Public Health and Public FearsPaul A. Offit, MD is the Chief of the Division of Infectious Diseases and the Director of the Vaccine Education Center at the Children’s Hospital of Philadelphia. He is also the author of The Cutter Incident: How America’s First Polio Vaccine Led to the Growing Vaccine Crisis (Yale University Press, 2005). In The Cutter Incident, Dr. Offit explains how a polio vaccine made in 1955 by Cutter Laboratories inadvertently infected some 200,000 people with live polio virus and how, in the wake of this tragedy, a single jury verdict against Cutter nearly led to the extinction of vaccine manufacturing in the U.S.
A conversation with Paul Offit, M.D., on the challenges facing vaccine development
Paul Howard, Ph.D.
Medical Progress Today
August 25, 2006
Paul Howard: After reading your book, it struck me that our national obsession with vaccine safety dates back even to Salk's polio vaccine. Do you think that is true?
Dr. Paul Offit: I don't think that the public was obsessed with vaccine safety in the 1950s. Cutter Laboratories made a vaccine that had live polio–virus in it, probably in every dose at least for [the two lots mentioned in The Cutter Incident]. In effect, they were injecting live polio virus into children that was causing them to have polio and some of them to die. And yet the polio vaccination effort continued. I can think of no equivalent of that today. The Rotashield vaccine was withdrawn from the market in 1998 after only a single death.
PH: I guess what I was thinking of was the debate after Cutter's vaccine was withdrawn—about whether continued vaccination efforts using Salk's vaccine [manufactured by other companies] were safe. Parents were agonizing about whether or not to bring their children in.
Dr. Offit: That was because doctors were agonizing. I think what happened was the American Academy of Pediatrics (AAP) took a conservative stance on Salk's vaccine, which I actually think was radical at the time. They basically said "We're not sure whether this is safe yet. We think time should go by before we can figure out whether it's safe." But if they had looked a little closer they would have seen that the Division of Biological Standards [at the National Institutes of Health] had developed much better safety tests. Post–Cutter, the vaccine was safe even when the AAP wasn't sure, although the CDC endorsed the polio vaccine. But the American Academy of Pediatrics didn't and doctors were caught between the AAP and the CDC and as a result many [parents] waited. Ironically, this meant that there was in effect a controlled national study on the efficacy of Salk's vaccine, which in fact showed that it had a powerful protective effect. At the time the American Academy of Pediatrics described its action as a "conservative choice," but I would argue that that was a radical choice because it exposed many children to polio who would have benefited from Salk's vaccine.
PH: The AAP didn't really understand what was at stake.
Dr. Offit: There are no risk–free choices there are only choices to take different risks. And in that case because polio was still epidemic in the United States, endemic and epidemic, by choosing not to get your children vaccinated you were choosing to risk them getting polio. And it became very clear shortly after the vaccination campaign began that that was the more dangerous choice. We are going through the same thing today with parents who are opting out of vaccinations for their children for, say, chicken pox. Don't misunderstand me, I'm all for people avoiding unnecessary risks, particularly for their children, but I think that people don't have a realistic assessment of what the real risks are.
PH: As a nation, we don't have a good sense of what the relative risks are or even how to measure them.
Dr. Paul Offit: We don't know what we should be really scared of. We're scared to death of the prospect of pandemic flu—yet epidemic flu kills 30,000 to 40,000 people every year. No one is in a panic over that. The nation is not in a panic over strokes and heart attacks that kill hundreds of thousands of Americans every year. Instead we're scared of botulism, and tsunamis, and plague bacillus, and all the things that are much, much less likely to kill us.
PH: Our priorities are misguided, or at least not well thought out. Do you think that's because the media and the plaintiff's bar have just focused on certain risks out of context? The plaintiff's bar obviously has its own agenda, but the media has some responsibility to put those risks in context and it doesn't. How can we make people more comfortable with these relative risks? How do we explain them in terms people can understand?
Dr. Offit: Yes. The plaintiff's bar is responsible for much of the misinformation about relative risks, and the media should do a better job. But doctors also need to do a much better job of educating their patients.
If you look back just a few years ago at the controversy surrounding the measles mumps rubella vaccine (MMR) that was generated by a single published paper by Andrew Wakefield  in which he argued that he believed that the MMR caused autism. That argument wasn't supported by any data. It was just a hypothesis. Wakefield's paper was published in The Lancet, a highly respected British medical journal. Based on that publication, over the next year his argument was widely reported in the medical presses and, and as a result, there was an increase in parents in the U.S. who chose not to have their children get the MMR vaccine.
In 2000, there were the hearings in Congress on MMR that generated an enormous amount of media attention, much more so actually than in the first two years, but it didn’t affect vaccination rates. In other words, it was the doctors and the medical community who were responsible for uncritically reporting bad information and I think that, sadly, that’s often the case.
Again, [Wyeth's rotavirus vaccine] Rotashield was taken off of the market because of a safety issue, which was widely reported in the media. As a result, the vaccine was given a scarlet letter and perceived to be unsafe even though you could actually make an argument that its benefits still outweighed its risks even in a developed country like the U.S. [But that argument was never made in the medical community by the people who were in a position to make it.]
PH: That's a very important point.
Dr. Offit: Right. Now, here's the flip side of this issue. After Rotashield was withdrawn Merck proceeded to do trials on their rotavirus vaccine [Rotateq], of which I am a co–inventor, but the consent form for the clinical trials was 15 pages long, single–spaced. It probably had a single paragraph on what the rotavirus can do to your child, and fourteen and a half pages on potential side effects (because it was written by Merck's lawyers) and what the last vaccine did. Basically, they did everything short of printing a black skull and crossbones on the consent form and yet they still managed to recruit 70,000 people into their study, the largest single study ever supported by a pharmaceutical company or run by a pharmaceutical company.
PH: How did they do that?
Dr. Offit: No one bothered to read the 15 page long single spaced form. Who would? Patients basically looked at their doctors and asked, "Do you think I should do this?"
PH: We've made the idea of informed consent so convoluted we've made it impossible to be informed.
Dr. Offit: I'm actually working on my next book on Maurice Hilleman, one of the greatest vaccine pioneers of all time. If you look at the informed consent form that Hilleman gave patients when he was testing his measles and mumps vaccine in the 60s, it was a 3x5 index card which had on a single sentence that said, "I allow my child to get an experimental mumps vaccine." That's all. On the bottom, it had room for the parent's signature.
Nothing about the disease, nothing about the vaccine, or the vaccine components, or the risks of the vaccine, just the card. Today, the pendulum has swung completely in the other direction, and informed consent forms are written by lawyers and are virtually incomprehensible. Honestly, though, in the final analysis, we're still conveying the same amount of information.
PH: This is an experimental treatment, be aware that you're taking a certain risk.
Dr. Offit: Risk is inherent in any medical treatment or procedure.
PH: And that leads into my next question. I was astonished reading about the early vaccine pioneers, who were inoculating their own families with experimental vaccines. Society had a radically different view of appropriate risks in medical research.
Dr. Offit: I just want to return to your first question for a moment: What can we do to make people more comfortable with vaccines? The answer to that question is that if you want to make people today as comfortable as my parents were with vaccines, let them see the disease, let them see the consequences of forgoing vaccinations, because they don't see it.
I mean not only do they not see the disease anymore because vaccines do work, but today's parents didn't even grow up with these diseases–most of these diseases have been eliminated for thirty years. Young parents have no experience with these diseases, and so they take the value of vaccines as a matter of faith.
But who are we asking them to have faith in? The pharmaceutical industry, doctors, and public health officials. And over the past 50 years there has been tremendous erosion in faith in all of those groups. In my research on The Cutter Incident, as I was reading the transcript of the Cutter court trial, I was struck by how respectful the juries were in their questions to hierarchy. The jury implicitly trusted scientists, trusted doctors, trusted pharmaceutical companies. It was clear that they thought Cutter was actually being railroaded and was very sympathetic to the company. You would never—or at least very rarely—find that kind of implicit trust today.
PH: Phillip Howard and his group Common Good make this point quite often, that Americans don't trust the "gatekeepers" any more, whether it's industry or public officials, to make decisions about what it best for the common good. There is a pervasive distrust of public and private institutions that leads to gross perversions of common sense.
Dr. Offit: I'll give you a perfect example. At the onset of the thimerosal controversy, when the idea was spreading that vaccines caused autism or that vaccines cause neuro–developmental delays, or that multiple vaccines could weaken or overwhelm the immune system, the CDC sensed that the public discussion on vaccines was tilting widely out of proportion to the real issues at stake and commissioned the Institute of Medicine to study the issue. What did the Institute of Medicine do? It formed a committee called the Immunization Safety Review, and let me quote to you from foreword to their findings:
Given the sensitive nature of the present immunization safety review study, the IOM felt it was especially critical to establish strict criteria for committee
membership. These criteria prevented participation by anyone with financial ties to vaccine manufacturers or their parent companies, previous service on major vaccine advisory committees, or prior expert testimony or publications on issues of vaccine safety.
PH: Who is left?
Dr. Offit: People who have never published a peer–reviewed article on vaccines. Given the dearth of knowledge available to them, what happened is that the IOM gave the CDC some really bad advice: that mercury containing preservatives (i.e. thimerosal) should be taken out of vaccines, not having any idea what it meant for them to be in there, or what it meant to take them out.
As a consequence, Wyeth stopped making its DTaP vaccine [for diphtheria, tetanus and pertussis]. It wasn't worth it for them to do an expensive retooling their manufacturing process to make vaccines that weren't making them a significant profit in the first place. It didn't hurt the company, but it certainly hurt the public health. There were instantly DTaP shortages and flu vaccine shortages, there was rationing of those products, and there is no doubt in my mind that there were children who suffered from those diseases, because they are common ailments and because they didn't get the vaccine. That's what you get from the "cleansing" of the committee to reach some abstract standard of objectivity.
PH: It is absurd that, at the end of the day, we have become so afraid of potential conflicts of interest that being an expert effectively disqualifies you from serving on a public committee.
Dr. Offit: Everyone at some level has a bias, for whatever reason. If the focus is on me, my perceived conflict is that I have worked with a pharmaceutical company and that means that somehow I'm willing to lie about vaccine safety. I think that's just wrong. People who publish papers on vaccines or devote their lives to vaccines, and who testify in front of federal advisory committees do so because first, they have an expertise and, second, because they think it's the right thing to do. In some ways I'm the poster boy for conflict because I have a patent on a vaccine that will probably make a lot of money for me. But that's not why I am a scientist, and certainly not why I've been working in this field for 25 years.
PH: I think you touch on this issue tangentially in your book when you talk about Salk and Sabin, and the kind of professional and career issues that were at stake in their race to claim credit for a safe polio vaccine. Anyone who wants to be successful and make a difference in the world is going to be operating from some kind of bias—or perspective, if you will.
Dr. Offit: Yes. But it's also that if you're good at it, if you're a good scientist, and Salk was a good scientist, and Sabin was an excellent scientist, then pharmaceutical companies who want to make good medical products will seek you out. Today, people who work with companies to develop new medicines are virtually precluded from having a voice in public debates because they're perceived as tainted.
PH: One last point on the issue of public education. You say that what we really need to do is to show the parents the disease, to make them understand the risks that they're taking by not vaccinating their children. Who needs to take the lead in doing that, in educating the public on the value of vaccines?
Dr. Offit: There are groups like the Vaccine Education Center here at Children's Hospital of Philadelphia which certainly puts out a lot of education materials; we get about 250–300 orders a day for our education materials, and we get that to parents through doctors. The American Academy of Pediatrics has a website, and it does some public service announcements. I also think that the Immunization Action Coalition headed by Deborah Wexler also does this. But we all could collectively do more.
PH: Does it need to be a national effort? And if so, who needs to step up to the plate?
Dr. Offit: The CDC
PH: The CDC?
Dr. Offit: Or the NIH, or the AAP, or state and local public health agencies should educate the public about their health. Ironically, this job always falls to the pharmaceutical companies, who obviously are going to be seen as biased—and today anything smacking of direct to consumer advertising is seen as evil—even though DTC is a good way to educate the public about diseases. Outside of industry, very few people are doing that kind of education.
PH: Looking back at the effort to develop the polio vaccine, where are we in the dynamic between weighing risks and benefits, especially with public health products like vaccines?
Dr. Offit: In regard to testing you mean?
Dr. Offit: We're way on the other side. I think probably the best example of that is the Jesse Gelsinger story.
PH: What is that?
Dr. Offit: You'll probably know it when you hear it. He was an 18–year old boy—treated here at the University of Pennsylvania medical center with gene replacement therapy.
PH: Gene therapy?
Dr. Offit: Right, so he has an enzyme deficiency, ornithine transcarbamylase (OTC) deficiency, which means he has to watch his diet every day, he has to take medicines every day, and because he's a teenager he doesn't do that, and he periodically goes into a coma and has to go to the hospital.
He's viewed as a perfect candidate for gene therapy. So they inject Jesse with a dose of weakened cold virus, adenovirus, which doesn't replicate very well at all frankly, and they clone in this gene to see if they can replace the gene that he is missing. But, he has a massive immune system response called a cytokine storm and, tragically, he dies.
That single incident set back the field of gene therapy because regulators and researchers are under tremendous pressure to be conservative and have become, as you might say risk averse. Well the fact of the matter is that every day children are admitted to the hospital with cystic fibrosis which is a genetic defect, or sickle cell disease, both of which are very well defined single gene genetic defects.
Doctors know exactly what gene is missing, they know exactly what gene it is you have to replace, but we're so careful about making sure we don't have a repeat of what happened to Jesse Gelsinger, which is to say to try something that could hurt somebody or worse kill somebody. As a result, gene therapy is now very, very slow moving. And as a consequence children will keep dying of diseases that could be treated with gene replacement therapy.
We just don't seem to be as compelled by the deaths that happen every day as by the risks that come with medical research. This is how lawyers think, but not how scientists should think. We are scared of being sued for using gene therapy to treat someone with sickle cell disease.
PH: In effect, you need something like the Good Samaritan provision for medical research, by which I mean that we recognize that if someone is going to risk their life to save another person's life in an emergency, that person should be indemnified from any accidental harm that may occur during that life saving action. The Good Samaritan shouldn’t be dissuaded by the potential of legal exposure.
Dr. Offit: Very interesting way to look at it.
PH: But if you're a physician working on gene therapy that may save ten thousand or a hundred thousand lives you are going to held to a higher standard than that single Samaritan trying to help a single person.
Dr. Offit: Yes. An unfair standard, I think. The history of medicine is very clear, and The Cutter Incident is just one of many, many examples. It's always trial and error, it's always a process of evolution, and someone invariably gets hurt. I mean look at the early efforts associated with kidney transplants or heart transplants. Through the prism of today's accomplishments in the field, they were barbaric.
PH: The example I am familiar with is that of childhood leukemia, which is largely curable now, but the early experiments with chemotherapy and bone marrow transplants were utterly harrowing to read about. And we’re taking about children suffering through round after round of brutal chemotherapy for years.
Dr. Offit: The difference is, those people are sick; doctors are treating somebody who is sick. I could make the same argument about gene therapy and Jesse Gelsinger, but it doesn't seem to apply today.
PH: For vaccines the problem is even worse. The very thing that makes vaccines such powerful public health tools, that you can treat the healthy and keep them healthy, makes it very problematic to develop new products and test them in the legal environment that we're in now.
Dr. Offit: I think it's reasonable to hold anything that you put into healthy children to a higher standard, compared to testing a treatment in someone who's critically ill. That makes sense to me. But the pendulum has swung wildly past what I would consider reasonable. There are grades of risk and risk toleration between a child with cancer who is dying and a healthy child who needs a vaccine. That's a healthy debate, and I welcome it.
PH: But even when you're looking at the case of something like the rotavirus vaccine, a product you're intimately familiar with, that has a certain risk to reward ratio in the U.S. and the E.U., but in Third World nations it's enormously helpful even assuming that there are intussusception risks like those arguably associated with Wyeth’s vaccine in 1998.
Dr. Offit: I couldn't agree more.
PH: So if we're not having that debate effectively in the U.S., how can we have it in the arena of global health, where what may seem like a trivial improvement to us may be a critical medical help for people in another environment?
Dr. Offit: Fred Clark and I were inventors of the current Merck vaccine, the Rotateq vaccine, and we weren't involved with the Rotashield vaccine by Wyeth. But I was on the Advisory Committee on Immunization Practices (ACIP) at that time, so I certainly saw all the things that happened, and when the Rotashield vaccine was put on the market, you know late August 1998, it was on the market for about 9 months and then there were these cases of intestinal blockages that occurred following their vaccine. It killed 1 child; it probably hospitalized about 100, in what were roughly 1 million doses that were distributed. Of the million children who received Rotashield, probably ten would have died from the disease. So the vaccine, although it caused one death, probably prevented ten deaths. You could have argued that the benefits of the vaccine clearly outweighed its risks.
We never had a discussion at the ACIP about risks and benefits—it simply had an adverse event associated with it, and that was the end of it. And so we killed the Rotashield vaccine for the United States. That was in October of 1999. In February of 2000, about four months later, there was a WHO meeting to which I was invited to speak, and there were many people representing health agencies from developing nations in that room, and Wyeth to their credit stood up and said "We'll give you this vaccine."
They had a technology sitting on the shelf that would save 2,000 lives per day in theory, or even millions of lives over a few years, especially taking into account the seven years or so that we've been without a rotavirus vaccine until now.
Wyeth was very socially responsible, and they said "Forget the patent, we'll show you the technology, we'll give you the strains, we'll help you build the buildings." They were great. Country after country, I only wish we had this on tape because it was an amazing moment, country after country in Asia, in Africa, in Latin America, stood up and said, "If it's not safe for American children, it's not safe for our children." It's amazing, considering that the risk/benefit ratios obviously in their countries were very different. But it wasn't about safety at that point, it was about politics.
PH: So, obviously that wasn't the fault of any U.S. actors, it was just the perception that if it's not good enough for the U.S., it's not good for them. Another parallel that struck me while you were talking is a parallel to a drug called Lotronex, for irritable bowel syndrome. As I understand it, when that drug was first marketed, there were similar intussusception issues and I think a couple of people died. Lotranex was withdrawn by the FDA and the manufacturer, GlaxoSmithKline.
But then a patient's group stood up and said "Irritable bowel syndrome can have a terrible impact on our lives, and we can be virtually housebound because of this disease, we are willing to live with that risk." The drug was put back on the market in 2002, albeit with a very aggressive risk mitigation plan.
But where are the people who are willing to stand up for a vaccine and say "We are willing to live with that risk", "We are willing to accept this trade–off in order to protect our children"?
Dr. Offit: When it comes to these diseases, no one thinks that it will happen to them or their children. About 25,000 kids used to get severe bacterial infections with a bacteria called Haemophilus influenzae type B (or Hib). 25,000 kids would get sepsis which is a very serious blood stream infection every year or meningitis. Last year that number was less than 50. Who are those 25,000 children who were saved? What are there names? No one knows. I mean I'm looking at my pictures of my two kids on my desk, and they certainly could have been one of those children but I never imagine that to be true. I give them vaccines but I never imagine that they would be one of the 25,000 children to be struck by that disease. You're right that people will never be as compelled to fight for these products because parents believe it will never happen to them, until it happens.
PH: Unlike every other drug—for cancer, arthritis, AIDS—the constituency for vaccines is invisible even to itself.
Dr. Offit: Yes, absolutely. Where's the passion? The passion always comes from someone who's hurt, not from someone who might be hurt. My parent can't believe that there's an anti–vaccine movement. They saw children die from measles, they saw children have meningitis or mumps, they saw polio, they saw all that. So, for them embracing vaccines was a very easy choice. Now people don’t see these diseases, because vaccines have virtually eradicated them.
But there is one exception. Now you're starting to see parents groups representing children who've died of influenza, because now it's becoming reportable, which wasn't true until two years ago. Now you're starting to see a groundswell from that regulatory change, and that actually has impacted ACIP's decision to move gradually towards a universal influenza immunization schedule, our country more so than any other country.
PH: Could you stop for a second and just explain that. What do you mean reportable? Who's reporting it? Or how is it categorized?
Dr. Offit: The CDC now collects data on childhood fatalities from influenza. It used to be that you didn't have to report those details to the CDC, or state or local health departments about a child who died of the flu. Now you do, and parents who've lost children to the disease realize that they're not alone. This is media and consumerism at its best, and I think that the thimerosal backlash is an example of consumerism at its worst.
PH: What role has the post–Cutter strict liability regime played in changing public opinion about vaccines?
Dr. Offit: Cutter opened that door of liability without fault, which was awful for vaccines, because vaccines were given to healthy children and it only prevents the disease it was supposed to prevent, it doesn't prevent everything else that occurs in the first few years of life. Vaccines were almost driven off the market by liability, it was that bad. In the mid–80s the U.S. was on the verge of losing its vaccine industry. We were the first country, not surprisingly because we have the most active tort bar. And it was so bad they put in place the Vaccine Injury Compensation Program, which obviously saved vaccines. I think it was a model for tort reform, it's not perfect but it's not bad, so vaccines are ahead of the game compared to other pharmaceutical products. It may be that drugs and medical malpractice cases will get there too. But vaccines are ahead of the curve because they were the first products almost eliminated by lawsuits.
PH: Have plaintiff's lawyers really been the ones who put thimerosal into the media spotlight and keep it there?
Dr. Offit: After the IOM report that advocated withdrawal of thimerosal from vaccines, ads from personal injury lawyers exploded. There were full–page ads in USA Today and the New York Times. These are $250,000 ads; I don't think these are parent groups buying that kind of ad space.
PH: Let's circle back to the innovation issue. You wrote about Basil O'Connor as the director of the National Foundation for Infantile Paralysis and his search for someone who could really drive polio vaccine development. He finally identified Jonas Salk as the person who could really lead the effort, and you write that it took a certain personality to do that. Do you think there is a real difference between the people who are doing basic research and the people who move translational research?
Dr. Offit: Yes, I think that was Salk's genius, he straddled that fence. He was an excellent scientist and researcher, who also in many ways turned his laboratory into an industrial plant. He was able to vaccinate 700 people in that Pittsburgh area and then come up with a protocol for how he thought manufacturers should make the vaccine and he was still involved with Park, Davis and Lilly when they were making their experimental polio vaccine. He really was like an industrialist in many ways.
PH: I remember you writing that, relatively early in his career, he accepted a grant to help confirm the typing of the various polio virus strains, which was an enormously time intensive, tedious thing to do, but he really took to it. He intuitively had the kind of mindset that can see something being broadened out and standardized.
Dr. Offit: You'd never see that today.
PH: Why is that?
Dr. Offit: Because the regulations are too stringent. I'm not saying it's necessarily a bad thing, I think it's just that the divisions are very clear between research and development. Let me put it this way, between research and the research of development. My experience developing the rotavirus vaccine was a revelation to me. Fred Clark and I started working on rotavirus in 1980 and by 1988 we figured out which genes made you sick and we figured out which genes coded for proteins that induced a protective immune response, and then we took this bovine rotavirus which was avirulent in children, which means it didn't cause any disease, and we cloned in these human genes which we knew would give you a protective response without causing the disease. We had a very thoughtful way of approaching the problem and we solved it in principle by 1988.
PH: That's amazing.
Dr. Offit: Then we went to four major pharmaceutical companies, and all four were actually interested, but we thought that Merck had the best scientists. So, by 1990 we had an agreement with Merck to produce the vaccine, and this was 16 years ago. For the next 16 years I watched them try and figure out how to buffer this vaccine, how to stabilize it, how much of each strain to include, how many different strains to include, how to package it, how to distribute it. The research and development dwarfed the original research, but it's an aspect of the process that never gets appreciated.
PH: And students getting out medical school these days don’t understand that part of medical development.
Dr. Offit: No, I don't think doctors understand it; I don't think anyone in public health understands it. I don't think I understood it frankly until I saw it happen day to day. I saw what Merck had to do to make that vaccine. And you know in the papers, for example, Fred Clark and I get all the attention, because we're the media darlings, we're in academia, we're perceived as "clean." But the person who developed the rotavirus vaccine to me is Penny Heaton, she's at Merck, she's the one who directed this clinical trial, she’s the one who supervised this whole operation. And she'll never get the credit.
PH: I frequently hear people say, "Government and academia do all the basic research anyway, what do you need pharmaceutical companies for?" But it's for what you just said; it's the difference between putting together a Model–T in your garage, which is one thing, and then putting together a production process that could mass produce 10 million Model Ts.
Dr. Offit: That's a very good analogy. I think everybody should go tour pharmaceutical companies with regard to, in my case, vaccine makers, and see just what it means to mass–produce something. Cutter was an example of this; it was a mass production problem. And that's invariably the problem. Especially when you’re talking about moving a vaccine into development, you're talking about producing tens to hundreds of millions of doses. That's not easy, scale up isn't easy. This is very much the point of the Hilleman book I'm writing, I mean no one knows Maurice Hilleman's name, the guy made 9 of the 14 of current vaccines. And in addition to mass–producing, he really did the primary research, and yet nobody knows his name. Why? Because he worked for a company. I just think it's a very much unappreciated art, what these companies do.
PH: What lessons, looking back at the Cutter Incident and your new research on Maurice Hilleman, what lesson should the people at the Gates Foundation or at the President's AIDS Initiative learn from these earlier vaccine efforts, if anything?
Dr. Offit: I think Gates learned that lesson in a sense. What Basil O'Connor and the National Foundation for Infantile Paralysis did was they showed how this tremendous pull mechanism could work.
They said "Ok, I'll tell you what, we will buy your polio vaccine, here's a formula on how to make it. You make it and independent of whether it gets licensed or not, we'll buy that vaccine."
For the companies their commitment made the production process at worst revenue neutral and at best profitable, and so they quickly pulled five companies into making that product. That's basically what Gates does. Gates says we'll pay for a malaria vaccine, we'll pay for a tuberculosis vaccine, we want to get companies interested in this, and they've pulled a couple of smaller companies and larger companies that will try and do it.
But more importantly what they've done, and I think this wasn't a lesson of Cutter, but Gates has changed the map of vaccines, they've tackled the biggest problem, with the disparity between the developed and developing world, which is establishing an infrastructure for giving vaccines. And for that they should be very, very much appreciated.
PH: In the best possible case you have people who just want to get something accomplished, for their own reputations or for their personal interests and they're going to push something through. On the other hand, once you begin to deal with governments, particularly in places like the Third World where you might not have the best transparency or accountability with government agencies, the money can just keep disappearing. Bill Gates' high profile ensures that there will be a lot of people wondering what happened to all of this money.
Dr. Offit: That's a great point, and Gates has been successful already. Initially with Hep B, they were very focused, "We're just going to do Hep B, we're just going to these 72 countries that are the poorest countries, meaning you know per capita $1000 US dollars or less per family earned per year and we're going to just target them." So you had immunization rates initially at 40%, they’ve gotten them up to about 70%, and that’s fabulous.
PH: How are the regulators, the FDA and the EMEA [European Agency for the Evaluation of Medicinal Products], playing into these kinds of efforts? Are they working with, I know you're talking about the pull mechanism of the Gate's Foundation, is there a push mechanism that regulators can use to help accelerate vaccine development?
Dr. Offit: Regulatory bodies like the FDA aren't public health agencies. They're just regulatory agencies, and their incentives are very, very different. They tend to be worried about not making mistakes, and, as we mentioned, medical innovation is fraught with risks. Their institutional incentives are more to slow things down than speed them up. Ironically, the vaccine development process in the U.S. has become so onerous that it's created more manufacturing capacity outside of this country, so you have the Serum Institute of India, which is excellent, and it doesn't have to live under the same sort of guidelines. Regulation is a good thing, and the The Cutter Incident is a reflection on why targeted regulations are a good thing, but the question is always "Have you swung too far in the other direction?" And I think that we have.
PH: Where do you think the Vaccine Injury Compensation system is right now, in terms of helping to rehabilitate vaccine production in the U.S., and what more needs to be done to build up U.S. vaccine capacity?
Dr. Offit: There's three things, I think, one is I think that the Vaccine Injury Compensation system should not allow people to sue outside of the program, and thimerosal is an example of that, if that litigation is any sense successful (it hasn't been successful at the federal level yet) but if it's in any sense successful the state level, in just a couple lawsuits, it could push the industry to the brink again.
PH: Well, I'd have to check my figures, but I understand that the industry has already spent $100 million dollars defending itself from thimerosal lawsuits. As the saying goes, a few more victories like that and you may as well have lost.
Dr. Offit: It's $200 million as of June of last year.
PH: Ok, $200 million. That's a lot of money for a winning record.
Dr. Offit: Right, and it's nothing. Merck spends about $1 million per day defending Vioxx. Take the Bendectin story. Bendectin lost 5 of the first 12 cases, but the company [Dow] did ultimately win all 5 of those cases on appeal. They didn't actually lose a single case, but they spent, and this was in the 1970s, which means it was a lot more money in 2005 dollars, but they spend about $100 million dollars defending the drug because it was worth it to them. But they finally pulled the product. Personally, I don't think you should have lay juries deciding issues of science and medicine because they can't do the issues justice.
PH: To sum up, where are we today in vaccine development?
Dr. Offit: I think there's good news and bad news about vaccines. I'll start with the good news. I think the good news is the Hepatitis B vaccine was the first vaccine given in a series of three doses that crossed the $100 mark, it was a landmark.
Remember vaccines will always lose to drugs, because they're given once or twice in a lifetime as compared to every day. So the markets will always be tilted towards drugs. That's not going to change. But you crossed the $200 mark with Prevnar, introduced in this country in January of 2000, which was the first billion–dollar vaccine. Prevnar cost about $58.00 per dose and was given as a series of four doses.
PH: I understand that Merck's new HPV [human papilloma virus] vaccine is being priced at $120 a dose for three doses.
Dr. Offit: So HPV vaccine crossed the $300 mark and it could be a $2-$2.5 billion dollar vaccine. These aren't big blockbusters like Lipitor at $7 billion. But they're solid performers, and the research and development of these vaccines started interestingly, during the creation of Vaccine for Children Program [VFC] the early 1990s. These research and development programs started then because there was a feeling that the VFC had to some extent stabilized things. And if anything, the VFC has gotten better, it's gotten better in the sense that if you look at the discount that the government was getting in the mid–1990s, Lederle with their OPV [oral poliovirus] vaccine is probably the best example, the VFC was probably getting 80–90% discounts, but now they get 10% to 15% discounts. On the other hand, vaccines will never be a big market product like drugs that are used every day. And because only big pharmaceutical companies make vaccines, they will always be competing with drugs for research and development dollars.
PH: There is more balance in the market now between vaccine producers and purchasers?
Dr. Offit: Right.
PH: That's very interesting. I recall reading an article, I think it was by Mark Pauly at Wharton, who suggested, if I recall correctly, that vaccine markets tend to become monopolies or oligopolies, but you seem to be saying that's not necessarily the case.
Dr. Offit: Well, no, I'm saying VFC isn't so awful. But it's always a little discomforting when the government is a big buyer, up in the 55–60% range. But with vaccines breaking the billion–dollar mark more companies will be drawn in and the market will inevitably become more competitive.
PH: Let me try and summarize what you're communicating, which is I think that we should have some optimism about the future of vaccine manufacturing provided a couple of things happen, one of which is that the Vaccine Injury Compensation Program is expanded along the lines that you suggest.
Dr. Offit: Well to finish that point I had started regarding possible weaknesses in the Vaccine Injury Compensation Program, I think that in addition to not allowing people to sue outside the program I think that they should extend it to maternal immunization which would really help vaccines like Group B Streptococcus. And I think they should include niche market vaccines, like lyme vaccine or CMV [Cytomegalovirus] vaccine, you know vaccines that aren’t necessarily going to being universally recommended for everybody but do help certain specific populations. Otherwise litigation will strangle vaccine development in niche areas.
PH: What about just a public health designation, whether it was a niche product or not, that might provide litigation protection for products for bioterrorism or the lyme vaccine?
Dr. Offit: I'd go farther. I think that the vaccine compensation program can be expanded to include drugs as well. I mean I just don't think it's fair to hold companies liable for a product that they've done safety testing on and efficacy testing on and then the FDA has licensed and then they find adverse effects when 20 million people take their product.
PH: You shouldn't hold a company liable for punitive damages when it's operating at the cutting edge of science?
Dr. Offit: Right.
PH: And the other factor that you're optimistic about is pricing, both at the domestic level (with vaccines like HPV) and with the Gates Foundation creating a powerful pull mechanism for new vaccines for developing countries?
Dr. Offit: Now there's a much bigger commitment to vaccine research and development programs at Wyeth, GlaxoSmithKline, Sanofi Pasteur, and Merck because of the recent success of HPV and rotavirus vaccines. Plus, drugs have become a little less attractive of late.
PH: Because of Vioxx?
Dr. Offit: Companies know that there is at least some litigation protection for vaccines, that's good. There's no comparable protection for drugs.
PH: Dr. Offit, thanks very much for your time. Your comments have been very enlightening.
Dr. Offit: My pleasure.
 Wakefield AJ et al, Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children, The Lancet. 1998, Feb. 28; 351: 637-641.
For more background on the Bendectin litigation, see "A Day Late and Dollar Short on Bendectin" on our sister Web site, Pointoflaw.com.
Paul A. Offit, MD is the Chief of the Division of Infectious Diseases and the Director of the Vaccine Education Center at the Children's Hospital of Philadelphia. In addition, Dr. Offit is the Maurice R. Hilleman Professor of Vaccinology and a Professor of Pediatrics at the University of Pennsylvania School of Medicine. He is a recipient of many awards including the J. Edmund Bradley Prize for Excellence in Pediatrics from the University of Maryland Medical School, the Young Investigator Award in Vaccine Development from the Infectious Disease Society of America, and a Research Career Development Award from the National Institutes of Health. Dr. Offit has published more than 120 papers in medical and scientific journals in the areas of rotavirus–specific immune responses and vaccine safety and is the co–inventor of a rotavirus vaccine recently recommended for universal use in infants by the CDC. Dr Offit was also recently a member of the Advisory Committee on Immunization Practices to the Centers for Disease Control and Prevention and is the co–author of three books titled Vaccines: What You Should Know (Wiley, 2003, 3rd Edition), Breaking the Antibiotic Habit (Wiley, 1999) and The Cutter Incident: How America's First Polio Vaccine Led to Today's Growing Vaccine Crisis (Yale University Press, 2005). He also has a book in press titled The Vaccine Makers: How a Former Chicken Farmer Led the Quest to Defeat the World's Deadliest Diseases (Harper Collins, 2007).