Editor’s Note: For more on the Pragmatica-Lung trial, read our Q&A with investigator Karen Reckamp, MD, MS.
The US Food and Drug Administration recently launched Project Pragmatica—an effort to allow for more pragmatic, patient-centric, and streamlined clinical trials. The first of these pragmatic trials, Pragmatica-Lung, is confirmatory phase III follow-up to the phase II Lung-MAP substudy in all instances S1800A.
The FDA’s Harpreet Singh, MD, who is director of the Division of Oncology 2, recently spoke with ILCN about the overall project and the Pragmatica-Lung trial, which has been designed to assess overall survival for ramucirumab plus pembrolizumab in patients with non-small cell lung cancer who were previously treated with immune checkpoint inhibitors and chemotherapy and had progressive disease at least 12 weeks after initiation of checkpoint inhibitor therapy.
ILCN: What was the impetus for Project Pragmatica?
Dr. Singh: Thanks so much for the question. FDA’s Oncology Center of Excellence (OCE) has led several efforts to instill efficiencies and more pragmatic elements into the clinical trial paradigm. Project Pragmatica is one of them, a concept born out of the data from Lung-MAP’s S1800A substudy, a small, randomized trial comparing pembrolizumab plus ramucirumab to docetaxel in patients with lung cancer who had progressed on immunotherapy.
While the overall survival results were compelling, the trial was small and not statistically powered for regulatory approval. I knew immediately when I saw these promising results in a patient population with such a high unmet need, that another, large, adequately powered randomized trial would be needed.
There was so much that we already knew, like the safety profiles of each agent used, the target patient population, etc., but we needed to answer one simple question: Does the combination of pembrolizumab and ramucirumab confer a survival benefit over docetaxel in patients with refractory NSCLC?
The concept has been floating around for many years; however, the convergence of OCE Director Richard Pazdur (FDA), National Cancer Institute Director Monica Bertagnolli, and FDA Commissioner Robert Califf—all of whom have led efforts to make clinical trials more patient-centric—really was a catalyst for this particular effort. The degree of coordination and communication required to literally break the mold of traditional clinical trials has been astounding, and it really did require high-level support from FDA, NCI, advocacy groups, and industry.
ILCN: With respect to safety, do we run the risk of relaxing eligibility criteria too much?
Dr. Singh: In this case, both drugs/biologics are known entities to the lung cancer community and practicing healthcare providers. It was important for us to allow the trial participants to reflect the greater patient community with lung cancer in terms of organ function, age, performance status, etc. The beauty of a pragmatic trial design is that patient care is built into routine clinical practice. By modernizing eligibility criteria, the population enrolled should be more diverse, and thus results should be more generalizable than your more traditional clinical trial. To be clear, we would not support such relaxed criteria in the face of a new biologic or molecular entity, or a new combination for which we had no existing safety data. But in the case of Pragmatica-Lung, healthcare providers can make informed choices about whether their patients are eligible for the trial.
ILCN: Regarding patients with performance status (PS) of 2 to 3, should they be studied in parallel phase II trials? Or do you think it’s warranted statistically to include these individuals in the primary endpoint? Might inferior outcomes in PS 2 to PS 3 patients potentially sabotage otherwise positive trials?
Dr. Singh: Again, thanks for the question! We believe that investigators and sponsors should make every effort to enroll a representative population of patients with PS 2 or 3 in their randomized trials. To facilitate this, flexible trial designs must be considered. One option could be to include an open-label safety study that can enroll and analyze patients with PS 2 or 3 separately in a parallel arm of a trial. We have talked about this concept in our Guidance to Industry on Inclusion of Older Adults in Cancer Clinical Trials. In some cases, this arm could still be enrolling at the time the trial is submitted to the FDA for registrational intent. This is a reasonable approach for drugs/biologics or combinations for which we have less experience.
I do think however, that where feasible, patients with PS 2 and 3 should be enrolled in the pivotal trial and analyzed as part of the intention-to-treat population, as part of the overall survival primary endpoint. Again, the goal of a pragmatic trial is to really streamline and simplify the research process. We discussed variations in statistical design and analysis for this trial, and ultimately the sample size did need to be increased from the original proposal to allow for more “noise” or heterogeneity in the patient population, clinical care patterns, etc.
I served on the ASCO-FDA-Friends of Cancer Research working group on performance status eligibility, and we published on this concept of risk in Clinical Cancer Research. Broadening eligibility criteria has the potential to increase the number of eligible patients and in turn shorten accrual time. This may also increase patient diversity and allow for results that are more broadly interpretable. Can a healthcare provider look at the trial participants and then look at the patient in front of them and be able to make a reasonable assessment based on the data in hand? The manuscript walks through some simulations on trial outcomes based on enrollment of patients with PS 2 and 3. It’s definitely worth a read!
ILCN: By eliminating the 3- to 5-year exclusion for prior malignancy, to what extent will protocol accrual be enhanced? What kind of language should be used instead? Would “no other invasive malignancy requiring ‘active therapy’” do the trick?
Dr. Singh: Another ASCO-FDA-Friends of Cancer Research working group addressed the issue of prior or concurrent malignancies and FDA published guidance on this topic to industry. I won’t get into the specifics of the wording, as we left that to the investigators who wrote the protocol, but the concept here is that patients with prior or concurrent malignancies whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational drug should generally be eligible for enrollment in clinical trials.
ILCN: What incentives are there to eliminate excessive case report forms and ceaseless data queries? How much money and labor will this save?
Dr. Singh: For the FDA, the benefits are as I noted above, to broaden eligibility criteria, shorten accrual time, and increase patient diversity to achieve results that are more broadly representative. I can’t speak to economic impacts for investigators and their institutions. That’s something that the clinical trials groups, the NCI, and the institutions involved may want to study if more pragmatic trials are launched in the future.
ILCN: External third-party clinical research organizations (CROs) might have incentives to push back on pragmatic trials since they profit from data inquiries and external audits. Have these companies registered objections? Will pragmatic trials reduce their influence?
Dr. Singh: I have not publicly nor privately heard of any objections from external CROs, but I think it is important to remember that not every trial is suitable for a pragmatic approach. So most trials, particularly for the novel therapies, will require detailed data entry.
I have heard that there are technical challenges with streamlined data capture using data systems that are not streamlined. So, the technology we have in place for clinical trial data capture, packaging, and submission require a great deal of information to be entered to close out tasks, and bypassing this to fulfill our pragmatic dreams has proven difficult.
Every step along the way has been a learning experience for all the collaborators involved. We have the support of NCI, SWOG, our FDA Commissioner, investigators, industry, and most importantly we are keeping patients at the center of it all.
