Executive Summary
Enrolling patients with stable brain metastases, HIV-positive status and other traditionally excluded groups could give sponsors a marketing edge, but trials should be designed to examine drug effects on such populations separately from the more traditional study population, stakeholders said.
Broadening the eligibility criteria for cancer clinical trials could enable sponsors to pursue novel labeling claims that help differentiate their products on the market.
However, sponsors must take care in how they design studies to incorporate populations that traditionally have been excluded from cancer trials, a multi-stakeholder working group concluded.
Trials should be able to examine a drug’s effects on the more traditional study population separate from that of those previously excluded populations who are at potentially higher risk of adverse events, panelists said.
“Overly restrictive eligibility criteria can impair clinical trial accrual and the applicability of trial results to heterogeneous ‘real-world’ patients who ultimately may receive the drug in the postmarket setting.” – FOCR draft issue brief
At the Friends of Cancer Research (FOCR) annual meeting last month, working groups comprising representatives from government, industry, the research community and patient advocates discussed proposals to expand and modernize clinical trial eligibility that, they hope, will trigger a culture change in how oncology trials are conducted.
Although restricting trial eligibility to a homogenous patient group improves the ability to detect a treatment effect, the primary purpose of eligibility criteria is to protect the safety of patients who are thought to be at increased risk of experiencing a treatment-related adverse event, a draft issue brief for the FOCR meeting states.
“However, excessive or overly restrictive eligibility criteria can impair clinical trial accrual and the applicability of trial results to heterogeneous ‘real-world’ patients who ultimately may receive the drug in the postmarket setting,” the brief states. “It also delays access to investigational agents for patients who may in fact stand to benefit.
Outdated Protocols Still In Use
Calls to move away from the traditionally strict limits on eligibility criteria for cancer trials have grown louder in recent years, particularly as the field has shifted from development of cytotoxic chemotherapies in favor of targeted agents and immunotherapies.
At the FOCR meeting in 2015, FDA Office of Hematology and Oncology Products Director Richard Pazdur cited the need to take a “much harder look” at the anticipated real-world experience of a drug through expanded trial eligibility criteria. (Also see “FDA’s Pazdur To Patient Advocates: Focus On Issues That ‘Drive The Show'” – Pink Sheet, 17 Nov, 2015.) The implementation plan for the Obama Administration’s Cancer Moonshot initiative also includes modernizing clinical trial eligibility criteria.
Common exclusion/inclusion criteria have developed over time and primarily through experience with cytotoxic chemotherapeutics. “Many of these are grandfathered from prior trial protocols, with little consideration as to whether they are truly appropriate for the specific clinical question being asked,” the issue brief states.
“Given the increase in complexity of cancer treatment, and the advent of novel therapeutic modalities, many have called for simplified, rational eligibility criteria,” the brief sates. “Newer, molecularly targeted agents generally do not have the same safety profiles as chemotherapies and often require additional biomarker-driven patient selection parameters that may severely limit the number of patients eligible for a trial; therefore, identifying opportunities to safely broaden eligibility has been recognized as a priority.”
Speaking about the need to look at enrollment criteria with a new mindset, oncologist Edward Kim, Carolinas HealthCare System, said: “We have to challenge ourselves to get rid of these assumptions and past practices. We all are comfortable in how we’ve been doing things in the last 10, 15, 20 years, and culture change has to start someplace.”
Building on an initiative launched by FOCR, FDA and the American Society of Clinical Oncology, working groups developed consensus-driven recommendations on when it is scientifically and clinically appropriate to expand eligibility criteria with respect to four patient groups: brain metastases, pediatrics, HIV-positive status, and organ dysfunction (see chart at bottom of article).
Labeling Claim Is The ‘Carrot’
Speaking from the audience, Tatiana Prowell, an FDA medical officer and breast cancer scientific lead who was on the brain metastases working group, said an incentive for sponsors to expand trial eligibility criteria is the potential opportunity for a labeling claim in the broader population.
“One issue that came up early on in our working group was how would industry respond to this,” Prowell said. “There were concerns expressed that if only one company were doing this, for example, when there are multiple drugs in a class and including these higher risk patients … in their clinical trial might make their drug look less safe, how would one respond to that?”
FDA approves indications based upon the patients studied in the trial, Prowell noted. “If you are the only company that has chosen to include … patients with brain metastases in your trial, then you may actually have a labeling claim and therefore an ability to advertise the only drug that’s been shown to improve overall survival” in such patients, she said.
A labeling claim could be “the carrot to industry that may help to soothe some of those reservations about being the only company that includes those higher risk patients.” – FDA’s Prowell
“I think that would be the carrot to industry that may help to soothe some of those reservations about being the only company that includes those higher risk patients, and I anticipate it might end up having a kind of domino effect,” Prowell said, noting that sponsors might not want to have the only product in a therapeutic area or class that lacks data supporting how a drug works in a particular patient population.
Trial Design Options
FDA Division of Biometrics V Director Rajeshwari Sridhara provided a regulatory perspective on trial design options with broader eligibility criteria and labeling considerations.
A randomized trial can be conducted “in a way that you can still get your indication as you had planned without expansions,” Sridhara said. The trial population could consist of a restricted eligibility criteria group – constituting patients that would have enrolled even if strict criteria had been in place – plus an expanded population group.
The intent-to-treat (ITT) population would constitute both groups combined, while a modified ITT population would consist only of the restricted eligibility group and serve as the primary analysis because “this is the population that you would have studied in any case,” Sridhara said. If the primary endpoint is met, hierarchical testing would allow for looking at the ITT population, followed by the expanded population group.
“Here the assumption is you have to show efficacy in that homogenous group of population and if the sample size is adequate in the rest of the population, then you can think about the inference in that subgroup,” Sridhara said.
The second option described by Sridhara involves simultaneously conducting a randomized, controlled study in the eligible population and a single-arm cohort in the expanded population. This option would apply only for confirmatory trials, with the ITT analysis based solely on the eligible population and descriptive statistics for the single-arm expanded population.
However, “this is not the best of options,” Sridhara said. Since it’s a single-arm study, “safety evaluation becomes tricky in this scenario.”
Elizabeth Garrett-Mayer, a biostatistician at the Medical University of South Carolina, said there needs to be “a clear definition of who is in the standard eligibility cohort and then who is going to be in the expanded eligibility cohort.”
There needs to be “clear definition of who is in the standard eligibility cohort and then who is going to be in the expanded eligibility cohort.” – Univ. of South Carolina’s Garrett-Mayer
“What we don’t want is for people, after the trial is over, to then start making those decisions about who should be in the expanded eligibility cohort and who is in the more traditional,” she said. “You don’t want to compromise the integrity of the process by making decisions after the data are observed about which cohort patients are assigned to.”
Whether a sponsor is able to secure a labeling claim in an expanded population is a case-specific decision that will depend upon the available treatment, prevalence of disease, magnitude of treatment effect and toxicity, Sridhara said.
The indication in the eligible population would be based purely on the mITT analysis in the case of a randomized trial that includes an expansion population. However, the indication potentially could be broadened to the ITT population if there is substantial evidence of efficacy. Alternatively, efficacy in the ITT and expanded population cohort could be reported, and separate reporting of toxicity in the expanded population also could be considered, Sridhara said.
Industry Moving Toward Fewer Restrictions
Pharma industry representatives talked about how companies are starting to design studies with more relaxed eligibility criteria.
Merck & Co. Inc. recently identified a recommended pediatric dose for Keytruda (pembrolizumab) and has begun to look for opportunities to implement a lower age limit in studies of the PD-1 inhibitor, said Eric Rubin, vice president and therapeutic area head for oncology early development.
Merck has begun to look for opportunities to implement a lower age limit in Keytruda studies.
Rubin noted that data have shown patients with tumors that have a very high mutation rate are very sensitive to pembrolizumab. This seems to be regardless of tumor type, and it is presumed that this would also hold true for pediatric patients, he said.
Ignyta Inc. Chief Medical Officer Pratik Multani also discussed the broad eligibility criteria for the Phase II STARTRK-2 trial, which is an open-label, basket study of the tyrosine kinase inhibitor entrectinib in patients with locally advanced or metastatic solid tumors that harbor certain gene rearrangements. The trial “casts a very wide net” in terms of eligibility in requiring that patients have one of the target gene rearrangements and be naïve to an inhibitor of that target, Multani said.
The trial includes a “non-evaluable for the primary endpoint” basket that captures data on patients who otherwise would not have qualified for enrollment, Multani said. “It’s essentially a way to incorporate compassionate use requests into the study itself so that we can capture as much data as possible in the same systematic manner.”
Developing Protocol Templates
Although the working group recommendations in each of the four areas are expected to be published in Spring 2017, this effort is not just about writing white papers, Kim said.
“We want to create documents that not only explain our rationale … and then implement it,” Kim said. “We’re finding partners out there to implement our new language for these clinical trials. We are giving templated language within these papers so that can be inserted into clinical trials, so that we can move forward and again try and really make sure everyone gets benefits.”
“We’ve got FDA at the table, we’ve got NCI [National Cancer Institute] at the table, we’ve got the stakeholders at the table to make sure that anything we implement can translate into a benefit for everybody and in the work-arounds that are approved it benefits our patients,” he said.
The working group recommendations will not only give sponsors a reason to re-evaluate trial eligibility criteria, they also will provide an impetus for FDA to push for changes in how such trials are designed.
Gwynn Ison, an FDA clinical reviewer, said published data that justify expanded eligibility criteria could help her make the argument to a sponsor that some trial enrollment restrictions are unnecessary. “We don’t always have grounds to be able to force a sponsor to agree to start enrolling these patients,” Ison said, “but I think if we’re able to give a practical way in which to do some of these, you may be able to start to see progress.”
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