Biopharmaceutical (biopharma) R&D stands at an inflection point, with the limiting factor for innovation no longer science or funding but the speed at which clinical trials can be completed because of a shortage of study participants and clinical site professionals such as principal investigators (PIs), site coordinators, and nurses.
In this environment, the most successful clinical trial sponsors (that is, biopharma manufacturers that are responsible for trial initiation, management, and financing) will be the biopharma companies that evolve their clinical trial delivery model to create a compelling value proposition for study participants and sites. This article explores the barriers to improving R&D productivity, including long clinical trial timelines and challenges to clinical trial recruitment, and actions sponsors can take to increase trial participants and improve the experience of clinical trial sites.
A golden era for biopharma innovation
Today, the biopharma industry has its largest and most diverse clinical pipeline in history, the culmination of decades of innovative research. The total number of distinct drugs in development grew from 3,200 in 2012 to 6,100 in 2022. Furthermore, this pipeline is increasingly diverse; 14 percent of assets use modalities validated over the past five years (predominantly various forms of cell and gene therapy).
The ability to deliver on this expansive pipeline has been enabled by government investment—including an estimated $18 billion made available for Operation Warp Speed and $48 billion invested each year by the National Institutes of Health alone—and private markets, with an estimated $146 billion in life sciences venture capital funding in the past three years.
Low R&D productivity driven by lengthy clinical trial timelines and increasing trial costs
Although the current climate for biopharma innovation is seemingly ideal, with 4,300 clinical trials starting in 2022 alone, R&D productivity remains stubbornly low. From 2012 to 2022, inflation-adjusted industry R&D spending increased 44 percent, from about $170 billion to $247 billion, (Exhibit 1). However, the number of US novel drug approvals remains flat at an average of 43 per year, meaning the attrition-adjusted cost to develop a single novel asset is now estimated to be as high as $2.8 billion.
Multiple factors underlie low R&D productivity, including consistently low success rates; only about 13 percent of assets that enter the Phase 1 trial stage go on to launch. In addition, development costs remain high (accounting for as much as 60 to 70 percent of total costs) and development cycles are long (taking an average of 12 years to develop a novel medicine). Furthermore, development timelines have extended. For example, according to McKinsey analysis, between the periods of 2011 to 2015 and 2016 to 2021, the average clinical trial lengthened from 41 to 44 months for Phase 3 trials and from 37 to 41 months for Phase 2 trials. Today, it is estimated that up to 80 percent of clinical trials fail to finish on time. At the same time, speed of clinical development is critical for biopharma companies and patients. For companies, the rise in “herding,” in which multiple companies focus on the same high-potential mechanisms of action (MoAs), increases the pressure to be first to market. Over the past 20 years, the top five most active MoAs in a given year saw an almost fivefold increase in the number of assets being developed, with the first product to market achieving outsize success. Furthermore, the passage of the US Inflation Reduction Act, which includes provisions to reduce drug prices, will influence which indications companies pursue and increase the importance of being first to market.
For patients with many indications, unmet need remains acute; more than 6,000 rare diseases have no known therapy, and numerous cancers (for example, pancreatic cancers, mesotheliomas, and brain cancers) have a five-year survival rate of less than 35 percent. For a pharma company with three to five investigational drugs entering first in human studies each year, a 12-month development acceleration applied across the portfolio can translate to more than $400 million in net present value for the sponsor and deliver incalculable benefits for patients and their families.
Challenges in recruitment for clinical trials
Although there are multiple levers to pull to improve R&D productivity, development acceleration is one R&D leaders can explore immediately and one that can have a greater impact on patients. In clinical trials, treatment durations are often fixed, and study start-up and close-out account for only a small portion of overall trial duration (with best-in-class timelines of about two months and one month, respectively).
Therefore, the biggest opportunity for sponsors to accelerate clinical trials is to increase the speed and improve the efficiency of clinical trial enrollment; however, participant recruitment is increasingly difficult. For example, the rate of clinical trial participants enrolled per site per month in oncology and nononcology Phase 3 trials declined by 14 percent and 54 percent, respectively, in the periods 2012 to 2014 and 2021 to 2023 (Exhibit 2).
Factors contributing to enrollment challenges exist on both the sponsor and site side of the equation. Sponsors require more participants than ever and are defining eligibility more specifically. Meanwhile, more complex protocols have increased the demands placed on sites at a time when clinical trial site staff turnover (PIs, clinical trial coordinators, and nurses) is at an all-time high, and physicians are less motivated to participate in clinical research because of changes to incentive models.
Increasing demand for trial participants
According to McKinsey analysis, over the past decade demand for trial participants has increased almost 10 percent as a result of more and larger trials; comparing 2019 to 2022, the total target enrollment of trials starting in those years grew 18 percent, from 2.2 million to 2.6 million (Exhibit 3).
Moreover, demand is spread unevenly, with disproportionately high trial volumes compared to overall incidence for some indications (for instance, multiple myeloma, cystic fibrosis, multiple sclerosis, non-Hodgkin lymphoma, and thalassemia).
Oncology poses a particular challenge; the number of required participants has increased from about 1.1 million in 2019 to about 1.3 million in 2022. (As a point of comparison, an estimated 1.9 million individuals were diagnosed with cancer in the United States in 2022.) Despite this considerable clinical research activity, only about 6 percent of US cancer patients are estimated to participate in a clinical trial. This participation rate is only 4 percent for patients receiving care at non–National Cancer Institute (NCI) centers compared to 19 percent at NCI centers. These trends in concentration of care are applicable across the world, including in other geographies where clinical trials are commonly run (for example, Eastern Europe and Western Europe).
The enrollment challenge is further exacerbated by an increased focus on precision medicine, whereby study groups are tightly defined with the goal of developing medicines that are highly effective in subsets of participants. For example, as of 2022, more than half of oncology trials are estimated to have a biomarker-defined target subpopulation. This is the case even with indications traditionally viewed as homogenous, such as lung cancer, which has more than ten subpopulations being investigated in clinical trials.
These industry-wide dynamics have made recruiting increasingly challenging. Whereas a site may have only a handful of (or zero) eligible participants for a given study, the time and financial burden of standing up a clinical trial at even a single site is undiminished for sponsor and site.
Rising burden on sites
As sponsors strive to generate more compelling data packages for regulators and internal translational research (to inform the next generation of drug discovery), the burden on sites has continued to rise. As a measure of trial complexity, the average number of Phase 2 and Phase 3 endpoints (specifically desired measurements of clinical trial outcomes) has increased from 17 in the period from 2013 to 2016 to about 21 in the period from 2017 to 2020, with many endpoints requiring specific equipment or training at the site level. Furthermore, although growing adoption of eClinical technologies theoretically reduces dependence on paper forms, sites typically need to implement or integrate five or more systems—including electronic data capture, electronic clinical outcome assessments, and electronic consent forms—before they can start to recruit study participants.
Challenging physician incentives
The United States continues to remain an important geography for clinical trials, with more than 83 percent of global Phase 3 industry-sponsored trials having at least one US site. While all physicians are determined to deliver the best possible care, current incentive models can make participation in clinical trials challenging. For example, in the United States, most physicians are assessed by Centers for Medicare and Medicaid Services (CMS) using a model based on Relative Value Units, which puts a low premium on clinical research activity. Furthermore, at a provider level, income from clinical research patient visits is often marginal in terms of overall revenue versus traditional standard-of-care visits.
Global turnover of healthcare staff (including PIs, trial coordinators, and nurses) is at an all-time high; an estimated 50 percent of clinical trial PIs participated in only one clinical trial between 1999 and 2015, a trend that predates the Great Resignation of the past few years. All of this contributes to the fact that more than two-thirds of global PIs remain “one and done” clinical trial investigators—a persistent trend over the past decade.
Five opportunities to accelerate recruitment to boost overall R&D productivity
Although addressing challenges of physician burnout and misaligned incentive models may be beyond the scope of most sponsors, the biopharma industry can take meaningful action to accelerate clinical trial recruitment. Sponsors can explore five areas in particular to answer this question: What would it take to make trial sizes 20 percent smaller than five years ago, cut recruitment timelines in half, and keep costs the same?
1. Apply innovative trial designs to reduce total required study participants
Minimizing the number of participants exposed to experimental therapies is a common goal of regulators and sponsors. Increased use of statistical innovation and predictive modeling—to optimize the number of clinical trial experimental groups and better estimate trial size to avoid statistical overpowering—can effectively help achieve this goal. Likewise, although not yet widespread, use of real-world evidence (such as borrowed algorithms) to supplement participants’ data has significant potential to reduce the number of required participants by enriching “control arms” (control patients) while not going as far as full synthetic controls (controls created using real-world data rather than actual enrollees). Additionally, sponsors continue to expand the use cases for innovative trial design beyond oncology. This includes umbrella studies to investigate multiple therapies in a single study (with the possibility to add arms as standard of care evolves), Bayesian clinical trials to reduce the number of clinical trial participants over the length of the study, and basket or multi-indication trials to more efficiently test novel therapies.
2. Differentiate with simpler, patient-centric protocols
The number of assessments (measures of results or conclusions) in trials has continued to grow due to new advancements in patient-reported outcomes, imaging, data collection, precision medicine, and digital technologies. The average number of assessments in Phase 2 and 3 studies increased from 17 in the period from 2013 to 2016 to 21 in the period from 2017 to 2020. This places a higher burden on patients, which negatively affects enrollment rates and engagement during the study. To address this, sponsors can conduct patient-burden protocol assessments to optimize study design and make informed choices. They could also use predictive models, past experience, and patient and investigator panels or surveys (for example, a pharma consortium’s participant questionnaire on patient satisfaction, experience, and areas for improvement during a clinical trial) to estimate the impact of additional assessments on the overall recruitment rate.
3. Take a data-and-analytics approach to site selection and management
Sponsors are increasingly using rich data sets of claims, electronic health records, and data from consortia to supplement their own historical data and build sophisticated, AI-driven models to inform country and site selection. These models, which predict the underlying drivers of enrollment for a given indication or therapeutic area, show much greater predictive power than modeling based on historical data alone. According to McKinsey analysis, these models typically can identify opportunities to accelerate recruitment by 15 to 20 percent by predicting sites that will recruit the fastest and reducing sites that won’t recruit. AI-driven models better account for factors such as site congestion (how many trials are currently occurring at a given site) and can expand the universe of available sites beyond where the sponsor has worked in the past. They can also create a flywheel effect by giving sponsors insights into how drivers of enrollment affect timelines (for example, how additional target endpoints will affect enrollment speed). Once a trial is under way, real-time performance tracking can identify when sites go dormant, and analytics algorithms can predict when enrollment will end, given the current trajectory and the potential impact of remedial actions.
4. Reimagine the point of delivery for clinical trials
Traditionally, treatment and monitoring visits for clinical trials have been conducted primarily at major hospitals or government health system hospitals, with sponsors favoring more experienced clinical trial sites. There is now an increasing emphasis on increasing convenience. This can include hybrid trial design to bring elements of the study closer to patients (for example, with home visits, telemedicine, pharmacy visits, and mobile units) and exploring new sites for clinical trials that may be more accessible to patients (including community or rural hospitals, where most patients are treated). When working with less experienced clinical trial sites, sponsors can expect to invest additional time and resources into site training and support, anticipate more questions during the start-up process, and potentially consider simplifying protocols, start-up processes, and site payments to reduce the burden. Exploring new trial sites (both within the United States and in new geographies) allows sponsors to reach pools of patients who might otherwise not have been able to participate in clinical research.
5. Reconsider site experience
Sponsors can take steps to improve the site experience and thereby position themselves as a “sponsor of choice.” McKinsey’s survey of clinical trial PIs has shown that trial enrollment and patient retention are both positively correlated with a high-quality investigator experience (Exhibit 4).
One key step in improving site experience is to simplify interactions with sponsors by designating one or a few points of contact to help ensure sites have an integrated experience and know whom to call when inevitable challenges arise. This point of contact can provide each site with bespoke support, which might include staff augmentation (or even chart review), support for physician referrals from nearby treatment locations, or partnership in trial marketing activities. Beyond the human connection, sponsors can use digital tools to provide sites with easy (and immediate) access to trial information, training material, and data on site performance.
Further, sponsors can reconsider key site facing processes (such as contracting, budgeting, or site initiation) to make these as frictionless as possible. Process simplification will depend on sponsors’ underlying processes but may include broader use of master service agreements, eliminating confidential disclosure agreements, simplifying budgeting processes, faster decisions on site selection, and greater use of virtual formats for site training.
Sponsors across the biopharma industry are collectively trying to accelerate clinical trial timelines by two to three years, reduce costs, and retain the highest-quality clinical trials with an enhanced PI and patient experience. Although pursuing the right science and advancing the best clinical assets are fundamental to R&D productivity, increasing patient enrollment and site engagement will ultimately be critical in achieving this ambition. No single change can address all the challenges, but a series of actions (in partnership with global sites) could materially reduce the collective international burden of clinical trials on the industry and patients.
