Levi Smith, PharmD, MS, PhD Candidate at Yale University highlights the path of a drug from target discovery all the way to clinical uses and applications.
Levi Smith is a PharmD with a master’s degree in Pharmaceutical Sciences. He is currently pursuing a PhD at Yale University in the department of cell biology. Levi uses animal models and cell lines to study the molecular mechanisms of Alzheimer’s disease, with an ultimate goal of identifying where pharmacological intervention would be beneficial. This interview highlights the path of a drug from target discovery all the way to clinical uses and applications (Here is a link to the Interview Recording).
Matt: Hi everyone! Matt Paterini here with The Nontraditional Pharmacist, joined today by Dr. Levi Smith, PharmD and PhD candidate. He uses his current education along with his pharmacist training to really dive into drug development and research. Thanks a lot for joining us, we certainly appreciate it.
Levi: Thanks for having me Matt. I'm really excited that I've found you guys. I'm glad that this tool [www.thenontraditionalpharmacist.com] exists and I'm glad you guys are recruiting people to participate because it's definitely something that's needed to help pharmd's discover what's outside a traditional pharmacy career, and I hope they find out as early as possible.
Now that I've completed my PharmD, I'm working on my PhD in the department of cell biology at Yale University. My research is all neuroscience. What I'm doing now is using animal models, as well as cell lines, to study the molecular mechanisms of Alzheimer's disease and trying to identify places where pharmacological intervention would be beneficial. A lot of my research has been focused on what is called hit-to-lead development, where we've identified a compound that works in an in vitro assay, such as a purified protein system, or in a cell-based assay. We then take that into animal models and we try to demonstrate efficacy and target engagement. I've got 3 projects that I'm managing now. Most are focused on drug development and I've been able to pull a lot on my pharmacy background to really accelerate these projects and be efficient about the questions that I ask, and the techniques that will be useful.
Matt: That’s an interesting story, as you mentioned we like to try and highlight different areas of the pharmacy profession across the spectrum and give people the exposure that they need, especially early in their career.
You described a little bit about your current role, but what steps led you to that current role and what was the process leading up to where you are now?
Levi: I started pre-pharmacy because I was interested in how drugs work. As I got into the professional phase I realized this is very clinical degree. I reached out to professors about opportunities to do some bench research in molecular biology at the university and got very lucky that a new professor, Dr. Erkine, was looking for people to start working in his lab. We met several times throughout the year to build up some basic techniques because the research we were doing in the lab was strictly molecular biology; things we hadn't had any training in pharmacy or pre-pharmacy. It was a whole new set of skills and principles to learn. After that first academic year, Dr. Erkine offered me to stay on for the summer and begin that research project. After a short while, my research project was going pretty well and I was in talks with faculty about being interested in going to grad school to enable the kind of work I really wanted to do. That's when the opportunity to pilot a dual degree program at Butler came about. We had an existing MS in the pharmaceutical sciences program, which was a thesis-based master's, but there had been talk for a little while about trying to bring the two together. I had an opportunity to meld those into a dual-degree program where I did additional coursework and full-time research on top of my PharmD, but at the end of that same amount of time, I was able to graduate with a master's in pharmaceutical sciences and three years of bench experience. Those research experiences enabled me to get to where I am, decide what I was interested in, what techniques I’d want to use, and learn how to read scientific literature. That's really what assured me that the PhD was where I needed to go.
Matt: OK. That makes a lot of sense. So PharmD, PhD, what's next? What are your long-term goals and how is where you are now on the path to where you want to be?
Levi: I'm really fortunate that right now I'm doing the work that I want to be doing. It's not the same setting, but I want to continue to work on drug development. I want to be working in a team where we have a target that we're interested in and we’re taking positive hits from screens of hundreds of thousands or millions of chemicals, and developing those into what would be a clinical candidate: a compound that we would then move into people. So, for me that would be something like an in vivo pharmacology role with either a biotech company or a pharmaceutical company but in industry where you really have the tools and the manpower and everybody's kind of together on this same goal of making meaningful therapeutics for needs that are currently unmet.
Matt: I'm glad you mentioned industry because when we talk about nontraditional pharmacy, a lot of people talk to us about industry. So this sounds like it's one specific area of industry, but how does that tie into maybe some of the other areas that people might be interested in and how do all of those dynamics play out?
Levi: I had the good fortune where I did an APPE rotation at Eli Lilly in a drug development role. I was with their musculoskeletal drug hunting team, working on early stage drug development, but while I was there, I also had classmates who were interns in business development or regulatory affairs or medical science liaison positions.
Matt: How does what you're interested in with drug development tie into what we would say is the larger industry picture?
Levi: The pipeline for a product coming to market and becoming a drug typically begins with an academic discovery. There are still some industry groups that do basic science research, but you begin with target discovery. A good example is the recent race for the PCSK9 inhibitors. That target came out of academia and there was a very clear translational value and industry groups jumped on it as a great drug target. The role I'm interested in will be the one in which we have a target and we’ve developed a system to screen for chemicals that can engage this system in what may be a therapeutic way. Then you go from those hits and you try to refine them. They go through chemistry and become more potent, more selective, weed out off-target effects or nonspecific effects. That compound would then go to clinical development and be handed off to a clinical development team.
Prior to the clinical development, you would have to do all investigational new drug (IND) enabling studies. This includes things like toxicity and pharmacokinetics (PK) so that you could file your IND, at which point you can go into the clinical trials and conduct your Phase I, II, and III clinical trials. At that point you're working with regulatory affairs to communicate with the FDA about what your trial design is, what your endpoints are, and what are meaningful endpoints in the clinical space you’re in. Once you get to the point of approval you've got more people working in regulatory affairs, which is definitely going to be made up of a lot of pharmacists who are working with the FDA. They work on what your package insert is, what your branding is, even the name of the drug. This all goes under scrutiny from the FDA and is put together in a new drug application (NDA) that is then submitted. You're probably going to get feedback. I've had the mixed fortune of pouring through some NDA's recently from some Freedom of Information Act requests, and it looks like there's a good deal of back and forth: it's not usually a "we submitted it and it got approved." Once your NDA is approved and before the product launches, you set up your medical science liaisons that have become experts in the literature or what is known in the clinical trial data. Then you begin marketing your product, which to my knowledge, engages a limited number of pharmacists (but there are still some). Community and clinical pharmacists may then engage with medical science liaisons at the manufacturer to appropriately incorporate the new drug into practice.
Matt: That's a great overview because we talk about some of these pieces along the way, but to tie it into the larger picture is great because I think a lot of people don't quite understand, or at least they've never been exposed to the process, and therefore haven’t heard about what it is from start to finish. That's helpful. What advice would you give to people that are looking to get into drug development/industry, and also specifically into the area you're focused on?
Levi: If you want to work at the bench on developing drugs, you pretty much must have a PhD. Even with my PharmD and a Master's in Pharmaceutical Sciences, I was not confident that I would be able to do what I want to do in industry. I would be able to work at a bench and run a protocol/do various assays, but I wouldn't have the upward mobility that I really want. If you want to lead a team, making scientific decisions about which questions to ask, and how to ask them, that’ll require a PhD. If that is what you want to do in terms of drug development, then the next step is pursuing a PhD. If you want to be in the business development side or in more of a clinical science side like the medical science liaisons, that's certainly something that a PharmD is more than adequate for.
Matt: It sounds like credentialing is very important, a PhD specifically, for drug development. To pursue a PhD after a PharmD, do selection committees look at your performance in your PharmD program or is it a number of other research experiences? What exactly goes into the criteria for pursuing a higher degree?
Levi: By far, the most important thing is your research experience. A PhD is absolutely a marathon and is in no way a sprint. What the committee that's accepting you wants to see is what research experiences have you’ve, that you know what it's like to be in a lab, and that you know what it's like to do research for an extended period of time. If all you can fit in is a summer to do two or three months of research, then that's adequate, but not reflective of the experience of a PhD program. If you're able string together a couple of those summers or if you could have projects that lasted longer than that, that's great. A lot of people take a year off if they don't feel like their application is strong enough and they get a technician position in the lab so they can really get hands-on experience.
Your GPA is a cut off, certain institutions are going to have a minimum value. A place like Yale gets hundreds and hundreds, if not thousands of applications to the programs and they just need some way to trim that down. Your GPA is an easy way to do so. You also have to take the GRE, a test largely focused in math. The General GRE is required for the programs I was looking at; largely molecular biology, cell biology, and biological sciences programs. There is a reading and writing component, but your reading comprehension and math are your most important. Again, institutions are going to have certain cut offs that make it easier to get through the pile. You're well prepared as a pharmacist to do well on that exam. I don't remember exactly what is and isn't on it, I know there's not calculus, but if you've been in the laboratory, if you get a prep book and do some practice questions, and prepare for the exam like all the other exams you've prepared for in pharmacy school, you would be more than equipped to do well; but, if you want to get into a good research institution, you're going to need to excel and be in the top percentiles of that exam. Research experience in the lab, taking the GRE, having a good GPA will help get into a PhD program.
Getting a great GPA is difficult for a pharmacy student because our programs aren't designed for something after - you're not meant to get straight A's in pharmacy school. It's much more of a "C is average” situation. Personally, I applied to my programs with a 3.59 GPA in my PharmD and in a 4.0 GPA in my master’s, which is pretty typical of a graduate program. When it came to applications, my experience was very hit and miss. I will tell you that these committees see a lot of applications and they know what to expect of someone who has a bachelor's in science. They don't really know what to think of a PharmD. I applied to probably 20 programs, which is a lot. My colleagues mostly applied to between 5 and 10, but I knew that I was a different candidate. I was probably going to get rejected from places just at face value, so I applied to a lot of programs. In terms of the ranking, it wasn't as though a certain ranking accepted me and everybody above that rejected me. There were programs that gave me interviews that were better than programs that had not given me an interview and this was all based on my application. I think a lot of that was the committee not knowing what to think of my background. I think it did help me that I had a publication in preparation when I applied and I was able to list that on some of my applications. Fortunately, the program at Yale I applied to was a very good program and it worked out that I ended up in a really good place for that kind of work that I want to do.
Matt: Well there you go, I mean you never know, right? And so school round 3, round 4 and beyond to pursue the drug development path. Drug development is your passion, but what would you say to other pharmacists or pharmacy students that are passionate about different areas in pharmacy, but don't know exactly how to pursue those? What would you say to those folks?
Levi: For me, you have to find that thing that when you're studying or you're thinking about drugs (since we're talking about pharmacy students); what's that thing that when the question gets in your head as to “how does this drug do that?” or “why this drug not that drug?,” it's not something that then just leaves your mind. Find the thing that really eats at you and you want to truly understand, so you take that extra time to go and figure it out. Not because it's going to give you a better score, not because it's something that you think will make you look good to have the answer to in class, but just because you need to know it. There's some reason that you just really have to understand this aspect of what you're thinking about. I've got so many friends that enjoy their job, they're passionate about the value that they bring to it, but they're still working for the weekend, they're working for their vacation. Given the amount of time you're going to spend in your career over the next 40 or 50 years, I want to be doing, and I want everyone else to be doing, something that they don't have to do, but something that they need to do because it's fulfills them in a way that nothing else does. I think that curiosity will guide you very well to find something that you can be happy in, and that will keep you sustained.
Matt: Really well said, I like that a lot. Levi, thanks for your time today.
Make sure you visit The Nontraditional Pharmacist and sign up for the Pharmacy Network. Register, create a profile, and we encourage everyone else exposed to this interview to connect with Levi through a comment on his blog post, through the pharmacy network through a friend request, or any other connection that you might find on that pharmacy network. So thanks again we appreciate it!