By Deborah Borfitz

October 2, 2019 | A startup founded by a small team of blockchain enthusiasts is intent on building the world's first clinical research ecosystem enabled by distributed ledger technology and governed by a nonprofit foundation. The vision and plans for this one-stop digital marketplace are described in a 40-page whitepaper available on the website of Triall, based in The Netherlands.

The first piece of the puzzle is an electronic trial master file application now undergoing pilot testing by contract research organization CR20, according to Hadil Es-Sbai, president and executive director of Triall. The application will get its initial user experience testing in a phase II, single-country study with approximately 50 participants. Registering or verifying registration of an essential document on the blockchain is a simple matter of right-clicking a mouse button.

Feedback from CR20 will be incorporated into a candidate version of a blockchain-enabled document management solution called Verial that is expected to be publicly available no later than early 2020, says Joost Flach, Triall's director of clinical affairs. This will be followed by the release of version 2.0 later next year, inclusive of procedures for minimizing the document management workload for end users. As research documents get scanned, they will be automatically classified, encrypted, authenticated, and signed using decentralized identifiers, he notes.

All essential clinical trial documents, including those specific to patient education and ethical and regulatory approvals, could be hashed on the blockchain, says Es-Sbai. So could study protocols and, importantly, statistical analysis plans (SAPs).

Although Triall's approach has a lot of overlap with eConsenting, the broader aim is to digitize the entire informed consent process "from filing all the way to reporting," Es-Sbai says. It will also assign study patients unique public/private key pairs, with the public part residing on the blockchain and used to consent to study procedures.

Critical documentation and steps in the eConsenting process can likewise be logged on the blockchain, he adds. The remaining challenges include uneven acceptance of eSignatures by regulators and ethics committees, and some sponsors and CROs that are too risk-averse to take advantage of the technology.

Registering a hash of an SAP before the start of a trial would force researchers to adhere to predefined outcome measures, preventing the all-too-common malpractice of p-hacking (aka data dredging) after database lock that can "significantly reduce the scientific merit of the study," continues Es-Sbai. Any alterations would be time-stamped and instantly visible on the blockchain to regulators, or scientific journal editors.

Processes requiring meticulous planning, execution, and documentation, such as database locking and unlocking, could also be improved using Verial software at either the case report form or database level, Es-Sbai says.

Here to There

Document and data management by investigators and research sites is a multifaceted problem due partly to discreet functions of eClinical solutions that don't communicate well with each other and differing standard operating policies and procedures around the world, says Es-Sbai. "The information stream is really scattered, not consolidated, resulting in errors and operational voids."

Smaller study sponsors and CROs also lack the means and tools to cost effectively track what is happening with multi-country, multi-site clinical trials in real time, Es-Sbai continues. They spend enormous sums on project management resources and keeping boots on the ground for on-site monitoring. That's because sophisticated and integrating tooling enabling efficient and risk-based management is affordable only for larger sponsors and CROs, which have the financial wherewithal to develop their own highly integrated systems and dashboards.

Academic research institutes have "really been left behind" when it comes to having the proper tools for governance and oversight activities, he adds.

The clinical research ecosystem envisioned by Triall will eventually offer application programming interfaces (APIs) connecting different eClinical systems, which will in turn enable the blockchain infrastructure to function as the "transparent and trustworthy identity and access management layer," says Es-Sbai. Triall also wants to translate best practices of the big players to the operations of smaller academic groups to make them more attractive as research partners to the larger companies.

The development roadmap has Triall serving as a platform for implementation of Verial in 2021, followed by development of a clinical trial management system and a dashboard that can integrate in-house study metrics with those from third-party eClinical providers. "We want to transform those so-called competitors into collaborators," Es-Sbai says.

Next-generation clinical trials are possible starting in 2022, he continues, whose most important features will be transparency, immutability and auditability. "We think blockchain will be the perfect enabler for global platform operation and interoperability between currently isolated eClinical solutions. But we also think that AI [artificial intelligence] or deep learning will play a crucial role in further advancing a risk management approach, which is necessary to keep clinical trials affordable in an age where we're gathering more and more clinical data points."

The end game is an online portal serving and connecting everyone involved in carrying out clinical trials, says Es-Sbai. It will be the go-to place to find "all the basic prerequisites" to plan, execute, manage and report on studies—as well as best practices and new interoperative methodologies—to add speed and cost effectiveness to the research enterprise.

Triall's five founders—Es-Sbai and Flach among them—are all still active in the clinical trials domain as entrepreneurs, consultants, or academics and share a common connection with co-founder and advisory board member Eric Claassen, Ph.D., an immunologist and professor at VU Amsterdam who has helped start over 20 companies in the life sciences. They launched Triall in February 2018.

Realizing they would need APIs and document management expertise, the founders identified blockchain solutions provider Sphereon as the "perfect partner" sharing the same vision and ambitions, Es-Sbai says. They also onboarded blockchain developer and serial entrepreneur Niels Klomp as chief technology officer. He is a fan of the open-source Factom blockchain protocol that will underpin the Triall ecosystem.

Protocol and Tokens

Factom, one of the older blockchain protocols used by the Gates Foundation and U.S. Department of Homeland Security, has been optimized for enterprise use cases, says Klomp. It was created in 2014 to tackle limitations of blockchains such as Bitcoin and Ethereum and offers transaction speed and security at a low fixed cost.

The protocol has two native tokens—Factoids and Entry Credits—while other blockchains are associated with a single cryptocurrency, Klomp explains. Factoids can be traded like any other cryptocurrency, but Entry Credits can only be used to pay for data entries on the blockchain.

Importantly, each Entry Credit will always cost one-tenth of a cent, Klomp continues, which is what makes anchoring large amounts of data on the blockchain affordable and the price predictable.

Factom is also efficient at organizing data, greatly reducing the time and cost associated with storage and retrieval from the blockchain.

Another advantage of Factom is that it includes a record-keeping system allowing users to create their own chains and entries on top of the blockchain, Klomp says. That makes it easy to prove or disprove that certain data was in the ledger and know when entries were made and manipulated.

Factom is itself a complete blockchain, providing an added layer of security, Klomp says. Every 10 minutes, it creates a new hash of all data collected in that window that gets anchored onto both the Bitcoin and Ethereum blockchains. Since their cryptocurrencies have a huge market capitalization, data manipulation would be prohibitively expensive. Entries on a Factom blockchain are effectively irreversible.

Triall has its own token, TLR, which Flach describes as "a common currency that can be used in a shared microeconomy." The tokens will sit atop the Factom protocol and will be used to gain access to clinical trial applications starting early next year.

Each stakeholder within the ecosystem may have a certain proportion of Triall tokens to use in a clinical trial to gain access to needed applications, says Flach. Their "voting rights" with the governing Triall Foundation will equate to their share of the tokens, notably how to direct funds in an incubator program. Holding a share of tokens, as Triall "members," also provides access to application discounts and premium (i.e., free) features.

Future excess income will get re-invested in the clinical community, explains Es-Sbai. He imagines the incubator program will fund innovative ways to improve study recruitment and retention by personalizing the attention and information given to subjects over the life cycle of a trial. Another strong possibility is opening the Triall ecosystem to low- and middle-income countries that could benefit from a library of good clinical practice training resources.

Es-Sbai estimates Triall will have the means to initiate two incubator programs by mid-2021.