Biobanking, consent, and commercialization in international genetics research: the Type 1 Diabetes Genetics Consortium.

BACKGROUND: and
PURPOSE: This article describes several ethical, legal, and social issues typical of international genetics biobanking, as encountered in the Type 1 Diabetes Genetics Consortium (T1DGC).
METHODS: By studying the examples set and lessons learned from other international biobanking studies and by devoting considerable time and resources to identifying, addressing, and continually monitoring ethical and regulatory concerns, T1DGC was able to minimize the problems reported by some earlier studies.
CONCLUSIONS: Several important conclusions can be drawn based on the experience in this study: (1) Basic international standards for research ethics review and informed consent are broadly consistent across developed countries. (2) When consent forms are adapted locally and translated into different languages, discrepancies are inevitable and therefore require prompt central review and resolution before research is initiated. (3) Providing separate 'check-box' consent for different elements of a study creates confusion and may not be essential. (4) Creating immortalized cell lines to aid future research is broadly acceptable, both in the US and internationally. (5) Imposing some limits on the use of stored samples aids in obtaining ethics approvals worldwide. (6) Allowing potential commercial uses of donated samples is controversial in some Asian countries. (7) Obtaining government approvals can be labor-intensive and time-consuming, and can require legal and diplomatic skills.

Introduction

The Type 1 Diabetes Genetics Consortium (T1DGC) is an international collaborative project where 34 countries organized into four networks worked toward the common goal of collecting and characterizing individuals with type 1 diabetes in order to develop resources for the purpose of identifying genes that increase (or decrease) an individual’s risk for type 1 diabetes. The basic mechanisms that trigger type 1 diabetes are poorly understood, and T1DGC has also facilitated the study of autoimmunity as a general phenomenon that may be implicated causally in type 1 diabetes. A complete list of the countries that participated in each of the four T1DGC networks can be found on the study website (www.t1dgc.org).

The T1DGC has fostered international collaborative gene identification in type 1 diabetes by (1) conducting research worldwide to ascertain, study, and establish a renewable source of DNA from thousands of families with at least two type 1 diabetic children and two parents (if available); families with one type 1 diabetic child and two parents; and matched pairs of diabetic cases and controls; (2) creating a database for the scientific community with standardized clinical, genetic, and medical history information that would facilitate the search for type 1 diabetes susceptibility genes, and a centralized DNA repository to allow targeted studies of genetic structure and function for type 1 diabetes and other autoimmune diseases; and (3) providing opportunities to extend the results of research to develop methods of risk prediction, prevention, and therapy in the area of type 1 diabetes.

The scale and complexity of this international project, along with its targeted focus on type 1 diabetes and other autoimmune diseases, highlight certain ethical and policy issues that are confronted with increasing frequency both in the field and in scholarship, as large sample repository research becomes more widespread. National biobanks have been established in many countries, and repositories to facilitate research investigating gene–environment interactions, pharmacogenetics, and a wide range of disorders and conditions have been established by the pharmaceutical industry, disease constituency groups, cooperative research groups, the National Institutes of Health (NIH), and even hospital consortia [1]. Numerous attempts to develop consistent and workable policies for biorepositories on a range of important ethical and policy questions, including scope of consent, oversight of future uses, recontact of participants, privacy and confidentiality, and intellectual property considerations are ongoing [2-8]. Our experiences with the Consortium in addressing many of these issues over time and all over the world provide practical examples to help inform biobanking policy and scholarship.

Methods, results, and discussion

Given the international nature of the Consortium, the T1DGC was constructed around four international networks: Asia-Pacific, Europe, North America, and United Kingdom. At the outset of the study, a 10-person Ethical, Legal, and Social Implications (ELSI) Committee was created with one or two representatives from each network, the Coordinating Center (Wake Forest University Health Sciences), and the two funding agencies (National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) and Juvenile Diabetes Research Foundation). It proved to be essential to have a committee with broad interdisciplinary and international composition. At various times in the study, ELSI issues required not only ethical expertise but also legal and diplomatic skills to resolve. The chair of the ELSI Committee devoted 10% of his time to this function over the course of the study. In part, this intensive engagement was needed to meet in person with researchers in each network to explain the nature and source of U.S.-imposed regulatory requirements dealing with the ethics of research. It was necessary both to reassure researchers in some countries that ethical and privacy safeguards were adequate in the United States and to explain the need for requirements that some international researchers viewed as excessive or arbitrary.

Basic informed consent requirements

The ELSI Committee began by reviewing consent forms used in similar studies, such as the National Human Genome Research Institute’s Haplotype Map (HapMap) project [9] and the National Heart, Lung, and Blood Institute’s Hemochromatosis and Iron Overload Screening (HEIRS) study [10]. In addition, network representatives surveyed local investigators in various countries to determine if our basic planned approach would be satisfactory or if there were issues that the committee had not considered. A draft consent form was circulated and revised several times, including testing for readability, before final approval by the Steering Committee. The final form (Appendix 1) served as a template that individual researchers could follow in seeking Ethics Committee (EC) or Institutional Review Board (IRB) approval. Additional model forms were developed, based on the initial model, for participants in affected sibling pair and trio families, including parents of minor study participants and assent forms for minor participants in different age groups; later, model forms were developed for case and control participants.

We recognized that consent practices differ around the world, that various ECs and institutions use different formats for consent forms, and that different committees may require that additional elements be added or that certain elements be worded differently. An explanatory document was therefore created to help guide investigators and oversight bodies in revising and reviewing site-specific consent forms (Appendix 2). Certain elements of the template were viewed as ethically essential to research with humans [11-13], to genetic and biobanking research [14-17], and to this study, or were required to be standardized for biobanking purposes.

The template was largely successful, as indicated by its widespread adoption in different countries. One aspect, however, proved somewhat problematic. Following what were considered to be best practices at the time, the template adopted a structured consent format that, at the end, restated each of the four core elements of the study (basic participation, central storage of DNA for future research, creation of cell lines, and recontact for participation in future studies) and that required the participant to signify agreement to each one separately. The alternative to this ‘check-box’ approach would have been simply to signify consent to the whole study as described in the entire consent form. The difficulty presented by the check-box approach was the tendency to look to the recapitulations that accompanied the check boxes, rather than to the fuller statement earlier in the form, for the operative permissions language. Because the check-box language necessarily was a summation rather than a complete restatement, it emphasized the genetic purposes of the study. As a consequence, the check-box did not explicitly restate that ordinary serum samples would be stored for nongenetic studies related to diabetes. The more focused check-box language, and inevitable variations in the translated versions, created some issues for the central repository that had to be resolved with the NIDDK Project Office.

Each researcher and country was allowed to change the model form to meet their special needs and concerns. Indeed, they could have entirely rewritten the consent form if they chose. To avoid the appearance of ethical imperialism and allow the flexibility to accommodate widely varying practices, understandings, and social conditions around the world, the ELSI Committee articulated a set of basic ethical standards that would satisfy the study’s core research ethics requirements, regardless of how they might be expressed in a particular consent form. These were as follows:

Each participant must be covered by a written consent voluntarily signed by a person with authority.

The consent form must explain the basic nature and purpose of the study in language that participants or their authorized representatives can understand.

The form must give specific permission to send blood samples to a regional network repository and a central repository located in the United States for storage and future research related to diabetes or autoimmune disorders. (We felt it important to mention the United States as the final destination due to widespread anti-American sentiment at the time.)

The consent form must explain DNA or genetic research in some way. Also, in order for cell lines to be created, the consent form must explain their nature and purpose in some way.

These core requirements presented no substantive problems in any country. Indeed, despite this flexibility to rewrite or write consent forms from scratch, all participating institutions started with the full template and most made only minor adjustments. The only major change was that some institutions declined to use the template’s structure of granting consent separately and specifically, using check-boxes, to each of four elements of the study (described above).

To ensure that basic requirements were met, we asked that revised consent forms be translated back into English; these back-translated consent forms served as the permanent record of their content. The consent forms were then reviewed by NIDDK. This review revealed a number of discrepancies in the critical permission language that arose during the translation and back-translation process – discrepancies that initially escaped the attention of the project’s staff. Consistency in this key language is essential to central storage for future research. For instance, some translated consents gave permission to store and use only DNA, and not plasma and serum, and some failed to mention the use of samples in studying the complications of diabetes or other autoimmune diseases. Some discrepancies introduced conditions or qualifications that were simply unacceptable to the central repository; for instance, a requirement that a local institution approve all future uses.

Several steps were taken to straighten out these problems. Some minor discrepancies were resolved simply by doing a more accurate back-translation or by asking the approving EC for a letter giving a clarifying interpretation that was consistent with the model template. Other discrepancies required the country to revise its approved consent form. Because this review by the central repository was not done at the earliest possible stage, it was necessary in one country to re-consent some participants who had been enrolled prior to correction of the consent forms. A few samples were ultimately destroyed when participants could not be re-consented. Biosample collectors are well advised to anticipate the likelihood of discrepancies of language and meaning, and to ensure that consent form changes and back-translations are reviewed as early as possible by the eventual repository, certainly prior to initiating sample collections.

Although considerable effort was required to adapt and translate consent forms for use in multiple study sites in many countries, in many respects, these challenges were quite similar to those faced in any large multicenter study [18]. The IRBs at many sites request changes, and a coordinated review of these changes is required to ensure that local preferences are balanced appropriately with the requirements of the study. Although this labor-intensive process is criticized with some justification in single-country studies, it is essential in multi-country studies. Fortunately, our experience suggests that centralized review of local changes to consent forms is workable and can indeed achieve an effective balance.

Creation of cell lines

Collected samples were used to create immortalized cell lines. Investigators were required to tell participants that a cell line would be created unless they objected, because it was felt that some people might oppose having an ongoing means to produce more of their DNA indefinitely, rather than only the quantity of DNA that is extracted initially. The following template language was used by most sites: ‘To allow more researchers to work with your blood sample, we are requesting permission to produce and store a living cell line, which means we will keep some of your white blood cells alive for future research. If you agree, this will give researchers a large supply of DNA without needing to draw additional blood samples.’

Nevertheless, people were given the option of participating even if they objected to creating a cell line. The other option would have been simply to exclude objectors from the study, but there was concern originally that this would make recruitment more difficult. However, less than 1% of participants in the Asia-Pacific, European, and United Kingdom Networks exercised the option to object to cell lines, but over 3% did so in the North American Network. This suggests that concerns about immortalized cell lines are low and are much lower elsewhere in the world than they are in the United States.

Uses of samples and information

The purpose of this study and future studies was stated somewhat broadly to include the ‘complications’ of diabetes and ‘other autoimmune diseases.’ It would not be useful to store samples in a central repository unless permission for a reasonable range of related studies is given, because it is not feasible to re-contact participants in more than 34 countries or research groups each time a particular study is proposed in the future.

The optimal scope of participants’ consent to uses of biospecimens in future studies is one of the liveliest controversies in genetic and biobanking research [1-8,14-17]. Although many investigators, scholars, and policy makers regard blanket consent as the best means of promoting research progress, others maintain that a narrower scope of research makes participants’ consent more meaningful and helps to guide oversight bodies’ review of future proposed research.

To protect the rights of participants and the Consortium’s purposes, other researchers are given access only if they are qualified and they propose to do relevant studies. In general, these requirements mean that all investigators seeking to use T1DGC samples and data must have their studies reviewed and approved by an EC or IRB; limit their studies to the purposes of the Consortium; provide information about the investigators and their affiliations, their funding sources, and the potential medical, scientific, and commercial applications of the research; ensure security of samples; agree not to share or distribute samples; and agree to destroy samples when work is done.

Contributing investigators, in order to pursue their own research, received DNA and a cell line from each participant's sample they contributed to the study. The Consortium therefore considered how investigators may use these retained samples collected from their own participants. In addition to restricting use to the study of type 1 diabetes, its complications, and other autoimmune diseases, the following policies were adopted:

If participants request to withdraw from the T1DGC study, contributors must be able to destroy their samples and information, including any samples or information that the investigator might give to their collaborators.

Contributors may not (unless permitted by an IRB or EC) attempt to identify their samples or link them to information that could identify the participants they came from, because they were collected under the understanding that they would be stored and studied anonymously.

Contributors who wished to pursue other lines of research, or make other uses of samples beyond these restrictions, could do so only by collecting additional samples outside of this study, using a separate and different informed consent.

Commercial uses

Intellectual property considerations are of increasing importance in all areas of biotechnology research, including genetic research [19-22]. The debate over whether scientific progress is best fostered by awarding patent rights or preserving open access is ongoing. Information-sharing is mandated by many research funders, prompting the need to address the possibility of ‘downstream’ commercial uses of study data.

The philosophy of this study was to make available as much information as possible, to as many qualified researchers as possible, in order to improve the health of people affected by type 1 diabetes. Therefore, this study placed its samples and data in the public domain for the benefit of science and medicine and did not claim any intellectual property rights (other than rights to control use and access to the database and biobank).

However, it is possible that other researchers or companies who have access to these public domain materials may be able to use them to develop something with commercial value or to claim intellectual property in some product of their research using these materials. The only way to prevent such commercial uses and claims would be to permit research access to only governments or nonprofit organizations, but that would weaken the purposes of the Consortium.

These policies allowing possible downstream commercialization were acceptable in Europe, North America, United Kingdom, and much of the Asia-Pacific region, but several Asian countries were concerned about commercial uses of their samples. These countries were permitted, if they wished, to flag their samples in the database as not available to profit-making companies or for researchers who intend to pursue commercial development of their discoveries. Only India ended up insisting on flagging their samples this way. For Thailand, it was necessary to state that the samples remained the property of the collecting institution, even when they were sent to the United States for central storage. This stipulation was deemed acceptable because it did not interfere with any of the Consortium’s or central repository’s policies about storage, use, and disposal.

Reporting results

Reporting the results of genetic research has become another topic of considerable scholarly and policy interest [14,23,24], in part because of high expectations that the discovery of genetic associations may lead rapidly to the development of effective treatments, and in part because of the difficulty in reconciling the limited value of complex genetic information in clinical applications with its inherent meaning for individuals. Thus, whether or not to report the results of studies like T1DGC is important both to determine and to explain to all involved.

The Consortium did not report any results directly to participants; it did only to investigators. Each investigator was allowed to decide whether to report any results to participants. Some investigators decided to report human leukocyte antigen (HLA) genotyping or autoantibody test results in the event that this information might be helpful for refining clinical diagnoses or treatment plans. Also, investigators always had the option of recontacting participants to notify them of the option for additional testing (without study funding) in the event that subsequent research reveals genetic information that has clinical importance. Updates on the progress of the Consortium, its findings, and its publications are reported on the T1DGC website, which participants can access if interested.

Government approvals

Any institution that receives federal funding for human subjects research must have a ‘Federal Wide Assurance’ (FWA) issued by the Department of Health and Human Services' (DHHS) Office of Human Research Protections (OHRP). This FWA requires a functioning EC that resembles the US’s IRB and assurance of compliance with various basic ethics standards. It was correctly anticipated that it would be a burden to require investigators in far-flung parts of the world to satisfy these requirements on their own. Initially, it was hoped that this requirement could be avoided by paying local investigators only through funds that the four multi-country networks administered, out of institutions with FWAs in Melbourne, Australia; Copenhagen, Denmark; Seattle, WA, USA; and Cambridge, United Kingdom, rather than enabling investigators to receive funds directly from NIH. However, the DHHS ruled that each investigator must affiliate with a local institution that has an FWA. Therefore, staff in the four Network Centers were trained in assisting investigators with using the OHRP’s website to meet this requirement. Also, to ease this burden, especially for investigators at institutions without functioning ECs, investigators were allowed to affiliate with institutions in their country that had existing FWAs as long as that institution’s EC agreed to assume oversight responsibility.

Another regulatory issue that had to be negotiated was the need in the United States to satisfy the requirements of the Health Insurance Portability and Accountability Act (HIPAA) privacy rule [25], in order to send data to Consortium participants. Similarly, the European Commission’s directive on personal data privacy sets forth protections that institutions in other countries must show before they can receive personal medical data from European countries [26]. To meet the European requirements, the Coordinating Center had to obtain certification for safe harbor status (similar to the US’s FWA). To meet HIPAA requirements, the Coordinating Center’s legal office initially expected that we use its standard ‘data use agreement’, but project leaders were concerned that it would alienate contributing investigators if the United States imposed yet another set of demanding regulatory requirements, especially ones containing threatening legalese.

The solution devised was to redraft the data use agreement to consist of a set of reciprocal assurances between the Consortium and its members, in a fashion that would satisfy both HIPAA’s requirements and those of the European Privacy Directive, and therefore presumably also the laws of other countries. In other words, rather than creating one set of agreements under European law that covered the sending of information to the Coordinating Center, and a second set of agreements under US law that covered the return of information to local investigators, a single agreement was written that served both purposes (Appendix 3). The reciprocity created by putting these mutual assurances in the same agreement helped to ease possible objections to US legal and ethical imperialism. Also, it was determined that this agreement needed to be signed only by the Coordinating Center and the four Network Centers, and not by individual contributing investigators in each network. These strategies worked well.

India and Thailand required approval by a central government agency before local investigators could participate, and before blood and DNA samples could be sent abroad. Their concern is that national resources will be exploited or expropriated for financial gain elsewhere, without commensurate benefit for their citizens. Sometimes (as in Thailand), government approval simply required reviewing and revising the terms of a ‘material transfer agreement’. Other times, this hurdle proved to be considerable. In India, the process of preparing the extensive proposal forms and shepherding them through the governmental review process consumed over 3 years – threatening the feasibility of that country’s full participation.

Conclusions and recommendations

As a long-term, large-scale international study, T1DGC has dealt with most of the major ethical and policy issues associated with biobanking, and indeed has seen several ‘best practices’ change over time. The Consortium faced fewer problems than those reported by some other, similar studies [27,28]. The Consortium’s success in identifying and addressing ethical concerns did not come easily but stems from several key strategies: (1) dedicating sufficient time, personnel, and resources to ELSI issues; (2) devoting hands-on attention to good communication, in order to ensure that concerns are understood and solutions are responsive and implementable; (3) being able to persist, redo, revise, and revisit in order to ensure that solutions are implemented; and (4) following up continually, and expecting new issues to arise over time.

Based on the experience in this study, several important conclusions can be drawn as follows:

Basic international standards for research ethics review and informed consent are broadly consistent across developed countries.

When consent forms are adapted locally and translated into different languages, discrepancies are inevitable and therefore require prompt central review and resolution before research is initiated.

Providing separate ‘check-box’ consent for different elements of a study creates confusion and may not be essential.

Creating immortalized cell lines to aid future research is broadly acceptable, both in the United States and internationally.

Imposing some limits on the use of stored samples aids in obtaining ethics approvals worldwide.

Allowing potential commercial uses of donated samples is controversial in some Asian countries.

Obtaining government approvals can be labor intensive and time consuming, and can require legal and diplomatic skills.

Although national, cultural, and language differences gave rise to many of the ethical issues encountered by T1DGC, many issues commonly arise in similar multicenter studies conducted entirely within the United States or Europe. Thus, T1DGC has been something of a bellwether for ethical issues in biobanking and genetic research. Because the best ethics are preventive, we hope that what we have learned can help others anticipate and preemptively address these and similar issues in their own research.