Blockchain Papers

Olivia Choudhury, Noor Fairoza, Issa Sylla, Amar K. Das

The cost of conducting multi-site clinical trials has significantly increased over time, with site monitoring, data management, and amendments being key drivers. Clinical trial data management approaches typically rely on a central database, and require manual efforts to encode and maintain data capture and reporting requirements. To reduce the administrative burden, time, and effort of ensuring data integrity and privacy in multi-site trials, we propose a novel data management framework based on permissioned blockchain technology. We demonstrate how our framework, which uses smart contracts and private channels, enables confidential data communication, protocol enforcement, and and an automated audit trail. We compare this framework with the traditional data management approach and evaluate its effectiveness in satisfying the major requirements of multi-site clinical trials. We show that our framework ensures enforcement of IRB-related regulatory requirements across multiple sites and stakeholders.

Mark E Abraham, A Vyshnavi, Chungath Srinivasan, P. K. Krishnan Namboori

No abstract is available for this record.

StanislawPeter Stawicki, SagarC Galwankar, Sebastian Clarke, Iain Craig · 11 authors

Technological progress is reshaping multiple domains of human activity, from financial transactions to medical care.[1] This paradigm shift represents a global movement that will transform our lives for generations to come.[2] The democratization of decision-making capacity, including consensus-based mechanisms for transaction verification, will enable global implementation of projects that were previously not feasible because of the requirement for centralized control.[34] Blockchain represents a decentralized ledger technology that operates by consensus and serves to democratize decision-making processes and to disintermediate traditionally understood intermediaries.[1] According to Deutsche Bank forecasts, by mid-2020's, approximately 10% of the worldwide gross domestic product could be regulated by blockchain-based solutions.[5] It is estimated that more than $400 billion will be invested in this technology in 2019 to advance its capabilities.[6] Within this broader context, it is important to understand that cryptocurrencies and financial transactions constitute only one small aspect of the blockchain concept, which also incorporates areas like verification, transparency, encryption, and maintenance of data integrity.[378] Blockchain technology appears to be following a fairly typical pattern of adoption, with multiple early entrants into the increasingly crowded and competitive cryptocurrency space and the fast-growing sphere of blockchain-based applications.[91011] It is the latter that will help truly define, and be responsible for the societal impact of, “the era of distributed ledgers” that is under way.[1112] The primary goal of the strategic global partnership between Litecoin Cash Foundation (LCCF, https://litecoinca.sh/) and OPUS 12 Foundation, Inc. (O12FI, http://www.opus12.org/), is to leverage our collective resources to establish early leadership in the development and implementation of practical, real-life, blockchain-based solutions in academic and clinical medicine.[11314] The practicality of the dual blockchain utilization, featuring both currency and application layers, becomes apparent with the realization that the need for ongoing data processing relies on constant verification and encryption activity throughout the entire network of blockchain nodes.[113] Thus, the approach selected by the LCCF-O12FI consortium creates significantly more synergy than a single-track approach based on subcomponent strategy. Within this context, the technology provides not only a “digital wallet” functionality for currency exchange, but also different blockchain-based use cases incorporating academic and medical information. In one example, cell phones are ubiquitous in low- and middle-income countries (LMIC) whereas electronic health records are not. Older, less costly cell phone technology would suffice as only SMS capability is needed to utilize blockchain or cryptocurrency, enabling broad access to the populations of LMICs. Blockchain can support information exchange across disparate data types, while providing digital payments on a global scale and across borders. The functional dimension of introducing the primary currency feature of Litecoin Cash (LCC) cryptocurrency has the potential to bring tremendous benefits to the areas of the world where banking services (and infrastructure) are severely underdeveloped, yet basic components for the successful adoption of cryptocurrencies clearly exist (e.g., limited internet access and mobile devices capable of supporting blockchain transactions). Much like entire regions of the world that essentially “bypassed” landline-based telephony following the introduction of cellular networks, many localities stand to “bypass and leapfrog” traditional banking, and progress directly to distributed ledger technologies.[151617181920] There is growing recognition of the role of microeconomies and the critical need for efficient, dependable, accessible, safe, and scalable financial transactions and infrastructures, especially in low-resource regions, a topic that was recently recognized with a Nobel Prize in Economics.[2122] Of note, this does not necessarily preclude traditional banking firms from participation; however, they will need to adapt to new competitive pressures across economic realities for which high-resource environment models are not optimized. Ability to appropriately scale current blockchain capabilities will be critical to such implementations.[32324] Blockchain-based mechanisms also allow for crossover of monetary value from various loyalty cards and rewards programs, similar to currency exchange between different nations. Such reward points (mileage, car rental, and hotel stay) can then become an alternative subsidy for healthcare services. This can, for example, help establish a modernized barter system where a patient could use their “frequent flyer miles” to pay for medical costs, exchanging their reward points for “health care coins” through an intermediary exchange market. Institutions, such as nongovernmental organizations, could turn “flyer miles” used to shuttle staff between locations into vaccine and medical equipment purchases. Further, direct and real-time transparent payment for services in healthcare could lead to a reduction of both “intermediary” insurance companies and inefficiencies in the system. This streamlining would result in substantial healthcare savings, translating to lower costs, more access for patients, and decreased overhead with increased revenue for clinics, hospitals, and providers. Security of the blockchain (including various “side chains” and “layers”) is of paramount importance to ensuring trust and wider mainstream adoption of this technology.[252627] The inherent risk in the concept of distributed ledger “democratization” is the possibility of emerging inequality due to maldistribution of infrastructure responsible for the maintenance and ongoing operations of the blockchain.[2829] Within this broader topic area, our group previously described the risk of ill-intended, third-party actors to project massive bursts of “hashing power” and effectively take over the blockchain for a limited duration of time.[1] This, in turn, allows such destructive actors to “double spend” cryptocurrency output to the detriment of the broader populace.[114] To effectively prevent the risk of the blockchain being “hijacked,” the LCCF Developer Team devised an innovative paradigm of agent-based mining (e.g., the creation of new cryptocurrency) that helps ensure democratization of the LCC generation/transaction process while providing sustainable, long-term security of the distributed ledger.[14] Another significant advantage of this prototype mining technique is that it is not based on technologies that are becoming increasingly energy and resource inefficient, thus not requiring ever greater amounts of energy to generate diminishing amounts of block rewards (e.g., “coins”). The synergy between secure mining processes and the need for the highest possible levels of distributed ledger security creates a unique environment for the development of blockchain-based educational and medical applications. Our joint implementation framework of blockchain-based application layer includes clearly stated and reasonably achievable milestones, each defined within the broader contexts of adoption readiness and resource availability. Parallel to these developments will be the phased introduction of LCC as a voluntary medium of exchange for various international medical programs (IMPs) collaborating within our global network of institutions, providers, and clinical sites.[30] The initial step in the strategic LCCF-O12FI collaboration will be the development of a cryptography-based “Secure ID” (SID) that will serve as the foundation for the future developments. This SID will contain each user's unique identifying information, accessible only to the end-user (incorporating various best practices in cyber security such as 2-factor or multisource verification), and shareable for viewing and information verification only with end-user's designees. The SID will also serve as a “Secure Key” to access other, downstream blockchain-based applications including “Academic Activity Logger” (AAL) and “Credentialing Document Repository” (CDR). We will now discuss the development and implementation of AAL and CDR. The AAL will be the first step toward the integration of blockchain technology into real-life academic international medicine (AIM) applications. Powered by the global LCC network, the AAL will help record and track activities by faculty members, facilitating the categorization and quantification of academic efforts into the following subtypes: (a) teaching, (b) clinical medicine, (c) community/government interactions, (d) research, and (e) other/miscellaneous. Each entry will include the activity date/time/duration as well as basic description, with a number of generic entries available through a drop-down menu. Activities entered by academic faculty will then be analyzed periodically and will serve as a basis for resource mobilization and allocation. Access to the AAL will only be possible using the SID, thus making the AAL a logical extension and a springboard for subsequent LCC blockchain-based implementations. On this foundation, the CDR and ultimately a “basic electronic medical record” (BEMR, see below) will be constructed. Although the task of constructing a high-fidelity, immutable, and accurate ledger of academic activities will not be easy, certain steps can be taken to minimize the likelihood of “false claims.” Much like the blockchain-based cryptocurrency paradigm, a secure mechanism for consensus building and data verification can be constructed. Such a “network of trust” (NOT) is technically workable and analogous to how “pretty good privacy” keys were distributed at signing parties attended by people known to each other, and also similar to the way “secure socket layer” certificate authorities work.[3132] For example, if Party A's certificate is signed by some Party B who is trusted by Party C, Party C can trust Party A's certificate, etc. The next developmental step in our strategic plan will be the implementation of the CDR, where provider credentials will be securely uploaded and stored in decentralized fashion. These documents will follow predefined credentialing requirements by most institutions globally such as record of college education/graduation, professional school record/diploma, professional licensing/verification/certification, and any additional elements deemed important to the safe conduct of AIM efforts globally. Uploading of credentialing information will be voluntary, and access to this information will only be possible with the permission of the record owner, utilizing his or her unique SID. Optimally, this important credentialing instrument will help providers verify their identity, education, and qualifications, and ensure that appropriate standards are followed by all stakeholders. The end-result will be the provision of safe and efficient care to the patients worldwide. Similar to the academic activity verification process, there will be important challenges to consider before successfully implementing the global CDR. In principle, there will need to exist some form of “data onboarding” authority. This should be performed by a “verification agent” (e.g., independent organization/group) with equivalent authority to that which it takes to set up a legitimate record of specific type (e.g., a medical school diploma and medical board specialty certification). In terms of identity verification, for example, the level of diligence required is similar to that already present in “know your customer” legislation. The case for verifying professional credentials would be similar, including the process of independent data validation and certification. Again, this is technically possible with a NOT arrangement as mentioned above; however, there will be obvious limitations inherent to the workability of credential verification similar to traditional efforts already in place. If a practitioner is claiming to possess credentials from some credentialing provider, only that particular provider really has (and only should have) the authority to confirm that. At the same time, there must also be a mechanism to revoke trust and to hardwire time-defined recertification processes based on the expiry of records currently on file. The final step in the strategic LCCF-O12FI collaboration will be the development of a super secure, BEMR that could be deployed in low-resource environments, utilizing rudimentary portable device technology, and containing fundamental health information for each end-user. Much like the SID, information stored on the BEMR would be owned by the end-user and could be shared with healthcare providers only with the end-user's consent, requiring SID as the “Secure Key” to unlock information. We recognize the substantial challenges in the global implementation of this concept, especially with regards to the enormity of healthcare-related data (often from multiple systems and sources), the need for privacy, timely and accurate access, and verification of data. Other potential shortcomings, at this time, include the need for further development of the technology, limited availability of expert knowledge, significant gaps in public awareness, along with growth-related issues of scalability, security, and user adoption.[6] Nonetheless, it is our hope that the lessons learned from other blockchain application layers will serve as the foundation for successful development, evolution, and adoption of BEMR.[1] There are many other considerations related to blockchain technology implementations in healthcare. Although full discussion of such a broad topic is beyond the scope of this manuscript, certain key ramifications must be discussed in the context of the proposed O12FI-LCCF initiatives. Blockchain technology may be an important tool for increasing transparency of how charities collect and allocate funds, propelling a much leaner system that will benefit intended recipients to a much greater degree.[1] This application of the blockchain technology will help verify the integrity of an organization's operations such as the transparency regarding the proportion of contributions distributed to medical and educational causes versus the overhead. In turn, the public, philanthropic donors, and potential collaborators will be able to make more informed choices regarding where their contributions can be allocated most efficiently. Pharmaceutical companies may utilize blockchain to keep track of medications manufacturing and shipment, supply, expiration, and possible points of contamination.[33] By extension, similar technological approaches could be useful for tracking opiates in this age of epidemic prescription drug abuse.[34] In such cases, blockchain would make it easier to investigate and determine the source of access as the supply chain would become much more transparent. Various built-in data verification and safety features could also be used to prevent duplication of medications from different providers and other hazards that occur with polypharmacy. Furthermore, the same tracking approaches could be used to secure food supply chains and safeguard against disease outbreaks.[35] Contaminated food products could be quickly and more efficiently traced to specific farms, processing or packaging plants for immediate identification, and removal from circulation. When combined with potential applications for AIM and global health equity, blockchain-based applications could help catalyze further innovation. First, they can enable universal access to financial resources by removing third-party intermediaries and offering transparent, secure, and accountable means for AIM financing.[36] Next, they could help facilitate multilateral financing mechanisms dedicated to health system development and strengthening.[136] In addition, they could reduce fraud and corruption through the use of immutable, tamper-proof transaction ledgers.[136] Finally, entire new capital markets for healthcare data could be created, providing better access (and opportunities) to patients, institutions, governments, researchers, and other key stakeholders.[136] Additional benefit offered by any token with fixed or “capped” supply as a medium of international exchange – subject to harmonization with region-specific laws and regulations – is the noninflationary character of such cryptocurrency. This, in turn, may help provide end-users with a protective mechanism against inflation and loss of monetary value – a phenomenon experienced across many LMICs.[3738] In conclusion, the global partnership between OPUS 12 Foundation (including its allied partners and subsidiaries) and LCCF provides a unique platform for the parallel development of both global currency support framework and medical/educational application layer for the academic international medical community.

Quinn DuPont

This article investigates ethical research risks associated with cryptocurrencies and the related family of digital "value" technologies. It provides an empirical analysis of innovation and recommends guiding principles for ethical research and development. Ethical research risks are identified through 1) an analysis of research methods and ethics disclosure practices in published empirical research; and 2) a survey of academic research practices and researcher opinions. These data identified multiple research ethics issues. It was discovered that most researchers have extensive and undisclosed industry relationships, have undisclosed conflicts of interest arising from token ownership, and report low use of institutional review or ethics guidelines, among other issues. Three novel research risks-conflicts of interest, risky methods, and disclosure-are then introduced and compared to the risks of conventional research. It is argued that these technologies introduce ethical risks and opportunities beyond their sector. These findings suggest a new class of ethical and normative research practice, comparable to fields such as bio-or nanotechnology ethics. Based on these analyses, eight principles for ethical research are described, with practical lessons for the researcher.

Yan Zhuang, Lincoln Sheets, Zon‐Yin Shae, Yin-Wu Chen · 6 authors

Patient recruitment for clinical trials is known to be a challenging aspect of clinical research. There are multiple competing concerns from the sponsor, patient and principal investigator's perspectives resulting in most clinical trials not meeting recruitment requirements on time. Conducting under-enrolled clinical trials affects the power of conclusive results or causes premature trial termination. The Blockchain is a distributed ledger technology originally applied in the financial sector. Its features as a peer-to-peer system with publicly audited transactions, data security, and patient privacy are a good fit for the needs of clinical trials recruitment. The "Smart Contract" is a programmable self-executing protocol that regulates the blockchain transactions. Given current recruitment challenges, we have proposed a blockchain model containing multiple trial-based contracts for trial management and patient engagement and a master smart contract for automated subject matching, patient recruitment, and trial-based contracts management.

David M. Maslove, Jacob Klein, M. Kathryn Brohman, Patrick Martin

BACKGROUND: Blockchain technology is emerging as an innovative tool in data and software security. OBJECTIVE: This study aims to explore the role of blockchain in supporting clinical trials data management and develop a proof-of-concept implementation of a patient-facing and researcher-facing system. METHODS: Blockchain-based Smart Contracts were built using the Ethereum platform. RESULTS: We described BlockTrial, a system that uses a Web-based interface to allow users to run trials-related Smart Contracts on an Ethereum network. Functions allow patients to grant researchers access to their data and allow researchers to submit queries for data that are stored off chain. As a type of distributed ledger, the system generates a durable and transparent log of these and other transactions. BlockTrial could be used to increase the trustworthiness of data collected during clinical research with benefits to researchers, regulators, and drug companies alike. In addition, the system could empower patients to become more active and fully informed partners in research. CONCLUSIONS: Blockchain technology presents an opportunity to address some of the common threats to the integrity of data collected in clinical trials and ensure that the analysis of these data comply with prespecified plans. Further technical work is needed to add additional functions. Policies must be developed to determine the optimal models for participation in the system by its various stakeholders.

Zeeshan Jan, Allan Third, Michelle Bachler, John Domingue

Peer-reviewing holds a significant importance in the process of scientific publishing. The process of peer-reviewing has been criticized for its defects, but research communities have faith in it, and hence, it is perceived as the backbone of scientific publishing. The process needs improvements in a number of ways, i.e, establishing trust in the pro- cess, preventing abuse, bringing transparency in the process and keeping the integrity of data intact. Moreover, the activity of peer-reviewing is carried out without any formal incentives. We present considerations in refreshing peer-review, and our approach to experiment in this space.

Mahsa Shabani

Blockchain-based platforms are emerging to provide solutions for technical and governance challenges associated with genomic data sharing. Providing capabilities for distributed data stewardship and participatory access control along with effective ways for enforcement of the data access agreements and data ownership are among the major promises of these platforms.

David M. Maslove, Jacob Klein, M. Kathryn Brohman, Patrick Martin

<sec> <title>BACKGROUND</title> Blockchain technology is emerging as an innovative tool in data and software security. </sec> <sec> <title>OBJECTIVE</title> This study aims to explore the role of blockchain in supporting clinical trials data management and develop a proof-of-concept implementation of a patient-facing and researcher-facing system. </sec> <sec> <title>METHODS</title> Blockchain-based Smart Contracts were built using the Ethereum platform. </sec> <sec> <title>RESULTS</title> We described BlockTrial, a system that uses a Web-based interface to allow users to run trials-related Smart Contracts on an Ethereum network. Functions allow patients to grant researchers access to their data and allow researchers to submit queries for data that are stored off chain. As a type of distributed ledger, the system generates a durable and transparent log of these and other transactions. BlockTrial could be used to increase the trustworthiness of data collected during clinical research with benefits to researchers, regulators, and drug companies alike. In addition, the system could empower patients to become more active and fully informed partners in research. </sec> <sec> <title>CONCLUSIONS</title> Blockchain technology presents an opportunity to address some of the common threats to the integrity of data collected in clinical trials and ensure that the analysis of these data comply with prespecified plans. Further technical work is needed to add additional functions. Policies must be developed to determine the optimal models for participation in the system by its various stakeholders. </sec>

Hao Dai, H. P. Young, Thomas J S Durant, Guannan Gong · 8 authors

The governance of data used for biomedical research and clinical trials is an important requirement for generating accurate results. To improve the visibility of data quality and analysis, we developed TrialChain, a blockchain-based platform that can be used to validate data integrity from large, biomedical research studies. We implemented a private blockchain using the MultiChain platform and integrated it with a data science platform deployed within a large research center. An administrative web application was built with Python to manage the platform, which was built with a microservice architecture using Docker. The TrialChain platform was integrated during data acquisition into our existing data science platform. Using NiFi, data were hashed and logged within the local blockchain infrastructure. To provide public validation, the local blockchain state was periodically synchronized to the public Ethereum network. The use of a combined private/public blockchain platform allows for both public validation of results while maintaining additional security and lower cost for blockchain transactions. Original data and modifications due to downstream analysis can be logged within TrialChain and data assets or results can be rapidly validated when needed using API calls to the platform. The TrialChain platform provides a data governance solution to audit the acquisition and analysis of biomedical research data. The platform provides cryptographic assurance of data authenticity and can also be used to document data analysis.

Lisa M. Rasmussen

No abstract is available for this record.

Edward Meinert, Abrar Alturkistani, Kimberley Foley, Tasnime Osama · 9 authors

BACKGROUND A blockchain is a digitized, decentralized, distributed public ledger that acts as a shared and synchronized database that records cryptocurrency transactions. Despite the shift toward digital platforms enabled by electronic medical records, demonstrating a will to reform the health care sector, health systems face issues including security, interoperability, data fragmentation, timely access to patient data, and silos. The application of health care blockchains could enable data interoperability, enhancement of precision medicine, and reduction in prescription frauds through implementing novel methods in access and patient consent. OBJECTIVE To summarize the evidence on the strategies and frameworks utilized to implement blockchains for patient data in health care to ensure privacy and improve interoperability and scalability. It is anticipated this review will assist in the development of recommendations that will assist key stakeholders in health care blockchain implementation, and we predict that the evidence generated will challenge the health care status quo, moving away from more traditional approaches and facilitating decision making of patients, health care providers, and researchers. METHODS A systematic search of MEDLINE/PubMed, Embase, Scopus, ProQuest Technology Collection and Engineering Index will be conducted. Two experienced independent reviewers will conduct titles and abstract screening followed by full-text reading to determine study eligibility. Data will then be extracted onto data extraction forms before using the Cochrane Collaboration Risk of Bias Tool to appraise the quality of included randomized studies and the Risk of Bias in nonrandomized studies of Interventions to assess the quality of nonrandomized studies. Data will then be analyzed and synthesized. RESULTS Database searches will be initiated in September 2018. We expect to complete the review in January 2019. CONCLUSIONS This review will summarize the strategies and frameworks used to implement blockchains in health care to increase data privacy, interoperability, and scalability. This review will also help clarify if the strategies and frameworks required for the operationalization of blockchains in health care ensure the privacy of patient data while enabling efficiency, interoperability, and scalability.

Katharine Gammon

No abstract is available for this record.

Vaso Rahimzadeh

Clinical research and health information data sharing are but ripples in a growing wave of reimagined applications of distributed ledger technologies beyond the digital marketplace for which they were originally created. This paper explores the use of distributed ledger technologies to facilitate single institutional ethics review of multi-site, collaborative studies in the dataintensive sciences such as genetics and genomics. Immutable record-keeping, automatable protocol amendments and direct connectivity between stakeholders in the research enterprise (e.g., researchers, research ethics committees, institutions, funders and regulators) comprise several of the conceptual and technological advantages of distributed ledger technologies to research ethics review. This novel-use proposal dovetails recent policy reforms to research ethics review across North America that mandate a single ethics review for any study that takes place across more than one research site. Such reforms in the United States, Canada and Australia replace prior institution-by-institution approval mechanisms that contributed to significant research delays and duplicative procedures for collaborative research worldwide. While this paper centers on the Common Rule revision in the United States, the single ethics review mandate is a noteworthy example of regulation evolving in parallel with advances in the dataintensive sciences it governs. The informational exchange capacities of distributed ledger technologies align well with the procedural goals of streamlining the ethics review system under the new Common Rule ahead of its official implementation on January 19, 2020. The ethical, legal and social implications of applying such technologies to ethics review will be explored in this concept paper. Namely, the paper proposes how administrative data from research ethics committees (REC) could be protected and shared responsibly, as well as interinstitutional cooperation negotiated within a centralized network of research ethics committees using the blockchain. Keywords: Blockchain, Data Sharing, Ethics Review, Governance, IRB, Research, Single Mutual Recognition

Giovanni Scarso Borioli, Jérôme Couturier

This article applies ‘outcome-driven innovation’ methodology, developed by Anthony Ulwick and popularised by Clayton Christensen, to the domain of clinical trials. Data were collected through in-depth, open interviews with doctors, nurses and researchers in the UK, France and Italy. Pain points for key players of the value chain were identified. The findings supported a multi-stakeholder approach to fully exploit the transformative potential of blockchain technology to resolve issues. The research identified a set of opportunities for innovators to improve the way hospitals conduct clinical trials using smart contracts and blockchain technology generally.

Kenneth Colon

Over the past decade, there have been many innovations in new payment and care delivery models and technology, from telemedicine to artificial intelligence (AI) to blockchain. These innovations, however, must be used in tandem to drive real change. We review each of these innovations and propose a model for how they can be combined to be greater than the sum of their parts. In doing so, we can create a global, decentralized health system that truly puts patient care at the center, while supporting and further enabling the clinicians who make this care possible, to deliver higher quality care at a fraction of the cost. Keywords: Artificial Intelligence, Behavioral Health, Blockchain, Collaborative Care, Decentralization,Direct Primary Care, Ethereum, Integration, Payment Models, Telemedicine, Virtual Assistants

Gábor Magyar

A blockchain powered Health information ecosystem can solve a frequently discussed problem of the lifelong recorded patient health data, which seriously could hurdle the privacy of the patients and the growing data hunger of the research and policy maker institutions. On one side the general availability of the data is vital in emergency situations and supports heavily the different research, population health management and development activities, on the other side using the same data can lead to serious social and ethical problems caused by malicious actors. Currently, the regulation of the privacy data varies all over the world, however underlying principles are always defensive and protective towards patient privacy against general availability. The protective principles cause a defensive, data hiding attitude of the health system developers to avoid breaching the overall law regulations. It makes the policy makers and different - primarily drug - developers to find ways to treat data such a way that lead to ethical and political debates. In our paper we introduce how the blockchain technology can help solving the problem of secure data storing and ensuring data availability at the same time. We use the basic principles of the American HIPAA regulation, which defines the public availability criteria of health data, however the different local regulations may differ significantly. Blockchain's decentralized, intermediary-free, cryptographically secured attributes offer a new way of storing patient data securely and at the same time publicly available in a regulated way, where a well-designed distributed peer-to-peer network incentivize the smooth operation of a full-featured EHR system.

Fabio Angeletti, Ioannis Chatzigiannakis, Andrea Vitaletti

Our personal data is now more valuable than ever. The uncontrolled growth of internet-centered services has led us to accept many compromises about how we share it. In the era of Internet of Things, personal data is collected continuously. Now, more than ever, we are in need of privacy-preserving applications where users always retain control of their personal data. In this paper, we present a secure way to control the flow of personal data in the specific case of the recruitment of participants for clinical trials. We take special care to protect the interests of both parties: the individual can keep its data private until an agreement is reached, and the Clinical Research Institute can be assured that it is acquiring useful and authentic data. We provide a proof-of-concept implementation and study its performance based on a real-world evaluation.

Mehdi Benchoufi, Philippe Ravaud

Reproducibility, data sharing, personal data privacy concerns and patient enrolment in clinical trials are huge medical challenges for contemporary clinical research. A new technology, Blockchain, may be a key to addressing these challenges and should draw the attention of the whole clinical research community.Blockchain brings the Internet to its definitive decentralisation goal. The core principle of Blockchain is that any service relying on trusted third parties can be built in a transparent, decentralised, secure "trustless" manner at the top of the Blockchain (in fact, there is trust, but it is hardcoded in the Blockchain protocol via a complex cryptographic algorithm). Therefore, users have a high degree of control over and autonomy and trust of the data and its integrity. Blockchain allows for reaching a substantial level of historicity and inviolability of data for the whole document flow in a clinical trial. Hence, it ensures traceability, prevents a posteriori reconstruction and allows for securely automating the clinical trial through what are called Smart Contracts. At the same time, the technology ensures fine-grained control of the data, its security and its shareable parameters, for a single patient or group of patients or clinical trial stakeholders.In this commentary article, we explore the core functionalities of Blockchain applied to clinical trials and we illustrate concretely its general principle in the context of consent to a trial protocol. Trying to figure out the potential impact of Blockchain implementations in the setting of clinical trials will shed new light on how modern clinical trial methods could evolve and benefit from Blockchain technologies in order to tackle the aforementioned challenges.

Mehdi Benchoufi, Raphaël Porcher, Philippe Ravaud

<ns4:p>Clinical trial consent for protocols and their revisions should be transparent for patients and traceable for stakeholders. Our goal is to implement a process allowing the collection of patients’ informed consent, which is bound to protocol revisions, storing and tracking the consent in a secure, unfalsifiable and publicly verifiable way, and enabling the sharing of this information in real time. For that, we will built a consent workflow using a rising technology called Blockchain. This is a distributed technology that brings a built-in layer of transparency and traceability. From a more general and prospective point of view, we believe Blockchain technology brings a paradigmatical shift to the entire clinical research field. We designed a Proof-of-Concept protocol consisting of time-stamping each step of the patient’s consent collection using Blockchain; thus archiving and historicising the consent through cryptographic validation in a securely unfalsifiable and transparent way. For each revision of the protocol, consent was sought again. We obtained a single document, in a standard open format, that accounted for the whole consent collection process: timestamped consent status with regards to each version of the protocol. This document cannot be corrupted, and can be checked on any dedicated public website. It should be considered as a robust proof of data. However, in a live clinical trial, the authentication system should be strengthened in order to remove the need for third parties, here the trial stakeholders, and give participative control to the peer-to-peer users. In the future, we think that the complex data flow of a clinical trial can be tracked using Blockchain, that a blockchain core functionality, named Smart Contract, could help prevent clinical trial events not to happen in the right chronological order: for example including patients before they consented or analysing case report forms data before freezing the database. Globally, we think Blockchain will help with reliability, security, and transparency, and could be a consistent step towards reproducibility.</ns4:p>

A. B. Ackerman, Anne B. Chang, Nadia Diakun-Thibault, Luca Forni · 7 authors

The President’s Precision Medicine Initiative (PMI) is “enabling a new era of clinical care through research, technology, and policies that empower patients, researchers, and providers to work together toward the development of individualized care”. Its commitment to privacy and security in the setting of responsible data sharing and transparency is articulated in the “Privacy and Trust Principles” and the “Data Security Policy Principles and Framework”, developed by an interagency working groups including the Office of the National Coordinator for Health Information Technology in conjunction with multiple stakeholders. In this paper, we review the threats to the security, confidentiality, integrity, and availability of PMI data. PMI organizations can mitigate these challenges through a new system architecture in development at MIT -- the OPAL/Enigma project -- which creates a peer-to-peer network that enables parties to jointly store and analyze data with complete privacy, based on highly optimized version of multi-party computation with a secret-sharing. An auditable, tamper-proof distributed ledger (a permissioned blockchain) records and controls access through smart contracts and digital identities. We conclude with an initial use case of OPAL/Enigma that could empower precision medicine clinical trials and research. MIT’s OPAL/Enigma challenges traditional data security paradigms. Centralized databases cannot assure security and data integrity, regardless de-identification and controlled access requirements. Safe, vetted queries that are distributed to private, encrypted databases assure that organizations and participants can share health care data with cryptographic guarantees of privacy with various stakeholders, assuring momentum for a new era of medical research and practice.

Greg Irving, John Holden

<ns4:p>Trust in scientific research is diminished by evidence that data are being manipulated. Outcome switching, data dredging and selective publication are some of the problems that undermine the integrity of published research. Methods for using blockchain to provide proof of pre-specified endpoints in clinical trial protocols were first reported by Carlisle. We wished to empirically test such an approach using a clinical trial protocol where outcome switching has previously been reported. Here we confirm the use of blockchain as a low cost, independently verifiable method to audit and confirm the reliability of scientific studies.</ns4:p>

Xin Liu, Anwitaman Datta, Ee-Peng Lim

The Information Age has made publishing, distributing and collecting information easier, resulting in the exponential growth of information available to us. Databases were once ledgers written by hand by a single person; today they can be vast stores of data agglomerated from a myriad of disparate sources. The mass media, formerly limited to newspapers and television programs held to strict journalistic standards, has expanded to include collaborative content such as blogs, wikis and message boards. Documents covering Judging of Sources nearly every topic abound on the Internet, but the authors are often anonymous and the accuracy uncertain.

Jim Vaught, Akin Abayomi, Tim Peakman, Peter H. Watson · 6 authors

Biobanking for clinical or research purposes includes the collection, processing, storage, and analysis of biological specimens. It is now well recognized that biobanking involves a complex array of technical and ethical/regulatory considerations. Biobanking policies and procedures are often documented by best practices that are usually voluntary but may be supplemented and reinforced by strict rules and regulations that govern informed consent, privacy, QC, and other critical issues. As biobanking has emerged as a global endeavor, with national networks and international collaboration becoming the norm, it has become even more critical that practices are coordinated and that quality standards are developed. Biobanking is also often a business endeavor, in that formal strategic and business plans need to be developed to ensure the long-term survival of the associated research programs. As new technologies are developed for using biospecimens to diagnose and treat disease, as well as to evaluate genetic risks, patients are becoming more aware of the importance and benefits of biobanking as part of the medical infrastructure. As a result, patients who donate biospecimens are becoming more interested in learning more about their own sample's use and in seeing the actual results of the research. One of the aspects of these evolving attitudes toward biobanking was addressed in a previous Q&A concerning biospecimen “ownership” in the January 2011 issue of Clinical Chemistry (Gronowski et al.; Clin Chem 57:540–4). From the broad array of issues that could be addressed, this Q&A focuses on a few critical issues that many biobanks are facing today: quality management, biobank network design, long-term sustainability, conveying the importance of biobanking to the public, and the return of research results to biospecimen donors. Five experts who are engaged in national and international biobanking programs discuss these complex issues here. What are some of the important issues related to quality management in sample collection, processing, and storage? Tim Peakman: Biobanks should aim to collect and store samples and associated data in the form most useful for scientific research. This means that they should represent the biological environment at the time of collection as closely as possible, and the introduction of variation through the way they are collected and processed should be avoided as much as possible. Where cases and controls come from different sources, this problem may be particularly acute (with the exception of purely genetic studies). In studies where samples are shipped to a different location for processing, the time delay between collection and stabilization may lead to loss of some unstable markers. Where samples are processed at local sites, maintenance of consistent intersite processing can be challenging. Odds ratios for many exposures are typically 1.2–1.5, so that introduction of uncontrolled or unmeasured variation may lead to weak associations' being overlooked, spurious associations' being further investigated, or significantly greater cost as sample size is increased to enhance power of the study. For many studies the greatest source of variation is at the preanalytical stage, in other words the collection, transport, and processing before stabilization at low temperature or on matrices such as blood spot cards. This can be managed by the implementation of a proper quality program that aims to make the collection and processing of samples as consistent as possible. Formal quality schemes such as ISO 9001:2008 may be suitable for larger studies, but whether a formal accreditation is obtained or a laboratory-based approach is taken, the quality management process should include full documentation of the sample processing trail (including dates, times, temperatures, location, operator, etc.), use of standard operating procedures (SOPs),7 training, audits, critical materials review, and so on. Practical steps to reduce introduced variability can be taken that aim to ensure the time from collection from the volunteer to stabilization is as consistent as possible across all samples and any preprocessing (such as clotting time for serum tubes) is standardized. Finally, quality of sample annotation should be ensured using approaches such as bar codes that maintain accuracy of sample attribution and avoid the risk of misidentification that can result in false positives. It is also important to empirically determine the stability of the samples under the particular collection protocol and whether this is sufficient for the intended purpose. Many analytes are quite stable in blood if they are transported and processed at 4 °C and, with a few exceptions, those analytes that aren't stable only degrade a small amount over 24 h. Establishing systems and processes to avoid this marginal loss may be expensive and unnecessary. Peter Watson and Lise Matzke: Quality management (QM) is an essential component of operating and maintaining a biobank. At the end of the day, it's “garbage-in, garbage-out,” or so they say. Operationally, biobanks must be able to track each biospecimen that is collected, processed, stored, and distributed from the facility to manage biospecimen quality and ensure effective future use. Quality is managed by an established system that verifies biospecimens are handled appropriately. Such quality systems involve the creation and maintenance of accurate process protocols, SOPs, and the activities that verify these protocols' being followed by biobank personnel (staff education and training). Further, standards and best practices set by international organizations such as the International Society for Biological and Environmental Repositories and the National Cancer Institute set guidance around the issues, provide a reference point for content of this documentation, and facilitate harmonization by national organizations and down to individual projects. Implementation of QM activities requires dedicated time and a resourcing strategy which can be very costly. Therefore the scope and scale of the program should be dictated by the scope and scale of the biobank and the nature of the research it is intended to support. A biobank supporting basic discovery research may choose a primary QM focus different from that chosen by a biobank that is intended to support multicenter validation studies. Adequate training and education of biobank personnel and a tracking mechanism to ensure training is current and role specific are essential parts of the overall QM strategy. This helps to ensure consistent and informed application of both quality assurance and QC measures. The process of review of a QM system allows for evaluation around what is and what is not working in the QM and the ability to make changes. There are several types of external assurance programs that are offered on the international stage that are complementary strategies to raise the standards across the discipline of biobanking. Some define an upper standard and use an external assessment process and measurement of product quality, while the focus for other programs is to define a minimal standard and concentrate on education. An example of the latter approach, which ties all these components of QM together, is the concept of biobank certification, which is broadly applicable for all entities handling biospecimens and is offered by the Canadian Tumour Tissue Repository and UBC Biobank Resource Centre. Helen Moore: Quality can mean very different things to different people. One might think of quality management as the process followed to determine that, in the end, you got what you set out to get. For biobanking, quality management would follow the complex set of procedures undertaken to enroll a research participant in biobanking and collect, process, annotate, and store biospecimens, and determine whether that process yielded biospecimens and associated data sufficient for the purpose collected. Foundational elements would include well-documented SOPs that are understood and accepted by those who are collecting, processing, and storing biospecimens, as well as training on SOPs and annotation of deviations from SOPs. Quality criteria must be set at the outset and suitable metrics and analytical tests used to evaluate the processes and determine whether the quality criteria have been met. Having a quality management plan in place for biobanking does not mean that perfection is expected; in fact, it is important that quality management be reasonable in scope and that errors be expected. For example, some level of biospecimen degradation may be unavoidable in some circumstances. Awareness of this possibility and being able to measure relative degradation is part of the quality management plan. Good quality management in biobanking at best can translate to higher quality and reproducibility of research results using the biospecimens. Akin Abayomi: In Africa, where extreme ambient temperatures are the order of the day in conjunction with potentially large geographical distances that samples may need to travel, attention to detail is critical. Clear and comprehensible SOPs and frequent training activities, particularly at sample acquisition research sites, are key to ensuring sample integrity. The emphasis is shifting towards minimizing preanalytical variables, which necessitates the need to have the capacity to bring the process of stabilizing the physiology of the sample closer to the donor. This is possible with good logistics and strategic team activity dovetailing with synchronized operations between the researchers and the biobanking teams. Communication is critical in this process. Kit development and dispatch to sites of collection with good training and harmonized operational activity all along the route of the sample until it gets to its final storage site are mandatory in this process. Where cell-line creation is part of the menu of operations, then the sooner the blood mononuclear cells are isolated and either frozen or processed the better the outcome. This process can start at the collection site to stabilize the cells and completed at a central facility. Staffing at peripheral collection sites will need to be upskilled and infrastructure adapted to this objective. Use of emerging room temperature storage and transportation technology to stabilize the whole sample at time of collection or soon after isolation of nucleic acids may be useful options in some environments. What are the advantages and disadvantages of centralized vs individual/local biobanks? Tim Peakman: There is no right or wrong answer to whether a study should adopt centralized or local sample processing and archiving. This will depend upon factors such as size of the study, daily volunteer recruitment rates and sample acquisition, sample processing throughput, complexity of the processing protocols, available budget, and the expertise of the study team. As a general rule, once studies reach a certain size and certain sample accrual rate, centralized biobanking offers a number of advantages but this does depend upon the study. Use of automation allows much higher numbers of samples to be processed on a daily basis much more consistently and with a robust, secure anonymized data trail. Quality data are recorded as part of the process and, if sample storage and retrieval are automated, samples can be stored and retrieved quickly from very stable, low-temperature environments with complete accuracy. Balanced against this, central services cost a lot to establish and maintain and often samples need to be shipped from collection centers that introduce delays in processing (although the effects of this can be largely mitigated using temperature-controlled shipping conditions) and increase transport costs significantly. Smaller single-site studies may benefit from local processing which is as quick as possible (and is therefore likely to preserve as many analytes as possible), is suitable for very complex protocols, and doesn't incur high setup or transport costs. This approach is limited to relatively small numbers of and can with process and variability the and requires maintenance of a data trail for studies with recruitment From that the cost sample for large studies is also increased with local need to the and of each for their study in their with an of the stability of the samples they are and processing and the costs of different Peter of At the biobanks are the of a complex activity biobanking, and some components of biobanking need increased to reduce research that of and biospecimen while need more to quality processing and and other components need both of networks can be centralized in but with distributed from and at the level are many quality, and factors that what is a facing organizations and research whether to or their A of these and the many and have often been to of the by the to in research is an essential and but of around infrastructure is The types of biobanks and research to be are other important is no only important considerations. as around issues such as reproducibility in research and the need for increased scale and quality in biobanks can only come with implementation of and the need for more components and of many types of biobanks Helen Moore: biobanks can advantages of increased of biospecimens, with systems for quality management, data management, and or local biobanks may provide advantages in and One way of these is biobanks so that individual biobanks use the or at and approaches to biobanking, the of biospecimens across different sites in a or biobank. An quality management program across the system would be an important of such a network and would include to different collection sites and a of collection and storage that might be in place at different It would be important to where approaches and processes could be at different sites, and for (and such where they could A network would good and education about the of the to answer such are to What is the of the is harmonization of approaches and quality management important to the final facilitate better biospecimens and better research through this Akin Abayomi: In Africa, where infrastructure is and can be through is an with a more central biobanks with effective to peripheral collection processing sites would the of the research team and ensure samples are as to that of the volunteer as possible. 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What are some of the issues facing biobanks in of long-term Peter Watson and Lise Matzke: Biobanks are expensive to and From collection of biospecimens to processing, storage, and activities, the of activities in a biobank is a biobanks are the biobanks in their and Further, as a research biobanks a complex and that is with biobank Biobank is therefore a of and usually the the importance of other aspects or should not be biobanks are often as not being secure they on or it is the complexity and variation of and that is the most important of this and it is the metrics to evaluate the relative importance of individual biobanks and the importance of biobanks other of research infrastructure that the critical of research are and all focus on the of research should in biobanks if the scope and need are not the for any and is very and not and the research to biobanking is recognized as an important part of particularly in the research their in to the research and then to a is At the end, the to to a set of the and standards by which biobanks should be able to at to ensure research quality, is the greatest to of individual The good is that these issues are now a part of an in the biobanking the of new strategies to these issues. Helen Moore: are often collected for specific research the research have been the research may be the biospecimens may have for research use. to the of biospecimen and the to support their storage and can be challenging. A greater emphasis on to the about the of biobanks in and to about the of biobanking, will be important to in biobanking. is about the actual costs of biobanking. The National Cancer Institute is a on the aspects of biobanking. The data will be in and in an that will be able to for about the costs associated with biobanking. Akin Abayomi: In environments with a of in and for the greatest for or is in and on to provide that can either as or as a strategy. Biobanking is not high on the and in environments its return in of and of a is not research that biobanking strategies have the of in to their research In such external can be used as to which will as a for the need to establish national and the right environment to the biobanking, and national research can biobanks better their to researchers and the Peter Watson and Lise Matzke: the of a biobank requires the biobank to be on and and key other words the of the For the the and to key is to researchers and the will the that is in biospecimen for while to the the emphasis is on the end biobanks are working for better these requires a different strategy from vs scientific to each in the design, and of a biobank. Helen Moore: Biobanks are an essential of the medical research and the for and in biobanks must be upon and It is important for the to that of research biospecimens, as well as the by biobanks of the biospecimens for current and future is to medical that may benefit the research and their In the the concept of for the good is to or who are for their they are to whether they would be to donate in the of an It is important now to the about of biospecimens for research. Such education must be across and Akin Abayomi: Communication in the of has to the and of national to and and to the from which samples will be requires a different strategy and of to the in The greatest will be from the of the and are important to effective and The in at the different can be quite and should not be For the national the importance of the is to bring to the advantages to be through not in of of its but also the of the benefits of biobanks requires the the of are critical in an strategy and form an important of overall An aware and informed is to but with this the evolving of The engaged is more and requires to on the emerging and role of biobanks in the return of research results to biospecimen and the that will result from review of and by Peter The issue of of research has become of the most and issues facing research and research in are in of data and the scale and of research data as by the in the of data from biospecimens. The complexity and of different are and the of of the and of biobanks that in between the and the research of the has an all an important issue and is often in the research by its nature and must be and to some from clinical There are both and to to this research biobanks not the clinical and should be to the for return of research is not the as an to raise issues or in the process of return of results from research and become to the biobank. Helen Moore: In larger and larger of research have become part of medical and technologies for and an important role in biospecimens. Such as well as established analysis approaches such as review, can some results that are as to the research In some cases the are of no or clinical but in other cases the may have clinical be such if in a research a clinical to be and researchers or biobanks not to be for the to research their as more is about and studies are for medical the between research and clinical are The of researchers and to return is a of much are the of what are and the benefits and of the to the research their Akin Abayomi: This is a complex clinical that will closer to the of as the concept of more of an It is to potentially useful from a or the the are and the ability to and data in an to the donors. The concept of will as a more to as and to patients more through on or or emerging issues that you will have on the future of biobanking. Tim Peakman: One of the for biobanks will be data This is likely to come from from use of the studies data and samples to other researchers and typically this involves the return of research data to the biobank once the is The of this is that it the for future of the of scientific that can be using these and the technologies used to biobanks will need to data data quality, and data are stored and in a data large biobanks are their expertise and to to large data on their sample For example, Biobank is the is about in the and of the whole and is an approach to collect data on people. data are very large and and of storage, and use. both from such as genetic and new analytical approaches and from by will be a data management in the of the of large biobanks is the of studies can use the should be taken to avoid using the of in a way that in the data It was on this basis that Biobank to the with the that in or it will be to the of all of the people. This a of the so that the can be used for other types of emerging are approaches for the and Helen Moore: across biobanks and research programs will be very important in the future of medical research to better individual in of disease, and to such data while the of individual research is a for the A better of biospecimen the effects of different biospecimen collection, processing, and storage on the of biospecimens, is need to attention to now so that can biospecimen practices for different analysis also need to be the by which biospecimens are and storing this with the biospecimens in This approach will be even more important in the future so that will be some assurance that collected and stored biospecimens are suitable or for for research and of specific as analysis technologies Akin Abayomi: will become an important of the future as a means of tracking samples and related can ensure the ability to track samples from to and to the use of in the should be able to a biological from a research site to primary or and the benefit that is in to a This will become particularly important with the use of cell-line technology in of both a quality assurance and a means of tracking and It will also as a means to in the scientific process and start the for on a standard operating quality