Darryl G. Glover

The Drug Supply Chain Security Act (DSCSA) and similar global regulations

 were designed to help protect the integrity of the medication supply chain by gathering data at each step of a medication’s journey. While the focus is on the “Approved Drug” supply chain, there has been little conversation or focus on the clinical drug supply chain. 

	Blockchain technology has the potential to positively impact clinical trial supply chains by improving the traceability of medications from active pharmaceutical ingredient (API) to patient, while facilitating the gathering of patient-level data in a HIPAA-compliant manner. This is done by having patients and other individuals participating in the network record data to the blockchain, which then moves that information to the appropriate system and groups with access to view that data. The data is auditable, immutable, and can help create a longitudinal record of a patient’s health status.

	What exactly is the blockchain and how can it be applied as a track-and-trace solution for clinical trial medications?

	To begin, let us define a few key terms related to blockchain technology

 A distributed ledger stores data, which is then housed on the systems of all trusted parties in a network. However, not all trusted parties can access all of the data.

The keys control the way that information is accessed and encrypted onto the blockchain. This well-vetted and established technology, first developed in the 1970s, gives individuals or organizations access to data while validating their identity. Furthermore, these keys determine who can access or add information to the blockchain.

This is the mechanism by which all parties in a blockchain network validate that data being placed on the blockchain is from a trusted source/participant. This is done by computer systems using a cryptographic proof.

These are executable pieces of code that perform a function, such as issuing a payment or transferring documents, when the conditions of a transaction are met. For example, a university has licensed its IP to a company and the content of the IP is made available once the licensing fee is received.

	The blockchain is a distributed digital ledger, which immutably records data. This means that it records data and then disperses a copy of the information to the trusted partners in the network. This distribution, but not full access to all data held on the blockchain, has several advantages. Firstly, each participant in the network validates that the data being placed on the ledger is from a member of that network. This has the advantage that 

someone from the outside or without the right permission (public/private key combination) cannot add data to the blockchain. This creates the security and validation of the immutable records being created. The impact is that someone from outside of the network cannot introduce false information, such as false serial numbers, into the system or read data that they do not have access to. While most attacks (hacks) do occur by someone inside an organization, the fact that an individual’s identity and actions are tracked through the use of their public/private keys decreases this as a source of attack. The distributed nature of the ledger, ultimately, makes it impossible to make simultaneous changes to all copies of the ledger and is a further safeguard against both internal and external attacks.

	While the blockchain is not as familiar as products from Google, Microsoft, or Apple, the technology behind it is quite well established, existing since the 1940s. The blockchain has just combined cryptography and public/private keys to create a “trustless” network (when the ability to trust the comprised systems does not depend on the intentions of any particular party). The blockchain, itself, has performed and carried out hundreds of millions of transactions securely since it was first introduced in 2009. Around 2014, the advent of smart contracts and improved transactions speeds began to occur as we entered the Blockchain 2.0 era.

	There are two main reasons why an organization would want to implement the blockchain:

	Data provenance is required for business or regulatory reasons and there is a requirement that this is recorded in a secure, immutable and, auditable manner.

		Bridging of internal or external IT systems is required in order to more easily move, gather, access, and view data holistically.

		While the initial applications of the blockchain focused on financial services, the concept of data provenance is being applied to fair trade goods, art, diamonds, designer clothing, solar energy and, the biopharma supply chain.  

	For the clinical drug supply chain, a root-cause analysis identifies three highlighted challenges that blockchain can resolve:

 The chain between a clinical study sponsor, study patient, and site is long and involves the use of multiple IT systems. In a world where all parties involved are linked via a blockchain, it would be possible to leverage encryption and access control so that the members (trusted participants) could get confirmation of the receipt of the product without having access to protected patient information and, in turn, provides the ability to validate patient identity.

By introducing smart contracts, the entire clinical trial process can benefit from using blockchain technology. The process/trial milestones can serve as stage gates for the smart contract. The process will only proceed beyond that point when required actions are completed and correct.

Before the initiation of a clinical trial, the sponsor must submit the parameters of the study to the appropriate regulatory authorities and various ethics committees (ECs) at the trial sites. At the study’s conclusion, the sponsor’s regulatory affairs department determines if all requirements have been fulfilled before accepting and then forwarding the results to the appropriate regulatory authorities for approval. The challenge that faces sponsors and regulators is how to ensure the validity of the data and to establish universal standards for that process. The implementation of blockchain technology can be the conduit through which such standards are implemented, since the validation and auditability of transactions are a core part of the technology.

	Clinical trials are designed to assess drug efficacy. This process presents three challenges to any organization sponsoring or participating in a study:

		How to trace what product is in the packages? 

		How to assure the correct data is collected? 

		How to ensure that the study site does not become unblinded?

	Several companies have adopted processes and applications to meet these challenges, but these are prone to human error. In practice, it often comes down to an individual validating the actions recorded in a software solution. Software systems, like interactive response technology (IRT) and randomization and trial supply management (RTSM), can assist yet lack the capability to validate events or transactions, like medication administration.

	A fourth challenge is presented to the industry upon the completion of a trial and during the process of data collection: 

		Are the results that have been collected complete and valid?

	On the surface, this challenge can be easily negated; however, regulations, like the European General Data Protection Regulation (GDPR), will bring more scrutiny to this important area. 

	The following example can serve to make these challenges more tangible:

	A few years ago, there was a Phase II study in Africa with a drug that was not stable at high temperatures. Because of this, it was important to ensure that the medication did not exceed a certain temperature. Upon examining the supply chain between plant and patient, this was quite challenging, as the placebo also needed to be preserved under the same conditions to prevent unblinding. Assuring this, in combination with providing the required documentation, proved to be an entire project by itself. 

	For this study, patients needed two different dosages at two different times. The physicians needed to confirm patient identity before administering the second dose. As many patients did not have photo identification, their identity was tracked using biometric data. The country’s EC requested that the biometric data should not to be shared outside of the clinical sites. The general problem boiled down to one of traceability between the physical and digital world while assuring patient and data integrity-all key factors to conducting a successful trial.

	This example demonstrates the complexity that can emerge in one small part of a study. If that complexity is added to the entire chain,  and also impacting external contract research organizations (CROs) and subcontractors, these challenges only grow exponentially. The blockchain becomes one key technology to alleviate these hurdles.

	The other challenge is preventing patients from participating in multiple trials simultaneously while ensuring that contracted investigators, the data they enter, and the patients actually participating are consistent with the records at the various clinical trial sites. The introduction of biometrics can help ensure the integrity and security of the study and its drug supply chain. The Internet of things (IoT)

-a network of interrelated computing devices and mechanical and digital machines-then can help collect and transmit adherence data and assist with the detection of adverse events and the physiological effects of the investigational drug on the patient.

	Regulations and application submission requirements can be viewed as a set of business rules that need to be adhered to-rules that can be managed on a blockchain. The regulatory audits and validation of the presented study findings and results is a slow, expensive, and labor-intensive activity. The introduction of the blockchain may alleviate this burden, as organizations can quickly demonstrate data validity due to the immutability of the records collected and the fact the authorities’ specifications were incorporated and executed by the smart contracts  implemented as part of that solution. 

	An essential element of a clinical study is ensuring that that there is sufficient supply of the API to supply the trial. To produce enough API, multiple plants may be tasked or contracted. Because the drug is at an early stage of the development life cycle, the productivity of a single plant may be lower than expected. This risk of having an insufficient trial supply can be mitigated by making available real-time inventory to the study stakeholders up and downstream. This can be accomplished by having the information recorded and updated on a clinical study blockchain.

	It is important to keep in mind that the API pilot plant has a critical role to play, as the API it supplies is the foundation upon which a clinical study report will eventually be submitted for review. The recording of this data on a blockchain then becomes the genesis record upon which all other data can be added and interconnected.

	The core qualities of a model built on blockchain technology helps reach the high standards required of a clinical trial by providing integrity, analytics, and traceability. Having, from an early stage, a good overview of a producer’s quality and ability to produce certain quantities of an experimental drug becomes an enabler to the study stakeholders. 

	With the investigational drug product and comparator supply source secure, the next stage in a clinical supply chain is packaging. The creation of “smart packaging” (merging the physical and digital worlds) can generate new data for the sponsor to use. Not only can an organization encode the identity of the product allowing for traceability, but additional sensors can collect data from the moment the treatment is placed inside the package. All of this information can then be recorded to the blockchain to create a complete record of a medication’s journey throughout the clinical study.

	In a world where the rapid movement of goods is routine, the ownership of the drugs and authenticity becomes harder to trace in a physical world with shipping documents. When we enable smart packaging for drugs in shipment and storage, a more interesting picture emerges, where all products down to the individual blister level can be located and storage conditions assessed. 

	With an assurance of authenticity during the trial, in later large-scale production, similar serialization and tracking techniques across a trusted blockchain-empowered network can prevent counterfeit product from entering the supply chain. 

	The purpose of a trial is to track patients’ responses to the investigatonal drug that was produced, packaged, shipped, and stored. At the end of the clinical supply chain, the data is provided to the sponsor for further analytics and analysis.

	It is evident that the three core qualities of a blockchain model also improve the quality of data collected, along with its provenance. Again, it is the validating nature of the technology that benefits the patient, sponsor, and all other stakeholders.

	Blockchain technology has many advantages in security, data protection, and the ability to bridge the disparate systems that manufacturers, CROs, and study sites utilize. This technology has the benefit of centralization without having all of the data located in one place, thus making it less vulnerable to external/internal attacks.

	A combination of the process of serialization and blockchain technology holds the key to ensuring clinical trial integrity and to overcoming the challenges presented in this article. It provides an assurance that’s missing in the industry today by leveraging the technology and knowledge of tomorrow.

, PharmD, MBA, is Chief Clinical Officer, iSolve, email: dglover@isolve.io; 

 is Business Unit Manager and Senior Consultant, CMAST

	2. Understanding the Fundamentals of the Blockchain, 

https://www.ibm.com/blockchain/what-is-blockchain.html

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