Amgen will not launch its biosimilar of AbbVie’s Humira in U.S. until 2023

One cannot watch a program on cable television without likely catching a commercial for Humira with its iconic mauve ribbon branding. AbbVie’s blockbuster drug, Humira (adalimumab) was the best selling drug of 2016, with net sales of over $14 billion, a 15% increase from 2015. While it was not the first approved TNFα-inhibitor, Humira was the first approved fully human monoclonal antibody in its class. The brand name Humira stands for “human monoclonal antibody in rheumatoid arthritis”. Remicade (infliximab), a mouse-human chimeric antibody, was the first approved TNFα-inhibitor and Enbrel (etanercept), a fusion protein, was the second. In 2001, pivotal results from ARMADA, AbbVie’s phase III double-blind, placebo-controlled trial involving 271 patients, showed a 50% improvement in ACR score (or, reductively, a 50% joint improvement) using Humira. Since then, Humira has become a staple in the armamentariums of rheumatologists, dermatologists, and gastroenterologists. After its original approval in RA in 2002, the timeline for indication approvals follows:

Humira-approvals-by-year

  1. Rheumatoid Arthritis (2002)
  2. Psoriatic Arthritis (2005)
  3. Plaque Psoriasis (2008)
  4. Adult Crohn’s Disease (2008)
  5. Juvenile Idiopathic Arthritis (2008)
    • Orphan
  6. Ankylosing Spondylitis (2008)
  7. Ulcerative Colitis (2012)
  8. Uveitis (2014)
    • Orphan
  9. Pediatric Crohn’s Disease (2014)
    • Orphan
  10. Hidradenitis Suppurativa (2015)
    • Orphan

In the United States, drugs qualify for orphan status if they treat a disease affecting less than 200,000 patients, thus meriting an additional 7 years of market exclusivity. With 10 indications and a few orphan designations to boot, it’s not difficult to see why Humira is one of the best selling drugs in the world. And, as of September 28, in a major win for AbbVie, their legal team successfully deterred biosimilar competitors until 2023 in the U.S. and until 2018 in Europe. Indeed, Amgen’s Amjevita was approved September 2016 in the U.S., yet it will not be commercially available any time soon.

Biosimilars 101

Most are aware of generics because most of the time, we can acquire generic drugs for a fraction of the cost of the brand-name drug. Biosimilars are essentially “the generic” of a biologic type of drug, but with a few important caveats as the analogy is imperfect.

Until the 1980s, all drugs were simple chemical entities. Take for example, aspirin, which has a very simple formula, C9H8O4. Aspirin is comprised solely of 9 carbon, 8 hydrogen, and 4 oxygen atoms. Because of its simplicity, every single time researchers synthesize aspirin, it is exactly the same with no variation. Humira is an antibody with a molecular weight 800X greater than aspirin. Biologic antibodies cannot be chemically synthesized like aspirin and the technological requirement of a cell line to produce an antibody just happens to be inherently variable.

While the U.S. pathway for the approval of generics (The Hatch-Waxmen Act of 1983) has shown considerable success in decreasing the price of drugs, the pathway for the approval of biologics (The Biologic Price Competition and Innovation Act of 2010) was likewise paved for prospective cost savings, yet requires an additional layer of scrutiny due to the inevitable variability of these cell-generated biologics. As the technology to produce antibodies like Humira is nontrivial and far more complex than the technology to produce a chemical entity like aspirin, AbbVie successfully delayed biosimilar competitors far past their market exclusivity date of 2016 to 2023 due to the dozens of formulation, manufacturing, and methods patents. As the goal of the biosimilars pathway was to facilitate cost savings, what does that mean for patients?

Cost savings of biosimilars

No one knows—no, quite literally, at least for the U.S., no one knows. Sure, there are U.S. cost savings projections in the ballpark of 15-30%. Indeed, Pfizer’s infliximab biosimilar, Inflectra, was recently introduced at a 15% wholesale acquisition cost (WAC) discount. And sure, Pharma manufacturers, insurance providers, and pharmacy benefit managers (PBMs) alike are touting in a very public relations-sensitive fashion the impending cost savings of biosimilars. The U.S. healthcare market herein is specifically differentiated as it quite unlike that of Europe, which may already be a decade ahead of the U.S. in its implementation of biosimilars. Furthermore, Inflectra is discussed not in terms of a general cost savings, but specifically a WAC discount, because the actual, effective cost savings to patients remains nebulous. Perhaps you have noticed that the American healthcare system is like a Rube Goldberg machine, where everything is intertwined, the outcome is non transparent, and Rube Goldberg, or the inventor, has left the building. There is nothing but speculation about the cost savings of biosimilars, yet the one trend emerging is the stark contrast between the U.S. and European healthcare systems.

Imagine the outcry and resistance if the United States government fully funded and mandated patients successful on Humira to switch to a trial biosimilar. Well, the Norwegian government successfully executed such an experiment/trial between 2014 and 2015 using an infliximab biosimilar, Remsima (the European counterpart to Inflectra). This aptly named NOR-SWITCH trial involving 482 patients showed that switching from infliximab originator to the biosimilar was non-inferior. By the close of the study year, in 2015, Remsima hit 80% market share at a steep 69% discount. While Inflectra only became commercially available at the close of 2016, penetration is expected to hit a nominal 10% market share in the U.S. at a 15% discount. Notably, as of August 2017, the European Medicines Agency has approved 35 biosimilars, whereas the Food and Drug Administration has only approved 6, which almost seems akin to the ratio of available cheese varietals. Aside from the ever-present concern of emergent efficacy or safety signals, it remains to be seen whether the U.S. healthcare system and all of its tentacles of complexity can pivot biosimilars into a meaningful cost savings to patients as the only thing we now for certain is that the the American leviathan in its current state has proven it is far less nimble than its European counterparts. For better or worse.

cheese

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Do vaccines cause autism? -Part II

“If you ask 99.9% of parents who have children with autism if we’d rather have the measles versus autism, we’d sign up for the measles, ” said Jenny McCarthy in 2010.

In 2015, the state of Washington reported the first U.S. measles death in 12 years.

Battleground #1: California: A Tale of Two Cities

“The Happiest Place on Earth”, otherwise known as Disneyland in Anaheim ironically served as the petri dish for the highly publicized measles outbreak in December 2014. While the origin of the measles outbreak was not identified, traveler/s could have arrived from any number of countries as Disneyland attracts visitors from around the globe. Thereafter, cases connected to the outbreak were confirmed in at least 7 other U.S. states as well as Canada and Mexico, thus demonstrating how rapidly and how far a measles outbreak can spread. Among infected California patients, 45% were unvaccinated, which enabled the outbreak to persevere.

A map of MMR kindergarten vaccination rates for the 2015-2016 school year across California counties reveals that it is the land of extremes and contradictions: a tale of two cities. While California is home to innovative tech startups, it also is a powerhouse of agriculture, an genesis of civilization. Billion dollar mansions with vaulted ceilings in Beverly Hills tower only a dozen miles from Skid Row, where tents, cardboard boxes, or simply the starlit sky serve as the roof for thousands of homeless. California boasts nature’s skyscrapers, the redwoods, which grow up to 250 feet tall, but never reside more than 50 miles inland from sea (level). Superimposing just about every demographic onto this map: net worth, income, political leaning, education, race, religion, work industry, etc. doesn’t recapitulate the MMR kindergarten vaccination trend. Because objections to vaccination seem convoluted, let’s superimpose some noteworthy (and partially tongue in cheek) commentary on to the vaccination map.

CA-map-kindergarten-MMR-vacccination-rates

Not to exaggerate the lack of vaccination coverage, in 2015-2016, California (94.5%) matched the national average (94.6%) among children in kindergarten and was not the least vaccinated state, which was Colorado (87.1%). Despite high overall coverage, susceptible pockets still exist. California reported 19 kindergarten schools with less than 50% vaccination rate. Herd immunity is defined as the requisite ratio of a vaccinated populace to prevent an epidemic. In a population in which a large number of individuals are immune, chains of infection are likely to be disrupted, which delays the spread of disease. It follows that the greater the proportion of individuals in a community who are immune, the smaller the probability that those who are not immune will come into contact with an infectious individual. Measles, in particular, is a highly contagious disease that can live up to 2 hours in an airspace where the infected person coughed or sneezed. Due to such a high contagious rate, the herd immunity threshold for measles is likewise high: 90–95%. Although most demographics do not capture the vaccination compliance trend in California, one variable did emerge as a fairly accurate vaccination exemption predictor. Private kindergartens had a significantly higher percentage of both medical and philosophical exemptions from vaccines than public kindergartens.

CA-vaccine-exemptions-school-public-private

The conjuncture of the infamous Disneyland outbreak and caches of kindergartens dangerously under-vaccinated by herd immunity standards prompted Richard Pan, a freshman Democratic Senator, and interestingly, also a practicing pediatrician, to introduce California Senate Bill 277. Signed into legislation in 2015 and enforced in 2016, SB277 effectively outlawed philosophical beliefs as a means to exempt children from school vaccinations. Only properly documented medical exemptions remain a viable option if you don’t want to home school your children.

As is a common combination, this measure was met with both immense success—vaccination rates skyrocketed—and passionate opposition—Senator Pan has since received death threats.

A Google search of the prominent figure on the opposing side of the vaccination debate, Andrew Wakefield, does not currently return any hits for death threats.

Battleground #2: Texas: Catalonia of America

Recall from Part I, Andrew Wakefield garnered international notoriety after publishing a henceforth-retracted paper that linked the MMR vaccine to autism. Years after the atypical retraction of a research paper and years after the ignominious revocation of his medical license, Andrew Wakefield still defends his anti-vaccination position—not from the pulpit of his hometown or former employment in Bath or London, respectively. Nay, Andrew Wakefield has since selected a residence that could not be more diametrically opposed to ancient Roman baths, fish and chips, and cold and moldy cobblestone streets. In 2007, Andrew Wakefield moved to Texas, the wide-open frontier of cowboys, BBQ, sunshine, and where the primary moisture source is now that which seeps out from the brim of a ten-gallon hat on a smoldering day.

Asked in 2011 by The New York Times if he still believed MMR causes autism, he was unequivocal. “Is that a serious question?” he asked. “Yes, I do still think MMR is causing it.” Wakefield has since appeared all over Texas at screenings of Vaxxed, a recent film he directed, and has testified at many city councils. “Wakefield doesn’t just have a dog in this fight; he is the dog,” said Indiewire’s review of the film.

“Texas is now the center of the antivaxxer movement,” said Peter Hotez, an infectious disease researcher at Baylor College. The Lone Star State (97.6%) exceeded the national average (94.6%) of kindergarten vaccine coverage, however, like The Golden State, contains worrisome pockets of low coverage. For example, one school in Austin reported 60% MMR vaccination coverage, which is well below the measles herd immunity threshold. Prior to the passage of SB277, California was the most populous of the 18 U.S. states that permitted philosophical exemptions from vaccines. Now Texas holds such a title with 27 million residents and boasts steadily increasing rates of philosophical exemptions.

TX-philosophical-vaccine-exemptions-elementary

In California, a Democrat, successfully introduced SB277. In Texas, Jason Villalba, a Republican, penned a bill just like California’s SB277. However, this bill was quickly scrapped and a newly energized PAC named Texans for Vaccine Choice sprung up in its wake. The PAC’s goal is to safeguard a parent’s right to opt out of immunization requirements and their website states, “Help us take a stand for liberty”.

Like Catalonia is to Spain, Texas has a history of threatening to secede and a culture of pride, independence, and liberty. The latter and its nuances are becoming more important in the vaccine discussion. Vaccination rights defenders frequently harbor a deep distrust of government. According to a Nature editorial, “They often suggest that vaccination is…an infringement of personal liberty and choice.” If one believes to have the moral right to philosophical exemptions to vaccines, do others, who are too frail to receive vaccinations like immune-compromised cancer patients or the elderly, have a moral right to the benefits of herd immunity?

Before we delve into philosophical ideals that underpin the vaccine debate, let’s zoom out from the big contenders of California and Texas and investigate any national trends as both Republicans and Democrats have been sponsoring vaccine-related legislation.

National trends

Predictors

According to the Pew Research Center, older adults and Democrats, separately, are more likely to say that childhood vaccines should be required. As with all surveys, the wording of the question and whom you ask (this study has n = 1840) may affect results. Nevertheless, it is interesting that these differences across both age and party affiliation did not materialize back in a 2009 survey. What was happening around 2009? Wakefield’s seminal article was published in 1998, but then the vaccine debate in the U.S. was just barely a kindle. By 2009, the wild fire was roaring. In the year that followed, Jenny McCarthy gave her incendiary interview to Frontline and Andrew Wakefield’s paper was retracted and his medical license revoked.

With regard to the age dichotomy, it seems remiss not to remark that older adults are likely to have either witnessed or heard about someone with an infectious disease. Of course, until 1945, the United States of America had its most public of figures, a president, paralyzed from the waist down due to polio.

Non-predictors

Gender, education, race, and ethnicity are not significant predictors of views on vaccines. According to the Pew Research Center, there is a slight trend that Hispanics believe vaccines should be required.

One cannot ignore the legacy of race and trust issues in the health care system dating back to the infamous Tuskegee clinical study conducted between 1932 and 1972 by the U.S. Public Health Service. With the concomitant discovery of WWII atrocities performed by Nazi doctors in the backdrop, several important bioethical standards arose during this time. In the U.S., the National Research Act of 1974 established institutional review boards (IRBs) that require that all patients involved in study be willing and voluntary participants. Mostly importantly, IRBs contain informed consent, which has since been the cornerstone governing ethical healthcare to date. Interestingly, informed consent is now often evoked in opposition to vaccination and is also related to the aforementioned notion of personal liberty.

For our final section, let’s scrutinize the primary pillars of vaccine opposition. Data will be cited for due measure, however, the focus will be on philosophies behind the objections, which is less often discussed, yet likely more requisite in order to string a productive dialogue between both sides of the debate.

Philosophical objections to vaccines

Vaccine Objection #1: Institutions/individuals in the vaccine business have dubious motives

“[There is] way too much conflict of interest [about private industry working with public health]. Like Paul Offit, who profits off of the vaccine he invented,” said Jenny McCarthy.

“When Jonas Salk invented the polio vaccine he was a hero — and I’m a terrorist?” said Paul Offit. Dr. Offit is a pediatrician at Children’s Hospital of Philadelphia and the co-inventor of a vaccine against rotavirus, a diarrheal disease that kills 600,000 children a year in poor countries.

Is the individual or the government responsible for maintaining health? If something goes wrong, is someone liable? If so, who? How much profit is acceptable in the healthcare field?

For physicians, it appears they are barely breaking even from vaccines as one study demonstrated that costs of vaccine administration exceeded reimbursement from some insurers and health plans. For pharmaceutical companies, the vaccine market is estimated as $24 billion, which is substantial, but only represents 1-3% of a trillion-dollar global pharmaceutical market. All 4 giants currently manufacturing vaccines (GSK, Sanofi-Aventis, Merck, and Pfizer) could stop making vaccines tomorrow and remain solvent. Vaccine production is a risky business in itself because the premise entails administering a drug to healthy people. If anything befalls an individual, it may be attributed (incorrectly) to the vaccine. Indeed, vaccines were the first group of medical products that were nearly decimated into extinction by lawsuits. In 1974, a British research team claimed the pertussis vaccine caused permanent damage in 22 children. Like the Wakefield article linking MMR to autism, this claim was scientifically debunked. Notwithstanding, a plaintiff in a lawsuit received remuneration from Pharma to the tune of $1.13 million, which was equivalent to more than half of the pertussis market at the time. Perceiving liability and a precarious change of winds, many risk-averse Pharma companies decided to abandon the vaccine business, which only comprised a small segment of their portfolio.

In order to stave off an emergency of vaccine shortages, Congress intervened by passing the National Childhood Vaccine Injury Act (NCVIA) in 1986, which included a program designed to protect Pharma from lawsuits. Because of the protections embedded the NCVIA, at least a few Pharma manufacturers remained in the business and a vaccine shortage crisis was averted. Those with vaccine objections view the NCVIA as a government-sponsored bribe shielding the pharmaceutical industry from liability. Perhaps, but without Congress’s intervention, Pharma companies seemingly would have been sued into oblivion. How then would you have obtained a vaccine if you so desired?

The healthcare field is rife with unique expectations unlike any other field. Physicians are expected to be benevolent while simultaneously shouldering liability. For example, when attendants on a plane ask for medical help, one expects a physician on board to nobly raise his or her hand, failing to realize that the situation is fraught with legal liability if anything goes wrong, or if the plane has crossed state or international borders.

In the United States, vaccines are generally accessible and affordable. In contrast, the diseases they prevent are costly and would exert an enormous strain on the healthcare system. If you contracted either diphtheria or tetanus, preventable by a DTaP for about $20 (or, a $51.67 vaccine, QuadracelTM, which also covers polio), your probability of hospitalization is 100%, which means you sitting in a hospital bed is inevitable. The inpatient costs are estimated as $16,982 for diphtheria and $102,584 for tetanus. It seems reasonable to speculate that Pharma companies could profit more if patients opted out of vaccines, contracted a disease, and were administered relevant other drugs in an inpatient setting. (The sky-high cost of our current healthcare system merits its own blog post.)

disease-hospitalization-vaccine-cost

Vaccine objectors also allege that pharmaceutical companies instill dangerous excipients, such as thimerosal, into vaccines, which make people sick. Thimerosal is a mercury-containing compound that has been used as a preservative in vaccines since the 1930s to prevent potentially life threatening contaminations with harmful microbes. The FDA cites 27 publications from around the world that support the claim that thimerosal is safe. Furthermore, all vaccines routinely recommended for children 6 years of age and younger are already available in formulations that do not contain thimerosal. A common misconception is that Pharma companies sprinkle in a few toxic preservatives like consciously turning the wheel on a pepper grinder over a meal. In biology, one does not have the ability to check off a Santa Claus-like wish list of all the perfect desirable parameters. Rather, researchers scan thousands of options before selecting the best with which to move forward. Other times, researchers simply choose the solution they more or less stumbled upon, because, first and foremost, it worked. The origin of thimerosal was the latter: it worked by preventing contamination and researchers didn’t just throw in a splash of mercury for good measure. Optimization comes later through iteration…

In addition to concerns about thimersoal, vaccine objectors find the CDC’s recommended immunization schedule suspect. Since 1983, the CDC has significantly increased the number of recommended vaccines and shots. As one would expect, the CDC goes to great lengths to justify their recommendations, citing a dramatic decrease in the number of vaccine-preventable diseases. Despite being inoculated with more vaccines, children today are actually exposed to fewer antigens than ever due to Pharma’s optimization in manufacturing over the years. If you were shown the data, would you believe it?

antigens-vaccines-time

Vaccine Objection #2: Increasing prevalence of autism is related to vaccines

Many researchers from around the world revealed there is nominal evidence linking the MMR vaccine to autism. One meta-analysis of over 14 million children found i) the MMR vaccine dose is at least 95% effective in preventing measles and ii) exposure to the MMR vaccine was unlikely to be associated with autism. So if MMR doesn’t cause autism, why is there a rise in autism?

Peter Bearman, a Columbia University sociologist, accounts for more than 50% of the observed increase in autism: 25% can be attributed to diagnostic accretion, 15% to greater awareness, 10% to parental age, and 4% to spatial clustering. To clarify, diagnostic accretion means that some children who would have been diagnosed as mentally retarded a decade ago may now be diagnosed with autism. Spatial or geographic clustering refers to a phenomenon, currently occurring in West Hollywood, wherein a neighborhood of parents and specialists spread awareness of a disease in a positive feedback loop, which produces more autism diagnoses. It is worth mentioning that diagnosing autism is inherently challenging because there is no definitive biomarker. Rather, physicians subjectively chronicle a child’s behavior and development. To wit, Leo Kanner, the first to describe autism in 1943, coined the term “refrigerator mothers” hypothesizing that cold, unloving mothers beget autistic children. With the prospect of such a hurtful stigma in the 1940s, do you think parents, especially mothers, would have visited a physician only to receive the blame for an autism diagnosis? Even today with the general cultural acceptance of autism, parents agonize over whether they could have done something to prevent it, hence the discussion of vaccine safety particularly among parents with an autistic child.

autism-cases-time-reasons

Approximately 46% of increasing cases of autism are unaccounted for and thus, likely ascribed to genetic and/or environmental factors. While autism, asthma, type I diabetes, and food allergies are all on the rise, only the increasing diagnoses of the former seem to be contentious. It is easy to conflate correlation and causation as the CDC’s increasing vaccine schedule is indeed concomitant with the rise of autism. However, such a theory conveniently ignores the fact that we are living in a very different world and engaged in very different activities than our ancestors. Namely, our eating habits have evolved and we are constantly exposed to pollutants and toxins. Decoupling all these variables in addition to the fact that autism may be multifactorial means a definitive simple answer for the rise in autism is challenging, if not unlikely.

correlation-causation-comic

In the meantime, on whom does the burden of proof lie? As it has already been determined that MMR is not the sole cause of autism, most vaccine objectors believe that the burden of proof rests on others to prove that something else definitively causes autism otherwise their vaccine suspicion stands.

“In science credit goes to the man who convinces the world, not the man to whom the idea first occurs.”

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Do vaccines cause autism? -Part I

Infectious diseases have impacted the lives of everyone, including many American presidents, not just memorably FDR. George Washington likely suffered from 9 various diseases. Adams, Jefferson, Van Buren, Harrison, Polk, Taylor, Lincoln, Arthur, Harrison, Wilson, Coolidge, Eisenhower, Ford, and Carter all have ties to various diseases.

Unlike the past, the vaccine debate has become more intertwined in our daily conversations than several decades ago. As with Ford and Carter, political decisions can influence the population at large, which is why the discussion of vaccine safety is important and timely.

gerald-ford-receiving-swine-flu-shot

Political decisions have important implications

Howard Markel, the director of the Center for the History of Medicine at the University of Michigan and a historical consultant to the CDC, says the most challenging decision facing officials is when to institute mass vaccination programs as vaccines inherently carry risks of complications, which can lead to ethical dilemmas. Unlike iron, which will always have a 1811K melting point, 13.81 kJ/mol heat of fusion, and 211 GPa Young’s modulus, vaccines are biologics that will not act precisely the same on every individual all of the time. This bears repeating; vaccines are biologics that will not act precisely the same on every individual all of the time. As citizens of the world, we share the understandable, yet unattainable, expectation that public health officials should make decisions to guarantee our safety without exception.

In 2002, Vice President Dick Cheney recommended a national smallpox vaccination program as a prudent counterterrorism measure following the 9/11 attacks. President George W. Bush vetoed this proposition because it may have resulted in hundreds of deaths. Let’s do the math we know. Based on past experience, it is estimated that between 1-2 people out of every 1 million people will die as a result of life-threatening reactions to the smallpox vaccine. Thus, with a current U.S. population of 320 million, 320-640 people would die from the vaccine administration alone. The smallpox vaccine has historically been effective in preventing infection in 95% of those vaccinated, so if our entire population were inoculated in advance of an outbreak, 16 million people would still die. Given smallpox is considered to be fatal in up to 30% of cases, if an outbreak occurred and no one was vaccinated, 96 million people would die. In other words, 0.0001-0.0002% of people would die from the vaccination alone, 5% would die from an unsuccessful inoculation in the face of disease, and 30% would die from the disease directly.

To throw an uncertainty wrench in our mathematics, historically the first dose of the smallpox vaccine offers protection for 3-5 years, with decreasing immunity thereafter. Therefore, maintaining a population immune to smallpox would be significantly more challenging than maintaining a population immune to, say, measles, mumps, and rubella (MMR) because an MMR vaccination is effective for 20 years. If one were exposed to smallpox, a vaccination 4 to 7 days after exposure may offer protection from disease or modify the severity of disease. Since 2001, the U.S. government has taken actions to improve its level of preparedness against terrorism. For example, the U.S. currently has enough vaccine stored to inoculate every person in the United States in the event of a smallpox emergency. However, if there were an outbreak, 320 million people would essentially have 4-7 days to get vaccinated. Can you imagine everyone running to his or her primary care physician or to a CVS Minute Clinic? Such is the nature and responsibility associated with disease management. In February 2017, Bill Gates counseled world leaders about the plausible prospect of bioterorism in years to come.

Decisions regarding vaccines are non-trivial and they are made in the wake of uncertainty. Before we delve too far, let’s settle on a definition.

Definition: Vaccines 101

According to the World Health Organization (WHO), which was established in 1948 as a specialized agency of the United Nations, “A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe, its toxins or one of its surface proteins. The agent stimulates the body’s immune system to recognize the agent as foreign, destroy it, and “remember” it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters.”

Similar to ordinary pairings such as salt and pepper and cat and mouse, vaccines are now inevitably linked to autism. This marriage originated the 1998 when a seminal and henceforth fully retracted paper by an academic researcher, Andrew Wakefield, and a dozen colleagues associated vaccines with autism. These assertions beget a dispute in the United Kingdom, which pervaded to the United States and other countries, and has precipitated newfound levels of scrutiny and concern over the safety of vaccinations.

Wakefield study correlates vaccines to autism

A pediatric gastroenterology unit in London evaluated 12 children who presented with loss of acquired skills and gastrointestinal pain, yet exhibited prior normal development. According to the article, the “onset of behavioral symptoms was associated, by the parents, with measles, mumps, and rubella vaccination in 8 of the 12 children.” It seems worthwhile to highlight that the parents noted this association. “All 12 children had intestinal abnormalities.” It also seems worthwhile to note that we are batting a thousand here: 12 children all exhibited intestinal abnormalities and all presented with an onset of behavioral changes. At this point, there are two scenarios: this is either a snapshot of a hidden epidemic that may foreshadow future trends, or this is a massive sampling error containing non-random subjects. Given this paper was accepted into The Lancet, a journal of which has one of the highest scientific reputation in the world, second only to the New England Journal of Medicine, it seems safe to speculate that the peer reviewers assumed the former.

The main findings of the paper, echoes of which extend now two decades later, linked autism to a recent MMR vaccine in 9 out of 12 children. Wakefield et al speculated that the measles virus in the MMR vaccine entered the child’s gastrointestinal system, permeated through the gut entered the brain, and triggered autism.

wakefield-lancet-article-table-1

Deer investigation, article retracted

Five years later, British reporter, Brian Deer, investigated the assertion by Wakefield et al that the MMR vaccine causes autism in children. Deer’s revelations were publicized in the Sunday Times of London, the United Kingdom’s Channel 4 Television network, and the British Medical Journal (BMJ). His investigation led to the longest-ever ethical inquiry by the United Kingdom’s General Medical Council (GMC).

Deer alleged that Wakefield had been hired to undermine the safety of the MMR vaccine by a lawyer, Richard Barr, in order to raise a class action lawsuit against the drug companies manufacturing the vaccine. Wakefield charged £150 an hour for his services in this endeavor, which eventually totaled £435,643 (then about $750,000 USD). Given this hourly rate summed to more than eight times his reported annual salary as a physician, Deer alleged this created an incentive for Wakefield to not only pen the article, but to keep the speculation going for as long as possible.

In June 1997, 8 months before the article was published in The Lancet, Wakefield filed a patent on products for a single measles vaccine from which he could profit only if confidence in the ubiquitously recommended triple MMR was impaired.

Moreover, most parents of the children in the study were clients and contacts of Richard Barr, the lawyer attempting to build a class action lawsuit. The study by Wakefield et al was conducted in the Royal Free Hospital in London, yet none of the 12 children lived in London. Indeed, one child was flown in from the United States. Is the Royal Free Hospital prestigious enough to merit flying across the Atlantic Ocean for care? Inspectors at an independent health regulator recently found the Royal Free Hospital at risk of providing poor care to patients after it failed 8 of 83 key indicators. Indeed, not Royal Free Hospital, but rather St. Marks Hospital in Harrow is the UK’s leading referral center for bowel disease and is 1 of only 14 worldwide to be recognized as a center of excellence by the World Organization of Digestive Endoscopy.

andrew-wakefield-and-brian-deer-portraits

If we were to assume that those 12 children were random, could 12 children be representative of a trend? For perspective, after successfully completing Phases I and II of a clinical trial, Phase III investigates a drug in approximately 100-3,000 patients. In order to understand the uncertainty of Wakefield et al’s study involving a sampling of 12 children, let’s review some tenets of statistics.

Power is the probability that the test correctly rejects the null hypothesis and it depends on three factors:

  • statistical significance criterion
  • magnitude of the effect of interest in the population
  • sample size used to detect the effect

Let’s specifically analyze sample size. Sampling error is the error caused by observing a sample instead of the whole population. Twelve children divided by 7 billion humans on earth equals 0.0000001714%. To be fair, a Phase III clinical trial is only 1-2 orders of magnitude larger.

One could theoretically find 9 out of 12 centenarians who have smoked their entire life. That doesn’t mean smoking is good for you. In fact, even with some data on centenarians that 60% of men and 75% of women were smokers still does not mean smoking is good for you. Correlation does not imply causation. Maybe smoking is good for you or maybe those people just had superb longevity genes that even smoking couldn’t diminish? This example illustrates the nuance of science and semantics. Statistics matter, but only when done properly, do not necessarily imply causation, and we don’t know for certain.

Oft ignored, a line in the Discussion of the article reads, “We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described.” (That line belies that Wakefield has not since budged from his original proposition.)

Following Deer’s investigation, in January 2010, the General Medical Council (GMC) ruled that Wakefield acted unethically in his research linking vaccinations to autism. Furthermore, the GMC ruled that the paper published in The Lancet in 1998 must be fully retracted. In May 2010, Wakefield was struck off the UK medical register. While The Lancet partially retracted Wakefield’s research in 2004, the article was fully retracted in February 2010.

“It was utterly clear, without any ambiguity at all, that the statements in the paper were utterly false,” said Richard Horton, The Lancet Editor-In-Chief who still holds the title. “I feel I was deceived. The Lancet had done what it could to establish that the research was valid, by having it peer-reviewed. But there is a limit, he said, to what peer-review can ascertain. Peer review is the best system we have got for checking accuracy and acceptability of work, but unless we went into the lab or examined every case record, we can’t ever finally rule out some element of misconduct. The entire system depends upon trust. Most of the time we think it works well, but there will be a few instances – and when they happen they are huge instances – where the whole thing falls apart.”

Peer review is regarded as the non-infallible, yet best practice attrition that polishes academic work to a smooth stone. In science in particular, single-blind review is the norm, which means that The Lancet reviewers see the names of Wakefield and his colleagues who submitted the manuscript, but Wakefield and his colleagues do not see the names of The Lancet reviewers. Wakefield likely appeared to all, including the reviewers, an independent, respectable researcher with a pedigree. He grew up in affluent Bath, England as the son of two doctors—his mother was a family practioner and his father was a neurologist. Wakefield was privately educated and studied medicine at St. Mary’s Hospital Medical School (now Imperial College School of Medicine). The reviewers likely read the manuscript, acknowledged at minimum, the decent reputation of the lead author, Andrew Wakefield, noted the very few number of patients in the study (n = 12), and thought perhaps this MMR-autism signal is similar to the green light in Gatsby, not symbolizing the dream of Daisy, but rather a faint pulsing signal through the fog portending a stable, bright, clinically significant trend of the future. One does not review a manuscript mulling over the ways in which the data could be corrupt and manipulated. One reviews a manuscript deciphering whether the implications are rigorously justified by the science.

Reverberations following Wakefield article

Following the controversial claims that MMR may be linked with autism, 48% of family doctors reported that parents were less willing to vaccine their children. Uptake of the vaccine in 2 year olds located in Wales fell from a quarterly peak of 94% in 1995 to 78% in 2003. In Swansea, vaccinations rates of 2 year olds fell to 67.5%.

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“If you ask 99.9% of parents who have children with autism if we’d rather have the measles versus autism, we’d sign up for the measles. I’m not for starting an epidemic of another disease. We just want there to be some type of conversation, once. Sit down with our side, with our doctors and scientists, to take a look at what we’re talking about. We’re not an anti-vaccine movement. We’re pro-safe-vaccine schedule. Until we have that conversation, people are going to think it’s an anti- and pro- side,” said Jenny McCarthy in 2010. After her son was diagnosed with autism, McCarthy is at the forefront organizing a movement of parents concerned about a link between vaccines and autism.

What is seen cannot be unseen. Even though the seminal article by Wakefield et al was fully retracted, the seeds of doubt regarding the safety of vaccines have been sowed. Please stay tuned for our next blog post, Part II, in which we will discuss the implications and statistics that has ensued since the 1998 watershed cementing the marriage between vaccines and autism.

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Pharma marketing look to little Amarin’s fish oil Vascepa

In August 2015, the Food and Drug Administration (FDA) reached a unique settlement permitting Amarin to promote its prescription fish oil pill for off-label uses. Only a few years ago, Big Pharma giant Johnson & Johnson agreed to pay $2.2 billion to settle charges of false marketing practices. Due to a slew of recent hefty penalties ranging millions to billions of dollars, most pharmaceutical companies have recognized they are subject to elevated legal, regulatory, and public scrutiny. The community’s eyes are cast upon tiny Amarin to see whether it can turn Pharma’s nefarious reputation around by displaying squeaky-clean ethics and scientific rigor in light of the nebulous marketing leeway established from the ruling.

Fish oil 101

Michael Pollan’s seminal 2006 book, The Omnivore’s Dilemma and Robert Kenner’s documentary Food Inc (2008) have brought food technology and the agribusiness to forefront of popular culture. The food revolution is underpinned by the fact that our diet has drastically changed over the past 10,000 years, yet our genes have changed very little. The spontaneous mutation rate for nuclear DNA is estimated at 0.5% per million years. Thus, over the past 10,000 years, our genes have only changed at a rate of 0.005%. In particular, the ratio of our consumed omega-6 to omega-3 fatty acids radically changed over time. This ratio during the Hunter Gatherer and Agriculture phase of our diet was approximately 1:1. However, recently this ratio in Western culture has ballooned to 10/1-25/1, indicating we are significantly deficient in omega-3 compared to our ancestors. The dearth of omega-3’s in our diet has generated substantial awareness, which has lead to prevalent commercially available products like fish oil.

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Vascepa (Amarin) vs. Lovaza (GSK) vs. Generic

There are 3 types of omega-3s: EPA (eicosapentaenoic acid), DHA (docosahexaenoic acid), and ALA (alpha-linolenic acid). EPA and DHA are derived from fish traditionally, whereas ALA comes from walnuts, chia seeds, soybean oil, and flax. The type of omega-3 is notable because the ratios of omega-3’s are what differentiates the various commercially available products: Amarin’s Vascepa, GlaxoSmithKline’s blockbuster drug Lovaza, and the generic over the counter fish oil. To note, Vascepa has the highest relative EPA, Lovaza has the highest relative DHA, and Dr. Tobias (highly ranked generic on Amazon) has the highest relative excipient/filler.

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Timeline of significant events

In 2004, the FDA approved Lovaza (developed by Reliant) to reduce triglyceride levels in adult patient with severe (≥ 500 mg/dL) hypertriglyceridemia. In 2007, GSK acquired Reliant and with GSK’s powerful marketing machinery behind Lovaza, it became a blockbuster prescription.

In 2012, a competitor arrived on the scene concomitant with the FDA’s approval of Vascepa (Amarin) for the same indication of reducing triglycerides in adult patient with severe (≥ 500 mg/dL) hypertriglyceridemia as per findings from the MARINE clinical trial. Amarin conducted a second clinical trial called ANCHOR, which was designed to treat patients with high, but not severe, triglycerides (200 mg/dL to less than 500 mg/dL). It is not a coincidence that the ANCHOR study enlisted a patient population for which Lovaza did not and still does not have an indication as doctors sometime engage in writing off-label prescriptions. If Amarin could expand the Vascepa label to contain a population for which doctors were already writing off-label prescriptions, Amarin could effectively commandeer that market by providing those hedging doctors with a less risky alternative in our highly litigious country.

In 2013, an FDA panel voted against recommending such an expanded drug label for Vascepa. Not surprisingly, Amarin shares aptly plummeted and have yet to recover. In spring of 2016, the FDA agreed not to appeal a court ruling that said Amarin had a free speech right to tell doctors about studies supporting the use of Vascepa for indications not approved by the FDA as long as they are truthful. This agreement set up an optional protocol for Amarin to submit marketing materials to the FDA for approval twice a year if it seeks to obtain preclearance of marketing material. “With more truthful and nonmisleading information readily available to healthcare professionals about the potential of Vascepa to improve cardiovascular health, this settlement serves the public interest by supporting informed medical decisions for tens of millions of patients with persistent high triglycerides,” said John Thero, Amarin’s chief executive in a statement [10].

The FDA and cardiovascular community is waiting with baited breath as Amarin is slated to publish in 2018 their 8,000-patient study, REDUCE-IT, to assess whether Vascepa prevents heart attacks, strokes, and certain heart procedures in people with high triglycerides.

Future of Pharma marketing

“This is an interesting development, but I don’t think it changes how companies can market their drugs,” said Patti Zettler, a former FDA associate chief counsel who is now a Georgia State University College of Law professor.

The truth of the matter is there will be no head-to-head trials–for fish oil or any other pharmaceutical drug. Clinical trials cost millions, capital of which only Big Pharma can front, and no one wants to conclusive evidence their product is inferior to a competitor. The litany of research conducted and opinions proffered does not provide a consensus for whether or not fish oil (Vascepa, Lovaza, or generics) is the panacea to heart disease, which is the leading cause of death for both men and women in America. But fish oil also hasn’t really definitively killed anyone either? Perhaps certain combinations of omega-3s work best for specific patient populations, but those indications have never been teased out and are extremely difficult to tease out in onerous clinical trials.

Whether Amarin can navigate these uncharted off-label marketing waters will determine the trajectory not only of this tiny one-trick-pony Pharma company, but also determine partially the fate of Pharma’s declining reputation and future marketing tactics.

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