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Overcoming Challenges in Clinical Trials for a Rare Cancer


At the 2021 Cholangiocarcinoma Foundation Annual Conference, experts discussed clinical trials in cholangiocarcinoma and the ways in which clinical trials overall can be made more available to patients.

Clinical trials are an integral part of progress in cancer therapeutics, but it can be challenging to pull off large trials in rare diseases such as cholangiocarcinoma. At the 2021 Cholangiocarcinoma Foundation Annual Conference, experts discussed clinical trials in cholangiocarcinoma and the ways in which clinical trials overall can be made more available to patients.

Susan Pandya, MD, vice president of clinical development at Agios Pharmaceuticals, provided an example in the ClarIDHy study, a randomized phase 3 trial of ivosidenib. This therapy is already approved for the treatment of acute myeloid leukemia with IDH1 mutation, and the study is examining its potential role in cholangiocarcinoma with the IDH1 mutation.

Ivosidenib’s development in cholangiocarcinoma began in 2014 with a phase 1 study and just saw the submission of a supplemental new drug application in February 2021. This timeline serves as proof that progress is possible in rare disease settings when industry, patient advocates, and the academic community work together, Pandya said.

“Operationalizing a study in a rare cancer has many challenges, and the feasibility is often raised as a gate for decision making,” she said. To mitigate this challenge, researchers cast a “broad net” across several countries to determine the feasibility and took a hands-on approach in maintaining momentum as they searched for motivated investigators. Around 200 sites were considered, 80 were interested, and 49 sites in 6 countries participated in the study.

This trial design also offered a pre-screening consent, which helped identify patients with IDH1 mutations early, Pandya said. That provided an opportunity for patients receiving first- or second-line chemotherapy during the pre-screening phase to later choose to join the trial. Of 780 pre-screened patients, 187 were eventually randomized.

To raise awareness, Agios extended reach to scientific conferences, engaged with advocacy groups to make information available to patients, and created print and web-based resources to create more awareness around the trial.

Balancing efficiency and inclusivity is another challenge in clinical trials and eventual drug approvals. Lola Fashoyin-Aje, MD, MPH, deputy director for the Division of Oncology 3 in the Office of Oncologic Diseases at the FDA, discussed drug development considerations that provide patient access and address a broader population.

“It’s important, particularly as more drugs are developed, to consider how we can expand the pool of patients who have access to these drugs, either through clinical trials or once they are approved,” Fashoyin-Aje said. The American Society of Clinical Oncology (ASCO) has been working to develop a framework to broaden trial criteria for about 5 years, she noted. Over time, criteria have become more and more restrictive, which is one reason why just around 3% to 5% of cancer patients take part in trials.

Broadening eligibility criteria can benefit both patients and researchers by early access to investigational drugs, faster trial accrual, more complete safety and efficacy data, earlier identification of drugs that may not be effective, and generalizable results, she said. But it can also pose risks, like greater heterogeneity limiting the interpretation of result. It may also be more difficult to identify efficacy signals and interpret safety. Safety concerns may also require more frequent patient monitoring.

Progress in adopting new suggested frameworks has been slow, Fashoyin-Aje said. The FDA has taken a proactive approach trying to operationalize ASCO’s framework in disease-specific contexts, including cholangiocarcinoma. The key points in vetting current trial criteria are identifying those considered important in all trials as well as those used frequently that may not be appropriate.

There is tension between drug development efficiency and studying more diverse populations. FDA has encouraged measures like enrolling a cohort of patients that can be analyzed for the primary analysis as well as a cohort of patients that, based upon relaxed criteria, can provide information on different dosages either once the drug is approved or shortly thereafter.

In rare disease settings, platform trials and common control groups can also help promote efficiency. Another potentially huge barrier, trial-associated burdens involving things like travel to large academic centers, needs to be addressed, she added. It can take innovation, such as leveraging technology; using telemedicine and eConsent; decreasing procedures when feasible; and decentralizing trials, allowing patients to get things like lab work done locally rather than at the large center where the trial may be based.

“That’s something that we’ve been discussing well before the COVID 19 pandemic and trying to develop some guidance around that,” Fashoyin-Aje said during a post-presentation panel discussion. “Part of what has been identified is the intensity and frequency of these clinical trial requirements.”

She noted that it can be a virtually full-time commitment to take part in a trial—something that some patients just cannot manage. And especially with drugs that are already approved for other indications that have been proven to have a tolerable safety profile, intensive monitoring is not as necessary.

Another growing aspect of research and clinical practice, patient-reported outcomes (PROs) can also be used to complement clinical evaluations, since they directly reflect symptomatic adverse events patients are experiencing. This practice can help with dose optimizations earlier on and avoid clinical holds due to uncertainly about optimal dose later, Fashoyin-Aje said.

“Adoption of practices that improve access and facilitate adherence to clinical trials and that help generate data that are generalizable is really critical to improving outcomes for all patients,” she concluded. “Sponsors should employ rational and streamlined eligibility criteria, flexible trial design and analyses, and multi-pronged and multi-staged approach to dose optimization.”

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