Context.—The number of paraffin blocks submitted for patients enrolled in clinical research trials appears to be declining.
Objective.—To obtain information on laboratory policies and procedures in complying with requests to submit paraffin blocks for research.
Design.—A questionnaire was sent to members of a voluntary market research panel composed of pathologists representing a broad spectrum of experience and practice settings. The questions addressed departmental policies and the likely responses to requests to submit pathology materials for patients enrolled in clinical trials.
Results.—The survey was completed by 609 of 762 pathologists (80%) who responded to the invitation. More than 90% of respondents stated that they comply with these requests. Although 14% have a policy precluding the release of blocks for research, 84% of those will send limited tissue samples in lieu of blocks. When tumor is confined to a single block, most laboratories will not release the block but will send unstained slides. Very few laboratories require reimbursement before releasing tissues.
Conclusions.—Pathologists attempt to comply with requests for materials but usually refuse to release the only diagnostic paraffin block so that materials are retained for possible future needs. Other problems identified in this survey include difficulties in getting blocks returned when needed and poor communication between researchers and laboratories. Lack of reimbursement and inadequate consent are not significant barriers to release of materials.
Translational research done in conjunction with clinical trials is an important tool in developing new treatment modalities and improving patient outcomes. Most current randomized phase III clinical trials of cancer treatments prospectively seek patient consent to collect and store formalin-fixed, paraffin-embedded tissue (blocks and/or unstained sections). Despite this consent, however, the percentage of cases in which tissue is submitted to central repositories has decreased in recent years. Comprehensive data on accrual percentages are not readily available, but information from the North American Breast Cancer Group indicates a decline in submissions from more than 90% in the 1990s to approximately 80% today (unpublished data 2009).
The reasons for declines in block submissions are not clear and few data are available on how pathology laboratories respond to requests for paraffin blocks for research purposes. Most publications on this subject have focused on specific issues such as specimen handling, ethics, or informed consent1–3; there have been no systematic assessments of pathology practices.
To gain insight into possible barriers to the submission of blocks on patients enrolled in clinical trials, a questionnaire was sent to a large number of pathology laboratories asking for their typical responses to such requests.
This survey was done in March 2010 using a market research panel composed of a representative cross section of members of the College of American Pathologists: 16% of the panel members have been in practice for 6 to 10 years, 39% for 11 to 20 years, and 45% for 21 or more years. About one-sixth practice in academic settings. Those who would not be expected to receive requests for blocks on cancer patients (eg, forensic pathologists, transfusion medicine specialists) represent only a small percentage of panel members (exact number not available).
E-mail invitations to participate in the survey were sent to 1302 panel members; 24 e-mails were returned as undeliverable. Of the remaining 1278 pathologists, 762 (60%) responded to the invitation. The questions used in the survey are listed in Table 1.
Data were analyzed in aggregate; there was no ability to segregate responses by individual or by practice setting.
Of the 762 pathologists who responded to the invitation, 609 stated that they receive requests to submit tissue blocks for research purposes (question 1); the remaining 153 pathologists exited the survey.
More than 90% of the respondents stated that they comply with requests to send tissue for clinical trials (Table 2). Most of the 65 who chose “Other” to question 2 indicated in their comments that they comply with the request by following departmental and hospital policy. Ten indicated a need to obtain approval from their local institutional review board before submitting materials. Six stated that the pathologist would contact the requestor to determine what materials to submit and 6 said they comply on a “case by case” basis. Only 5 of 597 respondents (0.8%) state that they refuse all such requests.
Eighty-five of 597 institutions (14%) have a policy that prohibits sending any paraffin blocks to another institution for research studies (question 4). This is the pathology department's policy more often than that of the institution (Table 3). Among the 11 commenters who said “Other” to this question, 4 cited “state law” as the origin for this policy. The most common reason given for this policy was to preserve material for future use by the patient (Table 4). Question 7 asked if there is an exception to the policy when the patient has signed a consent that expressly provides for their release: 40.7% said yes, 27.2% said no, and the rest (32.1%) were unsure; however, for those with such a policy, 84% (69 of 82) said they would send tissue samples in lieu of blocks (Table 5).
Only 15% of those surveyed release the paraffin block when the tumor is confined to a single block, but 72% will send unstained recuts or a portion of the block (Table 6). Of the 48 comments received on question 3, almost all said they would attempt to send either a block or recuts, but this was determined on a case by case basis. Similarly, when asked if the likelihood of sending materials would increase if they could send unstained sections or portions of the block (question 18), 80% (455 of 571) said yes. More than 70 comments were received on this question, many referring to a responsibility to maintain materials for possible future use by the patient and a resultant inability to release the only diagnostic material available. There were several comments about limitations in staffing preventing the ability to procure block cores or recuts without reimbursement.
Most departments (79%) have a policy requiring patient consent before releasing any materials (question 9), but the requirements vary among laboratories (Table 7). Among the 50 respondents who said “Other” to question 10, 15 were unsure of the department's requirements on consent, whereas 13 cited the need for approval by another department (institutional review board, legal, research, ethics committee). Only 6.6% of respondents said that the consent form is “usually” or “often” inadequate to release paraffin blocks, whereas 29% said “sometimes” and 39% said “rarely” or “never” (question 11).
When asked if their department asks for reimbursement for costs associated with sending materials (question 12), 29% (171 of 585) said yes; however, only 39 of those 585 laboratories (6.7%) require reimbursement before they will send materials (question 13). A small number of those not requiring reimbursement in advance stated that they are “usually” reimbursed (Table 8), but most survey respondents did not answer this question. Interestingly, although many complained about the time involved in providing this service and the lack of reimbursement, only 73 of 456 pathologists (16%) said that this inhibited their department's willingness to send materials (question 15).
Most respondents (61.5%) knew that paraffin blocks could be retrieved when needed (question 16). When asked if a mechanism to quickly and easily retrieve blocks on request would change the willingness to send blocks (question 17), 46% said no, 28% said yes, and 26% were unsure. There were many comments to questions 18, 19, and 20 noting difficulties in getting blocks returned. Multiple respondents stated that they do not know where these blocks are sent and some no longer release blocks because of difficulties in retrieval. It was noted by several respondents that blocks are not returned when clinical trials are completed.
When asked if the originator of the request influenced the likelihood that blocks would be sent (question 19), 86% said yes, but the 72 comments on this question were mixed and suggest that laboratories tend to be more receptive to well-recognized, noncommercial, and National Cancer Institute–sponsored trials compared with vendor-funded studies or requests from unknown entities. There was no apparent trend toward favoring local researchers; some respondents said they are more open to requests from intramural researchers while a similar number expressed the opposite view.
Many revealing comments came from question 20 regarding what problems are encountered submitting materials to trials (124 comments). Some of these comments described issues unique to the respondent's institution, such as logistics of block storage and retrieval, but a few frustrations were cited repeatedly: requests perceived as “unreasonable” (ie, demands for too much material), time needed to comply, lack of clarity or specificity in requests, poor communication by research coordinators, and lack of knowledge about pathology or histology among personnel tasked with collecting blocks. Several individuals commented that requests made in a spirit of cooperation and respect were more likely to be honored than those perceived as “demands.”
The results of this study indicate that there are no systematic barriers to the release of tissues for research purposes and that most laboratories attempt to comply with requests. Lack of reimbursement and concerns about adequacy of patient consent in particular do not appear to be significant obstacles. This study clearly shows that concerns about the integrity of the patient record, specifically the likelihood of paraffin blocks being exhausted and/or not returned when needed, has a major impact on the likelihood of their being released. Given the growing reliance on image-guided needle biopsies for primary diagnosis and the reduction in average tumor size for some cancers (eg, breast), the increasing frequency of cases with limited diagnostic tissue likely represents the most important reason for the decline in block accrual.
Previous publications on release of tissues for research purposes have distinguished between large tumors in which multiple blocks are available (eg, colonic or ovarian carcinoma) and small neoplastic lesions that are confined to a single block.3,4 Mills et al4 stated that when diagnostic tissue is confined to a single paraffin block, such blocks must be preserved within the responsible pathology department. It appears from this survey that most pathologists follow this recommendation. Refusal to submit the only diagnostic block is also consistent with official College of American Pathologists policy on custodianship of specimens,5 which states “The responsibility to maintain diagnostic material also includes providing appropriate material for institutionally approved research…as long as…diagnostic material remains available in the pathology file for future patient care needs” [italics added].
Similarly, the college's policy on informed consent6 states that “at least one block of diagnostic tissue should be preserved for the minimal retention time of paraffin blocks and should not be used for research, education, quality control, or any other non-diagnostic activities.”
The comments received in this survey indicate that pathologists usually comply with these requests but not by simply sending whatever material is requested. Instead it appears many pathologists try to exercise judgment in deciding what materials to release. Many comments were received about assessing the case to determine whether there is sufficient tissue to release the block and, if not, what can be released while retaining materials for future patient needs. These commenters indicated an unwillingness to release the block when the entire lesional tissue will likely no longer be available and the patient has not expressly consented to this. Many mentioned that requests are handled on a case by case basis. Although this suggests that most pathologists attempt to responsibly manage material for the benefit of individual patients, the result is reduced accrual of blocks for clinical trials.
A related issue involves skepticism about the return of materials when needed. Multiple respondents noted that this was often difficult, sometimes impossible, and tended to inhibit future releases. Although almost half of respondents said that a mechanism to easily retrieve blocks would not change their willingness to release them, this likely reflects a lack of confidence about their return when needed. In most cases the pathologist does not know where the block is stored or how to retrieve it. Some clinical trials have a process for returning blocks, but it appears this information is not readily available to laboratories. Lack of a uniform and reliable method for retrieving blocks clearly contributes to pathologist's hesitancy to release materials.
Adequacy of consent information provided to laboratories was not found to be a significant problem, but there is considerable variation in the details of the consent provided to the pathologist. Some respondents noted that pathologists have neither the time nor the expertise to determine if the consent is adequate to release all diagnostic material; one mentioned that in this case they “release the block and hope for the best.” From these results it appears that pathologists are less concerned about adequacy of the consent than they are that the study has institutional review board approval. Although the consent information provided to laboratories may not represent a major barrier to release, lack of communication about institutional review board approval is a potential obstacle. For those laboratories with a policy precluding release of blocks for research, explicit patient consent does not usually overrule the policy.
A number of respondents commented on lack of reimbursement for costs associated with retrieval and submission of materials, but the data suggest that pathologists rarely refuse to release blocks solely for this reason. Nonetheless, it is likely that this issue (real or perceived) is at least a minor contributor to the decline in block submission.
A small number of respondents stated unequivocally that they were prevented from contributing blocks because of state law or restrictions placed by accreditors. Clinical Laboratory Improvement Amendments of 1988 and the College of American Pathologists require laboratories to retain tissue blocks for at least 10 years (New York State has a 20-year retention requirement), but there is nothing in state or federal law that prevents laboratories from sending blocks to another facility for additional testing when needed. It is not clear why some pathologists have been advised that they cannot also send blocks to another facility for research testing when the patient has given informed consent for this testing and when the blocks can be retrieved. This discrepancy may be partly related to concerns about getting blocks returned but may also be due to erroneous legal advice that this is prohibited by statute. Although not directly addressed in this study, some pathologists and other physicians believe that patients are the rightful owners of their excised tissues; however, no state or federal laws establish individual property interests or ownership rights in tissue specimens used for research.7,8
In summary, declines in submission of paraffin blocks to clinical research trials appears to be due mainly to pathologists' desire to retain access to diagnostic material for future patient needs. This decline is exacerbated by poor communication between clinical trials coordinators and pathology laboratories and by doubts about getting materials returned when requested. Researchers may be able to improve accrual of pathology materials by developing clearer mechanisms for return when needed, by disclosing precisely where these blocks are stored, and by more consistent reimbursement for costs associated with reviewing and preparing materials for release.
The College of American Pathologists (Northfield, Illinois) provided support for this study.
From the Department of Pathology, St Jude Medical Center, Fullerton, California.
The author has no relevant financial interest in the products or companies described in this article.