In April of 2017, the FDA approved valbenazine (Ingrezza) as a treatment for tardive dyskinesia (TD), a neurological disorder featuring Parkinsonian-like involuntary movements, which is found in many people who have taken antipsychotic medications for a prolonged period. From the perspective of the FDA, which in 2014 had designated valbenazine as a “breakthrough therapy”—a designation that speeds up the approval process—the launch of Ingrezza marked a major milestone. “Tardive dyskinesia,” stated Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, “can be disabling and can further stigmatize patients with mental illness. Approving the first drug for the treatment of tardive dyskinesia is an important advance for patients suffering with this condition.”
Two months later, Mathis—along with four of his colleagues at the Center for Drug Evaluation and Research at the FDA—published an article in America’s premier medical journal, The New England Journal of Medicine, “Efficient Trial Design—FDA Approval of Valbenazine for Tardive Dyskinesia,” which heaped effusive praise on the drug’s manufacturer, Neurocrine Biosciences of San Diego, CA. As the authors declared in a sentence that was turned into a pull quote, “A pharmaceutical company with no products on the market was able to navigate regulatory demands effectively and develop a novel treatment for an iatrogenic condition first identified more than 50 years ago.”
According to Mathis and his FDA colleagues, Neurocrine blazed a trail that other drug companies would do well to emulate. “An important lesson for drug development,” they concluded, “is that creativity and partnership [between the FDA and drug companies] in both development and review can effectively overcome long-standing clinical challenges.” For Neurocrine, as the authors acknowledged, this partnership entailed special privileges; for example, only one phase 3 trial was required to provide evidence of Ingrezza’s efficacy—instead of two, as is typically the case.
Ingrezza has already been phenomenally profitable. Sales of the drug in 2019 amounted to about $750 million—up from around $410 million in 2018. And Neurocrine CEO Kevin Gorman believes that blockbuster status—sales of $1 billion or more—is easily within reach, as the untapped market for the drug remains significant. As he stated in January of 2020, “We still have a lot of work to do as a majority of people suffering from tardive dyskinesia remain undiagnosed and untreated.”
Likewise, the second FDA-approved drug for TD, deutetrabenazine (Austedo), which Teva Pharmaceutical Industries Ltd—the giant American-Israeli joint venture, whose US headquarters are based in Parsippany, NJ—rolled out in August of 2017, brought in about $410 million in 2019. In a call with analysts in late 2019, Teva CEO Kare Schultz said he eventually expected Austedo sales to reach $2 billion a year. The prospect of huge profits is why Teva was willing to shell out $3.5 billion in 2015 to gobble up Auspex Pharmaceuticals, a company whose only major asset was deutetrabenazine, a compound then already undergoing Phase 3 clinical trials.
While the two new TD drugs are both destined to boost the bottom-lines of their respective manufacturers, they will do so at considerable expense to both patients and society. The retail cost of a standard dose of each drug, for one patient, is about $80K a year.
Moreover, this steep price can hardly be attributed to the huge drug development costs often required to produce major innovations. Although the FDA classified Ingrezza as “a breakthrough therapy,” the first TD drug out of the gate, like the second, bears a close molecular resemblance to tetrabenazine, a generic drug, initially discovered in the 1950s, that has long been used to treat TD on an off-label class. All three drugs—Ingrezza, Austedo and tetrabenazine—belong in the same class—VMAT2 inhibitors.
“Both new TD drugs are what Marcia Angell [the former editor of The New England Journal of Medicine] has called ‘me too drugs,’ meaning that the only advance is a small tweak of an existing compound,” said John Abramson, a lecturer at Harvard’s Chan School of Public Health and the author of Overdosed America: The Broken Promise of American Medicine (2008). “And the reason they both cost so much is that American drug companies, in contrast to their counterparts in other wealthy countries, have the power to charge whatever they can get away with. And a hundred thousand dollars a year or more is not uncommon—particularly for new brand-name drugs that can be marketed as specialty drugs.”
The “specialty” designation is supposed to apply to only a small number of complex compounds designed to treat complex conditions, but in practice, it applies to various expensive new drugs such as the TD drugs.
According to its mission, the FDA strives to be “responsible for advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medical products…to maintain and improve their health.” Yet, with the two new TD drugs, questions abound.
Do they constitute a significant innovation? And by forming a close partnership with Neurocrine and fast-tracking the new TD drugs, has the FDA succeeded in helping the public get the accurate information it needs about TD to improve their health? Or has the FDA instead helped promote disinformation, as industry critics allege?
This last question is critical, as there is overwhelming evidence that a series of aggressive (and sometimes illegal) marketing campaigns that drug companies rolled out to sell their “atypical” antipsychotics helped cause the very “epidemic of TD” that the industry is now profiting from.
Me-Too Drugs Are Recast as Novel Agents
In their efforts to explain why the two new TD drugs, which they typically refer to as “novel VMAT2 inhibitors,” are more effective than their generic equivalent, the psychiatrists who recommend them struggle to make a convincing case. In a 2019 article published in The Journal of Clinical Psychiatry, titled “FDA-Approved Medications to Treat Tardive Dyskinesia,” Joseph McEvoy from the Medical College of Georgia, argued that the “[two] new medications can be life changing for individuals with TD.” The primary reason why the two new drugs “are believed to be better treatment options than off-label tetrabenazine,” he wrote, is “due to tetrabenazine’s pharmacokinetic profile that requires higher, more frequent doses.”
In a recent phone interview, McEvoy added a few details about his reasons for supporting the new TD drugs. “Due to its short half life, tetrabenazine,” he stated, “has to be taken three times a day. And since people with severe mental illness are often very disorganized, it’s difficult to get them to do this. In contrast, Austedo needs to be taken twice a day, and Ingrezza just once.”
McEvoy has served on the advisory board for both Teva Pharmaceuticals and Neurocrine Biosciences. According to ProPublica, he received roughly $32,000 from Neurocrine in 2018.
In its updated practice guideline for the treatment of schizophrenia issued in the fall of 2019, the American Psychiatry Association (APA) also highlighted the shorter half life of the generic tetrabenazine as a major disadvantage. Below a chart summarizing the features of the three drugs such as the dosing requirements, the roughly dozen authors, who participated in the committee’s deliberations, concluded, “In general deutetrabenazine [Austedo] or valbenazine [Ingrezza] is to be preferred over tetrabenazine because of the greater evidence base.”
This begs an obvious question: why is there considerably less scientific evidence about a generic drug that has long been in use? When asked for an explanation, Sheldon Benjamin, a professor of psychiatry and neurology at the University of Massachusetts Medical School in Worcester, who served on the APA’s schizophrenia practice guideline committee, said that although “tetrabenazine, which the FDA has approved to treat involuntary movements associated with Huntington’s disease, has been used quite a bit over the last few decades to treat TD, there was never any funding to do large-scale trials to determine its effectiveness for this indication. In contrast, the two new TD drugs have both been studied extensively.”
These comments simply point out that the makers of the new TD drugs had more financial resources to devote to research and say nothing about whether the generic, which has been approved for TD in several foreign countries, is less effective in reducing TD symptoms. In fact, a 2017 meta-analysis published in The Journal of Comparative Effectiveness Research, which reviewed prior studies of both tetrabenazine and Ingrezza, noted that the 12 studies of the generic all “demonstrated significant improvement in TD.”
The APA’s framing of the state of the scientific literature on TD, whereby more evidence is readily understood to be synonymous with significantly better evidence, has recently been critiqued by Jeffrey Lieberman, a past president of the APA. In a lecture delivered in 2019, “Explaining the Renewed Interest in Tardive Dyskinesia,” Lieberman linked the steadily increasing number of publications on TD in psychiatric journals over the past few years—22 in 2015, 31 in 2016, 54 in 2017 and 61 in 2018—with the approval of expensive brand-name drugs. “Clearly, there has been renewed interest in TD,” stated Lieberman, “mainly prompted by the introduction of new drugs, which have marketing budgets associated with them. It is not all bad, but it just shows you what I think is obvious to people: Money talks.”
As Benjamin also noted in the interview, the American Psychiatric Association’s position is to encourage insurers to cover the new TD drugs, as APA sees it as its mission to make sure that all patients can get access to every FDA-approved drug. At present, most Medicaid plans cover both Ingrezza and Austedo, as do about a third of Medicare plans. And many major commercial insurers have recently added the TD drugs to the other specialty drugs in their formularies.
The Marketing of Atypical Antipsychotics and Today’s “Epidemic of TD”
For the pharmaceutical industry, patients suffering from TD represent a growing stream of potential customers: that’s because the aggressive marketing of the atypicals, which were first launched in the 1980s, increased the overall use of antipsychotics, which, in turn, has led to hundreds of thousands of new cases of TD. And once an adult develops TD, it isn’t likely to go away, so these patients will all require chronic treatment.
There are currently 79 clinical trials that focus exclusively on TD. According to a statement from Neurocrine, which was provided by its PR representative, Spectrum Science, “TD is estimated to affect 500,000 people in the United States; it is estimated that only about 20 percent of patients with TD have been diagnosed, and only half of those patients have been treated with a VMAT2 inhibitor like Ingrezza.”
In a 2017 article that appeared in The Journal of Clinical Psychiatry, titled “Epidemiology, Prevention, and Assessment of Tardive Dyskinesia and Advances in Treatment,” Leslie Citrome, a professor of psychiatry and behavioral sciences at New York Medical College, and colleagues put forth three arguments to support Neurocrine’s claim that only a small percentage of patients with TD have been diagnosed and treated. This is the usual claim that drug companies make when they market new psychiatric drugs; the irony in this case is that Neurocrine is arguing that the number of people suffering from this iatrogenic neurological condition was much greater than psychiatry, as a field, had long recognized.
Citrome’s paper appeared shortly after both new TD drugs were approved by the FDA. According to ProPublica, in 2017, Citrome received about $718K from drug companies, including $24K from Neurocrine to promote Ingrezza and about $4K from Teva to promote Austedo, and in 2018, the corresponding figures were $686K in total, including $126K from Neurocrine and $97K from Teva. It is meant to be a paper that supports the expanded use of the TD drugs, without placing any blame on the industry—and the field of psychiatry—for both creating and spreading this neurological disorder.
Here are the three arguments made in the paper:
Argument number one: The second-generation antipsychotics turned out to cause more TD than was originally thought.
When the first generation antipsychotics were introduced in the 1950s—namely, chlorpromazine (Thorazine) and reserpine—psychiatrists quickly saw that these drugs induced Parkinsonian symptoms (known as extrapyramidal symptoms.) Patients often exhibited many disabling motor movements: jerky movements of arms and legs, facial grimacing, and so forth. But it took some time before psychiatry began to realize that these immediate drug-induced symptoms could lead to a permanent neurological condition, which they named tardive dyskinesia, meaning “later onset” of such motor dysfunction. One of the most common symptoms was a rhythmic thrusting of the tongue.
As psychiatrist Peter Breggin, who wrote a chapter on tardive dyskinesia in his book, Brain-Disabling Treatments in Psychiatry (1997), and has testified in numerous cases on behalf of plaintiffs who have sued drug companies for causing disabling TD, put it in a recent interview, “TD is not so much a side effect as a main effect of antipsychotics. It’s something that they typically cause. And drug companies know this, so they rarely contest it.”
In the 1980s, after all of the first-generation antipsychotics, including the biggest seller, haloperiodol (Haldol), which was approved by the FDA in 1967, had lost their patent protection, drug companies reasoned that they could best market their successors—the second-generation antipsychotics or “atypicals”—if they could claim that these new drugs—Risperdal, Zyprexa and others—were much less likely to cause Parkinsonian symptoms as well as TD. As the atypicals appeared on the market in the mid-1990s, the press touted this supposed breakthrough. As the Associated Press reported in its 1994 article announcing the FDA’s approval of risperidone (Risperdal), which was featured in The New York Times business section, this drug “reduced side effects, like uncontrollable muscle rigidity, tremors and body shakes, that are caused by antipsychotic drugs.”
But by the early 2000s, psychiatrists began noticing that the older antipsychotics were often given in much higher doses than the newer drugs and that when this factor was taken into consideration, there was little difference in the TD rates between the two sets of drugs. As Stefan Leucht, a psychiatrist at the University of Munich, and his co-authors concluded in a 2003 paper in The Lancet, “New Generation Antipsychotics Versus Low-Potency Conventional Antipsychotics: A Systematic Review and Meta-Analysis,” mean doses less than 600 mg/day [which is less than the typical dose often given to patients] of chlorpromazine or its equivalent had no higher risk of [TD] than new generation drugs.”
A couple of years later, a large study funded by the National Institute of Mental Health (NIMH)—known as the CATIE study—also found that the older drugs did not cause much more TD than the newer drugs. The authors of the CATIE study also reported that one of the key reasons why drug companies were able to tout significant differences was that they used particularly low doses in their clinical trials. As they reported in 2005 in The New England Journal of Medicine, “The dose ranges approved by the FDA for quetiapine [Seroquel] and ziprasidone [Geodon] may be below their optimal therapeutic doses, and the recommended doses of risperidone [Risperdal] (6 mg per day or less), intended to limit extrapyramidal symptoms [a group of side effects that includes TD], may not encompass its full therapeutic range.”
The CATIE study has been widely accepted as definitive, and it is what Citrome was referring to when he wrote that the “decreased risk [of TD] was less than originally expected.” However, another way of looking at the matter is that in rolling out the atypicals, drug makers engaged in an aggressive marketing campaign that went beyond the science and was later refuted by more rigorous research.
Argument number two: Because the indications and off-label uses for these agents [antipsychotics] have expanded over the last two decades, a larger number of patients are receiving antipsychotic medications than in the past.
This assertion is true, but it ignores a dark chapter in the marketing of atypical antipsychotics. The driver for this expanded use of antipsychotics over the last couple of decades has also been the industry’s aggressive marketing campaigns, for which several companies have been repeatedly sanctioned.
Take the case of risperidone (Risperdal), which Johnson and Johnson released in 1994. As Steven Brill reported in his probing 2015 feature entitled, “America’s Most Admired Law Breaker,” when launching this atypical, the company sought to expand the market beyond just the patients with schizophrenia who had used its first-generation antipsychotic Haldol. Based on his review of internal documents, Brill found that “the business plan…projected an average of more than $1 billion in U.S. sales of Risperdal every year through the turn of the century…That meant that Risperdal would have to be used by tens of millions—not simply a portion of the one percent of Americans having the most severe psychotic disorders.”
To achieve these results, Johnson and Johnson engaged in behavior that is prohibited by the FDA. It encouraged doctors to prescribe the drug for indications—say, dementia—for which it had not been approved. For these illegal activities, the company was eventually fined over $3 billion.
The makers of a few other second-generation antipsychotics have also been fined for similar illegal behavior. For example, in 2009, Eli Lilly was also forced to pay $1.4 billion for marketing olanzapine (Zyprexa) to elderly patients with dementia and to children.
Despite these hefty penalties, these unethical marketing campaigns turned out to be a success in the long run. According to a 2011 study, antipsychotic use for indications without FDA approval more than doubled between 1995 and 2008. The estimated revenues associated with off-label use in 2008 alone amounted to $6 billion.
Even though this illegal promotional activity stopped several years ago, its after-effects are still being felt. The reason is that the FDA does not prohibit doctors from prescribing drugs for off-label use. “Once this type of misinformation gets into the ether, it’s difficult to root it out, and prescribing doctors often rely on what they once heard from drug company reps rather than on what they read in the scholarly literature,” stated Adriane Fugh-Berman, a professor in the department of pharmacology and physiology at Georgetown University, who directs Pharmed Out, an initiative designed to advance evidence-based prescribing among health care providers.
The argument made by Citrome and colleagues in their paper implied that this expanded use of antipsychotics typically benefits these non-psychotic patients, and that the increase in TD is a risk offset by those benefits. Yet, as Richard Friedman, a professor of psychiatry at Weill Cornell Medical College and a New York Times columnist, warned, the use of atypicals to treat various forms of anxiety was a “worrisome trend” due to the lack of convincing scientific evidence of their efficacy for this purpose and the potential hazards with long-term use, such as TD.
The makers of atypicals did manage to get FDA approval for a few new indications for antispychotics, such as an adjunct to antidepressants in the treatment of severe depression or for suicidality. But as Consumer Reports concluded in 2011, “the available evidence indicates that antipsychotics aren’t very effective at treating ‘resistant’ depression and aren’t the best choice for this use for most people” on account of the serious side effects.
Neurocrine, the manufacturer of Ingrezza, is adamant in advising patients, who have been prescribed antipsychotics for anxiety or other off-label uses and are now suffering from TD, not to go off these drugs. “Stopping or switching your antipsychotic medication [regardless of what the medication is being used for] may not be an effective way to manage TD,” it warns.
Argument number three: Patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD.
This argument ignores the wealth of research questioning whether the long-term use of antipsychotics is actually effective. The longitudinal study of psychotic patients conducted by psychologist Martin Harrow, a professor in the department of psychological and brain sciences at Indiana University, found the opposite to be true.
Harrow summarized one of his major findings in a 2018 letter to the editor in World Psychiatry, “We also compared a good‐prognosis sample of patients prescribed antipsychotics for 15‐20 years with a good‐prognosis sample of patients not prescribed antipsychotics for 15‐20 years. In both comparisons, those patients not on antipsychotics for 15‐20 years had fewer symptoms and better outcomes after the first 2‐3 years.”
As can be seen, taken together, the three core arguments mentioned in the Citrome paper are meant to present TD as an unfortunate but necessary risk associated with drugs that nearly always provide a clear benefit to patients. But the paper ignored the long-term research on outcomes with antipsychotics, and the fact that the expanded market for TD drugs arose, in part, because of the industry’s aggressive—and sometimes illegal—marketing of the atypicals. Likewise, for Citrome and colleagues, the new TD drugs can also be understood to constitute an unequivocal scientific advance in psychiatric care.
Exculpate the Antipsychotics and Blame the Patients
Industry-affiliated psychiatrists have also attempted to shield the antipsychotics from responsibility for causing TD by blaming the neurological impairment on the faulty genes of affected patients. In a recent article, “Advances in Tardive Dyskinesia: A Review of Recent Literature,” in Psychiatric Times, Brian Miller, a professor of psychiatry at Augusta University in Georgia, argued that some patients have a genetic makeup that puts them at high risk of developing TD.
Miller estimated that the prevalence of TD in patients diagnosed with schizophrenia was 8.3 percent. He based that figure on a 2019 French study of over 600 patients, 90% of whom were taking atypical antipsychotics. In the introduction to this six-page lit review, which is followed by a two-page ad for Neurocrine’s Ingrezza, he wrote, “Meta-analyses have identified several risk genes for TD with moderate effect sizes.”
In an apparent nod to the tentative nature of these findings, Miller characterized all these risk genes “as potential candidate genes associated with TD.” A half page below these words, he included a table that alludes to roughly a dozen risk factors for TD—including various widely accepted ones such as increasing age and illness duration. Nevertheless, the factor mentioned at the very top of Miller’s list is genetics.
The Selling of the Disease to Doctors and Patients
For decades, TD was a neurological condition known only to the psychiatrists who treated patients with severe mental illnesses. The conventional wisdom was that in order to prevent the development of TD, psychiatrists should rely less on the antipsychotics that cause it. As a 1988 article published in Acta Psychiatrica Scandinavica concluded, “TD is best prevented by a course of neuroleptic medication involving…minimal doses and shortest possible length of treatment. The main TD treatment principle consists of a gradual dose reduction, possibly over years.”
Even though the antipsychotics are now widely prescribed and TD is more common than it was a generation ago, the American public still knows relatively little about this iatrogenic condition. With the approval of the new TD drugs, the manufacturers see a need to introduce TD to the culture at large. But this messaging involves not so much explaining the disease as selling it. “These public education campaigns can be extremely effective because it appears as though the drug companies are just passing on public health information. But this is rarely the case,” said Adriane Fugh-Berman, the drug industry critic at Georgetown University.
The makers of the two new TD drugs are targeting two groups in particular with their PR campaigns: doctors and psychiatric patients (and/or their caregivers). To influence doctors, the two TD drug companies are funneling money to a large number of them.
According to ProPublica, in 2018, Neurocrine paid $6.2 million to approximately 7000 doctors, most of whom are psychiatrists, for promotional activities related to Ingrezza. Likewise, in 2018, to promote Austedo, Teva shelled out $6.05 million to slightly over 8000 doctors. The amount varied from a high of a little over $100K to psychiatrists like Citrome who conducted extensive research to a low of about $15 to psychiatrists who might have received a free lunch from a drug rep. “Research shows that even doctors who receive small payments are likely to change their behavior by prescribing more of the company’s drug,” said Fugh-Berman.
The number of doctors getting such payments from the companies—many of whom, like Citrome, are getting payments from both companies—represents a significant percentage of America’s roughly 40,000 licensed psychiatrists. These payments, Neurocrine stated, in its prepared response, are “standard practice in the industry,” noting that “these healthcare professionals…are compensated for their time and expenses for research, scientific studies and educational speaker programs.”
To reach patients, Neurocrine has begun an expensive national TV ad campaign, which includes one-minute spots such as this ad.
In the ad, a patient diagnosed with schizophrenia who is experiencing TD says, ”I know I shouldn’t change or stop my medication, so I was relieved there are treatment options for TD.” The ad directs viewers to consult a website, talkaboutTD.com, which is run by Neurocrine. The page devoted to “Managing TD” features the phrase, “talk to your doctor about treatment options.” Upon clicking the words, “treatment options,” readers are led directly to the website of Ingrezza, where this drug is the only treatment option mentioned.
Neurocrine has also funneled money to numerous mental health advocacy groups, including the Alliance for Patient Access, American Brain Coalition, Caregiver Action Network, Depression and Bipolar Support Alliance, International Bipolar Foundation, Mental Health America, Movement Disorders Policy Coalition, National Alliance on Mental Illness, National Council for Behavioral Health, National Organization for Tardive Dyskinesia, and the Schizophrenia and Related Disorders Alliance. These groups have, in turn, helped Neurocrine get its message out. For example, three years ago, Neurocrine worked with various partners to declare the first week in May “TD Awareness Week”—an initiative that is now recognized by 30 states as well as Washington, DC.
Society Pays the Bill
If present trends continue, within a few years the nation will be spending several billion dollars a year on the new TD drugs. This expense will place a huge burden on society at large. Cash-strapped state governments may well have to increase their Medicaid budgets; private insurers will face a major new drug expense that they will likely pass on to plan members in the form of higher premiums.
From a public health perspective, is this spending on the expensive new TD drugs, which are little different from the generic equivalent, worth it? Would public money be better spent on housing and various support services for the homeless and others suffering from chronic psychiatric ills? And, to take a longer view, given that the TD “epidemic” has been fueled by the increased use of antipsychotics, would it be more “cost-efficient” for society to provide more generous coverage of non-drug therapies for those with common problems like depression, anxiety, and insomnia, as well as for those with psychotic episodes?
“Physicians are often knowledgeable about drugs—but not about the harms that they cause,” said Fugh-Berman of Georgetown University. “So it is not uncommon for them to embrace treating adverse events—in this case, tardive dyskinesia—with another drug. In contrast, both physicians and policy makers are much less likely to think about other ways of reducing the adverse events in the first place.”
The House Oversight Committee has been investigating the soaring costs of prescription drugs, and the new TD drugs provide yet another example of this pressing problem. According to a survey published in Health Affairs in 2019, between 2008 and 2016, the cost of brand-name oral drugs rose by 200% and the cost of so-called specialty drugs rose by 450%. In contrast, during those same years, the rate of inflation as measured by the consumer price index rose by 12%. About a month ago, the House Oversight Committee called the CEO of Teva, which is the maker of the TD drug Austedo, to Congress to explain why his company raised the price of a drug for multiple sclerosis from $10,000 in 1997 to $70,000 today.
The development, approval, and marketing of the TD drugs also provides a case study of a larger ecosystem that fails the public. The FDA often strives to help drug companies get their drugs to market quickly, and once it approves a drug, the companies can use this “seal of approval” in their marketing campaigns. Then academic physicians with ties to the pharmaceutical companies publish articles that tout the benefits of the new drugs in medical journals. And the drug companies then launch their marketing campaigns—on TV, on the Internet, and through patient-advocacy groups—that often masquerade as public health campaigns.
The House Oversight Committee, as it investigates the financial burden that drug companies are placing on the American public, might want to add the new TD drugs to its list of examples to review.
MIA Reports are supported, in part, by a grant from the Open Society Foundations