The impact of clinical trial monitoring approaches on data integrity and cost—a review of current literature
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Monitoring is a costly requirement when conducting clinical trials. New regulatory guidance encourages the industry to consider alternative monitoring methods to the traditional 100 % source data verification (SDV) approach. The purpose of this literature review is to provide an overview of publications on different monitoring methods and their impact on subject safety data, data integrity, and monitoring cost.
The literature search was performed by keyword searches in MEDLINE and hand search of key journals. All publications were reviewed for details on how a monitoring approach impacted subject safety data, data integrity, or monitoring costs.
Twenty-two publications were identified. Three publications showed that SDV has some value for detection of not initially reported adverse events and centralized statistical monitoring (CSM) captures atypical trends. Fourteen publications showed little objective evidence of improved data integrity with traditional monitoring such as 100 % SDV and sponsor queries as compared to reduced SDV, CSM, and remote monitoring. Eight publications proposed a potential for significant cost reductions of monitoring by reducing SDV without compromising the validity of the trial results.
One hundred percent SDV is not a rational method of ensuring data integrity and subject safety based on the high cost, and this literature review indicates that reduced SDV is a viable monitoring method. Alternative methods of monitoring such as centralized monitoring utilizing statistical tests are promising alternatives but have limitations as stand-alone tools. Reduced SDV combined with a centralized, risk-based approach may be the ideal solution to reduce monitoring costs while improving essential data quality.
KeywordsRisk-based monitoring Clinical trial monitoring Source data verification Centralized monitoring Statistical monitoring Remote monitoring
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
- 1.Food and Drug Administration (2011) 21 CFR part 312, subpart D: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312&showFR=1&subpartNode=21:18.104.22.168.3.4. and 21 CFR part 812, subpart C: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=812&showFR=1&subpartNode=21:22.214.171.124.9.3
- 2.The International Conference on Harmonisation (1996) Guideline for good clinical practice: E6: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf
- 3.Food and Drug Administration (1988) Guidance for industry: guideline for the monitoring of clinical investigations: http://www.ahc.umn.edu/img/assets/19826/Clinical%20monitoring.pdf
- 4.Funning S, Grahnén A, Eriksson K, Kettis-Linblad Å (2009) Quality assurance within the scope of Good Clinical Practice (GCP)—what is the cost of GCP-related activities? A survey within the Swedish Association of the Pharmaceutical Industry (LIF)’s members. Qual Assur J 12(1):3–7CrossRefGoogle Scholar
- 7.European Medicines Agency (2014) Reflection paper on risk based quality management in clinical trials: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/11/WC500155491.pdf
- 8.Food and Drug Administration (2014) Guidance for industry, oversight of clinical investigations—a risk based approach to monitoring: http://www.fda.gov/downloads/Drugs/…/Guidances/UCM269919.pdf
- 12.Andersen JR, Byrjalsen I, Bihlet A, Kalakou F, Hoeck HC, Hansen G, Hansen HB, Karsdal MA, Riis BJ (2015) 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 79(4):660–668. doi: 10.1111/bcp.12531 CrossRefPubMedGoogle Scholar
- 15.Mitchel J, Kim Y, Hamrell M, Carrara D, Markowitz J, Cho T, Nora S, Gittleman D, Choi J (2014) Time to change the clinical trial monitoring paradigm. Appl Clin TrialsGoogle Scholar
- 16.TransCelerate (2013) Position paper: risk-based monitoring methodology. http://www.transceleratebiopharmainc.com/wp-content/uploads/2013/10/TransCelerate-RBM-Position-Paper-FINAL-30MAY2013.pdf
- 17.Lienard JL, Quinaux E, Fabre-Guillevin E, Piedbois P, Jouhaud A, Decoster G, Buyse M, European Association for Research in O (2006) Impact of on-site initiation visits on patient recruitment and data quality in a randomized trial of adjuvant chemotherapy for breast cancer. Clin Trials 3(5):486–492. doi: 10.1177/1740774506070807 CrossRefPubMedGoogle Scholar
- 19.Bakobaki JM, Rauchenberger M, Joffe N, McCormack S, Stenning S, Meredith S (2012) The potential for central monitoring techniques to replace on-site monitoring: findings from an international multi-centre clinical trial. Clin Trials 9(2):257–264. doi: 10.1177/1740774511427325 CrossRefPubMedGoogle Scholar
- 21.Lindblad AS, Manukyan Z, Purohit-Sheth T, Gensler G, Okwesili P, Meeker-O’Connell A, Ball L, Marler JR (2014) Central site monitoring: results from a test of accuracy in identifying trials and sites failing Food and Drug Administration inspection. Clin Trials 11(2):205–217. doi: 10.1177/1740774513508028 CrossRefPubMedGoogle Scholar
- 27.Pronker E, Geerts BF, Cohen A, Pieterse H (2011) Improving the quality of drug research or simply increasing its cost? An evidence-based study of the cost for data monitoring in clinical trials. Br J Clin Pharmacol 71(3):467–470. doi: 10.1111/j.1365-2125.2010.03839.x CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Korieth K (2011) The high cost and questionable impact of 100% SDV. Cent Watch Mon 18(02)Google Scholar
- 33.Hullsiek KH, Kagan JM, Engen N, Grarup J, Hudson F, Denning ET, Carey C, Courtney-Rodgers D, Finley EB, Jansson PO, Pearson MT, Peavy DE, Belloso WH (2014) Investigating the efficacy of clinical trial monitoring strategies: design and implementation of the cluster randomized START monitoring substudy. Ther Innov Regul Sci. doi: 10.1177/2168479014555912 PubMedCentralGoogle Scholar
- 34.Sax A, Keegan M, White D, Turner JR (2012) Risk-based monitoring: the new regulatory landscape, and conjectures on the future of clinical trial execution. J Clin Stud 4(5):26–33Google Scholar