HD Insights spoke with experts from industry, academic centers and advocacy organizations about the art of trial recruitment. These excerpts provide insights into how they engage and retain our HD community for a clean trial that reaches completion.
Brian Beers, Global Product Lead, Huntington’s Disease, for PTC Therapeutics, Inc.
Jody Goldstein, Director of Clinical Operations for the Huntington Study Group
Seth Rotberg, Huntington’s Disease Advocate and Associate Director of Community Development at Health Union
Eileen Sawyer, President, Medical Affairs at SwanBio Therapeutics*
How has the big picture in trial recruiting changed in recent years?
Eileen: The most visible change, of course, is social media and the ability to investigate more studies in-depth through the internet. This is particularly true for rare diseases, where information was scarce at one time. It can be a conduit to the partnership among patient communities — and that partnership still needs to be the linchpin of trial work.
Telemedicine has also been pushed out much faster than it would have been because of COVID-19. This has impacted recruiting and the course of the trials tremendously, and I think for the better, considering the accessibility problems of many in the rare disease population.
Seth: We are slowly starting to see companies work with patient advocacy organizations to make the community more aware of upcoming clinical trials. Some companies even put together focus groups or advisory boards to gather feedback on clinical trial design and protocols. However, we still have a long way to go before we make this part of the process for all companies to include the patient perspective throughout drug development.
Social media also plays a significant role in getting the word out about trials. Patient advocacy organizations and patient advocates can help spread the word about what trials are recruiting participants. I feel more compelled to listen to a fellow advocate or nonprofit in the community than a company, since it’s easier to relate and trust them. One unique way of making people aware of trials is through the nonprofit, I AM ALS, which rates trials with their own patient-centric trial
Jody: In HD, recruiting has become more competitive. Five years ago, there weren’t many studies, but now the number has increased dramatically, and many studies are asking for 100, 200, 300 participants. When you have a rare disease, and only about 30% of people with the disease are participating in trials, you’re competing for the same population!
What are the key elements of your recruiting strategies in rare disease populations, and in HD in particular?
Brian: Working with the HD patient advisory groups from very early on in research to understand what patients are looking for is so important, letting them know what we are working on. Since 2009, around the time when we first started working on our program, we’ve been engaged with these associations and listening very closely to the needs of the patient and looking for guidance from the community on what’s important for them.
The primary approach to recruiting is obviously first through the investigators participating in the trial, but we would certainly reach out to patient organizations such as HDSA as well as broader organizations like the European HD Network and Huntington Study Group.
Right now, our PTC518 Phase 1 trial is in the Netherlands, where they are recruiting healthy volunteers, and our clinical research organization specializes in recruitment of this study population.
We raise awareness for trial, and as we have more details about our trial, we’ll either speak at or otherwise address those forums. We won’t do the active recruitment down to the personal level — it will be more of an awareness, but we have the chance to say at those meetings, “These are our sites — to participate, go there.”
The clinical study protocol details very specifically what type of enrollment criteria needs to be met in order to qualify for the study, depending on what type of therapeutic you have and what type of indication you’re going for. We tailor these so that we can try and get, in some cases, a population of study that’s going to be the most informative. This can be based on many different factors, whether it’s an earlier phase or a later phase, for example.
We talk to the potential site managers to ensure that we’re not being overly selective — make sure that there are actually patients out there that meet those criteria. So it’s really it’s a back and forth, a slow build over time as we have these sets of interactions.
Jody: For the past 27 years, the HSG has been conducting and recruiting for clinical trials in the HD community with
a network of HD experts. Personally, I have had the chance to see the big picture on recruitment, from all angles — the site/patient side, the industry side, and the HSG side.
Recruitment for a rare disease population is an art; it is not just about the numbers. If I were to isolate one key factor for success, it is to understand that recruitment is a picture you are painting, with relationships the fulcrum of every part of the process. It’s all about knowing your population, it’s knowing the disease and it’s understanding the relationships. Companies come to HSG to run studies because of the longstanding relationships that we have with our sites, the relationships that the sites have with their patients and families, and the relationships the HSG forms with the sponsors. This formula creates a successful recruitment strategy of working together to achieve the same goal.
The HD community and patients rely on the HSG sites to learn about new clinical trials. We know from our metrics that a majority of participants are recruited directly from the HSG sites. When I was a study coordinator at UC San Diego, we used our relationships with the patients and families and the HSG connections to become a top recruiting tiger team site and successful clinical research team. Everyone working collectively as a team increased patient awareness of clinical trials and made our participants feel like partners in the study.
Working now in project management at the HSG, when I lead a study, I work closely with the sites to help them identify and recruit potential participants for our clinical trials. I ensure that they have proper HD training, support and the resources to be successful, including connecting HSG sites for referrals. Recruitment takes a village.
Eileen: Patients are generally really hungry for anything that might offer potential treatment; they are very willing to be engaged. For drug companies, it’s a matter of making sure that we are tapping into the structures that they’ve built to communicate with companies. HD Enroll is a major presence and resource of trial recruiting now. Education and awareness are essential.
Build a trial that is as patient-friendly as possible. Engage with them early, wherever they are, in your own development process, so that you’re hearing from them about what’s important, what are the needs that must be met, so that you can be sure that you’re going to deliver something that fits these needs. Be careful in all your communications, so you are not over-promising, which can be easy to accidentally do with enthusiastic patient populations.
The Huntington’s disease community is very well-organized, with well-recognized and attended meetings and organizations that have clear agendas and multi-year strategies. Not all rare diseases are like this. This makes partnership all the more available and important for drug developers looking to recruit.
Once you have a patient-friendly trial, it comes down to the patient recruiting at the individual site level. The sponsors are less involved in that, but there are things that they can do to make it helpful. There are services that are specialized in coordinating travel for trial participants, for example. We can help support sites as they work to try to schedule around patients or accommodate any difficulties they have.
Seth: Engaging the community members and associations is vital. One of the big areas that is missing is understanding the unmet needs of the community and making sure they align with what the company is looking for. I understand how important data is through natural history studies and observational studies, but it’s just as important to engage with the community and gather their feedback to make sure your findings align with the community needs.
How do you plan around the potential for screen failure and dropout in trials?
Jody: To begin, you need to understand how many participants are needed to finish the study to show a positive effect. Our HSG biostatisticians calculate how many participants we need
to screen to enroll, which might vary from study to study.
More importantly, the HSG study team carefully trains our sites individually and in groups about the protocol eligibility criteria by providing examples and scenarios. We work with our sites and ask them to pre-review their databases with specific study criteria to narrow down a group of potential participants. From that starting point, the sites have prescreening conversations with a group of potential participants and possibly bring them in for a clinic visit to confirm their current status. Once this process is completed, this practice ensures that sites are bringing in the best possible candidates for the study. The HSG study team is also available to answer questions and review potential participants. The HSG has utilized this process to successfully decrease the screen failure rate and ensure enrolling people interested and eligible for the study.
Brian: Screen failure is always a key thing to think about when planning a clinical trial. You could have a patient that looks on the surface like they may qualify, and then they go through the screening process and find out that they fail for X, Y or Z reason. It’s disappointing because, first and foremost, the patient was interested in being a part of the trial; they had invested time in the process hoping to qualify, only to learn they’ve failed. So, what we do is we try and understand key reasons a patient might fail and tailor the screening process so that these elements are evaluated first. That way we can learn quickly whether they will fail on the more likely reasons, so as not to put them through more burdensome (and sometimes slightly painful) procedures unnecessarily.
Then there is the difference between the number of people who consent to trial versus those who actually start, and those who finish. This can vary a lot from study to study, and it’s always one of those things that we try to forecast so we can try and ascertain how many patients we’re actually going to have.
What are the main reasons trial recruitment and retention fail?
Seth: Besides a failure to use the associations and patient advocacy groups optimally, a company may not establish appropriate criteria. I’ve seen trials come up, and I look at the criteria and I’m thinking, that seems a little strict. To avoid failure, I think the first step is speaking with the community earlier on, prior to even figuring out the clinical trial design. Let the design be decentralized so it doesn’t require as many in-person visits, impacting the patient and caregiver. If they have kids, it could be child care, things like that.
Early on, get community feedback and buy-in before you start, so participants know who the PIs are, who the clinical coordinators are, who their point of contact is. This is the biggest insurance against failing enrollment or failing to finish, and the pharmaceutical company or biotech having to go back to the start of the trial and go through the FDA again, facing a big delay.
Brian: There are many reason why recruitment may fail. Some common reasons are perhaps overly strict selection criteria or it could be simply due to the rarity of the disease and poor selection of sites. Poor retention of trial participants could be due to the time burden placed upon the patient for participation. Either study visits are too long, too painful or invasive, or even too far away from home to keep going. There could also be issues with the study medication that causes a patient to withdraw. Maybe the medication causes adverse events or reason may be as banal as a medication tasting bad.
Jody: Once it is time to implement a study, I have always felt that retention starts with recruitment. The most important aspect of retention is knowing your patient population and who is the right fit for each type of study. This feeds back into having relationships with your patients and families and knowing who will be interested, willing and able to maintain study visits. Recruitment and retention can fail if you are not fully vested in the population you are working with, i.e. knowing your participants, knowing HD, and knowing how to develop the design of the protocol to fit those participants.
To reduce the chance of a failed study, HSG creates a study development plan for a sponsor. The initial step is to set up a research advisory board to help design the study and eligibility criteria. These criteria are based on our past HD trial experience. Next, the HSG convenes a patient advisory board that consists of patients with and without clinical research experience and family members who provide critical feedback on the draft protocol. These processes bring the researchers and HD community together to work towards a successful study design and brings success to recruitment and retention. To avoid failure, make HD patients and families part of your study team!
How do HD patients need to be supported and accommodated to ensure trial completion?
Eileen: This comes back to engaging the patient community. Some trials are set up so they have patient panels or seek patient input during the design. When they do this, the participants have been trained a little bit about drug development, understand what the different phases of trials are and the questions they are trying to answer and that sort of thing, so they both have input into the trial requirements and understand what is being asked of them and why.
HDSA was doing one of these — forming a standing body that companies can come to and ask questions help them make their trials more appropriate to patient populations, answering the patient important questions, making them easier to participate in. For example, particularly when you are dealing with some of these degenerative conditions where people are losing functionality of various types, we ask about what makes it easy or hard for them to even just get around, get to the clinic visits, get to the various assessments. Those things eventually end up being very big barriers. So you can try and build accommodations for those into your trial.
Jody: HSG has found that the best way to support participants in a trial is to make their voices heard. We work with the sites to determine any potential barriers and find solutions. About 15 years ago the HSG published a paper on conducting participant calls to help engage participants, and let them speak directly to the HSG study principal investigators and pharmaceutical company representatives.
Since that time, HSG has conducted participant calls during the study and at study closure. Through the collective effort of the HSG study team and the sponsor, participants have expressed their appreciation for being informed about the study progress and the interest of the study team in their well-being..
*Eileen Sawyer’s comments represent her own views and do not reflect that of her current (Therapeutics) or past (uniQure) employers, SwanBio Therapeutics and uniQure, respectively.