A New Framework Addresses Ethical Concerns With the Use of Biopsies in Clinical Trials

Mark J. Ratain, MD

Mark J. Ratain, MD

In acknowledgment of under-regulation for research biopsies in clinical trials, a group of researchers has developed an ethical framework that will require physicians to define how the information obtained from a tissue sample will be beneficial for the trial research and the patient.¹As the use of biopsies becomes more widespread in clinical trials, researchers in the pharmaceutical and diagnostics industries believe it is critical that sponsors, the FDA, institutional review boards, and scientific review committees all review clinical trial protocols for ethical standing.

One concern among researchers is the potential risk that biopsies host to patient-participants in clinical trials. When multiple biopsies are taken, it increases the chances of adverse events that impact the study results and the well-being of the patients involved. Patients are also not always well informed about these risks and tend to underestimate them.

The scientific contribution of biopsies is another concern among these researchers. The ethical framework includes a recommendation for clinical trials’ sponsors to justify their need to extract tissue biopsies throughout the study. However, the most critical concern is the oversight by governing bodies that allows clinical trial sponsors to continue taking multiple biopsies without noting the potential risks and scientific contribution of these tests.¹

On the other hand, blood-based biomarker testing, including liquid biopsies, have fewer associated risks for patients and lower costs for collecting the samples. However, when conducting clinical trials, “everything has to be fit for purpose,” said Mark J. Ratain, MD, professor of medicine, director of the Center for Personalized Therapeutics, and associate director for clinical sciences, Comprehensive Cancer Center, the University of Chicago. Ratain explained though that there are many opportunities for blood-based testing to inform dosing, treatment effect, and more during the course of treatment, and even encouraged exploratory blood-based biomarker research.

Ratain provided guidance on the current landscape for research biopsies in clinical trials and talked through the recommendations and how the new ethical framework can improve clinical trials during an interview withTargeted Oncology. He also explained the potential role for liquid biopsies and blood-based biomarker testing within clinical research.

TARGETED ONCOLOGY: Can you discuss the background on the ethical framework for including research biopsies in oncology clinical trials?

Ratain:I've been doing direct development for a few decades. I think the notion that we should be getting a sample of tumors before and after treatment has a significant scientific rationale, but it only makes sense if it's done properly. The point here is either do it right or don't do it. There's a lot of physician doing it improperly.

For example, [in our analysis of the impact of post-treatment biopsies in phase I clinical trials], we demonstrated that it was not being done right and these biopsies were being done at both a cost to sponsors and risk to patients without any scientific knowledge.

The FDA is very concerned, appropriately, about toxicity in new drugs but they have not had any concerns about the risk of these biopsies, which for some drugs, may outweigh the risk of the drugs themselves. [Also], the pharmaceutical industry has been very concerned about the cost of drug development, yet they put these biopsies into studies. In many cases [biopsies] are mandatory, and they increase the cost of the study without a clear scientific value. If you want to make [biopsy] a mandatory part of the study, there has to be a good reason.

TARGETED ONCOLOGY: What is your recommended framework for use of research biopsies in clinical trials?

Ratain: We see many clinical trials with mandatory biopsies and exploratory endpoints. We're saying “no” to this. It's one thing if you want to collect some blood or something superficial, but, otherwise, it's unacceptable.

For companies who say it's an important secondary endpoint, we say that's fine, but you can’t do high-risk procedures like sticking needles into a patient’s chest, and you have to select patients very carefully. The other implication of this being a secondary endpoint is it then becomes publicly reportable because secondary endpoints have to be [reported] on clinical trials.gov and therefore, the whole world will see the results. [That] may not be what the sponsor wants.

[These are our recommendations]. One, if you want to do these biopsies, you have to say what you're going to do with the information and these need to be properly reviewed. [Currently], these sponsors put biopsies into the protocol, but don't tell you what to expect. When it’s time to execute the protocol, there may be instructions like "use a very large needle and you need to go in 6 different times to get a sample,” [where] if you knew that ahead of time you might not do it. [Our framework is], saying that things like that should be told up front so it can be reviewed accordingly and reviewed by the FDA.

Two, if patients are going to go through this optionally or as a mandatory part of receiving an investigational drug—patients will want that information disseminated and it makes a lot of sense that if it's a publicly funded study [the information] should be disseminated. The complications of biopsies have not been considered a complication of a protocol, so we're saying track and publish this stuff.

Recommendation 3 is about [executing] more thoughtful operations. Recommendation 4 says that if there's a complication of a biopsy, there's a complication of a study and it should be handled as such. Then it should be reported to institutional review boards, sponsors, and the FDA to be tracked, all as part of the study package.

Recommendation 5 is to make sure we have a better consent process, and recommendation 6 says that all the information has to be there so that it can be reviewed accordingly, whether by the FDA, institutional scientific committees, or ethics committees.

I think this is pretty important, and as I said, it's been a barrier for patients and some investigators. I wouldn't do research that I believe is unethical in order to get funding from the National Cancer Institute (NCI) or the pharmaceutical industry.

TARGETED ONCOLOGY: What do you hope comes out of these recommendations in the future?

Ratain:I hope that we do fewer biopsies and when we do them, we get useful information.

TARGETED ONCOLOGY: Do you see liquid biopsy serving as a more widespread alternative?

Ratain:It depends on what the question is. Everything has to be fit for purpose. Liquid biopsies are not going to get the answers to some of the questions being posed by some of the investigators, but neither are some of the [tests they are conducting]. Pharmacokinetic studies could get some of these answers, but they aren't being done.

TARGETED ONCOLOGY: What other challenges exists with the use of liquid biopsies in clinical trial settings?

Ratain:With liquid biopsies, it’s about asking different questions. Blood-based biomarkers, in my opinion, are under-utilized in general. I consider pharmacokinetics to be a blood-based biomarker.

The recent approval of erdafitinib (Balversa), where dosing is guided by a blood-based biomarker—serum phosphorus, is a good example. There are many opportunities to use blood-based biomarkers, whether it’s for demonstrating that you have the right amount of the drug in the patient or demonstrating a treatment effect—hypothetically, the number of tumor cells or the number of mutated cells decreases—but biopsies are being done for all kinds of reasons. The cynic in me wants to say that companies want to acquire the tissue and it's unclear what they'll do with it.

TARGETED ONCOLOGY:How do you hope that this research statement helps to improve clinical trials?

Ratain:If sponsors follow this, trials will be cheaper and [could be] equally informative. So, we're either going to save money and [decrease] patient risk or we are going to improve the knowledge that will be gained.  

TARGETED ONCOLOGY: Although you’re recommending changes to the way biopsies are use in clinical trials, what is your opinion about liquid biopsy overall for disease treatment of management?

Ratain: I would not say that you can replace all research biopsies with liquid biopsies. Liquid biopsy is a buzz word. There are many blood-based biomarkers, including getting tumor cells or DNA from the blood. Liquid biopsy is just one type of blood-based biomarker, but there are many blood-based biomarkers that can be used. I don't have any problem with people doing exploratory blood-based biomarker research. I would encourage more of that in an exploratory nature because there's not a risk involved and the costs of collection and processing are quite low. I'm in favor of more blood-based biomarkers, one of which includes the type of studies that people refer to as liquid biopsies.

Reference:

Levit LA, Peppercorn JM, Tam AL, et al. Ethical Framework for Including Research Biopsies in Oncology Clinical Trials: American Society of Clinical Oncology Research Statement [published online July 25, 2019].J Clin Oncol.doi: 10.1200/JCO.19.01479.