Sticking to the Plan: Undue Burden Created by Protocol Deviations

Jim Wahl, vice president, client services, TruLab

In the clinical trial ecosystem these days, patient-centricity has become quite the buzzword. And for good reason: Incorporating the patient perspective into study design and execution is downright good for business. According to a report by The Economist Intelligence Unit, which compared 4,000 clinical trials including significant patient-centered elements with 20,000 traditionally run trials over a five-year period, the trials that prioritized the patient experience were nearly 20% more likely to end with positive results (87% chance of product launch versus 68%, respectively).¹

Yet, even with this burgeoning understanding in the industry, many studies still leave a lot to be desired when it comes to protecting the needs of the patient—an unpleasant truth that Joel Vandenbrink found out when he took part in a clinical trial for Crohn’s Disease just a few years ago.

Protocol deviations heap undue burden on patients

Over the course of his participation in the months-long trial, not one but two of Joel’s samples were lost due to protocol deviations, which required him to come back in for collection. These additional trips not only increased his already substantial burden—including stool and blood samples needing to be collected every four to eight weeks and multiple colonoscopies—but it also left him with a bad taste in his mouth regarding the study as a whole. When asked how this experience affected him during TruLab’s webinar “Patient Burden in Clinical Trials: Ethics of Biospecimen Management,” Joel did not mince words:

“It reiterates that you are just a specimen and a number on a page. You are a means to an end, and you start to begin to feel a little bit not taken care of. Just a lack of care, and if it goes far enough, you begin to feel like you're being dehumanized,” Joel said. “You’re just part of this thing, where they need these specimens from you, and nobody really seems to care what happens and how you’re treated along the way.”²

Protocol deviations are not patient-centric

Sentiments like these—feelings of “not [being] taken care of” and being “made to feel like a lab rat,” as Joel goes on to describe his experience later in the webinar—are consistently tied to the industry’s pervasive challenges with patient recruitment and retention. And this is indeed a serious problem: Upwards of 80% of clinical trials experience costly delays due to their failure to recruit and maintain adequate sample sizes.^3,4 While “having a positive, trusting relationship” with researchers is commonly cited as a facilitator to participation, studies also show that the inverse is an even greater barrier, particularly among minority patient populations.^5,6 Indeed, “the rapport built between the investigating team and the participant plays a vital role in retention,” write Subramani Poongotha, et al.⁷

It’s also, importantly, these negative feelings that patient-centric approaches to clinical trials attempt to mitigate. As Joel’s experience demonstrates, designing trial protocols that minimize deviations can go a long way toward nurturing these integral relationships.

But that isn’t just because it reduces inconveniences. As the Tufts Center for the Study of Drug Development recently pointed out, some protocol deviations can be so significant that they “put the rights and safety of study volunteers at risk.”⁸

Regulators are taking action

It’s perhaps no wonder, then, that the FDA has started to take notice, making “patient-centricity a matter of regulatory necessity,” Meerim Almazbek explains.⁹ While protocol deviations remain the number one cause of enforcement action by the agency—30% of all warning letters sent to sites are for failure to follow the established protocol—the agency is doubling down on its commitment to patients with the introduction of its Patient-Focused Drug Development guidelines.^10,11 Among the many facets of this systematic guidance, “minimizing the burden of patient participation in clinical trials” is central.

But it also comes down to data integrity: How many samples can a trial site lose before the overall data gets called into question? How trustworthy is a clinical trial methodology that passes the burden of its mistakes onto patients? According to Julius Wilder, MD, PhD, principal investigator and associate professor at Duke University’s School of Medicine, these are the types of questions the FDA will be thinking about as the patient burden becomes increasingly front of mind when determining what high-quality research looks like.¹²

The imperative is clear: Sponsors can no longer afford to not do their utmost to minimize protocol deviations that harm the patient-centricity of their studies.

Jim Wahl, vice president, client services, TruLab

References

1. The Innovation Imperative: The Future of Drug Development. The Economist Intelligence Unit. June 28, 2018. https://druginnovation.eiu.com/
2. Patient Burden in Clinical Trials: Ethics of Biospecimen Management. TruLab. June 30, 2022. https://trulab.com/recording-june30th/
3. Desai M. Recruitment and Retention of Participants in Clinical Studies: Critical Issues and Challenges. Perspectives in Clinical Research. 2020 Apr-Jun;11(2):51-53. doi: 10.4103/picr.PICR_6_20. Epub 2020 May 6. PMID: 32670827; PMCID: PMC7342339.
4. Getz K. How Much Does a Day of Delay in a Clinical Trial Really Cost? Applied Clinical Trials. June 6, 2024. https://www.appliedclinicaltrialsonline.com/view/how-much-does-a-day-of-delay-in-a-clinical-trial-really-cost-?
5. Sheridan R, Martin-Kerry J, Hudson J, Parker A, Bower P, Knapp P. Why Do Patients Take Part in Research? An Overview of Systematic Reviews of Psychosocial Barriers and Facilitators. Trials. 2020 Mar 12;21(1):259. doi: 10.1186/s13063-020-4197-3. Erratum in: Trials. 2020 Oct 8;21(1):840. doi: 10.1186/s13063-020-04793-2. PMID: 32164790; PMCID: PMC7069042.
6. New Poll Shows Minority Populations Support Clinical Trials to Improve Health of Others. Medical Xpress. July 31, 2013. https://medicalxpress.com/news/2013-07-poll-minority-populations-clinical-trials.html
7. Poongothai S, Anjana RM, Aarthy R, Unnikrishnan R, Narayan KMV, Ali MK, Karkuzhali K, Mohan V. Strategies for Participant Retention in Long Term Clinical Trials: A Participant-centric Approach. Perspectives in Clinical Research. 2023 Jan-Mar;14(1):3-9. doi: 10.4103/picr.picr_161_21. Epub 2022 Jul 23. PMID: 36909219; PMCID: PMC10003583.
8. Getz K, Smith Z, Jain A, Krauss R. Benchmarking Protocol Deviations and Their Variation by Major Disease Categories. Therapeutic Innovation and Regulatory Science. 2022 Jul;56(4):632-636. doi: 10.1007/s43441-022-00401-4. Epub 2022 Apr 4. PMID: 35378712; PMCID: PMC8979478.
9. Almazbek M. How Patient-Centered Strategies Are Transforming Clinical Trials. Clinical Research News. September 2, 2022. https://www.clinicalresearchnewsonline.com/news/2022/09/02/how-patient-centered-strategies-are-transforming-clinical-trials
10. Getz K, Smith Z, Jain A, Krauss R. Benchmarking Protocol Deviations and Their Variation by Major Disease Categories. Therapeutic Innovation and Regulatory Science. 2022 Jul;56(4):632-636. doi: 10.1007/s43441-022-00401-4. Epub 2022 Apr 4. PMID: 35378712; PMCID: PMC8979478.
11. CDER Patient-Focused Drug Development. U.S. Food and Drug Administration. https://www.fda.gov/drugs/development-approval-process-drugs/cder-patient-focused-drug-development
12. Patient Burden in Clinical Trials: Ethics of Biospecimen Management. TruLab. June 30, 2022. https://trulab.com/recording-june30th/