Tissue Specimens in Clinical Trials: A Double-Edged Sword

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Apar Kishor Ganti, MD, MS, FACP

Apar Kishor Ganti, MD, MS, FACP

AN INCREASING number of clinical trials require the submission of tissue specimens, either from archived specimens or increasingly from fresh biopsies taken after enrollment into the trial. These specimens can be either mandatory, required to determine whether a given patient has the required biomarker to be eligible for enrollment, or optional, needed for correlative studies to be done at a later date. 

Benefits of Tissue Specimens 

IN TRIALS where the administration of the study drug is based on the presence or absence of a biomarker (eg, the NCI-MATCH study and the ASCO TAPUR study), prospective testing of specimens determines eligibility for the study and the specific treatment that should be used. In studies where tissue characteristics have been studied retrospectively, these correlative analyses have provided invaluable evidence that has been instrumental in changing the treatment paradigm for these patients. Classic examples include the identification of the lack of efficacy of cetuximab (Erbitux) in KRAS-mutated colorectal cancer and the efficacy of gefitinib (Iressa) in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. 

Dr. Ganti is Staff Physician, VA Nebraska Western Iowa Health Care System, and Professor of Medicine, Division of Oncology-Hematology, University of Nebraska Medical Center, Omaha.

Logistic Challenges 

THE EFFECT of the logistics of obtaining these specimens on trial enrollment cannot be underestimated. Even in large academic centers that have research associates and assistants specifically assigned to research-related activities, obtaining tissue samples for clinical trials involves a lot of time and effort. 

In situations where a trial specific biopsy is mandated, multiple additional layers of complexity often lead to treatment delays. The time to onset of treatment in these situations—from the time the patient has signed the consent form—can be as long as 5 to 6 weeks. This can be unacceptably long for patients whose disease may be progressing rapidly or for those who are anxious to get started on some treatment to help control their disease. 

If archived samples are permitted, there has to be close coordination between the clinical team and the pathology department, where these samples are often archived. Another consequence of the need for specimens is physicians may not screen patients who do not have sufficient preexisting samples or who they think are reluctant to undergo an additional biopsy. In settings where the oncologists are part of a single-specialty group and consult practices at other institutions for pathology and other services, this requirement adds an additional burden on the research staff. 

"If large institutions with significant track records of patient accrual report such problems, imagine the logistic hurdles in smaller academic institutions and community practices."
— Apar Kishor Ganti, MD, MS, FACP

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The clinical pathology department is the steward of the clinical tissue, and this often results in tension between the clinical research team and the pathology department. The major source of conflict is whether using the tissue for research, especially if not needed for determining eligibility for the treatment trial, would benefit the patient more than any future need for clinical care. The end result is the patient is not offered the study in question, or a decision is made not to open the trial. 

There have been few studies analyzing this issue. Lim et al studied the impact of research biopsies on study enrollment in non–small cell lung cancer.1 They found the median time from consent to the start of treatment in trials that mandated a research biopsy was 54 days, compared with 14 days in trials that did not mandate a biopsy. Almost 30% of patients had clinical deterioration prior to starting treatment or had insufficient tissue on the biopsy specimen for analysis and hence could not be treated on study. 

In another similar analysis, Garcia et al evaluated the time and effort needed for tissue acquisition for clinical trials at their institution.2 They observed the median duration between consent and the onset of treatment was 28 days if tissue was requested, compared with 7 days if tissue was not requested (P < .001). Interestingly, they found if tissue submission was not mandatory, but rather recommended, it was sent in 16% of cases where it was required if available and 0% of cases where it was optional. 

Both these analyses are from large institutions, well known for their clinical research expertise. If these large institutions with significant track records of patient accrual report such problems, imagine the logistic hurdles in smaller academic institutions and community practices. 

Possible Solutions 

ONE POSSIBLE SOLUTION would be to allow testing at local laboratories. Currently, a majority of sponsors mandate central laboratory testing (ASCO’s TAPUR study being a notable exception). Although standardization is understandable, using other certified laboratories will decrease the time to treatment. This approach would also provide validation of the test in a real-world setting. However, this may necessitate a change in statistical planning to allow for possible discrepancies in testing results. 

"The importance of understanding the science of cancer should be balanced by the practical issues of tissue acquisition during the conduct of clinical trials."
— Apar Kishor Ganti, MD, MS, FACP

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Using liquid biopsies would be another option. Although this approach would definitely decrease the amount of time spent in the coordination of obtaining and shipping tissue samples, the technology currently exists only for a few selected mutations. Multiplex testing of blood samples is still in its infancy and not ready for prime time yet, but it may be a good option in the future. 

Balancing Science and Practicality 

THE COMMON BARRIERS for cancer clinical trial enrollment include the uncertainty associated with randomization, general discomfort with research, complexity and stringency of the protocol, lack of knowledge of trial opportunities, and fear that trial involvement would affect the physician-patient relationship adversely.3 Tissue requirements are likely to add to the complexity of the protocol and increase the trial burden on both patients and research staff. 

In present-day practice, where fewer than 5% of cancer patients are enrolled onto clinical trials, the additional burden of requiring tissue will lead to a further decrease in enrollment. Of greater concern, trials may enroll patients who are not representative of the larger population, affecting the validity of the study results. The importance of understanding the science of cancer should be balanced by the practical issues of tissue acquisition during the conduct of clinical trials. The perfect should not be the enemy of the good. ■

DISCLOSURE: Dr Ganti reported no conflicts of interest. 


1. Lim C, Sung M, Shepherd FA, et al: Patients with advanced non-small cell lung cancer: Are research biopsies a barrier to participation in clinical trials? J Thorac Oncol 11:79-84, 2016. 

2. Garcia S, Gerber DE, Saltarski J, et al: Time and effort required for tissue acquisition and submission in lung cancer clinical trials. J Thorac Oncol 11:S281-S282, 2016. 

3. Mills EJ, Seely D, Rachlis B, et al: Barriers to participation in clinical trials of cancer: A meta-analysis and systematic review of patient-reported factors. Lancet Oncol 7:141-148, 2006.