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Mandating biopsies in Clinical Research  

Last update: 01/07/2019

| Research News | Proposal for close calls?

Mandatory Exploratory Biopsies: A checklist for study reviewers and the study team By Karl Schwartz (patient advocate)  PDF Introduction:   The checklist provided here is based on the guidelines in Ethics of Mandatory Research Biopsy for Correlative End Points within Clinical Trials in Oncology. 1        The purpose is to help reviewers and researchers to weigh and communicate the risk/benefit potential – the rationale for mandating biopsies, particularly exploratory biopsies, as a condition of acceptance in clinical trials.   Procedures to reduce anxiety during the procedures may have improved.  The risks of core needle, CT-guided biopsies are low (about 5%), and serious complications are rare (less than 1%).2   However, there are other burdens to consider (such as lost time and the expense of travel to have the extra procedures), as well as the impact of the requirement on timely study accrual and the potential of biasing the study results by including or excluding patients with higher or low risk disease based on the accessibility of the tumor.   Whether there can be sufficient justification for exploratory biospecimen-based correlative studies can be in the eye of the beholder.   Certainly, not all of these can be fairly called “fishing expeditions.”   The reviewer’s assessments of the potential for the knowledge to be gained requires background in the science, but should also require of the scientist a directed explanation that is understandable to IRB reviewers, including patient advocates who are the liaisons with the patient community (the primary stakeholders).     For example, that a specific finding could apply broadly across many types of cancer or other classes of drugs, or is directed at a pivotal question of importance to patients will aid in the assessment.  The justifications that are well stated and understandable to advocate reviewers will also help researchers to gain the public trust.     Background for the public: Exploratory biospecimen studies look for associations between tumor features and certain outcomes – such as response (or resistance) to the study treatment. There may be billions of tumor features. Identifying which matter is very challenging. Thus, any associations that may be found cannot guide the care of patients in the near term.  Associations do not prove causality – that A caused B. (The rooster crowing at dawn does not cause the sun to rise.) So it follows the purpose of exploratory biopsies is for science: the knowledge that may be gained.  The findings cannot help the patient taking part in the study. So, it also follows that the study team must make the case to the ethics review board (the IRB) that the knowledge to be gained offsets the risk and burden of the biopsy procedure.

Considerations when Mandating biopsies
as a condition for taking part in a clinical trial

An overview of what we ask of patients who take part in clinical research

We owe a great debt to the patients who take part in clinical research.  Developing safer and more effective therapies for future patients could not be done without these heroic 'test pilots'.  

Let's fully appreciate that the participants receive into their blood a study drug about which there can be (depending on the phase of the study) substantial uncertainty about safety and efficacy.  

... Commonly these men, women, and children are required to have extra tests and procedures in order to protect their safety but also to answer study-related questions, such as how long the drug remains in the blood, or if a feature of the tumor sample they also provided predicts response to the study drug. 

... Extra scans may be needed to see if the tumor has responded to the study drug, and to determine how long a response has lasted. 

Increasingly, tests of the tumor sample are needed to determine if the patient is eligible for a study -- such as to determine if the molecule the study drug targets exists on the tumor.  This test is typically justified because it limits the risks of taking part in the study ... to the patients who are most likely to potentially benefit from the study drug. 

... Ideally, eligibility for such studies can be determined based on the archival tumor sample taken when the patient was diagnosed. However, a biopsy can be needed when archival tissue is not available or when it was stored in a way that makes the test unreliable. 

The risk and burden of a surgical biopsy can vary depending on location of the tumor.  The burden is also dependent on the patient's perception of the risk and the discomfort they anticipate; and on the number of procedures, such as when serial biopsies are required before, during, and after treatment with the study drugs. 

... The burden can increases when additional travel to the center is required, or when the costs are not fully reimbursed by insurance.

The ethics of requiring a biopsy as a condition for taking part in a study depends on many factors.  It can be ethical, controversial, or clearly inappropriate as briefly outlined here:   

-- Ethical when the sample is integral or essential if the purpose of study, such as to determine eligibility as described above, also improves the prospect for the participants to benefit.

-- Strong, controversial, or inappropriate  -- when there is no prospect for direct benefit and the scientific rationale for acquiring the samples is questionable.   The rationale is stronger when the purpose is integrative, such as when needed to validate a promising biomarker that has a good potential to help future patients.  The rationale is weaker if the tests are exploratory or the study size is too small to provide meaningful information.  

The IRB reviewing the study will consider if the extra procedure involve more than minimal risk with or without immediate prospect for direct benefit by the participants.  The review board will also consider the burden of the tests, the purposes, and the scientific rationale.

When might requiring a surgical procedure as a condition for taking part in a study be considered coercion?

COERCION “the threat of further harm may lead to the cooperation or obedience of the person being coerced.”  This can occur when the required biopsy procedures provide no prospect for direct benefit to the participant and the tests done on the samples have a weak scientific rationale (e.g. is EXPLORATORY). 

... While participation in a study is voluntary (is not forced), a very promising study protocol could be perceived as the patient's only chance to survive when there are not effective standard options for their life-threatening disease.  This can lead to a perception that harm will result if 'I am not accepted in the study.'

From the Belmont report - this section on the principle of beneficence provides guidance:

A difficult ethical problem remains, for example, about research that presents more than minimal risk without immediate prospect of direct benefit to the children involved. Some have argued that such research is inadmissible, while others have pointed out that this limit would rule out much research promising great benefit to children in the future. Here again, as with all hard cases, the different claims covered by the principle of beneficence may come into conflict and force difficult choices.

Questions reviewers might ask the study team regarding mandatory biopsies for clinical research:

	Can archival tissue be used to make the assessments on the tumor?
	Is the tumor assessment integral to the study -- (the primary study question could not be answered without it)?
	Is the tumor assessment integrative to the study? (needed to validate a promising biomarker - based on good preliminary evidence) What is the prospect that the findings will contribute to knowledge that is meaningful and significant to patients -- has the potential to benefit future patients? How reliable are the assays?  Are they CLIA approved?  Are the tests proven to achieve reproducible results? Is the study size large enough (sufficiently powered) to provide reliable answers? What would be a meaningful finding?  What is the next step if a meaningful finding is identified? Will the findings be pooled with data from other studies?  If yes, please outline the plan.
	What is the burden of the extra procedure -- including the frequency of the tests, relative to what is required for usual care? What are the actual or perceived risks of the procedure? Can the number of research tests be reduced in order to decrease the burden on the patients? Will it be feasible for all, or most, patients with this disease to safely provide tumor samples?
	What will be the impact of the required test on accrual - the feasibility of completing the study? Do other studies with similar promise ask less of the study participants?
	Other ... (a work in progress)

 

Proposal to mitigate the burden of extra tests in close calls 

When the research is deemed to be important (integrative) but the tumor sample is not required to answer the primary endpoint, look for other ways that the participants may benefit from having the extra procedures – such as to test for eligibility for the MATCH study.   

This added analysis on the same tissue sample might be judged by some parties as undue influence (a kind of payment to induce participation) but since the patients can have this procedure done (without cost) by entering the NCI MATCH trial  it does not seem to be undue influence to this advocate.

Karl Schwartz,  research advocate, PAL

Related News and Reports

	2017: Tissue Specimens in Clinical Trials: A Double-Edged Sword - The ASCO Post http://bit.ly/2uMHm31
	JCO, 2012: Ethics of Mandatory Research Biopsy for Correlative End Points Within Clinical Trials in Oncology http://bit.ly/1s0u1vx
	* FDA.gov: Informed Consent Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors http://1.usa.gov/1oZYWbv

Note that coercion and undue influence may be situational. For example, in a clinical investigation involving the surgical insertion of an investigational device, waiting to obtain informed consent until the potential subject is in the preoperative area may fail to minimize the possibility of undue influence.

In addition, statements that claim investigational test articles are safe or effective for the purposes for which they are being investigated are prohibited. (21 CFR 312.7(a) and 21 CFR 812.7(d).) Likewise, statements that inappropriately overstate the possibility of benefit should be avoided because they may unduly influence potential subjects. Careful wording is needed in order to avoid overstating potential benefits that may contribute to a subject’s therapeutic misconception.8

Furthermore, statements such as "FDA has given permission for the clinical investigation to proceed" or "FDA has approved the clinical investigation” should be avoided, because such statements may contribute to the misimpression that the investigation has FDA’s endorsement.

	Issues Surrounding Biospecimen Collection and Use in Clinical Trials Allison R. Baer, RN, BSN, Mary Lou Smith, JD, MBA, Deborah Collyar, BS, and Jeffrey Peppercorn, MD, MPH http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900874/
	CFR - Code of Federal Regulations Title 21 - Basic Elements of Consent http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.25
	An advocate's presentation - perspective on Giving-blood-and-tissue.pdf
	Earlier version:  Ethics of Requiring a Biopsy as a Condition of Trial Participation