For years, Sara worked in a hospital, making care possible for others. Now, after being diagnosed with breast cancer, she was the one in need of care.
Since 2011, the approval of more than 100 immuno-oncology(I-O) products have radically changed the cancer treatment landscape and the clinical trial pipeline. Rapid development of promising I-O therapies represents the greatest opportunity for cancer patients, but future progress is severely threatened by persistent challenges in clinical research.
The Society for Immunotherapy of Cancer (SITC) convened thought leaders from the National Cancer Institute (NCI), the Food and Drug Administration (FDA), biopharmaceutical companies, contract research organizations, and other major oncology professional organizations to address these challenges through meaningful discussion at a virtual summit that was appropriately titled Crisis in Clinical Research.
I had the privilege of joining this distinguished group of thought leaders and participating in a panel discussion on how we can reduce the burden of scientific review. The discussion was thought-provoking and worth sharing. Parexel is boldly taking action to drive our industry forward so we can all bring the best science to market, as quickly as possible, to make a difference for patients.
The I-O pipeline is thriving, but our existing research infrastructure can’t support the current clinical trial activity. In her opening remarks, Mary Dean, Executive Director, SITC, shared bleak statistics to frame the scale of the biggest challenges. 95% of institutions self-reported suffering from staff shortages, while clinical trial accrual is down 20% from January 2020. Development costs continually escalate each year (now topping out around $2.6 billion), and cycle times extend (The last report by Tufts Center for the Study of Drug Development found an 8% increase measured by time in months for the clinical phase of development). Academic research centers may be the most impacted and beyond the tipping point, due to the cumulative effects of staff shortages, complex protocols, and heavy administrative burdens from inefficient operating procedures.
Four different panel discussions shared different organizational perspectives and solutions to improve clinical trial processes, with a focus on these topics:
panel 1 – Streamlining data entry and collection
panel 2- Reducing burden/maximizing efficiency across sites
panel 3 – Increasing efficiency in study activation and conduct
panel 4 – Changing the clinical trial business model
Recurring themes that spanned panel discussions and webinar presentations included:
While no industry has been spared from resourcing shortages over the past two years, the impact of The Great Resignation has been exacerbated by clinical research inefficiencies and a distressed infrastructure.
David Hong, MD described how research is practically inoperable at MD Anderson through the center’s inability to compete with CROs and sponsors for coordinator and other staff salaries. High turnover impacts training and disrupts studies.
A range of proposed solutions that arose in panel discussions included formal mentoring programs, career pathways, remote working and job realignment to make entry-level jobs more exciting and strengthen the connection to clinical research outcomes.
Using creative staffing solutions, several panelists suggested that CRO resources can help offset the labor needs at sites, particularly for start-up and data intensive tasks.
Consensus on the key drivers of delays and costs centered on contracting, training, manual data entry, query management and the abundance of sequential processes (especially in cases of upfront committee review) that extend activation timelines to unprecedented levels.
Start-up best practices include regulatory documentation repositories (collect only what’s unique to a specific trial for sites that are used routinely), limited qualification assessments (similar to regulatory documentation, only qualify what’s unique to the protocol for sites that are used routinely), implementation of parallel processes (scientific and ancillary reviews that take place at the same time as IRB review), and a closer look at Australia (where the Phase I start-up timeline is the fastest in the world). In short, “let’s get into the 21st century” advised David Feltquate, MD, PhD of Palleon Pharma.
On the execution side, many panelists urged broader of adoption of risk-based monitoring approaches to avoid the need for 100% data review and query resolution – a significant and avoidable contributor to cycle time delays.
Protocol amendments are a fact of life in the current clinical trial environment, but also create significant delays, along with great burdens to sites and patients. The scope of amendments has increased to the point where the scope of changes are literally new trials, added David Hong.
Representatives from academic sites lamented the extra burden that comes with exploratory endpoints, with one investigator claiming that 80% of study workflows are spent here. There’s no question exploratory endpoints advance science but bring a heavy cost to site and patient burden. In fact, protocol complexity has led many institutions to instill enrollment caps due to site staff limitations and the need to protect patient safety.
Standardization is needed on so many different levels to drive efficiency – from data entry forms to common language in clinical trial agreements around patient safety, and arguably most importantly - a comprehensive suite of global data standards that create commonality and interoperability in processes from data collection to regulatory submission.
Data standards, adoption of direct EHR-to-EDC and automation are fundamental to creating efficiencies as data volumes and the amount of data sources continue to rise. Breakout discussion agreed the labor-intensive adverse event reporting process represents the biggest opportunity for improvement through automation, and direct data exchange. However, a lack of data standards and acceptance of natural variability among attribution interpretation is preventing progress. Following Stephanie Terzulli, PhD’s (Memorial Sloan Kettering Cancer Center) comments on “standardization first, then technology will follow,” panelists emphasized the need for large organizations such as the NCI, and global CROs to drive efforts in standards, and move away from point-to-point technology solutions in IT infrastructure.
Mike Buckley, MS of Memorial Sloan Kettering Cancer Center encouraged the audience to adopt open-source data standards (such as HL7 Fast Healthcare Interoperability (FHIR®) standard) to promote collaboration, data sharing and reduce research duplication.
The use of Clinical Pipe (Electronic Health Records (EHR)-to-Electronic Data Capture (EDC) application) in the LLS Beat AML Master Clinical Trial was referenced as the new gold standard for reduced data errors and time required by site staff for manual data entry.
Among the multiple stakeholders and research partners required to conduct a clinical trial, there’s plenty of separation, division and antagonism of competing interests when different organizations are responsible for different components of trial management. “Territorialization” of processes across partners creates bottlenecks and unnecessary delays.
To monitor sites uniformly and move away from site-level adjustments, and avoid redundant organizational level processes that promote redundancy, “we have to move together. We all need to adopt risk-based approaches and the same technologies like Clinical Pipe” declared Dannelle Palmer of OncoBay. David Feltquate also advised incorporating feedback loops to better inform the key functions that come together in the research ecosystem.
Without centralization, a trial with 70 different sites is akin to deploying a trial 70 different times to support different workflows and SOPs.
85% of cancer patients live in the community setting, so much of the discussion focused on how to bring trials to patients, through partnerships with local hospitals and physician practices. At least one renowned oncologist declared that it’s impossible to bring a CAR-T trial to the patient, but we’re closer to this reality than most people realize. As an experienced clinical researcher, I know the most complex protocols can be conducted in community and regional hospitals, and supported by remote schedule of events with physician telehealth.
Diversity remains a challenge as most trials struggle to broaden eligibility and enroll traditionally underrepresented patient populations. Decentralized trials and expanded research in the community is a first step. To solve this challenge, we must create an environment that doesn’t just fix the problems at academic centers and traditional research sites, but allows for expanded participation from physicians who are new to research. This is a different model with a longer-term return on investment.
We need to engage caregivers at every step, and constantly assess to make improvements. “If it’s good for patients, then it’s good for business” was the rallying cry among session chairs.
Leonard Sacks of the FDA predicted the biggest near-term gains will come from more widespread adoption of platform trials, trial networks and from the integration of research at the point of care. Platform trials offer the greatest benefits to patients through their ability to accelerate trials, evaluate multiple treatments over the course of a trial, drop ineffective treatment and reduce the probability of receiving a placebo. Trial networks provide the efficiencies of familiarization and standardization within a group of providers specializing in a particular indication. Trial networks can easily centralize processes and performance measurements within specialty areas.
Other forward-looking suggestions came from John Powderly, MD, who pioneered the integration of clinical research and patient care model when he opened Carolina BioOncology Institute in 2005. He spoke about building a clinical trial infrastructure to help patients navigate treatment options while under the care of their own physician. Located in the tobacco belt of the Southeast, Carolina BioOncology Institute does not compete with large academic centers and teaching hospitals for clinical trial patients. This model is one that can be replicated in other community settings to attract more patients outside of metropolitan research hub commuting distances.
The Crisis in Clinical Research Virtual Summit was designed to spark national conversations about solutions to longstanding issues through the organization’s convening powers to lead change. While there are no easy answers or magic bullets, the biggest message of the event was a resounding call to action. Organizations ranging from NCI and SICT to global biopharmaceutical organizations and CROs like Parexel must demand and drive change.
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