Brian Abramson:  Welcome to the Quimbee program, Vaccine Law 101. I am your faculty, Brian Dean Abramson. I am the lead author of the legal treaties, Vaccine, Vaccination, and Immunization Law published by Bloomberg Law in the American Health Law Association in 2018 with a second edition forthcoming in 2022. I am also an adjunct professor of vaccine law at the Florida International University College of Law.

  Due to the importance of vaccines in human civilization, legal structures have been developed that promote a general public policy interest in vaccination of the population against various contagious diseases. There are five major areas of vaccine law, government regulation of the development, testing, marketing, and distribution of vaccines, ownership of intellectual property rights relating to vaccines, funding of the development and distribution of vaccines and ensuring of access to recipients, vaccination mandates as a prerequisite to the access of rights, such as education or employment, and compensating adverse events alleged to have been caused by vaccines. This course covers the first of these areas, vaccine regulation.

  In order to fully understand the current state of vaccine regulation, it is necessary to review the history that got us to this point. The first vaccine, the smallpox vaccine, was discovered by an English physician named Dr. Edward Jenner in 1796. Jenner understood that people who had naturally become infected with cowpox tended not to get infected with smallpox. He reasoned that, if someone were intentionally infected with cowpox, they would similarly become immune to smallpox. Jenner tested his theory on the eight-year-old son of his gardener, first infecting the boy with cowpox and later exposing him to smallpox, known to be a highly deadly disease. Whether Jenner obtained fully informed consent of the boy or his parents is unknown, but no uninvolved party oversaw or even observed this effort, nor was Jenn required to provide his results to any governing body for review. Such an experiment would be considered highly unethical today and would in fact be illegal in most places.

  Jenner also reported his results based on that extremely small sample size of one test subject, a much less controlled situation than would be allowed today. Nevertheless, when Jenner published his findings, the results were quickly acclaimed around the world. And vaccination quickly came to be promoted in jurisdictions as far flung as Russia, Turkey, and the United States. The king of Spain famously recruited a number of orphans to use as live carriers of the virus to sail to Spain's colonies in the Americas.

  One of the first US federal laws in the field of health regulation was an 1813 law establishing a short-lived national vaccine agency to ensure supply of the "genuine vaccine matter," that is the real matter that would vaccinate people against smallpox, for the smallpox vaccine. Now, the reason this was necessary was that almost immediately after Jenner's announcement of his findings and the spread of vaccinations as a means to prevent smallpox, some unscrupulous people began selling false versions of the vaccine. And a federal agency was deemed to be necessary to ensure that the real version of the vaccine was distributed. However, in 1822, there was an incident in which the agent responsible for ensuring the quality of the vaccine matter accidentally distributed actual smallpox instead of the smallpox vaccine causing number of people to die, and the agency was repealed.

  This is typical of the history of pharmaceutical regulation. It is very often responsive to specific incidents which occur. There are some kind of a calamity, and in response legislation is enacted. A very similar example of this occurred with a 1901 incident in which a retired milk horse named Jim, whose body was being used as the host for the cultivation of tens of thousands of doses of diphtheria antitoxin, somehow became infected with tetanus, leading to those doses becoming infected, in turn leading to the deaths of 13 children in the Midwestern United States. This played a very significant role in generating interest in the federal government ensuring the quality of pharmaceutical products sold in the United States. And several pieces of legislation to this effect were passed over the course of the next few years. These initial statutes established the modern framework of safety and effectiveness as the measures by which pharmaceutical products are determined to be appropriate for introduction to the market.

  It is also important to understand the terminology surrounding vaccination. The FDA defines a vaccine as "an immunogen the administration of which is intended to stimulate the immune system to result in the prevention, amelioration, or therapy of any disease or infection." And in fact, a vaccine is sort of a trick. It's a substance that tricks your body into thinking that a dangerous microorganism is attacking it, and that an antibody response is required. Vaccination or inoculation, which is a more old timey term, is the process of administering a vaccine. The vaccine is the substance itself. Immunization, however, is the intended result, which could be achieved by some other means. For example, natural exposure to the disease or an antibody transfusion from someone whose blood already contains antibodies to the disease, which will render the recipient temporarily immune to the disease, but will not necessarily stimulate their body to produce its own antibodies.

  Vaccines typically contain multiple components with the actual microorganism component only constituting a very small fraction of the total vaccine material in any vaccine that is injected or otherwise administered. The microorganism component itself will have been treated in some way to make it less harmful to the body than the actual live microorganism. In some cases, the organism has been killed. In other cases, it has been bred through a long series of successive steps until the version that has resulted is no longer harmful to the human body. In some cases, it has been treated with something like chemicals or radiation to weaken it so that it cannot actually cause harm to the person. More recently, technology has been developed allowing a harmful organism to have part of itself spliced off and added to a harmless organism so that your body reacts as though the harmful organism were attacking it, when in fact the organism that is actually in your body is harmless to it.

  The development of mRNA vaccines, such as the current Moderna and Pfizer COVID 19 vaccines, introduces a new model of vaccination in which, rather than using the whole organism, you're using a strand of genetic material, which replicates some of the function of what the organism does. Basically, like a virus, it invades the cell and causes the cell to reproduce itself. But unlike the virus, it cannot thereafter continue to reproduce and harm the body. It can only produce a component which the body will react against.

  Other ingredients in a vaccine, besides the material of the organism, are called excipients. And there are a number of common excipients that are found in vaccines. First of all, the microorganism, after it has been killed or weakened, might actually not be strong enough to provoke any immune response in the body. So, vaccines contain substances called adjuvants. An adjuvant is an irritant, usually some kind of assault, that causes your body to feel like it's being attacked, even if the microorganism that is being introduced is no longer able to create that response.

  Vaccines can also contain antibiotics, which seems contradictory, but the antibiotics prevent contamination by other microorganisms, while preservatives added to the vaccine will increase their shelf life, which is particularly important. Or you have vaccines that have to be kept in very cold conditions or other specific conditions for a long period of time before they can reach their intended recipients.

  Vaccines are typically cultured in some medium. So, if you have a typical flu vaccine or a measles vaccine, there is some kind of animal substance in which that vaccine is bred to get to the point where it can be used in humans. Most commonly, these are chicken eggs. And by the way, the locations of the farms where chickens are raised to produce the eggs that cultivate the flu vaccine are considered top secret as a matter of US national security. There are some other animal serums in which certain vaccines are cultured. These may include bovine serums, which come from a cow, or porcine serums, which come from a pig. And the use of these can introduce issues with people who have religious objections to the use of materials coming from these animals.

  From a regulatory perspective, it is important to understand that every component in the vaccine, separately from the vaccine itself as a whole, must meet the same tests of safety and effectiveness. Furthermore, there are a number of combination vaccines that are available, such as the measles, mumps, rubella vaccine, or the diptheria, tetanus, pertussis vaccine. And combination vaccines have to go through clinical trials in their combined form to ensure that no unexpected results arise from the combination. When a new component is developed for a vaccine, such as a new adjuvant, it's typically tested by being substituted for the adjuvant in an existing vaccine for a period of time, with new clinical trials being conducted for the existing vaccine containing the new adjuvant, so that we have something to compare it with to make sure that it works and performs the function that it is supposed to.

  Like other drugs, vaccines are regulated by the United States Food and Drug Administration, the FDA, with vaccines specifically being the responsibility of the FDA's center for biologics evaluation and research, or CBER. No new pharmaceutical product can be introduced for sale or use in the United States without FDA approval. An effort to introduce such a product without FDA approval can result in criminal penalties. Obtaining this approval requires that the manufacturer of the product demonstrate to the FDA that the product is safe and effective for use. This, in turn, requires that tightly controlled and supervised clinical trials be conducted to develop data supporting these requirements.

  Now, vaccines are a bit different from most other drugs in the way that they can be tested for both these aspects. Regular drugs are tested for safety, purity, and effectiveness. Vaccines are different in that they are tested for immunogenicity, that is the tendency to provoke an immune response rather than effectiveness per se, and toxicity, the tendency to have unintended negative effects rather than safety per se.

  The reason for this is that vaccines function by tricking the immune system into thinking that the body is under attack by a dangerous pathogen resulting in an immune response. Unlike other pharmaceutical products, which are intended to alleviate a symptom or condition while minimizing negative effects, vaccines are intended to make the recipient feel a little bit sick, to introduce a little bit of a negative effect that the body will respond against. With most other pharmaceutical products, we really want to avoid causing an immune response in the body. Whereas, with vaccines, the entire point is to cause an immune in response in the body. However, this immune response must be determined to generate the appropriate antibodies to fight the disease. That is how we determine that a vaccine is actually effective.

  So, now that we have described what it is that we are looking for, the question moves to, what are the steps that we take to look for it? And that is where clinical trials come into play. I've mentioned them a couple of times during this presentation. Before a vaccine can be approved for use, it must go through several stages of well-defined clinical trials. There is not a statute that specifies the stages of clinical trials or how they are to be conducted, but these are well understood practices of pharmaceutical research.

  The first step is testing on animals. We test any kind of pharmaceutical substance on animals to make sure that it doesn't have some deadly effect and to make that it has some beneficial effect at all to bother testing it on humans. The animal model that is chosen for a particular test is going to be one for which it can be determined that there is some correlation between that animal and the human anatomy, so that you'll get useful results from testing this on the animal. And with vaccines in particular, we look for animals that have organ systems that are similar to the organs that are attacked by a particular virus. So, there are some viruses that grow in the lungs, and some viruses that attack the liver, or the mucosa, or some other area like that. And we look for animals that have that particular part of their anatomy. Most similar to humans. And that could be rats, or pigs, or some kind of monkey, those are the typical animals that are used in that sort of testing.

  There is a thing called the animal rule, in fact. In very rare circumstances, if you have a disease, like anthrax or like smallpox, if we were to consider a possible smallpox resurgence, where it is presumed that the vaccine is too dangerous to test in humans at all, but might be needed in case of an emergency where it is the only thing that can save lives in the event of, for example, a widespread attack with some kind of biological agent. In that case, you can have vaccines that are authorized for use by the FDA that have only ever been tested in animals, if those animal tests show that it is likely to be safe and effective in a dire emergency in humans. Outside of that, however testing has to be conducted in human test subjects.

  There are three specific rounds of clinical trials, phase one, phase two, and phase three clinical trials that are conducted. And these are conducted in conformance with good clinical practices, or GCPs, which include a number of different factors. The fact that participants in the trial can exit the trial if they wish. The fact that those overseeing the trial, whether it is the scientists participating in it or third party reviewers, can shut down the trial, if they deem that necessary. The fact that informed consent is provided to participants in the trial as to what they will be participating in and what they may be experiencing through that, what the risks are.

  All such trials must be overseen by what is called an institutional review board, or IRB. The IRB is not a government agency. Usually IRBs are committees affiliated with a university or a hospital. They're usually compensated for their role in participating in the oversight of a trial. The IRB's role is to look at all the data, the structure of the clinical trial, how it's being carried out, whether the execution of the trial conforms with the initial plans for the clinical trial, and what the results of the clinical trial are and whether they are progressing and showing what is to be expected. These are the kinds of review that are imposed at every point in the clinical trial.

  So, phase one clinical trials involve 40 to 50 people, typically. The first concern, the major concern, of a phase one clinical trial is whether the vaccine is safe. Now, at every stage in a clinical trial or every phase of clinical trials, in examining a pharmaceutical product, we are looking at whether it is safe and whether it is effective. But the focus shifts from one trial to the next. So, in phase one clinical trials, we're most concerned with whether we see any unusual effects that may call into question the safety of the vaccine. We're also beginning, even at that point, to look at what is the ideal dose of the vaccine. You don't want to provide too little of a dose and have it be ineffective. You don't want to provide too much of a dose, which first of all can have unintended consequences. And secondly can mean that you are using more of the vaccine than is needed to be distributed to the population, which can eventually cause supply issues.

  Phase two clinical trials typically have 400 to 500 people. So, in the phase one clinical trial, you're going to have 40 to 50 people, and they're generally going to be young, healthy, adults, unless it is specifically a clinical trial aimed at testing the safety and effectiveness of a product for a specifically older or younger population. And then, when you get into your phase two clinical trial, you will get into a broader population. You might have people who are in different age groups. You might have people with specific health conditions that you want to determine whether this vaccine or this pharmaceutical product will negatively interact with that particular condition. And of course, you are still looking at both safety and effectiveness.

  And then, finally, you get to the phase three clinical trial, and you have 4,000 to 5,000 people. Here, you're looking at whether it's safe for populations with rare, specific, medical issues. And you're really refining the dosing, and whether you need multiple shots, and what is the interval between doses.

  Another thing that manufacturers are doing during these clinical trials is determining what the contraindications to vaccination will be. Every vaccine that is distributed, has a list of circumstances under which someone should probably not receive that vaccine. And for some of them where testing has shown that there are very few adverse reactions and that the ingredients are generally safe, there will be very few contraindications, while other vaccines may have a substantial number of contraindications based on whether the recipient of the vaccine has immunological issues, or whether they are pregnant or lactating, or whether they have a previous history of allergic responses to ingredients in the vaccine.

  Normally, clinical trial phases last for a year to 18 months each. As each phase is completed, the results are examined, and the information that is gained from that trial is used to design the next round of the clinical trial. With the COVID 19 vaccines in particular, that process had to be greatly accelerated. And in order to accomplish that, what researchers did was to overlap the clinical trials, that is the phase two clinical trial started just a few months after the phase one clinical trials had begun and were based on the data that had been developed to that point. And the same thing with the phase three clinical trials being started a few months after phase two clinical trials were begun.

  In order to compensate for this speed at which this was being done, the clinical trials used about 10 times the number of people at each phase than would normally be seen. So, you had phase one clinical trials with 400 to 500 people, phase two clinical trials with 4,000 to 5,000 people, and phase three clinical trials with 40,000 to 50,000 participants at that phase.

  When vaccines are tested, the testing process has to be a little bit different from the way other pharmaceutical products are tested. You can compare this to testing a headache medicine. If you have an idea for what you think will work as a headache medicine, you find some people ideally who have a headache, or recurringly have headaches, or routinely have headaches. You give them this medicine and you see whether it makes the headache go away. With vaccines, you can't do this, because the vaccine is very specifically testing for whether the vaccine causes an immunogenetic reaction, which prompts the body to fight a particular virus. And the only way that you can really tell whether the body is successfully fighting that virus is when people are exposed to the virus.

  Now, you can't intentionally expose someone to a deadly disease. There are vaccine trials for less harmful diseases where test subjects are intentionally exposed to the disease, and those are called challenge studies. But you wouldn't conduct a challenge study with a disease like COVID 19. Although, some researchers suggested that, given the exigencies of the situation, they should be conducted. But generally, you wouldn't conduct a challenge study with that kind of virus, or with something like HIV, or something else that has a serious potential to kill even a young, healthy, adult trial participant.

  In those cases, what researchers do is they give part of their test population the actual vaccine, and they give another equally large, usually, test population, a placebo. And they tell the participants in the trial, "Go on about your lives." And over the course of the next few months, if they are participating in regular activities, and if there is a disease that is out there in the community, in the world, that people are liable to catch, then some number of trial participants will be exposed to that disease and will catch that disease.

  They determine between number of placebo recipients who became ill with a disease and the number of actual vaccine recipients who became ill with a disease. And they often go to a particular endpoint. For example, they wait until there are 50 instances of test subjects who have become ill with a disease and look at the proportion of those test subjects who did or did not have the vaccine. And if they conclude that 49 of the people who did get ill were unvaccinated, and only one person who got ill was vaccinated, that is a pretty strong indication that the vaccine is very effective, is about 95% effective, in preventing the disease in people who have received the vaccine.

  Now, this is not the only way to test whether a vaccine is effective. It is also possible to look at the levels of antibodies that are developed by the body in response to the vaccine. However, it's not always clear how the antibody level correlates with the ability of the body to defend against the vaccine. So, it is really important to have clinical trials where you actually compare the number of people who become infected with the disease after being vaccinated.

  Furthermore, even after all of these clinical trials have been completed, and all of the data has been compiled, and in fact after a vaccine has been licensed for use, it can still be discovered that there are problems arising from the use of that vaccine. An example is the 1999 rotavirus vaccine, which was licensed by the FDA, after a full set of clinical trials, and was determined, once it had entered the market for use, to cause intussusception, which is an intestinal tangling in about one in 10,000 infants who received the vaccine. And on the basis of that issue, it was pulled from the market and ultimately replaced by another rotavirus vaccine that did not have that issue.

  Historically, some researchers have sought to avoid the stringent requirements imposed by the FDA on clinical trials and their conduct by conducting clinical trials in other countries. And sometimes in third world countries where the local government does not have a particularly stringent method for overseeing clinical trial conduct and where, quite frankly, local officials can be bribed or otherwise convinced to look the other way while the researchers are carrying out clinical trials in what would be considered in unethical manner in the United States. The FDA does have concerns about the quality of controls and whether the population being tested is reflective of that, of US clinical trial participants. And they may require a researcher or a company that has conducted clinical trials in another country to then conduct some clinical trials in the United States, under US levels of supervision and other requirements.

  Researchers who have initiated clinical trials in the United States must report the initiation of these trials to the FDA. And these trials are basically all compiled in a large database of every clinical trial for every pharmaceutical product that is tested in the United States. And they really need to begin reporting to the FDA the fact that they're conducting clinical trials prior to the trial beginning, once they secure the oversight of an IRB.

  Recently, the FDA has ruled that all clinical trial results, including clinical trial failures, must be reported. Before 2021, there was not a requirement that clinical trials that were abandoned for having failed be reported to the FDA. But this requirement was instituted, in part, to ensure that the FDA has a record of what methods and methodologies have proven ineffective in the development of a working pharmaceutical product. So that if a company develops a new molecule and thinks that it has promise in curing a particular disease, and tests out this new structure, and it turns out that it doesn't work, the FDA will know that and will have a record of that, so that future researchers will know that this is not an avenue worth pursuing, or at least if they want to conduct further tests with this particular configuration that they'll need to make some modifications or figure out what went wrong with the initial test.

  Now we move on to the licensure of vaccines. Prior to beginning human testing, the manufacturer of a vaccine must file an investigational new drug application, or an INDA. The INDA indicates who this manufacturer is, who's conducting their research, how they intend to carry out their research, who their internal review board is going to be as soon as they secure that. Once this has been filed, the company can initiate its clinical trials and must again report those outcomes, whether good or bad, to the FDA. Once those phases of clinical trial testing are done, the manufacturer will file what it's called a biologics licensure application, or BLA. This initiates a period of review where FDA officials will look at all of the test data, and scrutinize it very carefully, and determine whether, on the basis of all that data, the manufacturer has demonstrated that they have a product that is safe, that does not have negative or unanticipated side effects.

  Very often, the FDA personnel reviewing the application will require the manufacturer to conduct some additional tests to address particular concerns that may come up over the course of FDA review, for example, with respect to the effect of this vaccine on a particular population that perhaps was not very well tested. This review can take months. Sometimes, it can take years. Over the course of this period, manufacturers may find themselves adjusting the vaccine ingredients or the methods of manufacture, and they must inform the FDA of any such changes. If there are any changes to the way that the vaccine is composed or manufactured that could conceivably affect the outcome on particular patients, then the manufacturer must conduct some new clinical trials to ensure that this reformulation or this change in manufacture hasn't changed the outcome in clinical trials.

  Once licensed or otherwise permitted to be used, and we're going to talk about Emergency Use Authorization shortly, the FDA retains authority to inspect the manufacturer and ensure that it is engaging in good manufacturing processes. The FDA can inspect specific batches of the pharmaceutical product to ensure that it is pure and potent, that it is effective, and that it hasn't been diluted in some way. The FDA can inspect manufacturing facilities to make sure that they are clean and hygienic, operating properly, have all of the necessary safeguards and precautions to ensure that there is not contamination of a product. They can investigate adverse event reports that are brought to the attention of the FDA.

  They can investigate false advertising in connection with a product. So, even if you have a fully licensed product, if your advertising suggests that your product is effective than your testing has shown, the FDA can pursue claims based on this, essentially, false advertising and require remedial action or impose fines. The FDA generally begins any kind of process of remediating defects shown either in the process or in the advertising by issuing warning letters. At the most extreme end, the FDA can require that a product be removed from the market and can institute fines against the manufacturer based on their practices.

  In some instances, clinical trials continue, even after the FDA has licensed a vaccine for use. These may be continuations of phase three clinical trials or entirely post phase three clinical trials called phase four clinical trials.

  There are systems through which adverse events, resulting from the use of a vaccine, are reported to the FDA as well as to the Centers for Disease Control, the CDC. The most well known of these is probably the Vaccine Adverse Event Reporting System, or VAERS, which is primarily monitored by the CDC. Manufacturers are required to report serious adverse events of which they become aware anywhere in the world. So, if there's a serious adverse event, a death, a crippling, a hospitalization for a period of time, and the manufacturer is aware of that, they have to report it to VAERS. Physicians also generally report adverse events through the VAERS system. They are not required to by statute usually, but are generally considered to be ethically required to report them when they become aware of them. And a physician who is aware of adverse events and fails to report it can get into trouble with the licensing organization for the practice of medicine in the state where they practice.

  Now, who else can report an adverse event to VAERS? Anyone in the world, the patient, their parents, their friends, people from across the street who see them passing by and think that they're having an adverse event to a vaccination. Because of this, VAERS reports are considered to be rather unreliable for use in fact finding proceedings, such as trials.

  What VAERS data is primarily used for is to spur investigations by the CDC, and in some cases by the FDA, to confirm whether serious adverse events are in fact related to vaccination. And where an adverse event is determined to be related to the vaccination, to figure out why it happened, if there was something in particular wrong with that batch of vaccines, or if there was something in the physiology of the recipient of the vaccines that made them particularly susceptible to an adverse reaction. Based on the outcome of such an investigation, the FDA may require the manufacturer to add to the list of contraindications some additional indication for which someone should not receive this vaccine.

  As we have seen during the course of the COVID 19 pandemic, licensure of a vaccine is not the only path by which it can reach the market. There is another mechanism that is available during an emergency, which is fittingly called Emergency Use Authorization. Under 42 USC Section 3bbb-3a(1), the Secretary of Health and Human Services is permitted to authorize the introduction into interstate commerce during the effective period of a declaration a drug, device, or biologic intended for use in an emergency. Now, the first aspect of that is there has to be a declaration of an emergency. And there are a number of different public officials, the Secretary of Health, the Secretary of Defense, the Secretary of Homeland Security, who can declare an emergency for various reasons, for which an Emergency Use Authorization might be an appropriate power to exercise. The Emergency Use Authorization or EUA power extends to products that are not approved, licensed, or cleared for commercial distribution, as well as those approved conditionally or for other uses.

  So basically, it allows a product that is in the developmental stages to be used to respond to the emergency. It also allows a product that is licensed for use, but not for that particular use to be used in response to the emergency. The standard for issuance of an EUA is that, based on the totality of scientific evidence available, including data from adequate and well-controlled clinical trials, it is reasonable to believe that the product may be effective in countering the emergency. Basically the FDA has to determine that it is more likely that this product will address the emergency helpfully than that this product will cause harm. The FDA can, and in some cases does, voluntarily impose higher standards upon itself, based upon the circumstances. An example of that occurred with the COVID 19 vaccines, where the FDA said that they would not issue an Emergency Use Authorization until there were two months of post phase three clinical trial data to review showing the safety and effectiveness of those vaccines.

  Furthermore, an EUA can be withdrawn if evidence is produced that makes it no longer reasonable to believe that the product is more likely to be helpful than harmful. For example, early in the COVID 19 pandemic, an EUA was issued for hydroxychloroquine. Tests were later conducted, which appeared to show that hydroxychloroquine had no beneficial effect and potential harmful effects in addressing the COVID 19 pandemic. And the FDA withdrew the EUA for that product.

  Interestingly, the first EUA ever to be issued was for a vaccine. It was for the anthrax vaccine that was available in 2005. Now, this is right around the time that the EUA statute was passed into law. So, it was one of the first substances for which it was possible to issue an EUA. And there was some thought at that time, there was some expectation, that, as pandemics came around, there would be issuance of Emergency Use Authorizations for new vaccines developed in response to those pandemics. However, during the period between 2005 and 2021, every pandemic that occurred passed too quickly for a vaccine to be developed against the disease during the period of the declared emergency. So, the first vaccine to be issued an EUA, since 2005, was the first of the COVID 19 vaccines for which this was done.

  Another aspect of FDA authority over vaccines is with the regulation of trade names. Now, in trademark practice, usually there are two kinds of basis for seeking a trademark registration. One is that we have used this product in commerce for a while, and customers have grown accustomed to the name, and therefore we're able to demonstrate that we have some connectivity between the name and what customers expect the product to be. Alternately, you can file an intent-to-use application, which is we're not using this name in practice yet, but we intend to use it. And we intend to secure our rights in this mark. You can't really get a use in commerce trademark registration for a vaccine, because in fact, the name has to be approved by the FDA before the name can be used on the product in commerce.

  In theory, a manufacturer could get approval from the FDA and begin marketing the vaccine under a certain trade name without filing a trademark registration application. But that's something that's highly unlikely to ever happen. Because, pharmaceutical companies are very possessive of the name and image of their products and want to be able to protect it as much as possible from the earliest moment possible.

  Now, the United States Patent and Trademark Office does its own examination to see if a proposed trademark is generic or descriptive. So for example, the Patent and Trademark Office won't allow a vaccine to be registered if the name of the vaccine was just the name of the disease and vaccine. For example, you couldn't register COVID vaccine as your trademark, because other manufacturers of such a vaccine would need to be able to describe their product correctly as a COVID vaccine.

  And the test that the United States Patent and Trademark uses is, first of all, is it generic or descriptive of the product? And secondly, is it confusingly similar to an existing mark? So again, you couldn't name your COVID vaccine Coca-Cola COVID vaccine. Even though the Coca-Cola Bottling Company doesn't make vaccines, it would lead people to think that this was somehow associated with a company that is well known for using the name Coca-Cola for its product.

  Vaccine manufacturers are allowed to submit up to three proposed names to the FDA's CBER, which again, oversees biological products. And the CBER tests these names to avoid possible medication or prescription mix ups. So, this is very similar to the US PTO's likelihood of confusion test, but whereas the US PTO is concerned that consumers might think that a product comes from a different company and therefore has whatever the qualities of that other company's product are, the FDA's review is solely concerned with whether two products are so similarly named that a pharmacist might fill a prescription incorrectly and thereby cause an adverse reaction because someone is getting a medication that has not been prescribed for them. The CBER tests these proposed names in ways such as reciting the names over the phone with different accents, with various background noises, and scribbling them out on paper in different kinds of handwriting to make sure that when [inaudible 00:44:30] do call in prescriptions, they're going to be recognized correctly by the pharmacists who are receiving them.

  Now, technically, a non-vaccine or a fake vaccine that is sold under a trade name that implies that it is a vaccine would be misdescriptive under the trademark laws, and would also be misbranding under the Federal Food Drug and Cosmetic Act. So, if you have a vitamin supplement and you either call it the COVID vaccine or market it as a COVID vaccine, then you'll be in violation of the law and various federal agencies. The FDA, perhaps the Federal Trade Commission, can come after you and impose various penalties and require you to cease using that method of advertising, and perhaps pull your product from the market, and issue some kind of restitution to a trademark owner if you are using something that is confusingly similar to what that trademark owner in fact has as their mark.

  The next major issue we're going to come into, in vaccine law, is biosimilars and registration of biosimilars. Now, with most pharmaceutical products, you have what are called generics. And a generic product, for example generic acetaminophen, is something with a chemical formula that identically matches the chemical formula of an existing product, which is available and perhaps licensed to be used on the market. And if you have a licensed product and a competing manufacturer is able to manufacture something that is in fact identical to that product, then they can very quickly get approval from the FDA to sell their competing version on the market.

  With vaccines, this is not possible, because whereas a typical drug is a molecule that may contain a configuration of thousands of different atoms, a vaccine is typically a biological product, and we're talking about millions and millions of atoms to develop its structure. And it's simply not possible for another party to exactly replicate down to the molecular level the vaccine that has been developed by the original manufacturer.

  Therefore, the FDA has this class of products that are called biosimilars. A biosimilar is a biological product that is highly similar to the original product and has no clinically meaningful differences from the original product. However, biosimilars are not genetic. The active ingredients need not be chemically identical. Now, the highly similar test refers to the chemical composition. It's basically, if you were to look at this molecule under a microscope, even though there would be some differences, there would be very few, it would appear very similar. Whereas, the no clinically meaningful differences test refers to the effect in terms of safety, purity, and potency, generally as demonstrated through human testing, through clinical trials similar to those conducted with the early original testing of the vaccine in the first place, although these may be much smaller sample size clinical trials and accelerated clinical trials based on the fact that you have a very similar product that you've developed. The legal significance of a biosimilar is the speed with which it can be granted a license to be sold on the market.

  Generally speaking, the development of new drugs takes a very long time, and the development of vaccines given their complexity often takes even longer than simpler pharmaceutical products. Generic drugs have long been listed in an FDA resource called the Orange Book. Drugs listed in the Orange Book would be granted a certain period of market exclusivity during which no competitor could come on the market with a generic version of that product. However, the Orange Book was not applicable to biological products.

  In 2009, the Biologics Price Competition and Innovation Act of 2009 was passed, creating something called the Purple Book, which specifically lists biosimilar products. If a product is listed in the Purple Book, then two things will arise from that circumstance. One being that the term of market exclusivity of that product will be extended by a certain amount, but also that once the period of market exclusivity ends, competitors will be able to get onto the market with a biosimilar product much more quickly.

  Typically, the manufacturer of a pharmaceutical product, including a vaccine, will protect its market for the product by having a patent, which competitors are not allowed to infringe. They're not allowed to make something that is identical to what is covered by the patent. However, patents only last for 20 years. And sometimes the testing and approval process for a vaccine can eat up seven, eight, nine years of that patent term. So, the BPCIA guarantees that the manufacturer of a biological product, including a vaccine, will have a 12 year period of market exclusivity. That is a 12 year period during which no competitor will be licensed by the FDA to market their competing product in the United States. In addition, the BPCIA provides a four year period of data exclusivity.

  Now, when you file for approval of your vaccine with the FDA, you have to provide all of your data, the composition, how it's manufactured, the clinical trial studies, how it was tested and how they were carried out. And eventually, all of that data becomes part of the public domain. But before that happens, the FDA gives you a four year period during which nobody else can see that data ,and that puts your competitors a step behind when they are preparing to try and come up with a product that competes with yours.

  Each of these exclusivities, this 12 year market exclusivity and this four year data exclusivity, can be extended for an additional six months for pediatric applications. Most vaccines are for children, and therefore are considered pediatric applications. The reason that this exists is because we do want to come up with products that benefit children, and therefore want to encourage manufacturers to develop these products, even if they're not going to have the full term of a patent to exploit the market for those products. The flip side of this market exclusivity is that, once this exclusivity ends, a competitor who does develop a competing product that is a biosimilar can file what is called an Abbreviated Biologics License Application, and this will fast track their product for FDA approval.

  There is also another level of similarity beyond a biosimilar product, and that is an interchangeable product. An interchangeable product is a biosimilar that has been shown to have the same clinical trial results in any given patient. So, unlike the biosimilar, which has to have no meaningful differences but you can have some differences, an interchangeable product is one for which, during the testing, it was shown that there are no differences in the effect of the product on the pool of recipients. The legal significance of an interchangeable product is that the prescriber, the pharmacist, the patient, any person in the chain of prescribing or administering that product can substitute the interchangeable product for the original product. And they don't need to consult with anyone or tell anyone, or make any record of it. It is simply understood that this is effectively the same product.

  In practice, it is actually extremely rare for biosimilar vaccines to be deemed interchangeable. There's only one example, to this point, of a vaccine being deemed interchangeable. And that is when the Pfizer vaccine was approved for licensure, the Pfizer COVID 19 vaccine, now sold under the name Comirnaty. It was deemed to be interchangeable with doses of the vaccine that were manufactured prior to licensure. Therefore, anyone along the chain, after this licensure, would still be able to use a pre-licensure manufactured dose. The difference is legal. There is no difference in its composition.

  The FDA did not specifically invoke its statutory authority in declaring that these were interchangeable. It merely announced that they are interchangeable. And that has left a little bit of a gray area as to whether, in fact, this has been statutorily deemed interchangeable or FDA was just using the term in a colloquial sense.

  Up to this point, we have been talking about the internal operations of the FDA and its relation to manufacturers who are seeking licensure of their vaccines. But what about third party challengers who wish to oppose decisions of the FDA? With respect to vaccines, this comes up from time to time with populations that are being required to receive vaccines and want to oppose FDA approval of those vaccines as a means of opposing vaccination mandates.

  In the 2004 case of Doe v. Rumsfeld, military personnel who were ordered to receive an anthrax vaccination, the FDA issued a license for the vaccine, but the personnel objected to that on the grounds that the FDA had not followed its proper procedures in making this determination. And the court actually sided with the military personnel and said that the FDA had not followed the proper notice and comment rule making procedures for making that determination and sent it back to the FDA to redo it. Basically, what happened in that case was that the FDA went back, went through the process again properly, and in fairly short order reissued the licensure of that vaccine. A subsequent effort by the military personnel to oppose its licensure then failed and the vaccination mandate was carried out.

  In the 2012 case of Coalition for Mercury-Free Drugs versus Sebelius, plaintiffs sought to bar the FDA approval of vaccines containing a mercury-based preservative called thimerosal. And they were found to lack standing due to the fact that thimerosal-free vaccines for the same diseases were available, and the mandates requiring vaccination for those diseases did not specify which vaccines had to be used. So, the complainants had the option of using a vaccine that did not contain thimerosal. They didn't have any particularized injury due to the licensure of those vaccines.

  A similar issue arose in 2021 when the FDA licensed Pfizer's Comirnaty COVID 19 vaccine. At the same time, the FDA reauthorized the Emergency Use Authorization for vaccines produced by Pfizer before licensure of the Comirnaty vaccine. Plaintiffs challenged the continuation of the Emergency Use Authorization on the grounds that, now that there was a licensed vaccine, there was no reason to allow emergency use of the unlicensed doses. And the court, once again, held that the plaintiff showed no particularized harm through the continuation of the EUA and therefore lack standing to challenge it.

  One other area over which the FDA exercises authority with respect to vaccines is requirements for labeling and documentation. Typically, when a vaccine is transmitted to the administrator who's going to administer it to patients, it has to be accompanied by two kinds of documentation. One of these is the package insert, which is provided to the administering physician to provide them with information about how to administer this vaccine and what they need to know with respect to that. And the other is a vaccine information statement, which is provided to the patient receiving the vaccine, which provides rather simplified information about the effects of the vaccine. The package insert is a lengthy technical document, and it includes information about the vaccine ingredients, warnings, instructions for use, precautionary information, as well as contact information for the manufacturer. Whereas, the vaccine information statement provides basic information about the vaccine, instructions for a recipient who has a serious reaction to the vaccination, advising them to report this to the Vaccine Adverse Event Reporting System, or VAERS.

  In rare instances, vaccines may also need to be accompanied by an OSHA safety data sheet. The Occupational Safety and Health Administration requires that, where substances are shipped or stored in bulk, there has to be some information provided with them for those handling those substances in case there is a spill or an incident. And generally, the safety data sheet requires information about the flammability, explosiveness, toxicity if ingested or exposed to eyes or skin of substances. With vaccines, there's generally not going to be any kind of flammability, or explosiveness, or potential for environmental degradation, but there may be issues if large quantities of a vaccine are in fact ingested or exposed to eyes or skin. So, that must be included in an OSHA safety data sheet for the handling of such materials by workers.

  Now, going back to the labeling of vaccines for physicians. When a pharmaceutical product is licensed for a particular purpose, that is for the treatment of a particular disease or condition, a physician may generally use their judgment to prescribe it for another purpose for which it is known to have some effect, which is called off-label use. It will be very rare for there to be circumstances where a vaccine can be prescribed for off-label use. But in 2021 questions arose with respect to the COVID 19 vaccines, which were licensed for use for persons above or within certain age ranges. In some cases, these were prescribed by physicians for persons outside those age groups, which would be considered an off-label prescription.

  However, due to the unique circumstance of the US government owning all of the doses of the vaccine by contract with the manufacturers, the CDC had the authority to impose additional conditions on the prescription of those vaccines and basically had the authority to provide doses only to physicians who would agree to adhere to the uses of the vaccine authorized on the label. So, this would not necessarily prevent a physician from prescribing a vaccine to someone outside of an approved age range, but it would place them in violation of their agreement with a CDC if they did so, which is something that would be potentially negative for that physician.

  It is also worth noting that all vaccines in the United States are prescription drugs. There are two broad classes of pharmaceutical products in the United States, those that are available by prescription only and those that are available over-the-counter. In order for something to be available over-the-counter, it generally has to be something that is not easily susceptible to misuse or abuse.

  Arguments have been made that vaccines should be available over-the-counter. They're really not susceptible to abuse, because they don't have any kind of narcotic effect. And it's very difficult to overdose on vaccines, given their administration methods. Particularly, the argument has been made that nasal spray flu vaccines, which don't even require an injection, should be offered over the counter. However, the FDA has not taken up any of these suggestions.

  One interesting aspect of the prescription versus over-the-counter dichotomy is that states have the power to decide who can prescribe drugs and under what circumstances. Unlike most other pharmaceutical products, states have been very lenient in determining who can prescribe vaccines, and generally allow pharmacists to prescribe vaccines without the involvement of a physician.

  There are three models by which vaccines are prescribed in the United States. There is the prescription model where a physician's prescription is required. There is the pro protocol model where a physician provides a protocol to a pharmacist, a written document explaining how a patient should be assessed and then prescribed this vaccine. And the pharmacist can then take those steps without further involvement of the physician. And the model under which the pharmacist can prescribe without any involvement from a physician at all, even in terms of providing a written protocol. The specifics of these statutes are as varied as the states themselves, with pharmacists having diverse authority to prescribe vaccines based on the ages of the patients themselves and the different vaccines being prescribed.

  One last area of vaccine regulation to be addressed is the regulation of vaccines for animals. Now, this is something that we generally don't think of as being relevant to human populations. But there is some degree to which it is understood that vaccines administered to animals may leave residues that end up affecting the human population, particularly with respect to food animals, but also with respect to pets. And there are a certain number of incidences every year during which vaccines intended for animals are accidentally administered to humans, very frequently through accidental needle sticks by someone trying to administer vaccines to an animal.

  The vaccines themselves work identically in animals as they do in humans. They stimulate an immune response. But vaccines for animals are regulated by the United States Department of Agriculture rather than the FDA, which has much of the same authority over animal vaccines that the FDA has over vaccines for humans. At any given time, there are hundreds of different animal vaccines that are actively licensed by the USDA.

  Vaccines for animals do undergo clinical trials, although without many of the safeguards applied to clinical trials for human subjects. And like vaccines for humans, the authorization to administer vaccines for animals may be restricted by the states to licensed professionals. Although, many states do allow animal owners, particularly with respect to large livestock operations, to vaccinate their own animals. There is no legal requirement that adverse events following the vaccination of an animal be reported, although that practice is strongly encouraged. However, animal vaccines do require safety precautions in the event that a human is accidentally injected with or exposed to the vaccine, something along the lines of accidental injection in humans may cause severe inflammation or necrosis. That concludes my basic seminar on the law of vaccine regulation.