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Oncology Times – Clinical Trial Modifications to Expedite Drug Development

Oncology Times – Clinical Trial Modifications to Expedite Drug Development

The Friends of Cancer Research (FOCR) held its 15th annual meeting in Washington, DC, focusing on strategies to make cancer clinical trials simpler, less cumbersome, more diverse and accessible, and more patient-centered.

The conference featured keynote speakers, along with panelists who participated in writing three new white papers presented at the meeting. They includeed the following: Impact of the COVID-19 Pandemic Mitigation Strategies on Cancer Clinical Trials; Incorporating Patient-Reported Outcomes to Inform Dose Selection and Optimization; and Accelerating Investigation of New Therapies in Earlier Metastatic Treatment Settings.

“We’ve made these trials way too complicated,” said keynote speaker Richard Pazdur, MD, Director of the Oncology Center of Excellence (OCE) at the FDA. “I think we have to simplify trials.” He announced Project Pragmatica at the FOCR meeting; it is a new FDA project to encourage the development of simple trials with minimal eligibility criteria and the single endpoint of overall survival.

Agreeing on the need to simplify trials was keynote speaker Monica Bertagnolli, MD, Director of the National Cancer Institute (NCI), who said, “There is too much bureaucracy.” She emphasized that clinical trials have to serve the needs of patients and their caregivers in a timely manner, and that trial administrators have to be “smart and strategic and streamlined.”

Bertagnolli added, “We want to integrate clinical care and clinical research…We can merge those two worlds.” The key, she said, is trial design that is not an excessive burden and doesn’t complicate care delivery. She described this approach as a fit-for-purpose research design that is right for patient needs within a community infrastructure.

Changing Trial Protocol

A theme at the meeting was that the time has come for trial protocol simplification and modifications because of adjustments and flexibilities forced by the COVID-19 pandemic, which the first meeting panel explored.

“The time is right for change,” noted Gary Smith, MT, MGA, Chief of NCI’s Clinical Trials Monitoring Branch. COVID adjustments included remote consent, shipping investigational oral medications directly to patients, telehealth visits, and remote auditing. The FOCR and the American Society of Clinical Oncology partnered in a task force to evaluate how trial modifications adopted during the pandemic affected the conduct of clinical trials. The task force states in its white paper that “if the impact of these changes, especially on data quality, has been sufficiently minimal, then maintaining these beneficial flexibilities could lead to increased patient access to future clinical trials and could speed the conduct of trials, thus accelerating new treatment discovery.”

The task force is conducting its evaluation in two phases and will design and run a statistical analysis to compare pre-COVID with COVID-era changes to assess the impact on trials. If its findings indicate minimal adverse consequences to data quality, the task force will issue recommendations to retain the trial protocol changes going forward. Preliminary findings from Phase I indicate that the mitigation strategies adopted during the pandemic “did not greatly impact data integrity,” the task force has concluded. But it noted more detailed analysis is needed.

At the end of the day, will pharma and NCI accept these trial protocol modifications? asked task force co-leader Joseph Unger, PhD, MS, Associate Professor in the Cancer Prevention Program, Public Health Sciences Division, Fred Hutchinson Cancer Center. He said that, if the changes lead to more accessible and diverse trials, it is in their best interest to do so.

“That’s to everyone’s benefit,” Unger said, noting that trial sites were able to adapt very quickly to new mitigation strategies during the pandemic, and the hope is that the resulting benefits in terms of trial access, diversity, and retention outweigh any minimal differences in data quality.

COVID laid the groundwork for changes that could be adopted going forward, said Therica Miller, MBA, CCRP, Executive Director of Enterprise Clinical Research Operations at the Icahn School of Medicine, Mount Sinai. She cited care at home and establishing better partnerships with local clinics as additional benefits of trial modifications.

“We should be nimble” in making trial modifications according to patients’ needs, she said, and there may be a need for training programs that educate the workforce on these trial changes.

Patient-Reported Outcomes

The second panel at the FOCR meeting explored the value of incorporating data on patient-reported outcomes (PROs) early in the drug development process. The panel’s white paper states: “PROs should be included in early-phase clinical trials to better understand tolerability and to inform dose selection for future clinical trials and clinical use, as well as aiding with the selection for most appropriate PRO instruments for the late-phase trials with registration intent.” The paper states that PROs should be part of the process of establishing safety and efficacy, pharmacokinetics, and pharmacodynamics.

To encourage PRO reporting, patients need to be educated about a trial treatment so they can be more engaged and have more autonomy and be part of shared decision-making, said Kristin McJunkins, MEd, Director of Health Professions Advising & STEM Connect at Yale School of Medicine. “Having clear communication, both in-person and in writing, is really important,” she noted.

“We know that patients are happy to fill out questionnaires” on side effects and adverse reactions if they understand a study’s goals [and] why the study information is being collected, and [they] believe that they are helping other patients, said Devin Peipert, PhD, Assistant Professor of Medical Social Sciences at Northwestern University’s Feinberg School of Medicine. “We need to draw a straighter line between the PROs we use in clinical trials and the PROs we use in clinical practice,” added Peipert, who was recently appointed Chair of the Patient-Reported Outcomes Working Group for the ECOG-ACRIN Cancer Research Group.

Metastatic Disease Therapies

In presenting the third white paper, panelists emphasized the need to use investigational therapies in earlier metastatic settings in clinical trials. The paper notes that between January 2013 and July 2022, more than 61 percent of oncology approvals for novel molecular entities were for patients with metastatic disease who had received prior therapies. These patients may have had complications or residual side effects that could interfere with the evaluation of an investigational therapy.

“Conducting trials in earlier metastatic settings (included but not limited to first-line therapy) as a strategy to support initial approval…has the potential to maximize the benefit of innovative treatments and expand access to more patients with metastatic disease more quickly,” the paper stated.

The OCE at the FDA has launched Project FrontRunner to begin a discussion among stakeholders in the development of new cancer drugs on shifting the use of such therapies to an earlier timeline in the metastatic setting. The OCE intends to propose for use on a voluntary basis a framework for drug sponsors “that helps identify clinical development programs that may benefit more patients earlier in the course of their disease,” the white paper stated. It is envisioned that this earlier timeline strategy will “improve the data available at the time of approval to facilitate a benefit-risk assessment.” Pazdur noted that Project FrontRunner could be used for jump-starting pediatric trials.

“With the increase in the number of approved cancer treatments, there is a need to continually optimize treatment strategies for newly diagnosed patients with metastatic disease,” states FDA’s Project FrontRunner website. The program’s lead Lola Fashoyin-Aje, MD, MPH, Acting Associate Director at the OCE, said the initiative is meant to change culture. “We owe that to our patients,” she said.

From the standpoint of patients, Project FrontRunner can offer new, potentially effective treatments to a much larger patient population earlier, emphasized Anne Quinn Young, MPH, Chief Mission Officer at the Multiple Myeloma Research Foundation. “We really do appreciate this effort,” she said.

The white paper notes that, from the outset, there was recognition that the Project FrontRunner model “may not be appropriate for every clinical setting or investigational drug.” Thus the paper provides a proposed framework for considering whether this approach is suitable for a given investigational therapy in a given clinical trial.