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.


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.


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.


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%.


“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.


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.


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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