Craig Morgan

	Much has been said about the impact of the so-called Millennial generation-those born since 1980-on the workplace, its value system, and culture. By 2025, millennials will make up the majority of the workforce.

 In response, companies are clamoring to understand how to recruit, motivate, and retain these workers; according to one estimate, the HR consulting market alone is valued at $150 billion annually for the millennials segment.

 On the consumer side, millennials are poised to reshape the economy, as their collective experiences are changing the way products are bought and sold, forcing companies to examine how they do business. According to Goldman Sachs, millennials have an affinity for technology that is reshaping the retail market; with product information, reviews, and price comparisons in hand, millennials are turning to brands that can offer maximum convenience at the lowest cost.

 But what is the current and expected impact of this demographic on clinical research? And, perhaps more importantly, what should we be doing about it?

	Recently, many have successfully argued that it is important not to fall into the trap of over-generalizing millennials, and that the generational divide may be overstated and not so wide.

 But for clinical research, the cultural nuances and motivational drivers that make this demographic unique are the very elements that can make or break a clinical research study. As the impact of millennials on society increases, it is critical that we take a hard look at these differences and how they may impact stakeholders in the clinical research value chain, from sponsor companies and investigative sites to patients. Millennials are impacting clinical research as both increasing numbers within the patient pool and as key players in trial planning, administration, and investigation of studies. As with other sectors, millennials are making their mark on clinical research-a mark that many anticipate will change the industry as we know it.

Millennial Mindset: The Collaborative Clinician

, reported on the changing expectations of 

millennial physicians and how it is impacting patient care. The report explores the changing expectations of clinicians and how they prefer a collaborative approach to nearly all aspects of their practice, with a hyper focus on patient-centricity. For clinical trials, this means that millennial investigators are likely to be even more focused on what matters to patients, not just what is important to the sponsor organization. Forty-four percent of millennial doctors say they most value patient-centricity,

 and with patient-centricity at the forefront, the inherent complexity of clinical trials and the highly-regulated operating environment may be at odds with a patient first mindset. 

	Perhaps more importantly, the purpose-driven approach of this generation may offer important clues for how to recruit and retain clinical research participants in the future. Rather than just appealing to the individual benefits of participating in a study, sponsors may also benefit from appealing to the larger societal benefit. A global LinkedIn survey of over 26,000 millennials found that employees who feel like their work creates positive impact are more likely to be fulfilled and stay on the job longer.

	Ambitious and team-oriented, millennials prefer a tight-knit, cross-functional working approach that values social interaction.

 Having grown up in an environment that promotes teamwork, most millennials like working in groups and prefer a sense of unity over division and collaboration over competition. What might this mean for clinical research programs? Matthew Howes, executive vice president, Strategy & Growth for PALIO, wrote, “We should expect this generation to tear down walls between sponsors, vendors, and sites involved in clinical programs. Drug development of the future will see research sites and investigators brought in before protocols are developed to create a highly collaborative team environment.”

 Howes also asserts that with millennials, “The days of the cowboy clinician are fading with the sunset.” With it, more interdependent organizational models are emerging as millennial clinicians prefer working in research teams, hospitals, and other cohorts. Open to change and multitasking, they thrive in a dynamic, fast-paced environment. If harnessed effectively, this has the potential to improve the quality of protocols and streamline study execution by facilitating communication between sponsors and research staff. Taken to the other extreme, operating in a collaborative fashion may also carry the risk of slowing down decision-making as compared with more traditional top-down approaches.

Technology is integral, not just an enabler

	Millennials have impacted the evolution of technology and are used to instant and mobile communication. As a result, they are often skeptical of legacy entrenched systems that are inefficient, cumbersome, and lacking in transparent communication mechanisms. This has important implications for both research teams as well as patients. 

	Online patient communities such as PatientsLikeMe, as well as patient advocacy groups, offer hubs that sponsors are increasingly utilizing for patient recruitment purposes.

 and Yelp also post reviews of facilities that conduct clinical trials, allowing participants to be more informed about what to expect. 

	For clinical study teams, using technology to enable real-time collaboration across sites, sponsors, and contract research organizations (CROs) will only increase in importance as the millennial workforce grows. No longer willing to muddle through business processes with outdated platforms that rely on email communications and Excel, we can expect these workers to drive the industry further toward cloud-based technologies that promote real-time data access and collaborative workflows.  

	PricewaterhouseCoopers’ 14th Annual Global CEO Survey on global talent concluded that, “Irrespective of the long-term aims and ambitions of an individual company, the ability to attract and retain millennial talent will be a vital step to achieving it.”

 The same can be said for millennial patients (and to a lesser extent practitioners) in clinical research. It is only when we leverage new ways to engage with these purpose-driven patients that clinical research will evolve to the next level. Beyond patient engagement, sites, sponsors, and CROs will increasingly find that embracing technologies that promote cross-organizational collaboration in real-time is no longer optional but expected and necessary. 

	As digital pros at ease with social media, millennials will push study teams to find faster and more transparent ways of working with patients. Being a click or tap away from investigators, study staff, and patients will become the norm.

	1. Hyder, Shama. Study Reveals Surprising Facts About Millennials In The Workplace. Dec. 5, 2013. Available at:  

https://www.forbes.com/sites/shamahyder/2013/12/05/study-reveals-surprising-facts-about-millennials-in-the-workplace/#55c959ea12be

	2. Pfau, Bruce. What Do Millennials Really Want at Work? The Same Things the Rest of Us Do. 

https://hbr.org/2016/04/what-do-millennials-really-want-at-work

	3. Millennials: Coming of Age (Infographic). Accessed in April 2017 at: 

http://www.goldmansachs.com/our-thinking/pages/millennials/

	4. Vesty, Lauren. Millennials want purpose over paychecks. So why can’t we find it at work? 

https://www.theguardian.com/sustainable-business/2016/sep/14/millennials-work-purpose-linkedin-survey  

	5. Young, Charlie. 5 reasons you want millennials on your team. Available at: 

http://www.inman.com/2015/04/01/5-reasons-why-you-want-millennials-on-your-team/

	6. Howes, Matthew. Marginalization of millennials: Changing the clinical research landscape. CenterWatch. June 6, 2016. Available at: 

https://www.centerwatch.com/news-online/2016/06/06/hard-look-millennials-clinical-research/http://www.centerwatch.com/news-online/2016/06/06/hard-look-millennials-clinical-research/

	7. Banks, Linda. Using social media for clinical trial recruitment. 

https://pharmaphorum.com/views-and-analysis/using-social-media-for-clinical-trial-recruitment/  

	8. Growth reimagined: Prospects in emerging markets drive CEO confidence. PwC 14th Annual Global CEO Survey Report. Available at: 

https://www.pwc.com/gx/en/ceo-survey/pdf/14th-annual-global-ceo-survey.pdf 

Articles

The importance of examining this generation’s influence on the clinical trial value chain.

Millennials and their Impact on Clinical Research

	Over the past decade study startup, encompassing the activities associated with site identification, feasibility assessment, selection, and activation, has become a priority improvement area in the conduct of clinical trials

	Numerous factors can adversely impact study startup and its efficiency, in an industry plagued by rising development costs and increasing complexities. Complex protocols (leading to increased difficulty in finding patients who meet the inclusion/exclusion criteria)

, competition for sites, contract and budget negotiations

, regulatory changes and compliance for global studies

, and others, contribute to significant trial delays.

	It’s difficult to understand why there is so much variation and why there are so many inefficiencies and delays in study startup, this was the impetus behind this research. In a recently completed comprehensive study, The Start-up Time and Readiness Tracking (START) II, 2017 conducted by Tufts Center for the Study of Drug Development (CSDD) a significant difference in cycle times between new vs repeat sites and organizations (sponsors vs. contract research organizations (CRO)) was observed, however the percentage of sites never activated remained at 11%, a figure which has not changed substantially in over a decade

. The primary reason cited was budgeting and contracting problems, which has been a challenge identified in much published work

. Given the new technology solutions and practices, as well as, the increasing number of dedicated personnel managing site relationships it’s surprising and disappointing that the industry has not been about to make any headway in reducing the number of non-active, non-enrolling (NANE) sites.

	Given the plethora of new approaches and solutions now being deployed to improve the study startup process the Tufts CSDD research provides a baseline upon which future studies can be conducted to gauge progress. The study was funded by an unrestricted grant from goBalto, a technology solutions provider.

	The research examined a number of areas associated with study startup, including site identification, study feasibility and recruitment planning, criteria for site selection, staffing and resources, and study startup process improvements and opportunities.

	Differences between respondents working at CROs or sponsor companies according to whether they had a dedicated functional group to support site initiation activities or a localized group for these activities were examined. Both subgroups were examined across a number of measures, including cycle times for site identification, site selection, activation, and new and repeat sites. Additionally, the groups were assessed on satisfaction with current processes, percentage of sites selected that are never activated, level of technology investment, and perceived time savings due to technology.

	The respondents were comprised of 403 unique organizations and three-quarters were US-based. More than half of respondents worked in sponsor companies 53% or CROs 24%, with additional responses from sites, medical device companies, academic institutions.

	Site identification cycle time was defined as the time taken to identify appropriate investigative sites. Site selection cycle time was defined as the time from site identification to feasibility and receipt of site qualification information to final site selection decision. Study start-up (also referred to as site readiness and site activation) cycle time was measured as the time that all initial sites (i.e., non-backup or contingency sites) are activated or from the time the site selection decision is made until all sites are initiated and ready to enroll.

	The research found that cycle times were shorter for repeat sites than they were for new sites (Figure 1). Clinical operations teams typically rely on relationships with principal investigators built over time, and while the idea of using all repeat sites might seem like a logical and sure win way to speed study startup it is important to point out that research suggests for a typical multi-center study 30% of sites selected are new, of which 13% are completely new to clinical research. Institutional knowledge about sites is frequently dated and soiled within departments and may not be relevant to the therapeutic area under investigation, for example, rare and orphan disease trials often require companies to work with sites and investigators they have not interacted with in the past. Moreover, study teams are blinded to problems inherent with this approach-namely, it limits opportunities to engage with new sites that could be more effective than those familiar to the study team

	According to the research companies do not use one single source of data to identify sites; a mix of non-evidence-based approaches are used including personal networks, proprietary databases, and recommendations from study teams. Although clinical research professionals recently have been seeking access to accurate site-level performance metrics to aid investigative site identification. Use of site-level data to predict enrollment may be a more attractive option for increasing the pool of evidence available to support study startup decision making

	Figure 1. Estimated time (in weeks) it currently takes for (initiation activity).

	The greatest differences were observed between sponsor and CRO practices. Cycle times reported by CROs-in comparison with those reported by sponsors-were significantly shorter: site initiation cycle times were 5.6 weeks shorter (20%) for repeat sites and 11 weeks shorter (28%) for new sites (Figure 2). Overall, CROs report completing all site related activities 6-11 weeks faster than sponsors.

	Figure 2. Estimated CRO vs. sponsor cycle times

	The trend to outsource clinical trial operations to CROs is rooted in intense competition to improve productivity, driving sponsors to contain operational and infrastructure costs while completing projects better, faster, and more efficiently. These external service providers can achieve economies of scale unavailable to sponsors when they combine the volumes of multiple companies. Although the differences were not statistically significant, the research found that on average CROs dedicate 18 FTEs to site selection and 30 to activation, compared with an average of 12 and 13, respectively, for sponsors. CROs also report a lower level of site non-activation at 8.7%. One potential explanation for these results is that sponsors are relying more on CROs to manage site activity and CROs have been able to invest in more processes that would create efficiencies.

	Many of the improvement areas cited involve new technologies or changes in organizational processes and require a great investment of resources and time. Despite many attempts at improvement within organizations, gains in end-to-end cycle time have not been made.

	Practices intended to streamline study startup timelines include the use of technology investments to expedite the collection of clinical data and to help sponsors/CROs better monitor clinical trial performance. New technologies include predictive analytics and site forecasting for investigator identification, automated online site feasibility and site scoring system for faster turnaround time, and electronic document exchange repositories to speed up essential document collection

. Many sponsors and CROs have also implemented clinical trial management systems (CTMS), electronic cloud-based solutions and online clinical document exchange portals

. Shared investigator databases are another resource that organizations are utilizing.

	CRO and sponsor subgroups also differ in technology investment. On average, those working at CROs are investing about 10% more frequently in all areas of study initiation (identification, feasibility, selection, and study start-up (i.e., activation)) and more frequently invest moderately to heavily across all areas when compared with sponsors (Figure 3).

	Figure 3. The extent to which respondents are investing in additional technology to support (initiation activity).

	According to the research 80% of respondents who have invested in technology report time savings. Respondents reporting their technology is adequate have 30% shorter cycle times than those with inadequate technologies.

	On average organizations with dedicated functional groups report more than twice as much investment (49% vs. 22%) than those without a dedicated function. However, the research uncovered no evidence that a centralized site identification and selection function offers a significant speed advantage. The study did reveal, however, that there are a few differences when comparing cycle times for centralized and localized groups in working with both repeat and new sites. Organizations with localized groups are slightly faster for these activities (6.2% faster for repeat sites and 3% for new sites; 

	Organizations with centralized functional groups were reported to be slightly slower for site selection and study start-up for both repeat and new sites, but slightly faster for site identification (Repeat: 3.3 vs 3.7 weeks; New: 5.8 vs 7.1 weeks).

	Figure 4. Estimated centralized vs localized functional group cycle times, repeat sites.

	Figure 5. Estimated centralized vs localized functional group cycle times, new sites.

	Despite the gap in perceived technology investment, both groups had similar views on their technology capabilities. However, organizations with centralized functions were more than twice as likely to report large time savings due to technology (25.9% vs 12.8%) and 11% less likely to report no time savings from technology (16.7% vs 27.7%).

	On average 10% of respondents reported that they are very satisfied with their study startup processes, whereas 30-40% expressed dissatisfaction. Respondents reporting that they are very satisfied have cycle times 75.5% shorter than those reporting they are completely unsatisfied. Overall, nearly 40% of respondents of respondents are still using unsophisticated methods (e.g., excel, paper-based systems), which may contribute to lower satisfaction levels.

	Nevertheless, irrespective of organizational structure – expertise, experience and project management are equally important to both groups who face similar challenges and see the same opportunities for improvement.

	Respondents were largely aligned on what measures would be most effective at enhancing various study startup activities. The top cited option for enhancing site identification was “pooling and sharing data on site performance” with 88.9% of respondents indicating that it would enhance the process, for site selection the top cited option was to “get better evidence of a site’s true potential before selection” at 95.7%, and for activation process enhancements “central IRB/Ethics approval process” at 94.5%.

	This research presents new benchmark metrics on the comprehensive cycle time from site identification through site activation. Overall, the study startup process is still very long-5 to 6 months total duration on average-a figure that has not improved over the past decade.

	There is still a pervasive need for effective solutions across the industry despite many commercially available options (IMS Study and Site Optimizer, TransCelerate Shared Investigator Platform, and Investigator Databank) and internal solutions (e.g., internal investigator dashboards and site feasibility software)

	There is wide variation and inconsistency in study startup practices within and between sponsor companies

. Given the high cost, of initiating one site, which has been estimated at $20,000 to $30,000 plus another $1,500 per month to maintain site oversight, the prevalence of delays, and inefficiencies associated with study startup activity, sponsor and CROs are continually looking to improve their study startup cycle times.

	The full report, subsequent mini-reports, as well as the groundbreaking START research conducted in 2012 are available for download from the goBalto Resource Center (https://www.gobalto.com/resource-center).

 CTTI recommendations: efficient and effective clinical trial recruitment planning. https://www.ctti-clinicaltrials.org/projects/recruitment. Accessed November 29, 2017.

 Abbott, D, Califf, R, Morrison, B. Cycle time metrics for multisite clinical trials in the United States. Therapeutic Innovation & Regulatory Science. 2013;47:152–160. http://journals.sagepub.com/doi/abs/10.1177/2168479012464371

 Lamberti, M, Mathias, A, Myles, J, Howe, D, Getz, KA. Evaluating the impact of patient recruitment and retention practices. Therapeutic Innovation & Regulatory Science. 2012;46:573–580. http://journals.sagepub.com/doi/abs/10.1177/0092861512453040

 Peters S, Lowy P. Protocol amendments improve elements of clinical trial feasibility, but at high economic and cycle time cost. Press Release. Tufts Center for the Study of Drug Development. January 14, 2016. Available at: http://csdd.tufts.edu/news/complete_story/pr_ir_jan_feb_2016. Accessed February 20, 2017.

 Financial and operating benchmarks for investigative sites: 2016 CenterWatch-ACRP collaborative survey. https://www.acrpnet.org/resources/financial-operating-benchmarks-investigative-sites. Accessed August 24, 2017.

 Morgan, C Restricting Regulations. International Clinical Trials. 2017 http://www.samedanltd.com/magazine/13/issue/281/article/4693

 Miseta, M Is There A Solution to the CRA Shortage Problem? January 4, 2018. Clinical Leader https://www.clinicalleader.com/doc/is-there-a-solution-to-the-cra-shortage-problem-0001

 Morgan, C Removing the Blinders in Site Selection. Advance Healthcare Network. August 3, 2016 http://health-information.advanceweb.com/Features/Articles/Removing-the-Blinders-in-Site-Selection-2.aspx

 Sears, C, Cascade, E. Using public and private data for clinical operations. Appl Clin Trials. 2017;25:22–26.  http://www.appliedclinicaltrialsonline.com/using-public-and-private-data-clinops

 Sullivan, L. Defining “quality that matters” in clinical trial study start up activities. Monitor. 2011;25:22–26. 

 Lamberti, M, Brothers, C, Manak, D, Getz, KA. Benchmarking the study initiation process. Therapeutic Innovation & Regulatory Science. 2013;47:101–109. http://journals.sagepub.com/doi/10.1177/2168479012469947

 Morgan, C. The need for speed in clinical study start up. Clinical Leader. http://www.clinicalleader.com/doc/the-need-for-speed-in-study-startup-0001. Accessed August 27, 2017.

 Sears, C, Cascade, E. Using public and private data for clinical operations. Appl Clin Trials. 2017;25:22–26.

 Schimanksi, C, Kieronski, M. Streamline and improve study start-up. Appl Clin Trials. 2013;22:22–27. 

Numerous factors can adversely impact study startup and its efficiency, in an industry plagued by rising development costs and increasing complexities.

Molasses in Study Startup Efficiencies

	As the size, complexity, duration, cost, and globalization of clinical trials has grown over the last several decades, pharmaceutical and biotech companies have increasingly moved to outsource clinical activities to contract research organizations (CROs) to achieve a wide range of objectives. From achieving scale to accessing deep domain expertise in a given therapeutic area, CROs enable the flexibility that sponsors rely upon to deliver on increasingly demanding clinical research objectives and timelines. Large CROs are particularly well-suited to offer a one-stop shop of service offerings, in an attempt to expand both specialized capabilities and geographical reach to service the large Phase III global studies that have become commonplace. As a result, demand for CRO-conducted clinical trials is on the rise. In 2014, the global drug discovery outsourcing market was USD 14.9 billion and is expected to reach USD 25 billion by 2018, while the market for CRO-conducted clinical trials in 2014 was USD 23.1 billion and is expected to increase to USD 35.8 billion by 2020

	In response to intense competition and the need to offer a comprehensive portfolio of service offerings, the CRO industry has been undergoing significant consolidation in recent years. As such, a number of noteworthy mergers and acquisitions (M&As) have occurred recently:

		ICON acquired the Mapi Group, a health outcomes consultancy that specializes in late-phase research. The deal makes ICON the world’s second largest provider of late phase services.

		InVentiv Health and INC Research, merged to form the world’s second largest CRO with net revenues estimated at $3.2 billion.

		Quintiles merged with IMS Health to improve trial execution using real-world data, creating a company with market cap close to $18 billion.

		Quintiles also recently acquired DrugDev

, a technology company that has built an integrated suite of products to improve study startup activities, investigator payments and clinical operations.

		PPD, a global CRO, acquired Acurian to gain analytics-driven feasibility capabilities

, and recently acquired Evidera to expand their ability to conduct real-world-research.

		LabCorp acquired Covance for innovative risk-based patient monitoring tools to drive greater R&D productivity

 and recently announced a pending acquisition of the CRO Chiltern.

		SynteractHCR was acquired by Amulet Capital Partners.

		Parexel to be acquired by Pamplona Capital.

		PRA Health Sciences acquired Symphony Health Solutions in order to integrate healthcare data analytics with their clinical research services.

	In 2016 alone, $24 billion was spent on CRO M&As.

 Additionally, according to a 2017 report by Industry Standard Research (ISR), 60% of the market share in clinical trials is controlled by the top 9 CROs.

 With all the M&A activity happening in the CRO industry, does this trend have benefits that extend beyond just CROs into the pharmaceutical industry as a whole?

Benefits of CRO Consolidation for Sponsors

	Sponsors of large, global Phase III clinical trials want a competitive CRO market with plenty of quality CROs with global reach to choose from. These sponsors are also looking to form strategic partnerships and preferred provider arrangements with just a few large CROs, as this is far easier to manage.

	From a CRO perspective, winning one large $200-300 million Phase III study can be a huge benefit for the bottom line. As a result, there is pressure within the CRO industry for mergers as a way to quickly expand reach into places like the Middle East, North Africa, and parts of Asia other than China and India, in order to be attractive to large sponsors. Additionally, mergers can provide a quick way for CROs to expand their offerings beyond clinical services in order to attract business from all aspects of the drug development lifecycle.

	This M&A trend in the CRO industry provides a number of benefits for sponsors:

		Increased Scalability and Geographic Presence-As CROs expand their global reach through M&As, sponsors gain access to on-demand scalability for their clinical trials.

		Access to Additional Therapeutic Expertise and Service Capabilities-Many CRO mergers are driven by the desire to add additional therapeutic expertise and service capabilities to their offerings.

 As CROs expand their offerings, sponsors gain the ability to access more services from a single partner.

		Technology improvements-The right technologies, especially for site identification, selection, and startup activities, can make a big impact in shortening clinical timelines and the overall success of a clinical trial. By providing economies of scale, CRO M&As can allow CROs to invest in technologies that significantly improve operational efficiencies and data integrity in clinical trials.

		Cost Savings-CRO M&As allow sponsors to have access to “one-stop shopping” with their CRO partners. Sponsors save money through the operational efficiencies that needing fewer partners to run their global trials provides. Additionally, cost savings in the operations of the CRO itself due to economies of scale generated by being a larger enterprise be passed on to sponsors.

	While the CRO consolidation phenomenon is overall a positive trend for the pharmaceutical industry, there are some drawbacks to consider:

		Less Business for CRO Service Providers-Those companies that provide services to CROs (e.g., labs, patient recruitment companies, EDC and IRT vendors, etc.) will lose business as their client's merge.

		Disruptions to Clinical Trials-There really is never a good time to accomplish a merger. The last thing any sponsor wants to hear is that the CRO that is running their trial was just bought out or is undergoing a merger. Inevitably, in-progress clinical trials will be affected by CROs mergers-labs will likely be shut down in the middle of running the trial, requiring transfer of all data, samples, and knowledge to a different site.

		Less CROs for Sponsors to Choose From-Presently, there are still plenty of CROs for sponsors to consider when looking for a clinical trial partner. However, if this consolidation trend continues, we may eventually reach a tipping point where there are significantly fewer options available.

	While CRO consolidation may create some disruption in the short term, having less CROs available for sponsors may ultimately provide some benefit. With less options available, pharmaceutical companies and CROs may be forced to create more long-lasting, win-win partnerships. Collaborative partnerships will inevitably lead to more operational efficiencies in the drug development process, ultimately reducing the time required to get effective therapies to patients in need.

	Mergers in international enterprises are difficult to accomplish due to a myriad of issues (e.g., cultural differences, IT, tax considerations, etc.) That said, CRO mergers have the potential to be significantly beneficial to both sponsors and CROs, as well as the clinical trials industry as a whole. A fact that will continue to fuel the consolidation trend, with mergers of large CROs and smaller “boutique” CROs that have a specific therapeutic focus accounting for much of the activity. As aptly noted by Henry Levy in the Journal of Commercial Biotechnology, “What has been outsourcing on demand with many external service providers and redundant internal functions will become an integrated model of outsourcing with a limited number of strategic partners and long-term relationships

	But CRO consolidation comes with its share of new challenges for the industry. While the Tufts CSDD research indicates that technology adoption in the CRO industry is higher than with sponsors, CRO merger activity may actually hinder efforts to adopt new technologies due to organizational bureaucracy and enterprise integration challenges. Additionally, as CROs grow in size, their ability to maintain shorter cycle times as indicated in the Tufts CSDD research may be challenged due to lack of organizational agility. In the end, these are familiar operational challenges also faced by sponsor companies involved in M&A activities. When implemented effectively, CRO mergers can add significant value to the pharmaceutical product development lifecycle, and ultimately provide benefits to sponsors, CROs, and the patients who rely on their life-saving medicines.  

	Craig Morgan, Head of Marketing for goBalto

 “Changing R&D models in research-based pharmaceutical companies.”  J Transl Med. 2016; 14: 105.  Published online 2016 Apr 27. Available at:  

https://www.ncbi.nlm.nih.gov/pubmed/27118048

 PharmSource: Market Intelligence http://www.pharmsource.com/market/how-big-is-the-market-for/

 “ICON acquires Mapi Group,” BusinessWire, July 27, 2017. Available at: 

http://www.businesswire.com/news/home/20170727005556/en/ICON-Acquires-Mapi-Group

 “InVentiv Health, INC Research merger creates top 3 CRO,” BioPharmaDIVE, May 11, 2017. Jacob Bell. Available at: 

http://www.biopharmadive.com/news/inventiv-health-inc-merger-cro-manufacturing/442550/

 “Quintiles and IMS Health to Combine in ‘Merger of Equals’,” New York Times, May 3, 2016. Chad Bray. Available at: 

https://www.nytimes.com/2016/05/04/business/dealbook/quintiles-and-ims-health-to-combine-in-merger-of-equals.html

 “On Site: QuintilesIMS to Buy DrugDev,” Journal of Clinical Research Best Practices, Vol. 13, No. 7, July 2017. Available at: 

http://www.firstclinical.com/journal/2017/1707_OnSite81.pdf

 “PPD Acquires Acurian,” CenterWatch, August 27, 2013. Available at: 

https://www.centerwatch.com/news-online/2013/08/27/ppd-acquires-acurian/

 “Evidera to Join PPD, Creating the Global Leader in Real-World Research,” August 9

http://www.ppdi.com/News-And-Events/News/2016/Evidera-to-Join-PPD

 “LabCorp Completes Acquisition of Covance,” BusinessWire, February 19

http://www.businesswire.com/news/home/20150219005757/en/LabCorp-Completes-Acquisition-Covance

 “LabCorp just signed a billion-dollar deal for a healthcare company you've probably never heard of,” Business Insider, July 31

http://www.businessinsider.com/labcorp-acquires-chiltern-ma-in-contract-research-organizations-2017-7

 “Amulet Capital Partners, LP Announces Acquisition of SynteractHCR,” Business Wire, May 25, 2016. Available at: 

http://www.businesswire.com/news/home/20160525006356/en/Amulet-Capital-Partners-LP-Announces-Acquisition-SynteractHCR

 "PAREXEL International Enters Definitive Agreement to be Acquired by Pamplona Capital Management for $88.10 Per Share in Cash" Available at: 

https://www.parexel.com/company/news-events/press-releases/2017/parexel-international-enters-definitive-agreement-be-acquired-pamplona-capital-management-8810-share-cash

 “PRA Health Sciences to acquire Symphony Health Solutions,” CenterWatch, August 10

https://www.centerwatch.com/news-online/2017/08/10/pra-health-sciences-acquire-symphony-health-solutions/

 ISR Reports "2017 Edition of the CRO Market Size Projections: 2016-2021". Available at: 

https://www.isrreports.com/reports/2017-edition-of-the-cro-market-size-projections-2016-2021/

 “Merck Serono and Quintiles Announce Innovative Clinical Development Partnership,” BusinessWire, May 15

http://www.businesswire.com/news/home/20130515005861/en/Merck-Serono-Quintiles-Announce-Innovative-Clinical-Development

 Levy H. Integrated outsourcing transforms and increases R&D productivity. J Commer Biotechnol. 2013;19:49–54. doi: 10.5912/jcb635. Available at:  

http://commercialbiotechnology.com/index.php/jcb/article/view/635

As the size, complexity, duration, cost, and globalization of clinical trials has grown, pharmaceutical and biotech companies have moved to outsource clinical activities to CROs to achieve a wide range of objectives.

The Emergence of the Few: M&A in the CRO Industry

Upfront planning drives process improvements that boost quality of the eTMF and the study overall


	
	Benjamin Franklin is often credited with this wise warning: If you fail to plan, you are planning to fail. When it comes to study startup (SSU), and site activation in particular, these words ring true, especially as the clinical trials sector embraces planning as key to boosting study quality. With the availability of workflow-based SSU tools, proactive planning is within reach for stakeholders who view this function as pivotal to improving quality, as measured by audit-readiness and the likelihood of passing regulatory audits.
	
	Planning works by getting it right from the beginning-prior to study activation-and requires sponsors and CROs to identify what is needed to reduce risk by determining:

		Which sites/investigators/sub-investigators will be used

		Which artifacts need to be identified and structured

	Too often, these issues are not hammered out upfront, resulting in problems brewing, but not being identified until much later, after completed documents, artifacts, and metadata have already been released to the trial master file (TMF) or the eTMF. This poses a significant challenge, as measured by performance metrics that signal bottlenecks or breakdowns in study execution. For example, one performance metric that determines compliance suggests that regulatory quality assurance should occur four weeks after site activation.

 With this timeframe, problems such as missing or incomplete documents may go unnoticed until this late date, when the study is already well underway.
	
	A better strategy is to employ processes that take an upfront approach to preventing or mitigating problems associated with document completion. Research suggests that workflow solutions that start from the beginning of the clinical trial-with developing the study package, for example-facilitate a quality assurance process, which can build in risk avoidance 21 weeks earlier, well before study activation, allowing for insight much sooner.


	
	Using this workflow-based approach to SSU, study quality improves through greater adherence to timelines, and ultimately, by the percentage of artifacts flowing into the TMF that meet quality standards. This leads to an improvement in quality as the study activation portion of SSU generates an estimated 40% of all TMF artifacts in the study lifecycle.


	
	This article focuses on the growing link between planning and study quality, and how building it into SSU is fundamental to better study performance. And downstream, it enhances audit-readiness through greater accuracy of study documents and artifacts that are defined upfront and eventually flow into the eTMF.
	
	


	
	With research showing a continually stagnating timeframe for conducting clinical trials

 and a trend toward overhauling study performance

, quality improvement is moving center stage. As a starting point for this wide-ranging effort, quality has been defined as the ability to effectively and efficiently answer the key performance question(s) about the benefits and risks of a medical product or procedure while ensuring protection of human subjects.

	Numerous initiatives have emerged that emphasize quality in a big way. Each initiative serves a different purpose, but generally, they focus heavily on process improvement. One example is Metrics Champion Consortium (MCC), which has several existing and planned quality-oriented working groups. For instance, the Study Quality Trailblazer Team helps member organizations set an example for the rest of the industry by demonstrating that investing time and resources upfront can yield higher quality clinical study performance at a lower cost than fixing quality issues as a study unfolds.

 The Trailblazer Team recently released a white paper, which uses data from the Tufts Center for the Study of Drug Development (CSDD) to document that study quality is actually on the decline despite major advancements in technology over the past 20 years, often due to issues that are preventable.

 In addition, SSU has been cited as a major cause of long cycle times, which have stagnated for two decades.


	
	There is also the Clinical Trials Transformation Initiative (CTTI), which offers a Quality by Design (QbD) approach to clinical trials meant to identify errors that could jeopardize both patient safety and the ability to obtain reliable results and meaningful information about the trial. QbD defines quality in clinical trials as” the absence of errors that matter to decision making”.

 Landray et al report that applying QbD principles to clinical research involves stakeholders ensuring that a quality management plan has been developed alongside the protocol and prior to study activation.

 Moreover, critical indicators of trial quality should be assessed on an ongoing basis so corrective actions can be made early.
	
	

Complementing industry-wide initiatives, this accent on quality is being played out through the growing volume of research on the subject. The Tufts CSDD has reported site activation, in particular, as being sorely in need of improvement. They measured cycle times for various portions of SSU, and found that study activation, defined as the period of time from site initiation to first patient in, was deemed the most inefficient, with a coefficient of variation of 1.4

. When the coefficient of variation, a measure of spread or variability relative to the mean, exceeds 1.0, this indicates high variability.


	
	Wide variability in study activation could be due, at least in part, to a lack of standardized processes and little or no upfront planning. Research by Kleppinger and Ball highlight the need for a quality systems approach from the planning stages of a clinical trial.

 In particular, they state that standards have the most value and are most effective when implemented from the start. Moreover, they stress simplifying protocols and the number of desired outcomes, and suggest using validated instruments and definitions.
	
	As the industry turns its attention to better planning, regulatory bodies are spearheading efforts to ensure study quality, most notably via the November 2016 release of the first new Good Clinical Practice guideline (GCP) in twenty years.

 Put forth by the International Conference on Harmonization (ICH), the guideline, known as ICH-GCP E6(R2), includes a section dedicated to risk-based Quality Management, and states that the sponsor should implement a system to manage quality throughout all stages of the trial process, including the beginning. This section addresses topics such as Critical Process and Data Identification, followed by sub-sections that describe risk factors, namely risk identification, risk evaluation, risk control, and more.


	
	Across the industry, proactive planning for improved clinical trial quality is in the early stages, but with the availability of workflow-based tools for site selection and for guiding sponsors and CROs through SSU, process changes are starting to take root. 

	Through workflows, it is possible to launch the planning process by structuring artifacts specific to study activation. This facilitates the exchange of data among systems, such as electronic data capture tools, the clinical trial management system, and databases of principal investigators. With this capability, any and all needed documents can be defined. This is a major first step because on average, more than 400 artifacts within those documents can be structured using a workflow-based tool in accordance with a company’s standard operating procedures. From this group, an estimated 60 artifacts will ultimately flow into the TMF or eTMF, representing only the final ones, such as the completed clinical trial agreement (CTA), for example, which is composed of numerous sub-artifacts, including contract language, indemnity, confidentiality agreement, data privacy agreement, and budgets.
	
	Importantly, artifacts and documents can be created 17 weeks before site activation, making it possible to ensure the quality of these artifacts and associated metadata downstream, facilitating audit readiness at the site level (

 Making this process change can yield significant improvements to study execution. Specifically, the regulatory quality assurance process, which should occur four weeks after site activation, means that there is a 21 weeks lag between the development of the artifacts and documents and the regulatory quality assurance review. This can be eliminated with the use of upfront workflows, which provide stakeholders with insight months earlier.
	

	This approach allows stakeholders to implement the necessary process changes to become best-in-class performers as evidenced by better cycle times and substantial improvements to TMF quality, i.e., fewer errors, and data that are more easily retrievable. Too often, this is not happening today, as many companies still rely on homegrown systems that lack the capacity for upfront planning, as well as data exchange among e-solutions, and audit readiness.
	
	The TMF Performance Metrics Working Group of MCC is working to address these industry-wide shortfalls by creating output that will define basic performance metric sets followed by advanced sets. Going forward, the working group will provide its members with an array of performance-based features to gauge TMF quality. These include a TMF artifacts mapping tool, critical success factor and key performance questions, a TMF assessment schedule, and numerous other tools.

	Linda Sullivan, MCC Co-founder and President, remarks, “As organizations implement IT solutions to support various clinical trial processes, you would expect their TMFs to improve, but a significant amount of upfront planning is needed. We suggest organizations follow this easy to remember T-M-F pneumonic. T refers to taking the time to establish expectations about quality as well as what should be in the TMF. M refers to measuring the TMF by comparing portions of the TMF against the expectations throughout the study, and F refers to fixing problems quickly to make for a more efficient process.”
	 
	For a long time, Sullivan has been encouraging stakeholders to engage in risk assessment efforts from the start, instead of relegating it to a costly afterthought.

 Similarly, short videos about TMF quality, released by Pfizer, make this point.

 After interviews with regulators, internal stakeholders, and customers, the gathered intelligence was distilled down to three basic factors that define TMF quality, namely completeness; timeliness; and document quality, i.e. are all documents accurate, retrievable, and properly indexed. To achieve this level of quality on a massive scale, involving millions of documents, an all hands-on-board approach is needed from the beginning.


	
	Performance metrics are gaining traction because of their ability to track how a clinical trial is unfolding. But because performance metrics measure performance after the fact, they need to be part of a proactive planning strategy to maximize their benefit. This involves defining the documents and artifacts that will ultimately improve study quality. A significant part of this effort entails devising workflows that will keep the study on track and will also yield complete and accurate documents and artifacts that will eventually flow into the TMF.
	
	This focus on quality is a major predictor of study conduct as it is key to reducing risk and helps sites position themselves for audit readiness. While building in quality can result in TMF improvement, it houses completed documents, meaning it lacks the ability to track a study in real-time or near real-time. To address this issue, planning for quality needs to start at the beginning. And for SSU, a complex part of the clinical trial process that contains an estimated 40% of TMF artifacts, planning can make a strong impact on improving study quality.
	
	By 

		Metrics Champion Consortium. TMF Metric Initiative. 2017	

		Study startup around the world: A preliminary view from goBalto. ChromoReport. March 2017. Available at: 

https://www.gobalto.com/chromoreport-mar2017

		Trial Master File Reference Model. Available at: 

https://tmfrefmodel.com/2015/06/16/version-3-released/

		Getz K. Assessing and addressing site identification and activation inefficiencies. Tufts Center for the Study of Drug Development. March 2016.	

		Envisioning a transformed clinical trials enterprise in the United States: Establishing an agenda for 2020: Workshop Summary. Institute of Medicine. 2012. Available at: 

With the availability of workflow-based study start-up tools, proactive planning is within reach for stakeholders who view this function as pivotal to improving clinical trial quality.

Craig Morgan

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