By Donald Kellerman, vice president of clinical development and medical affairs, Zosano Pharma
The COVID-19 pandemic came on us abruptly in early 2020 and changed everything during the last nine months of 2020 and into 2021. It was a true crisis. The clinical trial process was not spared, and numerous workarounds had to be implemented to ensure that good clinical practice principles were still being followed during this extraordinary time. This crisis forced creative thinking, as crises often do, and great quotes have been made about crises being catalysts for innovation. One of my favorites is from the economist Milton Friedman from 1982:
“Only a crisis – actual or perceived – produces real change. When the crisis occurs, the actions that are taken depend on the ideas that are lying around. That, I believe, is our basic function: to develop alternatives to existing policies, to keep them alive and available until the politically impossible become the politically inevitable.”
Coming off the crisis, many of the creative solutions implemented because of COVID-19 may actually improve previous work processes and should become part of standard practice going forward. Several good articles about improvements in process and software to help implement these new processes have been written and more will be forthcoming. Of particular interest will be an examination of the vaccine clinical development programs, and how these were performed so quickly. But right now, it would be extremely valuable for a group of industry clinical research professionals and study coordinators to get together to do a look back on some of the things that were implemented during the pandemic to determine which were improvements over previous practices, how to optimize these processes, and what the “next normal” should be.
The following are some new approaches that should be considered for your next protocol. Obviously, these are just my opinion, but I think it is an optimal time to think about what we learned last year and what changes should be made for your next study regarding a monitoring plan, data collection, and communication.
1. Get On Board With Remote Monitoring – And Make It Continuous.
On-site monitoring visits were not possible for much of 2020. So, just as we learned to work from home out of necessity, we also learned that nearly all aspects of monitoring a clinical trial could be done remotely. Many sponsors had already moved to a risk-based approach following the 2013 FDA guidance, and the pandemic forced us to be even more nontraditional in how we monitored subject safety in ongoing investigations. For some aspects (eConsent, eTMF), systems and software were already in place to facilitate remote review, but some uploading of documents was a bit cumbersome, in part because this activity had not been anticipated. Going forward, easy-to-use systems should be put in place at the study start to facilitate remote monitoring. Decisions should be made and agreed upon at study start as to which documents will be available electronically and which ones may need to be uploaded to a portal.
The shift that I hope will be taking place is that monitoring will become a more continuous activity done both remotely and to a lesser extent, in person. It should not be an activity that only occurs when a CRA physically visits an investigative site and sits in a windowless room for several hours, and then does not occur again until the next visit. With timely data entry, electronic case report forms, and electronic study records, most aspects of the research subject experience, including subject safety, can be reviewed (monitored) remotely. But this requires a change in behavior and documentation of the remote monitoring activities using something like a monitoring report form. It requires clinical research staff, at the start of a study, to plan and develop a checklist of those activities that can best be done remotely versus those that need to be done on-site. It also will require shifting some of the costs currently allocated for on-site monitoring to remote monitoring.
Of the many monitoring activities, the raison d’etre of on-site monitoring is source document verification (SDV). It’s hard to argue that this isn’t important, because data integrity is of paramount importance, and no one advocates lesser data quality. However, it was recently estimated that up to 25% of the R&D budget is spent on SDV,1 so finding a less expensive means of doing this, or reducing the percentage of fields that are fully verified, is certainly worth considering. In the authors’ review of three large trials, they found that concomitant medications (dose, frequency, indication) were the most frequently noted errors. Although everyone would agree that a database should be as perfect as possible, in my experience it is rare that the doses of concomitant medication get any discussion in the clinical study report.
Artificial intelligence will likely help the monitoring process going forward. We already use edit checks to the case report form to eliminate some erroneous entries, and the availability of electronic medical records may allow for comparison software to be used for other aspects of monitoring.
I do believe the on-site visit will remain an important part of the trial oversight process. It should become a less frequent event and should focus more on study conduct issues and maintaining relationships with the research staff. Reviewing many of the subjects’ records remotely will allow the CRA the opportunity to interact with the investigator and study staff with more targeted questions about subject safety, issues with the protocol, and, ultimately, case report form completion. It will be analogous to the hybrid office approach in which some work activities are done remotely, with some days in-office for face-to-face meetings.
The monitoring process was already evolving and if properly designed from the start, it can be greatly improved and become a more rewarding, more collegial experience.
2. Be Smarter About The Data We’re Collecting – Which May Mean Collecting Less Of It.
In 2020, many study sites had to close for some time, or subjects were scared to visit a hospital/clinic setting and did not show up for visits. Unfortunately, this led to some procedures not being completed and some data not collected. In some cases, these were critical data, and workarounds needed to be put in place. But in other cases, the data that were not collected were not that critical. This made me ask the question, “Are we collecting a lot of unnecessary data?” Did we really need respiration rate at every visit? It seems that data that end up in an appendix of a clinical study report (CSR), with little or no discussion, probably did not need to be collected. Nonetheless, they were collected, paid for, source document verified, queried, and listed as an appendix in the CSR…and then never read.
Why do we collect data that never ends up being discussed in the CSR? I have some theories. Much effort goes into the design and writing of the protocol, with all the most senior people reviewing and discussing, and the finalization is a triumphant event. Unfortunately, protocols describe procedures and not necessarily the precise data to be collected, and the case report form design and finalization does not seem to go through the same rigor. The CRF is often designed by a junior member of the team, and the starting point is usually what was collected from the last similar study. So, there is not a process where every item that is collected must be justified and vetted. Also, there seems to be no penalty for collecting useless information, but if something that should have been collected was not, then there are repercussions. Therefore, the system is stacked toward collecting more, often useless, data rather than only those data that are absolutely necessary.
We need a system where every data point that is going to be collected is vetted and justified, as if you were spending your own money to purchase what is being collected. There should be financial rewards for minimizing the collection of unnecessary data.
3. Use Digital Technologies For Communication – On A Schedule.
So, grudgingly, in 2020 we went to a new form of video communication as an alternative to in-person meetings. And you know what? It worked. I think it is a better communication mode than a phone call. I had a doctor’s visit using Zoom, and it was almost as good as an in-person visit. Now that we are all trained on how to do these calls and position our cameras so our heads don’t look gigantic, we should use these tools in the clinical trial process. I think these tools are ideal for staying in touch with the investigators/study coordinators and could really improve communication. Zoom, RingCentral, and Microsoft Teams are superior to teleconferences for communication and should be used for team calls with all clinical trial staff, particularly investigators and coordinators.
The advantage we will have with new studies is that we can plan for these calls as part of the clinical trial process. The calls should be scheduled as a 15-minute event occurring every two to four weeks. The investigator’s/coordinator’s time for these calls should be included in the study budget, and brief agendas for the calls should be used. Televisits on a regular basis will allow for enrollment updates (let’s get rid of enrollment logs) and discussion of topics/issues on an ongoing basis. This seems far better than letting issues fester until there a crisis or leaving it for discussion at an on-site visit. This mode of communication is another tool to help monitor a study without getting on an airplane, renting a car, and then discussing difficult topics in a windowless room.
Changes In Costs, Changes In Behavior
Will moving to performing more of the monitoring activities remotely reduce costs? Maybe, but the greater gains are in efficiency and flexibility and making it an ongoing activity, as opposed to only occurring at a physical visit. The costs of remote monitoring plus on-site monitoring can be estimated, and soon we will get better at knowing how much this hybrid approach costs. Real savings can be gained from only collecting data we absolutely need. But the real change will come when people embrace some of the things we learned in 2020 and use the tools to create a more fluid and ongoing working relationship between investigators’ staff and clinical research personnel. That will require courage, flexibility, and willingness to improve, because once the mask mandate is fully lifted, and the majority of the population is vaccinated, people will want to go back to the old way of doing things. But if you just read this article while working from home, you already have modified your way of working, so use that to remind yourself that it is time for the next normal.
- Andersen RA, Byrjalsen I, Bihlet A, et al. Impact of source data verification on data quality in clinical trials: an empirical post hoc analysis of three phase 3 randomized clinical trials. Br J Clin Pharmacol 2015 Apr; 79 (4) 660-668.
About The Author:
Donald Kellerman, Pharm.D., is the vice president of clinical development and medical affairs for Zosano Pharma and has more than 30 years of experience. He has led registration trials in the respiratory, allergy, ophthalmology, cardiovascular, and neurology therapeutic areas. Previously, he worked at MAP Pharmaceuticals, Inc.; Inspire Pharmaceuticals, Inc.; Glaxo Wellcome, plc; Sepracor, Inc.; Ciba-Geigy Corporation; and E.R. Squibb and Sons, Inc. He served as project leader for Flovent, Advair, and Xopenex. Kellerman received his B.S. and Doctor of Pharmacy from the College of Pharmacy at the University of Minnesota. He has authored major sections of eight NDAs, created labelling strategy for several pharmaceutical products, and has co-authored more than 80 publications.