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Performance of Biopsies in Clinical Research

Harvard Medical School, Program in Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA

To the Editor:

I enjoyed reading the thoughtful editorial¹ and accompanying article,² which address the ethics of obtaining research-related biopsies as part of a clinical trial. There is no doubt that subjects should have a clear understanding of the lack of personal benefit to the performance of correlative biopsy procedures, if such procedures are of unproven clinical value. However, there are several points in the editorial by Drs Helft and Daugherty that deserve further discussion. The authors feel that the "widespread practice of serial research biopsies" has not yet been shown to have yielded "generalizable knowledge that is of vital importance."¹ It is difficult to know how frequently serial biopsies are used in the conduct of clinical trials, but I remain unconvinced that this practice is truly widespread. Ironically, I have often argued that it is not widespread enough, and for that reason I feel that we have done a disservice to future patients. Such correlative studies serve many valuable goals, including determining whether a new drug affects its intended target (which would place response data into proper context), and whether a predictive profile can be identified that enables us to tailor the use of the drug to patients who would benefit the most. Despite their potential value, there are unfortunately many disincentives to incorporating serial biopsies into clinical trials. These include the need for adequate funding to collect specimens and to subsequently use them for research, the extra time required to obtain informed consent for these correlative research studies, the perception that correlative research studies will dissuade a patient from participating in a clinical trial, and the possible conflict that industry sponsors may have regarding supporting research that could ultimately restrict the use of a drug to only a small subset of patients. Regarding this last point, I am not saying that this has actually occurred, and I recognize that several correlative studies have already been supported by industry. In addition to these considerations, only recently have rationally designed drugs become available whose mechanism of action is amenable to performing correlative studies. Given these considerations, it is not surprising that the authors cannot find many examples of how serial biopsies have yielded information of clinical benefit at the moment. Furthermore, I would also argue that it is irrelevant whether previous studies using research-related biopsies (for example) have yielded clinically valuable information. It is only important that future studies using serial biopsies have the potential of yielding important information in the context of a new drug or new clinical setting. We are not so smart as to be able to predict whether this potential will be realized, but it is important to try. We already have excellent reason to believe that certain classes of agents (like epidermal growth factor receptor inhibitors, trastuzamab, and selective estrogen receptor modulators to name a few) easily lend themselves to this approach.

Finally, Drs Helft and Daugherty propose that performance of research-related biopsies should be an "optional (not mandatory) condition of clinical trial enrollment, only if or until the scientific contributions of such biopsies have been fully established."¹ I understand the spirit of this recommendation, but do not think that it is practical for three reasons. First, if the value of serial biopsies has already been fully established for a given drug and/or disease setting, we would no longer need to perform them in the context of a clinical trial. Second, this suggestion implies that we have a moral obligation to offer patients an investigational agent, without perceived impediments (like performance of serial biopsies) to patient participation. In so far as a clinical trial is an experiment of unproven benefit, and is designed for the purpose of providing an answer to an important question, I disagree with this. I would have no problem mandating that serial biopsies be a requirement for clinical trial participation in some circumstances because they are designed to provide a better understanding of how an unproven agent works (or does not work), and they allow us to obtain the best data possible to help guide our decisions for future patients. For this reason, I think that we actually have a moral obligation to include correlative biopsies in appropriate clinical trials, rather than make them optional. Third, I do not think it is practical to make performance of biopsies (for example) optional because I suspect that many patients might not want to expose themselves to added procedures if they did not have to do so. In contrast, I can easily envision a patient saying, "I am interested in the opportunity to participate in this trial, realizing that this unproven drug may not work, but hoping that it does" and "I accept that part of the condition for participating in this study is the need to perform biopsies that will be of no benefit to me, but might help my doctors take better care of patients in the future." This is not coercion on the part of clinical investigators—it is honesty regarding the uncertain value of a drug, and the need to learn as much as possible about it, for the benefit of future patients.

These two articles are thought-provoking,^1,2 and my disagreement with some of the points should not take away from the authors' attempts to better define the role of serial biopsies in clinical research. I congratulate them for their efforts and hope that these articles stimulate more discussion of this important topic.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author indicated no potential conflicts of interest.

REFERENCES

1. Helft PR, Daugherty CK: Are we taking without giving in return? The ethics of research-related biopsies and the benefits of clinical trial participation. J Clin Oncol 24:4793-4795, 2006[Free Full Text]

2. Agulnik M, Oza AM, Pond GR, et al: Impact and perceptions of mandatory tumor biopsies for correlative studies in clinical trials of novel anticancer agents. J Clin Oncol 24:4801-4807, 2006[Abstract/Free Full Text]

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