June 29, 2020
Tufts CSDD – Teckro Industry Research on Investigative Site Protocol Perceptions
In the last decade, protocol design has become increasingly complex with significantly more endpoints, inclusion/exclusion criteria and distinct procedures. Still, research staff are heavily reliant on paper and desktop computers to access the protocol instruction. Ken Getz, deputy director for the Tufts Center for the Study of Drug Development (CSDD) presents the current state of protocol design and complexity facing investigative research staff.
Ken originally presented this segment in a longer webinar addressing clinical trial inclusion and diversity titled "No One Left Behind: Addressing Clinical Trial Access and Issues Blocking Physician Participation."
Thank you. And what I'd like to do is really touch on where sponsors can really improve access for investigative sites, perhaps more the sites that are already operating. So as you think about once you expand the pool of investigative sites, how do we keep them in our studies? Many sponsors look at this as essentially an effort to do cross, to become the partner of choice for investigative sites, to ensure their success, to think about accessibility in terms of operating support for investigative sites so that they can meet some of the challenges of conducting clinical trials.
The tough center for the last 20 plus years, has been characterizing protocol design trends. And obviously the design of the protocol itself has a huge downstream impact on the feasibility of the trial and the ability of the investigative site to execute successfully. And this is one area where we often see that sponsors are not nearly as aware as they need to be about the impact of complexity on performance. If you look just at the design of our protocols and here we're only looking at the most recent 10 year period and we're looking specifically at protocols or pivotal trials or phase III studies.
And you see dramatic increases in the number of endpoints, almost a doubling with a much larger number of tertiary and secondary and more miscellaneous endpoints, a 60% increase in the number of inclusion and exclusion criteria, similar growth in the number of distinct procedures that have to be conducted in order to support the endpoints. And an area where we've seen more modest growth, 25% growth over a 10 year time horizon is in the number of planned volunteer visits. That slower growth really indicates that a larger number of procedures are being performed at every single patient visit.
On the right hand side of this slide, you see the growth in data volume. And this is just a really important area for us to think of because it another way of characterizing the burden of supporting a protocol. We've seen nearly a 200% increase in the number of data points that support a pivotal trial. We're now approaching an excess of 2 million data points for a single protocol, and that growth is coming largely from the non-core area data that is supporting those tertiary and exploratory miscellaneous endpoints.
One other point to make here is that a lot of the data we collect, we're pushing out even past the clinician out to the patient themselves. So patients are being brought in to play an even larger role in providing and collecting their own data. One other data point we've tripled the number of data sources to support or to contribute to the study database. So today, on average, a clinical trial involves six unique data sources, including wearable devices, smartphones, etc.,
where the investigative side often has to act as the technical support for many of these newer data sources. It doesn't take much to recognize that as complexity has increased, the burden on the investigative site has increased as well. And as we move to more remote and virtual models, that burden will continue where the site has to play an even larger role. We've seen very, very high growth in the work effort, which includes not only the number of procedures that the site has to implement, but the time that they have to commit to them as well.
And this, of course, has an impact on recruitment and retention performance, among other performance measures. When we look across all therapeutic areas, we typically have to double the planned enrollment timeline today in order to achieve the target enrollment rate and the cycle time. When you look at complex protocols to those that are simpler is nearly double the length, 73% longer. On average, complexity is also associated with the incidence of protocol amendments.
The number one reason we amend our phase two through four protocols is to relax the eligibility criteria because it's been so difficult to find patients based on our initial inclusion and exclusion criteria. And the typical amendment, as many of you know, is unplanned. It's unbudgeted. It adds about three months of time and costs about a half a million in direct costs to implement.
So I want to tell you about two studies that the center has been involved with this year. The first is a study that is currently underway. It's a working group study. With sponsors and crows, where we're continuing to update our protocol, design, benchmark data and look for predictors of performance.
And that's a study that we anticipate will be completed in December of this year. And we also just recently completed a study in collaboration with tech grove, where we went out to investigative sites to really understand how they are referencing, how they're using the protocol guide them and to provide reference for their instructions in terms of executing the protocol. And it includes responses from 228 investigative site personnel. This first slide looks at how often sites are accepting different sections of the protocol.
And as you'll note right away, so many of the sections are accessed very, very frequently. In fact, well over 90% are reporting accessing the majority of these sections in the protocol to find useful information that will guide execution, the schedule of assessments, eligibility criteria, scripts, screening procedures, et cetera the two areas where we are three areas, rather, where we see much lower frequency of access include adverse event reporting, data reporting requirements and the management of toxicity. These are also the primary areas where we see much lower levels of helpfulness, perceived helpfulness from the site, and which suggests an improvement opportunity.
We suspect that these areas are given these lower ratings and their access less frequently because they typically involve multiple parties internal to the sponsor and external eye as to provide guidance. The sponsor is own peers. Regulatory authorities as well as safety representatives are all providing guidelines that sites have to try to navigate and reconcile. And so these may be areas where you see work contradictory instruction and you may see more confusion.
Here we're looking at how sites typically access information in the protocol, and we're also looking at the amount of time that it typically takes. And one point that really jumps off the page immediately and one that we consistently see with most sites is that the approaches that are used are generally less sophisticated, the use of a desktop computer or a paper copy or reference card. We also see a very, very high percentage that tell us that they very or somewhat often go to the study monitor directly for that information. And the two areas where we see the lowest level of frequency and access is the tablet version and the smartphone version, areas that we anticipate will increase under more of a remote environment.
I want to also point out that although the study monitor receives a very high percentage, 80% of sites who indicate that they very or somewhat often contact the monitor for information, it's also the most time consuming where almost 60% tell us that this interaction typically exceeds 20 minutes of time. The last area I just want to touch on again to frame our thinking about how to be a sponsor of choice or a partner of choice is the protocol of Amendment area. You'll recall, I mentioned a moment ago that a protocol amendments increase with more complex protocol designs. And in this particular study, we also learned that the most common way that protocol amendments are communicated to sites is perhaps one of the less sophisticated approaches, the use of e-mail, and that in fact, the use of a sponsor or 0 portal received a very, very small percentage, less than 15% So we view this as another area where you would expect to see increased use of more sophisticated communication technology.
One last point I just want to make here is that despite the use of less sophisticated methods, the vast majority of sites report that they're competent, that they're using the most up to date version of the protocol. So that's good news for us. But again, we're looking at increasing sophistication as we move and migrate to more hybrid or decentralized clinical trials.
Full results are available in the new report Tufts CSDD – Teckro 2020 Study on Investigative Site Protocol Administration Referencing Practices.