Collecting Data from Multiple Study Sites
Case study shows how one CRO ensured high-quality, consistent data in a difficult therapeutic area.
High-quality data is an important part of any clinical trial. However, getting consistent data from multiple study sites can be a challenge for clinical trial sponsors and investigators.
This article will use a case study from the abatacept 2 (ABA2) clinical trial to demonstrate how clinical trial sponsors and investigators can leverage contract research organizations (CROs) to develop and implement data monitoring practices that lead to reporting consistency across clinical trial sites.
The practices used in this clinical trial contributed to the first drug approval for acute graft-versus-host disease (GHVD)—a potentially life-threatening complication after allogeneic hematopoietic cell transplantation (HCT).
Background
The ABA2 trial was an investigator-initiated multi-center study to assess the safety, efficacy, and immunologic effects of adding the drug abatacept to the current standard of care for acute GVHD prevention for patients who had allogeneic HCT using a fully matched (8/8) or mismatched (7/8) unrelated donor.1
Physicians use allogeneic HCT as a potentially curative treatment for patients with certain blood cancers and disorders, like leukemia, lymphoma, or sickle cell disease. However, allogeneic HCT uses blood stem cells from a related or unrelated donor. Acute and chronic GVHD happen when the donor’s cells see the recipient’s cells as different and attack them.
Acute GVHD is a leading cause of morbidity and non-relapse mortality after allogeneic HCT, especially for patients who do not have a fully matched unrelated donor.1 The ABA2 trial tested whether abatacept could decrease acute GVHD.
The challenge: Historically unreliable data
Prior to the ABA2 trial, the FDA had not approved a drug for acute GVHD prevention. The trial’s primary endpoint relied on high-quality data for GVHD clinical staging. If the study produced promising results, the study team planned to publish the results and perform a Phase III study to further evaluate the safety and efficacy of abatacept for GVHD prophylaxis.
However, the study team faced a major challenge. GVHD data are historically unreliable. Clinical staging—which ranges from grade I (mild) to grade IV (life-threatening)—varies greatly between transplant centers and is frequently not agreed upon by independent reviewers with concordance ranging from 40 to 72%.2,3 The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multi-center clinical trials.4
The ABA2 study team needed to ensure the 14 study sites all reported GVHD clinical staging consistently to evaluate the study endpoint.
The solution: training and best practices
The ABA2 team used CIBMTR CRO Services to provide specialized site monitoring on the clinical trial, including the review of acute GVHD data reporting for consistency across the study sites.
Recognizing the difficulty to obtain high-quality, consistent GVHD data in an area where highly trained clinicians frequently disagree, CIBMTR CRO Services created an intensive therapeutic area training course and implemented best practices for their clinical research associates (CRAs). This ensured all assigned CRAs gained the expertise needed to review GVHD data in a standardized manner and understand when to request additional clarification from the site clinician.
The training included modules on GVHD with real-world exercises that allowed the CRAs to gain familiarity with:
- GVHD staging and grading
- Common challenges in GVHD data
- Source documentation
After passing an exam, the CRAs completed co-monitoring visits to demonstrate competency in reviewing GVHD data and CRAs were not cleared to monitor on their own until they demonstrated competency. Monitors were required to take detailed notes other internal team members reviewed for consistency and accuracy. The notes ensured an easier transition in case of staff turnover.
Throughout the clinical trial, the CRAs had access to in-house HCT physicians at the CRO who could assist with particularly difficult cases.
The CRO also implemented a flexible staffing model to adjust to the changing needs of the project. Some points of the project required many fully dedicated CRAs; some points required a few partially dedicated CRAs. This flexible staffing model helped keep the project on time and on budget.
In highly specialized fields, such as HCT, a CROs training methods and experience does matter both in accuracy and efficiency. Reviewing GVHD data is labor intensive. In this case, the CRAs reviewed more than 4,000 documents from 186 subjects at the 14 clinical trial sites.
The experience gained in the structured training program with competency assessments allowed the CRAs to efficiently review the data for inconsistencies, know where to look for the highest quality information, and discern when clarification from a clinician was required.
The CIBMTR CRO Services leaders also observed the number of forms a CRA could review doubled or tripled as the CRA gained experience in the therapeutic area.
The ABA2 clinical trial produced high-quality, concordant acute GVHD data. These data demonstrated that adding abatacept to matched or 7/8 mismatched unrelated donor HCT was safe, reduced acute GVHD, and improved severe acute GVHD-free survival. The results were especially significant in patients who received a 7/8 mismatched unrelated donor transplant.1
The study team, led by Leslie Kean, MD, was confident in the high-quality data. The clinical trial outcome was so promising the team partnered with the pharmaceutical company that manufactures the drug to submit a marketing application to the FDA for the approval of abatacept for acute GVHD prophylaxis. The team also used real-world evidence from the CIBMTR outcomes database to support the marketing application.5 The FDA inspected the trial and issued no sponsor or site findings.
On Dec. 15, 2021, abatacept became the first FDA-approved drug for acute GVHD prevention.6 This was a major development for improving patient outcomes and expanding the option of HCT to many more patients with blood cancers and disorders, especially those who are ethnically diverse for whom a fully matched related donor often cannot be identified.7
Kean and the pharmaceutical company are collaborating on a follow-up study called the ABA3 clinical trial (NCT 04380740), which analyzes additional dosing of abatacept and its effects on incidence and severity of chronic GVHD. They have expanded the responsibilities of CIBMTR CRO Services to include project management, data management, and site management.
This case study exemplifies how clinical trial sponsors and investigators can leverage CROs to implement data monitoring practices that lead to reporting consistency across clinical trial sites.
References
1. Watkins B, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021. 39 (17), 1865-1877.
https://ascopubs.org/doi/10.1200/JCO.20.01086
2. Weisdorf DJ, Hurd D, Carter S, et al. Prospective grading of graft-versus-host disease after unrelated donor marrow transplantation: a grading algorithm versus blinded expert panel review. Biol Blood Marrow Transpl. 2003. 9, 512–8. https://www.astctjournal.org/article/S1083-8791(03)00162-9/fulltext
3. MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems. Biol Blood Marrow Transpl. 2002. 8, 387–94. https://www.astctjournal.org/article/S1083-8791(02)50024-0/fulltext
4. Harris AC, Young R, Devine S, et al. International, multicenter standardization of acute graft-versus-host disease clinical data collection: A report from the Mount Sinai Acute GVHD International Consortium. Biol Blood Marrow Transplant. 2016. 22 (1), 4-10. https://www.astctjournal.org/article/S1083-8791(15)00602-3/fulltext
5. Kean LS, Burns LJ, Kou TD, et al. Improved overall survival of patients treated with abatacept in combination with a calcineurin inhibitor and methotrexate following 7/8 HLA-matched unrelated allogeneic hematopoietic stem cell transplantation: Analysis of the Center for International Blood and Marrow Transplant research database. Blood. 2021. 138 (Supplement 1), 3912. https://ashpublications.org/blood/article/138/Supplement%201/3912/482177/Improved-Overall-Survival-of-Patients-Treated-with
6. Voelker R. Drug approved to prevent graft-vs-host disease. JAMA. 2022. 327 (5), 417.
https://jamanetwork.com/journals/jama/article-abstract/2788549
7. Qayed M, Watkins B, Gillespie S, et al. Abatacept for GVHD prophylaxis can reduce racial disparities by abrogating the impact of mismatching in unrelated donor stem cell transplantation. Blood Adv. 2022. 6 (3), 746–749. https://ashpublications.org/bloodadvances/article/6/3/746/477917/Abatacept-for-GVHD-prophylaxis-can-reduce-racial
Including Women of Childbearing Age in Clinical Research
March 26th 2024In recognition of International Women's Month, we're featuring this recent talk between Associate Editor Miranda Schmalfuhs and Marie Teil, Global Head of UCB’s Women of Childbearing Age Program. They speak about the specific challenges women with chronic illnesses face when accessing appropriate treatment and participating in clinical trials, UCB's Women of Childbearing Age Program and it’s most successful strategies, and much more.
Improving Engagement While Maintaining Data Integrity & Validity
March 19th 2024In recognition of Women's Health Month, we're featuring this recent talk between Associate Editor Miranda Schmalfuhs and uMotif's Chief Product Officer, Julia Lakeland, discuss new technologies improving patient engagement and reducing the emotional and logistical burdens of participation, ethical considerations that should be addressed when implementing those technologies, while ensuring patient privacy, and much more.
