Clinical Trial Biopsies: Ethical Concerns Raised About Disclosure, Follow-Up

Maurie Markman, MD

Editor-in-Chief of OncologyLive

Senior vice president for Clinical Affairs and National Director for Medical Oncology Cancer Treatment Centers of America, Eastern Regional Medical Center

The critical role of translational laboratory research in the development of novel targeted cancer therapeutics cannot be overstated. While the traditional approach of treating all patients with a given histology (eg, colon, breast, prostate) with a new cytotoxic agent remains a relevant strategy in many clinical settings, antineoplastic drug development increasingly is characterized by a crucial link between a therapeutic drug and a molecular biomarker whose role is proposed and then formally evaluated through a rigorous investigative pathway. Recent examples of this highly successful critical new paradigm include BRAF mutations in metastatic melanoma,¹ and ALK rearrangements in non-small cell lung cancer.²

Unfortunately, two recent reports have challenged certain assumptions in the drug development process that raise ethical concerns, individually and collectively, which the clinical cancer research community must address.

In the first report, a comprehensive review of a single major research institution’s experience with image-guided biopsies performed for research purposes noted a not insignificant risk of complications associated with these procedures (5.2% overall; 0.8% major), ranging from a high of 17.1% for intrathoracic procedures to less than 2% for abdominal and pelvic biopsies.³ Further, a number of these events required subsequent operations to correct the problem or hospital observation and management.

Rather remarkably, despite clearly appreciated possible serious and even life-threatening side effects associated with these clinical procedures performed solely for research purposes, the investigators found only a minority of the study consent forms (10%) actually discussed specific procedure-related risks.3

When patients agree to participate in a research study where a tumor biopsy is required to generate knowledge that may not be relevant to their own care, there is an acknowledged agreement between the research subject and researcher that the study results will be published for the specific purpose of assisting the investigative community in its quest to improve clinical outcomes for future patients in a given setting. Therefore, failure of a research team to publish the results of their efforts⎯which include information obtained through the performance of potentially dangerous biopsies undertaken solely for research purposes⎯could be a serious ethical concern.

Unfortunately, this concern is made quite real in a report of the publication record of 90 early-phase clinical trials presented at either the annual meetings of the American Society of Clinical Oncology or the American Association for Cancer Research from 1995 to 2005 where an invasive research-related biopsy was performed for the purpose of obtaining pharmacodynamic information.⁴ For 22.2% of these studies, a manuscript apparently never appeared in the peerreviewed literature. Further, even where there was a formal publication, no pharmacodynamic data were reported in 17.8% of cases, and incomplete data were reported in 23.3% of cases.

One study found that most consent forms for participants did not delve into the risks related to potentially dangerous research biopsies, and another study reported that results from clinical trials involving invasive biopsies often are never published.

A number of justifications were provided for this rather disturbing publication record, including simple failure to ever complete the trial, inadequate numbers, or poor assay results, yet the issue of the obligation to the research subject remains. Just imagine the scenario if an investigator were required to go back to a research subject or the family, and explain that despite their assurances that the information obtained from this nonclinically relevant and potentially dangerous biopsy would be helpful, no manuscript describing the study results was ever published or the paper never included data obtained from the biopsy. And, of course, this discussion would be even more problematic if a patient had suffered an adverse event as a result of a procedure undertaken solely to obtain this information.

The issues raised in these two papers should be considered by all investigative groups conducting early-phase cancer clinical trials mandating research biopsies. Further, Institutional Review Boards responsible for the oversight of such studies might wish to consider how their own procedures could be strengthened to ensure the ethical conduct of such studies and the adequacy of the informed consent process.

References

1. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation [published online ahead of print June 5, 2011]. N Engl J Med. 2011;364(26):2507-2516. doi:10.1056/NEJMoa1103782.
2. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
3. Overman MJ, Modak J, Kopetz S, et al. Use of research biopsies in clinical trials: are risks and benefits adequately discussed [published online ahead of print November 5, 2012]. J Clin Oncol. 2013;31(1):17-22. doi: 10.1200/JCO.2012.43.1718.
4. Freeman GA, Kimmelman J. Publication and reporting conduct for pharmacodynamic analyses of tumor tissue in early-phase oncology trials [published online ahead of print August 21, 2012]. Clin Cancer Res. 2012;18(23):6478-6484. doi:10.1158/1078-0432.CCR-12-1384.