05/28/19

The ADHD Fairy

In case you didn’t know, there is a risk of psychosis when using ADHD stimulant medications, such as amphetamine (Adderall, Vyvanse) and methylphenidate (Ritalin, Concerta). A study published recently in The New England Medical Journal indicated the risk was low, with about 1 in 660 patients who used prescription stimulants diagnosed with new-onset psychosis. The lead author of the study, Dr. Lauren Moran, said the risk was low enough that she could not recommend not prescribing Adderall. “But from a public health perspective, there’s so many millions of people being prescribed these medications that it actually leads to thousands of people at increased risk of psychosis.” Using data from the CDC on ADHD, that meant in 2016 about 5,730 children between the ages of 2 and 17 who were taking ADHD stimulants would be diagnosed with new-onset psychosis.

Medscape reported Dr. Moran said the takeaway point was “that it’s really important to screen for potential risk factors.” These risk factors could include a history of bipolar or other psychiatric disorder, a family history of psychiatric illness, or use of cannabis (See: “Gambling with Cannabis and Psychosis”). “If patients have those risk factors, I would shy away from using the amphetamines. You don’t want to have two things that could potentially further increase the risk for psychosis.”

Moran noted that there are many college students in the area around McLean Hospital and that in her anecdotal experience as a psychiatrist working in a unit that treats patients with psychotic disorders, she’s “been seeing cases of young individuals coming in with psychosis” after stimulant use.

Moran said at the beginning of their study, a patient had a 50-50 chance of getting Adderall or Ritalin. But there has been a dramatic increase in Adderall prescriptions, to almost four times as many prescriptions for Adderall. In her experience, ADHD patients hospitalized for psychosis recovered in two weeks; some took as long as two months. But Moran is not suggesting ADHD medications are too dangerous to prescribe. Rather, she’s trying to raise awareness. “Physicians need to be aware of this when prescribing and people who are getting these medications from friends in college need to know this is a risk.”

Speaking to STAT News, Dr. Anthony Rostain said he did not think the results of the Moran et al. study was shocking. The package insert already warns of a small risk of psychosis with ADHD stimulant medication. “It will just simply be important to mention to people that the amphetamine-based compounds have a slightly higher risk… I think the take-home here should be that everyone should be informed when they are starting a medicine about risks like psychosis.” One of the risk factors he gave for psychosis was abusing the drugs—crushing and snorting them. So the implication is that the individuals at risk are those who abuse this medication, which is admittedly an issue on college campuses.

But is that the real problem, namely that the people at risk are those who are abusing ADHD stimulants? First let’s consider the industry ties of the two doctors cited here. Rostain has been a consultant to Arbor Pharmaceuticals, an amphetamine maker, and to Shire, which sells Vyvanse and developed Adderall; Dr. Moran reported only receiving a grant from the NIMH to investigate the risk of psychosis with prescription stimulants. Is Rostain contributing to some misdirection of the issue because of his industry ties?

Did you know that so-called “challenge studies,” where amphetamine and methylphenidate were used to instigate symptoms of psychosis, were done in the name of science? Robert Whitaker co-wrote a series of articles that described how beginning in 1972, psychiatric researchers used amphetamine, methylphenidate and ketamine “to deliberately provoke psychotic symptoms in more than 1,200 schizophrenic patients.” In some cases, the level of psychosis experienced by these patients was called “severe.” Some of these experiments were conducted by prominent researchers at the National Institute of Mental Health. David Janowsky’s work established the idea that psychosis-inducing drugs “could be used as ‘challenge agents’ to turn patients into models for studying psychotic illnesses.”

Symptom-exacerbation experiments were pioneered by Dr. David Janowsky of Vanderbilt University. In 1974, he reported success in developing a new tool for studying schizophrenia. He found that giving schizophrenic patients methylphenidate (Ritalin) caused ”a dramatic intensification of preexisting symptoms, such as hallucinations and delusions,” and that amphetamine also exacerbated their psychosis. Both drugs are known to release dopamine, a messenger chemical in the brain, and Janowsky’s experiments provided indirect evidence that the biological mechanism of psychosis involved an overactive dopamine system.

Dr. Jeffrey Lieberman, currently the department chair of psychiatry at Columbia, did several challenge studies with methylphenidate. In a 1987 study, 34 stable outpatients receiving antipsychotics were given methylphenidate and then withdrawn from their antipsychotics. Three weeks later, they were given another infusion of methylphenidate. They were then followed up for 52 weeks or until they relapsed—in other words until their symptoms returned.

In a 1990 study, 38 patients who met the criteria for schizophrenia or schizoaffective disorder were given methylphenidate. These were patients experiencing their first acute psychosis. The methylphenidate produced an increased psychopathology seen in the worsening of their symptoms. And in a 1987 article, Lieberman and his coauthors commented that methylphenidate appeared to have a greater “psychotogenic potency” than amphetamine. They hypothesized there was a subgroup of schizophrenic patients who exhibited psychotic activation with psychostimulants. “This biologic phenomenon may be clinically exploitable and should be investigated further.” Also see “Psychiatry, Diagnose Thyself! Part 2” for more information on challenge studies.

MacKenzie et al. found an association between the use of stimulant medication and psychotic symptoms in children and adolescents at risk of mental illness. Psychotic symptoms were found in 62.5% of the participants who had taken stimulants versus 27.4% of participants who had not taken stimulants. All participants who had used stimulants and experienced psychotic symptoms were sons or daughters of a parent with either a major depressive disorder or bipolar disorder. “The association of current use of stimulants with current psychotic symptoms and the close temporal relationship between stimulant use and psychotic symptoms in youth who started and stopped stimulants indicated a potential causal relationship.” See “Tip of the ADHD Iceberg” for more information.

ADHD stimulants are addictive. Ritalin and Adderall are Schedule II controlled substances, meaning they are considered to have a high potential for abuse, with their use “potentially leading to severe psychological or physical dependence.” Methamphetamine adverse effects can include convulsions, memory loss, severe dental problems and even death. “Cocaine and potent stimulant pharmaceuticals, such as amphetamines and methylphenidate, produce similar effects.” The effects of amphetamines are similar to cocaine but occur slower and last longer.

Chronic abuse produces a psychosis that resembles schizophrenia and is characterized by paranoia, picking at the skin, preoccupation with one’s own thoughts, and auditory and visual hallucinations. Violent and erratic behavior is frequently seen among chronic users of amphetamines and methamphetamine.

A 2015 study by Clemow and Walker reviewed the literature on ADHD medication misuse. The authors found that elevations in brain dopamine levels seemed to be necessary to both their efficacy in ADHD and in their potential for abuse. The data suggested ADHD medication misuse was a common health care problem for stimulant medications, “with the prevalence believed to be approximately 5% to 10% of high school students and 5% to 35% of college students, depending on the study.” Conversely, nonstimulant ADHD medications did not suggest a potential for abuse. “In light of these findings, the data suggest a need for close screening and therapeutic monitoring of ADHD medication us.”

And if that is not enough to raise concerns with the use of amphetamine and methylphenidate to treat ADHD, there is evidence that challenges their long-term effectiveness. The National Institute of Mental Health (NIMH) funded a nationwide, long-term study of the effectiveness of stimulants in treating ADHD by many of the long-time advocates of stimulant medication. In 2007 the authors finally published their evaluation of long-term effectiveness. The Jensen et al. study concluded: “By 36 months, the earlier advantage of having had 14 months of the medication algorithm was no longer apparent.” The Swanson et al. study said: “All five propensity subgroups showed initial advantage of medication that disappeared by the 36-month assessment.”

So where does this leave us with regard to ADHD? Is it even a valid diagnosis? In Debunking ADHD, Michael Corrigan said ADHD diagnosis in its current form is a diagnosis of normal, using eighteen very generic, commonly observed childhood behaviors to justify giving the medications. “Coincidentally or conveniently, ordained by the all-knowing creators of ADHD as proof of ADHD’s existence, these eighteen childish behaviors … seem to drive parents and educators crazy.” ADHD is a negative label that some want you to believe is real. Like the stories of about unicorns, fairies and leprechauns, “the diagnosis of ADHD is a brilliant work of fiction.” In Our Post Human Future, Francis Fukuyama also suggested ADHD wasn’t a disease, but rather, “just the tail end of the bell curve describing the distribution of perfectly normal behavior.”

Young human beings, and particularly young boys, were not designed by evolution to sit around a desk for hours at a time paying attention to a teacher, but rather to run and play and do other physically active things. The fact that we increasingly demand that they sit still in classrooms, or that parents and teachers have less time to spend with them on interesting tasks, is what creates the impression that there is a growing disease.

For more information on ADHD, see: “ADHD: An Imbalance of Fire over Water or a Case of the Fidgets?”

03/26/19

Runaway Pharma Gravy Train

The Pharmaceutical Research and Manufacturers of America (PhRMA) spent $27.5 million on lobbying in Washington last year. This was a new record, surpassing the previous high set in 2009, when PhRMA spent over $27 million. “The new record also topped 2017’s lobbying spend—$25.43 million, at a time when Trump was taking office and pricing was often on the airwaves—by about 8%.” The increases parallel steadily increasing prices for several years. For example, Medicaid drug costs nearly doubled to $31 billion.

Rep. Elijah Cummings initiated an investigation of 12 pharmaceutical companies in an effort to uncover pharma pricing practices. Cummings sent letters seeking information and documents about the companies’ pricing practices. This is the first step of the Committee on Oversight and Reform’s review of pricing practices. The Committee will also hold hearings in order to hear from experts and patients affected by rising drug prices.

The Centers for Medicare and Medicaid Services projects that spending on prescription drugs will increase more rapidly than spending on any other health care sector over the next ten years. The federal government bears much of the financial burden of escalating drug prices through Medicare Part D, which provides drug coverage to approximately 43 million people. The government is projected to spend $99 billion on Medicare Part D in 2019. In 2016, the 20 most expensive drugs to Medicare Part D accounted for roughly $37.7 billion in spending.

The hearing was held on Tuesday, January 29, 2019, just two weeks after Rep. Cummings sent out his letters. There also seems to be bipartisan support to rein in drug prices. FiercePharma wondered whether this was real bipartisan unity or just talk. Rep. Mark Meadows, A Republican from North Carolina, said President Trump asked him to make sure the House knew on this issue, “He’s serious about working in a bipartisan way to lower prescription drug prices.” At the hearing Cummings acknowledged Trumps support, but said: “But tweets are not enough—we need real action and meaningful reforms.”

STAT News reported that Cummings is asking for “10 years worth of sales, revenue, pricing, rebate, discount, and commercialization data.” Additionally he’s asked for information detailing research and development expenses; information on patents and indications; employee compensation and bonus details; each company’s interaction with federal agencies; and details of company’s contracts with PBMs (pharmacy benefit mangers). Although his probe already includes most of the country’s largest pharmaceutical companies, he’s not finished. “There’ll be more.” Other congressional committees, such as Energy and Commerce and the Senate Finance Committee, are planning to do their own investigations.

The ten most expensive brand-name drugs accounted for $15.6 billion of spending in the catastrophic coverage phase of the Medicare Part D benefit in 2015. While the number of prescriptions fell by 17%, the Part D payments for brand-name drugs increased by 62% from 2011 to 2015. The payments for about 94% of commonly used medications more than doubled. The percentage of Medicare Part D beneficiaries who paid at least $2,000 out-of-pocket for their drugs almost doubled from 2011 to 2015. Cummings is focusing his inquiries on drugs that are among the costliest to Medicare Part D. If you’re curious, there is a link in the article to a list of the companies and drugs for conditions ranging from arthritis, cancer and cholesterol to diabetes.

An NPR and Center for Public Integrity investigation found drug companies have penetrated almost all aspects of the process that determines how their drugs are covered by taxpayers. Doctors on obscure committees advising state Medicaid programs receive free dinners and consulting contracts with the pharmaceutical companies. Speakers who don’t disclose their financial ties to the pharmaceutical companies are asked to testify about the companies’ drugs. State Medicaid officials are invited to attend all-inclusive conferences for free where they mingle with drug representatives.

Beyond that, drugmakers use other tactics to get their products paid for by the Medicaid programs: lobbying state lawmakers to achieve their goals or helping doctors fill out extra paperwork to get Medicaid to pay for the costlier drugs as Warner Chilcott did. The result is that Medicaid sometimes spends more than necessary and may pay for medicines inappropriate for patients.

The drug companies say they are not responsible for the problems. A spokesperson for PhRMA said: “As an industry, our priority is ensuring that patients have access to the medicines they need . . . . States should consider changes to Medicaid that are in line with the intended goal of ensuring robust access to medically necessary drugs.” Pharmaceutical companies have strong incentives to be included on states’ lists of approved drugs. Doctors are far more likely to prescribe an approved drug to Medicaid patients and may encourage other insurers to do the same. To gain a spot on the coveted lists, drug makers offer the states “supplemental rebates,” which are on top of other price concessions required by federal law. “The drug committee meetings where those list decisions are made are a frequent destination for drug company representatives — and those who benefit from their largesse.”

Across the country, drugmaker representatives and pharma-friendly clinicians with industry ties swarm these low-profile drug committees, a review of meeting minutes shows. Center for Public Integrity and NPR reporters saw similar dynamics play out this spring in meetings in Arizona, Washington, D.C., and Louisiana. The committees, usually known as pharmacy and therapeutics committees or drug utilization review boards, are typically made up of volunteer pharmacists and doctors.

Critics of the practice say when pharma companies target these committees, the states don’t get good deals. They also can make bad decisions for their patients. Three out of five doctors voting on state Medicaid decisions received perks from pharmaceutical companies. There are at least 38 states with doctors serving on their Medicaid drug committees who collected more than $1,000 from pharmaceutical companies while they served on the committees. Consider that while this amount may point to how money influences Medicaid decisions, a study in JAMA Internal Medicine, “Pharmaceutical Industry-Sponsored Meals and Physician Prescribing Patterns for Medicare Beneficiaries” found that when doctors get as little as a $20 lunch, they are more likely to prescribe the company’s drugs.

As compared with the receipt of no industry-sponsored meals, we found that receipt of a single industry-sponsored meal, with a mean value of less than $20, was associated with prescription of the promoted brand-name drug at significantly higher rates to Medicare beneficiaries. The differences persisted after controlling for prescribing volume and potential confounders such as physician specialty, practice setting, and demographic characteristics. Furthermore, the relationship was dose dependent, with additional meals and costlier meals associated with greater increases in prescribing of the promoted drug.

The NPR article told of a nonprofit organization, the American Drug Utilization Review Society (ADURS), whose mission is to provide a forum of leadership and support for its members. It hosted a free conference for Arizona state Medicaid officials in Scottsdale, where Michael Magnotti, an endocrinologist, gave a talk on diabetes. He was paid $1,545 for the talk by Sanofi-Aventis; and he received more than $108,000 in consulting fees from pharmaceutical companies for that year. Sanofi S.A. is the world’s fifth-largest multinational pharmaceutical company. And it was one of the companies to receive a letter from Rep. Cummings.

A more disturbing ADURS conference took place in 2003 when Purdue Pharma helped to fund it. A speaker told his audience that addiction from the medical use of opioids was rare, and he then described a phenomenon called “pseudoaddiction.” A slideshow of the presentation (linked in the STAT article) said pseudoaddiction included “appropriate drug seeking behavior” such as demanding doses before they are scheduled. In support of his claims, he referenced a letter published in the New England Medical Journal back in 1980: “Addiction Rare in Patients Treated with Narcotics.”

This article has been repeatedly misused by pharmaceutical companies (like Purdue) as they assert that the risk of addiction from the medical use of opioids is almost nil. The potential influence of pharmaceutical companies like Purdue on opioid prescribing and the opioid epidemic has received significant attention in the media. Currently 24 states and Puerto Rico have sued Purdue for downplaying or concealing the risks of its painkillers. See the book by Barry Meier, Pain Killer for more on this issue. Also see “Doublespeak in the Opioid Crisis,” Part 1 and Part 2 for more about the misuse of the 1980 article. See “Giving an Opioid Devil Its Due” for more on Purdue Pharma. This concern is now being looked at in the research literature.

A new study released on January 18, 2019 in JAMA Network Open suggested there may be a link between aggressive marketing, drug company money and overdose death rates. The researchers found that counties receiving pharmaceutical marketing of opioids to physicians subsequently experienced increased mortality rates. Commenting on the study, Science Alert said while the study did not demonstrate a cause-and-effect relationship, it did suggest that frequent trust-building visits, like lunches sponsored by drug sales reps, did more to promote prescribing the company’s drugs than high-dollar payments to physicians. One of the researchers said: “What seems to matter most wasn’t the amount of money doctors were paid, it was the number of times they were paid.”

Our findings suggest that direct-to-physician opioid marketing may counter current national efforts to reduce the number of opioids prescribedand that policymakers might consider limits on these activities as part of a robust, evidence-based response to the opioid overdose epidemic in the United States.

While Pharma’s spending on lobbying and advertising to doctors (and consumers) continues to rise, so do the negative consequences. Pharma knows marketing has a tremendous potential to grow its profits. So spending on lobbying has increased alongside that of marketing to doctors and consumers. The public pays a price by permitting these activities to continue unhindered. Unchecked greed seems to have helped facilitate the opioid crisis. Hopefully the efforts of legislators like Elijah Cummings will make it out of their respective committees and into law. We need to stop the runaway Pharma gravy train.

01/23/18

Opioid Epidemic Price Gouging

The FDA recently approved Sublocade, the first once-monthly buprenorphine injection in its fight against the opioid epidemic. Indivior, the company which also sells Suboxone film, projected it would be available on the market sometime in the first quarter of 2018. Sublocade is a drug-device combination product. “It is injected by a healthcare professional (HCP) under the skin as a solution, and the delivery system form a solid deposit, or depot, containing buprenorphine.” The initial procedure will to be to start with daily stabilizing doses of Suboxone for at least seven days before the first injection of Sublocade.

After initial formation of the depot, buprenorphine is released by the breakdown (biodegradation) of the depot. In clinical trials, Sublocade provided sustained therapeutic plasma levels of buprenorphine over the one-month dosing interval.

Prescribing information for Sublocade said the recommended protocol was two monthly doses of 300 mg followed by 100 mg monthly maintenance doses. “Increasing the maintenance dose to 300 mg monthly may be considered for patients for whom the benefits outweigh the risks.” Sublocade will come in prefilled syringes of 100 mg and 300 mg. It will carry a boxed warning of the risk of serious harm or death if used intravenously.

The Indivior announcement of Sublocade’s approval indicated Sublocade will be distributed through a restricted distribution system, “which is intended to prevent the direct distribution to a patient.” This restricted release to only healthcare professionals is because of the risk of serious harm or death if someone were to attempt intravenous self-administration of Sublocade. Intriguingly, the boxed warning in the prescribing information wasn’t as clear on the intent of the restricted distribution system to prevent patients from having direct access to Sublocade. The harder it is to get a hold of Sublocade, the harder it will be to figure out a way to hack into the buprenorphine it contains.

The FDA is requiring postmarketing studies to assess four things. First, whether patients would benefit from a higher dose. Second, whether Sublocade can be safely started without a dose stabilization period of Suboxone. Third, to assess the feasibility of administering Sublocade at a longer inter-dose interval than once-monthly. Fourth, to determine a process for transitioning patients stabilized long term on Suboxone film to a monthly dose of Sublocade without the loaded dose in the first two months of treatment.

I assume the study to see if patients would benefit from a higher dose fits into the above prescribing information that maintenance doses could be increased up to 300 mg monthly. But I have this nagging question of whether Indivior felt unsure about the safety risk of maintenance doses above 100 mg. So they wanted to be safe rather than sorry, knowing there was always Suboxone film to supplement Sublocade in a pinch. And postmarketing studies could look at whether higher maintenance doses put people at risk in some way.

The procedure of having an initial “dose stabilization” period on Suboxone before injecting Sublocade helps ensure the individual has really stopped using opioids before their injection. The required postmarketing study will help evaluate whether that’s necessary. My initial thoughts are that given the significant amount of buprenorphine in the depot, clinically the dose stabilization period should remain, especially if this is done when the person is an outpatient. If the person’s pattern of use isn’t stable enough to reach a week of daily Suboxone use, they should probably try inpatient drug treatment to stabilize first before Sublocade.

Depots containing either 100 mg or 300 mg have a significant amount of buprenorphine. So I’m concerned about thoughts of assessing the feasibility of administering Sublocade at longer inter-dose intervals, which would require even higher doses. I guess the thinking behind the longer inter-dose interval study is anticipating of having/keeping Sublocade patients on the treatment for an indeterminate length of time, perhaps years.

Except for the supposed convenience of a once-monthly shot, why would someone who is stable on Suboxone film long term want to switch to Sublocade? If you have demonstrated the discipline, stability and willingness to successfully maintain opioid abstinence with Suboxone, why switch to Sublocade? I do know why Indivior would want you to switch. The average monthly cost for Suboxone is $132, while the average monthly cost for Sublocade is $1,580. The cost for Sublocade puts it in the ballpark for Vivitrol, which costs around $1,687 per month.

STAT News quoted one addiction professional who said: “It’s potentially a game changer. . . . This could become first-line [medication] for opioid addiction.” But Sublocade is just the first injectable buprenorphine product to be approved. A similar medication, known as CAM 2038, is made by Braeburn Pharmaceuticals and it could be get FDA approval by January 19, 2018. The president and CEO of Braeburn said: “This new technology has the potential to greatly influence the way patients are treated today. . . [It can] free patients from the daily decision and reminder of the disease.” Did this guy ignore or just forget about the Warnings and Precautions on the Sublocade medication guide?

It says: “Buprenorphine can be abused in a manner similar to other opioids; Warn patients of the potential danger of self-administration of benzodiazepines or other CNS depressants while under treatment with Sublocade.” Pain treatment should be with a non-opioid analgesic whenever possible. “If opioid therapy is required, monitor patients closely because higher doses may be required for analgesic effect.” Sublocade won’t free patients of the daily reminder of the disease, because it is the daily reminder.

STAT said long-acting buprenorphine could make future inroads within the criminal justice system. “In recent years judges, wardens, and health officials have warmed up to Vivitrol, citing fears that daily tablets of buprenorphine can be diverted or abused.” Additionally, the criminal justice system has been more receptive to Vivitrol because Alkermes has been doing targeted marketing with them to promote Vivitrol for a number of years. However, the approval of Sublocade adds a second monthly injectable alongside Vivitrol and potentially could diminish “one of the biggest competitive advantages held by Vivitrol.”

STAT also pointed to another likely financial incentive for Invidior to put Sublocade into the market. Medicaid spending on buprenorphine last year was five times higher than for Vivtrol. But those spending statistics could be partly due to the cost discrepancy between monthly Vivitrol and Suboxone and not the preference for buprenorphine. However, it is likely Invidior will be able to slice off a nice chunk of non-negotiated drug price income for Sublocade from Medicaid.

Another STAT article discussed a study published in The Lancet, Lee et al., that found both Vivitrol and Suboxone had comparable effectiveness outcomes during 24 weeks of outpatient treatment. STAT quoted Dr. Nora Volkow, director of NIDA as saying she hoped the study will change the widespread prejudice patients don’t do as well on naltrexone as they do on buprenorphine. Apparently it didn’t. In the very same STAT article, two different doctors, not involved in the study, said the study showed buprenorphine was more effective than Vivitrol. However, the lead author of the study, Dr. Joshua Lee told STAT: “Both medications worked quite similarly and, therefore, both should be discussed as treatment options.”

The study findings pointed to by the two doctors included the following: its easier to initiate and patients stay with the treatment (buprenorphine) longer. Fewer participants successfully started Vivitrol treatment, as it required a three day period for detoxification, whereas Suboxone participants could begin as soon as the onset of withdrawal symptoms began. The differences in induction rates were 72% for Vivitrol and 94% for Suboxone.

Naltrexone (Vivitrol) is an antagonist, meaning if there were residual levels of opioids in a participant’s body they would immediately be thrown into acute withdrawal. The delay was medically necessary. Naltrexone is also not an opioid, while Suboxone (buprenorphine) is. The induction period with Vivitrol was expected by the study authors themselves to be more difficult. They didn’t get the easement of acute opioid withdrawal that the Suboxone group did—and yet, 72% were successfully inducted into the study.

Curiously one individual pointed to where many of the overdoses in the study occurred after detox, apparently indicating more occurred with Vivitrol. Yet she failed to comment on the fact that of the five fatal overdoses in the study, THREE were in the Suboxone group!

There were more relapse events (defined as 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use.) for the Vivitrol group, but “most or all of this difference [was] accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures.” The more difficult time intiating patients into Vivitrol treatment effected the over relapse rates. “However, once initiated, both medications were equally safe and effective.”

The Lee et al. study was actually the second study to demonstrate that Vivitrol was as effective as Suboxone in maintaining short-term abstinence. The previous study was a smaller Norwegian study, Tanum et al., that followed its participants for 12 weeks. The bottom line is replicated results are more difficult to rationalize away.

Diversion and abuse of Suboxone has been evident from the time it was approved by the FDA. The approval of Sublocade would hopefully nullify the diversion and abuse problems experienced with Suboxone, if you have the money or insurance for it.

Bringing buprenorphine into the realm of “a restricted delivery system” to prevent direct distribution to patients also seems to be where some justification for the added cost factor comes in. But I wonder to what extent dispensing Vivitrol and Sublocade in a medical setting can justify the high cost. Is there price gouging going on? This is now the second time that technological innovation has extended patent exclusivity for Indivior’s buprenorphine products. Read more about how Reckitt Benckiser, the parent company to Indivior and Indivior itself accomplished this in “The Opioid Buzzard.”

11/14/17

Pharma’s Not Getting the Message

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?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

03/14/17

Fentanyl: Fraud and Fatality

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?

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”

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, 2016 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

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 26^th 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

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.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: STAT News