Kenneth Getz is a senior research fellow at the Tufts Center for the Study of Drug Development.

Kenneth Getz

The remarkable speed in which sponsors have developed and delivered COVID-19 vaccines and treatments has intensified an already high interest among sponsor companies in compressing drug development cycle times. And there are numerous targeted opportunities in their sights—from protocol design and vendor and site identification to study start-up and patient enrollment; from clinical data management and study closeout through statistical analyses and dossier preparation.

Until recently, however, efforts to target and achieve speed and efficiency have focused on tasks and timelines within clinical phases. Now, more attention is being devoted to the breakdowns that occur between phases when clinical data and operations transition from one research phase to the next. These transitions—also referred to as “white space”—may be ideal targets for information technology, open collaboration, augmented analytics, and machine learning to accelerate program durations, improve performance, and lower costs.

Over the years many sponsor companies—some with assistance from consulting firms and contract research organization (CRO) partners—have measured the white space between their programs’ clinical phases. Regrettably, the results of, and insights from, these exercises have neither been shared publicly nor published.

Recently, my group at the Tufts Center for the Study of Drug Development (Tufts CSDD) was able to conduct a robust analysis based on all drugs and biologics approved between 2008 and 2018 (n=377). Although the transition time between Phase I and II could not be reliably measured due to wide variation in early-stage activity supporting development programs, we were able to measure transition times between the completion of Phase II and the start of Phase III pivotal trials. In our analysis, Tufts CSDD only looked at non-expedited review programs to remove the effects of an accelerated regulatory process.

Tufts CSDD found that for all non-expedited development programs approved between 2008 and 2018, 82% had between-phase transitions (white space) of 17 months on average; 18% had no white space as Phase II completion and Phase III pivotal trial timelines overlapped. Our study also found that white space durations have increased during the past decade. During 2008 to 2013, the mean white space duration was 12 months; between 2014 and 2018, the mean white space duration between Phase II and III pivotal trials nearly doubled to 21.6 months.

To supplement our data analysis, Tufts CSDD interviewed clinical operations, regulatory, and data management executives. The sponsors interviewed widely agree that white space inefficiencies have represented a persistent challenge for decades and that attempts to compress phase transition time have been elusive.

They point to four primary causes of between-phase inefficiencies:

The time-consuming back and forth with regulators and health authorities.

Mistakes sponsors make in gathering inappropriate and incomplete inputs into decision-making late in the process.

The failure to anticipate downstream needs (e.g., manufacturing of clinical trial supplies).

The inability to build the appropriate level of internal consensus and alignment around key decisions.

Most companies acknowledge that they expend substantial resources and time in administrative activity preparing, submitting, and sharing results with regulatory authorities. They also note the inefficient and time-intensive internal process, and post-regulatory meeting, of finalizing the Phase III pivotal trial protocol. One sponsor estimated that they spend on average four to five months of time on this back-and-forth alone.

White space durations are extended during protocol planning when external inputs—from scientific leaders, regulatory agencies, and health authorities—are insufficient, incomplete, and require second-guessing. Misunderstanding of global regulatory environments and the uncertainty around reconciling multiple and diverse scientific and regulatory inputs contribute significant time inefficiencies and delays.

Several executives interviewed believe that to mitigate risk, sponsor companies seek more-than-necessary input from, and spend too much time on relationships with, regulatory agencies during phase transitions.

Sponsor companies also suggest that whereas they generally know their program’s objectives extremely well, they fail to obtain the necessary inputs and insights from Phase II data to optimize critical Phase III decisions. Several sponsors note, for example, the critical and often inadequate role that Phase II data plays in informing primary Phase III endpoint(s), dose-finding, and dose-selection decisions. One executive observed that the failure to properly interrogate and leverage Phase II data is a common problem that ultimately forces sponsors to amend and expand later-stage clinical trial activity to make up for these shortcomings. She suggested that more flexible and adaptive designs may play an important role here.

Many of the executives interviewed suggest that despite the high volume of data collected during Phase II clinical trials, white space inefficiencies are partially caused by collecting the wrong—or an insufficient amount of the right—Phase II data.

Most sponsors note the opportunity to shorten white space by anticipating where problems will occur, developing contingency plans, and responding proactively. Doing so permits companies to make faster decisions and cues up organizational resources to handle situations as they unfold.

Several interviewees, for example, mention the importance of anticipating and coordinating ethics committees and boards of health dispersed widely around the globe. Some acknowledge the importance of planning the commercial formulation of the investigational drug or biologics before initiating later-stage pivotal trials. As one sponsor explained:

“It’s essential that large, treatment-testing studies utilize a commercial formulation of a drug so there’s no question about bioequivalence. But manufacturing that formulation—especially like the complex ones that are becoming more commonplace—can take months or even years to scale up.”

Given high growth in the volume of Phase II data collected, there is wide consensus among sponsor companies that data and analytics—enhanced by artificial intelligence (AI) and open collaboration models—can play a key role in accelerating white space timelines. Another recent Tufts CSDD study found that the typical Phase II protocol generates 2.2 million data points today, up from 378,000 data points 10 years ago. This is nearly a 500% increase and the highest area of growth in data volume per protocol per phase.

Several sponsors go even further and argue that machine learning and other AI-enhanced analytics, combined with information hubs and collaboration solutions, represent a clear and essential approach to best leverage protocol data volume and limited human capacity and competency. In this vein, several months ago, 10 major pharmaceutical companies announced that they had formed a new corporation—Accumulus Synergy—to support collaboration between industry and health authorities. The new non-profit entity will utilize a cloud-based platform to compress the white space caused by the back-and-forth between sponsors and regulatory agencies. The founding companies anticipate substantial acceleration through real-time collaboration, cross-agency harmonization, data exchange, and submission.

In the transition between development phases, there is no defined timeline in which key decisions have to be made. White space inefficiencies represent a unique opportunity for sponsors to accelerate development timelines because they are a function of administrative, project management, information processing and exchange. The efficiencies between phases may be easier to achieve as they rely far more heavily on internal team expertise, collaborative effectiveness, and their interaction and exchange with regulatory authorities. Within-phase efficiency gains rely heavily on improvements in relationships with a large and growing number of external service providers—a more complex, fragmented and difficult area from which to consistently glean speed improvements.

As we imagine opportunities and solutions that are now available to accelerate drug development timelines, the possibility of compressing white space may finally be within our grasp.

Articles

Compression between phases to accelerate cycle time.

Characterizing White Space in the Quest to Drive Development Speed

Throughout the pandemic, the global public has had a front-row seat in an emotional theater of drug development. Daily news updates and more in-depth profiles have covered scientific breakthroughs, new collaborations, commitments, clinical trial activity, and preliminary results from interim assessments. And, as a result, public awareness of the role and importance of the pharmaceutical industry has increased sharply and public perception has improved dramatically.

This is a unique moment and a rare opportunity for drug development stakeholders to hit the reset button and enter a higher level of partnership and engagement with the public and patient communities. But until now, the pharmaceutical industry has largely emphasized one side of the story. The focus-to-date has been inward—on the industry’s innovativeness, productivity, passion, and commitment.

With late-stage vaccinations in the process of receiving Emergency Use Authorizations (EUA), the clinical research community—in collaboration with public health officials and the clinical care community—needs to expand its focus outward to collectively engender trust and support for the great science that the world is witnessing.

In addition to conveying gratitude for study volunteers who participated in COVID-19 vaccine and treatment clinical trials, the clinical research enterprise must also demonstrate respect for the public and patients through complete transparency and disclosure, in plain language, of the results of its COVID-19 clinical trials; and it must provide consistent and easy-to-understand patient and public education focusing on the “last mile” between the availability of safe and effective new vaccines and the societal importance of, and obligation in, their uptake.

As early as this past April, Pew Research reported growing public support for the pharmaceutical industry. This could not have come any sooner. Only eight months earlier (September 2019), Pew Research reported that the pharmaceutical industry was the most poorly regarded of all industries, having finally received the lowest rating of all those evaluated. Many may recall a Pew Research study published several years ago showing that the pharmaceutical industry’s reputation had fallen sharply putting it on par with the oil and used car industries.

In July 2020, the Harris Poll conducted among several thousand Americans noted that 54% gave the pharmaceutical industry positive ratings. This was a remarkable 22 percentage point increase above the results that Harris had reported in February 2020, one month before widespread lockdowns went into effect. Harris noted in its report that pharmaceutical companies were “… the only industry to sustain reputation gains through the pandemic. While other industries—such as grocery, retail, technology, consumer products and financial services—also rose during the spring and summer, most spiked in May and have since flattened or dropped back to typical pre-COVID levels.”

And a global poll conducted by Caliber Research in September 2020 reported that public perceptions of the pharmaceutical industry had improved measurably around the world. The poll solicited responses from more than 13,000 people. Caliber noted that “COVID-19 is playing a very important role in reminding people of the [pharmaceutical industry’s] importance and relevance, especially in markets like the U.S. where the pandemic’s positive reputational impact has so far been the greatest.”

Between April and October 2020, news coverage of coronavirus drug development activity appeared several times per week. Beginning in early November, however, daily coverage became the norm as preliminary results of late-stage COVID-19 vaccine trials, funded by Operation Warp Speed, were publicized. Pfizer-BioNTech was the fist to announce in early November followed by Moderna in mid-November and AstraZeneca-Oxford University later in the month. In December, regulatory agencies including the FDA’s Center for Biologics Evaluation and Research (CBER) will begin making decisions with regards to EUAs. Through the Operation Warp Speed program, drug and biologic development will be more than 80% faster than the typical clinical duration for vaccines.

A number of nongovernmental committees and panels are providing input and expertise to inform emergency access and approval, as well as vaccine distribution and logistics decisions. These committees include the Vaccines and Related Biological Products Advisory Committee (VRBPAC), which provides input into EUAs and approvals of vaccines. The Center for Disease Control’s (CDC) Advisory Committee on Immunization Practices (ACIP) provides input into the distribution of vaccines and their use. In partnership with these committees, CBER and the CDC have far greater public transparency.

Collectively, these agencies and committees now face the difficult task of facilitating unprecedented development and commercialization speed while reassuring the public that no corners have been cut and that these treatments and vaccines are in the most competent and capable hands.

Operation Warp Speed leadership has yet to clearly indicate publicly how COVID-19 vaccines will be allocated. And although ACIP, the CDC, the National Academies, and outside consultants have all been meeting to discuss prioritization of COVID-19 vaccines when they are available, lack of clarity and simple messaging tailored to the lay community has contributed to speculation in the media and ultimately public confusion and concern. At the outset of the pandemic, public confusion and concern began mounting—and has not abated—with the poor availability and apparent mismanaged distribution of personal protective equipment and the antiviral medication remdesivir.

The majority of the public worldwide supports vaccines. But a vocal minority—very often without rational or scientific basis—is against vaccination. Concerns over a link between vaccines and autism, for example, persist despite scientific evidence to support it. Public confidence in vaccines varies by country and by communities within a given country.

The media tends to exacerbate the problem. They report adverse patient conditions and/or patient deaths associated with the time of a vaccination, but not the results of investigations into the cause of death. These investigations, completed long after misinformation has been in circulation, typically show that the condition and/or death was unrelated to the vaccine.

For COVID-19 vaccines to be widely embraced and to deliver on their promise, they must engender public confidence and trust. Clinical research and healthcare professionals must ensure that their messages about vaccines and their distribution are balanced and transparent in depicting risks, benefits, and uncertainties. Messages must also be customized to the community that they target. Plain, non-technical, tailored communications in the mass and social media will go far in helping to build this balance and transparency. Consistent and simple—but not oversimplified—communication is essential. Creative communications developed by a collective of major advertising agencies will be highly valuable input here.

Media briefings will also prove helpful as many reporters have little to no background in medical research and healthcare. Partnerships with patient advocacy groups will also help ensure that communications reach a broader community via sources that are perceived as trusted and credible.

Producing and distributing plain language summaries of COVID-19 vaccine clinical trial results will also play a major part in building public and patient trust. At this time, the pharmaceutical companies leading Operation Warp Speed late-stage vaccine trials have signaled their primary intent to publish the results of their clinical trials in medical journals and on the NIH ClinicalTrials.gov registry. But this is not enough. These channels are primarily geared toward the scientific and medical community. Plain language summaries should be disseminated—simultaneously with the publication of technical summaries—to patients who participated in the clinical trials through public-facing healthcare communication channels, patient advocacy groups, mass media outlets, and digital and social media.

Despite unprecedented investments in vaccine development and distribution, public confidence in COVID-19 vaccines is hopeful but tenuous. This is due in large part to historical context, the lack of clarity and transparency from government agencies and the clinical research and healthcare professional communities. It is also due to the spread of misinformation since the pandemic began.

Global vaccination programs that rid the world of COVID-19 will succeed only if there is widespread belief and trust that these vaccines are safe and effective, that policies for prioritizing and executing their distribution are equitable and rational, that every individual has an important part to play. Translating the scientific progress and promising new vaccines into successful vaccination programs will require overcoming the significant challenge of building public trust and confidence through frequent, comprehensive, consistent, customized, balanced, and straightforward communication and education.

MBA, Deputy Director and Research Professor, Tufts CSDD; Chairman of CISCRP. Reach Ken Getz via email at 

Battle for trust ensues as vaccines are set for approval.

Public Trust and the ‘Last Mile’ for COVID-19 Vaccines

Of the more than 1,600 active clinical trials of treatments and vaccines for SARS-CoV-2 (COVID-19), four vaccine trials are in late stage (Phase III) activity. These promising candidates have received funding through the Operation Warp Speed (OWS) program from the US federal government. The primary aim of OWS is to rapidly develop and distribute a sufficient amount of safe and effective vaccine doses to immunize the U.S. population against COVID-19.

A look at the placement and conduct of these late-stage clinical trials offers insight into site engagement practices necessitated by global public health urgency. What do these site engagement practices tell us about sponsor confidence in meeting extremely aggressive enrollment timelines and demanding trial execution requirements? Do these practices signal a shift in where sponsors can be expected to conduct clinical trials in the future?

This article summarizes the results of a study that we have performed to answer these questions. Our goal is to assess COVID-19 site placement practices and to compare them with historical practices.

Classifying Phase III COVID-19 vaccine trials site segments

For this assessment, we have included all locations where Phase III COVID-19 vaccine studies, under Operation Warp Speed, are actively enrolling patients as of October 8th. Sponsors who were engaged in studies fitting these criteria are Moderna, Inc., Janssen Pharmaceuticals (in partnership with the Biomedical Advanced Research and Development Authority or BARDA), Pfizer, Inc. (with BioNTech), and AstraZeneca (with Oxford University).

 to identify the investigative sites participating in each of these four active Phase III COVID-19 vaccine trials. Although investigative sites in these trials continue to change, this study examines all sites that were actively enrolling as of October 8th. Data from ClinicalTrials.gov was supplemented by press releases, news articles, and other publicly available information to segment investigative sites into five categories based on the following definitions:

Site Networks (SN): defined as a collective of independent sites that derive the majority of their income from clinical research grants.This includes dedicated independent sites that are permanently part of, or affiliated with, a network. Sites within this category are generally for-profit organizations;

Academic Medical Center (AMC): defined as any site which has a major affiliation with a teaching institution. This includes any site that is a member of the Association of American Medical Colleges as a Medical School Member or a Hospital/Health System Member. Sites within this category are generally not-for-profit organizations;

Health System: defined as any entity that is, or is affiliated with, a system that includes a hospital. Sites within this category are both for-profit and not-for-profit entities. Some for-profit health systems have established not-for-profit entities within themselves for the purpose of carrying out clinical research, a factor that makes this segment difficult to classify;

Independent Medical Practice (IMP): defined as any community-based, independent clinical care provider that is not part of a larger health system. Sites within this category are generally for-profit organizations;

Government Entity (GE): defined as any site that is funded and administered by the federal government. The two major types of government entities include Veterans Affairs organizations and Indian Health Service affiliates. Sites within this category are not-for-profit organizations.

Sites supporting AstraZeneca and Oxford University’s COVID-19 clinical trial were not named in ClinicalTrials.gov; in the US, only the zip code and city name were provided.To identify and classify these sites, we used not only press releases and local news articles, but also cross-referenced the AZ site locations with sites participating in the other three sponsors’ studies.

Overall, we found that approximately half (53%) of Operation Warp Speed (OWS) clinical trials are placed within site networks; one-third (34%) of clinical trials are placed within academic medical centers; 5% within health systems; and the remaining 8% are roughly evenly placed within government entities and independent medical practices (see Table 1 below).

With the exception of Janssen’s late stage COVID clinical trials, site networks and academic medical centers operating in the US were the dominant two settings. SNs and AMCs combined to account for almost 90% of all clinical trial settings for AZ, Pfizer and Moderna programs; these two segments together account for 75% of sites conducting the Janssen clinical trial. For-profit site networks were the largest category in every clinical trial except for those sponsored by AstraZeneca, where AMCs comprised the majority.

Site networks made up at least two-thirds of both Moderna and Pfizer’s study sites; whereas they only accounted for about 40% of sites in Janssen and AstraZeneca’s clinical trials. The similar site placement patterns observed in Moderna and Pfizer’s clinical trials may in part be due to their use of the same contract research organization (PPD).

Academic Medical Centers account for over half of AstraZeneca’s sites (52%), making them the only sponsors to have engaged more AMCs than SNs.

Janssen has almost five times as many government entities as the next closest sponsor with 10% of all clinical trials being placed within federally-funded institutions. This is in part due to Janssen and BARDA’s higher relative utilization of Veterans Affairs offices.

Table 2 below shows that Janssen’s COVID-19 clinical trial is the most evenly dispersed across for-profit and not-for-profit organizations. Moderna and Pfizer are the most heavily weighted toward for-profit investigative site settings (68-70%) vs. not-for-profit settings (24%-28%).

Comparing COVID-19 trial placement to past placement practice

The most striking observation in this study is the remarkable consistency of placement practices over time including those testing new treatments and vaccines for COVID-19. In 2013, a study from the Tufts Center for the Study of Drug Development (CSDD) noted that “53% of all global FDA-regulated clinical trials are now conducted by independent, community-based principal investigators”.

 This 53% share of the total site landscape is identical to the share captured by site networks in COVID-19 vaccine trials.

Academic medical centers have held on to a more modest share of industry-funded clinical trials. In a 2007 report, Tufts CSDD noted that “today, only one-third of all industry-funded clinical trials are placed within academic clinical trials offices”.

Our study found a similar percentage —34% — of late stage COVID-19 vaccine clinical trials are being conducted within academic settings.

Academic medical centers have not been alone in their inability to increase market share of industry-funded clinical trials. Government entities — such as Veterans Affairs offices — have captured an even smaller share of this market. This is due in part to the protracted contracting, negotiations, and bureaucracy that historically contribute to slower study start-up times there when compared to that of site networks and dedicated investigative sites.

 Academic medical centers have leveraged their experience, prestige, infrastructure, and patient volume to maintain their market share. The VA setting, on the other hand, has been a consistently less attractive place for industry-funded trials.

 During the pandemic, with increased interest in public-private collaboration, the VA setting for industry-funded clinical trials will likely receive greater visibility.

Comparing sponsors of late stage COVID trials, those companies most closely collaborating with government and non-profit partners (e.g., AstraZeneca and Janssen) have placed their clinical trials in a higher relative percentage of academic medical centers. In the case of AstraZeneca, this decision is consistent with the company’s historical site placement practice: In 2007 AstraZeneca’s R&D director Ellis Wilson remarked that, “by mitigating bottlenecks on the critical path, academic sites are becoming more attractive and may even start to account for a growing proportion of trial placements. The pendulum is swinging back in their direction. And pharmaceutical companies want to be their partner of choice".

In the past, sponsors have relied on independent, for-profit investigative sites when speed and efficiency are paramount. In today’s COVID-19 vaccine landscape, the same holds true. Moderna and Pfizer’s studies, with their heavy reliance on for-profit sites, are moving the fastest in the race to prove the safety and efficacy of their vaccines.

Given the consistency observed in investigative site placement practices, we can assume that there will be a similar consistency in sponsor experience with participant diversity and inclusion for their COVID-19 trials. We can expect to see the same levels of proportional representation by participant demographic subgroup: White and Asian participants will be overrepresented, and participants from minority communities — most notably those of Black and African descent — will be underrepresented. This is particularly concerning given the higher observed rate and severity of COVID-19 cases among minority communities. Indeed, a lack of diversity has already been documented in both the NIAID Adaptive Covid-19 Treatment Trial (ACTT-1) and the Gilead-funded remdesivir study.

It is interesting to note the very low percentage of investigative sites from health systems and independent medical centers participating in these late stage COVID-19 clinical trials. Although these segments offer access to a large volume of patients within clinical care settings, combined they account for less than 10% of total sites. Similar to pre-pandemic conditions, these entities have been less attractive settings when compared to site networks and academic medical centers that offer larger numbers and more dedicated personnel; higher levels of experience and competency; and substantially greater research infrastructure.

 Hospitals and independent medical centers were also the slowest to respond during the early stages of lockdowns throughout the US, and these sites were among the most likely to suspend their clinical trials at the outset of the pandemic.

Community hospitals often find themselves being passed over during site selection in favor of academic medical centers which boast experienced investigators and specialized researchers.

 This is another reason why new investigators and health systems are not participating in COVID-19 clinical trials: sponsors place a high value on prior experience rather than total potential for accessing and attracting a large and diverse patient population. This fact makes it difficult for new investigators and sites to get their foot in the door for new clinical trials, and nowhere is this trend reflected more than in this research. Sponsors and CROs are choosing to place their study sites within entities that have proven track records, and the result is that site networks and AMCs account for over 85% of late stage COVID-19 vaccine trial sites.

Some independent medical practices and health systems are turning to partnership as a way to win and participate in more trials. The integrated research organization (IRO) is an emerging model that is allowing multi-specialty practices and community health systems to be involved in clinical trials as a research care option for their patients. Privia Health, Tryon Medical Partners in Charlotte, North Carolina, and the AMC of Wake Forest University Health, for example, are benefitting through partnership with IRO Javara Research to participate in COVID-19 vaccine trials which other health systems in the same geographic areas in some cases have not managed to secure. We can expect to see these integrated research partnerships become more common as other health systems and medical practices recognize the high-profile COVID-19 studies that IRO partners have been able to win.

In the race against time, during a pandemic that has, to date, claimed nearly 250,000 lives, sponsors and CROs are placing their COVID-19 clinical trials in the same places that they have been doing so for decades. Site networks and academic medical centers continue to dominate- and the majority are based in the US. Independent medical practices, health systems, and government entities are playing a relatively small role in late stage COVID-19 clinical trials. Sponsor company site placement practices may likely contribute to participant disparities by race and ethnicity typically seen in pre-pandemic clinical trials unless remedial and innovative approaches are utilized.

https://www.appliedclinicaltrialsonline.com/view/principal-investigators-take-lead-fda-regulated-studies

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, Tufts Center for the Study of Drug Development

Comparing late-stage COVID-19 vaccine trials to historical practices.

Investigative Site Placement Practices to Support Operation Warp Speed

New drugs and biologics approved in 2018 signal an exceptional period of change and opportunity in global drug development. This past year, the FDA approved 59 novel small-molecule (NDAs) and large-molecule biologic (BLAs) therapies-the highest number in history (see chart below). 

	This is a remarkable achievement, particularly in light of the anemic number of annual approvals that we saw in the 2005 to 2010 period. At that time, several industry watchdogs and prognosticators cautioned that the industry had exhausted its ability to develop truly novel and innovative therapies. They could not have been more wrong.

	What is most notable about 2018’s approval volume is not only the scientific innovations that produced them, but also where they originated, how they were funded, and the operating models, services, and technology solutions that supported them throughout the R&D process.

	One revealing feature that sets the 2018 class of approvals apart is the fact that 73% were approved under “priority review” status, meaning they were recognized by the FDA as important, truly novel treatments warranting an accelerated regulatory process. They are therapies targeting medical conditions for which there is no available treatment on the market or they offer substantial improvement over current therapies, including a standard of care.

	One-third of all new approvals in 2018  are first-in-class offering a novel mechanism of action-a new way of treating a particular disease. This is another record achieved by last year’s approvals. They represent exciting, truly novel breakthrough therapies, including next-generation vaccines, new antibiotics for drug-resistant infections, combination therapies, nanomedicines, microbiome or bacteria-based treatments, and gene therapies. 

	Immunotherapies have been one of the leading headliners (e.g., checkpoint inhibitors, CAR-T therapies, and other adoptive cell transfer drugs) and they top the list of breakthrough therapies receiving approval.  The first immunotherapy was introduced less than a decade ago; there are now nearly 2,000 cancer immunotherapies in small and large animal studies and in human testing. And immunotherapies that have already been commercialized to treat one form of cancer are now pursuing and receiving regulatory approval to treat many other cancer-related diseases.

	In addition to novel therapies, the FDA also approved the use of a record number of already-marketed drugs to treat new disease conditions and to be offered in new formulations that are more effective, accessible, and/or convenient to patients.

	In addition to notable areas of scientific innovation, new 2018 drug and biologic approvals also reveal a major shift in the composition of the drug pipeline and in the types of companies sponsoring drug development activity. Historically, the majority of new drug approvals targeted increasingly crowded chronic diseases affecting large numbers of people. Nearly 60% of approved drugs today target rare diseases that represent very small markets relative to those for chronic disease-or blockbuster-therapies.

	More than one-quarter (27%) of all new approvals are precision medicines. They rely on biomarker and genetic data to identify a far more targeted patient subpopulation that has a much higher likelihood of responding to a new treatment safely and effectively. According to the Tufts Center for the Study of Drug Development (Tufts CSDD), half of all drugs in the overall R&D pipeline-and about 80% of all drugs in development for cancer-related diseases specifically-now rely on biomarker and genetic data to target therapeutic agents.

	And whereas new approvals were historically dominated by the largest, top 50 pharmaceutical and biotechnology companies, today the majority of approvals are for drugs in development programs sponsored by small companies-many that are funded by private equity and venture capital. Sixty-percent of new approvals were from sponsors submitting their very first application to the FDA. This, too, is a record achievement.

	Small companies have unique needs, including a heavy reliance on outsourcing to support discovery, preclinical, and development activity; a proclivity to seek more open collaboration and data sharing models; and far more limited resources.

	In 2018, approximately $150 billion was spent on global R&D activity. Tufts CSDD estimates that R&D spending has been rising 6% annually since 2000. Nearly nine out of 10 drugs entering clinical testing fail, with wide variation in failure rates across different disease conditions. Investigational cancer treatment failure rates are among the highest. Drug development processes are highly complex and inefficient, with durations that have shown little to no improvement in more than three decades. And, on average, the typical drug generates a relatively low and declining return on its development investment, given the high capitalized cost-now estimated at $2.6 billion-to successfully bring a single drug through FDA approval.

	To remain viable, drug developers must transform long-standing R&D operating processes and practices that are largely insular and sequential, supported by redundant resources and personnel and that underutilize key assets and expertise. The growing prominence of precision medicines and treatments for rare diseases and targeted patient subpopulations-all requiring more complex clinical trial designs and longer durations to identify and recruit patients-intensify the pressure on drug developers to accelerate this transformation.

	Another revealing quality of the graduating 2018 class of NDAs and BLAs is that some are part of an emerging new paradigm that holds promise in delivering better quality, speed, and efficiency at lower cost. According to the Economist Intelligence Unit (EIU), during the past five years, an estimated 3% to 5% of clinical trials were “patient centric,” in that they included patients in clinical trial planning and design and they were executed with approaches that supported greater participation convenience (e.g., use of mobile technologies, transportation assistance, home- and work-based participation). The EIU found that patient-centric clinical trials had Phase II and III enrollment rates that were 40% faster. They also noted that drugs approved with patient-centric clinical trials had higher success rates and a greater likelihood of receiving formulary approval by insurers. Although the numbers are small at this time, we anticipate having more data on approvals in the coming years to further demonstrate the impact of this new operating paradigm.

	A growing number of new approvals are also being developed in an environment that favors more open, precompetitive data and information-sharing. New approvals also favor increasing use of external collaborations and service providers that offer scientific and operating expertise and operating advantages, smarter use of resources, and greater leverage of data and analytics to inform, manage, correct, and predict.

	During the past several years, we have seen massive investments by traditional R&D players and new entrants, consortia, the capital markets, and the public sector in data and data management capabilities and technology solutions and applications.  There is an enormous appetite currently for more sophisticated analytics, including machine learning and natural language processing to analyze a much higher volume of data from diverse sources (including clinical data and real-world evidence such as electronic health and medical records); to prioritize and target resources; to identify and interpret data patterns; to assess and mitigate risk; to manage complex logistical and manufacturing processes; to benchmark practices and, increasingly, to predict scientific and operating outcomes and performance.

	Patients and patient advocacy groups are playing a growing role in helping to direct and even fund drug development programs, to define clinically meaningful outcomes, and to push the scientific community to provide higher levels of relevance, convenience, flexibility, and transparency. 

	We are getting closer to being able to aggregate and look at data across the entire R&D and commercialization continuum. Components of an historically fragmented and disaggregated system within drug development and within the broader healthcare arena are becoming increasingly connected and integrated to share and make better use of scientific and operating data to support open and collaborative learning-what the National Academy of Sciences calls a Learning Health System-where every response a patient has with a commercially-available or investigational therapy informs personalized treatment as well as public health outcomes. As integration unfolds, we expect clinical research and clinical care to converge to drive efficiency through the removal of intermediaries and redundant fixed infrastructure and labor-intensive activity. And we expect patients, payers, and providers to play active roles in the development of new treatments.

	We have a long way to go to realize the full promise of this new operating environment and to navigate critical issues like data ownership, data privacy, data compatibility, and the gleaning and refereeing of insights in the data. But, as we revel in 2018’s new drug and biologic approvals, we are already seeing truly novel scientific innovations generated by a changing community of sponsor companies piloting and operating under an evolving drug development paradigm.

	There are now more than 11,000 active molecules in the R&D pipeline-a 5-7% year-over-year rate of growth across the span of two decades-to address unmet medical needs and improve patients’ lives. This is indeed an unprecedented moment.

, MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both based in Boston, MA. email: 

Record numbers point to new R&D operating environment, driven by a changing community of sponsors.

Kenneth Getz

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