By Laurence Burke, Director Project Management, ERT
For clinical trials to be truly successful, adherence to protocols is essential. However, as trial designs become more complex, sponsors are seeing a worrying fall in compliance levels amongst both investigators and patients. In this article we discuss the reasons for the drop in compliance and how mobile technology can help reverse this trend.
Tufts Center for the Study of Drug Development (CSDD) found that between 2000 and 2003 the median number of unique procedures per protocol across all therapeutic areas and phases of development stood at 20.5.1 This figure increased almost 50% by 2008-2011.2 Amendments to protocols are also high and result in trial delays, greater costs, and more patient drop-outs. In 2016, Tufts CSDD studied data from 836 protocols finding that 57% had at least one substantial amendment, with 45% being deemed “somewhat” or “completely” avoidable.3
For site staff, increased procedures and amendments inevitably increase the burden placed on them. Tufts CSDD have calculated that median units of work rose by 64% across the decade.1 It therefore comes as no surprise that the US Institute of Medicine believes that this rise in complexity and workload is causing some investigators to stop participating after just a single trial.4
Mobile technologies such as electronic patient reported outcomes (ePRO) and electronic clinical outcome assessments (eCOA) can help address this problem. For example, ePRO/eCOA is able to send out automatic site visit reminders, include training features, instructions etc, all freeing up investigators’ time to focus on the humanistic aspects of their jobs.
For patients, an increase in protocol complexity and patient eligibility have played a part in both drop-out and compliance levels - between 1999 and 2002 the screen-to-complete ratio was 52%. However, by 2006 this had dropped to just 28%.1
Although patients enter into trials with the intention of completing tasks fully and on time, compliance levels diminish as the weeks pass. A 2011 paper co-authored by Phil Skolnick of the National Institutes of Health and published in the journal Molecular Interventions highlights these low levels of compliance.5 In the first trial, a Phase Ib trial of the antidepressant amitifadine, 30% of patients failed to meet the threshold for compliance: no trace of the drug or its metabolite was found in at least three out of four blood tests taken over an eight week period. Compliance in the second study, a Phase III trial of bicifadine, fell from 67.5% to 53.6% by week 12. As a result, because only a subset of patients took the medication as dictated by the protocol, the final datasets in the trials were distorted.
Using electronic technologies such as ePRO/eCOA as part of the trial can help offset the problems an increase in protocol complexity brings with it for patients and sites alike. For example, patients can be sent daily text reminders and those who receive them are more likely to take their treatment within a predefined one hour window. According to a paper in which 60 studies with text reminders were reviewed, it was found that 77% reported improved outcomes, with 40% seeing increased adherence to medication and 18% improved appointment attendance.6 Also, in 2016 the Journal of the American Medical Association published findings that among chronic disease patients medication adherence increased from 50% to 67.8% with the use of text reminders.7
Patients are also more likely to attend site visits, complete ePRO/eCOA questionnaires and take their medication on time when they receive mobile reminders. Sponsors and sites are able to monitor the compliance rate of individuals closely because of time stamping. These benefits are clearly shown in a post-marketing cardiovascular outcomes study of 13,000 people conducted by one of our clients. Site visits rose by 5% when ePRO was used with the drop-out rate falling by 4.5%. When scaled across the full 13,000 person study, these improvements would have shortened the trial by four months and saved $14 million.
The patient and investigator benefits of mobile technologies are ultimately felt by sponsors. High rates of compliance produce high-quality data. In the field of ePRO/eCOA the confidence this instills is new. With paper diaries, patients may well be completing forms in the car-park prior to a visit whilst claiming them to have been completed at the right time. Erroneous data and illegible handwriting are also major problems. Mobile ePRO/eCOA safeguards against these shortcomings, increasing the standards of quality.
Real-time data allows sponsors to focus their resources on sites that require extra help. Clinical Research Associates (CRAs) have access to real-time data on the activities of site staff, which helps to ensure that they comply with their contracts. Extra support can then be offered to struggling sites, potentially preventing an adherence issue before it arises.
These technologies also support more responsive, flexible trial designs. In a flu trial, for example, a sponsor can triage patients from weekly to daily diary entries when they record certain symptoms. Sponsors can gather daily data immediately and do not have to wait for a patient to visit the site. Equally, remote oversight reduces the burden on patients by reducing the number of site visits.
As trial designs become more complex, ePRO/eCOA can help reduce the burden on all involved, increasing compliance and data quality. Mobile ePRO/eCOA technologies provide the best solution. For sponsors, real-time data allows for closer monitoring than ever before, giving them confidence in the results; for patients, ePRO/eCOA helps them cope with potentially complicated new routines. The benefits for all stakeholders are manifold.
1. Getz, KA., et al. Assessing the impact of protocol design changes on clinical trial performance. Am J Ther. 2008 Sept-Oct; 15(5): 450-7.
2. Getz, KA., et al. Measuring the incidence, causes, and repercussions of protocol amendments. Ther Innovation & Reg Sci. 2011; 45(3): 265-275.
3. Getz, KA., et al. The impact of protocol amendments on clinical trial performance and cost. Ther Innovation & Reg Sci. 2016; 50(4): 436-441.
4. Burgess, LJ. & Sulzer, NU. The growing disparity between clinical trial complexity and investigator compensation. Cardiovasc J Afr. 2010; 21(5): 249-250.
5. Czobor, P., & Skolnick, P. The secrets of a successful clinical trial: compliance, compliance, and compliance. Molecular Interventions. 2011; 11(2): 107-110.
6. Kannisto, KA., Koivunen, MH., and Välimäki, MA. Use of mobile phone text message reminders in health care services: a narrative literature review. J Med Internet Res. 2014; 16(10): e222
7. Thakkar, J., et al. Mobile telephone text messaging for medication adherence in chronic disease. JAMA Intern Med. 2016; 176(3): 340-349.