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Applied Clinical Trials December 2021

Proactive, pervasive, and strategic planning lead industry into future.

Biopharma-Academic Collaborations in 2021

It’s a wrap. 2021 is almost over and 2022 is at our door. It’s also that time of year where industry predictions, outlooks and trends for the next year begin. While the next issue of 

won’t be available until February (a combined January/February issue), we will be posting contributed industry trends online. And, of course, you can always visit us for the latest news, contributed articles, blogs, and more.

But what follows is what the editors offer as top trends for the clinical trials industry for next year. Albeit, some of it may be wishful thinking.

Continued focus on diversity and inclusion in clinical trials representation. 

This is not a new problem in clinical trials. However, it’s had a resurgence due to the need for heterogenous populations to be included during COVID-19 vaccine trials. Across the board, it would be a better practice if the population studied was representative of the population intended to receive the potentially approved medicine.

Getting representative populations into trials is not easy. This year, the hope is that the many calls to action heralded this past year translate into actual solutions and processes to move that needle in clinical trials.

 We could not get out of the way fast enough for this wave of necessity during COVID. However, this year we should start seeing actual case studies of what works, what didn’t work so well, and proof of applicability due to the regulatory approval of medicines that used a decentralized process.

Influx of solutions, apps, and platforms for clinical trials. 

This has already started in a big way because of the previous trend. From medication adherence, to digital clinical trials platforms, to patient recruitment (see first trend) and retention, to study start-up feasibility...there is a whole new group of third-party service providers for industry to consider, vet and evaluate.

Continued focus on the relationship between CROs and sponsors.

 As the biotech and small biopharma sponsor space continues to grow, so does the need to conduct more clinical trials. CROs continue to focus on providing the right blend of services to those who haven’t traversed the clinical trials path before. Focusing on their true needs and not blowing up their small budgets is going to be key to good relationships and quality trials. So all in all, 2022 will be much, much more of the same.

 is Editor-in-Chief of Applied Clinical Trials. She can be reached at 

Articles

2022 Trends, More of the Same but More

The challenges in developing gene and cellular therapies have made headlines over the past year, as biotech companies have launched a wave of development programs despite ongoing concerns about treatment safety and efficacy plus unknown long-term effects. High price tags on these breakthrough treatments, moreover, threaten to block patient access to potentially life-saving cures and treatments. FDA scientists and reviewers are working to advance the field, with new guidances and advice for manufacturers on appropriate testing of treatments to minimize risks to patients and fill gaps in data.

New gene therapies for debilitating rare conditions stand to advance from an FDA collaboration with the National Institutes of Health (NIH) and a cadre of pharma companies, small biotechs and patient groups, formally announced Oct. 27, 2021. The Bespoke Gene Therapy Consortium (BGTC) will be managed by NIH’s Accelerating Medicines Partnership program and the Foundation for the NIH and will provide 

 to support the development of gene therapies to treat rare diseases.

To start, the BGTC plans to initiate preclinical and clinical trials for four to six monogenetic rare diseases that currently lack any treatment. Such advances will facilitate a better understanding of the biology and production of adeno-associated virus (AAV) vectors utilized to deliver gene therapies to individual patients. The Consortium will provide $76 million over five years from NIH and private partners to fund a range of research, such as establishing standardized analytical test methods to improve AAV production and use and to advance toxicology testing for preclinical development. The term “bespoke” reflects the need for efficient methods for developing highly individualized therapies to fit the genetic specifics of one or two patients.

The BGTC initiative has been under development for several months, as seen in remarks at the September 2021 PDA/FDA conference by Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), on how the program could standardize methods for developing and manufacturing bespoke therapeutics. Marks outlined efforts to leverage methods and data from one application to another to reduce prohibitive R&D costs that threaten product development and patient access. In advancing the development of gene therapies for very rare disorders, he noted the importance of collecting baseline natural history data on target diseases and of public-private partnerships to enable streamlined production through a “cookbook” for developing bespoke therapeutics.

This public-private collaboration is particularly timely in the wake of recent patient deaths and safety issues linked to experimental gene therapies involving AAV delivery. FDA’s Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) met in early September to discuss these concerns, 

 of preclinical animal models in predicting potential risks from viral vectors. Panel members cited the need for clearer standards related to gene therapy development, for more comprehensive patient screening, and for longer assessment of patients following treatment to better track side effects that may emerge later.

Even though the experts stopped short of recommending specifics curbs on developing these advanced treatments, FDA put a clinical hold on an early study for gene therapy from BioMarin. In addition, Pfizer halted studies on two experimental gene therapies following 

Meanwhile, CBER seeks to expand the resources and expertise for its Office of Tissues & Advanced Therapies (OTAT) to better oversee and provide advice on developing genetic and other advanced products. Despite a slowdown in biopharmaceutical research due to the pandemic, CBER officials continue to see a strong flow of applications to test experimental cell and gene therapies, many requesting meetings with OTAT staff to discuss research plans. OTAT director Wilson Bryan noted the importance of transparency on safety issues related to gene therapy in a presentation Nov. 12 at a meeting sponsored by Prevision Policy. One critical issue to explore is whether the effectiveness of gene therapy treatment wears off over time, warranting re-administration. To address this unknown and continuing safety concerns, Bryan emphasized the importance of long-term follow-up of all gene therapy patients—maybe following gene therapy patients “forever,” he commented.

FDA scientists are working to advance gene and cellular therapies, with new guidances for manufacturers on appropriate testing of treatments to minimize risks to patients and fill data gaps.

FDA Grapples with Promise and Perils of Gene Therapy

Phesi Inc. has recently analyzed protocol design data from 1,324,820 US patients, from Phase II and III single country clinical trials across a total of 1,580 cohorts. This data set represents 495 disease conditions with trials starting from 2010-2020. The results showed that Asian, Hispanic and Latino, Native Americans and Alaska natives, Native Hawaiians and other Pacific Islander patient subpopulations were all significantly and consistently underrepresented over the decade.

The data show Black and African American patients appear to have become better represented over the past decade, making up 14.92% of the data set, compared to 13.4% of the total US population in 2019 US Census Bureau estimates. This positive change is due to concentrated efforts from industry to improve racial diversification, as well as vital work undertaken by patient advocacy groups for diseases disproportionally impacting Black/African Americans in the US. This is a broad snapshot over trials over the last decade and the increased numbers do not mean the work to ensure true representation of Black/African American participants in clinical trials is done. Moreover, other racial groups are still markedly underrepresented in trials.

New diversity data from Phesi shows inclusion of Black and African American patients in clinical trials improving, but Asian, Hispanic and Latino groups significantly and consistently underrepresented

New Phesi Diversity Data Shows Inclusion Of African American Patients Improving, Other Minorities Still Underrepresented

Oncolytic virus (OV) immunotherapy is an innovative biological therapeutic approach to cancer treatment that deploys native or genetically modified viruses as therapeutic agents and transgenic delivery platforms that can selectively replicate within tumors, but not in cells of normal tissues. In 2015, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) approved the first-in-class OV therapy, talimogene laherparepvec (T-VEC, or Imlygic) from Amgen for the management of unresectable metastatic melanoma.

 This opened a new venue of cancer treatment utilizing live virus’ to specifically target malignant tumor cells for killing through direct lysis, and simultaneously stimulating the host’s innate immunity through mechanically designed features such as transgenes.

Oncolytic virus immunotherapy also brings some unique challenges for drug deployment programs and regulations. In this article, we provide a brief overview of the status of OV immunotherapy and offer some thoughts based on our experience planning for and carrying out early phase clinical studies in anticipation of registration.

Oncolytic viruses are either DNA or RNA viruses. In general, they can be categorized as natural (not genetically manipulated) and genetically modified strains in therapeutic development.

 There are more than 20 OVs are currently in various stages of clinical development for cancer treatments including coxsackie virus, paramyxovirus, reovirus, and seneca valley virus, measles virus (MV; paramyxovirus), parvovirus, poliovirus (PV; picornavirus), vaccinia virus (VV; poxvirus), adenovirus (Ad), herpes simplex virus (HSV), and vesicular stomatitis virus (VSV; rhabdovirus), etc. Among these, HSV and Ad are probably the two most commonly delivery platforms for the OVs immunotherapy (Tab 1).

 In fact, T-VEC is an HSV-based OV immunotherapeutic agent. Its viral vector is constructed to contain a granulocyte-macrophage colony-stimulating factor transgene (GM-CSF) for releasing the recombinant cytokine in cancer cells.

Table 1. Common Herpes Simplex Virus and Adenovirus in Clinical Development for Cancer Treatment

Annotations: 4-1BBL, (CD137L) tumor necrosis factor ligand superfamily member 9; CCL4, C-C Motif Chemokine Ligand 4; CTLA-4, Cytotoxic T-lymphocyte antigen-4; CYP-2B1, cytochrome P450, family 2, subfamily b, polypeptide 1; CXCL, C-X-C motif chemokine ligand; FLT3LG, fms Related Receptor Tyrosine Kinase 3 Ligand; GALV-GP R, envelope glycoprotein of gibbon ape leukemia virus. GM-CSF, granulocyte-macrophage colony-stimulating factor; HSV-tk, herpes simplex virus-thymidine kinase (HSV-tk) gene; hTERT, human telomerase reverse transcriptase; HSV1, human simplex virus Type 1; IFNα, Interferon α; IL, interleukin; MAGE-A3, melanoma-associated antigen 3; NAT, noradrenaline transporter gene OX40L, ligand for OX40 on antigen-presenting cells; PH20, hyaluronidase; TNF, tumor necrosis factor.

Oncolytic viruses are a versatile biological platform for cancer cell killing and biological drug delivery. The design features can be further improved. 

 The anti-tumor effects of the engineered OVs are mediated by direct lysis of malignant cells and boost human immunity against cancer cells. OVs can selectively infect and replicate inside cancer cells, reducing the tumor burden of the target malignancy through virus-mediated cell lysis. The infection of OV to cancer is selective, and the killing is, therefore, specific for malignant cells and not to the normal cells.

The OV can be modified by genetic engineering on the viral genome with intentional deletions by designs for efficacy improvements and/or attenuation in off-target infectivity and transmutability in addition to insertions of transgenes to strengthen desirable biological effects on human immunity, such as antigen presentation, local delivery of cytokine and chemokine.

The direct consequence of oncolytic action is the release of tumor-specific or associated antigens leading to the activation of immune effector cells, such as T killer cells, and their infiltration inside the tumor tissue.

 Therefore, the genetically engineered OVs could boost in vivo the human innate immunity, which consists of dendritic cells, macrophages, and natural killer (NK) cells, and recruit the adaptive immunity to fight cancer cells in stimulation by the recombinant biological modifiers delivered as the transgenic payloads of the oncolytic platform.

Furthermore, an OV can also modulate the tumor microenvironment (TME) either by nature or by designs such as the inserted GM-CSF transgene which can promote the maturation and differentiation of immune cells, such as dendritic cells, monocyte, and macrophages, towards improvements in innate immunity. The other biological effects are the TME becoming lesser immunosuppressive, thereby leading to enhanced anti-tumor effects through reducing immune evasion.

HSV-1 virus can infect endothelial cells causing disruption of tumor vessels and potentially facilitating immune cell migration into the TME.

Special considerations in clinical study designs for oncolytic virus immunotherapy

Oncolytic viruses are a new class of biologic drugs for cancer treatment. They are live viruses which could replicate naturally inside human systems, although they are altered structurally for specifically targeting malignant cells. Their unique modes of action and cross talks with the host immune systems post significant and unique challenges in clinical developments.

There are a series of specific issues for planning a clinical trial with an OV for cancer treatment. First and foremost, it should be kept in mind that the therapeutic effects of OVs are dependent on the viral biological characteristics and its interactions with the immunity in humans. Therefore, we should consider the clinical study designs and executions in the context of viral biology and human immune response. The pharmacokinetics and pharmacodynamics for traditional drugs of either small or large molecules are largely becoming irrelevant to OVs. The OV is viable and replicable in humans and may not be completely cleared from the body systems if infected, such as in the case of HSV-1 infection. Furthermore, it is the local and systemic immune response of humans that we need to consider carefully when we plan and design a clinical study with genetically engineered OVs for registration and therapeutic use.

Biosafety and infection control are critically important at the individual level, as well as perhaps their potential ecological impact. The regulatory guidelines in Europe and the US stipulate the principles and advise practical approaches for handling OV in early and late-stage clinical developments.

 Individual training for infection control and biosafety precaution is needed which should include, but is not limited to, didactic lecture on policies for the safe-handling and storage of the agent; on protocol of accidental exposure using viral-specific training materials to study personnel who prepare the and administer the viral agent. The study and safety protocol as part of the regulatory requirements for a facility to carry out an OV clinical trial in every aspect of executing a clinical protocol involved OV biologics drugs should be meticulously reviewed and approved by Institutional Biosafety Committee (IBC) and Institutional Review Committee (IRB). The facility’s biosafety level of handling the OV biologics should be compatible and certified.

OVs are evaluated for safety and efficacy in clinical trials to determine clinical utilities and usefulness in combination regimens. The recent trend in cancer clinical trials, especially for advanced solid tumors, is to add immune check point inhibitors (ICI) in combinations with the OV-based therapeutics. The structurally modified OV could alleviate resistance and synergistically enhance the anti-tumor effects from its immunosuppressive releasing effects in TME. However, the individual biological responses to specific viral challenges are immunologic reactions. Finding a maximum tolerated dose based on toxicology reactions could take a longer time than expected, since the dose limiting toxicity (DLT) is an immunologic response which could be dose independent. It may be necessary to carry out the first-in-human (FIH) study in an integrated and stepwise approach with single ascending dosing and multiple ascending dosing for patient safety reasons.

The pharmacokinetic and biodynamic studies should focus on biodistribution, viral shedding, monitoring transgene expression, immune effector cell reactions and other systemic cytokine and/or chemokine changes. Careful follow-up with imaging modalities for tumor size alterations in conjunction with biopsy after OV administration is recommended and required. In this case, the clinical criteria, and the approach for assessing the immune response and outcome with itRESIST are different from that in evaluation of chemotherapy.

OV’s are immunotherapeutic drugs which can also act as a platform for virotherapy and/or potential gene therapy. OV is theoretically appealing since it can be modified genetically according to our knowledge and understanding of tumor biology by design. The transporting transgenes as molecular entities for therapeutic purpose cab be further improved overtime. The transgenes can be made highly effective according to tumor’s pathophysiological characteristics and to viral biology for local delivery by injections. The intertumoral injections guided by imaging either with or without contrast-enhanced Ultrasound (US) or Computed Tomography (CT) can increase the therapeutic index by ensuring effective local drug concentration gradient, and likely reduce systemic exposure with less toxicities. However, the procedures are of high technical complexities which introduce some technical uncertainties for repetitive use if a protocol required in follow-up treatments or multiple applications. Under such circumstances, the personal and collective skill sets of study personnel, such as imaging, endoscopy, and deep biopsy, are required for successfully executing the clinical trial protocol

Oncolytic viruses are a special class of drug biologics. Successful clinical development requires a focus on viral biology and host immune response. There are unique features in clinical trial designs and executions associated with the structural variations of OV which are different from other drug classes used in the past. Since pharmacokinetics and pharmacodynamics in traditional senses are likely not applicable to OV drugs, the clinical trials should be planned carefully and adaptively in the context of viral biology and host immune response.

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FDA Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products. Guidance for Industry AUGUST 2015 

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Successful oncolytic virus immunotherapy clinical development requires unique features that focus on viral biology and host immune response.

Oncolytic Virus Immunotherapy: A Brief Overview and Considerations for Clinical Trial Planning 

FHI Clinical Inc. has announced its intent to acquire Triclinium Clinical Development Proprietary Limited (TCD), a full-service, South African-based CRO and a subsidiary of EOH. With this transaction, FHI Clinical will employ more than 425 global staff representing 12 countries. 

Headquartered in Centurion (Gauteng), South Africa, TCD has access to the South African market. South Africa accounts for most of the clinical trial activity in sub-Saharan Africa with the majority being infectious disease therapeutic studies. With approximately 285 employees already based in East and West Africa, FHI Clinical sees a unique opportunity to further expand its share of the ID market.

Current studies in TCD’s portfolio include both innovative vaccines and treatments spanning all phases of clinical research from single-dose Phase I trials to large multi-site Phase III and Phase IV trials.

FHI Clinical Announces Intent to Acquire South African-Based Triclinium Clinical Development (TCD)

FHI Clinical Announces Intent to Acquire TCD

Documentation is instrumental in proving the creditability of clinical trials. The documents need to be complete and accurate in order to ensure compliance with ethics, GCP, and applicable regulations. A database used for documentation occupies the center stage of the clinical research.

 The emerging concepts of clinical research transformation, such as decentralized clinical trials, patient-centric clinical trials and community-based clinical trials, are rapidly gaining popularity.

 This scientific perspective will welcome another major change post the paper to electronic transformation, predominantly characterized by the direct involvement of participants instead of the classical sponsor-investigator approach. The clinical research will presumably be an activity of mass, rather than an activity led by the medical personnel. As a restructuring effort, any major pharmaceutical companies will require to adopt various secondary changes in the upcoming years. These changes will range from the inclusion of advance data capturing technologies, like the Internet of Things (IoT), to the management of operational documents in the clinical research.

The trial master file (TMF) is a repository of all essential documents related to the management and conduct of clinical trials right from their inception to the completion of archival period, and is critical to any clinical trial management, essentially for ensuring compliance with applicable regulations.

 In the era of electronic processing-led transformation, TMF has transformed data from paper documents to an electronically managed database. eTMF (electronic trial master file) can handle multiple stakeholders from different geographies in real-time.(Figure 1)

A lean and robust system for the management of clinical trial documents is required for maintaining the momentum of a clinical research. Moreover, stringent regulations demand clean, complete, and diligent documentation of the clinical trial data that is meant to be audit and inspection ready at all times. Auditors are required to tally the data across scanned documents and their digital copies for validating the legitimacy and correctness of the documents. Clinical trials consist of documents being updated at different geographical locations by different staff members for meeting regulatory requirements. With the advancement in clinical research, constant expansion in the scope of study, and the complexity of studies, document collection will prove to be a challenge while accessing documents during inspection and synchronization.

When clinical trials involve multiple stakeholders from different organizational sites and geographies, revising documents using diverse software and keeping track of rapid updates in documents are not possible with the current versioning systems used in eTMF. The lack of stepwise versioning in a document creates conflicting versions of the document, leading to the disarray of version control and document parity mismatch in eTMF.

Any lack of oversight affects record-keeping, thus, ensuing costly reiterations, inaccuracy, and even risks to safety of patients.

 Although eTMF promises a secure archival of clinical records, it also encompasses severe complexities of being a cumbersome process.

The eTMF lacks crucial mechanisms that would enable easy identification of revisions made to the content of a document.

 Moreover, it allows files to be downloaded on local computers, which may be susceptible to possible fraudulent activities with a limited scope to identify the origin of these data breaches.

Additionally, searchability in the dashboard of eTMF is unstandardized and not user-friendly. The board search function and the use of non-uniform naming conventions by multiple stakeholders make it difficult to perform a quick search and locate the required files.

Inaccuracies and missing data is unavoidable. The massive amount of source documents generated by various sources such as lab, sponsors, sites, vendors etc. tend to introduce scalability problems leading to unreliable access management, thereby leading to a considerable wastage of time and effort. Document storage should provide reliable ‘role-based’ access control and prevent unauthorized access or modification of the trial data. Document revisions should be made with consensus among all the stakeholders involved during the entire trial period.

A clinical trial involving researchers from sites across diverse locations requires data to be cleaned and checked for inaccuracies before synchronizing it with other site data. Missing any of the requirement should alert the data operator at the corresponding site itself. Continuous trial data, like sensor data, should be automatically captured during the auditing phase.

Dispersed clinical trials lack the element of trust and transparency because of the enormous amount of data being generated and the documents shared with sites. The clinical trial volumes are increasing at a rapid pace with a projected annual growth of 5.7% until 2028.

 This growth is expected to present extra challenges for data collection and data preservation.

 Keeping this in mind, it is foreseen that eTMF will not suffice the need of a database for the fair and robust documentation of clinical trials. However, there does exist a technology which can be a one-stop solution to all these requirements—Blockchain.

Blockchain is a transactional ledger of a growing list of records called blocks. The blocks are chronologically ordered and linked cryptographically to their previous blocks.

 Each block contains hash of the previous block, timestamp, and the transaction data. Addition or alteration of the chain requires consensus from majority of sharing parties called nodes. Like other databases, blockchain is basically governed within an organization by a committee. This committee oversees the blockchain governance rules placed within an organization and regulates the entire blockchain system.

 Some of the salient features of a blockchain system are

Decentralized—The participating nodes are dispersed at multiple locations and connected only through a networking protocol, and yet their collective computational power and storage define the entire blockchain.

Immutable—Requirement of a huge computation power makes it practically impossible to alter blocks once they are added to the blockchain

Version control—Version control of all essential documents and any transactional activity is easily managed and disseminated in real-time. This activity is visible to all stakeholders. 

Access control—Blockchain provides different levels of access control to ensure that sensitive data is not accessed or modified by an unauthorized user.

Transparency—The documents evolve in the blockchain i.e., they are created, processed, and finally archived in the tool itself. This assures trust and transparency amongst various stakeholders pertaining to the data shared on blockchain.

Collaboration—Organizations can easily collaborate with one another through gossip protocol (a tool in blockchain that enables communication with stakeholders through computers).

Public blockchains, private blockchains, consortium blockchains and hybrid blockchains are the four basic forms of a blockchain network. Each of these platforms has its own set of advantages, disadvantages and ideal applications. The implementation team chooses the blockchain type depending on a variety of factors such as process requirements, size, usage and user base. Blockchain is the foundation that can be leveraged using platforms like Ethereum, Hyperledger Fabric, R3 Corda etc. In addition, blockchain has two kinds of licenses i.e., open-source and proprietary. While in the proprietary license, case procurement depends entirely on the service provider, the open-source licensed blockchain doesn’t require procuring. A few eTMF vendors do support blockchain but as far as the established vendors are concerned it is still a long-drawn process for them to move eTMF to a blockchain based solution.

Thus, this technology embraces vital features of healthcare and allied industries for successful documentation that involves multiple stakeholders where documentation is a crucial entity.

How will blockchain help in the digitization of eTMF?

Use of a blockchain network allows distributed storage of the eTMF data on blockchain in a more reliable and secured manner. The chronological ordering in blockchain largely prevents a 

 Blockchain infuses confidence among stakeholders for genuineness and sanctity of the entire clinical trial data stored in an eTMF-blockchain flow.

 It prevents analytical remodeling of the document and ensures document traceability to provide a robust and non-hackable automation tool with shareable parameters.

Blockchain technology enables the following features to enhance the eTMF functionality:

Secure and restricted access—Access management becomes highly secure with different levels of restrictions on users. Furthermore, automation via chain codes help in identifying the flow of data and ensuring that the stakeholders adhere to GCP (good clinical practice) guidelines.

Decentralized network—The decentralization feature of the tool enables a sturdy network to ensure that the stakeholders are well-connected. For e.g., if there is a failure at one node, the data can be fetched instantly from other nodes with maximum guaranteed uptime.

Trust and non-repudiation—Since blockchain ensures the controlled access and security of data, pharmaceutical companies would have a higher level of trust on it. The use of blockchain will ensure that the pharmaceutical companies, investigators, patients, Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and regulatory bodies have absolute confidence in the data, and that the informed consent is thorough, accurate and complete.

Version management—By managing the versions of documents on the blockchain, compliance to guidelines and regulations is ensured, and a standard is established. Each user/organization will view exactly the same data at any given point of time without any conflict unlike the traditional process of eTMF.(

 Users/organizations can even view the version history for auditing purposes.

Figure 4 eTMF using Permissioned Blockchain

The eTMF-blockchain technology offers a myriad of application benefits. These benefits predominately cater to the enhancement of efficiencies in terms of data quality and integrity while ensuring compliance to ethical standards. This will allow continuous sharing of clinical data between trial entities making it more reliable, credible, and transparent.

 This will also pave the way toward exploring a myriad of new application-based, future-proof solutions, such as:

Bifurcating channels for public and private data sharing.

Adding options for the provision of consensual access to regulatory bodies.

Eradicating paper as well as traditional eTMF systems by replacing them with e-forms.

Creating artificial intelligence- enabled tools to investigate data correctness and the execution of clinical trials.

is the Head of Life Sciences ADD Research & Innovation, and ADD A&I;

is a Developer; all of TCS ADD Platforms. 

is the Former Head of Research and Innovation for TCS ADD Platforms. 

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eTMF-blockchain technology offers a myriad of application benefits to data quality and integrity while ensuring compliance to ethical standards. 

Future of Clinical Trial Documentation Management: eTMF Integrated with Blockchain 

Many sites are concerned that Decentralized Clinical Trial (DCT) models will cut the site from research altogether. Terms such as “siteless trials” have been used to describe DCTs; however, some enterprises disagree with that notion. Medable, a DCT company, launched the Site Network Council (SNC) to bridge the gap between DCTs and study sites. In this interview, Mary Costello, Head of Site and Investigator Networks at Medable, and Stephanie Abbott, Clinical Research Director at Western Washington Medical Group, will discuss the changing landscape of DCTs.

Moe: Medable launched its SNC in September of this year, but it is a concept that you have been thinking about for some time.

Describe the ideas that led to the creation of the Council.

 When I joined Medable, part of my responsibility was to bring a site perspective to product development, as historically sites have often been cut out of the development process. We announced the SNC in September, but we really launched it at the beginning of 2021 and have been working together for months. One of our main goals was to identify whether technology slows sites and encumbers their work or helps. Could tech be better designed, and how could we help?

Even with this goal, the SNC didn’t just look at Medable’s platform. Instead, we looked at the entire research process from a site perspective, and a lot of our work has been focused on on-site training, which is a significant pain point for staff.

 Medable’s SNC has had several discussions about sites’ pain points regarding technology. As the research director of a site, I’ve experienced a lot of pain points! There are similarities and differences in that pain depending on where you come from and if you’re a free-standing site, part of a network, or are an academic institution. Even so, we’ve uncovered a lot of common themes

 One other important element of the SNC is our focus on inclusivity to learn from many points of view. We have eight inaugural members that represent a wide range of different clinical sites. We have traditional standalone sites that only do research, such as Rochester Clinical Research. We have an academic medical center and several blended healthcare practices. We have a member that is responsible for bringing research into Federally Qualified Health Centers (FQHCs). We have Sun Valley Research Center at the border of Mexico and California, which works with a predominantly Hispanic population. VitaLink Research, now part of Velocity Research, a network of sites in the Southeast, is also a member and, we’re planning to expand into other parts of the U.S. and the EU.

By having access to real-life insights from a range of sites, we can build a flexible solution that can be tailored to all. This group brings different experiences so we can bounce ideas off each other. In addition, they offer a transparent window into all research environments to help Medable create decentralized clinical trial workflows that meet sites’ changing needs and enable greater participation in DCTs.

Moe: Could sites be cut out of the research process altogether with DCTs?

 This is one of those times when words matter—and anyone referring to decentralized trials as siteless trials hasn’t considered the vital role that the site team plays in supporting research. The phrase removes the linchpin of trials, practically excommunicating a whole group of key stakeholders. Why do we want to remove the human connection from clinical research? It makes no sense, especially as the connection between the patient and the study team is the #1 reason why patients stay enrolled in trials.

The site model will undoubtedly evolve as the definition of what comprises a site becomes more dynamic to include pharmacies and other unique settings. All will need to adjust, but good technology should provide greater flexibility to both sites and patients. Sites want easy-to-use technology that allocates high-value resources to clinical needs and focuses more on patients. We don’t believe that research will become completely remote. Instead, Medable wants to design solutions that work for all stakeholders and for every type of research setting, hybrid, virtual, or in-person. I am passionate about this because the site relationship is why patients stay in a trial. They may come for the promise, but they stay for the people.

Medable never wants to take the site out of the research equation. We believe it remains the core of research, and we want to support sites in this evolution and provide more flexibility. Technology disrupts our traditional clinical research model, and we may see some research conducted in local pharmacies soon. We will have to be creative—especially for those in rare disease trials and patients who live hundreds of miles from a traditional site—and work to support a variety of situations. However, sites will still be the cornerstone of research.

 At Western Washington, we had various opportunities to participate in decentralized trials over the past year or so. Similarly, in healthcare, telemedicine wasn’t previously happening, and healthcare payors didn’t support the use of telemedicine at first. But then comes COVID, and we needed to reinvent how we can meet people where they are, regardless of the circumstances.

The silver lining from this horrible pandemic is that we were all forced to get creative and try new research methods. Now we have another layer, more ways to deliver care, and that is huge. If our industry is not able to evolve, then we will not be able to provide the treatments to patients or get them approved in a reasonable timeframe. It’s a balance—leverage modern technology and bringing humanity back to healthcare and clinical research.

Moe: We’re all using so many different eClinical technologies today. How can sites get more proficient at using these technologies?

 I think what’s hard right now is that we have so many different technologies – for instance, EHR systems, CTMS systems, EDC systems (which people are talking about retiring). There are the TransCelerate sponsored single investigator platforms, but then even some of the original founding sponsors aren’t using that platform. Should the site invest in the technology when some of it becomes obsolete? And which solutions should they bet on for their future?

As a bridging strategy, some sites have hired digital natives—staff who don’t have a background in patient care but know modern technology. They may be just out of school, but they’ve never touched paper their whole career. The site brings them in to train patients on using eClinical technologies, support the staff, and troubleshoot, but this is an added cost to the site. At Medable, we are working to develop solutions that fit into sites’ everyday workflows and are easy for them to use and manage.

That is how we will drive and shape the industry because there are a lot of fast followers in the tech space—once you lead, many will follow. Yet, there are very few willing to be the first to cross the chasm.

 I am a healthcare provider by training, and I have worked in research for over 20 years. And, if I have to need to download a big training manual to use new technology, I’m not going to read it. If it doesn’t work intuitively, then it might as well be broken. On the other hand, we are consumer users of technology, so we get the basics—we have iPhones and bank online, and we expect technology to be almost as easy to use in the clinical research environment. I think someday sites will get fed up and not deal with it anymore.

We have turned down studies because they come with unruly technology. We can’t hire enough people with enough skillsets to manage those types of trials. I have one vendor we don’t work with because it takes at least three hours to onboard a patient using their product despite promises that it will streamline that process. On the other hand, initiatives like those of CTTI and Medable with its Site Network Council set higher expectations, and sponsors will either step up or not have many choices but to step out.

, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.

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A Resource for Connecting Patients to Trials

The lung is a complex organ, and the clinical trials processes that support new therapies for lung and respiratory disease are equally complex. Streamlining these processes with new approaches, including artificial intelligence (AI), could significantly improve the speed and quality of respiratory clinical trials while lowering costs. This article will discuss steps investigators and sponsors can take now to streamline trials and accelerate the time to market for lifesaving and life-changing therapies.

According to Eastern Research Group, it can take more than a decade to get a new drug to market, and respiratory trials are among the most expensive. And, according to the Biotechnology Innovation Organization (BIO), 58% of respiratory drugs fail in the last phase of the clinical trial process.

A first reason cited for failure is that pulmonary trials require a high number of subjects to achieve strong statistical significance. The conventional measures used to assess trial participants, such as the six-minute walk test, can introduce variability that is not directly related to lung health, and this affects the data. A more precise quantitative method for assessing lung structure and function in clinical trials would complement existing measures and potentially require fewer subjects.

Finding and recruiting appropriate subjects that meet inclusion criteria is a challenge for nearly all trials. Unfortunately, patient data is not readily accessible to investigators, and physicians have a difficult time staying informed about current trial opportunities for their patients.

Lastly, Roots Analysis data show that recruitment and retention issues make it difficult to find viable clinical trial sites. In fact, 37% of research sites do not meet subject accrual goals and more than 10% fail to enroll a single patient.

 Respiratory trials that involve imaging are especially challenging for sites given the complexities of subject breathing training, acquisition protocols, data security and more. These challenges create costly delays for new therapies and stop some promising trials altogether. These delays come at a time of continual increases in incidence, prevalence and mortality from lung disease and a need for technological and therapeutic advances that can be addressed with better approaches to imaging, recruiting and clinical site preparedness.

Over the past decade, better hardware and software have enabled trial sponsors to rely on more precise quantitative imaging-based data for respiratory clinical trials, providing much more detailed information about the condition of the lung.

Quantitative imaging has several advantages over conventional measures. First, imaging biomarkers offer reliable, objective measures of structural lung changes, such as the ability to measure airway wall thickness with millimeter precision using quantitative CT (QCT). A second advantage is repeatability. While a subject might have some variability in a spirometry effort, imaging data is likely more reliable and repeatable, especially when sites are adequately trained to collect imaging for clinical trials.

Imaging biomarkers can also be useful for subject selection by applying inclusion and exclusion criteria. A BIO study found that the probability of success for a given drug to graduate from Phase I to approval doubles when preselection biomarkers are used.

If highly precise imaging measures can be used in a trial, it’s likely that fewer subjects will be necessary to reach a statistically significant result. One study on this topic showed that a trial with 550 subjects using conventional measures could have been reduced to 130 patients if QCT measures were used.

 Reducing the number of subjects can speed trials and lower costs.

Focus on the right clinical trial subjects

Reducing the number of required trial subjects is a great start, but it can still be challenging to find the right patients for a respiratory trial; research firm Roots estimates $3.2 billion is spent on patient recruitment alone.

 Rich insights contained within imaging data can help address this challenge, however. Thanks to AI, sponsors can use imaging-based biomarkers to objectively and quantitatively determine which patients are ideal candidates for a clinical study.

Markers of emphysema, COPD, interstitial lung disease (ILD), asthma, and lung cancer are now used to identify viable trial participants. If, for example, a new emphysema drug trial is targeting individuals with upper-lobe predominant emphysema with a disease burden of 50% or more, an automated AI-powered analysis of multiple chest CT scans can surface candidates who match the specific criteria. The entire sourcing process is automated, which is an obvious benefit for trial sponsors as well as treating physicians whose patients may be included in promising trials based purely on their existing scan data.

Clinical trial site training and best practices

The challenges of managing a clinical trial site include proper training, consistency, equipment calibration, and maintaining high standards for efficiency and compliance. It’s not easy. Staff turnover is high, scanners get upgraded, and the need to retrain makes the trial process even longer and more costly. Adding imaging-based biomarkers to this process needn’t add complexity. We’ve successfully trained site personnel to ensure images are acquired using specific CT protocols and process controls that ensure scanner settings and breathing instructions are executed properly by a trained, certified technician on a calibrated CT scanner.

Technology, including AI, that supports earlier and more accurate diagnosis and management of lung and respiratory disease, is now more accepted across healthcare and biopharma. For clinical trials specifically, bringing quantification and objectivity to patient selection and trial management will improve the economics and patient impact of drug discovery and commercialization. It’s not hard to see how greater lung imaging precision, providing AI-enabled data on exact location and nature of damage, is invaluable in drug development, especially when this same technology is also becoming the standard of care for patient diagnosis and therapeutic guidance around the world.

, is the President & CEO of VIDA Diagnostics

Thomas DW, Burns J, Audette J, et al. Clinical development success rates 2006-2015. Biotechnology Innovation Organization, Washington DC. June 2016.

Dirksen and colleagues found that “using quantitative CT (QCT) measures, power analysis showed that the effect would be significant in a similar trial with 130 patients” vs. 550 subjects with conventional measures. Source: 1 - Dirksen et al, A Randomized Clinical Trial of a1-Antitrypsin Augmentation Therapy, Am J Respiratory Critical Care, Vol 160, 1468-1472, 1999

Biotechnology Innovation Organization (BIO), Pharma Intelligence, Quantitative Life Sciences; “Clinical Development Success Rates, 2011-2020,” February 2021, Page 18

Dirksen et al, A Randomized Clinical Trial of a1-Antitrypsin Augmentation Therapy, Am J Respiratory Critical Care, Vol 160, 1468-1472, 1999

Steps that investigators and sponsors can take to streamline trials and accelerate the time to market for lifesaving therapies.

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