In Focus: Rethinking the Complex Process for Cancer Trials

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Applied Clinical TrialsApplied Clinical Trials-05-01-2024
Volume 33
Issue 5

Faced with a host of variables inherent to oncology studies, researchers look to inventive ways to boost efficiencies—and hopeful improved patient access.

Image Credit: © Supapeach - stock.adobe.com

Image Credit: © Supapeach - stock.adobe.com

Compared to non-oncology trials, it’s fair to say that cancer studies occupy a league all their own. There are no healthy cohorts involved; no placebo is in play; the patients endure near toxic levels of the tested medication in Phase I trials to get the dose right; and each patient brings to the study his or her own medical and treatment history, including comorbidities and a list of failed cancer treatments.

Even their diets need assessment, to see if the patient has eaten something that could reduce absorption of an oral drug. Acid in the stomach could affect absorption.

Other salient points that add to the complexity of a cancer clinical trial: There are many types of cancers and different signaling pathways—at least 12 of them.1

Throw into this mix the difficulties associated with recruiting cancer patients. An example: A Phase I-II interventional trial listed in ClinicalTrials.gov first posted in September 2019 has not recruited the 210 patients with advanced solid tumors and lymphomas needed for the trial.2 The study’s sponsors are looking to fill the trial’s six different cohorts. Some require a certain gene mutation, others, no gene mutation, but patients must have endured failure after failure on other cancer treatments. One cohort lists 13 inclusion criteria. The exclusion criteria number more than 20.

It is no wonder some researchers are rethinking the cancer trial process. In January, members of the American Society of Clinical Oncology (ASCO) published a commentary highlighting a few areas that, if streamlined or addressed, they say would improve recruitment, especially of minority groups, and allow them access to novel therapies. The group is calling for the creation of partnerships between research centers and local providers, where the vast majority of cancer patients are treated.3

“The population that we treat in those trials are out-of-the gate different,” says R. Donald Harvey, PharmD, medical director, clinical trials office, director, Phase I clinical trials section, of the Winship Cancer Institute, Emory University, and lead author on the ASCO commentary. “These are individuals who have had cancer for a period of time” with different disease and treatment histories; they have had standard treatments that they couldn’t tolerate or didn’t work, or that eventually failed them at some point. “In cancer, we have all those variables to deal with,” says Harvey.

In other trials, for instance, in cardiology or neurology, Harvey continues, the first time a drug is used is on healthy volunteers. “They are getting a stipend, often being housed overnight. There are very few variable drugs they are on,” he notes.

Romillie Cruz, MD, senior medical director for the cancer specialty contract research organization (CRO) Simbec-Orion, emailed a list that echoed some of Harvey’s points and added others. These patients:

  • Have rapidly evolving disease.
  • Are mostly an older patient population.
  • Generally have multiple comorbidities if their disease has metastasized.
  • Endure doses that could be near toxic levels (maximum tolerable dose).

As for the trials themselves, says Cruz, the endpoints are death-related.

At Simbec-Orion, she adds, all oncology trials have adaptive aspects, “especially with respect to the impact of drug safety on dose selection.” The drug’s effect is constantly assessed against a prespecified target. “This approach to hypothesis testing from a different angle allows protocol flexibility with respect to “doses administered potentially near toxic levels,” says Cruz.

In the Harvey paper, the committee listed a few trial-connected areas that need change. One is clarification of the FDA’s Form 1572 investigator statement, now 14-years-old.4 The group, he says, knows it is necessary to record, for example, which third-party vendor is collecting specimens and to verify that group’s bona fides. “Our argument is, it has gone too far,” says Harvey. “If a lab is certified every year by the College of American Pathology, then that should be enough” to put on the 1572. In the paper, Harvey argues, that “Overly conservative sponsor and CRO interpretations and application of the Form 1572 requirements has turned the form into a data-collection tool for cataloging medical providers and ancillary facilities.” The result: “Superfluous supplemental documentation and no regard for downstream implications, time toxicity, or resource requirements,” he adds.

Simbec-Orion is based in the UK. Principal investigators in trials there and in European countries do not want to be governed by a US-based regulation, when it wasn’t required by the European Medicines Agency (EMA). What would help, says Cruz, would be if the FDA, EMA, and UK’s Medicines and Healthcare products Regulatory Agency, develop a “common informational form to initiate a regulated clinical program.”

Harvey says research centers and local providers need to enter into partnerships to reach those patients who cannot or will not travel to the trial’s centralized location. These decentralized clinical trials are vital, he says, because eight out of 10 cancer patients are treated in the community. A recent study shows that overall, only 7% of cancer patients participate in a trial.5

But sponsors, Harvey asserts, are fearful of losing control of data, which is why they prefer a centralized location. As for the issues on the community side, those healthcare providers would argue that they don’t have the staff, the money, or the confidence to conduct a trial.

Says Harvey: “It is complicated, to put it mildly.”

Christine Bahls is a Freelance Writer for Medical, Clinical Trials, and Pharma Information

References

1. Foster, M. Cancer Pathways. Mary Crowley Cancer Research. July 20, 2023. https://marycrowley.org/2023/07/20/cancer-pathways/#:~:text=%E2%80%9CAlmost%20all%20of%20these%20modifications,identified%20by%20Hanahan%20and%20Weinberg.%E2%80%9D

2. ClinicalTrials.gov. A Phase I/II Study of CPI-0209 in Patients With Advanced Solid Tumors and Lymphomas. https://clinicaltrials.gov/study/NCT04104776?term=r.%20donald%20harvey&page=2&rank=13&a=19#participation-criteria

3. Harvey, R.D.; Miller, T.M.; Patricia; et al. A Call to Action to Advance Patient-Focused and Decentralized Clinical Trials. Cancer. 2024. 130 (8), 1193-1203. https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.35145

4. FDA, Information Sheet Guidance for Sponsors, Clinical Investigators, and IRBs. Frequently Asked Questions – Statement of Investigator (Form FDA 1572). https://www.fda.gov/media/78830/download

5. Unger, J.M.; Shulman, L.N.; Facktor, M.A.; et al. National Estimates of the Participation of Patients With Cancer in Clinical Research Studies Based on Commission on Cancer Accreditation Data. J. Clin. Oncol. Published online April 2, 2024. https://ascopubs.org/doi/10.1200/JCO.23.01030

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