phuse emerging trends & technology · double spend spending money or other items of value more...

Project: Blockchain Title: How Blockchain Can Transform The Pharmaceutical And Healthcare Industries PhUSE-WP005

Working Group: Emerging Trends & Technology

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PhUSE Emerging Trends & Technology

How Blockchain Can Transform The Pharmaceutical And Healthcare Industries



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Contents 1. Purpose and Scope of This Document .............................................................................................. 4

2. Background: .................................................................................................................................... 5

3. Definitions/Glossary: ....................................................................................................................... 6

4. Introduction to Blockchain ............................................................................................................. 10

4.1 What is Blockchain? ............................................................................................................... 10

4.1.1 Key Benefits .......................................................................................................................... 11

4.2 How Blockchain Works ........................................................................................................... 12

4.2.1 Foundational Principles ......................................................................................................... 12

4.2.2 Protocols............................................................................................................................... 14

4.2.3 Pros/Cons of Blockchain vs. Status Quo ................................................................................. 16

4.3 What Problems are we Trying to Resolve? ................................................................................... 17

4.4 Blockchain Benefits Seen from Across Industries.......................................................................... 19

5. Use Cases for Blockchain in the Pharmaceutical and Healthcare Industries .................................... 20

5.1 High Level Use Cases .............................................................................................................. 21

5.1.1 Accelerating Patient Recruitment for Clinical Trials by Accessing EHR/EMR ........................... 21

5.1.2 Incentivizing Patients and Enabling the Access of Patient Data for Clinical Research .............. 22

5.1.3 Traceability Across the Drug Supply Chain ............................................................................. 24

5.2 Recommended Use Case 1 and 2 for Proof of Concept ................................................................. 25

5.2.1 Use Case 1: Capturing Efficiency and Ensuring Quality in the Supply Chain Using Smart Contracts 26

5.2.2 Use Case 2: Patient Data Access and Transparency ............................................................... 27

5.2.3 Implementation Proposal ...................................................................................................... 30

6. Getting Pharmaceutical Industry Ready for Blockchain: Needs, Risks, Barriers, and Priorities ......... 31

7. Conclusion ......................................................................................................................................... 34

8. Disclaimer......................................................................................................................................... 34

9. Revision History ................................................................................................................................ 35



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10. Acknowledgements ................................................................................................................... 35

11. Project Leader Contact Information ........................................................................................... 35

12. References ................................................................................................................................. 36

List of Figures Figure 1. Business Benefits of Blockchain Technology………………………………………………………………11 Figure 2. Centralized and Distributed ledger………………………………………………………………………….…13 Figure 3. Stakeholders in the Pharmaceutical and Healthcare Industries who may Benefit from Blockchain Technology………………………………………………………………………………………………………….…18 Figure 4. Use Case: Accessing EHR/EMR Data for Clinical Trials…………………………………………….…21 Figure 5. Use Case: Incentivizing and Enabling the Access of Patient Data……………………………………………………………………………………………………………………………………...…23 Figure 6. Use Case: Traceability across the Drug Supply Chain…..………………………………………...….25 Figure 7. Capturing and Sharing PRO in Clinical Trials………………….………………………...………………..27 Figure 8. Patient Survey on Data Sharing……………………………………………...……………………….………..28 Figure 9. Blockchain Enhanced Trials……………………………………………...……………………….………………29 Figure 10. Implementation Framework……………………………………………...……………………….………….31

List of Tables Table 1: Comparison of Ethereum and Hyperledger-Fabric………….……………………………………….…14 Table 2: Pros/Cons of Blockchain vs. Status Quo………………………..……………………………………..….…16 Table 3: Known Use Cases across Various Industries………………….……………..………..………………..…19 Table 4: Pre-requisite for Adoption……………………………………………..………………………..….……..….…33



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1. Purpose and Scope of This Document This paper will make the case that blockchain is a disruptive technology for the pharmaceutical and healthcare industries and a cultural movement that our industries would be wise to embrace. Moreover, we argue that now is the time for action.

A confluence of factors lead us to believe that blockchain is the next great technological advancement of our time and of particular relevance to the pharmaceutical and healthcare industries. These include the following:

• Federal and state regulations for industry interoperability and accountability • Worldwide demand for patient-oriented healthcare • Cross jurisdiction and cross condition nature of the

pharmaceutical and healthcare industries • Unsustainable industry wastage, fraud and mounting

costs • Inefficiencies of traditional R&D process • Inherent capabilities to improve trust, transparency, auditability and security of

transactions • Blockchain’s unique ability to effectively negotiate the tension between patient data

privacy and data sharing • Massive amounts of investments and continuous innovation in blockchain technology

In spite of all this, blockchain is not magic, but it undeniably has the potential to disrupt the status quo. It is a technology infrastructure, software, and a cultural movement towards more accountable transactions and decentralized processing. Subtly, it is also a movement towards greater security and near real-time machine to machine transactions which perhaps represents its greatest transformational benefit. This paper will define and provide context on blockchain, explore use cases relevant to the healthcare and pharmaceutical spaces, and make proposals on how to get started. Let’s begin!

Understand the impact of blockchain and be part of the

transformation!



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2. Background: Our peer-based collaboration started with a simple question in early 2017 at a roundtable discussion entitled, “How Can Blockchain Provide End-to-End Patient Solutions?” We identified a desire to increase awareness on this topic, including further development of our own education, and a need for an initiative to accelerate the adoption of blockchain in our industry. That is, we cannot harness blockchain’s transformative potential working individually; success vitally depends upon collaboration among stakeholders, including regulatory authorities, industry, patient groups and many others.

We resolved to find an organization where we could share ideas and exchange information freely. Under the auspices of PhUSE, a non-profit organization that collaborates with the FDA and EMA, we became the first PhUSE Blockchain workgroup.

This white paper demonstrates how uninformed interest in a novel subject, fueled by self-education and identification of opportunities, can rapidly turn from notion to product, and how progress is made when engaged people make connections through their networks. Our group includes volunteers from cross-functional backgrounds and areas of expertise. We share this white paper to inspire other like-minded professionals who are eager for change and for all those seeking the opportunity to be a part of this transformational event.

Only through industry collaboration to understand the potential impact of blockchain can we help accelerate drug development and patient care



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3. Definitions/Glossary:

Abbreviation or acronym Definition

API Application Program Interface. Code and protocols that allow two software programs to communicate (e.g. share data). Acronym is context dependent and can also mean Active Pharmaceutical Ingredient

Blockchain An immutable, decentralized, digitalized and distributed ledger of data transactions, recorded in chronological order

Blockchain protocols Set of cryptographic programs that are used to create a specific blockchain system

CDC Centers for Disease Control and Prevention (US)

CDISC Clinical Data Interchange Standards Consortium. It is a non-profit organization that develops data standards to streamline clinical research and enable connections to healthcare.

CLINRO Clinician-Reported Outcomes

CRF Case Report Form

Cryptography The computerized encoding and decoding of information

Disruptive technology A technological solution that displaces an established technology or industry

DLT Distributed Ledger Technology1 allows for transactions and data to be recorded, shared, and synchronized across a distributed network of participants



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Double Spend Spending money or other items of value more than once

DSCSA Drug Supply Chain Security Act

DQSA Drug Quality and Security Act

EDC Electronic Data Capture

EHR Electronic Health Record, a synonym for EMR

EMA European Medicines Agency. Responsible for evaluation and supervision of medicines for people and animals in the European Union

EMR Electronic Medical Record, a synonym for EHR

Enterprise systems Application software that supports business operations

FDA Food and Drug Administration. A federal agency of the United States Department of Health and Human Services. The FDA is charged with overseeing medical products, tobacco, food and veterinary medicine

FDA’s RAPID Food & Drug Administration Real-time Application for Portable Interactive Devices

FHIR Fast Healthcare Interoperability Resources. An electronic standard to exchange healthcare information

GCP Good Clinical Practice

GDPR Global Data Protection Regulation. Legal framework for the collection and processing of personal information for people within the European Union

GMP Good Manufacturing Practice



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Hash/hashing A hash is a function that converts an input of letters and numbers and computer files into an encrypted output of a fixed length. A hash is created using an algorithm (e.g. SHA256)2

HIPAA Health Insurance Portability and Accountability Act (US)

LOINC Logical Observation Identifies Names and Codes. A database and standard for identifying medical laboratory observations

Metadata A dataset that describes and gives information about other data

Nodes Network participants in a distributed ledger network

Oraclize Oraclize is integrated with a number of blockchain protocols and its service is useful and accessible also for non-blockchain applications3

PBFT Practical Byzantine Fault Tolerance

PhUSE Pharmaceutical Users Software Exchange

PoA Proof of Authority

PoC Proof of Concept

PoS Proof of Stake

PoW Proof of Work

PRO Patient Reported Outcomes

Provenance An immutable audit trail of ownership and location as it changes over time, enabling a single source of truth

RWE Real World Evidence



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Smart Contract A computer protocol intended to digitally facilitate, verify, or enforce the negotiation or performance of a contract. Smart Contracts allow the performance of credible transactions without third parties mediation

USCIITG United States Critical Illness and Injury Trials Group network

WHO World Health Organisation



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4. Introduction to Blockchain This section will define blockchain, summarize its advantages over legacy technologies, and provide an overview of its use in other industries. Subsequent sections will address the application of blockchain specifically to the pharmaceutical and healthcare industries.

4.1 What is Blockchain? Blockchain is a type of Distributed Ledger Technology (DLT) that can record any transactions of value and share it across a peer-to-peer network. The concept of a shared ledger, managed and maintained by the community it serves, is not new. Rai stones used in the Island of Yap in 500 A.D. were a form of limestone currency traded by verbal agreement. During a transaction, the stones themselves did not change hands (some weighed 4 tons), instead transfer of ownership was recorded through chatter across the community4. Thus, a shared ledger was born, updated and approved by group consensus. Blockchain can be a private platform with vetted participants or a public open network, such as Bitcoin, where anyone can participate in the maintenance of the ledger. Bitcoin has played a significant role in popularizing blockchain technology and illustrates the problem blockchain originally set out to solve—no central authority—as envisioned by Satoshi Nakamoto’s seminal 2008 paper5. In the present day, blockchain application has evolved into a platform for enabling decentralized computation across many industries. Within a blockchain each node contains a full, replicated copy of the global ledger; it uses an algorithm called a consensus model to prevent synchronization issues between nodes, including the “double spend” problem. Using Smart Contracts, blockchain can support a vast array of use cases that apply far beyond the finance sector, including healthcare, energy, industry, and research by providing a mechanism that allows untrusted entities to interact and collaborate.

A significant amount of attention is currently directed towards this technology; however, many of these non-financial use-cases are still in their infancy and poorly understood by potential adopters. In the healthcare sector alone, blockchain technology could improve how information flows across the entire value chain from drug discovery and clinical trials, through to manufacturing and sales and marketing. While blockchain faces unique implementation challenges, this technology has already demonstrated the potential to revolutionize our ability to inform, deliver, and measure patient care.



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4.1.1 Key Benefits The key benefits of blockchain technology are outlined in Figure 1, and include:

• Its inherent traceability • Trust • Security and provenance

The potential to simplify processes, increase reliability, and improve accuracy through the pharmaceutical supply chain and conduct of clinical trials represents opportunities such as financial efficiency, security gains, and others.

Figure 1. Business Benefits of Blockchain Technology Blockchain represents the expansion of a distributed database, with the unique capability to fully automate transactions and instantly update an audit log. With medical data transactions, a blockchain can deliver cost-effective improvements that are impossible with existing technology. Unlike with legacy systems, the technical feasibility of a solution is not so much dependent on the data being handled, but rather on the underlying governance protocols. Ultimately, the goal of each protocol is to achieve consensus, but there are varying degrees of portability, accessibility, and immutability core to the blockchain application. To properly review protocols in the context of use cases, permission and transaction speed are two important additional considerations.



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4.2 How Blockchain Works 4.2.1 Foundational Principles

a. Digital trust and consensus models The underlying structure of a blockchain is rooted in the desire to validate and synchronize data that is spread across a decentralized network of computers creating a ‘digital trust by design’. A blockchain typically consists of a network of computers (Fig. 2) containing a shared ledger comprised of transaction data that has been broken into pages, called blocks. Each block is linked to the previous block using a cryptographic hash function, thus forming a chain, and ensuring that the chain of blocks cannot be corrupted as new blocks are created. As new transactions enter a blockchain network, a consensus model is used to determine which next set of validated transactions will comprise the next block. Proof of Work (PoW) and Proof of Stake (PoS), also known as mining, are geared more towards public networks that yield a cryptocurrency that has value. PoW: nodes are incentivized to mine (process that selects the next block) because there is a monetary reward for finding a correct solution to the cryptographic puzzle. This token or cryptocurrency generates value creation which is a critically important concept in blockchain and sets it apart from how traditional, centralized application services work. PoS: the security of the consensus model is much more closely tied to the value of the cryptocurrency because nodes with the most amount of value associated with them are the nodes that have the greatest say in deciding the next valid block. The reasoning is that those are the nodes with the most to lose if something goes awry. If the underlying cryptocurrency has no value, PoS suffers from what has been called the “nothing at stake” problem. Proof of Authority (PoA): For private networks, one of the most popular consensus models is PoA, in which a subset of the network nodes are selected as authorities and get to determine the next block. Ethereum, for instance, supports the Clique PoA protocol, and other groups such as Parity have developed their own implementations of PoA including Tendermint and Aura.



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Figure 2. Centralized and Distributed ledger

b. Authentication In blockchain, identity is established using a pair of numbers called a key-pair, which consists of a public key and a private key. The private key is secret and known only to the owner, while the public key (or an address derived from it) is visible to others on the blockchain. The ownership of a private key is what defines identity on a blockchain. Before an individual submits a transaction into a blockchain, they must sign the transaction using their private key. This signature is what enables the blockchain to verify the authenticity of the transaction. It is possible for one private key to be associated with multiple public keys.

c. Immutability Every node in the blockchain maintains a fully replicated copy of the ledger. To ensure that the ledger being distributed across the network is the verified version, a mechanism to resolve conflicts between multiple ledgers is required. With multiple participants simultaneously approving different blocks of transactions, it could potentially be difficult to discern which copy of the ledger to follow. However, as described in Section 4.2.1a (Trust), each block of transactions contains a reference to the block before it; this linkage is encrypted using a hash function to establish a “chain” of blocks. Using a consensus model, the network of nodes determines the next valid set of transactions (block) that should be adopted blockchain network-wide. If a scenario occurs where more than one block is selected, such as when two different mining nodes find valid solutions, the conflict is resolved when subsequent valid solutions are found and a longer chain emerges, which is then selected as the valid branch.



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4.2.2 Protocols There are many protocols out in the market such as Ethereum, Hyperledger, IOTA, R3 Corda, OpenChain, and others. Whilst the working group does not endorse one protocol over another, we have chosen two of the most widely used protocols for comparison (Table 1):

Table 1: Comparison of Ethereum and Hyperledger-Fabric

Type of Protocol Ethereum Hyperledger - Fabric

Transaction Speed

Approximately 15 per second Approximately 160 per second

Access Public blockchain (can be private) Private permissioned blockchain

Programs All parties can see and track all transactions, progress updated in real time

Only invited parties can access shared ledger

Smart Automation

Smart Contracts to enable programmable automation when certain conditions are met

Oraclized chaincode allows for automation within supply chain processes at benchmarks

Cryptocurrency Ether, provides incentivization

Lack of tokenization and PBFT consensus provides faster transactional throughput

Governance Can be encoded and enforced by Smart Contract

a. Ethereum After Bitcoin, Ethereum is the second largest blockchain platform by market cap, and one of the most popular public blockchain protocols for enterprise systems. Ethereum is specifically built for the execution of Smart Contracts and automation of actions upon meeting benchmarks6. The Ethereum blockchain is also permission-less and open. Ether provides the base currency to perform transactions within Ethereum. Emerging healthcare applications use private Ethereum networks with consensus models including implementations of PoA and PoS. Due to its use of cryptocurrency, Ethereum could provide a blockchain for incentivizing participation for patient data exchange.



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b. Hyperledger Hyperledger, an open source, collaborative effort led by The Linux Foundation®, has several projects (frameworks) of varying complexities to allow blockchain-centric transactions. These include: Fabric, Sawtooth, Iroha, Burrow, and Indy7. Private permissioned blockchain using oraclized chaincode could allow for automation within supply chain processes at prespecified benchmarks. For example, because Hyperledger Fabric is a private permissioned blockchain, it only allows participants with permissioned access to be part of the ecosystem. Practical byzantine fault tolerance (PBFT), the underlying consensus algorithm, provides transparency and specific governance for all members within the blockchain system while rejecting malicious and misaligned parties. Within the context of a patient data use-case, a permissioned chain would allow the proper sharing of data and the applicability of participating nodes throughout hospitals. Due to various legal and regulatory provisions within the US (Health Insurance Portability and Accountability Act [HIPAA]) and the EU (Global Data Protection Regulation [GDPR]), data would not be readily available. Hyperledger could provide a network of internal nodes that provide greater data security and protecting against ransomware attacks compared to enterprise systems. However, this protocol would not be conducive to the data exchange model since it neither offers an incentivizing model nor an underlying currency.



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4.2.3 Pros/Cons of Blockchain vs. Status Quo

Table 2: Pros/Cons of Blockchain vs. Status Quo PROS OF BLOCKCHAIN CONS OF BLOCKCHAIN • Increase efficiency across the industry by

establishing trust among peers (less repetition of work, such as data entry, data cleaning, etc.) • Full audit trail (ability to track the source of

information) • Disintermediation reduces the number of

required intermediaries between parties. It shifts the responsibility of validation from a central authority to the distributed network • Faster transactions in specific use-cases • Lower transaction costs by eliminating

third-party intermediaries and overhead costs for exchanging assets • Transparency and auditability of signed

transactions allowing for more transparency and full disclosure of the information • Permanent and immutable/indelible records • Clearing and settlement with smart

contracts to manage claims in a transparent, responsive, and “irrefutable” manner; ability to enforce claims by triggering payments automatically when certain conditions are met and validated. • Reduced counterparty risk by revealing

trusted data to another counterparty ahead of trade time to provide greater transparency • Protect information database against failure

or attack as data is kept decentralized between parties

• Limited scalability and processing power: blockchain versions today, like Bitcoin and Ethereum, can only process a small fraction of the transactions per second that traditional companies like Visa process. In order for blockchain to become mainstream, it must solve scalability concerns. It is taking longer and longer for a transaction to be validated by consensus and added to the chain (especially in a public chain). • Lacks ease of use: understood by a

small number of experts. Requires end user friendly interfaces • A new shift of paradigm requiring

holistic thinking and approach • Unknown long-term return on

investment • No standardization and validation • Cost of storing data for indefinite

period • No data deletion allowed, only

updates of data. Potential impacts on GDPR for personal data. • Private key management is currently

quite complex and non-intuitive, leading to potential loss of digital identity on the chain and possible loss of access to own data

Threats: industry not ready and regulations not in place, complex processes, lack of knowledge, long-term ROI, change management, no standardization

Strengths: Trust, security, transparency, full audit trail

Weaknesses: technical immaturity, not all data is digitalized, scarcity of skills, replaces part of current applications, APIs to be developed

Opportunities: empower patients and increase trust, accelerate drug development, improved treatment and care, reduce fraud



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4.3 What Problems are we Trying to Resolve? We have identified several different areas where blockchain can be harnessed to provide or support solutions in the pharmaceutical and healthcare industry (Fig. 3). High-level examples of how blockchain could be applied to our industry include the following:

• Empower patients to control and access their data (EMR/EHR, Health Apps, Advocate groups, etc.) and decide who and what data is shared peer-to-peer

• Incentivize and reward patient data sharing, while ensuring trustworthiness and control over the data stream

• Protocol algorithms allow system agnostic real-time data sharing and availability during public health emergencies across various healthcare systems

• Address inefficiency of drug development process for patient populations with high unmet patient needs by bringing new drugs early to market and using patient health data consented for:

o Real World Evidence (RWE) analysis o Safety/Efficacy assessment o Recruitment into clinical trials o Research of the disease and other unmet needs particularly rare diseases

• Provide a longitudinal view of the patient’s health journey by enabling permissioned access to patient information for healthcare professionals to better assess patient’s health, identify the best course of treatment, and better understand the patient’s disease

• Enhance the drug supply chain process by ensuring the validity and distribution from raw materials to production as well as the controlled distribution of end-product to pharmacies and hospitals (tamper-free and according to drug specifications)

• Provide a mechanism for real-time, secure, transparent, and auditable collaboration in clinical research amongst a group of peers

• Provide a mechanism for secure, efficient, and transparent recruitment of subjects for clinical trials, with ability to digitally streamline the process

• Improve data integrity of clinical trials with full audit trail of each record (raw data) to mapping into standards and removing the need for manual quality checks.

• Data transparency for patients, healthcare practitioners, and regulatory authorities to access information in real-time, enabling faster submission for drug applications

• Compliance with data privacy and permissions such as GDPR • Compliance with the US FDA’s DSCSA (Drug Supply Chain Security Act), and Drug Quality

Supply Act in the US and Falsified Medicine Directive in the EU



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• Oversight of vendor and third parties’ deliverables in clinical trial/research with nearly real-time data, thus establishing robust processes quickly and efficiently.

Figure 3. Stakeholders in the Pharmaceutical and Healthcare Industries who may Benefit from

Blockchain Technology

The potential benefits of implementing the above applications are profound. However, as with any new technology, processes need to be established to support it from access management to a full system lifecycle. The system must be compliant with relevant regulations and codes, such as HIPAA, Good Practise (GxP), GCP and GMP. According to Jim Nasr, former CDC Chief Software Architect, “blockchain cannot operate on its own and requires off-chain technologies to enable it to access data sources or tap into additional functionality needed for the delivery of a realistic healthcare application. Therefore, blockchain is just one playground in the software theme park8 of interoperable software”. In other words, blockchain still needs enterprise systems and APIs to enable end-to-end solutions. It is critical to perform an assessment of when, where, and what data will be shared peer-to-peer before creating a business case. Only then can one assess the impact within the organization (return on investment and relationships to company strategy), including all potential risks and benefits, and determine whether blockchain will be worth the investment for a particular use case.



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4.4 Blockchain Benefits Seen from Across Industries There are a widespread number of use cases across various industries that report many benefits. Table 3 gives some examples but is not an exhaustive set.

Table 3: Known Use Cases across Various Industries Industry Objective Example Food Supply Chain

Provide traceability to improve food transparency and efficiency. The solution will enable quick identification and removal of contaminated foods, tracing food origin and its journey through the supply chain (e.g: was the food produced safely, responsibly, grown sustainably, etc.). This transparency will help foster a safer and better food system9

IBM, JD, Walmart China, and Tsinghua University

Government

Enable real-time exchange of patient-level data within the USCIITG network for (influenza) in 2017/201810

US FDA’s RAPID and Booz Allen Hamilton

Define a secure, efficient, and scalable exchange of health data using blockchain technology. It is to explore the exchange of owner-mediated data from several sources, such as EMRs, clinical trials, genomic data, and health data from mobile devices, wearables and the “Internet of Things”, with initial focus on oncology-related data. The collaboration will address new ways to leverage the large volumes of diverse data in today’s biomedical and healthcare industries11

IBM and USA FDA

In 2008, developed e-Health to enable capturing, storing and sharing of EHR/EMR data to patients and physicians. Estonia has introduced ePharmacy, eTax, eResidency among other solutions12

Republic of Estonia and Guardtime

Counteract severe economic crisis and hyperinflation in Venezuela, launched the first phase of its state-funded cryptocurrency. The “petro” will help Venezuela raise cash and will be backed by the country’s oil reserves—the world’s largest—and will be accepted as payment for things like national taxes and public services13

Republic of Venezuela

Energy and Utilities

Grant consumers a new way to buy prepaid electricity using smart meters integrated with wallet addresses, 3G SIMs, and a

EMS Invirotel



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server connection to compute an up-to-the-minute bitcoin price14

Transportation Develop prototype for electric-car-charging stations. In 2016, blockchain-based smart contracts to authenticate users and manage the billing process15

RWE and Slock.it

Consumer-Retail Industry is heavily fighting against counterfeit; smart tags will be embedded in sneakers to verify authenticity of the product16

Nike, Adidas

Insurance-Retail Create an immutable history and origin of retail items. Since 2015 Edgelogic, an Australian software company, is using the digital currency to create an online record book called Blocktrace (now Everledger), which will allow insurers and purchasers to check the history of a precious stone (diamonds) and what crimes or claims have been made against it17

Aviva and Everledger

Pharmacy- Retail

Improve efficiency, transparency, and operation of supply chain finance in pharmaceutical procurement. Overall, the platform reduces the turnover time of funds on both sides of the supply chain and allows banks to be more informed and grant access to funding for small and medium pharmaceutical retailers18

IBM and Sichuan Hejia

Other Enable validated digital signatures for documents and contracts, verify authenticity, and encrypt and transmit documents securely19

Stampery

5. UseCasesforBlockchaininthePharmaceuticalandHealthcareIndustries

In this section, three proposed high-level use cases including an in-depth exploration of two proposed use cases tailored to the pharmaceutical industry are made to provide an overview of blockchain implementation specific to clinical trials. To deliver these use cases, it is recommended to engage with blockchain experienced technology companies. However, because blockchain remains an emerging technology with a predicted implementation timeline of 5-10 years according to Gartner 20, there are challenges and many misconceptions, complexities, and undeveloped standards. Many of these expert technology providers are start-up companies with limited ability to demonstrate a track record.



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Other existing blockchain providers include management consulting companies that either partner or bring blockchain competencies in-house, bespoke blockchain providers or collaborative groups. The proposals for implementation in the pharmaceutical industry described in subsequent sections consider the collaborative groups approach where multiple sponsor companies form a joint coalition in partnership with technology providers, regulators, academia, patient groups and industry standards organizations to accelerate adoption in a phased approach.

5.1 High Level Use Cases

5.1.1 Accelerating Patient Recruitment for Clinical Trials by Accessing EHR/EMR Clinical trial recruitment is a common challenge, especially for special patient populations like pediatrics and patients with rare diseases. Recruitment can take up at least one third of the total clinical trial duration. In addition, approximately 20% of sites recruit no patients. This adds additional cost to the conduct of clinical trials, delaying the right treatment access for patients. On average, it takes 14 years for new drugs to reach the 1st market (cost of over 1 billion USD)21. These timeframes and costs have not improved in over a decade.

Figure 4. Use Case: Accessing EHR/EMR Data for Clinical Trials



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Companies currently use different efficiency strategies to speed up drug development. But what if blockchain could help resolve some of these challenges we face today? For example, in Figure 4, if a patient is interested in participating in a clinical trial due to unmet needs (e.g. no adequate or available treatment) and owns their data, he or she could contribute a set of EHR/EMR (using FHIR standards) data anonymized through the blockchain (e.g. demographic, disease history, etc.). As a result, this allows researchers to access the information and verify the inclusion and exclusion criteria. The researchers or investigators (e.g. virtual sites) would have access to a pool of data and any patient who qualifies could be requested to provide additional data and to e-sign the e-Consent. In the best possible case, the recruitment for a given trial could be completed in the space of one day with a substantial amount of the data already collected, allowing clinical trial to begin on Day 1 or Day 2. The patient data would be shared from a public or private blockchain (on-chain) to a private clinical trial permissioned blockchain with investigators, the sponsor (pharmaceutical company), vendors, central laboratories, etc. where the data can also be shared through internal systems/databases (off-chain). Taking into consideration the data integrity, interoperability, near real-time access, additional security, and other benefits blockchain can provide in comparison to the available systems, this means that the drug can potentially be available 3-5 years sooner than a traditional drug development process.

The above concept might be far from realization as most countries do not have all their health records stored electronically nor are able to access them easily. However, the Estonian government22 is a good example of years of planning and over 10 years of investing to digitalize all population health and medical records. Their decision to use blockchain places Estonia as one of the most technologically advanced countries (named the most “digitally advanced” 23), enabling Estonia to spearhead implementation of other cutting edge e-services such as e-prescription, e-tax, and others24. We should learn from these experiences and leverage blockchain solutions to our advantage.

5.1.2 Incentivizing Patients and Enabling the Access of Patient Data for Clinical Research Studies have consistently shown that as many as 87% of patients are motivated to share their health information to help other patients and contribute to research25. Accessing EMR data has been challenging as patients are seldom the true proprietors of their personal health data. Therefore, health data mining and the sale of health records comprise a multi-billion-dollar industry whereby intermediary companies purchase patient and provider data from commercial pharmacies, insurance companies, and EMR systems26. These data are usually anonymized,



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analyzed, and resold for research purposes such as for clinical trials, RWE studies, etc. The patient in turn has neither control over the future use of their medical information, nor any direct knowledge of the individuals and companies handling their data. In fact, despite signing consent forms, most patients may be completely unaware that their data are sold and resold27.

Figure 5. Use Case: Incentivizing and Enabling the Access of Patient Data

Blockchain technology enables an open source platform by storing HIPAA-compliant demographic data off-chain, allowing pharmaceutical researchers to directly purchase anonymized data from patients (Fig. 5). When the purchase of a full dataset is initiated, the Smart Contract matches the demographic data to its corresponding medical data. This process thereby links the demographic dataset and the hashed medical dataset for use in addition to initiating payment into the patient’s wallet (e.g. using health tokens or ether). The pharmaceutical researcher then decrypts the combined health record for analysis. By using the blockchain as the central hub in this sample architecture there is a lowered risk of a large-scale HIPAA violation even if the off-chain database were to be compromised. While such an exchange has the power to both reduce the cost of research and return ownership of health data to patients, its implementation will be dependent upon the presence of an interoperable EMR system. Using blockchain technology, this type of formerly unachievable data exchange may become a reality in the near future, thereby bolstering the notion that even anonymized data still belongs to the patient.



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5.1.3 Traceability Across the Drug Supply Chain We have seen the drug distribution network grow immensely in scope and complexity while lagging behind other industries in its ability to simplify and secure the process. Amongst other issues, current supply management systems lack visibility (transfer of ownership) to track the authenticity of the medicine from manufacturers to the patient. Globally, counterfeit drugs sales amounted to $75 billion in 2010 according to World Health Organization (WHO). This 90% increase in fraudulent drug sales over 5 years leading to approximately 100,000 deaths worldwide. In Asia, Africa, and South America, counterfeit drugs comprise between 10-30% of total medicines sales. Despite massive seizures, a single Interpol operation in 2015 seized $81m worth of counterfeit medicines, arrested 150 people and removed 2,500 fraudulent websites28. The issue of counterfeit drugs is pressing, poses a risk to patients, and has a large economic impact. Governments around the world are tightening the supply chain integrity to slow down the global flow of counterfeit medicines. The European Commission and European Parliament produced the Falsified Medicines Directives published in 2011, stipulating that pharmaceutical drug supply chains serialize their products for track-and-trace by Feb 201929. The US Congress introduced the Drug Quality and Security Act (DQSA) in 2013, giving the industry until 2023 to build an electronic, interoperable system to identify and trace certain prescription drugs as they are distributed in the US30.



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Figure 6. Use Case: Traceability across the Drug Supply Chain

Blockchain can help to resolve current challenges in the supply chain, by providing traceability until the point of delivery (Fig. 6). Blockchain can provide the immutable and interoperable shared ledger using Smart Contracts, updated, and read by all participants in the drug supply chain, creating the ability to monitor the journey of the product through serialization from manufacturers, distributors, re-packagers, and wholesalers before reaching patients; creating full visibility throughout the drug supply chain process. The immutability of the blockchain limits the possibilities for fraud and increases the overall trust in the product and the supply chain. It allows the quick identification and removal of contaminated drugs and can improve the management of shelf-life and waste of expired products. 5.2 Recommended Use Case 1 and 2 for Proof of Concepts This section will explore two proposed use cases selected as low hanging fruit to readily demonstrate the value of blockchain as the first step to industry adoption, based on the following criteria:

ü Demonstrable characteristics of blockchain

ü Practical

ü Generalizable so can be transferred across multiple work flows in our industry

ü Modular ü Scalable



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ü Cost saving ü Attractiveness from a regulatory and

compliance point of view

ü Builds on trust and reputation of our industry

5.2.1 Use Case 1: Capturing Efficiency and Ensuring Quality in the Supply Chain Using Smart Contracts

This recommended use case describes how supply chain, third parties, and even contract research organizations (CROs) and sites can form a private blockchain networks using Smart Contracts for benchmarking activities that trigger payments. In contrast to traditional methods, a Smart Contract can be facilitated, verified, and executed digitally without much human interference, thereby avoiding errors and delays. This is achieved by programming computer codes and rules that will be automatically executed when conditions are met (e.g. If X happens before time Y, then enforce Z). 5.2.1.1 Problem Statement

In 2015, the market size for global outsourced pharmaceutical manufacturing was an estimated $71.6 billion31. In packaging alone, there are vendors in many areas such as bottling, blister packaging, tube fill, and suspension fill. In addition, in the $19.2 billion outsourced drug discovery market, contractors need to ensure quality from compound discovery and validation as to deliver a candidate with good pre-clinical safety profile. Ensuring the integrity of these massive supply chains is the utmost challenge for the alliance companies as described previously. 5.2.1.2 Analysis of Blockchain Solution

Using a blockchain-enabled management tool, companies can perform end-to-end tracking in the supply chain (Fig. 6). Assets, such as raw materials, Active Pharmaceutical Ingredients (API), and packages, can be digitally inventoried, and a decentralized immutable record of all transactions created, allowing end users (who has access to the blockchain key) to track these assets from sourcing to delivery. To unlock the full power of blockchain, the technology should be forward deployed to contractors and subcontractors to ensure the integrity of the whole supply chain. For example,



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everything from shipping containers to truck deliveries could be equipped with sensors that transmit business-related data (such as temperature- cold chain) to a platform using the Internet of Things (IoT). The data is visible to all personnel with key access and can be analyzed in real-time. If the quality of the containers (as judged by the analysis data collected by sensors) falls below an acceptable threshold, indicating a potential breach of contract, the Smart Contract can be triggered, and the system will automatically deliver an insurance proposal, penalty to freight forwarder or distributer centers, and order of product replacements. Because of the enhanced transparency and automation, communication or data transfer errors can be greatly reduced. Companies and contractors can streamline their processes on data validation, drug accountability/inventory management, labelling, and audit through the use of distributed ledger technology. In addition to increasing efficiency, blockchain also helps to enforce contractual terms in a timely manner.

5.2.2 Use Care 2: Patient Data Access and Transparency This use case enables patients to join the blockchain network at specific time points on their clinical trial patient journey to access their data directly such as through activity monitors (Fig. 7) or indirectly through third-party lab databases. This area is being explored in healthcare for EMR/EHRs with healthcoins offered to patients whenever their data is used, and also by companies such as Encrypgen, Nebula Genomics and Luna for genomics data. Because it is patient data being handled, secure encryption, privacy and confidentiality of transactions are kept intact (with data potentially still stored in a separate database). This solution enables patients to control access and also receive full disclosure of their own data at will (refer to section 5.1.2). This would be a private network for patient data transactions and a public network recommended for the incentivized use of tokens.

Figure 7. Capturing and Sharing PRO in Clinical Trials



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5.2.2.1 Problem Statement The pharmaceutical and healthcare industries have historically struggled to increase support from the general public (patients) to join clinical trials. This is largely due to low levels of trust regarding the transparency of drug safety. A recent survey conducted in 2017, by HealthUnlocked32 on 126 patients confirmed a strong interest for patients with chronic diseases to access and share their data (Fig. 8). This survey showed motivations for wanting to share data include having the ability to help others through research using their data while accessing reports on data transactions conveniently using Apps.

Figure 8. Patient Survey on Data Sharing

Patient data in clinical trials is an asset that informs regulators on the outcomes of a clinical trial protocol relating to the efficacy of a drug, safety assessments, and patient preferences. Standardized and verified data collection tools have provided the acceptable format and process for data provision to enable a label claim or meet any regulatory expectation. Studies on 257 Sponsor companies and CROs (Tufts and Veeva, 201733) show that during database lock activities (using EDC) at the end of a study, sites still takes an average of 8.1 days for patient data to be entered after the visit. This data then has to be cleaned, integrated, migrated, and transferred as a final package within an average of 36.3 days.

0% 20% 40% 60% 80% 100%

Pharmaceutical Companies

Healthcare Researchers

Government Bodies

Technology company for…

Patients with a similar condition

44%

91%

30%

30%

79%

Would you be willing to share your medical health records anonymously with the following groups? Select all of the the

groups you would share data with. Yes Responses.



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The evolution of traditional site-based trials to remote or virtual trials (such as “Remote”) can greatly benefit from blockchain for patient eligibility, consent, distribution of investigational drug, and remote assessments to meet regulatory requirement. This enhanced model would enable the prospective collection of data points from potential patients even before a clinical trial starts. This would provide not only eligible patients to enroll from Day 1, but also a large amount of study data already collected and cleaned. A patient eConsent process on a rolling basis would allow patients to provide multiple permissions for the use of their data (across multiple trials) (Fig. 9).

Figure 9. Blockchain Enhanced Trials

This expanded use case would be similar to the efforts made in a two-year agreement between IBM and the FDA. This partnership aimed to utilize blockchain for sharing oncology related patient data sourced from various CRFs from clinical trials, genomic data, wearables and medical records to accelerate research and development. Another example is from a mock experimental study by Mehdi Benchoufi and Philippe Ravaud 34 whereby patient consent was put onto a blockchain where all versions of consent data were verified and associated with the correct versions of the protocol. Even when revised, using the concepts of hashes of the original data, the original versions of the consent where maintained.



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5.2.2.2 Analysis of Blockchain Solution Patient data is a valuable asset and must be protected and handled using strict guidelines. In the blockchain world, this asset can be monetized, converted to hashes for monitoring change during transactions, and can be transferred from one party in a blockchain to another (with permissions and consents from the owner of the data who remains as part of the network). As stated by Maria Palombini from IEEE-SA, “alluring feature of blockchain is the ability to negotiate the tension between patient data privacy and sharing”.

The explosion of wearables, sensors, and genomic screening (e.g. by companies such as 23andMe) have accelerated the gathering of patient data in recent years. Sensors are becoming smarter and cheaper than ever, while genomic screening costs are plummeting. Furthermore, cloud architecture and analytics provide a solid foundation for data sharing and data processing. Wearables companies like Fitbit35 have started regulatory filling processes with FDA to enable consumers ownership over their own health. According to Gartner 36, by 2020 40% of employees will be able to cut their personal healthcare costs by wearing a fitness tracker. Other companies like Apple have started offering access to remote clinical trials through its Research Kit, simplifying the process for both recruiters and participants. Blockchain is a clear enabler in this overall ambition, with 2 basic roles: first, it allows patients to grant permissioned access to their data; and second, in a complementary process, Smart Contracts automate compensation for data purchase through tokens dispensed into patients’ smart wallets. For patient data in a clinical trial, we propose starting with the metadata level of data and defining the critical and valuable data (assets) that will enable a significant benefit to the clinical trials cost, patient safety, and data integrity. Examples include electronic PROs or CLINROs data, EMR/EHR, imaging, and blood tests including genetic sampling. 5.2.3 Implementation Proposal Considering the pre-requisites for adoption, these use cases could commence as proof of concepts to demonstrate where an existing process is enhanced with blockchain to enable true comparison with the standard systems.

PILOT PILOT PILOT!!



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To begin, define the asset, and the metadata that would go on the blockchain. Next, incentivize blockchain validation of each transaction, and deliver a fast and effective user interface for reporting obfuscation of patient identity. Finally, as seen below, follow a phased framework starting on one data type in a pilot then scaling up to multiple types through the collaboration model. The steps for setting up any new technology system should follow the same vendor selections, qualifications, start up, management and review (Fig. 10).

Figure 10. Implementation Framework

Finally, the benefit of collaboration is in harmonizing related vendors under an umbrella of standards that still allows the value of the asset contained in the blockchain to remain intact. This collaboration should enable trust to build quickly among different stakeholders (including patients and regulators) and can improve the reputation for the industry.

6. Getting Pharmaceutical Industry Ready for Blockchain: Needs, Risks, Barriers, and Priorities

In this section, we share our prerequisites for blockchain exploration and adoption in our industry. To make the use cases described in Section 5 a reality, attention and thoughtful action in response to these pre-requisites is a necessity.

Develop Core Team With Senior Leadership Sponsorship

•Perform Deep Dive Needs Analysis•Gain Consensus on Problem Statement

Find and Join Cross-Industry Collaborative Group Working on Similar Use Case

•Non-profit Group e.g. PHUSE or IEEE•Industry Incubator e.g. Pfizer&•Deloitte

Determine with Collaborative Group if Standards Exist

•Select Blockchain Protocol•Select Standard Integrations and Nomenclatures

Prepare Relevant Agreements for Proof of Concept

•Vendor Partner Selection•Blockchain Technical Partner Selection

Perform Proof of Concept• Document and

Share Results • Scale up

Perform Proactive Change

Management on Adoption Process



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Table 4: Pre-requisite for Adoption Pre-requisite Recommended Actions Understanding regulations and compliance

It is critical to understand regulatory compliance such as GCP, and data privacy laws (HIPAA, GDPR). Due to lack of regulations and standards on this new technology it’s essential to collaborate within the industry and regulatory agencies. How can we give access to authorities for auditing transactions? Clinical trials audits typically include these contracts and payment systems which would also need to be visible and accessible by regulators when requested.

Talent Adopting blockchain will require a rare breed of cryptographers and blockchain-literate subject matter experts to develop this new technology to ensure a smooth implementation.

Pick the correct use case

Blockchain is not the solution for every business problem. Start by identifying the needs that the current system is not able to support, then customize your best blockchain use case solution with a clear value proposition. Integration with existing systems and processes should follow. Clearly understanding your reasons for exploring blockchain and the desired outcomes of all parties will help steer proof-of-concepts effectively and support decisions to stop, go, or grow them. This should in turn avoid premature ends or sunk cost reasoning.

Create the right network

A cross-industry collaboration with regulators will accelerate adoption. Join or create a consortium of necessary participants in exploring and applying blockchain. The network structure should formalize some of the stakeholder management and communication essential for successful technology adoption.

Strategic alignment

Consider your strategic focus (ROI and trade-offs) and choose the best-fitting use case for your organization by measuring KPIs against time, cost, quality, and reputation.

Effective risk management and avoidance

Adopt a collaborative approach to risk management by performing a risk assessment plan. Ensure the right level of stakeholder engagement and right skill sets for implementation. More importantly, conduct pilots and proof-of-concepts in small iterations to address all possible issues and streamline processes before scaling up. The inter-dependent nature of blockchain means that risks to one party may be applicable to others or may carry knock-on risks. Execute a bold proof of concept (PoC) as this will identify real-life risks and opportunities to maximize the potential of this technology.



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Exit strategy In a distributed smart contract network, consider how easy it will be to change models, if necessary, since information is shared. What if parties decide to return to a centralized system? This should be detailed in a charter to which all parties consent as part the agreements. Legal clauses in this consideration should be added to contracts.

Change management plan

It is essential to prepare the organization for the paradigm shift. Identify your stakeholders and blockchain champions to drive for quicker adoption of the new technology across the organization. This collaborative approach will require mutual recognition and transparency of interests among all participating stakeholders (Fig. 3).

Industry standards

Standardization is critical to enable blockchain-to-blockchain integrations, especially in the flow of assets/transactions from one network to another, and even more so when there are multiple networks and/or consortiums. Such interoperability minimizes the cost of implementation in the long run.

Reputational damage

Ignore the ‘wild-wild-west’ reputation of bitcoin that affects the reputation of the agnostic blockchain protocol. Instead concentrate on understanding and explaining the qualities of blockchain that will have benefits in pharma.

Cost Proof of concept in start-ups is expected to reduce the cost of infrastructure; remember to hire and train talent with the right skill competencies. Participating and collaborating in a consortium will leverage the implementation of existing blockchain platforms to optimize cost. While the time and cost may be greater than creating your own vanguard, the consortium approach ensures no one member bears all the costs of PoCs, you gain insight from diverse perspectives, and you cover several prerequisites by necessity. Once established, it is expected that there will be significant cost efficiencies to scale up the solution. Multiple single-player solutions would be unappealing for some companies that would need to deploy various APIs for the different e.g. supply chain blockchains. Clarification is needed on who pays for the transactions and maintenance of the network. In terms of the additional code, it needs to be taken into account how this becomes applied to the enterprise systems and if this will be fully integrated and not hosted.

Architecture Being in a heterogeneous environment, we need to deal with off-chain transactions to avoid problems of reconciliation and duplication. This will support blockchain as a single source of truth as adoption increases.



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Governance model

As with all software; there will always be bugs; if a smart contract does not form as required, additional tools may be employed to resolve any dispute. We will need to gain consensus on these tools as adoption increases.

Other digitized tools

Cloud-computing and IoT will enhance the digitization of physical assets into data points for example in supply chain, allowing for real-time analysis of supply chain activities.

Vendor selection

There has been increased activity by large pharmaceutical companies partnering with blockchain experts to deliver proof-of-concepts of smart contracts with payments solutions. Choosing the right vendor to understand the user stories (business processes) and have the right capabilities will be critical to implement blockchain successfully.

7. Conclusion We acknowledged that through joint collaboration we will see quicker adoption of blockchain in piloting robust use cases and processes supporting its implementation. It is an exciting time for this technology to demonstrate its benefit and potentially transform the pharmaceutical industry. The argument that blockchain is simply another database can be dispelled when one understands that blockchain’s benefits reside in its unprecedented provision of transparency, immutability, and efficiency, while bolstering trust and reputation. These benefits enhance access to data and can increase the volume, veracity, validity and velocity at which patient data becomes available for research and patient care. Technologies to analyze and visually report on these types of data assets also need to mature to maximize blockchain’s full potential. Adoption of blockchain technology by the healthcare and pharmaceutical industries will undoubtedly require efforts across industry and interests; however, we believe that this paper can provide a launch point from which we all, as industry collaborators, work to bring forth one of the most promising technological paradigms of our time.

8. Disclaimer The opinions expressed in this document are those of the authors and should not be construed to represent the opinions of PhUSE members' respective companies or organizations or FDA’s views or policies. The content in this document should not be interpreted as a data standard and/or information required by regulatory authorities.



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9. Revision History

Date Author Version Changes 25April2018 See Section 10 v1.0 First edition

10. Acknowledgements Editors: Disa Lee Choun, Adama Ibrahim, Christopher Hart, and Aji Barot Contributors: Nicole Tay, Jim Nasr, Karin Beckstrom, Marek Cyran, Jeremy Walsh, Hariprasad Radhakrishnan, Eric Du, Anders Bergkvist, Fernand Maes, Will Ivy, Zakaria Arrassi, Marc Casals, Yusuf Ghadiali, Imran Shakur, Mayur Joshi, Richard Shute, Bob Clay, and Selina Lee Additional Contributors: Maria Palombini, Kenneth Ng, Philip Clothiaux, Kenneth Getz, and Jared Trotter, Agi Stachowiak, and Caroline Loder We offer our heartfelt thanks to all the participants, consultants, service providers, and especially the PhUSE team for all their hard work and enthusiasm.

11. Project Leader Contact Information Name: Disa Lee Choun Disa Name: Adama Ibrahim Enterprise: UCB Enterprise: Biogen E-mail: [email protected] E-mail: [email protected] Name: Christopher Hart Name: Aji Barot Enterprise: Manchester Informatics Enterprise: HealthUnlocked E-mail: E-mail: [email protected] [email protected]



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