BIOPRESERVATION AND BIOBANKING Volume 12, Number 6, 2014 ª Mary Ann Liebert, Inc. DOI: 10.1089/bio.2014.0039
Factors that May Influence the Willingness of Cancer Patients to Consent for Biobanking Ussha Pillai, Kathleen Phillips, Graham Wilkins, Robert C. Baxter, Diana E. Benn, Nicole R Parker, Ross C Smith, and Deborah J Marsh
Background: Broad or general consent given by cancer patients for their tissue, blood, and clinical information to be stored in institutional biorepositories is fundamental to enable future ethical translational cancer research. The decision to consent for biobanking will contribute to the development of advanced diagnostic and prognostic tests, as well as new therapies to improve patient outcomes. While the rate of patient participation in biobanking programs is generally reported as high worldwide, few studies have investigated factors that may influence this decision. Biobanking at our medical research institute, an associated public (government-run) university hospital, and private hospital has been established for over 20 years, with collection of certain tumor types embedded in the research culture of these institutions. In this study, we investigated factors that may influence a cancer patient’s decision to give broad consent for biobanking of their specimens. Methods: Data on patient consent were collected over a 6-month period from both government and private hospitals associated with our medical research institute. Factors considered included gender, patient age at surgery, type of malignancy (breast, duodenal, cervical, endometrial, gastric, liver, esophageal, ovarian, pancreatic, pelvic, uterine, or vulval), type of institution where surgery was performed, and timing of consent. Results: Of 171 cancer patients, 159 (93%) gave broad consent for biobanking of their tissue and blood specimens for future cancer research projects receiving ethical and scientific approval. None of the factors analyzed was shown to influence a patient’s decision to contribute biological specimens and clinical data to a biorepository for future medical research. Conclusion: Biobanking for future ethically and scientifically approved research projects in an established institution is an initiative that receives strong support from patients undergoing cancer surgery, independent of factors including gender, age, type of tumor, type of institution where surgery was performed, or timing of consent.
Introduction
T
he importance of cancer patients as enablers of translational cancer research cannot be overestimated. Stored residual tissue from cancer patients, not required for their diagnosis, is often held in institutional biorepositories worldwide and includes fresh frozen or paraffin embedded tumor and normal tissue, blood, serum, or plasma, and in some cases other body fluids such as ascites or saliva. The value of these samples is greatly enhanced by the collection of parallel diagnostic, treatment, and outcome data. Research studies use these specimens to enable translation of discoveries made in model cancer systems to patient populations where they inform new diagnostic and/or prognostic tests, as well as being integral to the design of new cancer therapies. Undoubtedly, our current level of under-
standing of cancer biology and the progress made thus far in treating cancer has been greatly informed by access to biobanked samples from cancer patients.1 There are a number of models of informed patient consent for biobanking, largely driven by the ethical guidelines of different countries and various institutions within countries. Studies have investigated models of patient preference for broad or one-time general consent whereby patients agree to have their specimens stored indefinitely for any future ethically and scientifically approved projects, the exact nature of which may be unknown at the time of consent, versus consent for specific known projects.2–5 Broad consent enables specimens to be used in research projects accessing cutting edge technologies that may not have been developed at the time of patient consent without returning to the patient years, sometimes decades, later for the purpose of consent.
Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
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This is generally considered as the preferred model. While studies from around the world indicate that the majority of patients approached to consent for biobanking accede to this request, there are only a small number of studies that have investigated factors that may influence this decision.6–8 In this study we sought to examine a number of factors that may influence the likelihood of broad patient consent for biobanking.
Methods Study design The Kolling Institute of Medical Research (KIMR) Tumor Banks was established in 1992, with collection of specific tumor types embedded in the culture of this medical research institute and associated hospitals, specifically the public (government-run) university hospital Royal North Shore Hospital, Sydney, NSW, Australia (hereafter referred to as the public hospital) and the privately owned and run hospital North Shore Private, both located at a single site. This study took place over a 6-month period ( June to November 2013) and involved patients undergoing surgery to remove their tumor at Royal North Shore Hospital or North Shore Private. An opt-in model was used with patients being approached by one of three tumor bank staff (two female, one male; mean age 32 years, range 26 to 37 years) to give written informed broad consent for biobanking and collection of their clinical information, including pathology reports, treatment, and subsequent outcome data, after first being identified to tumor bank staff by their treating surgeon. Under this model, surgeons did not take informed consent. Informed consent taken by tumor bank staff ranged from 5 to 30 minutes, largely determined by the number of questions asked by the patient. Patients were not recontacted for collection of follow-up information; this was collected from their medical record. Data were recorded on factors that may conceivably influence a patient’s willingness to give broad consent for biobanking, including: gender, age at time of surgery, type of malignancy (breast, duodenal, cervical, endometrial, gastric, liver, esophageal, ovarian, pancreatic, pelvic, uterine, or vulval), whether surgery was undertaken in a public or private hospital, as well as timing of consent (preadmission clinic or on the ward, either pre- or post-operatively).
Participants and ethics statement Overall, 171 patients were approached to consent for biobanking during this study, 94 patients through the public hospital and 77 through the private hospital. Of these patients, 139 were female and 32 male, with gender bias reflecting the number of patients with breast or gynecological malignancies in this study. Median patient age was 62 years (range 20 to 89 years) at the time of consent (Table 1). The KIMR biobanking program is approved by the Northern Sydney Local Health District Research Ethics Committee under separate approvals based on tumor type (KIMR Gynaecological Tumor and Tissue Bank [Approval #0310-209B], KIMR and University of Sydney Endocrine and Oncology Surgical Unit Breast Bank [Approval #0308166B] and the KIMR Upper Gastrointestinal Bank [Approval #0111-178M]). Patients gave broad consent to having blood and tumor specimens collected and stored for future
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Table 1. Characteristics of Cancer Patients and Factors Tested that May Influence their Likelihood of Consent for Biobanking Variable
Study Cohort N = 171 (%)
Consent granted Yes (%) No(%)
Gender female 139 (81%) 129 (93) 10 male 32 (19%) 30 (94) 2 overall 171 159 (93) 12 Age in years at time of consent (median, 62 years) 20–29 2 (1%) 2 (100) 0 30–39 7 (4%) 7 (100) 0 40–49 26 (15%) 24 (92) 2 50–59 37 (22%) 34 (92) 3 60–69 52 (31%) 48 (92) 4 70–79 33 (19%) 30 (91) 3 80–89 14 (8%) 14 (100) 0 ‡ 60 99 (58%) 92 (93) 7 ‡ 20 and £ 59 72 (42%) 67 (93) 5 Cancer diagnosis* ovarian 41 (24%) 37 (90) 4 breast 40 (24%) 35 (87.5) 5 pancreatic 27 (16%) 26 (96) 1 liver 22 (13%) 21 (95) 1 endometrial 22 (13%) 21 (95) 1 gastric 5 (3%) 5 (100) 0 esophageal 4 (2%) 4 (100) 0 cervical 2 (1%) 2 (100) 0 duodenal 2 (1%) 2 (100) 0 vulval 2 (1%) 2 (100) 0 uterine 2 (1%) 2 (100) 0 pelvic 1 (< 1%) 1 (100) 0 Timing of request for consent preadmission 86 (50%) 81 (94) 5 clinic pre-operatively 26 (15%) 23 (88) 3 on ward post-operatively 59 (35%) 55 (93) 4 on ward ward (pre- or post-surgery) 78 (92) 7 pre-surgery (ward or 104 (93) 8 preadmissions clinic) Hospital public 94 (55%) 89 (95) 5 private 77 (45%) 70 (91) 7
(7) (6) (7) (0) (0) (8) (8) (8) (9) (0) (7) (7) (10) (12.5) (4) (5) (5) (0) (0) (0) (0) (0) (0) (0) (6) (12) (7) (8) (7) (5) (9)
*Surgery did not proceed for one patient, and tumor type was not recorded.
ethically and scientifically approved research projects. Patients were able to revoke their consent at any time, resulting in destruction of their samples and clinical information, with the caveat that samples may have already been used in research studies if revocation of consent was made months to years after collection of specimens. An example of patient consent documentation approved by the Human Research Ethics Committee used for tumor banking is in the supplementary material in the online version of the article at www.liebertpub.com/bio.
Statistical analyses Data analyses were performed using IBM SPSS software version 21.0 (SPSS Australasia Pty Ltd., Chatswood, NSW,
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Australia). The Fisher’s exact two-sided test was used to determine whether there were differences in patient consent in relation to factors considered that may conceivably impact on consent. P < 0.05 was considered statistically significant.
Results Whether patients granted consent, or not, for having their specimens included in a KIMR biobank was recorded under categories considered to be potentially influential for this decision, specifically gender, age in years at time of consent (10 year age brackets), tumor type (ovarian, breast, pancreatic, liver, endometrial, gastric, esophageal, cervical, duodenal, vulval, uterine, or pelvic), time at which consent was taken (preadmission clinic, pre- or post-surgery on the ward) and whether surgery was undertaken in a public or private hospital (Table 1). The consenting process required use of an interpreter for a single, non-English speaking patient with pancreatic cancer as per ethical guidelines. Characteristics of the patient cohort are summarized in Table 1. Of the 171 cancer patients approached to consent for biobanking, 159 patients (93%) gave their consent, including the patient who required use of an interpreter (Tables 1 and 2). In order to avoid the confounding issue of small group sizes for statistical analyses, some category classifications were combined. None of the factors tested—gender, age, tumor type, timing of request or hospital—influenced patient consent for biobanking (Table 2).
Discussion The ability of cancer biobanks to facilitate translational research relies fundamentally on consent being given by cancer patients for the collection and storage of biospecimens in excess of that required for diagnosis. Our consenting procedure for biobanking involves direct interaction between dedicated tumor bank staff and cancer patients to obtain their permission via informed consent (i.e., ‘opt-in’ model) to
Table 2. Analysis of Factors that May Influence Cancer Patient Consent for Biobanking Factor Gender female vs male Age in years at time of consent ‡ 60 yrs vs £ 59 yrs Tumor type liver vs all other cancers breast vs all other cancers pancreas vs all other cancers ovarian vs all other cancers endometrial vs all other cancers Timing of request for consent preadmission clinic vs ward (pre- or post-surgery) pre-surgery (ward or preadmissions clinic) vs post-surgery Hospital public vs private *Fisher’s exact 2-sided test.
p value* 1.000 1.000 1.000 0.156 0.693 0.486 1.000 0.566 1.000 0.379
having their samples collected and stored for future ethically and scientifically approved research projects. This is a broad consent suitable for longitudinal research conducted on biobanked specimens and corresponding clinical information.4 This model of broad consent is similar to that operational in some other Australian institutions.9 The importance of personal ‘‘face-to-face’’ interaction with a health professional regarding informed consent has been previously reported, providing patients with the opportunity to ask questions.10 The option to revoke consent has been recognized as an important factor for informed consent and was included in our patient consent documentation.11 Ninety-three percent of patients in this study consented for biobanking. Reported studies of patient consent for biobanking generally state similarly high levels of consent independently of consenting models used. While the small percentage of patients refusing consent placed limitations on performing some additional analyses, such as combinations of factors like age and gender, it is important to note the practical relevance of this study and the fact that our findings of high consent rate are consistent with other published studies of variable cohort size and geographical location. The Eastern Co-operative Oncology Group (ECOG) reported between 89.4%–93.7 % consent rate for future storage and use of biological specimens remaining after therapeutic cancer clinical trials.7 A meta-analysis involving multiple countries (Sweden, Iceland, the United Kingdom, Ireland, the United States, and Singapore) reporting on hypothetical willingness versus factual consent to open-ended storage of samples for cancer research projects showed that in the majority of cases, actual willingness to participate in biobanking was greater than hypothetical willingness based on public attitudes to biobanking research.8 Reasons suggested in this study as to why rates were lower in studies reporting on hypothetical willingness included the involvement of commercial interests and concerns regarding genetic research. Reasons for higher rates of consent for biobanking amongst cancer patients engaging in the consenting process included the realization of the potential that their choice could positively impact and enable future research, as well as contribute to an established trust relationship between themselves and health professionals involved in their care, that included a desire to ‘give back’ through participation. Another study of the attitude of male patients attending urology clinics to the potential donation of prostate tissue samples for research revealed that 84.5% of respondents believed they would be willing to donate to a biorepository if undergoing surgery.12 A US study reported over 86% of patients consenting to biobanking, with 83% requesting to be notified regarding incidental findings on their samples.13 There are limited studies presenting data as to the factors that may influence a cancer patient’s decision to consent to biobanking. Our study showed that there was no difference whether patients were male or female as to the likelihood of patient consent, consistent with other published studies.7,14 Furthermore, no differences were identified dependent upon patient age, consistent with a previous study.14 This was in contrast to an alternative study that reported a slightly increased percent of consent for biobanking in patients aged 65 years or over.7 In this study, a higher level of consent from older patients was suggested to relate to a greater sense of societal responsibility or perhaps a greater willingness to agree to the request of a health professional. A study
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investigating factors that may influence the decision of a male to donate to a prostate tissue biorepository showed higher willingness to donate in men over 55 years of age with a positive attitude to new discoveries in genetics and cancer.12 Whether surgery is conducted in public or private hospitals could be considered as an indirect measure of socioeconomic status in the Australian health system. Our study showed no difference in patient consent for biobanking between public or private hospitals. It was conceivable that the type of tumor a patient has may influence willingness to consent for biobanking. For instance, patients with a tumor type for which prognosis is generally poor such as pancreatic cancer15 might respond to requests for biobanking in a different manner from a patient with a tumor that has a relatively good prognosis. We did not observe any differences for consenting based on tumor type, although it is acknowledged that a limitation of our study is the number of samples in some of these categories. This finding was consistent with another study compiled of patients with tumors including breast, upper gastrointestinal, lymphoma, lung, melanoma, leukemia, and myeloma,7 as well as a study of patients with colorectal cancer, breast cancer, or hematological malignancy.14 A French study of 574 cancer patients also reported no influence of age, gender, or cancer type (colorectal, breast, or hematological malignancy) on consent for biobanking.14 Of note in this study, accurate recall by patients of whether they had consented for biobanking was statistically higher for patients who claimed to have received the consent form during follow-up or treatment rather than at first admission.14 The time at which patients were approached to consent for biobanking may then conceivably influence their willingness to consent; however, no differences were observed in the current study. It has been suggested that consenting pre-operatively may add to the anxiety many patients feel prior to surgery and further, that patients may feel that a decision to withhold consent may influence the quality of their clinical care, generating an element of perceived coercion surrounding this decision.16 Conversely, consenting post-operatively may raise issues of preoccupation with ongoing medical care and impaired judgement due to medication.16 In a study based on structured interviews of 30 English-speaking patients (age range 44 to 85 years; mean age 64.1 years) who had had surgery for cancer in the last 2 years, two-thirds reported that they would be more receptive to consenting for biobanking if approached post-surgery.10 At Royal North Shore Hospital, most cancer patients attend a preadmission clinic 1-2 weeks prior to their surgery; however, far fewer patients attend a similar clinic in the private hospital system, with breast cancer patients not required to attend at all. Advantages of embedding a consenting process into preadmission clinics include additional time for the patient to consider information supplied to them, a less stressful environment than immediately presurgery, and increased privacy for the patient, as tumor bank staff can consent patients in a private space prior to surgery that fosters a greater trust relationship. Advantages for tumor bank staff are also evident including that on the day of surgery, their focus can be on collecting and processing specimens and not on patient consent. A Canadian study of structured public deliberation determined that timing of consent should consider that the patient should not be in pain, should be of clear mind and able to make a decision;
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the patient’s clinical needs should be placed first and the nature of the biobank should be explained; the consenting process should nurture societal trust in biobanking; and that the consenting process should foster a positive relationship between the patient and the research team.17 Ultimately from the perspective of the patient, timing of consent is perhaps best considered on a case-by-case basis; however, collection of blood specimens for research projects designed to analyze potential tumor biomarkers in the circulation, such as microRNA or proteins directly related to the tumor, does require collection prior to tumor resection. As blood taken for research purposes is additional to that required for clinical management, the patient must consent to this procedure prior to surgery. For research projects wishing to analyze constitutive DNA however, the timing of blood collection is not critical. The high consent rate for tissue banking reported worldwide has been attributed to a number of reasons including altruism with the opportunity to help others, the hope that either oneself or close family will benefit from research conducted on specimens, a desire to please health professionals and/or respond to acts of kindness by health professionals.10,18–22 While not appearing to be large factors given the high rates of consent for biobanking generally observed worldwide, factors suggested to account for an unwillingness to consent to biobanking include concerns regarding breach of privacy,23 the value attached to human tissue by some cultures, as well as a perceived lack of control.18 Further, unlike for organ donation, public awareness of biorepositories is reported to be low,24 despite biobanks being listed in TIME Magazine in 2009 as one of the ‘ten ideas changing the world right now’.25 Studies that have investigated patient perspective of the impact of commercial gain from biobanked specimens versus not-for-profit research have reported that patients prefer their samples to be used for nonprofit research.12 Interestingly, one study of males attending a urology clinic found that both blood donors and organ donation card carriers were more likely to donate their urological tissue to a biobank for research purposes.26 The advent of next generation sequencing, emerging recommendations regarding return of research results, and the real possibility of incidental findings from research studies that may have major impact on the health of individuals and/or family members,27–31 may conceivably influence patient consent for future research on biobanked specimens, as public awareness increases regarding current research capabilities and what these can mean directly for the management of individuals’ health.
Conclusion Biobanking at established institutions to support ethically and scientifically approved research that may be months or decades away, receives strong support from patients undergoing cancer surgery. Patient consent for biobanking under these conditions was not shown in this study to be dependent on gender, age, type of tumor, type of institution where surgery was performed, or timing of consent. While the vast majority of cancer patients consented to biobanking in this study, reasons why 7% did not were unclear and likely involved complex decision making processes involving multiple factors specific to individual patients. The extent to which surgeons or other health professionals,
INFLUENCES ON BIOBANKING CONSENT
including tumor bank staff, may have influenced a patient’s decision to consent for tumor banking could be addressed in a future study. As countries move towards establishment of governance structures for return of research results, including incidental findings from research conducted on biobanked specimens, it will be important to carefully monitor the potential impact on broad patient consent for biobanking with ongoing studies of patient choices and attitudes towards biobanking.
Acknowledgments Jillian Patterson is acknowledged for statistical assistance. We would like to acknowledge the support of numerous surgeons, nurses, anesthetists, theatre staff, and pathologists who are integral to the complex networks that enable successful tumor banking. We would also like to acknowledge the generosity of patients who have contributed to KIMR tumor banks.
Author Disclosure Statement None of the authors has an institutional or commercial affiliation that poses a potential conflict of interest with respect to publication of this article. This work was supported by the Cancer Institute NSW, Sydney, Australia through funding to the Northern Translational Cancer Research Unit (11/TRU/1-10), the Australian Research Council (ARC) (ARC Future Fellowship [FT100100489] to D.J.M), and National Health and Medical Research Council (NHMRC) (NHMRC Senior Research Fellowship [APP1004799] to D.J.M).
References 1. Gundara JS, Sidhu SB. Tissue banking and its role in clinical and biological advances in oncology. Cancer Forum 2013;37:67–70. 2. Vermeulen E, Schmidt MK, Aaronson NK, et al. A trial of consent procedures for future research with clinically derived biological samples. Br J Cancer 2009;101:1505–1512. 3. Vermeulen E, Schmidt MK, Aaronson NK, et al. Opt-out plus, the patients’ choice: preferences of cancer patients concerning information and consent regimen for future research with biological samples archived in the context of treatment. J Clinical Pathol 2009;62:275–278. 4. Steinsbekk KS, Kare Myskja B, Solberg B. Broad consent versus dynamic consent in biobank research: Is passive participation an ethical problem? Eur J Hum Genet 2013; 21:897–902. 5. Wendler D. Consent for research with biological samples: One-time general consent versus a gift model. Ann Intern Med 2012;156:596–598. 6. Johnsson L, Hansson MG, Eriksson S, et al. Patients’ refusal to consent to storage and use of samples in Swedish biobanks: Cross sectional study. BMJ (Clinical research ed). 2008;337:a345. 7. Malone T, Catalano PJ, O’Dwyer PJ, et al. High rate of consent to bank biologic samples for future research: The Eastern Cooperative Oncology Group experience. J Natl Cancer I 2002;94:769–771. 8. Johnsson L, Helgesson G, Rafnar T, et al. Hypothetical and factual willingness to participate in biobank research. Eur J Hum Genet 2010;18:1261–1264.
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9. Wyld L, Smith S, Hawkins NJ, et al. Introducing research initiatives into healthcare: What do doctors think? Biopreserv Biobank 2014;12:91–98. 10. Braun KL, Tsark JU, Powers A, et al. Cancer patient perceptions about biobanking and preferred timing of consent. Biopreserv Biobank 2014;12:106–112. 11. Jurate S, Zivile V, Eugenijus G. ‘Mirroring’ the ethics of biobanking: What analysis of consent documents can tell us? Sci Eng Ethics 2014;20:1079–1093. 12. Fitzpatrick PE, McKenzie KD, Beasley A, et al. Patients attending tertiary referral urology clinics: Willingness to participate in tissue banking. BJU Int 2009;104:209– 213. 13. Marsolo K, Corsmo J, Barnes MG, et al. Challenges in creating an opt-in biobank with a registrar-based consent process and a commercial EHR. J Am Med Inform Assn 2012;19:1115–1118. 14. Mancini J, Pellegrini I, Viret F, et al. Consent for biobanking: Assessing the understanding and views of cancer patients. J Natl Cancer I 2011;103:154–157. 15. Hidalgo M. Pancreatic cancer. New Eng J Med 2010;362: 1605–1617. 16. Hewitt R, Watson PH, Dhir R, et al. Timing of consent for the research use of surgically removed tissue: Is postoperative consenting acceptable? Cancer 2009;115:4–9. 17. O’Doherty KC, Hawkins AK, Burgess MM. Involving citizens in the ethics of biobank research: Informing institutional policy through structured public deliberation. Soc Sci Med 2012;75:1604–1611. 18. Axler RE, Irvine R, Lipworth W, et al. Why might people donate tissue for cancer research? Insights from organ/ tissue/blood donation and clinical research. Pathobiology 2008;75:323–329. 19. Morrell B, Lipworth W, Axler R, et al. Cancer as rubbish: Donation of tumor tissue for research. Qual Health Res 2011;21:75–84. 20. Lipworth W, Forsyth R, Kerridge I. Tissue donation to biobanks: A review of sociological studies. Sociol Health Ill 2011;33:792–811. 21. Huber J, Herpel E, Jakobi H, et al. Two decades’ experience with a prospective biobank for urologic oncology: Research, clinical care, and the patients’ view. Urol Oncol 2013;31:990–996. 22. Allen J, McNamara B. Reconsidering the value of consent in biobank research. Bioethics 2011;25:155–166. 23. Goddard KA, Smith KS, Chen C, et al. Biobank recruitment: Motivations for nonparticipation. Biopreserv Biobank 2009;7:119–121. 24. Cervo S, Rovina J, Talamini R, et al. An effective multisource informed consent procedure for research and clinical practice: An observational study of patient understanding and awareness of their roles as research stakeholders in a cancer biobank. BMC Med Ethics 2013;14:30. 25. Park A. 10 Ideas Changing the World Right Now. Time. 2009. http://content.time.com/time/specials/packages/article/ 0,28804,1884779_1884782_1884766,0.0.html (accessed, July 16, 2014). 26. McKenzie KD, Fitzpatrick PE, Sheehan JD. Tissue banking: Relationship with blood donor and organ donor card status. ISRN Urol 2012;2012:475729. 27. Wolf SM, Crock BN, Van Ness B, et al. Managing incidental findings and research results in genomic research involving biobanks and archived data sets. Genet Med 2012;14:361–384.
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28. Johns AL, Miller DK, Simpson SH, et al. Returning individual research results for genome sequences of pancreatic cancer. Genome Med 2014;6:42. 29. Zawati MH, Knoppers BM. International normative perspectives on the return of individual research results and incidental findings in genomic biobanks. Genet Med 2012; 14:484–489. 30. Bredenoord AL, Onland-Moret NC, Van Delden JJ. Feedback of individual genetic results to research participants: In favor of a qualified disclosure policy. Hum Mutat 2011;32:861–867. 31. Egalite N, Groisman IJ, Godard B. Genetic counseling practice in next generation sequencing research: Implica-
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tions for the ethical oversight of the informed consent process. J Genet Counsel 2014;23:661–670.
Address correspondence to: Dr. Deborah J. Marsh Kolling Institute of Medical Research Royal North Shore Hospital St Leonards Sydney, NSW 2065 Australia E-mail: [email protected]
Factors that May Influence the Willingness of Cancer Patients to Consent for Biobanking Ussha Pillai, Kathleen Phillips, Graham Wilkins, Robert C. Baxter, Diana E. Benn, Nicole R Parker, Ross C Smith, and Deborah J Marsh
Background: Broad or general consent given by cancer patients for their tissue, blood, and clinical information to be stored in institutional biorepositories is fundamental to enable future ethical translational cancer research. The decision to consent for biobanking will contribute to the development of advanced diagnostic and prognostic tests, as well as new therapies to improve patient outcomes. While the rate of patient participation in biobanking programs is generally reported as high worldwide, few studies have investigated factors that may influence this decision. Biobanking at our medical research institute, an associated public (government-run) university hospital, and private hospital has been established for over 20 years, with collection of certain tumor types embedded in the research culture of these institutions. In this study, we investigated factors that may influence a cancer patient’s decision to give broad consent for biobanking of their specimens. Methods: Data on patient consent were collected over a 6-month period from both government and private hospitals associated with our medical research institute. Factors considered included gender, patient age at surgery, type of malignancy (breast, duodenal, cervical, endometrial, gastric, liver, esophageal, ovarian, pancreatic, pelvic, uterine, or vulval), type of institution where surgery was performed, and timing of consent. Results: Of 171 cancer patients, 159 (93%) gave broad consent for biobanking of their tissue and blood specimens for future cancer research projects receiving ethical and scientific approval. None of the factors analyzed was shown to influence a patient’s decision to contribute biological specimens and clinical data to a biorepository for future medical research. Conclusion: Biobanking for future ethically and scientifically approved research projects in an established institution is an initiative that receives strong support from patients undergoing cancer surgery, independent of factors including gender, age, type of tumor, type of institution where surgery was performed, or timing of consent.
Introduction
T
he importance of cancer patients as enablers of translational cancer research cannot be overestimated. Stored residual tissue from cancer patients, not required for their diagnosis, is often held in institutional biorepositories worldwide and includes fresh frozen or paraffin embedded tumor and normal tissue, blood, serum, or plasma, and in some cases other body fluids such as ascites or saliva. The value of these samples is greatly enhanced by the collection of parallel diagnostic, treatment, and outcome data. Research studies use these specimens to enable translation of discoveries made in model cancer systems to patient populations where they inform new diagnostic and/or prognostic tests, as well as being integral to the design of new cancer therapies. Undoubtedly, our current level of under-
standing of cancer biology and the progress made thus far in treating cancer has been greatly informed by access to biobanked samples from cancer patients.1 There are a number of models of informed patient consent for biobanking, largely driven by the ethical guidelines of different countries and various institutions within countries. Studies have investigated models of patient preference for broad or one-time general consent whereby patients agree to have their specimens stored indefinitely for any future ethically and scientifically approved projects, the exact nature of which may be unknown at the time of consent, versus consent for specific known projects.2–5 Broad consent enables specimens to be used in research projects accessing cutting edge technologies that may not have been developed at the time of patient consent without returning to the patient years, sometimes decades, later for the purpose of consent.
Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
409
410
This is generally considered as the preferred model. While studies from around the world indicate that the majority of patients approached to consent for biobanking accede to this request, there are only a small number of studies that have investigated factors that may influence this decision.6–8 In this study we sought to examine a number of factors that may influence the likelihood of broad patient consent for biobanking.
Methods Study design The Kolling Institute of Medical Research (KIMR) Tumor Banks was established in 1992, with collection of specific tumor types embedded in the culture of this medical research institute and associated hospitals, specifically the public (government-run) university hospital Royal North Shore Hospital, Sydney, NSW, Australia (hereafter referred to as the public hospital) and the privately owned and run hospital North Shore Private, both located at a single site. This study took place over a 6-month period ( June to November 2013) and involved patients undergoing surgery to remove their tumor at Royal North Shore Hospital or North Shore Private. An opt-in model was used with patients being approached by one of three tumor bank staff (two female, one male; mean age 32 years, range 26 to 37 years) to give written informed broad consent for biobanking and collection of their clinical information, including pathology reports, treatment, and subsequent outcome data, after first being identified to tumor bank staff by their treating surgeon. Under this model, surgeons did not take informed consent. Informed consent taken by tumor bank staff ranged from 5 to 30 minutes, largely determined by the number of questions asked by the patient. Patients were not recontacted for collection of follow-up information; this was collected from their medical record. Data were recorded on factors that may conceivably influence a patient’s willingness to give broad consent for biobanking, including: gender, age at time of surgery, type of malignancy (breast, duodenal, cervical, endometrial, gastric, liver, esophageal, ovarian, pancreatic, pelvic, uterine, or vulval), whether surgery was undertaken in a public or private hospital, as well as timing of consent (preadmission clinic or on the ward, either pre- or post-operatively).
Participants and ethics statement Overall, 171 patients were approached to consent for biobanking during this study, 94 patients through the public hospital and 77 through the private hospital. Of these patients, 139 were female and 32 male, with gender bias reflecting the number of patients with breast or gynecological malignancies in this study. Median patient age was 62 years (range 20 to 89 years) at the time of consent (Table 1). The KIMR biobanking program is approved by the Northern Sydney Local Health District Research Ethics Committee under separate approvals based on tumor type (KIMR Gynaecological Tumor and Tissue Bank [Approval #0310-209B], KIMR and University of Sydney Endocrine and Oncology Surgical Unit Breast Bank [Approval #0308166B] and the KIMR Upper Gastrointestinal Bank [Approval #0111-178M]). Patients gave broad consent to having blood and tumor specimens collected and stored for future
PILLAI ET AL.
Table 1. Characteristics of Cancer Patients and Factors Tested that May Influence their Likelihood of Consent for Biobanking Variable
Study Cohort N = 171 (%)
Consent granted Yes (%) No(%)
Gender female 139 (81%) 129 (93) 10 male 32 (19%) 30 (94) 2 overall 171 159 (93) 12 Age in years at time of consent (median, 62 years) 20–29 2 (1%) 2 (100) 0 30–39 7 (4%) 7 (100) 0 40–49 26 (15%) 24 (92) 2 50–59 37 (22%) 34 (92) 3 60–69 52 (31%) 48 (92) 4 70–79 33 (19%) 30 (91) 3 80–89 14 (8%) 14 (100) 0 ‡ 60 99 (58%) 92 (93) 7 ‡ 20 and £ 59 72 (42%) 67 (93) 5 Cancer diagnosis* ovarian 41 (24%) 37 (90) 4 breast 40 (24%) 35 (87.5) 5 pancreatic 27 (16%) 26 (96) 1 liver 22 (13%) 21 (95) 1 endometrial 22 (13%) 21 (95) 1 gastric 5 (3%) 5 (100) 0 esophageal 4 (2%) 4 (100) 0 cervical 2 (1%) 2 (100) 0 duodenal 2 (1%) 2 (100) 0 vulval 2 (1%) 2 (100) 0 uterine 2 (1%) 2 (100) 0 pelvic 1 (< 1%) 1 (100) 0 Timing of request for consent preadmission 86 (50%) 81 (94) 5 clinic pre-operatively 26 (15%) 23 (88) 3 on ward post-operatively 59 (35%) 55 (93) 4 on ward ward (pre- or post-surgery) 78 (92) 7 pre-surgery (ward or 104 (93) 8 preadmissions clinic) Hospital public 94 (55%) 89 (95) 5 private 77 (45%) 70 (91) 7
(7) (6) (7) (0) (0) (8) (8) (8) (9) (0) (7) (7) (10) (12.5) (4) (5) (5) (0) (0) (0) (0) (0) (0) (0) (6) (12) (7) (8) (7) (5) (9)
*Surgery did not proceed for one patient, and tumor type was not recorded.
ethically and scientifically approved research projects. Patients were able to revoke their consent at any time, resulting in destruction of their samples and clinical information, with the caveat that samples may have already been used in research studies if revocation of consent was made months to years after collection of specimens. An example of patient consent documentation approved by the Human Research Ethics Committee used for tumor banking is in the supplementary material in the online version of the article at www.liebertpub.com/bio.
Statistical analyses Data analyses were performed using IBM SPSS software version 21.0 (SPSS Australasia Pty Ltd., Chatswood, NSW,
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Australia). The Fisher’s exact two-sided test was used to determine whether there were differences in patient consent in relation to factors considered that may conceivably impact on consent. P < 0.05 was considered statistically significant.
Results Whether patients granted consent, or not, for having their specimens included in a KIMR biobank was recorded under categories considered to be potentially influential for this decision, specifically gender, age in years at time of consent (10 year age brackets), tumor type (ovarian, breast, pancreatic, liver, endometrial, gastric, esophageal, cervical, duodenal, vulval, uterine, or pelvic), time at which consent was taken (preadmission clinic, pre- or post-surgery on the ward) and whether surgery was undertaken in a public or private hospital (Table 1). The consenting process required use of an interpreter for a single, non-English speaking patient with pancreatic cancer as per ethical guidelines. Characteristics of the patient cohort are summarized in Table 1. Of the 171 cancer patients approached to consent for biobanking, 159 patients (93%) gave their consent, including the patient who required use of an interpreter (Tables 1 and 2). In order to avoid the confounding issue of small group sizes for statistical analyses, some category classifications were combined. None of the factors tested—gender, age, tumor type, timing of request or hospital—influenced patient consent for biobanking (Table 2).
Discussion The ability of cancer biobanks to facilitate translational research relies fundamentally on consent being given by cancer patients for the collection and storage of biospecimens in excess of that required for diagnosis. Our consenting procedure for biobanking involves direct interaction between dedicated tumor bank staff and cancer patients to obtain their permission via informed consent (i.e., ‘opt-in’ model) to
Table 2. Analysis of Factors that May Influence Cancer Patient Consent for Biobanking Factor Gender female vs male Age in years at time of consent ‡ 60 yrs vs £ 59 yrs Tumor type liver vs all other cancers breast vs all other cancers pancreas vs all other cancers ovarian vs all other cancers endometrial vs all other cancers Timing of request for consent preadmission clinic vs ward (pre- or post-surgery) pre-surgery (ward or preadmissions clinic) vs post-surgery Hospital public vs private *Fisher’s exact 2-sided test.
p value* 1.000 1.000 1.000 0.156 0.693 0.486 1.000 0.566 1.000 0.379
having their samples collected and stored for future ethically and scientifically approved research projects. This is a broad consent suitable for longitudinal research conducted on biobanked specimens and corresponding clinical information.4 This model of broad consent is similar to that operational in some other Australian institutions.9 The importance of personal ‘‘face-to-face’’ interaction with a health professional regarding informed consent has been previously reported, providing patients with the opportunity to ask questions.10 The option to revoke consent has been recognized as an important factor for informed consent and was included in our patient consent documentation.11 Ninety-three percent of patients in this study consented for biobanking. Reported studies of patient consent for biobanking generally state similarly high levels of consent independently of consenting models used. While the small percentage of patients refusing consent placed limitations on performing some additional analyses, such as combinations of factors like age and gender, it is important to note the practical relevance of this study and the fact that our findings of high consent rate are consistent with other published studies of variable cohort size and geographical location. The Eastern Co-operative Oncology Group (ECOG) reported between 89.4%–93.7 % consent rate for future storage and use of biological specimens remaining after therapeutic cancer clinical trials.7 A meta-analysis involving multiple countries (Sweden, Iceland, the United Kingdom, Ireland, the United States, and Singapore) reporting on hypothetical willingness versus factual consent to open-ended storage of samples for cancer research projects showed that in the majority of cases, actual willingness to participate in biobanking was greater than hypothetical willingness based on public attitudes to biobanking research.8 Reasons suggested in this study as to why rates were lower in studies reporting on hypothetical willingness included the involvement of commercial interests and concerns regarding genetic research. Reasons for higher rates of consent for biobanking amongst cancer patients engaging in the consenting process included the realization of the potential that their choice could positively impact and enable future research, as well as contribute to an established trust relationship between themselves and health professionals involved in their care, that included a desire to ‘give back’ through participation. Another study of the attitude of male patients attending urology clinics to the potential donation of prostate tissue samples for research revealed that 84.5% of respondents believed they would be willing to donate to a biorepository if undergoing surgery.12 A US study reported over 86% of patients consenting to biobanking, with 83% requesting to be notified regarding incidental findings on their samples.13 There are limited studies presenting data as to the factors that may influence a cancer patient’s decision to consent to biobanking. Our study showed that there was no difference whether patients were male or female as to the likelihood of patient consent, consistent with other published studies.7,14 Furthermore, no differences were identified dependent upon patient age, consistent with a previous study.14 This was in contrast to an alternative study that reported a slightly increased percent of consent for biobanking in patients aged 65 years or over.7 In this study, a higher level of consent from older patients was suggested to relate to a greater sense of societal responsibility or perhaps a greater willingness to agree to the request of a health professional. A study
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investigating factors that may influence the decision of a male to donate to a prostate tissue biorepository showed higher willingness to donate in men over 55 years of age with a positive attitude to new discoveries in genetics and cancer.12 Whether surgery is conducted in public or private hospitals could be considered as an indirect measure of socioeconomic status in the Australian health system. Our study showed no difference in patient consent for biobanking between public or private hospitals. It was conceivable that the type of tumor a patient has may influence willingness to consent for biobanking. For instance, patients with a tumor type for which prognosis is generally poor such as pancreatic cancer15 might respond to requests for biobanking in a different manner from a patient with a tumor that has a relatively good prognosis. We did not observe any differences for consenting based on tumor type, although it is acknowledged that a limitation of our study is the number of samples in some of these categories. This finding was consistent with another study compiled of patients with tumors including breast, upper gastrointestinal, lymphoma, lung, melanoma, leukemia, and myeloma,7 as well as a study of patients with colorectal cancer, breast cancer, or hematological malignancy.14 A French study of 574 cancer patients also reported no influence of age, gender, or cancer type (colorectal, breast, or hematological malignancy) on consent for biobanking.14 Of note in this study, accurate recall by patients of whether they had consented for biobanking was statistically higher for patients who claimed to have received the consent form during follow-up or treatment rather than at first admission.14 The time at which patients were approached to consent for biobanking may then conceivably influence their willingness to consent; however, no differences were observed in the current study. It has been suggested that consenting pre-operatively may add to the anxiety many patients feel prior to surgery and further, that patients may feel that a decision to withhold consent may influence the quality of their clinical care, generating an element of perceived coercion surrounding this decision.16 Conversely, consenting post-operatively may raise issues of preoccupation with ongoing medical care and impaired judgement due to medication.16 In a study based on structured interviews of 30 English-speaking patients (age range 44 to 85 years; mean age 64.1 years) who had had surgery for cancer in the last 2 years, two-thirds reported that they would be more receptive to consenting for biobanking if approached post-surgery.10 At Royal North Shore Hospital, most cancer patients attend a preadmission clinic 1-2 weeks prior to their surgery; however, far fewer patients attend a similar clinic in the private hospital system, with breast cancer patients not required to attend at all. Advantages of embedding a consenting process into preadmission clinics include additional time for the patient to consider information supplied to them, a less stressful environment than immediately presurgery, and increased privacy for the patient, as tumor bank staff can consent patients in a private space prior to surgery that fosters a greater trust relationship. Advantages for tumor bank staff are also evident including that on the day of surgery, their focus can be on collecting and processing specimens and not on patient consent. A Canadian study of structured public deliberation determined that timing of consent should consider that the patient should not be in pain, should be of clear mind and able to make a decision;
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the patient’s clinical needs should be placed first and the nature of the biobank should be explained; the consenting process should nurture societal trust in biobanking; and that the consenting process should foster a positive relationship between the patient and the research team.17 Ultimately from the perspective of the patient, timing of consent is perhaps best considered on a case-by-case basis; however, collection of blood specimens for research projects designed to analyze potential tumor biomarkers in the circulation, such as microRNA or proteins directly related to the tumor, does require collection prior to tumor resection. As blood taken for research purposes is additional to that required for clinical management, the patient must consent to this procedure prior to surgery. For research projects wishing to analyze constitutive DNA however, the timing of blood collection is not critical. The high consent rate for tissue banking reported worldwide has been attributed to a number of reasons including altruism with the opportunity to help others, the hope that either oneself or close family will benefit from research conducted on specimens, a desire to please health professionals and/or respond to acts of kindness by health professionals.10,18–22 While not appearing to be large factors given the high rates of consent for biobanking generally observed worldwide, factors suggested to account for an unwillingness to consent to biobanking include concerns regarding breach of privacy,23 the value attached to human tissue by some cultures, as well as a perceived lack of control.18 Further, unlike for organ donation, public awareness of biorepositories is reported to be low,24 despite biobanks being listed in TIME Magazine in 2009 as one of the ‘ten ideas changing the world right now’.25 Studies that have investigated patient perspective of the impact of commercial gain from biobanked specimens versus not-for-profit research have reported that patients prefer their samples to be used for nonprofit research.12 Interestingly, one study of males attending a urology clinic found that both blood donors and organ donation card carriers were more likely to donate their urological tissue to a biobank for research purposes.26 The advent of next generation sequencing, emerging recommendations regarding return of research results, and the real possibility of incidental findings from research studies that may have major impact on the health of individuals and/or family members,27–31 may conceivably influence patient consent for future research on biobanked specimens, as public awareness increases regarding current research capabilities and what these can mean directly for the management of individuals’ health.
Conclusion Biobanking at established institutions to support ethically and scientifically approved research that may be months or decades away, receives strong support from patients undergoing cancer surgery. Patient consent for biobanking under these conditions was not shown in this study to be dependent on gender, age, type of tumor, type of institution where surgery was performed, or timing of consent. While the vast majority of cancer patients consented to biobanking in this study, reasons why 7% did not were unclear and likely involved complex decision making processes involving multiple factors specific to individual patients. The extent to which surgeons or other health professionals,
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including tumor bank staff, may have influenced a patient’s decision to consent for tumor banking could be addressed in a future study. As countries move towards establishment of governance structures for return of research results, including incidental findings from research conducted on biobanked specimens, it will be important to carefully monitor the potential impact on broad patient consent for biobanking with ongoing studies of patient choices and attitudes towards biobanking.
Acknowledgments Jillian Patterson is acknowledged for statistical assistance. We would like to acknowledge the support of numerous surgeons, nurses, anesthetists, theatre staff, and pathologists who are integral to the complex networks that enable successful tumor banking. We would also like to acknowledge the generosity of patients who have contributed to KIMR tumor banks.
Author Disclosure Statement None of the authors has an institutional or commercial affiliation that poses a potential conflict of interest with respect to publication of this article. This work was supported by the Cancer Institute NSW, Sydney, Australia through funding to the Northern Translational Cancer Research Unit (11/TRU/1-10), the Australian Research Council (ARC) (ARC Future Fellowship [FT100100489] to D.J.M), and National Health and Medical Research Council (NHMRC) (NHMRC Senior Research Fellowship [APP1004799] to D.J.M).
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Address correspondence to: Dr. Deborah J. Marsh Kolling Institute of Medical Research Royal North Shore Hospital St Leonards Sydney, NSW 2065 Australia E-mail: [email protected]
