Guest Column | April 30, 2024

Early Exposure & Site Network Support Enable PI's Enduring Interest In Research

A conversation with Manish Sharma, MD, co-director of clinical research, START Midwest

Manish Sharma

Every part, parcel, and person involved in a clinical trial contributes in one way or another to the study’s execution and, hopefully, success. But principal investigators are the people who seemingly connect every activity and person to one another — whether it’s screening and enrolling patients, administering treatment and explaining it to patients and their caregivers, or understanding and abiding by regulatory requirements and sponsor expectations.

In this interview, we talked with a seasoned principal investigator whose work is dedicated solely to providing care to cancer patients in the context of Phase 1 clinical trials. Manish Sharma, MD, is the co-director of clinical research at START Midwest, a 40-person community site part of a global site network, The START Center for Cancer Research, with three U.S. sites. 

Reflecting on your career with START, what inspired you to explore clinical research? And what motivates you to continue serving as a PI?

During my oncology fellowship at the University of Chicago, I noticed a lot of the diseases in oncology don't have optimal therapies. Especially after the first or second line of treatment, we run out of options that are attractive for patients. As we learn more about the science of cancer, that opens up new avenues for treatment. We now have drugs that inhibit specific mutations in the KRAS protein like KRAS G12C, for example. We didn't have that a decade ago. Clinical trials bring those new therapies to patients and then ultimately, hopefully, improve the outcomes for them with FDA-approved and broadly available therapies.

Phase 1 is an interesting space to do drug development because therapies are being tested in humans for the first time. I found that fascinating. I did some additional training in clinical pharmacology, learning about drugs and how they interact with the body, and then went into a subspecialty of oncology where I could use that knowledge and training. For me, the motivation was “How do we get better therapies for patients who are facing a life-threatening illness?” Phase 1 research is a great way to do that.

What was your first experience serving as a PI on a clinical trial like?

I had great mentors at the University of Chicago who taught me but also gave me opportunities. They would get approached by sponsors and would say, “I've got a lot on my plate, but I have this junior faculty member who would like to gain more experience being a principal investigator and doing Phase 1 research. Would you be open to them being the principal investigator on this study?”

With their mentorship and tutelage, I got experience. And then as you start to gain experience, you develop your own reputation and you're able to get some momentum. Once you work with a certain sponsor or a certain group of people and they get to know you — they see you're doing a good job, you're attending teleconferences, you're responding to emails and phone calls, and you're advocating for your patients — then they reward you by offering you the next study and the next study.

It's also really important to be in a fertile environment for clinical research. You have to have the right kind of setup and you have to have staff to help you. Nobody's doing this by themselves. Research coordinators, nurses, pharmacists, data analysts, schedulers, and many others are important members of the team.. Then there’s the regulatory piece and getting protocols, budgets, and contracts approved. All these things that we do to get studies running require a whole big infrastructure to be successful. And that's one of the challenges for some PIs who may not be in an environment that has the infrastructure for success. But if you have the motivation and the desire and you're in the right infrastructure, there's a great opportunity for the next generation of PIs.

You switched from academia to an independent site network. What prompted that decision, and what are the differences between the two?

START Midwest started in late 2015, and by the time Dr. Nehal Lakhani, now my co-director, reached out to me in early 2018, they were treating more than 100 patients a year on Phase 1 trials. I'm from Michigan originally, so of course, there's a familiarity with the state, but also what was very intriguing about it was this was an opportunity for me to do Phase 1 research in a community setting. I don't think I would've left academic medicine to do conventional oncology private practice where you're seeing 30 or 40 patients a day. There's pressure to have a high volume of patient care. For me, this was a great opportunity to take care of patients, be an investigator on clinical trials, do research, interact with companies regarding new drugs, and help propel the field forward — all in the community setting.

Comparing your day-to-day life, what is different about the two?

In academia, I was applying for grants, writing a lot of papers to help build up my resume, working as an investigator, taking care of conventional oncology patients, sitting on committees, and teaching fellows and residents. Some of that was really fun, but it had a lot of different components.

Working as a co-director at START Midwest is a much more focused job. I’m just doing Phase 1 trials. Everybody's on that same mission to accomplish good things for these patients and give them opportunities that they otherwise wouldn't have.

Academic medical centers are very large. There, different people have different goals. Some of them are lab researchers, and some of them are clinical researchers. Different departments are all competing for resources, and they're somewhat bureaucratic just due to the nature of being large organizations.

Our organization is sleek and efficient. We're able to get studies open quickly, which is one of our main advantages compared to AMCs. Yet, we're on a lot of trials with them. They're great places. I know a lot of the doctors there, and we are friends, we interact at meetings. But what we're able to do here is get things open quickly and make efficient changes.

Let's talk about community sites and academic medical centers, as far as patient recruitment and enrollment. What are the differences?

Our patients don't necessarily have abundant resources. Grand Rapids is a relatively large city, but if you go outside of Grand Rapids, it gets wide open pretty quickly. Patients who can get to us within an hour or two drive can enroll in trials without having to get on a plane. We do get referrals from the University of Michigan, because patients will go there knowing the Michigan reputation, get a consultation, and then they'll tell them about us. Our menu of trials is very extensive, so when patients get referred in, it is very rare that we wouldn't have something for that patient. It's really a collaboration between us and the academic medical centers; we're not really in competition. It's about everybody trying to get as many patients on clinical trials as possible.

Given your breadth of experience, when you get a new study and are dosing the first patient, what is the mood? Is there still anticipation? Is there excitement?

A lot of excitement. There was a study recently where we dosed the first three patients in the world. Anytime you're dosing the very first human on a study, I tell the patient, they're a pioneer. And of course, we're a little bit anxious. We don't know whether they're going to have side effects with this new medication that's never been given to a human before. But that's very exciting because it emphasizes how we're at the cutting edge and that we're offering something to our patients that nobody else in the world has had before.

PIs need a heightened level of empathy and soft skills to care for people who have limited time or are running out of treatment options. Is that something important for PIs to have?

A hundred percent. We become close with our patients. They're with us for months, sometimes even years. We get to know their families. It's emotional, but that's why we're here. It's rewarding because even when we're not able to give them a drug that necessarily worked for their cancer, we're taking good care of them. We're offering good support when they're nearing the end of life. Part of being an investigator is recognizing when the time is appropriate to stop treatment and get them positioned at home where they can enjoy the remaining time that they have.

Sometimes, even though you're meeting that patient for the first time, you're giving them that difficult news that unfortunately they’re not a candidate for a study. And then other times, it's after a long relationship treating that patient and then finally getting to the point where it's time to focus on supportive care. We send sympathy cards to the families of our patients. I call their spouse or their closest family member when they do pass away and talk to them. And sometimes they come back and visit the staff, as they want to thank us for the care we gave.

You talked a little bit about some of the challenges of being a PI. What could sponsors understand better about you and your sites, and what could they do to support you better?

Sponsors should look for somebody intelligent, who's motivated, who's into research, who's able to do the job, and who's in the right environment. Especially with research-naïve staff, sponsors have to recognize the importance of providing support to the PIs, being available for questions, and being understanding of the fact that there is a learning curve.  When someone's a brand-new PI, they're going to have to learn what that job is before they're going to be a seasoned, experienced investigator.

Sometimes there's a tendency for sponsors to go with someone who's got 20 or 30 years of experience and has done hundreds of clinical trials, but we need to nurture the next generation of investigators. Allowing new PIs to gain experience in the right setup, with a senior person to mentor them, will give them the experience to do great things in the future.

PIs often participate in a clinical trial, and that's the last one they ever do. Have you seen that happen, and what could be some of the reasons for it?

It goes back to the infrastructure piece. When people are first starting out, they need mentorship and to be part of an organization that has people with experience. At START, we are a global organization with 25 PIs that do Phase 1 trials, some with decades of experience. Finding someone who can be a resource when you're just starting is predictive of who's going to stay in research. Somebody who has good mentorship, they're more likely to continue to do research.

Also, it’s challenging to do both conventional oncology care as well as research. It can be done, but it's not going to fit within the nine-to-five workday. There's going to be emails and calls and weekend things that come up. It is more challenging from a quality-of-life perspective to take all that on. Organizations like ours with full-time dedicated research physicians are set up for success in that way because we don't have to be pulled in other directions. Having more of those types of organizations, that is, the START model being scaled up and brought to other communities, would definitely help.

Speaking of resources, for how many trials are you serving as PI?

Currently, I have 39 active trials. A lot of those may have started in 2020, 2021, or 2022, as well as ones that just started a week ago. We're constantly opening new studies; we want to have enough studies open to match our patient population and offer the best options for our patients.

Understanding that, do you consider the many platforms you have to navigate as a necessary evil? Or, do you think “If they could just fix this, it would make my life so much easier”?

It is manageable, but I think the reason it is manageable is because our staff are so good at setting things up for us. We've moved away from a lot of paper. A lot of its electronic now. I get emails reminding me to go in and sign the data when the data are ready to be locked or ready to be processed for a study. So, there's a lot of reminders and triggers that you get from our staff and from the sponsor side.

But if it wasn't my full-time job, if I was doing that after hours and after a busy day of seeing 30 or 40 patients, it would be a lot. Phase 1 research is not a high-volume specialty. You might see 10 or 12 patients in one day, but then you have some time in the afternoon to catch up on emails, do teleconferences, and sign things. We're set up well for success because START centralizes all the budget and contract work, regulatory submissions, and things like that on our behalf. We have a lot of good people doing a lot of the heavy lifting, and that makes our job as a principal investigator easier. We can focus on the things we want to focus on, which is taking care of the patients, making clinical decisions, and then talking with the sponsors about the trial and reporting back on the data. And we're able to get studies open in six weeks, which is unheard of in the academic medical center setting. It's rewarding in that way, because we have a huge network of people helping us along the way, which makes it possible.

About The Expert:

Manish Sharma, MD, is the co-director of clinical research at START Midwest and a medical oncologist in Grand Rapids, Michigan. His clinical research interests include early phase drug development and clinical pharmacology trials for advanced solid tumors. He has served as the principal investigator on over 50 Phase 1 clinical trials. He has co-authored over 30 peer-reviewed papers on oncology drug development.

Dr. Sharma graduated from the University of Michigan Medical School and completed his residency in internal medicine at the University of California, San Francisco. He completed a fellowship in hematology/oncology and clinical pharmacology & pharmacogenomics at the University of Chicago. As an assistant professor of medicine at the University of Chicago, Dr. Sharma earned a career development award from the National Institutes of Health and dedicated time to teaching/mentoring fellows. He has been at START Midwest since 2018.