Mary Costello

Today’s headlines in clinical development tout the potential of decentralized trials, with some even going so far as to predict that trials of the future will bypass sites through a combination of centralized review, technology, and just-in-time clinical resources. To the contrary, keeping the site at the center of clinical research, even when taking a decentralized approach, is crucial for success and health outcomes.

Clinical trial designs today span a wide continuum, ranging from 100% site-based trials, where all interactions with study participants occur at the site, to 100% decentralized trials, where all interactions are remote and leverage wearable technologies supplemented by occasional visits by trial nurses to the participants’ homes. The latter are often referred to as “siteless” trials.

However, a large majority are a hybrid of the two. This is true even as decentralization, accelerated by the COVID-19 pandemic, jumped to a 77% CAGR between the second halves of 2019 and 2020, according to data from more than 1,000 trials.

Despite our extensive involvement in decentralized clinical trials (DCTs), we agree that “siteless” trials are not optimal. The term itself is counterintuitive. The principal investigator’s site, together with trial coordinators, should remain a key part of the trial ecosystem, whether the trial leverages a single site or a network of coordinated sites, local pharmacies, community clinics, and home health aides supported by wearable devices and platform solutions. Technology simply cannot replace people.

Recent industry experience offers a relevant analogy. Between 2005 and 2015, many pharmaceutical companies rapidly adopted salesforce automation tools for their sales representatives while cutting sales jobs at the same time. From its height at 101,000 sales reps in 2005, the number of reps in the US market dipped to 76,000 by 2010 and hit its lowest level of just 66,000 in 2012. Accenture research showed that one in four pharmaceutical sales rep interactions was replaced by digital alternatives, but it did not achieve the intended effect of improved profitability. The strategy backfired and sales dipped. Now, there are more than 100,000 pharma sales reps in the US, according to various estimates, and overall revenues have been setting records year over year. The ship has righted itself.

Today, we are on the doorstep of a similar technology revolution, largely accelerated by COVID-19 when clinical researchers had no choice but to leverage innovative digital technologies to continue their work. Now, the excitement around technology’s potential is soaring again. The innovative technologies enabling remote or decentralized trials have the potential to dramatically reduce the burden for patient participation in research and for sites who manage studies. Recent data backs this claim, with at least half of the respondents to a recent Association of Clinical Research Professionals’ (ACRP) survey anticipate ‘strong’ use of eConsent (63%), eSource (56%), remote monitoring (55%), and wearables (50%) post pandemic.

Industrywide, there is confusion over terms like “virtual,” “remote,” and “siteless” trials; hybrid trials; and even the DCT concept itself. On the one hand, the Society for Clinical Research Sites (SCRS), in a December 2020 white paper defined its subject thus: “For the purposes of this survey, ‘decentralized or virtual’ referred to studies that are fully virtual, meaning that all study visits are remote.”

 On the other hand, even a cursory review of current literature on DCTs will demonstrate phrases like “decentralized or hybrid,” blurring the distinction between trials with or without patient site visits.

The DCT concept traces back to the 2018 Clinical Trials Transformation Initiative (CTTI) white paper that specifies that “DCTs can be conducted as 100% decentralized or as a hybrid study in which the DCT offers the additional flexibility of incorporating both in-person visits and virtual visits into the study as appropriate.”

 Although the intent, was to standardize terminologies, this definition proposes that “decentralized” and “hybrid” are synonymous.

There is also some evidence of the impact of the COVID-19 pandemic changing perspectives on “siteless” or fully virtual trials, and hybrid DCTs. A July 2020 SCRS survey found that a mere 3% of clinicians “had participated in a completely virtual trial, where all visits are conducted remotely.”

 But the December 2020 SCRS white paper, based on a May-to-July survey, found that use of “the fully virtual approach” had risen to 15.46%. More recent data found that 22% of respondents conducted “siteless” trials pre-pandemic; 17% had done so during the pandemic “but not because of it,” and an additional 12% had done so “because of COVID-19.”

The clinical trial lexicon will continue to evolve, but “siteless” should not receive a dictionary reference.

Rather than a “siteless” trial, the better approach is to build fit-for-purpose clinical research with a next-generation site at its center. Some trials might be, in fact, wholly decentralized, but even those should incorporate a site whose role may be a different iteration of what a traditional site looks like today. The best-performing trials will continue to have human interactions between physicians and patients. They will not be without sites but, rather, be technology-enabled to reduce burdens and improve efficiency. That is what well-designed technology should do, for both patients and for trial administrators.

Among other benefits, DCTs promise to 1) improve the recruitment and retention of trial participants and 2) increase diversity in trial populations. Given that only seven of 100 enrolled patients complete trials

, ensuring patient retention through all means is vital to trial execution and research efficiency. Interactions with trial physicians, care coordinators, and operational staff are vital to these goals.

People are foundational to clinical research, and the physician/patient relationship is the building block for long-term participation in a trial. It also builds trust, something that is especially critical today as public confidence among minority communities has eroded dramatically since the start of the pandemic. Patients develop close relationships with their study coordinators, who spend time engaging on a very personal level and deliver tender care. Coordinators and site staff give hugs, call patients by their first names, and nurture the relationship. In fact, this is the number one determinant of a patient’s completion of a trial. A “siteless” experience takes this away.

DCT technology should assist site administrators in fostering a trusted patient relationship, while at the same time provide improvements in data quality, data collection, study startup speed, informed consent, regulatory compliance, and all the other goals of a well-run trial. In the aforementioned 2021 Avoca survey, respondents report the two most substantial benefits of DCT technologies are: retention of study participants (with a mean score of 4.2 on a 1-5 scale); and diversity of study participants (3.9). Technology along with real-life patient engagement are the one-two punch to overcoming two of our greatest trial obstacles.

Besides the obvious obstacle to better patient recruitment and retention of travel to and from trial sites, patients can also suffer from limitations in handling modern technologies, ranging from lack of familiarity with smartphones to poor WiFi connections in their homes. In these cases, site-driven, hands-on guidance is paramount to the success of a DCT–and is another instance where the personal touch provided by a trial site is important.

Another aspect of patient retention in clinical trials is the health of the patients themselves. Rochester Clinical has had direct experience with assisting trial participants in getting necessary (in some cases, lifesaving) medical attention to patients that was unrelated to the trial itself. Some of this diagnosis was captured in the initial intake of the patient, where gentle probing helped get closer to the root of illness or personal insights on the patient’s health. In other cases, trial managers uncovered new health problems that cropped up during the trial because of close monitoring. Maybe some of these cases would have been recognized even with a “siteless” trial leveraging wearable technology; maybe not.

While technology can make the process of getting patients signed up for a trial easier, thanks to eSource, eConsent, and remote monitoring tools, there’s a misconception that it reduces the need for a site and its people. On the contrary, these new technologies open the door for new expertise, including more technology support but do not change the fact that there needs to be a centralized location for research and the back-end aspects of a well-executed trial.

The life sciences industry is having the wrong conversation about DCTs. Rather than talking about how DCT technology can replace sites, the conversation should shift to how to better support sites with technology. Technology companies and site managers should not be at odds with each other. Instead, they should be collaborators in providing the best patient experience and enabling successful trials.

, “Why Decentralized Trials are the Way of the Future,” by Fan Gao, Maurice Solomon, Arnab Roy, and William Chaplain (April 5, 2021).

Association of Clinical Research Professionals, 

, “Delving into eConsent: An Industry Survey,” (January 14, 2020) by Neetu Pundir; Mika Lindroos; Jenna McDonnell; Bill Byrom; Spencer Egan.

“Patient Centricity and Virtualizing Technologies in a COVID-19 World.”

Clinical Trials Transformation Initiative (CTTI), “CTTI Recommendations: Decentralized Clinical Trials (September 2018).

Society of Clinical Research Sites, “Impact Assessment of Decentralized Clinical Trials (DCT) Awareness in the Clinical Research Industry,” (2018).

WCG Avoca Group, “2020 State of the Industry Report” (June 2021).

Advarra Report, “Retention in Clinical Trials: Keeping Patients on Protocols,” (March 23, 2021).

Articles

Has technology taken the industry too far?

Sites Still Necessary for Decentralized Trials

Nearly two-thirds of clinical research sites say they are willing to conduct hybrid or virtual clinical trials, and more than half say they would do “whatever is required” to conduct a virtual study.

 Patients are also eager to participate. In a recent study, 75% of patients say that collecting all study data from their own home is appealing and 73% like the idea of a hybrid trial.

While the convenience, speed, and potential data quality improvements that come with decentralized clinical trials (DCTs) are inspiring, implementing DCTs can seem intimidating to investigators who haven’t participated in largely virtual studies.

“Consider how to embrace DCTs in a way that creates opportunity for your site and your patients. We must innovate to meet patient needs,” said Amanda Wright, vice president of partnership development at Javara, an integrated research organization that, in partnership with Wake Forest Baptist Health, is working on a Phase III clinical research study to evaluate the safety and effectiveness of mRNA-1273, a vaccine candidate against COVID-19 sponsored by Moderna. “You don’t have to decentralize every element of every study. Start where you’re comfortable. Carefully evaluate which components of each study can be decentralized, such as using remote monitoring devices to collect vitals such as weight and blood pressure without an in-person visit.”

With proper evaluation and planning, sites can avoid unexpected obstacles and reap the benefits of a DCT. Here are five key considerations to enable an easier transition to decentralized research.

1. Change management: Know what to expect

DCTs do not mean studies are entirely virtual, and often follow a hybrid model that leverages digital technologies like eConsent, telemedicine, wearable devices, electronic clinical outcome assessments (eCOAs), and electronic health (eHealth) records for various parts of the process. These technologies can improve patient centricity by reducing the burden of in-person visits and manual activities like paper diaries. Additionally, DCTs provide patients with interpersonal reassurance and support with technology to enable interactions at a time and place that suits patients and caregivers, which often leads to a better-quality interaction.

The obstacles to DCTs for sites range from fear of irrelevance, difficulty transitioning from paper to technology, the potential for patient resistance, patient populations without access to the internet, and concerns about data security and privacy.

Sites can overcome those challenges to improve outcomes and experience for all stakeholders. DCTs benefit sites by providing

Expanded trial access and diversity of participants

Improved patient engagement and retention

Expedited patient identification and cost reduction

Increased capacity for additional studies

As sites become more comfortable with DCTs, they may realize that DCTs can actually enable a closer patient-physician/site relationship than a traditional, randomized clinical trial can. DCTs enhance the patient-physician/site relationship in a virtual world by providing modular options and more choices.

Even so, a thorough change management process is imperative. Map out the options best for your site and include those that are already part of your infrastructure (see Figure 1 below). When creating messaging to staff and patients about the new options, for example, reinforce that it is an opportunity to ease burden and improve the workflow for everyone. Highlight to study teams, investigators, and patients that there will be choices about how to participate in a study.

“Preparation is key. You may need to customize your strategy for subgroups that are less comfortable with technology. It’s also imperative to understand your population’s access to the internet. This will help inform your search for the right technology partner and your implementation plan,” explained Patricia S. Larrabee, founder and CEO at Rochester Clinical Research. “Staff will be excited that data collection is faster, in real-time, and that the risk of losing paper documents will diminish. Televisits are not without challenges, but they have allowed us to continue studies during the pandemic. We always need to be ready to see patients remotely and sometimes after hours, particularly to assess adverse reactions. DCTs make it possible.”

2. Technology:What to look for in partners and solutions

There are several technology solutions in the marketplace, so it can be challenging to evaluate what is best for each individual organization. Of course, a DCT technology solution must support principal investigators in managing the care and safety of patients, but what else should be considered? Should it be an end-to-end product that covers all your technology needs? Does the solution accommodate hybrid studies? What is important to look for in the user interface?

Typically, there’s no need to do a complete technology overhaul. The best approach is to integrate all systems, including existing systems, and ensure your primary solution is built modularly. It allows sites to customize which studies, or parts of a study, to decentralize, as not every site or patient is ready to digitize every element of the process. As critical, the platform must seamlessly integrate with wearables and patient-collected data.

“No one needs one more piece of technology that doesn’t talk to your other systems; it needs to integrate,” said Larrabee. “And even more so, it should not require a software engineer to use it.”

When it comes to ensuring patient centricity, opt for a solution that has a simple, single sign-on to provide patients with ‘one way in and one way out,’ as Wright suggests, to minimize the learning curve. This will also significantly reduce tech support burdens for sites. Another important consideration for patients is internet access. Look for a system and provider that can meet the needs of participants without consistent internet access. For example, some DCT vendors provide devices that can work as hot spots.

In addition to the technology itself, consider the provider. For example, the vendor’s product development efforts should be informed with input from sites, such as a core bench of site advisors, so product development does not take place in a vacuum. For example, sites say that redundant questions are a significant pain point of inefficiency. So platforms that incorporate such feedback into forms, workflows, product ideation, and other areas will yield greater success. Similarly, technology providers should have a patient advisory council that provides input to product development and participates in user testing.

“The vendor should demonstrate that product design and user testing included patients of all ages and technical abilities. We must not assume that all patients have internet access or smart phones with data plans. Trials need diverse participants, so we must be able to include those without access to internet or their own technology. A technology vendor who addresses that is key,” noted Larrabee. “We also want partners who understand the site perspective. Make sure you have a chance to try using the solution before making a final commitment to ensure it really does what they say it does. Finally, the solution must be HIPAA compliant.”

3. Charting the course: Planning and training

The recommendations provided by the Clinical Trials Transformation Initiative (CTTI)

, a public-private partnership co-founded by Duke University and the FDA, are an important foundation when creating your implementation plan and training. The recommendations cover topics such as protocol design, state-level telemedicine issues, drug supply chain, mobile healthcare providers, investigator delegation and oversight and safety monitoring.

Early in the process, it is critical to map out a plan for general implementation that includes a thorough training process for staff and patients. It’s essential that training goes beyond feature and function to incorporate the “why’s” for staff and patients. With any new process, understanding the why’s and how each person benefits helps to ensure success. Since coordinators will be a source of tech support for patients, establish a “super user” at each location.

Many sites have found that DCTs offer flexibility for staff to work from home on occasion. Mapping out work-from-home standards that align with security and privacy regulations may seem daunting, but many have found that the added flexibility helps retain valuable team members. And documentation provides everyone involved with the reassurance they need to embrace new processes and technology.

Be sure to carefully craft messaging for patients about the security and privacy of information. The message should reflect patients’ cultural sensitivities. For example, in some countries, patients may have fears about items such as images of a medication being stored on their mobile device. Real-time information also means real-time responsibility. Therefore, structures need to be in place for responding to data collected through the technology and it may require new decision-support processes—experienced DCT technology providers can help map this out.

“Update your operating procedures, job descriptions, and performance criteria accordingly to ensure tech proficiency,” added Larrabee. “Listen to the end users, appoint several champions, give them time to learn it, and most of all, make sure they can see the big picture. Make it work by listening and responding to their needs.”

4. Guiding principle: Patients drive process

Patient centricity is a common term today, but making sure patients are at the center of DCT processes and technology is the key to success. Considerations for patient safety, patient engagement, and logistics are all part of the equation. Here’s how to keep that commitment.

Patients need the ability to choose which elements of a study they wish to do remotely and which they prefer to do in person. Since one size does not fit all, modular flexibility is so important. There must be choices for patients—and physicians/sites. Platforms with an interface that mirrors consumer technology like Amazon or Google also go a long way in helping patients feel comfortable.

“This is an opportunity to reach patients we otherwise could not, and patients want choices,” agreed Wright. “Patient experience and engagement is critical to the success of any trial. The better your patient’s experience, the more likely they will participate in another trial or refer a friend or family member, too.”

Larrabee continued, “Our focus on patient experience can’t end at the in-person encounter. The technology we use to interact with patients and the way we use it, needs to reflect the same standards we adhere to for all other aspects of the patient experience.”

5. Cycle of improvement: Measure and adjust

As with any business process, the utilization of DCTs must continuously improve. However, as DCTs continue to evolve, the patient feedback loop is exponentially important. Surveying patients is a great start, but the industry also needs to respond to feedback with meaningful change with each new lifecycle.

DCT technology innately enables ease of information flow to make better clinical decisions. Measure operational and patient/staff experience results regularly—to both collect feedback and to have quantifiable metrics to evaluate against the next time. For example, one investigator site implemented a digital data collection tool to increase efficiencies for both patients and staff. Patients no longer had to fill out a handwritten document, go to the site, and turn it in. Staff were able to see the patient responses in real-time in the app instead of transcribing in writing from the patient’s paper document. Their patient experience survey results were excellent, with the majority rating as very good/good.

“Efficiency is key. We measured the efficiency of regulatory document submission and found an increase in speed of 50% by going digital in just that one area,” concluded Larrabee. “Service is important in our industry. Listen, listen, and listen more. Encourage your staff to give feedback as well; we are all still learning.”

Change can be difficult, but a transformation that eases the burden of trial participation on patients and enhances so many other aspects of clinical trials is more than worthwhile. No two sites or patients are the same. The industry must continue to listen to its constituents and strive to meet the challenges of diverse communities. As these experts have explained, things are evolving and far from perfect, but through collaboration and insights from all stakeholders, we can enhance the access, data quality, and efficiency of clinical research.

Milam, D., “Hybrid Decentralized Trials: Using Technology to Create More Patient-Centric Studies,” 

https://www.clinicalleader.com/doc/hybrid-decentralized-trials-using-technology-to-create-more-patient-centric-studies-0001

Tufts Center for the Study of Drug Development, “Rising protocol complexity is hindering study performance, cost, and efficiency,” Impact Report, Volume 20, Number 4, (July/August 2018). See full resource: 

https://static1.squarespace.com/static/5a9eb0c8e2ccd1158288d8dc/t/5b4de76e352f53bd7a416e1b/1531832174796/julaug-summary.pdf

Holland, A., “The Centricity of Decentralizing Risk-Based Clinical Trials.” 

Volume 34, Issue 7, (August 2020). See full resource: 

https://acrpnet.org/2020/08/10/the-centricity-of-decentralizing-risk-based-clinical-trials/

Tenaerts, P. and Randall, P., “Overcoming Barriers in Conducting Decentralized Clinical Trials,” 

https://www.appliedclinicaltrialsonline.com/view/overcoming-barriers-conducting-decentralized-clinical-trials

Head of Site and Investigator Networks, Medable

Decentralized clinical trials (DCTs) have ignited clinical transformation while the COVID-19 pandemic has fueled their rapid expansion.

Five Tips to Help Research Sites Implement Decentralized Clinical Trials

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.

  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.

  Published data indicate that IRT for clinical supply management will increasingly play a major role in managing global trials.

  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.

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). 

Site assessment of sponsor and CRO performance

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: 					

Unexpected amount and arrival time of supplies

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. 

, PhD, is Senior Research Fellow, Tufts CSDD, email:  

, MBA, is Director of Sponsored Research Programs and Associate Professor, Tufts CSDD; 

 is Global Director, Strategic Marketing, Fisher Clinical Services.

To whom all correspondence should be addressed

1. Swaminath, G. "Juggling Clinical Trial Supplies." 

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." 

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." 

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." 

http://www.lifescienceleader.com/magazine/past-issues3/item/3841-streamlining-site-and-patient-management?list=n/

Pressure to shorten study start-up timelines puts clinical supply management in the crosshairs.

Clinical Supply Capabilities, Practices, and Perceptions Among Investigative Sites

	The role of clinical supply chain management is changing dramatically. While often managed after the clinical operational strategy has been established, clinical supply professionals are now playing a more active role in development and study planning, managing mission critical activities, forecasting, and mitigating operating risk. A number of factors have contributed to this role transformation. 

	The rising volume of clinical trial activity combined with the difficulty of recruiting patients in mature markets (e.g., the United States and Western Europe) has prompted sponsor companies to engage larger numbers of investigative sites worldwide. Clinical supply chain managers face operational complexities introduced by the globalization of clinical research including producing and distributing supplies to remote regions around the world under a wide range of regulatory requirements on time. In addition, pharmaceutical and biotech companies conducting trials have more service providers handling all aspects of clinical operations than in the past, presenting increased logistical challenges for clinical supply managers.

	Tighter drug development budgets have pushed clinical supply managers to seek more efficient and lower cost solutions. In addition, more complex protocols, including those for adaptive trials and targeted therapies, have made forecasting dosage and quantity of investigational product more difficult.

 The trend towards targeted products has made the drug itself more expensive to produce. As a way of addressing the limited availability and higher costs of biologics and comparators, clinical supply professionals have looked to more tightly manage quantities of investigational drug and minimize overages.

 Additionally, as the proportion of biologics in company pipelines has grown, more investigational drug products have required cold-chain storage throughout the clinical supply chain.

	There is more pressure to start-up and perform studies faster. The push to move quickly into clinical testing leads to less time for active pharmaceutical ingredient production and stability testing before the product must be sent to the investigative sites.

 Supply chain professionals must be informed of local import and export regulations in an increasing number of countries and must ensure that supplies arrive at each location on time, taking into account potential shipment delays.

 Finally, competitive trial enrollment affects forecasting; clinical supply professionals are less able to predict which sites will need study supplies at what time.

	As drugs are currently being shipped to many different global markets with the demands of time zones, various climates, and multiple carriers, there is a need for companies to adopt new strategies. It becomes critical to integrate an organization's supply chain into overall clinical strategy. While adoption of new forecasting tools and technology can assist with simulation or forecasting, many of these resources require both staff and resources to implement properly. As pharmaceutical and biotech companies are faced with reducing their operating costs, they are now less able to invest in the resources that would allow for effective implementation.

	In response to factors challenging their function, clinical supply professionals have implemented sophisticated forecasting methods

 to better predict when and where clinical supplies will be needed. Some clinical supply managers have been using just-in-time or on-demand packaging and labeling

 or regional depots to address changes in the clinical supply chain strategy or forecasting during a trial.

 Newer technology solutions including integrated systems for clinical supply management

 and interactive response technology (IRT)

 which includes interactive voice and web response services (IVRS/IWRS) are being utilized. Sponsor companies have also turned to outsourcing their clinical supply needs, beyond packaging and labeling, to contract service providers to leverage their expertise, experience, and scale efficiencies.

	In order to track this unfolding transformation and to project the future role of the clinical supply management function, the Tufts Center for the Study of Drug Development (CSDD) conducted a study to assess the global clinical supply chain market. The study was supported by an unrestricted grant from Fisher Clinical Services. The results of this study offer insights for sponsors and CROs looking to more effectively manage the clinical supply function.

	The Tufts CSDD study used a mixed methodology comprised of a survey and a roundtable discussion. This approach provided Tufts researchers with the opportunity to collect both quantitative and qualitative data about the current and future state of supply chain management. It also built on the survey results through information provided by senior managers in a broader discussion. An online survey was sent to senior-level clinical supply chain professionals and then a roundtable discussion was held with 12 industry professionals from nine pharmaceutical and biotech companies. Tufts CSDD also sent invitations to roundtable participants to complete the survey prior to the meeting. In the roundtable meeting, Tufts CSDD shared the survey data and facilitated a discussion around key topics to gain additional insight into the survey findings and current market trends.

	Tufts CSDD developed the online survey of multiple choice and free response questions for senior-level managers in collaboration with clinical supply experts from industry and provider organizations. The survey link was distributed to Tufts CSDD contacts and commercial mailing lists by e-mail during January and February 2011. Participants were assured that responses were anonymous and confidential and that responses would be reported only in aggregate form.

	The survey examined clinical supply professionals' experiences and perceptions about the global supply chain and explored current trends, strategies, and practices. Survey questions focused on the following key areas: background and experience of the clinical supply manager; roles and responsibilities; management challenges and strategy; communication; technology and use of resources; outsourcing approaches; global regulatory issues; metrics used to measure quality and success; and future outlook. The roundtable participants explored many of the topics covered in the survey but also discussed other critical areas within the global clinical supply chain.

	Tufts CSDD collected 20 completed surveys from respondent organizations across large- and mid-sized pharmaceutical and biotech companies. Respondents were an experienced group with a median of 20 years of experience in the industry and 3.5 years in their current position; 80% were either vice president or director level staff. Respondents were also asked to identify the top three therapeutic areas in which their company conducts trials. The primary areas were oncology (n=13); CNS or neuroscience (n=9); cardiovascular (n=8); and metabolics/endocrine (n=7).

Management function and organizational structure

	An overwhelming majority of survey respondents (80%) indicated that their companies had a centralized supply chain and the remainder reported it was decentralized. Respondents reported to various departments including R&D, global clinical operations, development manufacturing, global pharmaceutical sciences, and technical services. Participants within the roundtable discussion indicated that the supply chain organizational structure had become more complex. Some participants reported that their supply chain was divided into two separate functions: a supply chain function responsible for drug supply activities and a manufacturing function which oversees execution.

	A senior-level supply chain manager's primary responsibilities included forecasting; managing supplier relationships; and tracking supplier performance metrics. Managers reported they were also responsible for selection and assessment of suppliers; developing outsourcing strategy; developing contracts; and negotiating contracts (Table 1). The survey also focused on identifying tools used for evaluating the accuracy of forecasting. Given that accurate forecasting has become the foremost responsibility of clinical supply professionals, it was surprising that many respondents still forecast manually. Seven in 10 respondents reported using manual approaches (i.e., Excel spreadsheets or mathematical modeling); 75% used forecasting programs; while 55% reported using web-based approaches (Table 2).

	The most widely discussed technology in the roundtable meeting was IVRS/IWRS for managing global studies. A few group members indicated using IVRS/IWRS for 90% to 95% of their studies with a few companies having internal IRT systems and others outsourcing this activity. Many participants reported within their clinical supply function they have staff resources to run predictive algorithms in IVRS/IWRS. However, IRT also has limitations as it was traditionally used to support inventory management and randomization but now is being used for other functions beyond its original purpose (e.g, forecasting and estimating overage). Use of this technology may not represent the best strategy for optimizing supply chain management as other technologies are available which have been specifically designed for forecasting.

	In addition to the new challenges of traditional clinical supply tasks, roundtable participants related that supply management has evolved into a more demanding and complex role that includes a diverse range of responsibilities. The role requires increased cross-collaboration and cross-functional coordination with input from various departments including clinical, QA, finance, IT, regulatory, and site staff.

	In particular, as responsibilities of forecasting and risk management have moved to the forefront, clinical supply professionals viewed these tasks as requirements for study success. Survey respondents identified forecasting supplies as the most demanding resource requirement area. Roundtable members indicated that cost pressures have led to a decrease in study drug overproduction; therefore, accurate forecasting was essential to having the study drug available for patients.

	Roundtable participants identified sourcing comparator drugs as a critical component of their role, and the comparator could require as much consideration as an investigational drug. Managers encountered a number of challenges in sourcing a comparator drug for a clinical trial. One key challenge can be seen in managing costs; as with investigational drugs, fluctuation in the demand for comparators as trial recruitment varies impacts global sites and numbers of patients involved. The unpredictability of enrollment may cause managers to over-source comparators. Given that the cost of comparators is spiraling and the demand for studies using comparators increases with the need for proof of efficacy of new drug therapies, the costs can be prohibitive for companies.

	Clinical supply participants acknowledged other demands placed upon them when purchasing comparators; certain global markets require that local comparators be purchased and prices vary widely. There may also be import and export restrictions and different GDP/GMP requirements. Comparator drugs may need re-packaging or re-labeling, and there are often local regulations that must be met in completing these activities. Given the difficulties in comparator sourcing and the limited control the sponsor has over other companies' production and distribution, roundtable participants were interested in the establishment of a comparator sourcing coalition. They felt that a forum to discuss the availability of drugs and establishing cooperative strategies for providing them would reduce many of the difficulties in purchasing and distributing comparators.

	Regulatory compliance is also a key function of the clinical supply role. This role includes managing the required documentation and labeling requirements of different countries as well as their translation. These responsibilities require keeping-up-to-date with changing regulatory requirements. Approximately two-thirds of survey respondents indicated that their organization is responsible for keeping current on regulatory requirements while 11% reported that a provider is responsible. The remainder (22%) reported that regulatory activities may be handled by either their Â­company or the provider depending on the study. Â­Respondents indicated that they most frequently monitor the FDA, EMA, and Japanese regulatory agencies. Other agencies that respondents track are the State Food and Drug Administration in China and the Drug Controller General of India.

	Nearly 60% of managers who responded to the Tufts CSDD survey indicated that they outsourced individual services for each trial. More than half of survey respondents reported that kit destruction was their most frequently outsourced activity, closely followed by returns, and then distribution and cold chain logistics (Figure 1). Nearly two-thirds of respondents indicated that establishing regional hubs would facilitate management of their supply chain, and 60% reported using functional and tactical/study-specific approaches to outsourcing. Roundtable participants reported variation in the degree of supply chain outsourcing. Some outsourced one or more activities individually (e.g., manufacturing; distribution; and IRT), while few companies outsourced their entire supply chain. A major theme, however, was the belief that supply chain outsourcing will increase based on their company focus on cost containment which includes decreasing internal headcount while increasing the individual level of responsibility among current staff.

	Clinical supply professionals ranked their foremost management challenges as short lead times, operations-supply team communication, protocol readiness/accuracy, the need for better forecasting, and a lack of visibility of their supply chain (Table 3).

	Participants in the roundtable discussion indicated a key challenge was minimizing waste and planning for minimum overage across studies. Although many of the participants used manual approaches to forecasting, some use of more sophisticated methods, such as Monte Carlo simulation, have become part of risk-mitigation planning. These methods allow managers to simulate situations that may occur before a study is actually conducted and allow for quick adjustments to variation in supply operations.

	Survey respondents acknowledged the potential benefits of new technologies, but they reported that the barriers to implementing them included cost, both in funding and resources, the difficulty of integrating new and existing systems, and also the lack of standards between systems. One survey respondent noted that top barriers included "the ability to justify new systems and the resources needed to dedicate to implementation," while another cited hurdles of "costs and integration with legacy systems."

	Clinical supply professionals also perceived that communication channels within their organizations could be strengthened. They noted that supply chain communication with clinical teams and study investigators was exceptionally weak. Survey respondents felt that communication could be improved with organizational changes such as improving the structure or alignment between functions within their companies, and that some partnering has already taken place.

	In addition to internal communication efforts, roundtable participants believed that establishing strategic partnerships could improve sponsor-provider communication. Presently, roundtable group members acknowledged more partnering with their outsourcing providers, including CROs, distributors, and suppliers. Some in the group noted the lengthy process of building trust and fostering a strong working relationship, especially between supply and clinical experts result in better communication between the groups.

	According to respondents, the top factors that influence the success of clinical supply chain management were study start-up timelines, location of study sites, number of study subjects, and development timelines. Roundtable Â­participants indicated that shortened timelines, both in terms of lead times and turnaround time of supplies to global sites; required a flexible approach and readiness to support any last-minute changes.

	Survey respondents also indicated that the key factors impacting clinical supply chain strategy were the number of trials being conducted, location of trial sites and regulatory requirements. Growing globalization and the need to comply with increasing global and legal regulations add to the complexity of the supply chain. Roundtable participants reported that regulations in Brazil, France, and the Ukraine are particularly problematic. They noted that standardizing their internal processes to deal with country/regulatory issues could potentially be beneficial to their efficiency. Also, having staff in the field increased knowledge of local regulations of clinical supply imports and exports as well as drug labeling.

	Respondents' priorities for the future included forming provider partnerships, reducing operating costs, and investing in technology. Company strategies will include developing partnerships with internal and outside providers as well as promoting collaborative work among providers to maximize efficiency. Additionally, integrating clinical supply Â­management outsourcing into clinical operations, particularly when this involves use of multiple CROs, may ultimately drive more integration of clinical supply management outsourcing. As new challenges emerge and the clinical supply professionals' role evolves, companies are continuously exploring new supply chain solutions. At this point, however, these solutions are not yet fully integrated into their supply chain management strategies.

	Given that companies are faced with spending constraints, we will most likely see more of the clinical supply chain being outsourced through multiple partnerships with providers as companies seek ways to maximize efficiency. The demand for highly skilled clinical supply professionals will possibly also increase, given the larger number of global trials and the added complexity of trials. While the application of technology will help resolve some of these issues, additional expertise will be required on the user end to manage and implement this technology.

 The authors would like to thank Rachael Zuckerman for her contribution to this article.

 PhD, is Senior Project Manager, e-mail: 

 MBA, is Senior Research Fellow both at Tufts Center for the Study of Drug Development. 

 BA, is Global Director, Strategic Marketing at Fisher Clinical Services.

*To whom all correspondence should be addressed. 

	1. R.S. Kumar, "Clinical Trial Supply Chain Management," 

	2. B. Moe, "On-Demand: The Next Generation of Packaging and Labeling," 

	3. F. Lis, D. Gourley, P. Wilson, and M. Page. "Global Supply Chain Management," 

	4. R. S. Kumar, "Evolving Clinical Trials," 

	5. D. McEntegart, M. Lang, B. Byrom, S. Bacon, J. Star, N. Dowlman, and G. Nicholls, "Optimizing the Supply Chain Through Trial Simulation," 

	6. M. Dittmer and A. Lechler, "Eliminate the Disconnect in a Systems Approach," 

	7. D. Meyer, "Maximize Information Flow," 

From tactical to strategic: tracking the evolution of global clinical supply chain management.