Good evening and welcome to the Marian Miner Cook Athenaeum. My name is Sophia Krivatsy, and I’m one of your Ath fellows this year. I recently read a novel in which the main character fled oppressive and suffocating homophobia in his tiny hometown and escaped to San Francisco in the ’80s. What began as long anticipated sexual freedom and a chance to find love in a community of acceptance quickly turned into a dark and devastating experience in a city that had fallen victim to an epidemic. While this novel itself was fictional, the story of this individual and his eventual loss of life was one that was shared by so many in this community as a result of HIV and AIDS. I’ve heard my parents reflect on how terrifying it was as a young adult. And I’ve seen stories depicted in current Midian books, but I don’t think I knew the true extent of its impact. As I learned more, all I could think about is how much power a disease like this had destroyed lives and how hard and quick the medical community had to have worked to begin to start to save them. It also became apparent to me that social stigma, power, and politics, truly did make this race a complicated one. Paul Beninger was one of these medical professionals helping uncover a cure. He began his career in drug development in 1987 at the FDA. First as a reviewer and manager for drugs to combat HIV-AIDS, an opportunistic infection, and then as a division director for medical devices. He joined Merck & Company in 1995 and gained experience and regulatory affairs, medical affairs and drug safety for a variety of different drug products. He eventually joined Genzyme as Vice President of Pharmacovigilance Vigilance in 2006. He has vast amounts of experience in all medical realms from research and development to reviews and approvals. He has experienced firsthand the complicated mazes that are regulations and pricing and has witnessed the stigma in politics that had made the road to the cure all the more complicated. Beninger has shared his years of expertise and knowledge through extensive publications and spoken works around the nation. Graduating from Claremont McKenna College in 1973, he then received his MD from the University of California, Davis and subsequently trained in Internal Medicine and Infectious Diseases. He also holds an MBA from St. Joseph’s University and a graduate Certificate in epidemiology from Tufts University. He’s currently Associate Professor of Public Health and Community Medicine at Tufts, where he also directs the MD/MBA and MBS/MBA programs. At this time I must remind you that the audio and visual recording is strictly prohibited. Please take this time to silence and put away your mobile devices. Trust me, it’s more fun this way. And please join me in welcoming Paul Beninger to the Athenaeum. (audience applauds) Thank you very much. Thank you, Sophia. You did your homework. Thank you. So it’s really an honor and a pleasure to be invited back by your alma mater, and so it is with me. I am very humbled to be here. So after 20 plus years of being an industry you get used to having a disclosure slide. So it may not be totally relevant but I felt like I needed to say it anyway. Reflections are all my own. I have no conflicts of interest, and I need to have a couple of shout-outs. One to Priya and I understand that she’s under the weather this evening, but it was just one of those total happenstance circumstances. We were standing on the food line last year when I was back for my reunion and she had that glint in her eye and said, “Give me your business card.” So shortly after that I got an email and we end up talking in the phone and here I am. Also wanted a couple of shout-outs to Meg Mathies and Bob Pinnell. They were really instrumental during my time here in terms of the support that I gained as a naive inexperienced undergraduate. So I’m thankful for them for their support. So this story actually starts, and I may actually get down and walk around a little bit. I get a little antsy standing. The story actually starts at 1981. It was the summer of ’81. And there were some very strange infections, unusual infections. And these were the kinds of infections that you usually see in people who have cancer. And it was a really bad sign. And these were in young men, young gay men, and nobody really knew what was going on, but there was a lot of concern. So here are a few pictures. In the upper left, we wouldn’t get to see this for some time but this is actually the HIV coming out of CD4 cells. In the upper right we’ve got pneumocystis. And in our day we called it carinii but now it’s jirovecii. And the lower left here we have toxoplasma. In the lower right we have a cocci. So, crypto, excuse me. And these were infections that we were seeing in a whole range of individuals who suddenly had a constellation of symptoms that we had never seen before. And it became epidemic. And it was two years before we eventually found out we’re able to identify the virus. So we go from that and we go 38 years, upper left hand corner, 38 years to PrEP. A pre-exposure prophylaxis. And I took this from one of the advertisements in the T, in Boston. Okay, so we have this incredible disconnect here from where things started to seeing this. And what is it really tied to? Well, we’re talking about a couple of drugs here. This is a combination drug, which is found to be really effective in terms of preventing infection. And I’ll come to this towards the end of my talk because I had a role to play in seeing that. Well, if any of you are fans of 2001 A Space Odyssey, you’ll recognize this. This was one of the opening scenes where they had Moon-Watcher who had just defeated his antagonist from the other side of the pond. And he took the thigh bone, he took the femur, threw it up in the air and then there was one slide later we’re talking about a space shuttle that was the shuttle going from earth to the moon. That’s what it feels like. It feels like going from Moon-Watcher to the moon is what’s happened in the 38 intervening years. So I wanna talk a little bit about that and I’m going to weave in my own personal story. And my daughter, Anna, actually provided me with a number of these slides from the New York AIDS Memorial that she took. So it’ll be peppered among the different slides. And actually the links are available there as well. So what this says, it’s very personal narrative, more details. What this is not. It’s not a how-to manual ’cause it can’t be done that way. Okay, it’s not as collection of secrets of success. It’s not dos and don’ts. The last one about dispensed advice. We just went through this at the table so I did dispense some advice so I have to take that one back. A few of the milestones that I will be touching on. First one said it was the syndrome was first identified in 1981 by the CDC and was published in the MMWR: Morbidity Mortality Weekly Report. And it was two years before the virus was identified. It was first called HTLV III because it was already known as human T-cell leukemia virus type III. And that got to be such a mouthful that it was renamed human immunodeficiency virus. Rock Hudson in his own day was an icon. So I see a few other gray hairs around here and recognize that they probably know who Rock Hudson was. And he came out with an AIDS diagnosis and died the subsequent, the following year. It wasn’t until 1987 and AZT was the first anti-viral drug to treat HIV and was found to be effective. And then the theme of the talk, Magic Johnson announced they he had HIV diagnosis in 1991. It was a year after that that Arthur Ashe, and I think probably some people recognize Arthur Ashe as a world-class tennis player for which the tennis ball is. In New York, in fact, I think it’s where the American competition was played this last couple of weeks. So the Arthur Ashe Auditorium. And then 1995 the protease inhibitors, which was the first of a new class of drugs that totally changed the picture of how HIV could be treated and change it to a chronic disease. So we’ll look at that a little bit in more detail. And then as I said, I jumped to 2019 about PrEP. Now, this last one I put on before, I put on earlier but no vaccines yet. Well, yesterday, I don’t know how many people saw it but there’s a new vaccine that’s being tested. And it has the best promise yet. So there have been hundreds of candidates and probably a dozen have gone into human trials, and none of ’em have worked. I remember one of the early meetings we have gone to about what the strategy ought to be and it was at the IOM and so to the medicine now the National Academy of Medicine, of what the plan was going to be to actually try and deal with the infection. Now both primary infection and the opportunistic infections. They said, it’d be two or three years before we have a series of drugs available for opportunistic infection. Check, that’s what happened. It’ll be, probably another five, maybe up to 10 years before we have a control of HIV. Check, that’s about what happened. Said, “Well, maybe it’ll be another 10 to 20 years before we have a vaccine. Not check, we still don’t have a vaccine. It’s just one of the most perplexing of medical problems today. And so I think what we have now have some optimism about it. It’s a mosaic virus that they’ve created and has really the best chance of being effective. So I really wanna focus attention on the right side here about the upper line, the blue line about the diagnoses of AIDS diagnosis and then the lower line about deaths. And you can see, and it’s 1995 to 1996 in there, about HAART. And that’s Highly Active Antiretroviral Therapy, HAART. The HAART therapy is what turned around the whole picture of infection to where individuals were actually able to live with AIDS. So it’s living with HIV. And that’s about where we are today, and we’re actually able to, I know as I’ve mentioned already, prevent infections. So about my own career interests. So my own career, I wasn’t really interested in medicine per se. I was interested in infectious diseases. I was interested in microbiology. I’ve read a book somewhere after my sophomore year in high school called the “Microbe Hunters” by Paul de Kruif and it was incredible. I said, “That’s what I wanna do.” Well, I didn’t know about infectious diseases at that time. It wasn’t being taught. I actually got here, I saw how it could be connected to infectious disease. But that’s what I saw as my career ambition. That’s what I focused on. Ah, yes. Okay, so fast forward now, get through medical school, internship with LA County, a little diversion to Japan to do research in hepatitis. Practice some martial arts, collect pottery, learn a little Japanese, and then come back and do my residency in Sacramento in Internal Medicine, and then to San Diego, do a fellowship in infectious disease. And so then I was just getting ready to attain my goals where I wanted to go. The person who brought me to San Diego, A. Browdy, died of a massive heart attack over this first Thanksgiving of my first year. And the person who took over, well, I say politely that he was lacking in social graces. And he didn’t support me. He didn’t support me to going into a career in academic medicine didn’t think that I really had what it took to be an academician in infectious disease. So married, first child we were going to have our second child in February of 1987 and it was existential. What was I gonna be doing? What was I gonna do? Well, he said, “I had to go look for something else.” There was the story behind that and I can tell that later. I didn’t know what I was gonna do, but I was determined to look at what the possibilities were. And I looked at some 30 odd opportunities. I had 17 interviews. I looked at everything and nothing really interested me. Then, and I was flipping through the journals, and then I saw this. Physicians Interested in Clinical Research. FDA seeks physicians for selected openings, da, da, da, da, da. When I read that I said, “I don’t have a clue “what FDA does.” And there was nothing in my medical education, my internship residency or fellowship that gave me any idea of what it is that FDA does. And it’s still true, by the way. This is 45 years later, or 40 plus years later. It’s still true. Students in medical school or through training don’t know anything about drug development. And they certainly don’t have any clue what FDA does. There’s no courses, there’s no lectures on it. They really don’t have any idea. So it makes my job interesting. So I flew out to Maryland, interviewed with some of the most wonderful popple in the world. Really iconic individuals in vaccines, in drug development in terms of the small molecules of the day. And basically made up my mind on the flight on the way back, that’s what I wanted to do. So we packed up. The Federal Government moved us from San Diego to the Suburb of Maryland and that’s where I started my career. I got there and I still didn’t know what they did. I joined the Division of Anti-infective Drug Products and there were about three people who had anything to do with what was going on with HIV and it was including my boss. I can jump. Yes, okay, we’ll do this and then I can pick up the story. All right, this is one of the major events on the mall. And you can see the Washington Monument over in the far right. Each one of these squares has 32 quilts in it and each quilt represents death. So we have approximately 20 going in that direction, 40 going in that direction. We have about 65,000 deaths represented by these quilts at that time. And when you were there you couldn’t help but be moved. It was absolutely overwhelming. There wasn’t a dry eyes, a dry eye in the place. It’s absolutely overwhelming to know what these represented. So this is the Parkland Building here. 5600 at Parkland, and this is about an activist group ACT UP! and they’re unhappy with FDA, okay, that they’re killing their friends because they’re not making drugs available or there are no drugs to be made available. They didn’t know that at the time. They learned quickly. They were very quick learners. I was on the 12th floor seeing all this going on down below, 18-floor building and actually saw this. And so this is a street eye view what was going on. So how do you develop a drug? What does FDA do? How do you approve it? What are the criteria? It’s just you’re going from knowing nothing, absolutely nothing to understanding regulations, understanding the process, understanding who the people are on the other side in terms of the clinical trials, understanding ethics, informed consent, institutional review, et cetera, et cetera. So it was an incredible education. Then towards the end of ’87 Reagan had just approved the package, a massive infusion of funds that will provide funds to FDA, NIH, CDC. So it was a really massive infusion. And for FDA it was to create a new reviewing division. And I was a member of that. So we started with 18 individuals and grew to 80 in two years. I interviewed hundreds of individuals, professionals, learned a lot. Learned about the interview process, learned a lot. Who are the other stakeholders? Well, NIH. They had quarterly meetings where people from all the country flew in. And we’re talking about clinical studies, talking about new drugs, talking about things that were in were in development before they actually got started. So there was a lot going on. Activists ACT UP! AIDS Coalition to unleash power: ACT UP! “Give us the drugs, we’re dying!” They were. They were dying. It was a nightmare. It’s a nightmare to see always people die. I was the reviewing medical officer for fluconazole, but I couldn’t do it during the day ’cause I was doing all the other things. So that was nights and weekends that I did that. Work environment, you had this sense of mission. I never felt anything like that before. It was absolutely mission. And you knew, you just knew what you had to do. Now this is one of my favorite slides. It’s the entire drug development process in one slide but I just wanna call your attention to the historical timeline at the bottom here. We have 12 decades and two points to make. The first is that as you notice these major statutory events, you’re getting faster. They’re getting closer together. There’s an acceleration that’s going on. Okay, so very true. Until we come to the User Fee Act, which every five years starting in 1992, ’92, ’97, 2002, 2007. The other thing to notice, well, you can’t really tell from the way it’s laid out here but up until the User Fee Act everything was reactive. Major catastrophe: statutory remedy. Major catastrophe: another statutory remedy. Okay, so behind every law was a tragedy up until the User Fee Acts and then everything turn around. It was proactive. It was prospective. The User Fee Acts as they came they were sunset, so they had to be passed or else everything would freeze. And it was then looking at all the little things that were going on. Can we tweak this or that? Can we do this or that? And that’s basically what happens. So there have been far fewer disasters since then. So the main point, there’s a lot to say about FDA. The one point I want you to walk away with is that FDA oversees 25% of the consumer spending. So it’s $2 trillion worth of spending out of approximately $8 trillion that consumers end up spending. So 25% of the consumer dollar. Now the comparison for the other networks. This makes more sense that way. If you look on the right about FTEs, full time equivalents, FDAs has about 17,000 individuals. CDC about 10, NIH about 18. So not too big difference. Maybe a two-fold difference overall. But the budgets, okay, the budgets are what’s different here. So FDA’s budget last year, it’s on internal budget with $3 billion. It’s the user fees that added another 2.6 billion. So if you round it up to six, you got $6 billion for an FDA budget. CDC is twice that. NIH is three times that. So it’s always been on the short end of the budgetary stick. And it was really essential for it to have user fees as the only way that it was gonna be able to keep up with the demands. At one point, the median review time was 30 months. Okay, you can’t plan anything if the review time for an NDA is 30 months. So that’s what really what instituted the User Fee Acts back in 1992. Progress. Okay, a lot of things happened. I’ll talk about some specifics in a moment, but one thing I wanted to say is that nature abhors a vacuum. Ordinarily, as you would expect in Federal Government, you could be years if not decades before you have a chance to be in a leadership position. Okay, I was a group leader in six months and I was the acting director by a year. There’s two points to make about this slide. The first is that drug development is a stage process. Phase one, phase two, phase three, phase four. In other words there’s expectations of goals that each of the phases is a logical systematic approach to development. The other point is if you look at the numbers at top 10,000, 10, and one. You can start with 10,000 molecules before you find 10 molecules that you’re ready to put in to clinical trials. That’s with humans. That’s a 1,000 to one. If you’re an industry, you could go your entire career before you end up having a molecule that would go in clinica trials. Okay, it really is mind-boggling when you think about it. The new biologic goals, things are probably improved by a factor of 10, so it’s probably 100 to one. So you could still go a long time before you come up with a molecule that would go into clinical trials. And then by the 10 to the one, very often, and that’s at least 10 to one, of 10 molecules before you have one that ends up being approved. So it’ high risk. High risk, high return, lots of arguments about that. I’m happy to address any of the questions you may have about that. But those are the numbers. So my own experience. It was my FDA experience that really everything downstream from that has followed from in one way or another. I was able to take advantage of one thing or one situation over another. I’ll talk to you in a moment about the pregnancy study ’cause I think that was one of my high points. It led to my job at Merck. And my job at Merck after it had a problem with Vioxx and it ended up with my job at Genzyme in Boston, which then being there led to the opportunity for me to one, teach as an adjunct and then to be just offered an opportunity to be a director of the MD/MDA program. Right person, right place, right time. Just a total accident. A gift, an absolute gift. So this is a study I wanna point out. My name doesn’t show up on this, but I work with Dr. Connor on this as a study to show that AZT could interrupt infection. Okay, and this is infection we’re talking about. The oral drug must be given in the third trimester, women that were expecting the third trimester. And at the time of delivery they would get an infusion of AZT. And if you look over here in the Zidovudine arm you can see that the infection rate was 8% where the placebo was 25%. The expectation was that AZT or Zidovudine would reduce infection by 50%. And if you see the arrow bars over there, it’s actually the 95% comft intervals, so they aren’t error bars, that you can see that it reduced it by two-thirds. So it meant that you could actually disrupt infection. And it was this. It was the basis then for what became, what’s become to be known as PrEP. Except it’s not an individual drug, it’s a combination of drugs. And obviously it does a better job than reducing by two-thirds. It’s like 99%. It’s really effective. So this was an extremely important trial. This was a major event. As a member of FDA, I couldn’t participate as an author. People at NIH did, people obviously the clinical investigators in a community and Ed Connor did, as the first author. So I was actually able to shepherd this through the advisory committee, FDA advisory committee to make the case that it could be done because what you’re doing is you’re exposing a lot of people, a lot of women, a lot of expectant women to a drug that potentially could excel, cause damage or have some, be fetotoxic in some way. So there was a lot of risks, there’s a lot of controversy. And ultimately the advisor committee supported the decision and they went ahead and gave him the green light for them to conduct the study. And so this is really a landmark study. Okay, so the central character here, Magic Johnson. Alive and living with HIV. So when he first was diagnosed, he didn’t have AIDS. He was diagnosed with the infection. And he received incredible care. And here he is 28 plus years later. 28 years, yes. And he’s still doing well. So one of the major icons of our day and still doing well. And he’s got a number of good things over the years in terms of his volunteer activities. Okay, so what are some of the legacies? Well, I think one of the biggest ones, probably the most important is that it changed how FDA did what it did. It was no longer a lumbering leviathan. It actually was responsive to community interests, community activists about how we can actually relate with them and actually improve the protocols and get to where we needed to go. So there was much more of the collaboration that went on. And actually it comes down here at the end about PCORI, the advisory committees. So they became much more involved. But this is back, and we’re talking about this. This is back in the mid to late ’80s, okay? So this is now is just playing itself out in the last decade. So the wheels turn very, very slowly. PCORI has only been, I think, since 2010 and I think that’s been one of the things that’s come out of this. The other is about, yeah, it’s about the process. Actually they changed the process itself. And I wanna show that in this slide here. So in reviewing the drug, I’ve mentioned earlier that it took 30 months before a drug could be approved, 30 months. Well, the User Free Act was intended to reduce it to a year. And then from a year it was 10 months. So the question is can we do better than that. So we said, “Well, if we have certain kinds of molecules.” So those that are our priority, those that are really important as opposed to the Me-too drugs, those that are already two or three versions out there. Maybe we can do a review in six months instead of 10 months. So that was the priority review, number one. Number two, we could talk about accelerating the process. So instead of using clinical endpoints we could use a surrogate marker. So we could use those things that didn’t actually show clinical benefit but had the promise of showing clinical benefit. So those were the accelerated products. Then number three was about fast tracking, was about expanding the pool, and the breakthrough products was expanding the pool yet again in terms of the substantial improvement over available therapy. So FDA has gradually, with statutory opportunity and some other enhancements, have been able to accelerate the drug development process in general. So for myself. So I moved on from the reviewing division. I had an opportunity to be a division director in medical devices. I mentioned at my table. I went to medical devices. I was the first physician division director for all engineers. Okay, and as engineers, they don’t know much about clinical development. So they made a lot of mistakes, and that’s how Bob Temple got involved and I worked with Bob Temple, and I was invited to be a division director. and so that was a great experience. So as you can imagine my wife was working long hours. I was working longer hours. We had two little girls, and we had that faithful lunch when my wife said, “I’ll stay home if you get a job in industry.” Okay, so that’s what happened. So my wife stayed home, had primary responsibility for raising our daughters. We’ve done very well and my job was to go in industry which translated to more opportunities, greater compensation and ultimately how I ended up here. I went to Merck after that or as a result of that and I was involved with some very important vaccines, HPV vaccine, okay? So I had actually made the case that the initial studies for HPV should be done in girls and boys, okay? I was overruled. I was actually in charge of regulatory affairs at that time. And it was just overruled. He said, “No, we can’t spend the resources “or take the time we needed. “Do this quickly as we can.” And I think it was a major mistake. It’s still a mistake. Because the vaccination rate of boys is a third or a quarter of what it is for girls. And I saw a television commercial just this last week trying to encourage young girls and young boys to get vaccinated. So it’s still an issue. I was involved with rotavirus vaccine. Another really interesting vaccine, diarrheal vaccine that has a huge impact in the third world. Measles, mumps, rubella and varicella vaccine. Now that one has to do with the Wakefield study. It’s hard to call it a study. It was actually fraud. It had to do with the present situation where we have talking about autism being associated with MMR. Okay, it was totally fraudulent. And yet families today that go to their pediatrician and ask whether they should be vaccinating their children with MMR say, “I’ve heard it causes autism.” Okay, not true. There wasn’t even a remote truth to it. It was totally fraudulent data. Thank you, Andrew Wakefield. I had an opportunity to move into Pharmacovigilance in around 2000. Right at the beginning of when Pharmacovigilance was just starting to grow, so participated in a lot of development at that time. Actually, it was a fantastic experience, ’cause I got to grow with it as the changes were happening. I also got my MBA while I was there as an executive. I had an executive MBA. Ultimately it led to an opportunity, well, okay. So it was Vioxx. Vioxx, Merck got in trouble with Vioxx. It caused cardiovascular effects. And they basically hid that information from FDA, okay? So they end up being sued. They saw potentially the same kind of a thing happening to Merck is what happened to Wyeth with the fen-phen problem, okay? And then led to its ultimate acquisition by Pfizer. Saw the same thing coming, decided that I was gonna leave Merck and got a job with Genzyme in Boston. So that’s what I did. During my time there, so I was involved with these products that I think have been successful and it played an important role, I think, in the care for patients. But these are the things that were actually important to me. I’ve mentored PharmD fellows. There’s a long story behind that, but essentially for seven years, first year I was mentoring him once a week for 45 minutes to an hour. So I had him for basically two years. So I had 100 hours worth of experience. The next fellow started the next year, and he started asking the same questions. So I started taking notes and then I would write things on the board, and I would take pictures of my notes on the board, and I collected those. And ultimately I wrote a book. I got a job. Now what? There are hundreds, if not thousands, of books out there about how to find a job, okay? There’s very, very little out there about how to keep a job. And the transition of going from college into the workplace is not, it’s not like that, okay? It’s like that. So there’s a disconnect. And the opportunity of a job is not the same thing as actually doing the job. And people end up making mistakes and they end up having issues, so I was actually able to, I think, provide guidance to a number of fellows and I think that they’ve all gone onto great careers. As Sophia mentioned I’ve got a certificate in epidemiology. I realized in that job I needed more quantitative skills. My street smarts weren’t gonna be good enough. I really needed to get some more academic training, so I got a certificate. And when I was done with that, they offered me a job that teaches an adjunct. So I was an adjunct teaching in the evening Pharmacoepidemiology while I kept my day job. Then the fateful day when the dean asked to see me, which I was really concerned about, and she said, “No, no, don’t worry about that. “I need somebody that’s just gonna take over “the empty MBA program.” So that’s kind of the ultimate irony coming back 360 to the career that I have now. So I did both jobs for three years and then I retired in 2017 from Genzyme and have been full-time at Tufts since then. So that’s my career. So this is different, okay? This is what I have on my website as directors’ comments. I will just let you take a look at ’em. So it’s not too much of what I accomplished per se, okay, it’s more a reflection of my own experience. You will feel in your very bones how messy life really is. I made joys and success, beat sadness and tragedy. You will discover wonder and you will bring your own meaning of happiness to your own lives in your own way. These are the drugs that I had major input in over my career. These are the publications since 2016. Most of them are first author, well, they’re all first author. Most of them are as sole author because one of the things that you can do. I gave hundreds of talks over a number of years and I kept them all. Well, the problem with the talk is it went off, okay? But I had an opportunity with the job at Tufts to actually translate them into manuscripts. And so I was able to publish many of the things that I had collected over the years. Anna, my daughter on the left; my wife, Betsy; and this is in front of the New York City Library. One of my favorite quotes. So I hope in the time, oh, I’m doing pretty well here. Okay, I hope with the time that you’ve learned a few things and I’m happy to answer any questions. (audience applauds) So we did this at our table, okay? What did you learn? So we had fun with that on our table. So anywhere. So we’ll now have some time for some questions, so if you’d like to ask a question, please just raise your hand and Laleh or I will bring the mic to you. And when you ask your question, please stand up and please do try to keep it brief so we can fit as many of you in as possible. Don’t be shy. Please, word. I’m thinking back to a rafting trip in Chile which was full of doctors, including one who was very interested and done work in (mumbles) and very interested in epidemiology. Now I asked her, this was the time when AZT was just coming in. What is the trade-off between something which keeps the vector alive in terms of deaths compared to not to just letting the patient die? She said, “That’s an easy question. “That people thought that AZT worked at that.” And she said, “A doctor has an unconditional duty “to cure her patient no matter what the outcomes are.” And I wrote several epidemiologists and said, and all other the doctors gathered around and said, “This guy goes double for us.” And I wrote several epidemiologists and said, “What’s the actual answer to that question?” And they said, “That’s a very good question, “but I wouldn’t touch it with a ten-foot.” Yeah, so I have two answers for that. The first is that the adage is cure sometimes, relieve often, comfort always, okay? So that’s the real answer. If anybody read “Cutting for Stone”? Read that? Fantastic book, okay? And it’s actually one of, in the key chapters in that book as well, okay? Cure sometimes, relieve often, comfort always. So I think that there’s a lot of things you can do in terms of caring for individuals who have terminal diseases, whether it’s Ebola, HIV, anything else that matters. Second answer has to do with the goal is not just to keep that patient alive. The goal is that’s a stepping stone to where we are today to be able to have prepped. So we didn’t know that then. We didn’t know what it was gonna take. We had hoped that we’ve been able to go to vaccine before then but we’re still not there yet. I don’t know. It may still be another five or 10 years before we have a vaccine. So you’ve learned a lot. There’s a learning process that goes on along the way. You can’t make a decision not to do something because of what the limit of your foresight is about what you think you’ve been able to accomplish. You have to do it. You have to try. And you learn, you learn from that and then you figure out what your next step is after that. He said, “Well, we’re not gonna keep this, “this person’s not gonna live “so we might as well just let him die.” You’ll never gonna get anywhere with that. So I think it’s a matter of recognizing this is a short term game to what your longer term plan is. My concern was not that they would live but they would live with circulate, continue to spread the disease.
Ah. Well, education is really a critical piece to all this, and we ask them to have, practice quote, unquote, “safe sex” so that there’s safe practices that are being done. And I think when we look at the epidemiology and see what actually happened then we’re able to accomplish that. Please. Are there any examples you think of today of progress maybe in something like a medicine or some other are that’s being stalled because of social attitudes or beliefs about a certain population group? Is there something analogous to what you were experiencing back then? I don’t know. Anybody think of anything in particular? Were?
Contract raising. Which? (faint voice talking) Contract raising. (faint voice talking) Well. Thank you for coming and speaking with us today. In one of my classes we’ve been learning a lot about the HIV-AIDS epidemic– Yes.
Specifically in international scale, and so I was wondering what do you think is the United State’s obligation with all of my medical research to the other HIV and AIDS community? Because I know that it’s a lot more prevalent in various countries in Africa, India, just other countries in general. Yeah, so I don’t know if I’m an outlier in thinking about this. I’m probably not. When you look at a map of the United States and you see whether the weather map or any other map, looks like United States is an island. You don’t know Canada’s there. You certainly don’t have any idea of Mexico and (mumbles), so it looks like it’s an island, okay? And I think a lot of people in policy positions think about the United States as an island. And that’s really, I think, that’s problematic. Because we saw clearly what happened with Ebola, okay? Something that happened there 12 hours later, okay? We had cases in the United States. 12 hours, okay? And that’s a sleep cycle. We can’t think of ourselves as an island, okay? We have to really think… Look what’s happened with polio, okay? We’re struggling to get, we’ve been, diminishing returns. We’re way out there, the 99.999 trying to get the last few possible sources of infection of polio, okay? And we’re sinking billions into trying to knock it off because the return is worth it. To obliterate polio is gonna be worth it. We’re not an island. We can’t act that way. So I think HIV is exactly the same thing. So we ought to be contributing to greater care of things that, it really is, I think, an issue for this country. Potentially affecting the health and you could say national security of it. maybe a stretch but certainly potentially affecting the health of this country. So again, I don’t know how much of an outlier I am on that, but I think we should be doing more. Please.
Yeah. Thank you for your talk. You mentioned that the activism fuels some of the changes in rules and regulations at the FDA. And the drug development had to be speeded up because of the activism of the gay community. What obstacles did you face at that time apart from the, what were the obstacles? Because obstacles tell you a lot about institutions and how they deal with it. Okay, so you saw the building that I was in, Parkland Building, 12th floor. So we started with about 16 people. By the time we got into the ’20s we outgrew the space that we had and we ended up moving to Nicholson Lane which is about two miles down the road off 355. And we were really all totally into ourselves. We grew, I think we probably ended up growing to 80 in that particular facility. But there was like zero support anywhere else in the agency. And when, on the cafeteria you end up talking to people and saying, “Why don’t you just let ’em die,” okay? So it was jarring, okay? You had people with totally different worldview on what you were doing and says, “Let ’em die,” okay? So we experience and we realized that we were happy to be at Nicholson Lane, okay? So we weren’t being disrupted in what we’re trying to do. Please. I appreciated the slide that you had of the many things that you’ve learned through your life and the experiences that you’ve had. And one of the points that you had on there was that you learned some universal truths, I was interested in knowing some of them. I’m sorry, say it again? You had a slide up there with things that you’ve learned in your life or throughout your life and your experiences and I was interested in knowing some of the universal truths that you said that you’ve learned. I think it was some of that. Where?
One more. Is that it? No, it’s the other way. I passed it. That one, yeah.
Here? There we go. Yes, okay. So your question is– (faint voice talking) Oh, yeah, the first one. First one. It says, “Over the span of my career “I gradually became aware of universal truths “that each of you can expect to experience in your own way.” Now I was curious as to which or what are some of those universal truths. I hope that those are all universal truths to follow. Oh, it’s the questions. (Paul laughs) I misunderstood this, I’m sorry. Okay, yeah. I hope any of the gray hairs here can share. So there are a number of sort of public health crises that seem like they’re on the sort of edge of becoming a massive problem and scientists sort of sit and wring their hands about these things. I’m wondering if you were at the beginning of your career, in starting at either the FDA or Merck, which project or public health sort of emergency that sort of starting to emerge you would want to work on now? If I were starting now, what would I wanna do? Okay, so I can look back and say right now one of the things I’m starting to work on is CRISPR, okay, and the ethical issues of CRISPR and I’m applying for an LCRO3 on the ethical issues associated with CRISPR. Because it’s taking us into a place that we have no idea. To me, the parallel is the atomic bomb when it went off. Afterwards you say, “Okay, it was a big bomb,” okay? We didn’t realize the existential threat that is represented. I think CRISPR is an existential threat. (faint voice talking) Yeah, yeah. It’s also maybe the most promising (mumbles), right? (faint voice talking) So it’s a two-edged sword. All the positive it can do, but all the dark stuff that it can do as well. So I would want to be very much involved with that as I’m trying to do from this side, from however I could get. I wanna be a part of what’s going on there. I have a question actually. Please. With regards to your book, I’m just curious as if there’s one thing in there, one piece of advice, that you think that we should all know as college students many of us who are gonna start work fairly soon, if there’s a takeaway that you’d like to give us. Okay, all right. So a dirty little secret, okay, it’s not yet, it’s not publicly published, okay? It’s free. I paid someone to set up the format, looks pretty and all that. But at this point, it’s actually just free. It’s 100 plus pages, I forget, 120 pages and I shared very willingly. I’m still trying to get it published by a publishing house and I don’t know if I will, but it doesn’t really matter. It’s full of what I said there at the end about my perspective, my advice, my worldview on things and there’s just lots of stuff in there. And I have a model for how to think about it, three concentric circles. The inner circle itself, okay? The next circle out is other and that’s, so the first circle and the third circle is organization. So the first circle is what do you need to know about yourself. Maybe it’s Myers-Briggs, maybe it’s Susan Cain’s book. How many Is are here? I’m a high I. Any other Is in the house? Introverts, any other introverts? I know this is CMC so I know there’s a lotta Es but there had to be some Is. Okay, all right, so there are some Is. So an I, you have to learn how to do E things in an I way. (woman laughs) Okay, you have to. I’m a high I. When I’m done here, I’m gonna go fall asleep, okay? ‘Cause that’s, so I’ve learned how to function like an E, but I’m a high I. So that’s the first circle. The second circle is other. It’s all the interpersonal dynamics. It’s all the soft skills, all the things you need to learn about how to get along in the world with other individuals. So it’s collaboration, teamwork, conflict resolution, negotiation, okay? And in certainly environments, management and leadership. But you’ve gotta learn those. And those are lifelong. You don’t just take a class and then you’re set, okay? These are lifelong. You keep maturing. And then the third circle organization is how do you function in organization, and that’s changing dramatically about what that is. But the point is you have to know about what your, the expectations are. And I would say that one of the terms in there that y’all ought to know is unwritten rules, okay? Unwritten rules. There are a lot of unwritten rules when you go into a company that if you’re not paying attention you’re gonna trip over them. I did many times, many times I’ve tripped over, over unwritten rules before somebody point it out to me or I ask, I said, “What am I missing here,” okay? So the unwritten rules are really critical. So unless you ask or unless you observe or unless you have a confidant or someone who’s a coach or a mentor it’s gonna be really hard to figure that out. I think it’s one of the biggest obstacles for people going in. You’ve learned the rules of how to be a good student, okay, and you gotta learn the rules about how to be a good employee (mumbles) Google and anyone else. Rules are different, but you have to know that. So that it, the organization. So that’s what the book does. It talks about it in that way. It had exercises and readings and blah-blah-blah-blah, but that’s the purpose of it. Very few books out there talk about how to keep a job. Please. Oh, sorry. Could you comment a little bit about the drugs for hepatitis C that we’re hearing that suddenly you could be cured. And how long did that take to develop and what were the complications of coming through a success? Well, it took a long time to really identify the virus. It was a lot harder than B. B was really easy. B, the very first thing they did was to take blood from infected individuals, spin it down, separate out, have the B virus and inactivate it. And that inactive B virus was a wonderful immunogen. So, and that was the first vaccine. Merck actually created that back in the ’80s and was incredible in terms of creating an immune reaction and gives lifelong immune reaction. So that was B. After the HIV epidemic, they had to make a component vaccine, so the, it was a genetic vaccine for B. C was really tough. It was hard to find it. It was hard to identify it. So it took years before they got that part figured out. Secondly, it took them a long time to really find a molecule that was going to truly inactive it. They found some things that are actually able to, with 40, 48 weeks of treatment, alpha interferon I think it was, it was really a difficult treatment. You had tremors, you had fevers, you were really under the weather for a year. And so people were relatively reluctant to go through that because it’s a chronic disease. Next was a drug, there are three types of hepatitis C: types I, II, and III. And the next drug that came along was actually found to relatively effective but it was still another 24 to 48 weeks of treatment depending on what the type was. The new treatment now is truly a cure, okay, and it will, and people wind up, people waited to line up to get this treatment. I don’t know what it would cost, 80,000, 100,000, it’s an expensive treatment, but it does work and it’s over 90%, I think it’s 95% in terms of effectiveness. There was a question over there, please. Hi, my name is Lea. I like asking alums this question. This is a little bit more personal so go as far as you want. But when you did go to CMC, can you just talk briefly about like your experience here and if there was anything that you would change or something like that back when you did go here– That would change while I was here? Yeah, and like what was your experience just in general. Well, I was, okay, I was a very naive, inexperienced adolescent and I was really nervous about going very far. And far was gonna be Northern California (laughs), so, and I looked at some places and it had some possibilities. But CMC was like an island for me, it was a great place. The other boys that I met, because it was Claremont Men’s College when I was here, was, it was a great place. I just really enjoyed it. I just loved doing everything that I was doing. Now, did I fail? I failed a lot, okay? I failed in my relationships, okay, I failed in my classes, and that doesn’t mean I got Fs, but, and I did poorly, okay? So I did, I got a lot of Cs. And I had a lot of breakups in relationships, okay, I had to learn a lot about relationships. So I learned a lot. So I don’t know what else to say to that. It was a good place, I met lifelong friends, I met the faculty that I’ve kept in touch with over decades, I just had a good experience. Please. Hi, thank you so much for your speech. I was just wondering while you’re at the FDA working for a cure for HIV/AIDS, I was wondering how were you in collaboration with like other international researchers or other governments. Sure. Okay, yeah, the question about collaboration with others. So HIV was probably the precipitating event to lead a collaboration with other regulators. So there was. The immediate one was Canada, okay? Health Canada wasn’t Health Canada then, okay? It was the Health Protection branch of which there were maybe a dozen people in the entire thing. So we actually collaborated on reviews. So I forget which drug it was that we did, but we came out with the approvals on the same day, so we synchronized our reviews. We were on the phone, we’re talking about this, and talking about that, we shared stuff, so we wanted to show a front, we didn’t want to be one day different, okay? We wanted to be totally collaborative. So that was one story. Europeans were then just changing their review system. Okay, so Europe 26 countries or whatever in European Union, I would say, there were 26 different reviewing organizations, okay, and they had a system that you could be approved in one country and they would have reciprocal relationship with other countries it would still take forever to get things reviewed. So when they created a system that allowed a single review that will apply to all countries, huge advance, okay? We helped with that, we participated with them, and they did it in levels. The first ones were cancer and HIV. Although the drugs went through all the individual country reviews, but those two they had a single review. So they created a whole new set of regulations and everything and a new system reviewing, everything was, so they did a lot of stuff. So that was that part. We worked with Mexico, we worked with Australia, we worked with Australia, we had a collaboration with Australia. That’s the Therapeutic Goods Administration TGA and we collaborated with them on a number of things. So it was an opportunity for us to be able to share and collaborate with other regulators on things, okay? Please. So you used to be with Merck when the whole global campaign for the price of the retroviral drug started. The question of price, pricing. Pricing. You must have been with Merck. Yeah. So the multinationals in the Merck, I mean companies here were on the other side of their whole campaign, what was, what were the debates like within Merck on the issue of pricing of HIV medicines? Yeah, well, certainly when I was at FDA price number came up. It’s like it’s not on the radar, okay? It’s not part of our charge. So I can’t recall the conversation about price as far as my experience at FDA. When I was at Merck, here we go, okay, Cancidas, caspofungin, intimately involved in the develop of caspofungin. And it was a once a day drug. Strongly lobbied for it to be, quote, unquote, “reasonable price” for the drug failed, okay? Failed. Marketing had total control of that and set the price for that drug. So very disappointed. And learned the power of marketing, okay? So often disappointed in decisions that were made. (faint voice talking) Which one? Does Cipla offer these medicines at $300 a year? This Indian genetic company that is– Oh, yeah, okay. So it was at $2.1 million for treatment, right, for the, I think it is. Like something like 2.1 million. Yeah, it’s, I don’t know what to say. It’s just shocking is not really the word. I don’t know, I don’t know what to say. Overwhelming. Other questions? Word. This will be our last question of the evening. (faint voice talking) Sorry, have– Have we learned something from other FDAs as to how to speed up the projects (talks faintly) Can we learn something, being about like regulatory process? (faint voice talking) So there’s the new law of the 21st Century Cures Act, I didn’t talk about it, okay, I’m kind of embarrassed about it because what it does is fundamentally relax the criteria for approval. And it makes me nervous, okay, so I usually don’t talk about it. (laughs) Because it’s no longer the randomized controlled trial, it’s like or experiences of, meaningful experience of treatment. That’s we’re back to anecdote again. So I’m nervous about it. I think we’re gonna try and stay as much away from that as possible. We just lost one of our best trustees. Yes, Neff, yeah. (faint voice talking) Yeah. Whose approach was to get this drug approved by the Chinese equivalent of this FDA and then take it from there. Okay, so they don’t have my trust. Fundamentally. (faint voice talking) They do not have my trust, okay? Too many things do not support me giving them my trust. All right, so that’s all the time we have for our questions this evening. So please join me in thanking Paul Beninger for his talk tonight. (audience applauds)