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“Ultimately, the best way to learn is by doing…”

Clinical drug trials mark the intersection of research and medicine, where the translation of lab experiments leads to advances in treatments, new protocols, or new drug therapies designed to improve patient care. The complex and lengthy nature of clinical drug trials poses a challenge for trainees eager to learn more about how they work. Many are uncertain about how to gain operational exposure to such trials. Dr. Dana Cardin, MD, a pancreatic cancer clinician-scientist shares some of what she learned along the way. She gives actionable advice on how scholars interested in pursuing a role in clinical trials can gain experience.

How did you get into running clinical trials in oncology/pancreatic cancer?

Cardin. I knew I had some interest in medical research early on. Before I went to medical school, I worked in a basic science research lab at University of North Carolina at Chapel Hill, after completing my undergraduate degree there. When I saw basic science experiments using mouse models of cancer and other illnesses to translate findings into treatments in the clinic, it excited me to see how discoveries in the lab could impact patient care.

I became drawn to oncology in medical school and ended up matching in that discipline. As a hematology/oncology fellow, I worked with and was mentored by Dr. Jordan Berlin, who has extensive experience running pancreatic cancer and phase I trials. Seeing clinical research up close helped me recognize the fit between my interests, skill set, and oncology research. During my mentored fellowship I wrote my first clinical trial protocol, followed it through IRB approval, enrolling patients, completing the study, then publishing it. It took a long time, but working through that process helped me realize that was the type of research that felt right for me.

What makes it difficult for trainees to gain experience in clinical trial research during training?

Cardin. The clinical trial process, in most cases, is long. There is no ‘instant gratification.’ Conversely, training windows are typically short in duration. As trainees rotate through a department or division, it’s difficult to see a full trial lifecycle. From beginning to end, each part of setting up and running a clinical trial requires time. Some parts take longer than others. For example, protocol development can range from months to years. Even once a protocol is written and a sponsor wants to open it at an institution, getting it activated typically takes about 2 to 6 months, depending on complexity and issues like contracting, budgeting, pharmacy review, and IRB review to ensure patient protection and the inclusion of appropriate risk/consent language in the agreement.

For medical students, most medical education is focused on patient care rather than trial development and infrastructure. Most PhD programs also lack comprehensive focus on clinical trial development. Learning about clinical trials takes a bit of planning by those who are really interested in pursuing that type of career path.

What is an effective way for students to learn more about clinical trials?

Cardin. Students (MD and PhD) and postdocs should pursue opportunities to gain lab experience (basic science or working with a clinician involved in clinical trials) for an introduction and practical experience. They can email Principal Investigators (PIs) running interventional studies to explore the type of science questions being considered and see if there are opportunities for new trainees in the PI’s lab.

In clinic we see patients on trials, and we talk about what it means and how the protocol works. We make sure fellows have access to the systems where they can pull the protocol. We talk through it with them.

How can trainees get deeper into clinical trials?

Often, mentors serve as the gateway for helping trainees learn what’s involved in coordinating and running a clinical trial — how to enroll patients in a study, devise and implement protocol, collect and analyze data. For deeper involvement, trainees can help develop protocols with their mentors, review example protocols, and/or work with experienced medical writers. As an example, we had a fellow who took a faculty position at University of Colorado. She worked on developing a protocol. Usually, you start with an example protocol. Another way we provide an opportunity for training is by pairing trainees with the PhD scholar we have on our team who helps with medical writing and protocol development.

One point to mention about protocols in clinical drug trials is that many drug trials are pharmaceutical-sponsored, so protocols are often pre-written (sometimes with input from physicians who advise companies). In those cases, the clinical researcher’s role is to evaluate available trials and decide what’s needed in their clinic and where they can meaningfully enroll patients.

There are also cooperative groups (largely, academic centers working together) that develop trials to answer important questions industry may not fund. Through networking, trainees can look for opportunities to gain practical knowledge of how these groups work.

More formal opportunities for training include programs like a Master of Science in Clinical Investigation (MSCI), which I did. You learn protocol development, statistics, ethics and other skills in this type of program. There are intensive one-week workshops (e.g., AACR/ASCO-type programs) where trainees apply with an idea and mentor, and they work with experts to develop a protocol and statistics to make it workable. Ultimately, the best way to learn is by doing—writing a trial, seeing it through, enrolling patients, and learning from mistakes.

What other aspects of clinical trials are important for trainees to learn about?

Cardin. Interacting with companies is an important part of my job. Sometimes, the projects that are important to our team may not be of interest to them. Learning how to negotiate to get something you need from drug companies when interests are not fully aligned is a great skill to develop. Engendering goodwill with the research community and participating through NCI or other NIH mechanisms where companies provide a pool of drugs at no cost are a couple of examples of how pharmaceutical companies contribute to research that doesn’t have a huge financial upside for them. There is also the possibility that a particular study could generate useful hypotheses or data. In oncology, even for rare tumor types where there may not be a big financial return, it can be beneficial for a company to have supportive data. Projects with negative results or ones that don’t yield any type of advancements, still generate valuable information that guide next steps.

The collaborative process involves reciprocity—in negotiating, contracting, budgeting, and building strong working relationships. Pharmaceutical companies rely on academic centers to gain access to patients and clinical expertise, and academic centers need access to the drugs pharmaceutical companies can provide. Both sides (scientists and the pharmaceutical industry) recognize that ultimately, progress in cancer treatment comes from testing new therapies and seeing new drugs get approved.

Sometimes relationships don’t work out. There’s a lot of uncertainty in developing and running clinical drug trials. I’ve had two studies this year end abruptly because the sponsor decided not to continue supporting the research. I don’t love it, but it’s partly how clinical trials work. You learn to make sure you have enough eggs in your basket that if one falls through, you have backup plans. These are good lessons to learn while in training.

How does the VUMC network of clinical trials work?

We build a portfolio that allows maximal impact for patients. In the Gastrointestinal (GI) Oncology Department we have many trials running concurrently. Overall, the program has over forty active trials spanning multiple disease sites (colorectal, liver, biliary tract, pancreas, esophagus, etc.). Trials are highly specific—different studies apply to different stages (localized vs. metastatic), treatment lines (first-line, or initial, primary treatment) vs. later-line (secondary therapies used if necessary), and even molecular subtypes (e.g., trials limited to patients with specific mutations). Each clinical trial has its own unique patient population. We try to meet the needs of the types of patients we’re seeing.

Luckily, here at VUMC we have a large research infrastructure that supports our work. Various teams manage the legal and other contractual requirements such as budget negotiations, IRB submissions, consenting/screening, and many administrative tasks. This allows me to focus on figuring out what studies we need, talking to companies, responding when companies ask if we’re interested, and working as a GI team of seven doctors to review protocols. We decide which studies to pursue… Is the population too rare? Will it be hard to find patients?  Is the question worth asking?

My goal is getting patients into studies and seeing them do well. Mostly, I do what I do because I like working with patients and taking care of them.

Dana Cardin, MD is an Associate Professor of Medicine (Hematology/Oncology) and Co-Chair of the Data and Safety Monitoring Committee (DSMC). As a Vanderbilt faculty member, she develops clinical trials in gastrointestinal cancers with a special emphasis on pancreas adenocarcinoma. She serves on the National Comprehensive Cancer Network Pancreas Adenocarcinoma Guidelines Panel and on the National Cancer Institute Pancreas Task Force.

David Merryman and his research group’s work in targeted drug strategies has led to multiple forays into industry collaboration and company development.

He admits that the path to drug development has been more nuanced than expected as he continues to work towards his ultimate goal of advancing a new drug into the clinical setting.

Reflecting on his experiences, he candidly shared his observations on navigating industry partnerships and starting a biotechnology (biotech) company.

How did your partnership with one of the largest pharmaceutical companies in the world materialize?

Merryman: I have two collaborators, both named Craig. Craig Lindsley is a medicinal chemist and pharmacologist. He runs the Warren Center for Neuroscience Drug Discovery. His group focuses on drug design. Craig Duvall works in biomedical engineering. He develops carrier-free RNA drugs. My lab identifies the mechanism and the need. They work to design the new drug or new delivery method. In collaborating with their labs, we’ve filed patents around new chemistry to deliver drugs.

Craig Duvall and I formed an industry partnership with Bayer in Germany to develop a drug for kidney disease as part of their kidney disease drug development program. The partnership dissolved prematurely when Bayer shifted away from that program towards developing biomarkers and clinical studies as the company faced increased litigation surrounding its acquisition of the Monsanto corporation, the manufacturer of the weed killer Round-Up. After a year, Bayer returned the patent it had licensed from Vanderbilt and ended the partnership.

After that, Craig Lindsley and I collaborated in making a new drug. Following a few failed attempts at partnering with various companies, we launched SERO Pharmaceuticals, a clinical-stage biotechnology company, which is about a year old. We’re trying to raise money to do IND (Investigational New Drug)-enabling studies and get to a clinical trial. For a couple of years, Craig and I were primarily looking to partner with a drug company. We didn’t want to start a company, but we ended up starting one anyway. One benefit is that we have agency over what we choose to focus on.

Would you share some takeaways based on your experiences?

Merryman: In academic medicine, discovery of new applications for existing drugs, or gaining a deeper understanding of disease progression, is important, but what’s more valuable to investors is having patentable materials, novel chemistry, or novel compounds that are patented.

Projects that are further along in development are more attractive to investors, as are ones that demonstrate knowledge of the toxicology features of a drug (whether the drug can make people sick). Surprisingly, in previous pitches, even with strong preclinical data based on animal models demonstrating a drug worked on the disease, a lot of the big companies told us to come back after we had human data. Once you get past a phase 1 clinical trial, lots of companies become interested, but it might cost around $10 million to do the trial. That’s a heavy lift.

Investors are also interested in the development of biomarkers. In a lot of drug development processes, investors either want a specific drug mutation that they can hone in on and they know exactly how it works, or they want biomarkers in the phase 1 trial that will give them confidence that a very expensive phase 2 trial will most likely work.

We had to be overly prepared for a fair amount of scrutiny from potential investors. There were lots of questions. Sometimes we were questioned about our knowledge of other projects that only the senior members of the companies we were pitching to had knowledge of. Companies could be vetting multiple projects simultaneously or evaluating their competition. The information we provided seemed disproportionate to how much feedback we received after being rejected. To move past the disappointments, it’s always been important for me to stay focused on my desire to develop drug therapies that can improve the lives of patients.

Preparing for the long game is helpful. You’ll kiss a lot of frogs. However, it’s also important to keep in mind that patents have a 17-year lifespan. You need to accelerate through the development process to get to your Investigational New Drug (IND) studies. And you have to factor in a minimum of two years for clinical trials, if they go splendidly fast. Companies that invest heavily in new drugs want at least ten years of protected patents where only they can sell those drugs.

Final thoughts?

Merryman: I’ve seen drugs succeed commercially that weren’t the best drug, but the scientist was savvy in lining up multiple investors. Networking and building relationships with potential investors and people in industry are important.

David Merryman, PhD, is the Walters Family Professor and Associate Chair for the Department of Biomedical Engineering. His research examines the role of mechanical forces in altering cardiovascular, pulmonary, and renal cell function at the gene, phenotype, and protein levels, with particular focus on the serotonin 2B receptor and cadherin-11.

Making the Rounds in Palliative Care, One Collaboration at a Time

Before it became the norm for trauma units and palliative care physicians to work together, at Vanderbilt University Medical Center (VUMC), Dr. Mohana Karlekar and her colleague, Dr. John Morris, the pioneering head of  VUMC’s trauma unit at the time, struck gold when they teamed up in 2007 to discuss how they could collaborate to improve patient care delivery.

One meeting set the tone for a partnership between their departments that has since become a seamless integration of trauma care and palliative care services that has helped shift the treatment protocol paradigm in their respective fields. In this Q & A, Dr. Karlekar shared her thoughts on this, and other collaborations that took shape during informal conversations or meetings and eventually led to initiatives that continue to expand the boundaries of interdisciplinary healthcare.

“…you should just walk around the unit and round with me!”

How did the collaboration between your palliative care department and the trauma unit come about?

When I first came to Vanderbilt University Medical Center, I was asked to meet with providers in any department who either had an interest in or needed palliative care services. When I finally caught up with John Morris, he said, “We need to start using palliative care in trauma.” This was in 2007. John thought that trauma patients could benefit from palliative care because by definition these patients all had serious illnesses. Some had been chronically ill with a complication like a fall. Others were once well but had experienced blunt trauma (i.e. from an MVC, Motor Vehicle Collision). He recognized that surgeons were not traditionally trained to communicate and having a team of clinicians who could help communicate difficult information around diagnosis and prognosis would help to deliver more goal concordant care.

In our first meeting, John began talking about all the ways we (palliative care providers) could be helpful in the trauma area. One day I was in the trauma unit for a consult with him and he said, “In fact, you should just walk around the unit and round with me!” They had at least thirty to thirty-five patients in the trauma bay, ICU and step-down unit at the time.

We went through in real time discussing what types of consults would be helpful or not helpful. It was very collaborative as we went back and forth, “In this case, I think yes, but not that one,” John would say. We decided that the patients who were appropriate for palliative care included ones that created ethical dilemmas (wide awake tetraplegic patients), had a poor prognosis (older adults with falls with a serious injury like traumatic brain injury), one with serious comorbidities who happened to come into trauma (patients with cirrhosis who had an MVC, or patients with traumatic injury with advanced heart failure. There was give and take on who might be involved from both our perspectives so it wouldn’t be stressful on either unit.

What began as, “Let’s get some consults through this robust relationship,” turned into a partnership where we now see a decent number of trauma patients. These days our palliative care trauma consults involve young people with bad brain injuries or older adults who fall, in addition to patients with terminal illnesses. Older adults have a higher incidence of bad traumatic events linked to falls, and it’s really awful to see.

That one conversation years ago led not only to patient care collaboration, but also papers published together and a quality improvement (QI) project focused on the frail and elderly. The project, Creating New Opportunities to Educate Families on the Impact of Frailty and Cognitive Impairment in a Trauma Intensive Care Unit: Results of a Quality Improvement Project, involved teaching nurses to screen for frailty and then consult palliative care for patients with frailty who were admitted to step-down, to discuss goals of care (more long term). I co-authored a book chapter with one of the surgical trauma doctors during COVID. We do yearly lectures for critical care fellows. The trauma team is involved in family meetings and trauma providers partner in palliative care service rotations. Since we started working together, we have always had someone from trauma in family meetings. Now, we work and communicate so well together that if someone from the trauma team can come, great, but they don’t always have to be there.

“We’re going to come up with a project together and this will be our baby.”

Can you talk about other collaborations you’ve been a part of?

Another one that started out as one thing and lead to something else was when I was asked to be a part of a group led by Dr. Gordon Bernard who had been tasked with doing palliative care research. We published COMPASS: A Pilot Trial of an Early Palliative Care Intervention for Patients With End-Stage Liver Disease. One of the group members, Cheryl Gatto, PhD, and I had a couple conversations and found that we were sort of kindred spirits. At the time, we didn’t know each other that well. We started talking one day about something that had happened within the project, and we both agreed that we needed to try to address the issue. From working together on that issue, Cheryl said to me, “Next time, we’re going to come up with a project together and it will be our baby.” I thought, Okay. I don’t know who you are, but you seem like a good person, so I’ll go along with it.

It took about five years, partly because of COVID and other stops and starts. She and I ran this pragmatic trial looking at this surprise question: Would you be surprised if this person died within a year? If the answer was “No, you wouldn’t be surprised by the high likelihood of death,” then you were prompted to do a palliative consultation. That was a trigger through what we used to call BPAs (Best Practice Advisory). Now they’re called CDMs (chronic disease management). The paper, Evaluating Performance of the Surprise Question to Predict 12-Month Mortality in Patients With End-Stage Liver Disease, was published in the American Journal of Hospice and Palliative Medicine. We now have approval to incorporate this CDM into eStar to be used in real time for inpatient clinical practice.

As we began collaborating–I know what my skills are and what my skills aren’t–though I can publish, I’m not a good statistician. So, I mentioned to Cheryl that we do a fellowship research project every year. I asked if she would be interested. She joined the project and for the last two years has been the research point person for which she really has no reason to do. She has a busy job running pragmatic trials with a colleague. She is very passionate about palliative care from personal experience and has been such a wonderful source of information. She picked my brain about certificate courses and ended up completing a certificate course in palliative care, even though she didn’t have to. Now we’ve become really good friends and collaborate on a number of things.

Considering all that she does…Operations Director for the VUMC Center for Learning Healthcare, running clinical trials with the center’s Medical Director, Dr. Matthew Semler…I wondered why she would ask for my help to run a project. She told me, “All you have to do is be the content expert.” That’s the other part of it as well. I told her OKAY but you’ll have to teach me. She sent me all these articles on pragmatic trials. She sent PowerPoints. I read about pragmatic trials, and she read about palliative care. I’m sure she knows more about palliative care than I know about pragmatic trials, but we both learned from each other. Beyond the projects we have our friendship which is the best part.

“A nurse in Zambia needs someone for her PhD mentor group.”

Another sort of accidental collaboration happened because a colleague at the cancer center Dr. Rajiv Agarwal, an oncologist who is a part of our inpatient Palliative Care Consultation service mentioned that a nurse practitioner in Zambia needed someone for her PhD mentor group. I said laughing, “We need to find a way to go to Zambia!” Time passed and I hadn’t heard any more chatter about it. I asked Rajiv for an update. He told me if I was interested, I should reach out to the nurse to find out. Again, recognizing my research skills/limitations, I pulled Cheryl in, and we had a call together with Rajiv and the nurse.

Eventually the nurse sent me the information. They had an NIH SHEPIZ (Strengthening Health Professional Workforce Education Programs for Improved Quality Health care in Zambia) Grant. She said they needed people to come teach in Zambia. I have a friend who by weird coincidence spent a year in Zambia about 25 years ago. She and I went last year and taught for two weeks in Zambia.

We created a certificate program for them. We met local leaders in healthcare and palliative care in Lusaka, Zambia. A year later, we’re rolling out a virtual teaching seminar to keep that going. They joined us as guest faculty for a journal club we did back in January. We talked about opiates and what it’s like to practice pain management in a country where opiates are minimally available. The hope is that this will continue to be an ongoing partnership and that there will be a layering effect where we can touch and connect with more people.

I think when we think about partnerships, (this transcends palliative care and medicine), sometimes asking the question out of curiosity can lead to the unexpected, “What could you do…can you try doing…?” Not being afraid to ask is the key. It would not have happened if I hadn’t said out loud, “Gosh that seems cool!” Sometimes we don’t ask. That was my favorite one [collaboration] and for me, it was very transformative to go there.

“Maybe we should all get together and collaborate.”

Are there any other accidental collaborations you’d like to share?

One more, maybe not so accidental. When I worked in New York city I used to take care of Riker’s patients. The whole top floor of the Bellevue hospital is a Riker’s Prison, a locked unit. I incorrectly thought I knew how to take care of incarcerated patients because I knew the rules there (at Riker’s) and thought I was pretty comfortable with caring for those patients. Fast forward. Two years ago, this patient was handed over to me from one of my partners, who I consider to be very much on top of things and wouldn’t take something at face value if it didn’t make any sense. She told me we have this patient coming in from one of the prisons, but he doesn’t have capacity, so the warden is his decision-maker. It was one of those busy days, so I listened and wrote down everything. I was by myself in the unit that day with a young fellow.

That evening as I was talking to a fellow to give them a hand off, I told her the healthcare decision-maker for the patient is the warden. I stopped in my tracks and said, “That doesn’t make any sense.” The fellow agreed. On my way home I said, “Let me make a call.” I contacted the ethicist. They agreed that the warden should not be the decision-maker. Eventually we tracked down the patient’s wife and I called her. She was surprised and grateful that I’d called her. I was annoyed with myself for taking something at face value at first, but then eventually I got it right. Then I thought this is probably what we all do.

We had one meeting with a group of people to try to figure out the right way to handle this type of situation. I was still upset. My office mate colleague next door does a lot of work with medical students. I explained the situation and gave her information she could disseminate, because the frequency in which we care for these patients is often enough that we know the scenario but not often enough that we’re skilled in what to do. She replied, “We should do an M & M (morbidity and mortality) training about this. Three to four months later we did an M & M for the medical residents to learn about this. We ended up using this topic for the research project for the fellows. That paper has been published in the Journal of Palliative Medicine.

There was a Grand Rounds that my colleague, Dr. Wes Ely did with several people from outside the institution on incarcerated patients, de-shackling. I emailed him and told him that our fellows had sent a poster which got accepted at our academy meeting and that we’re in the process of writing a paper. “Maybe we should all get together and collaborate I said.”

Now we’re working on a collaborative effort to improve the care of patients who are incarcerated. We’re starting with a needs assessment and survey to figure out where people are, then eventually we hope to be able to make some substantive changes. We’ve reached out to nursing leadership who are onboard, ethics, and hospital police. Our division chief, Dr. Tom Elasy, offered to help us create the survey. It started as this annoyance, and I found that other people were annoyed by that same issue, and it’s something people really feel passionate about. It became this small thing that’s catching steam–another example of how collaborations happen unexpectedly.

Dr. Mohana Karlekar is an associate professor of Medicine and Section Chief of Palliative Care at Vanderbilt University Medical Center (VUMC). She helped co-found the Vanderbilt Hospice and Palliative Care Fellowship.

Her areas of interest and expertise include primary palliative care education, the intersection of palliative care and trauma and more recently advancing palliative care in Africa and the care of hospitalized carceral patients. In 2018, she served on the Tennessee Palliative Care and Quality of Life Task Force and has served as chair of the Tennessee state palliative care council since 2019.

Biomedical science is no longer primarily conducted by brilliant individuals running their own labs and writing paper after paper using the same methodology that they have perfected over the course of their training and career. Even the seemingly simplest of projects likely requires use of another lab’s equipment or model, or utilizes multiple Core facilities and services. Some may see this approach as diluting the importance of each contributing author, but in fact it enables a far greater influence and benefit of any one individual’s work.

There are many reasons why successful scientists collaborate:

– It’s a chance to learn new scientific approaches and access new techniques, models and equipment.

– You can greatly expand your publication record. Although a series of middle author manuscripts won’t make or break a tenure package, it certainly demonstrates a collaborative scientist who fits well within the local research community. Tasks that seem routine to one lab may represent a critical control for a manuscript from another group and earn a spot on the authorship list. Likewise, engaging other people and their specialty area will allow you to level-up your own work and submit more compelling stories to stronger journals.

– Reading and editing the work of other people is a great way to learn better writing skills for manuscripts, grants and posters. Many useful style tips and tricks can also be gleaned from the way other people edit our own work. Once we leave the trainee state the opportunity to have someone thoroughly red-line our work diminishes and it is a gift when it happens. In academia, editing is how we show that we care!

– You can share the highs and lows. An academic career entails a lot of rejection and it can be hard not to internalize a rejected paper or a triaged grant. Writing and submitting with other colleagues that you know to be brilliant can help to convince you that a poor score really may be due to the vagaries of the review process rather than a personal attack or judgement. Two (or three) heads are better than one in planning a new line of attack and the celebratory champagne also tastes better when shared.

There are several ways to increase your collaborative reach:

–  First, do your research. Find local experts and contact them directly. Invite them (or a trainee from their lab) to present data at your lab meeting, or offer to present something to their group. Be clear about what you need and what you will offer in return such as authorship, funding, or future joint grant applications – particularly if what you are asking for might be costly in time or research funds.

– Graduate students and post-doctoral fellows are a great way to expand your reach. Serving on committees will introduce you to work that is going on in other labs and you may be able to offer your own expertise to enrich their projects.

– Internal seminars are a great place to meet new colleagues. Ask questions of the speaker afterwards, introduce yourself, and find your shared interests.

Some collaborations may only last as long as it takes to get a manuscript published, whereas others may last for years. But remember, if the grant application is successful you will be stuck with that person for years so a functional working relationship is just as important as the science itself. And sometimes, just sometimes, a simple scientific question results in manuscripts, funding, and friendship.

More Resources

Connecting Through Poster Sessions

Navigating Academic Relationships

Paper-Writing Checklists To Prevent Headaches Down the Road