Tag: pharmaceutical companies

03/23/21

The Trickery of Drug Approval

© Andriy Popov | 123rf.com

From all that the public is hearing and seeing about the COVID vaccines, both the pharmaceutical companies and the FDA have done an amazing job bringing the first two vaccines to market. In order to alleviate public mistrust of the “warp speed” development process, Dr. Anthony Fauci and NIH director Francis Collins publicly received their first dose of the Moderna vaccine. Dr Fauci said it was remarkable to be receiving it less than a year after the virus it treated was discovered. “What we’re seeing now is the culmination of years of research which have led to a phenomenon that has truly been unprecedented.” But will the pharmaceutical companies continue this standard of fast, safe and effective drug development?

In January 2020, just before the emergence of the pandemic, Harvard Medical School researchers published a study in JAMA that found the FDA is approving new drugs more quickly than ever before and using less stringent standards to determine if the drugs actually work. The lead author of the study told NPR “There has been a gradual erosion of the evidence that’s required for FDA approval.” As a result, patients and doctors “should not expect the new drugs will be dramatically better than older ones.” The use of expedited programs (Accelerated Approval, Fast-Track, and Priority Review) for new drugs increased over time, with 81% of new drugs benefiting from at least one such program in 2018. NPR reported the study found the median review time for standard drug applications was just over 10 months in 2018 compared to 2.8 years for standard and priority applications from 1986 through 1992.

The proportion of new approvals supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively, while the median number of patients studied did not change significantly (774 vs 816). FDA drug review times declined from more than 3 years in 1983 to less than 1 year in 2017. But total time from the authorization of clinical testing to approval has remained at approximately 8 years over that period.

Drug makers began to pay FDA fees to fund the review process as a result of AIDS activists protesting the slowness of the agency in the 1980s. In 1993, the first year after Congress passed the Prescription Drug User Fee Act, the FDA collected $29 million in fees. That amount rose to $908 million in 2018. The industry fees amounted to around 80% of the money spent on FDA employee salaries for drug reviews that year. The lead author of the JAMA study said: “There is some concern about the incentives that this created within the FDA … And whether it has created a culture in the FDA where the primary client is no longer viewed as the patient, but the industry.”

The Pharma Marketing Blog tracked the relationship of fees paid to the FDA by the pharmaceutical industry and the push for less rigorous scientific proof in clinical trials (and therefore faster drug approvals). He noted that there was a negative correlation between the rise in user fees and a drop in the number of warning letters sent out by the FDA to companies. There was also a positive correlation between drug user fees and adverse event reports, which track drug safety. See the following graphs taken from the Pharma Marketing Blog.

This hasn’t been the only recent evidence of how the pharmaceutical industry seems to be replacing patients as the FDA’s primary clients. Researchers published a study of the “Association between FDA and EMA [European Medicines Agency] expedited approval programs and therapeutic value of new medicines” in the October 2020 issue of the BMJ. The study sought to characterize the therapeutic value of new drugs approved by the FDA and EMA and how these ratings were associated with the regulatory approval process of the expedited programs of the FDA and EMA.

Over the past few decades both agencies have established programs to expedite drug development for serious conditions. The four main expedited programs of the FDA are: fast track (introduced in 1987), accelerated approval (1992), priority review (1992), and breakthrough therapy (2012). Emergency use authorization, under which the COVID-19 vaccines have been expedited, technically isn’t an FDA approval of the drug, but it authorizes the FDA to facilitate an unapproved product during a declared state of emergency. Its latest update occurred in 2017. The EMA has two expedited programs, accelerated assessment (2005) and conditional marketing authorization (2006). The EMA instituted a third program, PRIME, the priority medicines scheme, in 2016.

These expedited programs were intended to prioritize the most important medicines for faster access to patients, and are increasingly the route by which new medicines are approved. For example, the FDA approved 60% of new drugs through at least one expedited program in 2019, while only 34% of drug approvals in 2000 were expedited. The FDA and EMA guidance indicated that an expedited program should be reserved for drugs that are expected to show an improvement over the available therapies. “However, neither the FDA nor the EMA specifically requires data on, or makes regulatory approval contingent on, comparative effectiveness; most new drugs are approved on the basis of placebo-controlled trials or single arm studies.”

This means the therapeutic value of medicines that benefitted from the FDA and EMA expedited programs is uncertain. Using ratings of therapeutic value published by health authorities in four countries and an independent non-profit organization, the researchers “evaluated the association between expedited programs and ratings of therapeutic value for all new drugs approved by the FDA and EMA from 2007 through 2017.”

We found that less than a third of all new drugs approved by the FDA and EMA were rated by any of five independent organizations as having high therapeutic value—that is, providing moderate or better improvement in clinical outcomes for patients. Most of the increase in the number of new drug approvals over the past decade was driven by drugs rated as having low therapeutic value, which calls into question the common practice of using simple counts of new drug approvals as a measure of innovation. Rather, a more nuanced view of innovation is needed that takes into account the clinical benefits and relevance to patients of new medicines.

The study’s findings suggest that after FDA regulatory approval, there is a widening gap between the drug’s approval and the clinical and public health priorities of health systems, payers and patients in drug safety and efficacy. Contributing to this gap is the varying quality of clinical evidence available at the time of approval. This leads to uncertainty around the extent of clinical benefit of the respective drug. The study’s data emphasizes the importance of robust post marketing evaluation for expedited drugs. “Such an evaluation would confirm early evidence of efficacy and help to elucidate findings from several previous studies suggesting that accelerated approval, priority review, and fast track drugs were associated with increased safety related reports or labeling changes.”

The researchers suggested one step leading to greater assurance of timely completion of post marketing study requirements for expedited drugs could be to require that certain mandated studies enroll patients before the FDA or EMA grants approval. They also suggested that regulatory agencies explore whether additional explanations were necessary. These explanations could include elaboration in product labeling, press releases, or approval documents. They could provide more realistic expectations of benefit for expedited drug approvals by patients and clinicians. Their findings also had implications for the controversy around drug prices.

In the US, the largest public payers are required by law to cover most (Medicaid) or a substantial number (Medicare) of drugs approved by the FDA, regardless of the quality of the evidence supporting their approval or their therapeutic value. Previous studies of cancer drugs have found no association between clinical benefit and drug prices and reimbursement.

In conclusion, the researchers said while the FDA and EMA are increasingly using expedited programs to facilitate drug development, the absolute value of highly rated drugs approved by the FDA and EMA over the past decade was low. Policy makers could explore implementing therapeutic value ratings more widely for new drug approvals. This would align the evidentiary needs of regulatory approval and reimbursement decisions with informing patients and doctors about the benefits and risks of new drugs, particularly those approved by expedited programs.

It’s not so surprising, then, that so many Americans are hesitant to say they plan to get a coronavirus vaccine. It seems that the above discussed results of research into new drug development by the pharmaceutical companies is at least partly to blame. Many people do not trust the claims drug companies make about their products.

The Pew Research Center conducted a survey of Americans at the end of November 2020. Sixty percent said they would definitely or probably get a vaccine for the coronavirus, which was up from 51% in September. Thirty-nine percent say they will definitely or probably not get a coronavirus vaccine. About half of this group, 18%, said it’s possible they would decide to get vaccinated once people start getting vaccinated and there is more information available. “Yet, 21% of U.S. adults do not intend to get vaccinated and are ‘pretty certain’ more information will not change their mind.”

While public intent to get a vaccine and confidence in the vaccine development process are up, there’s considerable wariness about being among the first to get a vaccine: 62% of the public says they would be uncomfortable doing this. Just 37% would be comfortable.

Public confidence has increased since September that the research and development process will yield a safe and effective vaccine for COVID-19. Seventy-five percent of individuals now have a great deal or fair amount of confidence in the R&D process. However, one of the factors influencing whether someone intends to get a vaccine for COVID-19 is mistrust of the vaccine development process. Sixteen percent of Americans do not have much confidence in the process; 8% have no confidence that the R&D process will produce a safe and effective vaccine for COVID-19. Confidence in scientists remains slightly higher than before the pandemic.

With scientists and their work in the spotlight, 39% of Americans say they have a great deal of confidence in scientists to act in the public’s best interest, an uptick from 35% who said this before the pandemic took hold. Most Americans have at least a fair amount of confidence in scientists. However, ratings of scientists are now more partisan than at any point since Pew Research Center first asked this question in 2016: 55% of Democrats now say they have a great deal of confidence in scientists, compared with just 22% of Republicans who say the same.

Pharmaceutical companies have an opportunity when they resume the research and development process for new drug applications after the pandemic. Will they continue to use external committees of scientists vetting the data for new drug applications and produce truly independent recommendations and rejections? If pharmaceutical companies can maintain an open and transparent R&D process and develop drugs with a truly high therapeutic value, the confidence level of patients and their doctors would be higher than ever. For more on COVID, see “Learning from COVID Drug Development.”

01/26/21

Learning from COVID Drug Development

© Ilkin Quliyev | 123rf.com

On December 11, 2020 the FDA issued an emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine. Then on December 18th, the FDA issued an EUA for the Moderna COVID-19 Vaccine. The FDA News Releases for both drugs said the data provided clear evidence both vaccines may be effective in preventing COVID-19. The known and potential benefits for both drugs were said to outweigh the known and potential risks. “In making this determination, the FDA can assure the public and medical community that it has conducted a thorough evaluation of the available safety, effectiveness and manufacturing quality information.”

In December of 2019, no one knew COVID-19 existed and now there are two vaccines being distributed in the US that are both around 95% effective in preventing the novel coronavirus. Despite the unprecedented speed of their development, there were not any compromises with the safety or the scientific integrity of the process. According to Dr. Anthony Fauci, the speed was “a reflection of the extraordinary scientific advances in these types of vaccines which allowed us to do things in months that actually took years before.” He wanted to settle the concerns some people have about the rush of development and approval. Despite the politicization of the process, there was an independent body of people with no allegiance to the administration or to the pharmaceutical companies who were the first ones to review and then approve the data from the companies’ late-stage clinical trials. “We need to put to rest any concept that this was rushed in an inappropriate way . . . Help is on the way.”

The FDA requires that a vaccine be at least 50% effective, according to the latest guidance. By comparison, two doses of the measles vaccine is about 97% effective, and flu vaccines range from about 40% to 60% effective, according to the Centers for Disease Control and Prevention (CDC).

The FDA just finalized the guidance for EUAs in January of 2017. The purpose of this guidance was to explain the FDA’s current thinking on the authorization of the emergency use of certain medical products under certain sections of the Federal Food, Drug and Cosmetic Act, as it was amended or added to by the Pandemic Reauthorization Act of 2013 (PAHPRA).

The provisions in PAHPRA include key legal authorities to sustain and strengthen national preparedness for public health, military, and domestic emergencies involving chemical, biological, radiological, and nuclear (CBRN) agents, including emerging infectious disease threats.

The Washington Post published an article that addressed common concerns about the COVID-19 vaccines. First, it is not just the vulnerable who should get the vaccine. Vaccines protect more than just the person who is inoculated. The more people who are vaccinated means there are fewer people the virus can infect, “lowering the infection rate and the risk for us all.” Another reason is to protect those who cannot get it. The first two approved vaccines were only approved for individuals over the ages of sixteen for the Pfizer-BioNTech COVID-19 Vaccine and 18 for the Moderna COVID-19 Vaccine.

Your decision not to get vaccinated could affect other people around you. Individuals with a weakened immune system may need to rely on the immunity of others to keep them healthy. Not getting a vaccine would be like refusing to wear a mask. We will likely have to wear masks through 2021. In fact, vaccinated people should wear masks and follow social distance guidelines. While the vaccine is effective at reducing symptomatic illness, it is not yet known whether it reduces the likelihood of contracting the coronavirus and being an asymptomatic carrier.

As more people get vaccinated and the US gets to community or herd immunity, there will come a point when we can do away with the masks. “In the meantime, vaccination is a crucial tool. It doesn’t replace other tools but is a powerful measure that can help save lives and help the economy recover.” Allergic reactions can be treated without lasting consequences, but the same is not true for COVID-19. At this time, it is not known what component of the vaccine triggers allergic reactions, but there is not reason for people with food or medication allergies to avoid the vaccine as long as they are monitored in a health-care setting.

All viruses mutate and it may turn out that people will have to receive regular booster shots, like with tetanus or the flu shot. Enough mutations could eventually reduce the potency of existing vaccines. A study of the Moderna vaccine found it was effective for at least 119 days. But some experts believe immunity should last at least a year. “The theoretical necessity of future vaccinations doesn’t override the urgency of getting one now.”

For those worried about political interference in expediting approval, it’s critical to emphasize that no shortcuts were taken in research or the approval process. Vaccine safety was tested in phase 3 trials involving tens of thousands of participants. External committees of scientists vetted the data and produced independent recommendations to support vaccine authorization.

The Allegheny Health Network (AHN) posted a series of frequently asked questions (FAQs) and answers that addressed further questions about the COVID-19 vaccines. The further information there included that no doctor’s order will be necessary to get the vaccine, but you will have to schedule an appointment. AHN said the vaccine is free to all Americans and will be available at retail pharmacies. “Remember, some vaccines require two doses to be effective. It’s extremely important you get both and follow the suggested timeline.”

Who knows where we’ll be with COVID in another twelve months! But there are some things we’ve learned through this pandemic about drug companies and hopefully will continue to insist on. Drug development can be done quickly and safely. Pharmaceutical companies can be open and transparent about their research and allow truly independent, external committees to verify their findings. People can trust the results of drug development when the clinical trial process is not statistically or methodologically manipulated to show what the researchers want to find.

The widespread mistrust of science that became evident during the pandemic seems partly due to the previous manipulation of drug development by the pharmaceutical companies. Like good illusionists, they directed our attention to what they wanted us to see and away from what they wanted to hide. Going forward, open, transparent drug development can restore the trust that is now lacking for the COVID vaccine. During the pandemic drug companies showed they could do COVID Drug Development quickly and safely. We need to remember these things and hold the drug companies accountable to these standards.

03/26/19

Runaway Pharma Gravy Train

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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.

05/10/16

Opening the Off-Label Floodgates

© Christa Eder | 123rf.con
© Christa Eder | 123rf.con

On March 8, 2016 the FDA made a settlement agreement with the pharmaceutical company Amarin that allows Amarin to promote its drug Vascepa for off-label use to treat patients with hypertriglycerdemia, persistently high triglycerides. That is, as long as its promotion is truthful and not misleading. Amarin wanted to widen the population for whom they could recommend Vascepa to include other patients with different cardiovascular diseases, but the FDA initially ruled against this. Amarin’s stock price took a nosedive. Concerned with how their investors were reacting, the company fought back by suing the FDA. So what was this breakthrough medication worth taking on the FDA? Fish oil; Vascepa is prescription strength fish oil.

Amarin argued that it had a First Amendment right to market its drug for a broader patient group, “despite the lack of regulatory approval and the lack of evidence of an outcomes benefit for patients.” Justin Karter of Mad in America noted how the FDA settlement strikes at the heart of the drug regulatory system in the U.S. Amarin argued that companies should have the right to market their products consistent with what “a judge would consider to be neither false or misleading.” Be clear on what Amarin was saying. A judge, not the FDA, should rule on whether or not the marketing claims for their product were truthful and not misleading.

Where does a judge get the expertise to discern whether or not a company has made misleading, untruthful medical claims about their product? Pharmaceutical companies have paid millions of dollars for violating off-label promotion of their medications. One example is the blockbuster drug Neurontin, which has cost its parent drug companies millions of dollars in fines for “illegal and fraudulent promotion of unapproved uses.” An internal company email referred to Neurontin as “the ‘snake oil’ of the twentieth century.” This is but one example of the violations from multiple drug companies under the more restrictive FDA guidelines forbidding all off-label marketing.

In August of 2015, a judge in the district court of Manhattan ruled that Amarin could market its drug to the desired broader population. He also ruled the company could claim that Vascepa “may reduce the risk of coronary heart disease.” This was despite the fact that the FDA had called the claim misleading, as there was “supportive but not conclusive research” to that effect. The Amarin ruling, according to attorney Amy Kapczynski, “has the potential to unleash a flood of misleading marketing to physcians.” She believes that at some point, the FDA will have to take the issue to the Supreme Court.

Writing for FDA Law Blog, David Gibbons gave a detailed description of the legal aspects of the case. While Amarin was attempting to gain FDA approval for its off-label promotion of Vespacia, data from several high-profile cardiovascular outcomes trials cast doubt on the clinical benefit of triglyceride lowering. After reviewing the data, the FDA then asked an Advisory Committee to express its opinion on whether or not “Vascepa’s triglyceride lowering effect was sufficient to approve the drug for use in patients with persistently high triglycerides. The Advisory Committee voted 9 to 2 against approval for that indication.” So Amarin sued the FDA.

In a bold move, Amarin filed a civil complaint against FDA claiming that FDA’s threat of prosecution for misbranding Vascepa had a chilling effect on Amarin’s commercial speech that was otherwise protected by the First Amendment.  For that reason, Amarin sought declaratory and injunctive relief that would prevent FDA from prosecuting the Company for truthful, non-misleading speech concerning Vascepa, going so far as to detail, in its complaint, certain off-label promotional content regarding Vascepa that the Company proposed to disseminate.  Early in the litigation proceedings, Amarin filed a motion for preliminary injunction and the court heard oral arguments on the motion on July 7, 2015, and, on August 7, the court handed down a 71-page opinion in which it granted Amarin’s requests.

Commenting on the FDA settlement agreement in Amrain Pharma v. U.S. Food & Drug Administration for Mad in America, lawyer and mental health advocate Jim Gottstein said he thought that for all practical purposes, the FDA ban against off-label promotion of drug companies was dead. He noted that the ruling in the Amarin case was based upon a 2012 decision in Unites States v. Caronia that reversed a criminal conviction for off-label promotion.

In light of the settlement I think it is fair to ask where things stand with the FDA’s enforcement of its ban against off-label promotion and Department of Justice prosecutions of drug companies for off-label promotion leading to false claims.  I think the ban against off-label promotion is dead for all practical purposes.  The FDA could try and get a different ruling in another circuit and, if successful, ask the Supreme Court to rule, but since it didn’t ask the Supreme Court to take the case in Caronia, it doesn’t seem likely that it has any intention of trying to overturn Caronia.  This will give the drug companies free rein for off-label promotion.  Of course, anything that is false or misleading is still grounds for charges, but that is a far harder case to make.

Eric Palmer, writing for FiercePharma, noted that the free speech argument has been closely monitored by the pharmaceutical industry to see just how much leeway they might expect from the FDA in their ability to market for off-label use of their products. Another pharmaceutical company, Pacira, filed suit against the FDA after the August 2015 ruling in favor of Amarin.

Tracy Staton noted on FiercePharma that the FDA agreed to remove its limits on Pacira’s marketing of Exparel, which is now approved for pain treatment at any surgical site. She said that by making a deal with Pacira, the FDA avoided another court ruling on the free-speech issue, as it seeks to adjust its marketing rules. In an attempt to limit any broader application of the Amarin ruling, the FDA has said its Vascepa promotions would not have broken FDA rules in any case. As it did with Amarin, the FDA said regarding its agreement with Pacira: “It’s important to note that this resolution is specific to the parties involved in this matter.”

Parallel to these attempts to weaken the FDA regulations against off-label marketing, there was a January 2016 article published in JAMA Internal Medicine by Eguale et al. that looked at the association between off-label drug use and the risk of adverse drug events (ADEs).  Commenting on Medscape, Eguale said to his knowledge, theirs was the first systematic evaluation of the association between off-label use of drugs and the risk for ADEs. They concluded that off-label use of prescription drugs was associated with ADEs. “Caution should be exercised in prescribing drugs for off-label uses that lack strong scientific evidence.”

The study found that the majority of prescriptions (88.2%) were for approved uses. Another 9.5% involved off-label use without strong supportive evidence; and 2.3% were off-label, but had strong evidence supporting its use off-label. The ADE rate was higher for off-label use than for on-label use, “at 19.7 per 10,000 person-months vs 12.5 per 10,000 person-months.” When analysis was done according to the strength of supporting evidence for off-label use, there was an even higher rate (at 21.7 per 10,000 person-months) for use unsupported by strong scientific evidence. “Off-label use indicated by solid scientific evidence had a rate of 13.2 per 10,000 person-months, which was virtually the same as its on-label counterpart.”

The risk for adverse events also rose with the number of prescription drugs used by individual patients. Individuals taking eight or more medications had “a more than fivefold increased risk for ADEs compared to patients who used one or two drugs.”

[P]hysicians and physician organizations should recognize the enormity of the problem and be active participants in the promotion of cautious prescribing of drugs for off-label uses lacking strong scientific evidence.

Within an invited commentary of the study, “Off-Label Drug Use and Adverse Events,” Chester Good and Walid Gellad warned that the FDA and the courts needed to carefully consider the study’s findings as they contemplate any further relaxation of regulations to permit the promotion of drugs beyond their labeled indications. “In light of these concerns, the study of off-label drug use and adverse drug events by Eguale and colleagues … is particularly timely.”

Too bad the Eguale et al. study wasn’t published earlier. Maybe it would have had some influence on the FDA settlement with Amarin. The response of pharmaceutical companies with psychiatric medications to the Amarin settlement is a serious concern. They have already demonstrated a history of flaunting the more restrictive FDA regulations to the tune of billions of dollars in fines.

On March 31, 2016, the nonprofit organization Public Citizen published an updated analysis of all major financial settlements and court judgments between pharmaceutical companies and the federal and state governments. The time period covered by their analysis ran from 1991 through 2015 and included 373 settlements for a total of $35.7 BILLION. Financial penalties have declined sharply since 2013. The most striking decrease occurred with criminal penalties. “For 2012 and 2013 combined, criminal penalties totaled $2.7 billion, but by 2014-2015, the total had fallen to $44 million, a decrease of more than 98%.”

From 1991 through 2015, GlaxoSmithKline and Pfizer reached the most settlements—with 31 each— and paid the most in penalties, $7.9 billion and $3.9 billion respectively. Six additional companies, Johnson & Johnson, Merck, Abbott, Eli Lilly, Teva, Schering-Plough, Novartis, and AstraZeneca paid more than $1 billion in financial penalties. Six of the above eight were listed in the top 14 pharmaceutical companies by global sales in 2014. Thirty-one companies entered repeat settlements. Pfizer (11), Merck (9), GlaxoSmithKline, Novartis, and Bristol-Myers Squibb (8 each) finalized the most federal settlements.

Financial penalties continued to pale in comparison to company profits, with the $35.7 billion in penalties from 1991 through 2015 amounting to only 5% of the $711 billion in net profits made by the 11 largest global drug companies during just 10 of those 25 years (2003-2012). To our knowledge, a parent company has never been excluded from participation in Medicare and Medicaid for illegal activities, which endanger the public health and deplete taxpayer-funded programs. Nor has almost any senior executive been given a jail sentence for leading companies engaged in these illegal activities. Much larger penalties and successful prosecutions of company executives that oversee systemic fraud, including jail sentences if appropriate, are necessary to deter future unlawful behavior. Otherwise, these illegal but profitable activities will continue to be part of companies’ business model.

It seems to this point, risking the fines has just been a potential cost of doing business with medications. With the FDA failing to challenge the decision in Caronia and its recent settlement with Amarin, the floodgates for off-label marketing of medications may have been opened. I hope that Jim Gottstein’s prediction that FDA opposition to off-label marketing is “dead” turns out to be wrong. If he is correct, and the FDA does not actively oppose future off-label marketing of psychiatric medications, we will be flooded with adverse events from their off-label use.