Timing of consent for the research use of surgically removed tissue

Is Postoperative Consenting Acceptable?

Authors


  • The authors are all pathologists and/or scientists who are actively involved the practice of biobanking. They represent many different countries including the US, Canada, the UK, Spain, and Singapore and all are members of a biobanking association called the International Society for Biological and Environmental Repositories (ISBER). The consensus of opinion in this article is the result of a productive listserv discussion followed by additional E-mail correspondence, in which all the authors played an active role. The following ISBER members also made valuable contributions to the listserv discussion: Lisa Devereux, Carolyn Compton, Regina Gandour-Edwards, Mark Elliott, Lisa Miranda, Sharon Terry, Theresa Chow, Peter Geary, Ed Levine, Kathy Sexton, and Yaffa Rubinstein.

Abstract

Consent by patients to perform surgery (‘surgical consent’) and consent for the research use of residual tissue (‘research consent’) are desirable to respect individual autonomy and human dignity. In the past, documentation of these consents has been conveniently obtained before surgery by the same person using the same form. More recently, however, ethical concerns have forced a separation between the 2 consents so that they are now often obtained by different people using different forms, thus raising the possibility of obtaining the research consent postoperatively. The current study seeks to clarify the issues and explain why a postoperative informed consent process has distinct advantages in certain circumstances.

Consent by patients to perform surgery (‘surgical consent’) and consent for the research use of residual tissue (‘research consent’) is desirable to respect individual autonomy and human dignity. The need to obtain this research consent lies at the heart of ethical research involving human tissues, but it should be noted that in some jurisdictions and under certain circumstances, it is possible for researchers to obtain a “waiver of research consent.” This may occur if an Institutional Ethics Review Board (IRB) determines that the research use is of minimal risk and it is impractical to obtain the research consent. In the past, documentation of these consents has been conveniently obtained before surgery by the same person using the same form. More recently, however, ethical concerns have forced a separation between the 2 consents so that they are now often obtained by different people using different forms. This raises the possibility of obtaining the research consent postoperatively. Unfortunately, there have been uncertainties regarding this relatively new practice, and this has slowed down its widespread implementation. The current study seeks to clarify the issues and explain why a postoperative informed consent process has distinct advantages in certain circumstances. The points presented herein are based on a listserv discussion among members of the International Society for Biological and Environmental Repositories (ISBER).

Background of Surgical and Research Consent

Regulations concerning surgical and research consent have largely evolved in a reactive manner, in response to research misconduct and legal actions. The need for surgical consent was established in the early 1900s after a series of court cases in which patients alleged that their physicians had committed battery by performing surgery on them without their consent.1 The need for research consent was established after investigation of human experimentation by the Nazis during World War II. The resulting Nuremberg Code of 1947 states that informed consent of the human subject is absolutely essential for participation in an experiment.2 This was also a central requirement of the World Medical Association's Declaration of Helsinki in 1964.3 Investigation of malpractices in the Jewish Chronic Disease Hospital Study and the Tuskegee Syphilis Study4 brought further attention to the issue of research consent and led indirectly to the publication of the Belmont Report in 1979.5 This report provided the foundation of the so-called “Common Rule,”6 which is a US federal law requiring informed research consent and oversight of research protocols by IRBs. Subsequently, after the investigation of human radiation experiments conducted during the Cold War, the National Bioethics Advisory Commission (NBAC) was established.7 In their 1999 report on research involving human biologic materials, the NBAC recommended improvements in the consent process. One recommendation was to separate surgical and research consents into different forms, and the other was for research consent to be taken by someone independent of the medical team treating the patient to avoid any sense of obligation or coercion.8 Most recently, the organ retention case at the Alder Hey Children's Hospital in the UK has caused intense public concern regarding medical research practices including the use of tissues,9 and has led to the stringent regulations of the Human Tissue Act of 2004 and the formation of a statutory body to oversee human tissue research (the Human Tissue Authority).10

Emotionally charged debate at times of crisis has often been the stimulus for the evolution of consent regulations. However, it is important for the discussion of this subject to be well-balanced and for all aspects to be considered, including several important practical considerations. In this area, biobankers11–13 such as the authors of this article can make an important contribution. This is because as managers of the research consent process relating to the research use of tissues, we have the best possible understanding of the practical aspects of the consent process. In addition, as custodians rather than end-users of biologic samples, we can speak from an independent and unbiased position.

In our direct experience and in the literature, general consent rates for the research use of surgically removed tissue are high.14,15 It is also our experience that there is no perfect or optimal time during hospitalization at which to obtain research consent, and in practice, both preoperative and postoperative informed consent are well-accepted by patients. To give examples from different countries, an analysis of 2 comparable tumor biobanks in different provinces in Canada,16,17 each of which accrued greater than 500 cases in 2006, demonstrated that the response rates for patients referred to the biobanks for consent for the research use of surgically removed tissue were high and similar (consented/declined/unknown response rates of 96%/2%/2% and 90%/3%/7%, respectively). However, a preoperative consent process was dominant in the former biobank whereas a postoperative consent process was predominant in the latter (unpublished data). Similarly, an analysis of a biobank in Singapore,18 in which greater than 650 cases were accrued in 2007 and in which both preoperative and postoperative consent processes were deployed, demonstrated that the consented response rates for each process (94% and 88%, respectively) were again high and comparable (unpublished data). The best time to obtain consent, whether preoperatively or postoperatively, depends on the individual patient and his or her specific circumstances. For these reasons, and as discussed below, many centers around the world (represented in part by this group of authors) have begun to deploy processes to obtain postoperative research consent in addition to established preoperative consent processes.

Patient's Mental State May Be More Suitable Either Before or After Surgery

An individual patient's mental state may be more suitable for consent either before and after surgery. Some patients are extremely anxious in the preoperative period or may become overburdened by the admission procedures and by urgent/paramount decisions related to surgical consent. Some patients may be afraid that if they decline consent, it will influence the quality of their care through the course of their surgical treatment and therefore they may be more susceptible to coercion at the preoperative stage. Such patients are better able to provide a valid informed consent when their surgery is behind them. Other patients may be less amenable after surgery, when they may be preoccupied by subsequent medical care considerations or may have impaired judgment because of anesthetic or pain medications. Whatever the timing of the consent, its validity depends on the integrity and skill of the individual obtaining the consent, and whether they make an honest and reliable assessment of the patient's current state of mind.

Preoperative Scheduling May Be Difficult

Consent can be taken long before surgery, from the time of diagnosis in the outpatient clinic to the time of admission to the hospital for surgery, but this is often not possible for several reasons. Reduction in the time from diagnosis to admission for surgery reduces the window of time in which potential donors can be contacted. Furthermore, patients may be in a state of shock after having just learned of their diagnosis, or the appropriate personnel for taking consent may not be available in the outpatient clinic. After hospital admission, the preoperative period is often very busy, which may make it difficult for the consent taker to schedule a time in which to see the patient. Research consent generally takes 20 minutes and during this period the consent taker must provide answers to a wide range of questions relating to the risks and benefits of tissue donation, possible research uses of tissue, commercial access, opportunity to retract consent, et cetera. The individual obtaining consent must also find a time that is least inconvenient to the medical team, and during the busy preoperative period, gaining access to patients usually adds at least 15 minutes to the consent process. With the trend toward hospital admission on the day of surgery, the preoperative period can be so condensed that postoperative consent often provides the only viable option. The same applies in the case of emergency surgery.

Preoperative Research Consent Is Often Redundant

It is often difficult or impossible to predict whether an operation will yield useful research material. After surgery, the excised specimen must be examined by a pathologist and only after the samples needed for diagnosis have been taken can samples be released for research purposes. Often, no suitable material is available for research. If preoperative research consent has been obtained in such cases, then not only does this mean that precious research resources have been wasted, but also that the patient has been troubled unnecessarily. By contrast, postoperative consent is only carried out if there is useful material available and therefore it avoids all this redundancy.

Conversely, surgery occasionally yields tissue that is valuable for research in cases in which no useful tissue was expected. Preoperative research consent will often not have been obtained, and therefore the only way this tissue can be used for research in these cases is if consent can be obtained postoperatively.

An Ethical Objection to Postoperative Consent

One ethical objection to postoperative informed consent might be that patients may object to the storage of their residual tissue without consent. However, it may not be widely appreciated that the diagnostic pathology process involves the dissection, sampling, and analysis of representative fresh, frozen, and fixed samples, and in some cases resampling and reanalysis of the remnant portions of the tissues, such that the process to complete diagnosis can take many days or even weeks. During this time, all tissues removed during surgery, including these representative samples undergoing pathologic analysis as well the unsampled remnants, are typically held in short—term storage within the pathology department. Only after diagnosis is completed do pathology departments routinely assign the surgically removed tissues to 1 of 2 fates. This usually involves submitting the representative fixed and/or frozen tissue samples (and the stained sections derived from them) for long—term storage for possible future clinical use, and then disposing of the remnant tissues that have not been required for sampling to complete the diagnosis. It is generally accepted that these stored tissues can be used for research in the future, because their storage is primarily intended for and covered by the surgical consent. That is provided that a pathologist determines the tissues are surplus to diagnostic requirements, the proposed research is IRB-approved, and the tissues are deidentified according to IRB requirements. Analysis of the rationale for informed consent leads us to the conclusion that it should not be required for the collection and short—term holding of tissue in any format relevant to diagnosis (ie, fixed or frozen, remnant or sampled) during the diagnostic process. Similarly, it should not be required for the long—term storage of tissue samples in which there is an intended clinical use. In this context, it is the research rather than storage that makes consent necessary. Research yields information that has the potential to cause economic, psychologic, or social harm to the patient and specific types of research might cause the patient distress or “moral harm.”19 Therefore, in circumstances in which tissue is removed only for clinical purposes, in which this tissue is treated the same way regardless of whether the patient consents to research, and in which this tissue is held or stored for clinical use, there is no convincing ethical reason why consent should be required for this storage purpose.

As discussed earlier, in many instances postoperative consent may not only be more practical, but in some circumstances may in fact be more ethical. A virtue of accepting a window of time for the completion of the consent process, with defined limits but spanning both the preoperative and postoperative periods, is that it creates both opportunity and flexibility for patients who would wish to donate their tissues in the optimal format for research.

Biobanks Provide Good Governance for Postoperative Consent

It may be argued that if researchers are allowed to manage the postoperative research consent process for themselves, then they may be tempted to use samples even when consent cannot be obtained. However, if access to samples is managed by a third—party broker such as a legitimate biobank that follows ethically approved protocols, then this is not an issue. Biobanking is emerging as a recognizable discipline with distinct expertise, protocols and functional frameworks, and policy guidelines. National and international associations such as ISBER, the Public Population Project in Genomics, the Canadian Tumor Repository Network, and the US National Cancer Institute's Office of Biorepositories and Biospecimen Research,20–23 now provide a context for professional development and add legitimacy.24 The process of sample disbursement should include processes to ensure the protection of the patient's identity such as an “honest broker” system. Examples of this system have been described elsewhere,25,26 but the basic principle is that the honest broker is independent of the researcher and holds the “link” to patient identities that cannot be released to research investigators. The honest broker system can be integrated into the design of a biobank, or act on the behalf of the biobank. It may be an individual, an organization, or a system. The honest broker collects and provides health information to research investigators in such a manner whereby it would not be reasonably possible for the investigators, or other individuals, to identify the subjects directly or indirectly. The honest broker thus acts as a well—defined barrier between the clinical environment (in which fully identified confidential patient information is routinely exchanged as part of medical care) and the general research community (in which all information must be completely deidentified). The honest broker also ensures that research data, which are generally not clinically validated, are not used for clinical care.

Conclusions and Recommendations

Some ethics committees have been hesitant to endorse the relatively new process of postoperative informed consent. We hope that the above analysis will help to clarify the issues and encourage productive discussion. To summarize our position, we find that in some circumstances, it is a clear advantage to obtain research consent postoperatively. We do not find any reasonable objection to the process of postoperative research consent for the use of surgical tissues and associated medical data, provided that it is properly regulated. Therefore, we recommend the implementation of the following regulatory measures:

  • 1The postoperative consent process must follow a detailed and ethically approved protocol and all staff involved in this process should have received training in ethical issues pertaining to research consent.
  • 2For cases awaiting postoperative consent and the determination of consent status, the tissue samples should optimally be held under the custody of an IRB—approved, third–party broker. This is to ensure that the accession or processing of samples or linkage with health data for research does not occur before consent.
  • 3Tissue samples should be held only for a defined moratorium period that corresponds to the diagnostic process, during which a consent decision must be obtained. A moratorium period of between 1 and 3 months has been approved by some IRBs.
  • 4If no consent decision is obtained (ie, consent is neither granted nor refused), then samples not destined for storage for clinical purposes may be anonymized for research use, taking into account the local legal requirements (in the UK, Australia, Spain, and Canada for example, any research use would require IRB approval in cases in which consent has not been obtained).
  • 5If consent is refused, then samples must be destroyed, assuming that they are no longer required for diagnostic purposes.

This regulation will usually necessitate the adoption of the framework or services of a biobank to ensure that the processes are conducted, documented, and supervised both independently and impartially. It is recognized that this will incur additional costs that are inherent in the labor—intensive obligations that are performed by the biobank. However, ultimately, this will result in the improved public acceptance, participation, and availability of tissues and data for research.

Conflict of Interest Disclosures

The authors made no disclosures.

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