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Applied Clinical Trials
Pressure to shorten study start-up timelines puts clinical supply management in the crosshairs.
Sponsor companies and service providers have embraced more strategic management of their clinical supplies while regulatory pressures and the volume of global clinical trial activity have increased. Pressures to achieve shorter study start-up timelines and enroll larger numbers of globally dispersed study subjects have made clinical supply management even more complex. Downstream, investigative sites face numerous challenges including delays in receiving supplies; managing disparate supply deliveries; dealing with multiple vendors; labeling issues; and temperature excursions.
Current study planning and practice relies heavily on the use of interactive web or voice response technology (or interactive response technology), also referred to as IWR or IRT. These tools are often integral to investigative site management of clinical supplies.1 At minimum, IRT systems help to reduce site burden and expedite reconciliation and return of unused investigational product (IP) at the end of a study.2 Published data indicate that IRT for clinical supply management will increasingly play a major role in managing global trials.3 Improved IRT systems could allow for better support overall for timing of supply and re-supply, mitigating issues such as limited storage space available at the sites and support proper labeling. IRT can also be used to manage patient compliance issues with the use of mobile patient visit and medication reminders.4
Despite the large investment and major role that IRT plays in helping sites manage global clinical supply, there is little published data on IRT usage and its impact at the site level. Indeed, to our knowledge, investigative site experiences with, and perceptions of, clinical supplies have received scarce attention. Such a perspective would be invaluable to sponsors and contract research organizations (CROs) in identifying opportunities to improve study conduct collaborative effectiveness and efficiency.
To address this need, Tufts CSDD recently completed a study among several hundred investigative sites around the world to gauge their capabilities and experiences with clinical supplies.
Tufts CSDD, in collaboration with seven major pharmaceutical companies and CROs, developed an online survey for global site staff directly involved in managing clinical supplies. The survey was designed specifically for the role of study coordinators, investigators and sub-investigators, pharmacists, technicians, and Qualified Persons (QPs). An online survey was comprised of both multiple choice and open-ended questions. An invitation to complete the survey containing the survey link was distributed to Tufts CSDD contacts and mailing lists by e-mail during May and June 2013. Responses were anonymous and confidential and were reported only in aggregate form.
The survey examined three broad areas: site capabilities in handling clinical supplies, assessments of sponsor and contract research organization (CRO) abilities to handle clinical supply responsibilities, and key areas of opportunity and challenge. Approximately 4,500 emails were sent out to unique sites globally and 304 surveys were completed yielding a 7% response rate.
Overall respondents were primarily investigators (46%) or study coordinators (41%) while 13% were pharmacists. Respondents were distributed globally with 39% based in North America, 20% based in Latin America, and 30% based in Eastern and Western Europe. Sites conducted a median of nine trials per year across a wide range of therapeutic areas; the top therapeutic areas included cardiovascular trials (19%); central nervous system (17%); metabolic/endocrine (14%); and oncology clinical trials (8%).
Respondents conducted trials in a number of settings: one-third (31%) are in government/hospital settings, 36% are in academic medical centers, and 43% are in for-profit independent sites or site networks. Most sites reported using a central pharmacy (62%), while the rest used an in-house pharmacy or an outsourced pharmacy (9%) On average, there were 4.24 full-time equivalents dedicated to managing supplies and 2.91 part-time equivalents.
Overall, respondents perceive that they are generally well prepared to handle clinical trial drug supplies. There were a few exceptions: more than half of sites (54%) reported that the amount of space available at their center was "very adequate." In a separate free-text question, nearly three-fourths (74%) of 103 mentioned that they have limited storage space available on site.
Sites also indicate that they have limited abilities to handle novel therapies such as gene therapies or personalized immunotherapies. The highest proportion of sites said that they are able to handle vaccines (42%), blood and blood products (41%), and therapies with companion diagnostics (32%) (see Figure 1).
In general, the majority of investigative sites rate sponsor/CRO clinical supply responsibilities positively. Clinical supply availability, responsiveness to inquiries, and the quality of training are among the areas receiving top ratings. Respondents also indicate that sponsors and CROs perform well with respect to receipt and acknowledgement of drugs and supplies and documentation clarity (see Figure 2).
Throughout the survey, a relatively low proportion of sites rated sponsor and CRO performance as "Excellent," indicating widespread opportunities to improve. Investigative site responses—both closed- and open-ended—also reveal a number of areas where there are major opportunities for improvement:
Seventeen percent of respondents rated IRT "Poor" and "Fair" with respect to design, and 13% gave a low rating to IRT ease of use. More than one-out-of-four sites rated the number of IVR steps to get a drug dispensed as "Poor" to "Fair."
Another issue examined across sites was the frequency with which delays prevented dosing of first patient. Sites conducting trials in oncology, infectious disease, respiratory, and hematology were more likely to report delays preventing dosing of first patient than those in other therapeutic areas.
The most critical challenge in receiving supplies was having supplies arrive unexpectedly at a site. Nearly four out of 10 sites report significant challenges with receiving supplies at unanticipated times (see Figure 3). Other notable issues were having unexpected amount of drug, bulky packaging, and insufficient communication about receiving drugs or supplies. Other difficulties mentioned were logs that needed to be completed manually rather than in an automated fashion, ensuring proper security for drugs and supplies, and the need for proper instructions in handling drug.
Label design or formatting was also viewed as challenging. Some of the most frequently mentioned labeling challenges reported were difficulty in reading the kit number or label text and not enough room to write on the label.
Respondents reported challenges in the area of temperature-monitored supplies specifically with temperature excursions and dealing with defective or complicated equipment. Our analyses revealed further differences by therapeutic area. Sites conducting trials in oncology, infectious disease, respiratory, or hematology therapeutic areas were more likely to report challenges with temperature excursions than those conducting trials in other areas. This difference was statistically significant (p <.01). This finding is not surprising given that sites participating in research with temperature monitored products (e.g., oncology and hematology) are likely to report challenges with temperature excursions.
Another challenge to site staff is patient compliance. Respondents estimate that nearly one-quarter of patients experienced a compliance issue in 2012. Our analysis by site volume and region suggests that sites conducting a greater volume of trials per year experienced more issues with patient compliance than those conducting fewer trials per year, and those sites in the rest of world report more patient compliance issues than those sites based in North America and Western Europe. These differences were statistically significant (p=0006; p <.0001). Some of the issues contributing to patient compliance were sponsor or site specific, including poor labeling or instructions, including small font size, readability of labels, and use of booklet labels. Other issues included large or complicated packaging, side effects, and the length of a study. The last category of challenges was patient specific, such as lack of reminders or patient forgetting and patient education.
Overall, sponsor and CRO clinical supply practices receive a good first report card and this will serve as a baseline to measure against in the future. Sites indicate that in general they were satisfied with the availability of drug at their sites and rated most sponsor practices favorably. Top improvement areas include complicated IVRS processes; unexpected amount and arrival time of supplies; cumbersome delivery and return packaging; and defective equipment.
Differences in perceptions were observed across respondent subgroups, including study conduct setting, geographic region, and clinical trial volume. These differences suggest opportunities for targeted areas of improvement. Future Tufts CSDD studies will explore these differences in more detail. In an upcoming study, Tufts CSDD will also be examining the impact of logistical factors, such as the role of cold chain handling, requirements for temperature and time zones, storage and distribution, regulatory, and customs within the management of the global supply chain.
Clinical supply challenges were particularly evident in specific therapeutic areas: oncology, infectious disease, respiratory, and hematology. Increasingly, trials conducted in these therapeutic areas utilize temperature-controlled drugs and supplies and the costs involved in shipping and transporting clinical supplies are high and may require that current sponsor-site practices be re-assessed or evaluated. As more sites deal with temperature-controlled products and moving those through temperature and time zones as well as handling novel therapies, sites may require additional staff training, facilities, or technology. Given the industry's move toward more focused controls on shipping of various temperatures, sponsors' assessment of sites' practices could result in considerable cost savings for companies.
Investigative sites are asking for improvements in communication to help them accommodate supply shipments and returns more effectively and efficiently. An opportunity for sponsors to conduct site assessments of their supply practices, including evaluating use of technology and IRT systems, may help in this area. Investigator meetings are another mechanism that could offer sponsors and CROs a means to address communication channels among clinical supply and clinical operations functions. Lastly, routinely and systematically collecting feedback from sites will provide sponsors with valuable insights into relationship effectiveness and improvement areas.
Mary Jo Lamberti*, PhD, is Senior Research Fellow, Tufts CSDD, email: [email protected] Kenneth Getz, MBA, is Director of Sponsored Research Programs and Associate Professor, Tufts CSDD; Paulami Naik is Research Analyst, Tufts CSDD; Mary Costello is Global Director, Strategic Marketing, Fisher Clinical Services.
* To whom all correspondence should be addressed.
1. Swaminath, G. "Juggling Clinical Trial Supplies." Drug Discovery and Development (May 15, 2012). Accessed 9/30/2013. http://www.dddmag.com/articles/2012/05/juggling-clinical-trial-supplies/
2. English, M and Ma, A. "From Cradle to Grave: Tracking the Life Cycle of a Drug is a Complex process that Early Planning and IVR Technology can Help Ease." Applied Clinical Trials 16(8), August 2007, 50-54.
3. Kole, T. and Bedford, J. "Mitigating the Challenges of Global Trials: e-Clinical Best Practices for Managing Patients and Clinical Supplies in Emerging Regions." ContractPharma, November/December 2012, 60-64. http://www.contractpharma.com/issues/2012-11/view_features/mitigating-the-challenges-of-global-trials/
4. Murphy, J. and Whitaker, S. "Streamlining Site and Patient Management." Life Science Leader, February 2011. http://www.lifescienceleader.com/magazine/past-issues3/item/3841-streamlining-site-and-patient-management?list=n/