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HD InsightsCommand & Control: Study Principal Investigator

An HSG Study Principal Investigator (SPI) is usually involved from the very beginning, in the planning stages of the trial. The SPI works with the sponsor, whether industry or government agency or other funder, to assure an optimal study design, and assists in the organization of the clinical trial operations team. Early tasks involve working on the protocol and informed consent form, selecting the site, building the study team (e.g., Data Safety Monitoring Board, Medical Monitor, Study Steering Committee) and issues related to study budgeting.

During the course of the study, the SPI serves as an ambassador for the trial, presenting at medical conferences and patient advocacy groups, and communicating with study staff, site personnel, and study participants during study webinars.

Teamwork

The SPI does not work in isolation. Running multicenter clinical trials is really a team effort that often involves a very large group. Clinical trials for a neurodegenerative disorder such as HD can go
on for long periods of time in an effort to test potential disease-modifying therapies. Teams assembled to run these trials may work together for years, often developing close professional relationships.

Every member matters, and it’s truly a team effort to see these trials through. Some of the specialists involved in running trials include: Project Managers (PMs) who oversee the running of the trial; site monitors who are clinical research associates (CRAs) and visit sites to ensure study compliance, data accuracy and data entry; vendors comprising outsourced groups who perform critical activities such as labs, imaging, etc.; statisticians; sponsor personnel overseeing the conduct of the study, drug/placebo manufacturing and delivery, adverse event (AE) reporting, regulatory issues; the Medical Monitor and Data Safety Monitoring Board (DSMB) members overseeing study safety, budget and contracting personnel; and many others.

For HSG trials, the Study Steering Committee (SSC), usually chaired by the SPI, provides leadership and direction for the ongoing trial and includes sponsor representatives, the lead PM, Medical Monitor, Study Statistician, a patient advocacy representative, and a non-participating site HSG investigator and/or coordinator. At the HSG, we also consider the patients and families who participate in our trials as team members, and we dedicate time during the trial to keeping them informed about the trial.

Sponsor Advocacy and Planning

A major HSG SPI responsibility is working very closely with the study sponsor in planning and conducting the trial. Part of this is being an advocate for the trial, often right from the beginning. In addition to study design and conduct, these activities may include helping to raise funds to support the trial by speaking with potential investors. In addition, the SPI will often work to develop interest and excitement about the trial by speaking at HD advocacy organization meetings, and these activities will continue throughout the trial. 

Site Selection

As the study team is coming together, site selection generally comes next. The process of HSG site selection is collaborative, involving input from the sponsor, the SSC, the SPI, and HSG staff. Site selection is very study-specific, and we assess site capabilities and study feasibility through a site feasibility questionnaire to all interested HSG sites. These questionnaires are tailored to the specific trial and its requirements, and the responses to these questionnaires, combined with our past knowledge of site performance, inform the decision-making process.

Once sites have been selected, a major activity at the beginning of a trial is site startup — getting sites to the point where they are ready to enroll patients. Site startup involves agreeing on a budget, signing a contract, Institutional Review Board (IRB) approval, and training site personnel in the procedures of the study. An investigator/coordinator meeting to review and train staff on the study procedures precedes the start of the study, and the SPI usually has a major role in these meetings.

During the conduct of the trial, the SPI often works with sites to facilitate recruitment and retention, and deals with issues that arise regarding adverse events and protocol deviations in collaboration with the Medical Monitor.

Keeping Everyone in the Loop

The role of the SPI in a multicenter HD clinical trial can be quite time-consuming. The SPI is often involved in many aspects of the trial, and this usually requires participation in many regular meetings, and regular contact with study sponsor, Medical Monitor, and operations personnel. Regular meetings may include operations (often weekly), DSMB (usually quarterly depending on the trial), SSC (usually quarterly), investigator/coordinator (monthly), protocol deviations (usually quarterly), and others. In addition, the SPI may need to reach out to sites with particular questions, to better understand challenges for recruitment, or other issues during the trial.

An HSG SPI is often involved in presenting study design, interim analyses, and study results. During the course of a trial, there may be abstracts to write and present at external meetings such as the American Academy of Neurology. The SPI may also be asked to present the final results of the study and draft manuscripts reporting the results. 

Protected Time is Key

Finding the time to commit to being a SPI can be challenging, but the role can also be tremendously rewarding. For a large multicenter HSG clinical trial, an academic neurologist would probably need to commit 20-30 percent effort for this role. For many, this can be a significant challenge, especially for junior or mid-career neurologists. The budgets for these trials provide for salary support, making it possible for individuals to negotiate the needed protected time.

What Sometimes Keeps Me Up at Night

Being an SPI is a tremendous responsibility, so I could point to many things that could potentially — and have — kept me up at night. For large late-stage (e.g., Phase 3) trials, much is already known about the safety and potential adverse effects of the drug, but nonetheless, a constant concern in clinical trials is the unknown potential risks. This is especially true in early phase trials such as first-in-human trials. Constant vigilance is needed throughout all clinical trials to ensure the safety of study participants.  

Aside from drug safety, I also worry about the efficiency and integrity of the trials we run. Recruitment and retention are always areas that require extra attention and dedication. The longstanding and close relationships between HSG sites, HD families, and HSG staff have allowed us to be a leader in recruitment, retention, and conduct of HD clinical trials.

So You Want to Be an SPI?

Gaining the experience and knowledge to be a SPI usually involves participation in multicenter clinical trials, first as a site investigator, and then in other roles such as Medical Monitor, DSMB member, co-SPI, SSC member, etc. Here at the HSG, site investigators may be approached by biotech or pharma companies because of their clinical or scientific expertise — if these projects develop into an HSG clinical trial, we will invite the investigator(s) who initiated the projects to take on the SPI role. 

Of course, site investigators or others who have funding through other sources (e.g., NIH, FDA) have the opportunity to be an HSG SPI if the study is conducted through the HSG. The HSG can help in writing portions of a grant that involves multicenter collaboration and can provide operational resources.  

Often, biotech and pharma sponsors reach out to the HSG directly to provide advisory services, ranging from preclinical scientific advice to clinical trial design advice. As part of this process, we will involve HSG investigators, coordinators, and other HSG members (e.g., scientists, geneticists), and if these projects develop into HSG trials, we will work with the study sponsors to select appropriate SPIs and Co-SPIs. 

The HSG is dedicated to creating opportunities for academic growth for junior and mid-career investigators committed to HD. While the SPI role may be offered to a more experienced individual, we seek to involve more junior investigators in other roles so that in the future these individuals will be ready for the SPI role.  But there always has to be a first time! My involvement in the HSG, beginning as a site investigator and culminating in being an HSG SPI (and HSG chair), has been the most gratifying experience of my career.