft-abused version of the prescription painkiller OxyContin. It also has been added to Xanax pills.

The emergence of decentralized drug labs, using materials obtained from China, makes it difficult to police fentanyl sold as a street drug. A report from the Department of State’s Bureau for International Narcotics and Law Enforcement Affairs indicated China is still a major producer and exporter of fentanyl and other drugs for illicit international markets. Lax regulation, low production costs, and government corruption, mixed in with the country’s large chemical and pharmaceutical industries, makes China a perfect supply source for the materials needed for the illicit drug labs.

Fentanyl pills masquerading as hydrocodone were recently blamed for a wave of overdoses and 11 deaths in the Sacramento California area. The Sacramento Bee reported on April 13, 2016 there had been 51 fentanyl-linked overdoses since late Mach of 2016. By April 27th, the death toll was up to 14. The pills were exact replicas of a medium-strength opioid painkiller, Norco. The CDC discussed this outbreak in detail in one of their Morbidity and Mortality Weekly Reports (MMWR).

Analysis of the fake Norco pulls showed they contained fentanyl, promethazine, acetaminophen and trace amounts of cocaine. Normally used to treat nausea vomiting and motion sickness, promethazine is used here to boost the high of the opioid. Reporting for the Digital Journal, Karn Graham said the pills were exact replicas for the real ones. It was only pure luck that health officials were able to get one of the fake pills from an overdose patient in order to analyze its ingredients.  Keri Blakinger, writing for The Fix, said in Canada, British Columbia has declared a public health emergency from the increase of fentanyl overdose deaths in the province.

Lookalike oxycodone pills containing fentanyl have also appeared in Tennessee and Ohio. In testimony before the Committee on Homeland Security and Government Affairs in the U.S. Senate, Carole Rendon, the Acting U.S. Attorney for Northeastern Ohio said the overdose deaths from heroin and fentanyl had risen until they began to see an average of two overdose deaths per day in March of 2016.  She said: “Opioid addiction knows no boundaries. It is an equal opportunity killer of old and young, men and women, urban, suburban, and rural, rich and poor, black, white, and Hispanic. We are all at risk.”

In February, Tennessee officials warned about the availability of counterfeit drugs, specifically pills being sold as Percocet that actually contained fentanyl. David Reagan, the Chief Medical Officer of the Tennessee Department of Health said: “When people sell fake pills appearing to be oxycodone but actually containing the more powerful pain medicine fentanyl, lives are at risk.” During a traffic stop in May of 2015 a police officer discovered several 30 mg pills of what appeared to be oxycodone, with its signature A/215 stamp characteristic. Lab analysis showed they were fentanyl. In January of 2016, 300 pills stamped with the characteristic markings for Percocet were found to be fentanyl.

Even worse, counterfeit Xanax pills that contain fentanyl are appearing. In October of 2015 at least three people died from ingesting the combination drug in San Franciso. Saint Petersburg Florida reported that nine people died in Pinellas County from what was being sold as Xanax on the street. The pills were actually a combination of fentanyl and Xanax. The Daily Mail said the combination is sold as “Super Pill” on the street for as little as $5 a pill.

Last, and probably worst, there is another synthetic opioid coming onto the illicit drug market, W-18. It is 100 times more powerful than fentanyl; 10,000 times more powerful than morphine. And again, the likely source for the drug is China. Alan Hudson, an associate professor with the department of pharmacology at the University of Alberta, said W-18 is one of the most dangerous drugs in the whole spectrum of analogs. A tiny speck can cause respiratory failure and kill you.

Global News reported that the drug comes from a “W-series” of opioid compounds first discovered at the University of Alberta in Canada in 1982. Of the 32 compounds, W-1 to W-32, W-18 was the most toxic. As little as four kilograms of the drug is enough to produce millions of tablets. An Edmonton-area drug bust in December 2015 netted four kilograms of W-18.

Because of its potency, W-18 exponentially raises the stakes for potential overdoses. “It’s just too potent to even consider using.”  It was never listed as a controlled substance; never tested on humans. So it is technically legal and for sale online—typically from China. “Obviously somebody in China has picked up on the fact that W-18 is quite easy to make in large quantities and they’re trying to sell it to the North American market.”

If you are having trouble understanding why the practices above persist, think about basic branding, marketing and salesmanship. Established brands in the drug market include “heroin” and various pills like: “OxyContin”, “Percocet”, “Xanax”, and even “MDMA.” A significant segment of the drug market has a negative view of heroin, so they prefer to use pharmaceutical versions of opiates/opioids. So they seek out “OxyContin”, “Percocet”, and others. There is also a higher production cost for pills due to their stricter regulation. Pharmaceuticals are legally produced; heroin is not.

Over the past 100 years or so, the government has developed a regulatory process to give consumers some assurance that when they buy pharmaceuticals, they are getting what they paid for. Even with all the problems in the existing regulatory procedures, the modern pharmaceutical consumer is better protected today than they were during the time of patent medicines. THERE IS NO REGULATORY PROCESS FOR ILLICITLY PRODUCED DRUGS.

So if drug dealers and manufacturers want to increase their profits, they produce knockoffs of the more popular drug brands (like Percocet or heroin) by substituting cheaper products for the known brands. Since there is no regulatory process, they can and do sell knockoffs to their customers as the real thing with relative impunity. Illicit drugs today are truly a “buyer beware” market. The consumer/user is risking their health and their life as they seek out the newest, best high.