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Break on Through (to the Other Side)

December 13, 2021

Joint Scientific and Education Program Symposia on Barriers to Successful Clinical Trials 

Natasha Szuber, MSc, MD

Dr. Natasha Szuber (@NatashaSzuber) is a hematologist-oncologist at Maisonneuve-Rosemont Hospital, University of Montreal in Quebec, Canada, specializing in myeloid disorders, particularly myeloproliferative neoplasms, and has further interests in clonal hematopoiesis and iron metabolism. She received her MSc at McGill University in Montreal, her MD at University of Montreal, and did her Advanced Hematology Myeloid Fellowship at Mayo Clinic in Rochester, Minnesota. Dr. Szuber remarked that she was “born, raised, and currently still residing in Montreal…It's a beautiful, vibrant city if you can look past the orange construction cones and innumerable potholes!” 

While Dr. Szuber is “relatively new” to the ASH family, she is looking forward to collaborating further in coming years and was just selected to participate in the ASH Clinical Research Training Institute this year. Fun fact: Dr. Szuber enjoyed a “past life as an aspiring rock n' roll star, recorded three albums, and toured with my band across Canada before finally surrendering to the call to med school.” 

 

Jim Morrison might have been onto something. With the incantation “we chased our pleasures here, dug our treasures there,” he may have put his finger on the exhilaration of successfully designing and completing a clinical trial (yeah, I’m pretty sure that’s what he was talking about). Morrison was also perhaps intentional in his frenetic scream-sing that, success notwithstanding, we should be wary of the “gate” being “straight, deep, and wide,” ultimately prognosticating that it might not be so easy to “break on through to the other side…” In the same way penning a hit song requires a thriving melody, anchoring riff, complexity of sound eliminating bias toward the same chords over and over, and knowing your audience, so does devising and carrying out a sound clinical trial, in its own way. The latter entails rigorous planning and foresight, meticulously defining research questions and objectives, minimizing variation, and carefully selecting target populations and controls. And just as bum notes, redundant refrains, and throwaway lyrics can degenerate into a cacophony of failure, potential barriers to clinical trials seem omnipresent, at every stage of the process, and with layered choruses of complexity. Fortunately, there are a group of experienced players calling the tune on study design strategy improvement at this year’s ASH annual meeting, and they haven’t missed a beat, addressing contemporary hurdles to trial operations and how to overcome them. The key tracks they’re spinning? Diversity, equity, and inclusion (DEI); modernizing eligibility criteria; synthetic control methodology; and drug development paths and regulatory requirements in the “accelerated approval” era, among many others.  

An exciting playlist opener was Friday’s Scientific Workshop “The Regulatory Drug Approval Process: Getting to the Finish Line,” which included an ensemble of presenters covering both international and U.S. regulatory perspectives, as well as industry and clinical outlooks. Dr. Richard F. Little shared the strategic vision of the National Cancer Institute, focusing on broadening patient access to and minimizing logistical complexity of clinical trials, while Dr. Yoji Sato provided an international perspective using the example of Japan’s regulatory system pertaining to cell therapies. Dr. Angelo de Claro highlighted the U.S. Food and Drug Administration’s (FDA’s) engagement in expanding eligibility criteria across cancer clinical trials and enrolling underrepresented demographics through the FDA Oncology Center of Excellence initiative. Finally, Dr. Malte Peters discussed, from the industry vantage point, the need for collaboration from industry, investigators, and regulators in order to “get to the finish line,” adding that we are already seeing the “direct effects of these actions and efforts,” in contemporary trials. The workshop is available on demand on the virtual platform in case you missed it. 

Next, we turned the amp up to 11 (Spinal Tap fans in the house?) with the “Joint Scientific and Education Program Symposia on Barriers to Successful Clinical Trial Design & Accrual” live Q&A, which took place Saturday (available on demand on the virtual meeting platform) and was Co-chaired by Drs. Alan E. Mast and Grzegorz S. Nowakowski. It featured a brilliant chorale of panelists using a decidedly complementary approach to explore barriers to clinical trial design and accrual through the lens of DEI. As we become increasingly aware of existing gaps from a DEI perspective — the patent underrepresentation of gender, racial, demographic, socioeconomic, and rare cancer subsets in modern clinical studies — the metronome ticks loudly on us to bridge them. The discussion first addressed common mistakes in trial design, including the need to advertently broaden eligibility criteria when called for. As Co-chair Dr. Mast commented, “The common theme is that we don’t have a representative population … of the people who are going to receive the drugs,” citing racially driven biases in multiple myeloma trials as an example. On the topic of socioeconomic barriers and racial bias, Dr. Nowakowski reminded us that this is “something we all need to address.” 

Drs. Barbara E. Bierer and Nadine Barrett shared an exchange on vulnerable populations in clinical trials and how “we’ve been unintentionally or intentionally excluding” certain marginalized populations under the pretext of “protection,” challenging paternalistic patterns. “We need to plan for inclusion from the beginning,” Dr Bierer affirmed, “and that shouldn’t take longer or be more expensive.” The keynote of “deliberateness” and engaging minority communities early on resonated loud and clear. Dr. Barrett chimed in, almost with a chuckle, on her realization that we don’t need to “jump over” these barriers, as she put it, and that we can in fact change them. Lastly, on the topic of artificial intelligence and use of algorithm techniques in recent studies, Dr. Barrett summarized, “There’s a great opportunity for us to really step back and think about how we ensure that the data we’re using and the algorithms we’re developing are … operating from an equity, anti-biased, anti-racist perspective, and … [having] the level of rigor we need to address disparities and inequity.” A triumphant cadenza to close the curtain on this revelatory opus. 

Finally, we drop the needle on the Spotlight Education session “Approved, But Should We Use It? – Are the New Trial Designs Effective?,” with live Q&A on Monday at 10:30 a.m. We caught up with session chair Dr. Jonathan W. Friedberg, who shared with us an exclusive compilation of the session’s greatest hits. “The changing landscape of regulatory requirements for FDA approval has allowed several new hematology drugs to be approved based upon single-arm trials,” he explained. “Using a case study of a recent approval in diffuse large B-cell lymphoma,” he stated, “this session will review implications of these new approval mechanisms from the statistical, regulatory, industry, and clinical standpoints.” This session also reviews “limitations of single-arm trials, and how best to interpret them for practice … [as well as] the concept of synthetic control arms in studies, and the advantages and disadvantages to this use of ‘real-world’ data.” The ultimate goal of this discussion? “To provide a blueprint for practicing physicians on the optimal strategies to incorporate these new agents into clinical practice,” resounded Dr. Friedberg. Panelist Dr. Sumithra Mandrekar will then take the lead on biostatistical pitfalls and novel trial designs. “We are at an exciting time in the advancement of treatment options for patients with cancer, and a lot of this rests on being able to think creatively to design trials with the right endpoints, right treatments, and include the right subset of patients that can provide a clinically meaningful and statistically rigorous answer relatively quickly,” Dr. Mandrekar expressed. She further encouraged us to lend an ear to her coverage of “the perspective of FDA accelerated approvals using a specific example, and the conditions surrounding such an approval in the design and choice of endpoints.” She compellingly summarized, “This session will discuss [the] importance of accelerated approvals to advance treatment options for patients while paying careful consideration to utility of single-arm trial designs, appropriateness of the historical/synthetic controls to understand the treatment effect, and use of intermediate endpoints...” 

As the mic finally drops on this trio of sessions, having provided the perfect score to unravelling the challenges to developing and conducting contemporary clinical trials, we find ourselves facing the real music, recognizing that in order to improve our performance — to “break on through” these barriers to the other side (or simply, to change them) — we will require mindfulness, acceptance, flexibility, unprecedented collaboration… along with long rehearsal hours, dedication, and of course, a great riff and a cool jam space. 

Dr. Szuber indicated no relevant conflicts of interest. 

(L to R) Drs. Grzegorz Nowakowski Alan E. Mast, and Mark Winderlich during Saturday’s Joint Symposia Live Q&A.
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