Monday, April 4, 2016

Wakefield's "Vaxxed" Demands Less Safety

"This is not an anti-vaccine movie. We're just going to use ominous imagery to make people scared of vaccines."
- Del Bigtree, Vaxxed Producer [My paraphrase.]
This past weekend, Andrew Wakefield's factitious documentary Vaxxed: From Cover-Up to Catastrophe premiered in New York City at the Angelika Film Center, after being dropped from the TriBeCa Film Festival. A number of reporters and skeptics attended the film, live-tweeting the experience and writing up reviews of the movie afterward. You can read reviews at The Hollywood Reporter, STAT News, The Guardian, The Daily Beast, Indiewire, and others. The central story of the film, such as it is, is William Thompson and the CDC. For background on the saga, please read this reference guide. (As an aside, even though the impetus behind the film is William Thompson, the CDC researcher does not appear anywhere in the film. Instead, the audience is left with only recorded phone calls between Thompson and Brian Hooker. The transcripts were released last year in a book, which was discussed here, here, and here.) The movie alleges that the CDC covered up evidence that vaccines cause autism. However, according to William Thompson's own documents, which Matt Carey has kindly made publicly available at his blog Left Brain Right Brain, there was no cover up.

I have yet to see the film, so I will leave you to read those other reviews. Instead, I wanted to focus on a list of "demands" at the end of the film, helpfully posted by a Wakefield supporter on Twitter. The four demands would do little to help children or people with autism and would instead run counter to what the anti-vaccine community wants.

Wakefield's "demands", which wouldn't do anyone any good.
Vaxxed ends with four demands:
  1. That Congress subpoena Dr. William Thompson and investigate the CDC fraud.
  2. That Congress repeal the 1986 National Childhood Vaccine Injury Act and hold manufacturers liable for injury caused by their vaccines.
  3. That the single measles, mumps, and rubella vaccines be made available immediately.
  4. That all vaccines be classified as pharmaceutical drugs and tested accordingly.
As I said, if these demands came to fruition, they would not help the anti-vaccine movement at all and would be bad for everyone all around. Very simply, they are, at best, misguided and designed to appeal to people's emotions, rather than good sense.

Subpoena Thompson and Investigate CDC Fraud

The first of Wakefield's demands echoes something that the anti-vaccine community has been clamoring for since William Thompson was first outed by Andrew Wakefield and Brian Hooker as the CDC whistleblower two years ago. Since then, there have been a couple of speeches by Representative Bill Posey that have essentially fizzled. Congress doesn't seem all that interested in taking any action, and rightly so, considering there is no evidence of fraud. At most, this would be a waste of taxpayer money and Congressional time that could be better spent on more important things. As noted before, Thompson's own documents show that there was no coverup or research misconduct, nor did Thompson ever claim the CDC committed fraud. That allegation is something that originated in the fevered minds of the anti-vaccine movement.

Repeal the National Childhood Vaccine Injury Act

The second demand would be a very bad idea. The National Childhood Vaccine Injury Act (NCVIA) of 1986 (42 USC 300aa-10 and on) established the National Vaccine Injury Compensation Program (VICP), which ensures that those who are actually injured by a vaccine can receive compensation from the Federal government. The program is funded by a tax paid by vaccine manufacturers for every vaccine they sell. The act was created through a joint effort by the Federal government, parents, and vaccine manufacturers as a no-fault system that aimed to provide families with a more rapid process than the civil courts, more generous legal standards, and less financial burden. The program also protects manufacturers from lawsuits based on design defect claims (i.e., that the very design of the vaccine is bad and irreparably dangerous), some of which had no merit, and which threatened to drive companies to abandon vaccines altogether before the passage of the act. A common misunderstanding is that the VICP shields manufacturers from all liability; it does not. They are still subject to manufacturing and labeling defect claims in the civil court.

The following table summarizes some of the differences between a case that goes through VICP and a case that goes through the civil courts. A more detailed explanation of the difference can be found here.

Overall, VICP is more generous to claimants than the civil court system.
The biggest points to note are that in the civil court, plaintiffs must meet a higher burden of proof that the vaccine caused the injury. They must show that the vaccine's design was defective, that the defect caused the injury, that the risk of the vaccine is greater than the utility of it, and they must provide scientific evidence, subject to the Daubert Standard, to support their claim. By contrast, in VICP, they do not need to show that the vaccine was defective, and in many cases they need not even provide any evidence that the vaccine can cause the injury claimed. All they need to do is show that the injury either meets the requirements for a table injury or that there is a plausible mechanism and timing by which the vaccine might cause such an injury (the Althen Standard for causation, i.e., a medical theory causally connecting the vaccine and injury, a logical sequence of cause and effect, and a reasonable temporal relationship between the vaccination and the injury). In other words, the plaintiff would have a much harder time proving their case in civil court than in VICP.

Then there is the financial burden. The civil court favors those who have more money in a few different ways. First there's the process of discovery, which is allowed (and required) in civil court, but may be optionally allowed in VICP. While discovery may allow the plaintiff to find information that may help their case, the party with more money (i.e., the vaccine companies) could draw this process out, costing the plaintiff more money and delaying resolution of their case. Second, lawsuits cost a lot of money in general. There are attorneys' fees, expert witness fees, and so on. Under VICP, whether the claimant wins or loses their case, their legal costs (within reason) are covered and paid for by the program. In civil court, they would need to foot the bill themselves. That could bankrupt a family who may already be dealing with expensive medical bills.

At the end of the day, while repealing the NCVIA would potentially allow manufacturers to be "punished", the reality is that families who are actually harmed by vaccines would be the ones that would lose out. And as much as anti-vaccine activists and their followers complain about the VICP, they would have a much more difficult time of things in civil court.

Make Single Measles, Mumps, and Rubella Vaccines Available

For some reason, anti-vaccine activists do not like combination vaccines, like the MMR vaccine, despite there being no evidence that there is any difference in safety between the combination vaccine and single vaccines. Furthermore, splitting the MMR out into separate single vaccines would go against the anti-vaccine mantra that there are too many vaccines that kids get. Currently with the MMR combined vaccine, children get two injections (one at 12-15 months and one at 4-6 years) of the 0.5 mL vaccine, for a total of 1.0 mL. If the vaccine is split into single vaccines, children would get triple the injections (6 separate punctures) and triple the excipients (all the stuff in the vaccine beside the antigens), for a total of 3.0 mL of vaccines. Two doses of vaccines with the current vaccine, or six doses if this demand is granted. Given how anti-vaccine activists complain about so-called "toxins" in vaccines, it is surprising that they would be arguing for more.

There is also the questions of timing, cost, and completion. While single vaccines would allow parents to spread the MMR series out into six different injections instead of two, they would still likely need to get those in the same timeframe as the combined vaccine in order for their child to be protected from the diseases. That would lead to more visits to the doctor, resulting in more copays. The single vaccines would also cost more than the combined MMR, since they require triple the ingredients. They would also place increased burden on the doctor's office, as doctors would need to triple the space allotted to measles, mumps, and rubella vaccine storage. The increased costs of the vaccines and the cost of storage would drive up medical prices charged by doctors and, consequently, insurance prices. Finally, it's reasonable to question whether parents would complete the vaccinations, since there will be a greater burden on them to take time off of work to do so. That leaves the kids at increased risk of infection from these diseases.

As a brief aside, it should also be noted that Andrew Wakefield holds a patent for a single measles vaccine. As far as I'm aware, this single measles vaccine of Wakefield's has not undergone clinical trials to determine safety or efficacy, nor has it received regulatory approval. I wonder if these facts were disclosed in the film, since Wakefield would stand to make money if the combined MMR were abandoned in favor of single vaccines.

Classify Vaccines as Drugs and Regulate Accordingly

This demand is, perhaps, the least informed of the bunch. Vaccines are classified as biological products, medical products that are derived from living organisms. Like other drugs, biologics are intended to treat diseases (or in the case of vaccines, to prevent or mitigate them), and they are, technically, a subtype of drug. Because of the differences between non-biological drugs and biological drugs (for simplicity, from here on, I'm going to use "drug" to refer to non-biological drugs), the regulations between a product defined as a "drug" and one defined as a "biologic" also differ slightly. For instance, unlike most drugs, biologics are required to be manufactured under aseptic conditions from start to finish to avoid microbial contamination by things like bacteria or fungi. The regulations for drugs are found at 21 CFR 200-299 and 21 CFR 300-499, and biologic-specific regulations are found at 21 CFR 600-680

From the very beginning of manufacturing, vaccines (and biologics in general) must follow very tight production controls. Even a minor change in the process can result in significant changes in the final product. By contrast, a drug can be manufactured using a variety of different methods without significant differences in the final product. This allows the drug manufacturer to change production methods at any time down the line without creating a therapeutically different product. This also allows for generics to be made using different methods. So while a drug manufacturer could make minor changes to the manufacturing process without having to conduct additional clinical trials to show that the finished product has an equivalent safety and efficacy profile to the previous version, the only way for a vaccine maker to get approval for any changes would be to conduct additional clinical trials comparing the new vaccine to the previous version, since they are, in effect, producing a completely new product. From the manufacturing standpoint, then, regulating vaccines as drugs would end up making vaccines less, not more, safe.

Vaccines have to go through all of the normal steps that drugs have to go through to be approved. Both new vaccines and new drugs must first be tested in vitro and in animal studies before clinical trials can begin in humans. Both require submission of an Investigational New Drug application. Both require phase I studies in humans to determine initial safety. Both require phase II studies to gather additional safety data, start to gather efficacy data, and to work on proper dosage. Both require larger phase III trials to continue gathering safety and efficacy data and to solidify the dosage and administration. New vaccines and new drugs are both required to follow Good Manufacturing Practices and Good Clinical Practices during all phases of development (from animal testing through post-marketing). But because of the nature of how vaccines are used, because they are given to healthy people to prevent disease, they must meet a stricter balance between risk and benefit, where even rare adverse reactions must be very carefully considered. Furthermore, vaccine manufacturers are often required to conduct phase IV (post-market) clinical trials for new vaccines to continue gathering more safety data.

Once vaccines are approved, there is another difference between how they are regulated versus how a drug is regulated. If an adverse event occurs after administration of a drug, only the manufacturer is required to report it to FDA. Healthcare professionals and patients are optional reporters. For vaccines, however, in addition to the manufacturer, healthcare providers are also required to report adverse events to the Department of Health and Human Services. That requirement was put in place by the National Childhood Vaccine Injury Act of 1986 (another reason why demand #2 is ill-advised).

The bottom line, though, is that vaccines are regulated as drugs already, because biologics are a subtype of drug. There are just some minor differences due to the nature of biologic vs. non-biologic drugs, and some of the regulations for biologics are more stringent than if they were subject only to the non-biologic drug regulations. The result is that if Wakefield's demand #4 were granted, and vaccines were regulated as non-biologic drugs instead of biologics, vaccine safety would decrease.

Conclusion

While the demands at the end of Vaxxed appeal to the viewers' emotions, and, on the surface, seem reasonable, once we take a closer look at the details, it should be readily apparent that matters would become worse rather than better. But perhaps that is the goal. Make vaccines less tenable so that the argument to get rid of vaccines altogether seems reasonable and is more likely to come to pass. Unfortunately, public health would suffer. We would see more disease, more permanent disabilities, and more death. Those who suffer real vaccine injuries would have a more difficult time getting compensation. But how many people who see this film will have the knowledge to get past the surface veneer, the seemingly reasonable sheen that hides the darker and more dangerous outcome? My guess is very few.

8 comments:

  1. Thank you Todd this is your usual strong work. I particularly like the table comparing NVICP and open court. Also thanks for the cogent explanation of the difference between biologics and pharmaceuticals.

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    1. Thanks, Liz. Most people who know a little bit about vaccines and the anti-vaccine movement can probably recognize what's wrong with those first three demands, but I'd wager fewer people know much about the last one. Luckily, I've got some formal study under my belt on the regulations.

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  2. Thank you for providing this detailed analysis.

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  3. Do Wakefield, Hooker, et al. have any pseudo-justification for splitting up the MMR into single vaccines? As I've read back through the transcripts from Wakefield's press material following his Lancet publication, he immediately jumps on the idea of singles vaccines. Although I know the *real* reason he makes this suggestion (his own vaccine patent), I've never seen what he offers as his "evidence" for single vaccines being safer.

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    1. I can't recall any justification backed by evidence. Somehow, according to Wakefield, the MMR results in virus-strain measles remaining in the gut, but I don't recall him explaining why or how the same would not be true of the single measles vaccine.

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  4. First of all, great article! I have forwarded the link to some of my family members who are supporting the movie. I hope they can see why they should not take it seriously. I do have one question though (out of ignorance), related to something you mentioned in the article:

    "Currently with the MMR combined vaccine, children get two injections (one at 12-15 months and one at 4-6 years) of the 0.5 mL vaccine, for a total of 1.0 mL. If the vaccine is split into single vaccines, children would get triple the injections (6 separate punctures) and triple the excipients (all the stuff in the vaccine beside the antigens), for a total of 3.0 mL of vaccines."

    I'm not following how dividing a single vaccine into 3 separate vaccines would require an increase in excipients. Why would each of the single vaccines need to be 0.5mL in volume?

    Sorry if this is a dumb question, but I am just starting to research this stuff, so there is a lot I do not know.

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    1. "Sorry if this is a dumb question, but I am just starting to research this stuff, so there is a lot I do not know."

      No, it is not a dumb question. It turns out there are just a bunch of details that you just don't know. I did not know them until someone told me.

      There is a physical limit on how little fluid you can put in a syringe. One milliliter is less than a quarter of a teaspoon (about 0.20 teaspoon). So 0.5 milliliter is than 0.1 teaspoon, and one third is 0.0333 teaspoon.

      Get a quarter teaspoon, and fill it up with water. Make sure the water tension does not make a dome above the level. Then try to pour it out into six equal size drops. That water tension is pretty strong when there is a larger surface versus volume ratio (I do have a one eighth teaspoon measure, and it is only good for dry ingredients because the water tension creates a sizable dome).

      Plus, because it is a live vaccine it is not stored more than eight hours in its liquid form. The vaccine comes in a powder that is mixed with a specified liquid to be used in the specified time period:
      http://www.immunize.org/askexperts/experts_mmr.asp#storage

      That last little bit is what I was really surprised to learn. The part about getting small quantities is from my own experience with trying to get very small dye batches for fabric (it (and I was just trying to measure dry powder!).

      But there it is, like everything in life it is just a bit more complicated than we thought.

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