TrialSite News celebrates its six-month birthday with the end of 2018.  We track, monitor and report on global clinical trials with an emphasis on the research site; their activities, breakthroughs and business dealings. Of course, with TrialWatch and PriceWatch we track the sponsor as well—instrumental commercial driver in the drug development ecosystem. 2018 was an important year for clinical research—a period of breakthroughs. We expect more of the same in 2019. Frankly, even with considerable industry insight and site and trial tracking algorithms, it is difficult to keep up with the tremendous pace of change, advances, and continuous innovation in the clinical trials space.

For example, research and development breakthroughs, therapeutic area and investigational treatment advancement, specialization and intricate division of labor, as well as infusion of innovative approaches and technologies occur on a near daily basis. Given our focus on trial site updates with select original content, we anticipate a fast and furious 2019. We will continue to track and report on select, meaningful events, activities, and results in the coming year.

Predicting the future is not our business, but we are certain that the number of clinical trials, and possibly approvals, will increase. Food and Drug Administration (FDA) approved drugs grew from 46 in 2017 to 59 in 2018. Exciting new treatments in nearly every therapeutic category are on the way. Risk and cost continue to rise as failure rates hover at 70 percent for Phase II trials and 50 percent for Phase III trials. As we move into 2019 the following themes will intensify:

  • Patient-Centricity manifesting in many forms (care happens where health happens and follows the patient)
  • Sponsor & Site continue to rediscover each other in old and new ways
  • Disruptive technologies (AI, Apps & wearables, big data, provider to sponsor technology standards, etc.)
  • A rediscovery of the critical value of professional competencies including a brand new accreditation standard from the Alliance of Clinical research Excellence and Safety
  • Intensified collaborative networking and deal making around targeted platforms and novel approaches
  • Commitment to Real-World Evidence and the ongoing fusion of interventional and observational data
  • Continued incremental embedding of clinical research into care settings bringing research to the patient
  • Dedication to market-driven, organizational responsiveness (control cost, increase value)
  • Ongoing sponsor “pivots” from blockbuster to precision-targeted, high-value platforms
  • Academic centers spin off more IP & commercialization efforts
  • Sponsor and CRO attempts to advanced optimal engagement with providers as well as integrated site networks

The TrialSite News team collectively has worked with clinical research sponsors, CROs, investigator sites, and vendors over the past two decades. This work has ranged from breakthrough regulatory submission models and technologies to implementation and utilization of sponsor to site data, and document exchange software to patient recruitment services imminently driving adoption of an exciting new research site accreditation standard with the Alliance for Clinical Research Excellence and Safety (ACRES). This comprehensive and systems-focused site accreditation and standard will raise the bar across research sites worldwide—a vital prerequisite in our opinion for across the globe site performance increases.

As the number of clinical trials worldwide grows, the complexity of the clinical trial sector expands in parallel. A siloed and piecemeal approach to quality, performance, and excellence will be challenged with ongoing initiatives from sponsor-specific initiatives such as the Lilly/PAREXEL China partnership to ongoing industry consortia, such as Transcelerate.  As mentioned, an entirely new clinical research site accreditation standard goes live in 2019. Numerous other innovative dynamics will emerge in 2019 based on many existing collaborations as well as those in the works. What follows are some end of the year observations with comments on trends forthcoming topics.

Clinical Trial Growth

As of December 2018, 292,915 studies are registered with Clinicaltrials.gov, 140,402 are “non-U.S. only” (48 percent); while U.S. only trials equaled 101,721 (35 percent). Over a decade ago, the U.S. was the predominant hub of clinical trials with Western Europe a solid second, but times have changed. Today the U.S. still leads with 117,343; Europe hosts 82,861 trials and China is rapidly growing with 31,576 trials and counting.

The below graph, provided by Clinicaltrials.gov depicts the tremendous registered clinical trials growth over the past 20 years.

Recruiting studies—those sponsors actively seeking patients—totals 49,263. Of all recruiting trials, 57 percent are non-U.S. only, 38 percent are U.S. only and 5 percent both U.S. and non-U.S. according to the U.S. government information site.

The following table provides a summary of trial type by numbers reported and results posted by Clinicaltrials.gov (as of December 20, 2018).

[table id=16 /]

Economic Drivers

Clinical trial stakes are paramount. Advancements in science and medicine that are successfully commercialized represents the highest priority around the globe. Demand generated by heretofore unprecedented demographic conditions drives intensifying market pressures. The invention, development, and commercialization of disease treatments and cures represents a compelling and powerful societal priority in most advanced and emerging economies. Those over 65 years of age worldwide will total more in populations than children under five for the first time in history. Falling fertility rates and dramatic increase in life expectancy pose new challenges and opportunity. New advanced and effective drugs generate enormous returns in the developed world. Targeted therapies and drugs for rare disease and specific cancers or autoimmune disorders are generating billions of dollars for successful sponsors. Monoclonal Antibody HUMIRA alone generates $18 billion annually. In the U.S., healthcare spend has passed 18 percent of total GDP or a staggering $3.5 trillion dollar annually with projections to $5.7 trillion by 2026. The global biopharmaceutical market has surpassed $1 trillion, and biopharmaceutical markets in the U.S. alone approach $500 billion. They are projected to grow to over one trillion in the 2020’s.

China’s economy has moved into the number two slot worldwide behind America. Its population currently is estimated to be approximately 1.4 billion people and its middle class—4 percent of the population in 2002–now represents 31 percent or 420 million people. Its health markets for this vast population are barely tapped by western biopharmaceutical companies. Already the second largest pharmaceutical market at $122 billion, its projections point to $175 billion by 2022. Biopharmaceutical research and development, and clinical trials are prized in China. Although still a centralized economy, it is infused with capitalistic characteristics and shrewd, driven business culture. With its nationalistic “Made in China 2025” focus, they have identified the pharmaceutical sector as a nexus of national security value—hence a focus on innovation and homegrown research and development.

Drug development is a risky, high-price tag business. Volatility certainly reigns—evidenced by one recent announcement that the government slashed patented western drugs by 70 percent. China’s pharmaceutical industry may go through Schumpeterian transformations over the next few decades as the creative destructive forces of global market economies will churn everywhere. Presently, a fragmented and scattered pharmaceutical sector counts to 6,000 domestic manufacturers and 14,000 distributors. With moves to strengthen intellectual property and compliance, China’s regulatory agency also embraced the industry’s International Conference on Harmonization (ICH). China’s economic status represents considerable risk as well. Productivity is on the decline and the state governing apparatus is pervasively, and some would argue perversely, intertwined with commerce in complex and myriad forms. It’s underlying economic system may in all actuality represent more risk than many may truly understand. Sun Tzu’s ancient Art of War represents necessary reading for advancing business there.

Europe represents 22 percent of total pharmaceutical market sales and will continue to play an instrumental role in clinical trials. The European Federation of Pharmaceutical Industries and Associations reports that over 1,900 EU companies operate to support the biopharmaceutical ecosystem there. European biopharma R&D employs nearly 700,000 and generates three to four times more employment. Often well-paying positions, clinical trials in Europe represents a considerable economic engine. Drug development represents one of the most lucrative, high-profit industries in the world. It will continue to grow and thrive, but there will be grand winners and losers, which means that all bets and strategic decisions are important.

Industry Clustering, Funding & Battles for Talent

The global life science industry has traditionally operated in geographic regions or “clusters.” This process has been accelerating in the past years with the move to precision and targeted treatment platforms; where there are geographic “winners and losers.” Common known clusters in the U.S. include:

  • S. Northeast/Tri-State Pharma Corridor
  • Boston/MA biotech
  • San Francisco Bay Area biotech
  • RTP Biotech & CROs
  • DC/Maryland biotech
  • San Diego biotech

As measured in biotech cluster venture financings for 2017, the ranking was as followed:

  1. Boston/NE
  2. San Francisco Bay Area
  3. San Diego
  4. China
  5. UK
  6. NY/PA/NJ

In the United States (and and elsewhere) clinical trials are highly clustered around urban areas with healthcare/social services facilities, which might explain why rural communities are underrepresented in clinical research. This reflects a global trend toward global urban economic regions of influence. Numerous other clusters exist, including rapid growth throughout China, traditional areas around the Rhine River (Germany and Switzerland) and the UK. There are also pockets in the Low Countries (Benelux) and Scandinavia, not to mention the group of sizeable companies in Japan and innovative groups in Korea. Regardless of part of world, large segments of the population that must have better access to general medical care and the market will increasingly respond with the inclusion of clinical research via “patient-centric” trials models. The future of clinical trials will include telehealth (and other technologies and re-engineered services) bundled together into patient-centric integrated and responsive clinical research programs. This “bundled” ecosystem will include a myriad of ventures and sponsors forming countless alliances and partnerships in a relentless effort for finding the winning model.

Life science clusters that are centers of clinical research attract billions of dollars, creating vibrant economic activity and reinforcing the broader economic “winner take all” world. By September 2018, U.S. healthcare ventures had raised $23.4 billion already surpassing 2017 numbers—pharma and biotech took in 62 percent of this total. These considerable sums of money flow into just a handful of primary metropolitan areas (clusters). Considerable challenges are faced with the continuous growth of such clusters. Cost of living dramatically rises in these zones; housing becomes difficult to nearly impossible to find; talent becomes scarcer while competition is fierce. Sponsor outsourcing to CROs only contributed more to growing strains. Industry has attempted to circumvent shortages (and cut costs while improving data quality) in operational circumstances, with schemes such as risk-based monitoring which gains momentum but with questionable results given the time, financial investment and business process re-engineering challenges.   Technology, smart collaborative management, mobilized and motivated talent and tailored strategies based on science, platform, etc. must be utilized to work around pervasive constraints and obstacles.

Pitchbook reported for 2018 life science ventures–predominantly biotech-related concerns–raise funds at a torrid pace and at a 10-year high. In addition to the funding of a healthy stream of new drug targets, investors will seek to make bets on disruptive forces, such as AI-driven solutions to drug discovery and clinical research.  All of this will continue to fold in 2019.

Is the Outsourcing Trend Tipping the Other Direction?

Contract Research Organizations (CROs) experienced explosive growth over the last decade as the global biopharmaceutical industry sought to drive efficiency and productivity while scaling across a global business landscape. These service providers offer end-to-end clinical offerings to pharmaceutical, biotechnology, and medical device companies as well as to non-profit, governmental, and academic centers. Core services include initial drug discovery, toxicology studies, bio-analytical services, study and development program design and consulting, not to mention regulatory affairs and a suite of post-marketing and drug surveillance services. Still a boutique industry in 2000, it crosses the very big $39 billion in 2018 and will grow past $50 billion by 2021.

Although the CRO sector is dominated by several “full -service” firms such as IQVIA, LabCorp, PAREXEL and PPD, it includes over 1,000 companies vying for business across the global landscape. The CRO market space combines centralization and consolidation with global fragmentation and cut-throat competition elements based on strategic or in some cases tactical advantage (e.g. location and access to investigator sites or patients; specialized knowledge or service capacity). The commercial sponsors (e.g. biopharma) outsourced so many programs, trials, and activities over the last decade that perhaps in the process changed forever how clinical research process works moving forward. Due to intense outsourcing and organizational changes over the past decade, some clinical sponsors may have lost important engagement ties with research sites. CROs in some cases have mad bold moves to directly buy integrated site networks directly. But trial sites represent “the last mile.” Sites struggle alone unless they are part of a bigger, well organized operation. Sponsors seek trial sites that perform and align with geographic and therapeutic-area strategies that guide site identification and recruitment. Over the past few years clinical sponsors have sought to reconnect with research sites as well as to engage patients directly in the quest for patient-centricity.

Rules and regulations required modernization due to rapid globalization and evolution to precision therapy models. For example, in 2016 the ICH adopted the revised E6 guideline “Integrated Addendum to Good Clinical Practice” (GCP), further harmonizing regulatory implementation. This addendum impacts the full clinical trial life cycle for the research value chain—whether outsourced or not—worldwide. Sponsors are now more mindful of how to proactively navigate and advance study design and risk management and study monitoring. As CROs represent the sponsor, they too will adjust and adapt to embrace quality, site engagement and risk-based management in response to the march of modernization which transformed the industry over the past 20 years. Consequently, regulators and industry (sponsor, CRO, research site) move toward an updated standardized framework to harmonization for improved quality and efficiency for purposes of global new drug application submissions.

CRO outsourcing will continue to grow but how the sponsors and outsourcing partners collaborate may morph over time. The CRO represents an inseparable part of the global clinical research value chain now. The broad array of CRO services, functional programs, mission-critical data management investments and rapidly evolving models penetrating and incorporating integrated site networks have gone beyond return to any past scenario. But the market will evolve and a shifting set of strategies, tactics, and initiatives emerge and unfold as sponsors compete in the race to discover better treatments and cures to satisfy market demand.

Reemergence of the Research Site

More than a decade ago the global biopharmaceutical company discovered the economic and practical benefits of outsourcing models. During the blockbuster wave this made sense. CRO outsourcing waves brought tremendous shift in the clinical trials value chain. Fast forward to the last handful of years, and there are full throttle moves into precision and personalized medicine; rapid-pace biological, molecular, and genomic innovation; patent cliffs everywhere; and the emergence of value-based care coupled with calls for patient engagement and patient-centric trials.

Provider care and clinical trials were separated by clear boundaries. Provider care exists to promote the health and well-being of patients while clinical trials are utilized by sponsors (and provider-initiated trials) to produce generalizable knowledge valuable for future patients. With the move toward value-based, patient-centered care we increasingly observe the embedding of clinical research into the care setting—in some cases bringing the research directly to patients at physician’s office. Consequently, evolving approaches and technology platforms will emerge to nurture, support and facilitate patient-centricity. The sponsor will be drawn into clinical research to care settings. We suspect that the care setting will morph to include social determinant of health forces-hence community organizations, social services departments and other agents may become more intertwined in clinical research.. The blurring of the provider and clinical research lines requires intelligent, ethical, legal, and compliant regulatory and operational models. This is beyond the scope of this article but of vital interest for the competitive sponsor, and industry health–over the next decade.

Recruiting and retaining investigator sites has always been difficult—patients even more so. Each sponsor has often operated on some form of an internal “80-20 rule” with research sites. Innovative technology platforms and shifting business and industry norms have made networking between sponsor to investigator (and site); sponsor to CRO and even sponsor to patient now more feasible—digital engagement was on everyone’s mind. The commercial sponsor culture begins to form great interest in the research site again. But there must be prerequisite scale, operational efficiency and advanced capability hence the ongoing influence of the CRO intermediary—particularly of interest in forming deep ties with integrated site networks. A revitalized and burgeoning interest in site connectivity, engagement, and collaboration, despite ongoing and parallel outsourcing of much of the operational activity to CROs. Consequently, industry groups such as Transcelerate and CTTI have announced initiatives to facilitate and support sponsor to site engagement.

Industry surveys touting investigator site rankings of sponsors attract newfound attention. Third-party organizations, such as publishers, survey over 1,300 investigative sites across multiple countries to rate and rank the best biopharmaceutical companies to work with. Winning sponsors, those deemed to be responsive by sites, are awarded kudos and recognition and hence build research brand for enabling:

  • Sites relations represents a fundamental anchor of the sponsor’s clinical operations strategy
  • Site input in trial design
  • Dedicating well-trained, attentive staff to support sites to be successful
  • Support ease of access to sponsor through multiple channels (investigator portals, email, phone, etc.)
  • Streamlined training services
  • Support for operational and regulatory excellence
  • Support sites to implement patient engagement services including innovative technology augmentation for patient convenience

Research sites primary focus needs to be personal patient care and developing the capacity and operational efficiency to consistently undertake clinical research. Whether a large academic research center, a mid-sized provider, specialized network of research sites or boutique research providers, we believe the underlying forces driving patient-centered care will remain the same for sites of quality. Physicians, nurses, research coordinators and research staff represent the face to the patient. In an increasingly complex clinical trials world, the fundamentals will remain the same—the participant must be valued. And depending on geography, culture or demographic one patient engagement strategy may or may not work. Sites and sponsors struggle to find sufficient numbers of patients in strategic therapeutic areas. Research site retention continues to represent a fundamental problem with the “one and done” investigator turn-over problem. Evidence uncovers that investigator sites statistically undertake one trial and then cease research participation. Why?  In many cases the strategic directives, systems and processes are not designed for research site success. Research sites struggle with the following:

  • Workload balance (balancing trial and medical care obligations to the patient)
  • Time and staff requirements (initiate and implement a trial; investigator and staff time)
  • Data and safety reporting
  • General dissatisfaction with financial-related issues (patient & contractual terms, etc.)
  • Operational support (compliance, standards and processes)

Overcoming these challenges requires innovative solutions that may or may not be solved directly by sponsors but rather by third-party entrepreneurial ventures combined with purpose-driven, sponsor, CRO and research site participation and collaboration. Research sites are in most cases part of provider organizations. These organizations are often part of health systems that have increasingly adopted pervasive electronic health records.  As medical care and research lines blur compelling new ways to leverage real-world data from various systems will take on paramount importance. Industry has formed groups to pilot this convergence and will continue to do so. New combinations of research business and data models will continue to emerge and evolve.

Research site shortages (again in many cases the result of “one in done”) will continue to represent a material impediment to research progress.  There is no one accurate count of total research sites worldwide. Estimates of total global clinical investigators vary by source.

IMS (now merged with Quintiles to form IQVIA) estimated 492,000 total investigators worldwide while others such as DrugDev (now part of IQVIA) at the time estimated 150,000. TrialSite News has developed what could be one of the most accurate investigator database worldwide and count the total closer to 400,000—but this factors in Chinese investigator rapid growth. The “one and done” problem persists till and when patient-centric, site-friendly models flourish—we are years from this but trends portend positive movement. Sponsors are experimenting either by sharing investigator database (Transcelerate model), enabling direct sponsor to site web-based federated platforms or capitalizing on aggregated provider data and emerging health record standards, to name a few examples of experimentation. A myriad of initiatives encourage broader and deeper investigator and patient recruitment opportunities. The year 2019 will see a continued push for competitive differentiation to operational efficiency. Sponsors will refine or reformulate and advance research site strategies based on shifting therapeutic program agendas and site and patient engagement needs.

Emergence of Patient-Centered Research Models

As drug development moves from blockbuster to precision-medicine models the underlying clinical trials systems, processes, and approaches will morph over time.  Growing pressures facing commercial sponsors from productivity declines and mounting generic and biosimilar competition to value-based pricing and research site and patient shortages to market demand and patient-centricity represent material tests to ongoing research success. The emergence of technology progress, coupled with an openness to change processes and approaches—will continue to disrupt the clinical research industry moving forward. Already sponsors collaborate with partners and research sites to experiment with new patient-centered models. Key enabling technologies include:

  • Social networks/social data
  • Big data/personalized data
  • Cloud computing and emergence of AI & machine learning
  • Mobile/GcP compliant Apps & Telehealth platforms

Follow the news over the last couple years and it is crammed with stories of sponsors leveraging some combination of these technologies with vendors, CROs, research sites, and novel approaches to design and execute patient-centric research models. TrialSite News maintains a robust research data base inclusive of patient-centric use case, sponsor, vendor, and underlying technologies involved. This is available for our readers upon request. We will also closely monitor patient-centric research models and how they evolve in 2019.

Conclusion

TrialSite News cannot help but think that Schumpeterian creative-destructive forces  impact the global clinical trials arena. Commercial sponsors are capitalizing on present strengths but making calculated bets for future success. They are in various stages of strategic shifts and pivots toward establishing leading precision targeted, high-value, new treatment platforms of the future, where medicine will be more directed, specific and targeted to the specific patient’s health needs. The sponsors further understand that mounting forces are changing the leverage dynamics toward the payer—and ultimately various markets’ demand for value. In the United States alone, over 120 million residents now are covered by some form of public payer coverage plan. Payers will increasingly seek to institutionalize value-based care throughout the system. Of course, in many other countries universal public payer is a way of life. This trend dovetails with other synergistic forces and pressures including patent cliffs, growing generic and biosimilar competition.  The sponsor, CRO, research site and patient must come together in evolving ways.

In many regards, quality, legal, and compliance will need to catch up with the countless pilots and initiatives around digital engagement already at play today. Sponsors may transform their CRO strategies—turning the outsourcing dial up in some areas while in other areas reestablishing direct connectivity with research sites and even patients. CROs are themselves change agents—working to build deep integrated site networks through partnership or acquisition. General economic conditions could change at any moment, making the sponsor organizations, CROs and research sites ever vigilant about organizational agility, flexibility and the ability to adjust and move while not incurring too much additional cost. Many sponsors have been shaking up their talent and managerial ranks, changing leadership and shuffling the cards for this very reason—to ensure realignment with priority; maintain agility and control costs. Sponsors will experiment and make significant to bold bets leveraging heretofore not available options to seize on opportunities to innovate and importantly, stake a claim in rich intellectual property fields ahead of their competitors. The visionary will be thinking years ahead.

Converging forces of payer-driven, value-based care, precision-medicine, health provider consolidation, competition, patient expectation for clinical research in the medical care setting, will shape the future drug development ecosystem including clinical trials. The mountain of opportunity one sees today may become a valley of death in five years. But business as usual today represents unacceptable risk in a few years. A vision to provide higher value, evidence-based treatments is followed by transformation of the drug development value chain including a reshaping of how clinical trials are conducted. We anticipate a highly dynamic environment will continue emerging in 2019, supporting considerable disruption and opportunity from executive level to the research site facilities and patients to participate in shaping a positive future.

Author

Daniel O’Connor

Mr. O’Connor has spent nearly 20 years providing technology and services to the clinical trials and health technology industry. An entrepreneur, he has been instrumental in building a few different ventures focusing on FDA 21 Part 11 enterprise document management, technology-enabled patient recruitment services, clinical document and safety data exchange, as well as population health and community care coordination for at-risk populations. Mr. O’Connor has built a comprehensive research site data base and intelligent clinical research site news curation engine with TrialSite News. Involved with delivery of innovative population health and community care coordination solutions for at risk patient populations, he is also spearheading a new research site accreditation standard with Alliance for Clinical Research Excellence and Safety. He earned his combined MA and JD from the University of California (Los Angeles and Hastings College of the Law) and undergraduate from San Francisco State University.

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