JCS Volume 15 Issue 4

Volume 15 Issue 4

Journal for Clinical Studies PEER REVIEWED

Enhancing the Data Journey in Oncology Clinical Trials

Diabesity

Implications for Treatment and Drug Development

FDA Focus on the Safety of Gene Therapy Products Achieving GCP Compliance in Oncology Trials

The Balance between Obligation, Idealism and Realism

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Contents 4

FOREWORD

WATCH PAGES 6

Journal for Clinical Studies MANAGING DIRECTOR Mark A. Barker BUSINESS DEVELOPMENT info@senglobalcoms.com EDITORIAL MANAGER Beatriz Romao beatriz@senglobalcoms.com DESIGNER Jana Sukenikova www.fanahshapeless.com RESEARCH & CIRCULATION MANAGER Jessica Chapman jessica@senglobalcoms.com ADMINISTRATOR Barbara Lasco barbara@senglobalcoms.com FRONT COVER istockphoto PUBLISHED BY Senglobal Ltd. Unite 5.02, E1 Studios, 7 Whitechapel Road, E1 1DU, United Kingdom Tel: +44 (0) 2045417569 Email: info@senglobalcoms.com www.journalforclinicalstudies.com

FDA Focus on the Safety of Gene Therapy Products

Within the past 6 years, the US Food and Drug Administration (FDA) has approved a growing number of cellular and gene therapy products to treat a variety of conditions such as multiple myeloma, retinal dystrophy, prostate cancer, and type 1 diabetes (T1D). The FDA defines genome editing as the process by which DNA sequences are “added, deleted, altered, or replaced” at specified locations in the genome of human cells. Asher Madan at Clarivate outlines the FDA Focus on the Safety of Gene Therapy Products.

REGULATORY 8

Transparent, Pret-a-porter Operations Quality Measurement & Other 2024 Priorities for Drug Manufacturers & the Supply Chain

In Life Sciences manufacturing quality and compliance, the global digitalisation drive continues a-pace as the pressure builds to innovate, collaborate and contain costs. REPHINE’s Dr. Eduard Cayón rounds up the latest trends and challenges facing drug makers and their supply chain partners.

10 Achieving GCP Compliance in Oncology Trials: The Balance between Obligation, Idealism and Realism Good Clinical Practice (GCP) provides an internationally accepted standard to ensure subject safety and data integrity in clinical trials incorporating ethical and scientific guidelines. Amer Alghabban, author of The Pharmaceutical Medicine Dictionary, The Dictionary of Pharmacovigilance explains the balance between obligation, idealism, and realism in oncology trials.

RESEARCH & DEVELOPMENT 14 Enhancing the Data Journey in Oncology Clinical Trials Clinical trials are the springboard for progress in modern healthcare, guiding the development and evaluation of new treatments and nextgeneration therapies for patients. Trials exist at the critical juncture

Journal for Clinical Studies – ISSN 1758-5678 is published quarterly by Senglobal Ltd.

The opinions and views expressed by the authors in this journal are not necessarily those of the Editor or the Publisher. Please note that although care is taken in the preparation of this publication, the Editor and the Publisher are not responsible for opinions, views, and inaccuracies in the articles. Great care is taken concerning artwork supplied, but the Publisher cannot be held responsible for any loss or damage incurred.

This publication is protected by copyright.

Volume 15 Issue 4 Winter 2023 Senglobal Ltd.

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Journal for Clinical Studies 1

Contents where scientific innovation meets real-world patient care and offer the promise of improved health outcomes and an enhanced quality of life. Yet as innovative as clinical trials are, the industry itself is still ripe for innovation from within. The structure and setup of clinical trials, coupled with the technologies that facilitate them, play a pivotal role in shaping their success or failure. Andrew Zupnick and Craig McIlloney at Catalyst explain the data journey in Oncology Clinical Trials.

18 Regenerative Medicine: Hype and Hope or Safety and Efficacy?

Regenerative medicine, and the underlying stem cell technology on which it is based, offers considerable hope to patients suffering from trauma and chronic disease. Despite this, regenerative medicine can be highly controversial. Professor Peter Hollands shows why regenerative medicine claims relating to safety and efficacy are often disputed, because it is still in its infancy.

TECHNOLOGY 20 Revolutionising Hypertension Management Through Personalised, Data-driven Dose Optimisation In the late 1990s, Pfizer’s revenue stream was predominantly fuelled from the sales of antihypertensive drugs. The climax, so to speak, of its rigorous anti-hypertensive research efforts was the discovery of Viagra's unanticipated vascular system consequences. When the team at the Pfizer European Research centre, where the cardiovascular work was undertaken, proposed closing it all down, to move on to the next big thing, it was met with surprise and resistance from the commercial teams. Dr. Paul Goldsmith and Dr. Mike Taylor at Closed Loop Medicine outline how revolutionising hypertension management through personalised, data-driven dose optimisation.

22 Diabesity: Implications for Treatment and Drug Development The term “diabesity” has been used to refer to the twin pandemics of type 2 diabetes (T2D) and obesity. It was originally used after experiments showed that overfeeding healthy subjects to an overweight, but not obese, average body mass index (BMI) of 28 kg/m2 led to deterioration in fasting and postprandial (after meal) glucose tolerance. We now know that this glucose intolerance is related to insulin resistance, and it can be reversed by subsequent weight loss. Simon Bruce and Jack L. Martin at ICON plc show the implications for treatment and drug development.

on developing the diagnostic tools to identify the highest priority targets in each patient.

MARKET REPORT 30 Global Outsourcing and Vendor Management: Key Influence Factors and Strategies In the pharmaceutical industry about one-third of all drugs in the pipeline of the top ten pharmaceutical companies were initially developed elsewhere. Sponsor companies have continued their push to lower their operating costs while leveraging expertise to help manage growth in drug development pipelines. Tahseen Khan, senior writer on Drug Development clarifies the key influence factors and strategies in global outsourcing and vendor management.

34 Paving the Way for a Robust Research Ethics Review Structure in Malaysia The foundation of good research is built on sound ethical principles, which require a good rationale, a solid methodology and proper consideration of the important ethical issues that may arise from the research. The main task of research ethics committees is to ensure the above principles, so all research involving human subjects will have adequate protection of their dignity, rights and safety. Asha Thanabalan, Hans Van Rostenberghe et al. at Clinical Research Malaysia aim to lay out the current challenges faced by various research ethics committees in the region, detailing the current Malaysian ethical and review landscape and present NERCIM as a proposed way forward to address these issues.

LOGISTICS AND SUPPLY CHAIN 38 Developing Effective Supply Chain Strategies Utilising Forecasting Technology Drug development has evolved considerably over recent decades, along with the clinical supply chains that underpin the continued advancement of human health. Caitlyn Clauss at Almac Clinical Services outlines how to develop effective supply chain strategies utilising forecasting technology.

THERAPEUTICS 24 Emerging Treatments for Spinal Cord Damage Injuries to the spinal cord can cause permanent paralysis and even lead to death, with little or no hope of regaining lost functions once the trauma has occurred. Dr. Jerry Silver at Case Western Reserve University looks at his spinal cord research to try and understand why nerves that are damaged through spinal injury don’t regenerate, as well as identifying non-invasive, easy-to-administer strategies that can promote robust functional recovery.

26 Precision Medicine: Targeted Therapy in Pediatric Oncology Patients Targeted therapy depends on targeting unique receptors or proteins in the malignant cells, thus leading to fewer chemotherapy-induced adverse effects. Subhajit Hazra and Sara Ahmed Zaki demonstrate how to achieve the highest benefit from the targeted therapy, to focus 2 Journal for Clinical Studies

Volume 15 Issue 4

Corporate Profile

Ramus Corporate Group is a union between Ramus Medical, Medical Diagnostic Laboratory Ramus and Medical Centre Ramus. All the companies are situated in the Ramus building in Sofia, Bulgaria. They are certified in compliance with the requirements of ISO 9001:2015.

Ramus Medical is full service CRO, working CTs in a variety of therapeutic areas and medical device.

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Medical Centre Ramus with Phase I Unit

Medical writing for drugs and devices Scientific review of documentation Clinical trial management Monitoring Data management Regulatory advising and services during clinical trial

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Total laboratory automation with Abbott GLP-System Bioanalytical laboratory – ISO/IEC 17025:2017 accredited

PK/PD studies Medical devices investigations Phase I–IV Non-interventional studies

Medical Diagnostic Laboratory Ramus (SMDL-Ramus)

Others:

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30 clinical laboratories in Bulgaria and North Macedonia 325 affiliates for sampling in Bulgaria and North Macedonia More than 20 years’ experience in the CT field as central and safety laboratory; Largest PCR laboratory in Bulgaria Laboratory System integrates cluster generation, sequencing, and data analysis

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Medical Diagnostic Laboratory Ramus Ltd

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Ramus Medical Ltd Tu

to Cito

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26 Kapitan Dimitar Spisarevski Street, 1592 Sofia, Bulgaria Dimitar Mihaylov Tel./Fax: +359 2 841 23 69 Marketing Director www.ramusmedical.com email: office@ramusmedical.com

Journal for Clinical Studies 3

Foreword Cancer has become the second leading cause of death worldwide. At least half of all cancer cases occur in low and middle income (LMI) countries. However, all countries are facing an increased demand for health services for cancer treatment, and a changing and more expensive environment in diagnosis, and treatment, including radiation therapy.

from the research. The main task of research ethics committees is to ensure the above principles, so all research involving human subjects will have adequate protection of their dignity, rights and safety. Asha Thanabalan, Hans Van Rostenberghe et al. at Clinical Research Malaysia aim to lay out the current challenges faced by various research ethics committees in the region, detailing the current Malaysian ethical and review landscape and present NERCIM as a proposed way forward to address these issues.

Clinical trials are the springboard for progress in modern healthcare, guiding the development and evaluation of new treatments and next-generation therapies for patients. Trials exist at the critical juncture where scientific innovation meets real-world patient care and offer the promise of improved health outcomes and an enhanced quality of life. Yet as innovative as clinical trials are, the industry itself is still ripe for innovation from within. The structure and setup of clinical trials, coupled with the technologies that facilitate them, play a pivotal role in shaping their success or failure. Andrew Zupnick and Craig McIlloney at Catalyst explain the data journey in Oncology Clinical Trials.

I would like to thank all our authors and contributors for making this issue an exciting one. We are working relentlessly to bring you the most exciting and relevant topics through our journals.

Beatriz Romao, Editorial Manager, Journal for Clinical Studies

Targeted therapy depends on targeting unique receptors or proteins in the malignant cells, thus leading to fewer chemotherapyinduced adverse effects. Subhajit Hazra and Sara Ahmed Zaki demonstrate how to achieve the highest benefit from the targeted therapy, by focusing on developing the diagnostic tools to identify the highest priority targets in each patient.

In this journal, we will also explore more about diabesity. The term “diabesity” has been used to refer to the twin pandemics of type 2 diabetes (T2D) and obesity. It was originally used after experiments showed that overfeeding healthy subjects to an overweight, but not obese, average body mass index (BMI) of 28 kg/m2 led to deterioration in fasting and postprandial (after meal) glucose tolerance. We now know that this glucose intolerance is related to insulin resistance, and it can be reversed by subsequent weight loss. Simon Bruce and Jack L. Martin at ICON plc show the implications for treatment and drug development.

The foundation of good research is built on sound ethical principles, which require a good rationale, a solid methodology and proper consideration of the important ethical issues that may arise JCS – Editorial Advisory Board

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Hermann Schulz, MD, Founder, PresseKontext

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Ashok K. Ghone, PhD, VP, Global Services MakroCare, USA

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Jeffrey W. Sherman, Chief Medical Officer and Senior Vice President, IDM Pharma.

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Bakhyt Sarymsakova – Head of Department of International Cooperation, National Research Center of MCH, Astana, Kazakhstan

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Jim James DeSantihas, Chief Executive Officer, PharmaVigilant

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Catherine Lund, Vice Chairman, OnQ Consulting

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Mark Goldberg, Chief Operating Officer, PAREXEL International Corporation

Cellia K. Habita, President & CEO, Arianne Corporation

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Maha Al-Farhan, Chair of the GCC Chapter of the ACRP

Chris Tait, Life Science Account Manager, CHUBB Insurance Company of Europe

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Deborah A. Komlos, Principal Content Editor, Clarivate

Rick Turner, Senior Scientific Director, Quintiles Cardiac Safety Services & Affiliate Clinical Associate Professor, University of Florida College of Pharmacy

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Elizabeth Moench, President and CEO of Bioclinica – Patient Recruitment & Retention

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Robert Reekie, Snr. Executive Vice President Operations, Europe, AsiaPacific at PharmaNet Development Group

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Francis Crawley, Executive Director of the Good Clinical Practice Alliance – Europe (GCPA) and a World Health Organisation (WHO) Expert in ethics

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Stanley Tam, General Manager, Eurofins MEDINET (Singapore, Shanghai)

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Stefan Astrom, Founder and CEO of Astrom Research International HB

Georg Mathis, Founder and Managing Director, Appletree AG

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Steve Heath, Head of EMEA – Medidata Solutions, Inc

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4 Journal for Clinical Studies

Volume 15 Issue 4

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Our approach to advancing your therapies beyond milestones to transforming lives

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A biotech-focused Oncology CRO

Resourcing and functional solutions

helping to bring next-generation therapies to cancer patients in need

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Journal for Clinical Studies 5

Watch Pages

FDA Focus on the Safety of Gene Therapy Products Within the past 6 years, the US Food and Drug Administration (FDA) has approved a growing number of cellular and gene therapy products to treat a variety of conditions such as multiple myeloma, retinal dystrophy, prostate cancer, and type 1 diabetes (T1D). The FDA defines genome editing as the process by which DNA sequences are “added, deleted, altered, or replaced” at specified locations in the genome of human cells.1 Among recent product approvals in the US, Abecma (idecabtagene vicleucel), from Celgene Corporation, came to market in March 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma after ≥4 prior lines of therapy (e.g., immunomodulatory agent, proteasome inhibitor, anti-cluster of differentiation 38 monoclonal antibody). In June 2023, Lantidra (donislecel-jujn), from CellTrans Inc, was approved for the treatment of adults with T1D who are unable to approach target hemoglobin A1c because of current repeated episodes of severe hypoglycemia despite intensive management and education.

Applications for Cellular/Gene Therapy Products An area in which cellular and gene therapy products are increasingly being explored is the realm of rare diseases. In April 2023, the FDA’s Office of Therapeutic Products hosted its third annual RegenMedEd workshop focused on giving rare disease patients a platform to share their experiences with gene therapy clinical trials.2 A number of patients and caregivers talked about living with haemophilia, Friedreich’s ataxia, late-infantile neuronal ceroid lipofuscinosis type 2, and other conditions. One panelist who was diagnosed with haemophilia emphasized how he was able to “live fully” after taking part in a gene therapy trial and encouraged others to do so because it had significantly improved his quality of life.

During the April workshop, the FDA noted that it plays an important role in promoting the development of regenerative medicine treatments and “ensuring approved products are safe and effective for patients.” While gene editing offers curative potential for many rare and difficult-to-treat diseases, the technology is associated with a number of concerns, the agency stated.

A paper in 2021 described clustered regularly interspaced short palindromic repeat (CRISPR) and its associated protein (Cas9) as the “most effective, efficient, and accurate method of genome editing tool in all living cells.”3 The authors summarised that CRISPR/Cas9 genome editing involves 3 steps: recognition, cleavage, and repair.

The investigator-designed, single-guide RNA (sgRNA) binds to a target sequence in a gene through complementary base pairing.

Cas9 makes a double-stranded break in the DNA, allowing the manufactured DNA strand to be inserted into the location of the break. Finally, the double-stranded break is repaired by the body’s 6 Journal for Clinical Studies

cellular mechanisms. Despite the promise of CRISPR/Cas9 editing, “immunogenicity, effective delivery systems, off-target effect, and ethical issues have been the major barriers to extend the technology in clinical applications,” the authors stated.

In October 2023, the FDA convened a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) to discuss the benefit-risk profile of exagamglogene autotemcel (exacel), from Vertex Pharmaceuticals, Inc (Vertex), for the treatment of sickle cell disease (SCD) in patients aged ≥12 years with recurrent vaso-occlusive crises. If approved, exa-cel would potentially be curative after one treatment, according to Vertex. However, the treatment uses CRISPR/Cas9 gene editing, which the FDA cautioned can generate off-target genomic changes.

Investigators need to identify regions in the genome that could be impacted by CRISPR/Cas9 because “off-target effects could lead to lethal genetic mutations that cause loss of gene function,” the authors of a 2020 paper noted.4 During the CTGTAC meeting, several panelists expressed concern that off-target gene editing of autologous hematopoietic stem cells may lead to malignancies in patients administered exa-cel. To address this issue, Vertex proposed a 15-year follow-up study to monitor study participants who had received exa-cel for malignancies and other long-term adverse events. The advisory committee backed this proposal and further highlighted the need to assess the risk of off-target editing with the SCD treatment and also in future CRISPR/Cas9 products.

The advisory committee stated that CRISPR/Cas9 has been associated with a risk of mutations that can cause loss of function, but tumours may also occur. In a paper published in 2022, the authors exposed various human cells to CRISPR/Cas9 editing.5 They discovered that the process caused an increase in large rearrangements of DNA, which can theoretically give rise to cancer.

The investigators suggested adding checks for retrotransposition to ensure the safety of CRISPR/Cas9 editing techniques when used in medical or agricultural products. gRNA and Double-Stranded Break Repair According to presentations that occurred during the October 2023 advisory committee meeting, one method of determining how gRNA may affect a patient’s genome is through the use of in silico methods.

Software such as CRISPRme use algorithms to detect unintended areas where gRNA may alter a cell’s DNA. However, any sequence that is identified by such software should be confirmed through in vitro or in vivo means. It is important to note that just because a DNA sequence has been identified does not mean gRNA will interact with it. Cells have 2 main mechanisms of DNA repair.6 One is direct reversal of the chemical reaction responsible for DNA damage, and the other is the removal of damaged bases followed by their replacement with newly synthesized DNA. Volume 15 Issue 4

Watch Pages

According to several CTGTAC members at the October meeting, the body’s innate ability to repair DNA may counteract any possible unintended damage done to the DNA through CRISPR/Cas9 editing.

Toward the end of the advisory committee meeting, several panelists commented on how “groundbreaking” the field of gene therapy is.

One CTGTAC member summarised the committee’s perspective by stating that gene therapy is “something that is not straightforward, it’s new, and we’re all learning here.”

Gene therapy is a learning process not just for investigators and clinicians, but also for the regulatory agencies that make decisions regarding the availability of treatments in their respective countries.

These agencies have to balance unmet medical need with possible long-term risks posed by gene editing. While gene therapy offers curative potential previously not seen in the field of medicine, investigators need to remain cautious in order to ascertain its safety. This is especially true in terms of gene editing techniques such as CRISPR/Cas9 that can cause off-target changes to a patient’s genome, possibly causing malignancies years after treatment.

REFERENCES 1.

2.

Advisory Committee Meeting: FDA Briefing Document BLA#125787/0.

Food and Drug Administration Website. https://www.fda.gov/ media/173414/download#:~:text=FDA%20defines%20human%20 genome%20editing,nuclease%2Dindependent%20genome%20editing%20 technologies Workshop: Clinical Trials: The Patient Experience. Food and Drug

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AdministrationWebsite. https://www.fda.gov/news-events/fda-meetingsconferences-and-workshops/clinical-trials-patient-experience-04132023 Asmamaw M, Zawdie B. Mechanism and applications of CRISPR/Cas9-mediated genome editing. Biologics. 2021;15:353-361. https://www.ncbi. nlm.nih.gov/pmc/articles/PMC8388126/ Naeem M, Majeed S, Zahir Hoque M, Ahmad I. Latest developed strategies to minimize the off-target effects in CRISPR-Cas-mediated genome editing. Cells. 2020;9(7): 1608. https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC7407193/ Tao J, Wang Q, Mendez-Dorantes C, Burns K H, Chiarle R. Frequency and mechanisms of LINE-1 retrotransposon insertions at CRISPR/Cas9 sites. Nature Communications. 2022;13: 3685. https://www.nature.com/ articles/s41467-022-31322-3 Cooper GM. The Cell: A Molecular Approach. 2nd edition; 2000. DNA Repair. https://www.ncbi.nlm.nih.gov/books/NBK9900/

Asher Madan Asher Madan, MBBS, is a Senior Content Editor for the Cortellis suite of life science intelligence solutions at Clarivate. After medical school, he worked on tuberculosis research and contributed to a number of technology outlets. His current role includes reporting on FDA advisory committee meetings, drug approvals, and workshops.

Email: asher.madan@clarivate.com

Journal for Clinical Studies 7

Regulatory

Transparent, Pret-a-porter Operations Quality Measurement & Other 2024 Priorities for Drug Manufacturers & the Supply Chain In Life Sciences manufacturing quality and compliance, the global digitalisation drive continues a-pace as the pressure builds to innovate, collaborate and contain costs. REPHINE’s Dr. Eduard Cayón rounds up the latest trends and challenges facing drug makers and their supply chain partners.

2023 has been a demanding year for Life Sciences manufacturing, with continued pressure to innovate, bring costs down and overcome very real global supply chain disruption through improved visibility and contingency planning.

The most significant and serious pharma R&D projects are concentrated in the biotech space now. Although small-molecule developments are still a focus of investment, this once dominant field is becoming steadily less strategically important. As a natural consequence, increased technology use has become a priority – both to support designated innovation, and to help deliver this efficiently and safely. Efforts to digitise and automate manufacturing operations and processes in smarter ways have seen a sharp acceleration in initiatives over the last year, coupled with a renewed commitment to tech-based process monitoring and improvement – among operations of all sizes.

Agility, flexibility, and robust transparency in front of regulators are among the reasons drug producers are upping their game technologically. All market players realise now that targeted technology use offers not only a way to expedite product delivery and contain risk and cost; but also connect in more fluid and traceable ways with other entities – from regulators, to supply chain partners, to clinical trial participants and sponsors.

Tools are much more accessible and affordable now, certainly. As a result, digitalisation of manufacturing operations and associated quality control has become a competitive imperative. That’s as manufacturers across the world, from India and China, to the Middle East and South America become more technologically advanced, and at an accelerating pace. Even active ingredient (API) producers are investing in automation of operations monitoring processes that were previously managed manually.

Digital tool use isn’t just for manufacturing operations oversight or laboratory quality control processes either, but also overall Quality management. Changes to everyday working practices during pandemic lockdowns, and extended remote working, have added impetus for Quality-related process change. Hybrid working and remote collaboration are now seen as an enduring model – supported by the cloud as a secure hub for sharing and exchanging information, across global operations and along the supply chain.

That’s as the benefits have been felt in process efficiency, and in overall transparency.

8 Journal for Clinical Studies

Feeding into these already established digital capability priorities, we have seen the growing need for: Accelerated Adaptability The pandemic underscored the significance of being adaptable and swiftly shifting production, research and development, not least because of the need to respond promptly to new viral or bacterial threats in the future. All of this demands that operations are comprehensively and reliably monitorable, and that relationships along the supply chain are strong but fluid, underpinned by a continuous, consistent information flow.

Global Collaboration The development of treatments and vaccines for COVID-19 benefited from an unprecedented collaboration among governments, organisations, and corporations, setting a new precedent for addressing other diseases in the future. Ensuring that the lines of communication are open, standardised and tamperproof will be essential in fostering more spontaneous and timely exchanges, eliminating process bottlenecks.

Supply Chain Innovation Disruptions in supply chains due to the pandemic have prompted companies to diversify their suppliers and consider local or regional production. This has an impact on supplier quality control and compliance monitoring, with implications for audits and ongoing reporting. mRNA Technologies mRNA-based vaccines proved efficacious against COVID-19, prompting the industry to explore further therapeutic applications for the technology. As manufacturers’ ambitions grow, there are quality monitoring and control implications both for new production lines and international supply partnerships.

Telemedicine & Digitalisation The integration of telemedicine with pharmaceutical services has the potential to revolutionize drug delivery and monitoring, making it more precise and tailored to individual patient profiles. Such integration could include digital tracking of medication adherence; remote consultation for prescription adjustments; and even the use of AI-driven analytics for predicting patient responses to certain medications.

Regulation & Expedited Approvals The speed with which COVID-19 vaccines were developed and approved has spurred discussions about streamlining regulatory approvals in emergency scenarios without compromising safety.

Ethics & Equity Ensuring equitable access to essential medications and treatments is likely to remain a salient concern, in the wake of discussions Volume 15 Issue 4

Regulatory

around global access to COVID-19 vaccines. Ethical considerations play a vital role in healthcare policy and decision making. This is essential to balance the interests of the various stakeholders, including patients, healthcare providers, pharmaceutical companies, and government bodies. This balance is crucial in biopharma research and development, where the allocation of resources and prioritization of medical needs must reflect a commitment to serving the global community, not just the most profitable markets.

A Growing Focus on Unmet Clinical Needs The growing focus on unmet clinical needs, targeting previously neglected diseases and rare conditions, is driven by advances in personalized medicine, innovative partnerships, regulatory incentives, and increased patient advocacy. These efforts represent a shift towards more inclusive and responsible healthcare, emphasizing the need for broader access and treatment options across various health conditions.

Digital Transformation Drives As the whole Life Sciences industry strives to be more agile, responsive and competitive, the pressure is mounting for manufacturers to remove manual systems for process monitoring.

As they digitise capabilities, companies must be able to provide system validation and evidence of secure traceability; so vouching that generated reports have not been tampered with or faked.

A More Active Effort Towards Net Zero Finally, and importantly, the pharmaceutical industry is deepening its commitment to sustainability and to achieving Net Zero. Specific drives in 2024 are likely to include:

For manufacturers themselves, smarter operations and supply chain monitoring presents an opportunity to reduce the cost of production and its management, especially for conventional products whose prices are steadily declining.

Trends Evolving in 2024 In 2024, we can expect many of the themes above to continue to develop and accelerate. That’s in addition to other priorities that will emerge or gain momentum during the year, including: Increased Pressure on R&D to Innovate R&D organisations being under pressure to accelerate the pace of innovation, focusing on emerging technologies and personalised therapies. Even in the large generics markets like China, traditional drugs manufacturers are diversifying into biotech where the potential market is large and lucrative.

Lateral Tie-ups Between Complementary Specialists Alliances between pharmaceutical companies and tech specialists will multiply and flourish, particularly in the digital health space. Success will depend on the ability of those respective parties to communicate with each other on the same level, which includes their ability to standardise and streamline quality measures so that these are consistent and meaningful to both parties. www.journalforclinicalstudies.com

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Energy efficiency improvements: e.g. to adoption of renewable energy and more efficient manufacturing processes; Adoption of eco-friendly packaging; Green chemistry: the growing implementation of environmentallyfriendly practices in drug production; Waste management: proper disposal of pharmaceutical waste to prevent a negative environmental impact; and Sustainable supply chains: more ethical sourcing and responsible material procurement.

Together, such initiatives reflect the industry's commitment to environmental responsibility, aligning with global sustainability goals.

Dr. Eduard Cayón Dr. Eduard Cayón is Chief Scientific Officer at REPHINE, which provides bespoke technology and manufacturing supply chain compliance consultancy and third party auditing. REPHINE offers services all around the world from four primary locations – Stevenage in the UK, Barcelona in Spain, Hyderabad in India and Shanghai in China.

Dr. Cayón, who holds a Ph.D. in Organic Chemistry, is a deeply experienced pharmaceutical industry consultant and auditor.

Journal for Clinical Studies 9

Regulatory

Achieving GCP Compliance in Oncology Trials: The Balance between Obligation, Idealism and Realism Compliance with GCP provides assurance that the data and reported results of clinical investigations are credible and accurate and that the rights, safety, and confidentiality of participants in clinical research are respected and protected.

Hence, to protect public health, only sufficiently and verifiably GCP-compliant studies are accepted by regulatory authorities.

Oncology trials, with their inherent complexity, length and number of amendments have a higher risk of protocol noncompliance. Many of these challenges can be mitigated through study-specific risk-based measures including; adaptive trial designs, risk-based monitoring, protocol-based GCP training, vigorous feasibility process (at programme, protocol, site and investigator level), correcting and preventing root causes, administrative tools and other measures.

Inherent GCP Compliance Challenges in Oncology Trials Good Clinical Practice (GCP) provides an internationally accepted standard to ensure subject safety and data integrity in clinical trials incorporating ethical and scientific guidelines. GCP, which is incorporated into regulations, must be followed when generating clinical trial data that are intended to be submitted to regulatory authorities for marketing authorisation. Sufficiently and verifiably GCP-compliant studies can detect and mitigate against biases that may confound analysis of clinical trial outcomes. While each therapeutic area has its own unique intrinsic challenges when conducting clinical trials, oncology can be particularly testing with many inherent characteristics including: A. Trial Design: Cancer therapies can have highly variable modes of action which sometimes necessitates: •

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Complicated inclusion and exclusion criteria; while some exclusion criteria are fact-based, others might be with no clear delineation (e.g. theoretical, precautionary) in the respective protocols, as to which exclusion criterion has been drawn from known fact/data (which means that non-compliance could impact patient safety) and which is theoretical. While investigators must comply strictly with all exclusion criteria, this has often led to non-compliance by many investigators.

Frequent dose modifications caused by toxic effects.

Numerous prohibited concomitant medications: In Phase I oncology trials, for example, where patients’ cancers have proved refractory to standard therapies, and where patients’ prognoses at trial entry are very poor, many investigators (in agreement with or upon request from the patients) try or add another (protocol-prohibited) therapy if they do not perceive the trial therapy to be successful after a few doses. Again, while the default setting is for investigators to strictly comply with the protocol, the final decision on a patient’s therapy belongs to the patient and her/his physician in such difficult circumstances.

Being a study investigator is not, in all its dimensions, above the fact that the investigator is the patient’s physician.

Tight schedules of clinical assessments for patients who may already be enduring disease-related and drug-related fatigue.

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The potential negative impact of this issue can sometimes be mitigated by aligning study schedules with those of the clinical site to minimise the burden on site staff and patients, and can improve compliance.

Numerous laboratory tests; this can obviously have a negative impact on the compliance/willingness of patients but can also be a burden for the investigators who could miss the review and/or its documentation of some of the numerous laboratory reports which, in turn, can be considered as a serious GCP noncompliance as it could mean lack of safety monitoring in general or, in particular, for dose escalation purposes. This challenge can be mitigated by avoiding excessive tests which are not required to substantiate safety or efficacy endpoints.

Long trial duration: The length of oncology trials (and/or followup) can have a negative impact on the patients’ compliance and drop-out rates. The long duration of trials can also result in the need to deal with potential changes in trial personnel (sponsors, monitoring staff, investigators, site coordinators, suppliers, service providers, etc.) with associated potential impact on continuity, experience, familiarity with procedures, knowledge, training needs, etc.

B. Pharmacological Factors: Since the pharmacological effects of some oncology investigational medicinal products (IMPs) generally influence cell proliferation or cell division, a large number of adverse events (AEs) are frequently reported. The high number of AEs together with, at times, the difficulty to discern AE causality (whether the AE is disease- or comorbidity- or concomitant drug-related or is an IMP-related AE), can result in either over- or under-reporting of AEs. The newness of some oncology therapies adds to this challenge as the knowledge of their pharmacology is more limited than that of those with known pharmacology or pharmacological class rendering the investigators’ AE causality assessment to be more speculative. Regardless of its cause, there should be no delay in reporting the event within the specified timeframe.

For immuno-oncology trials, implications of delayed onset of related adverse events are not always foreseen in study design and there is often a lack of clarity about “standard vs. study-specific” toxicity management. When study protocols do not mitigate these issues, indirect non-compliance can invariably occur. Treatmentrelated AEs also often contribute to patients’ non-compliance. Mental health and educational specialities could play a considerable role in mitigating cancer patient non-compliance.

The toxicity profile of many cancer drugs as well as the various schedules and routes of administration used pose additional design challenges to blinding.

C. Recruitment Challenges: Patients recruited to the study frequently have constrained treatment choices.

• •

Patients’ disease already at advanced stage and refractory to existing therapies.

Patients’ awareness that they may not derive benefit from participation per se or because optimal dose of the Volume 15 Issue 4

Regulatory •

•

• •

D. •

•

•

•

investigational therapy is unknown at that stage (could be one of the trial objectives) so low (perhaps sub-therapeutic) doses are used which can cause patients’ reluctance to participate and/or to drop-out. The latter issue can sometimes be mitigated where multiple ascending dose (MAD) studies, to determine the maximum tolerated dose (MTD), can be designed, where possible, to use a starting dose which is considered to be potentially beneficial.

Where standard therapies have failed, some patients are in such a desperate state to receive a “novel therapy” that they may resort to hiding certain medical history or data to be eligible for the trial. Some of these situations can be mitigated by the introduction, where possible, of expanded access so long as the patients do not meet any safety exclusion criteria.

Oncology trials often face particularly high competition for patients and sites.

Trial duration might not be clear at the beginning, which may dissuade some patients from participation and/or increase dropouts.

Requirements of Clinical Research versus Common Clinical Practice: Administrative/documentation requirements: By far, the additional and particularly detailed documentation, records and data required in oncology clinical trials pose a big challenge to investigator sites’ personnel. In clinical research, while all data are equal … some data are more equal than others!

A major issue typically is encountered when source documentation, to support critical data entered into the CRF, is missing; for example, to confirm eligibility that a subject had received at least one first-line chemotherapy or if they had radiation regimens treatment prior to enrolment in the study.

Also, a protocol may require that an anti-emetic be given along with study chemotherapy and this would need to be documented (drug, administration time, route, and amount given). However, the standard at some oncology clinics is not to document dosing times of such standard medications.

Other administrative requirements may be perceived by the site team as challenging their integrity. For example, while obscuring erroneous data entry, destroying a wrong record or backdating information might only be considered as bad administrative management in normal clinical practice, it could be construed as a potential sign of “scientific misconduct” in clinical research.

The most efficient means to tackle data quality issues is a preventive approach through planning prior to and at study site start-up. Effective Good Documentation Practice (GDP) training on “Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring and Available” (ALCOACCEA) together with the provision of efficient templates and simple, clear procedures for entering sequential observations and making insertions or corrections that enable timely collection of important source data can pay dividends in mitigating several problematic compliance issues.

Regulatory requirements such as having trial monitors, auditors and potentially regulatory authority inspectors monitor, audit and inspect clinical sites to ensure/verify compliance with GCP, patients’ safety and data integrity are invariably above and beyond the norms of standard clinical practice. The perception and, consequently, the interaction of some oncology investigators do not always align with the obligations of the sponsor and/or regulators. These issues are best mitigated with smart interactive pre-trial training that should aim to raise awareness of the rationales for the regulatory requirements and their applicability to all therapeutic areas regardless of disease severity, regimen complexity, and acute care requirements,

www.journalforclinicalstudies.com

remove misunderstandings and align the common objectives.

Unfortunately, very often the time allowed and quality of the GCP training provided during investigator meetings leave a lot to be desired: typically scheduled at the end of the agenda, confined to 25 minutes, and “clinically” tiresome in content and/ or delivery style. GCP training at investigator meetings and site initiations should, at a minimum, be: A. designed based on the protocol to highlight “what matters” and what could go wrong so that it can be avoided; B. Interactive, to engage the investigators and their team.

Common Audit/Inspection Findings, Possible Contributing Factors, and Mitigation Strategies: •

Lack of documentation of the consent process and/or not using the ‘current’ version of the informed consent document: No record describing how the consent was conducted. As oncology trials tend to be long, there could be a high number of protocol amendments and hence (where warranted, e.g. new safety information) several corresponding informed consent forms. In a busy oncology clinic, this may lead to forgetting to document the informed consent or some other oversight, or using the wrong (superseded) version of informed consent form.

•

Possible remedies/prevention: Include emphasis in the initial training and subsequent reminders (where needed) that consent is a process rather than an administrative task. This may impact how consenting and re-consenting is conducted and documented. The site can also incorporate a brief description of the consent process into the patients’ notes.

Use tracking methods/tools for ICF versions. An electronic method accessible to the research team can also help eliminate these issues.

•

Missing source documents: This issue is usually particularly amplified in oncology trials where there could be substantial volume of medical records for each patient. If, for example, a biopsy report is missing, the monitor cannot verify important elements such as the diagnosis (e.g. if based on biopsy data).

•

Possible remedies/prevention: Plan and execute, in collaboration with site staff, a robust trialspecific documentation system prior to trial start.

•

Incomplete medical history: For example, the medical history records available do not support protocol-required documentation of failure of at least two prior chemotherapy regimens; records of previous therapies are missing.

•

Possible remedies/prevention: The site can be encouraged to use a progress note template to capture protocol-required histories in addition to standard clinical data. Also, one can integrate the request for pathology reports, from referring oncologists at the preparatory/recruitment stage.

•

Source documentation not appropriately signed and dated.

Oncology trials have exceptionally large volumes of records. If, for example, laboratory reports have not been signed and dated, this could, in the first instance, mean that they were reviewed but the review was not documented/confirmed (by signature and date). However, unless proven otherwise, it could also mean that the omission was the result of failure to review these reports.

The latter is a more serious type of non-compliance as it could have potential safety implications.

Journal for Clinical Studies 11

Regulatory Other examples include situations where a patient is seen by a physician who has not been delegated by the principal investigator, or was delegated but the delegation was not documented on the site delegation log. Naturally, the former is problematic as it could imply that a physician, who is not assigned (and not trained on the trial protocol) may have conducted a trial procedure.

•

Possible remedies/prevention: Create forms with places for signatures and dates when possible to act as a reminder to sign and date. Strengthen the clarity in the patients’ notes that the patient is in a research project and the importance of data verification, etc.

•

Repeated similar protocol non-compliance: Oncology trials, with their inherent complexity, length and number of amendments have a higher risk of protocol non-compliance. If a pattern is identified across sites in a trial, possible root causes could, in fact, reveal inadequate or improper protocol feasibility (impractical or hard to follow), too many amendments without corresponding re-training, as well as lack of initial involvement of some stakeholders (e.g. oncology site staff, etc.) who would be tasked with the practical implementation of the protocol.

•

•

•

•

Possible remedies/prevention: A vigorous feasibility process (at programme, protocol, site and investigator level) can afford a realistic of assessment of the capability to conduct the clinical trial through seeking a review from additional relevant stakeholders such as a site study coordinator and/or an experienced sub-investigator, i.e. triallists, not just opinion leaders. Likewise, ensuring assessment for the need for re-training, could also pay dividends.

SAEs inadequately processed, not reported, or reported late to the sponsor: The high volume of adverse events typically seen in oncology settings, together with the heavy workloads in oncology clinics, frequently impinge on the compliance with the required processing of adverse events. Other factors include inadequate awareness/ training of site personnel on the reporting requirements of adverse events in clinical research compared to non-research settings. Changes in personnel with no training given invariably compounds this deficiency. Other factors include lack of clarity in trial protocols on which adverse events need not be reported (e.g. because they are considered to be due to the cancer, etc.).

Possible remedies/prevention: Ensuring that the training given to investigator sites (at investigator meetings or site initiation visits, etc.) is “effective”, i.e. using certain smart training strategies such as the provision of examples or case studies which are created based on the trial protocol and therapeutic area, verification of understanding and evaluation of the training with tests at the end of the training.

These strategies have been shown to be very effective as both motivational and as a deterrent against the endemic lack of attention during the training sessions and most importantly in mitigating the non-compliances under question. They are also well-appreciated by regulators.

Lack of or late responses to data queries from sponsors: While the lack of or late response to data queries is noted in all trials, the prevalence in oncology trials is much higher and, regardless of the root causes, is considered to be a non-compliance by the site with their GCP and also contractual obligations which can, in severe cases, negatively impact the conduct of the trial

12 Journal for Clinical Studies

particularly when the resolution of the queries and resultant data, or data correction, have an impact on safety assessment and reporting. While this remains a clear non-compliance by the site, abnormally very high numbers of data queries across trial sites should warrant investigating whether, amongst other possible root causes, the CRF itself is badly designed or the respective part of the protocol is lacking clarity.

•

Possible remedies/prevention: Adequate dry runs of the CRF as well as seeking CRF reviews from, often missed, direct stakeholders such as a site study coordinator could well pay dividends to avoid such situations.

Also, there could be unexpected benefits and useful feedback from the provision of interactive training workshops, which incorporates examples of potential wrong CRF entries to verify understanding to better identify deficiencies in the CRF design.

Such trainings prove particularly productive if accompanied by a training effectiveness test at the end which provoke lateral thinking and identification of otherwise invisible problems.

•

Ineffective monitoring: For example, the source data verification (SDV) is conducted well by the site monitor, but major or even critical non-compliance could be missed. For example, SDV is almost 100% healthy but, unlike most sites in the trial, neither serious adverse events (SAEs) nor AEs have been reported from the site – very unusual in oncology trials. Tick-box monitoring is often a contributing factor and/or lack of awareness of AE identification and/or reporting.

•

Possible remedies/prevention: Effective smart risk-based monitoring has been shown to mitigate this and similar issues as it focuses on the global picture rather than non-critical data or processes.

Major GCP compliance issues can be prevented by adapting a risk-based approach for all trial procedures taking into account key factors including, but not limited to; novelty of the therapy, complexity of procedures and respective schedules, eligibility peculiarities, consent, safety, primary end points, randomisation/ blinding, etc: • • •

Risk-based approach to GCP training which is created after an assessment of the potential risks related to the specific protocol.

Outsourcing-related risks and required oversight.

Smart fact- and data-driven risk-based oversight and quality assurance programme (including but not limited to audits).

Amer Alghabban Amer Alghabban, pharmacologist, is a senior executive with over 30 years’ experience within pre-& clinical R&D, pharmacovigilance and GxP (GLP, GCP, GCLP, GVP) QA. Invited speaker at over 130 conferences, the author of The Pharmaceutical Medicine Dictionary, The Dictionary of Pharmacovigilance, and others. Previous positions; VP QA Compliance & Training at Karyopharm, Global Head QA at Merck Serono, Global Head GxP QA at Arpida, Clinical QA Manager at Novartis, and first Pharmacovigilance Compliance Officer of the MHRA, Assistant Editor for 11 medical journals and Course DirectorRQA Pharmacovigilance Auditing Course.

Email: amer@gxpcomplianceandtraining.com

Volume 15 Issue 4

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Journal for Clinical Studies 13

Research & Development

Enhancing the Data Journey in Oncology Clinical Trials Clinical trials are the springboard for progress in modern healthcare, guiding the development and evaluation of new treatments and next-generation therapies for patients. Trials exist at the critical juncture where scientific innovation meets real-world patient care and offer the promise of improved health outcomes and an enhanced quality of life. Yet as innovative as clinical trials are, the industry itself is still ripe for innovation from within. The structure and setup of clinical trials, coupled with the technologies that facilitate them, play a pivotal role in shaping their success or failure.

The choices made in trial setup – from patient recruitment strategies to data collection methods – directly impact the success and cost of a trial. Efficiency is crucial at every point in the drug development process. The industry has moved from paper-based data collection methods to the use of electronic data capture (EDC) systems and healthcare providers have moved to electronic health records (EHRs). While these EHRs and EDC systems are digital, the connection between them mainly is not digital, but analogue.

This non-digital connection creates an opportunity for innovative approaches using technology to better streamline trial processes, enhancing data accuracy, reducing cost, and expediting the development of new therapies.

Data Transformation in Clinical Trials The transformation from paper-based to electronic-based records has expanded exponentially. Clinical research has not been immune to this. More than 3.6 million datapoints were collected in a 2021 Phase III clinical trial, which is three times the amount collected in similar protocols ten years prior.1 As medical records transitioned to EHRs and clinical data moved from paper to electronic clinical forms in EDCs, electronic information has become more standard across the clinical research industry. If EDC is managed well, costs and errors should decrease. But this digital transformation has not been without hurdles, including adoption and technological.

In this white paper, we delve into the implications of EHR to EDC technology, dissecting its role in enhancing the efficiency, accuracy, and integrity of clinical trials, as well as the roadblocks keeping this technology from becoming standard at scale. We also share our perspectives on the future of EHR to EDC technology to innovate design and deliver better trials.

Undertaking EHR to EDC Integration In July 2018 the U.S. Food and Drug Administration (FDA) published its guidance to “modernise and streamline clinical investigations through the use of EHR data”2 with motivation for clinical researchers to work toward “interoperable or fully integrated” EHR and EDC systems.3 14 Journal for Clinical Studies

Although EHRs and EDCs are standard practice for clinical trials, the systems are distinct and often noninteroperable. Even today someone at a treatment site manually transcribes data from one system into another. As the industry has grown in complexity, the volume of data being analysed in clinical trials has increased. Clearly this task is ripe for innovation. Despite the technological challenges and regulatory intricacies that come with innovation in healthcare technology, the benefits of automating the flow of data from EHR to EDC for clinical trials are undeniable.

Streamlining data collection, enhancing accuracy, enabling realtime monitoring, and facilitating seamless collaboration from patient data and sites to clinical trial teams for analysis and reporting through to regulators are compelling reasons for successfully integrating EHR to EDC. There are powerful benefits to EHR to EDC interoperability from site, clinical research organization (CRO), and sponsor perspectives, as well as some challenges as to why interoperability has yet to become universal at sites.

Decreasing Site Burden and Error Clinical trial sites prioritise their mission to serve patients and help uncover new drug therapies. Treating patients and keeping them active and engaged in the clinical trial process while also complying with Good Clinical Practice (GCP) and study protocols are more than enough work for clinical research staff to handle. Requiring staff to manually transcribe data from EHR or other electronic forms into EDC requires significant site resources that could be better focused on patient care.4 Repetitive, human-led data transfer also comes with the potential for human error. In a literature comparison, an observational study mapping between EHR to EDC found that efforts for manual data entry “could have resulted in over 300 data queries” versus 30 times fewer with direct linkage from EHR to EDC.5 Once properly mapped, interoperability of EHR to EDC can reduce transcription errors to nearly zero, which helps to keep trials on track while using accurate data. Reducing site burden is a significant benefit of EHR to EDC technologies and is something we as an industry should adopt so site resources can be better focused on patient care.

Increasing Data Flow Speed and efficiency in clinical trials are pivotal. On average, drug development takes 10 to 15 years from start to finish,6 and a significant portion of that development time happens at the clinical trial stage.

Within a clinical trial, data from a recent patient visit with a physician may exist in the EHR system. In our experience, particularly at larger academic cancer research centres, to transcribe a visit into EDC can take up to four weeks.

Instead, if patient data transfers instantaneously, sponsors have access to their data sooner to analyse it and act upon it. Faster data access leads to faster trials, faster drug development, faster approvals, and faster patient access to life-changing drug therapies.

Volume 15 Issue 4

Research & Development With so many clear benefits, interoperability of EHR to EDC seems a significant approach that sites should consider. While paperbased records and manual transcription may still be functional, technology ensures sites are more efficient and effective while saving multiple resources. Unfortunately, many clinical trial sites are still reluctant to adopt EHR to EDC systems. Technology and industry leaders continue to work to minimise or remove challenges that keep sites from realising benefits of EDC. Some of the challenges include noninteroperable systems, potential privacy concerns, and the addition of another system to the portfolio of technologies sites are already using.

Reducing Trial Costs Drug development is expensive with each treatment therapy estimated to cost billions of dollars.7 The adage that “time is money” rings true in the clinical trial ecosystem. Most trials run on incredibly tight budgets, with research and development necessitating the majority of spending. Yet, manual data transfer is labour intensive, costly, and prone to errors, as discussed above. While an EHR to EDC linkage carries initial setup costs, it can ultimately save money over time. Approximately 20% of total study cost is apportioned to replicating and substantiating data.8 Sites would realise cost savings via a reduction in time for site staff to enter data, which could ultimately translate to reduced site budgets for sponsors. Eliminating human error in data transcription results in fewer data queries, which also saves sponsors money. One estimate puts the cost at $28 to $225 per data query.9 Perhaps most impactful, any automatic data flow would not need to be source verified. Instead, some quality checks or perhaps just verification for a trial’s most critical data would be needed, significantly reducing the need and cost for on-site source document verification (SDV).

Combining all three benefits with the adoption of EHR to EDC interoperability can provide significant cost savings over the course of a clinical trial.

Noninteroperable Ecosystems The benefits of EHR to EDC outweigh many of the hurdles for adoption.

Site Challenges Across healthcare, EHR systems are inconsistent and disparate.

While Fast Healthcare Interoperability Resources (HL7 FHIR) standards have made a minimum level of interoperability achievable, digital records, including those that predate 2014, are not userfriendly and cannot speak to each other or share data easily. In the clinical trial sector, this lack of interoperability causes challenges in site adoption. Data mapping and transformation tools help smooth the process, but interoperability must be frictionless, affordable, and easy to manage for EHR to EDC technology to appeal to clinical researchers and sites.

Technology Fatigue One of the issues trial sites face today is too much technology. Because healthcare systems were not built on interoperability, sites may use a different system for each trial function: scheduling, televisits, eConsent, EHRs, trial management, and more. There is resistance to EHR to EDC solutions because it’s another login, another area of change, and another unlinked technology adding to site burden instead of reducing the burden.

Enhancing Data Capture CROs aim to ease site burden and reduce costs while offering technology systems that integrate seamlessly, lead to better and more accurate data, promote data currency, and improve data flow www.journalforclinicalstudies.com

outcomes. Trial sites have individual infrastructures and preferences, which leads to preferred specific technologies, including EHR to EDC systems. CROs may also recommend EHR to EDC systems, which helps to benefit sponsors and sites on oncology full-service trials.

Our approach is flexible and technology-agnostic in that we develop processes to partner with multiple validated, industry-leading EHR to EDC technologies, all to help lower barriers and increase adoption by administrators and technology providers.

CROs should use their expertise to help companies navigate the operational complexities of running trials, including the challenges that come with data transfer. As with many aspects of trial operations, we know that solutions and technologies are not a one-size-fits-all approach.

Technology Integration Benefits Sites and sponsors benefit from a CRO-managed technology integration approach.

Site Benefits With our technology-agnostic approach, Catalyst can support a site or site network with whichever EHR platform or EHR to EDC technology preference is currently used. Our experience has been to work across client trials using multiple platforms, using the strong, established partnerships we have with technology providers, including EHR to EDC tools. We help sites leverage these existing partnerships, providing guidance and assistance to strengthen choices. Our method helps sites streamline their technology, while reducing operational costs they shoulder. When this technology replaces manual transcription of data from EHR to the EDC, sites are then enabled to save costs and time.

Sponsor Benefits With EHR to EDC integrated, sponsors benefit from the speed of data capture to the increased speed in accessing data. Normally data processing time is reduced and transferred to the EDC in near realtime – with cleaner data. With faster access to data directly from EHR without risks of transcription errors, sponsors can act and analyse the data sooner. Combining that with the promise of reduced SDV, this translates to faster trials and increased cost savings.

Keeping Pace with Technology With any growing area of technology, change takes time. We will continue to recommend EHR to EDC as part of full-service trial operations. We believe within five years, EHR to EDC technology is expected to be a tool most research centers – even smaller trial sites—leverage to streamline and speed their trial process. In fact, we have experienced site networks requesting specific EHR to EDC technologies during our clinical management process.

When EHR to EDC technology is used as a standardised tool applied across multiple sites, trial networks see clear value from a cost perspective and with staff familiarity of the technology. It’s exciting to see this momentum, and we believe these value-added approaches make the benefits of EHR to EDC more accessible to any site network.

As EHR to EDC tools progress and become more interoperable with other data sources in the healthcare system, such as wearable devices and remote patient monitors, healthcare providers and clinical trial operations can equally benefit from better insights into patient health and clinical trial outcomes. This directly impacts other key issues in the trial ecosystem, such as patient safety, trial accessibility, patient engagement, and patient recruitment.

While regulatory receptivity toward finding EHR to EDC solutions may be strong, technological acceleration for more advanced use Journal for Clinical Studies 15

Research & Development cases of EHR to EDC at sites may cause some to stumble. At this stage, industry partnerships and problem-solving are solid catalysts toward adoption and growth at scale of EHRs to EDCs within clinical trials.

Adoption of EHR to EDC technology will significantly influence a trial several times over through reducing site burden, increasing cost savings, and improving data accuracy. As we continue to evaluate and recommend EHR to EDC system partners and platforms, we will see increased adoption and acceptance.

REFERENCES 1.

2.

3.

4.

5.

6.

"Rising Protocol Design Complexity Is Driving Rapid Growth in Clinical Trial Data Volume, According to Tufts Center for the Study of Drug Development.

GlobeNewswire. January 12, 2021. https://www.globenewswire.com/newsrelease/2021/01/12/2157143/0/en/Rising-Protocol-Design-Complexity-IsDriving-Rapid-Growth-in-Clinical-Trial-Data-Volume-According-to-TuftsCenter-for-the-Study-of-Drug-Development.html Accessed 14 Nov 2023.

FDA In Brief: FDA issues policy to facilitate the use of electronic health record data in clinical investigations | FDA Accessed 25 Oct 2023.

Use of Electronic Health Record Data in Clinical Investigations Guidance for Industry (fda.gov) Accessed 25 Oct 2023.

Senerchia, Cynthia M., Tracy L. Ohrt, Peter N. Payne, Samantha Cheng, David Wimmer, Irene Margolin-Katz, Devin Tian, Lawrence Garber, Stephanie Abbott, Brian Webster, Using passive extraction of real-world data from eConsent, electronic patient reported outcomes (ePRO) and electronic health record (EHR) data loaded to an electronic data capture (EDC) system for a multi-center, prospective, observational study in diabetic patients, Contemporary Clinical Trials Communications, Volume 28, 2022, 100920, ISSN 2451-8654, https://doi.org/10.1016/j.conctc.2022.100920. Accessed 14 Nov 2023.

Ibid.

Sun, Duxin, Wei Gao, Hongxiang Hu, Simon Zhou, Why 90% of clinical drug development fails and how to improve it?, Acta Pharmaceutica Sinica

7.

8.

9.

B, Volume 12, Issue 7, 2022, Pages 3049-3062, ISSN 2211-3835, https://doi. org/10.1016/j.apsb.2022.02.002. Accessed 25 Oct 2023.

Ibid.

Sundgren, PhD, Mats, Nadir Ammour, MBA, DMD , Dan Hydes, Dipak Kalra, Richard Yeatman. "Innovations in Data Capture Transforming Trial Delivery." Applied Clinical Trials, 1 Aug. 2021, Volume 30, Issue 7/8. Accessed 14 Nov 2023.

Stokman, P Ensign, L Langeneckhardt, D Mörsch, M Nuyens, K Herrera, D Hochgräber, G Cassan, V Beineke, P Kwock, R Voortman, A Vogelgesang, S Boussetta, S & Bitzer, B. (2021, 3 12). Risk-based Quality Management in CDM An inquiry into the value of generalized query-based data cleaning. Journal of the Society for Clinical Data Management 1(1) doi: 10.47912/jscdm.20.

Accessed 25 Oct 2023.

Andrew Zupnick Andrew Zupnick, PhD, Vice President, Oncology Drug Development, Catalyst Oncology, has focused exclusively on oncology for over 20 years and serves as the vice president, Oncology Drug Development for Catalyst. He leads Catalyst’s full-service oncology solution, supporting study optimisation, delivery oversight, training, and new initiatives across the commercial and operational teams to keep Catalyst at the forefront of industry trends and cutting-edge oncology therapies. Andrew is a cell and molecular biologist with a Ph.D. from Columbia University and a B.S. from MIT. He brings a broad base of oncology experience to Catalyst. Andrew began his professional career at Prologue Research, a niche oncology CRO, which was founded out of what became the James Cancer Center at The Ohio State University and acquired in 2010 by Novella Clinical.

At Novella, Andrew led the growth of the organization’s oncology division into a market-leading oncology specialty CRO. After the acquisition of Novella by Quintiles, Andrew spent nearly seven years working within the standalone CRO subsequently rebranded to IQVIA Biotech in 2019.

Craig McIlloney Craig McIlloney, CStat, MSc, BSc Hons, Vice President, Data Sciences, Catalyst Flex, brings 25 years of experience with large and small CROs to his role with Catalyst. As vice president of data sciences, he is responsible for global data management, biostatistics, statistical programming, and medical writing teams. He’s held various roles across biostatistics and programming functions, including project, program, local, regional, and global management of more than 800 staff. As the previous vice president of biostatistics and programming for a large CRO, Craig drove the company’s expansion into Asia. His work has focused on various therapeutic areas, including oncology, infectious diseases, dermatology, endocrine/metabolic disease, hematology, nervous system disorders, circulatory conditions, respiratory disease, digestive system diseases, genitourinary disease, and musculoskeletal disease. Craig’s leadership experience spans activities across various delivery models, including FSP, full-service, and hybrid models. He earned a B.S. (Hons) degree in statistics from the University of Glasgow, U.K. in 1994 and an M.S. in applied statistics from Napier University, Edinburgh, U.K., in 2000. He is a chartered statistician (Cstat) with the Royal Statistical Society and was previously a director of the Statisticians in the Pharmaceutical Industry (PSI).

16 Journal for Clinical Studies

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Journal for Clinical Studies 17

Research & Development

Regenerative Medicine: Hype and Hope or Safety and Efficacy?

Regenerative medicine, and the underlying stem cell technology on which it is based, offers considerable hope to patients suffering from trauma and acute or chronic disease.

Despite this, regenerative medicine can be highly controversial in terms of claims and weaknesses relating to safety and efficacy, the regulatory aspects, the ethical and social aspects, the commercialisation of stem cell technology and – most importantly – the scientific and medical basis of the proposed technology. Regenerative medicine is in its infancy and we must all be very aware that at present, hype and hope are the backbone of the technology. When safety and efficacy are the backbone, then we will truly be in a new trusted area of clinical practice which patients can access with confidence.

The issue of patient safety and treatment efficacy in regenerative medicine is arguably the most important factor in the future of the technology and at present we are in a position of extremes. This is because technology such as bone marrow stem cell transplantation, peripheral blood stem cell technology (using mobilised bone marrow stem cells) and cord blood stem cell transplantation are practised globally with a high level of safety and efficacy. There are many centres of excellence around the world where experts carry out these transplants with extensive regulatory guidance. Patients enjoy optimised safety and efficacy when they are treated by these experienced teams in a perfect setting.

In stark contrast, there are a rapidly increasing number of stem cell-based ‘treatments’ for which there is little or no safety and efficacy data. These are often provided by stem cell ‘clinics’ and prey on vulnerable patients who are often looking for a ‘cure’ when traditional medicine has been unable to help. This is the dark side of regenerative medicine.

The safety and efficacy of treatments offered using stem cellbased regenerative medicine is defined and controlled by the relevant regulatory authorities. Once again, as with safety and efficacy, the regulation of regenerative medicine technology falls into two extremes.

The first extreme is in countries such as the UK and USA, where regulation is well developed and therefore patients are protected and can undergo regenerative medicine treatments with confidence. In the UK, for example, there is the Human Tissue Authority (HTA), the Human Fertilisation and Embryology Authority (HFEA) and the Medicines and Healthcare Products Regulatory Agency (MHRA).

These organisations come together to regulate every aspect of stem cell technology, making the UK one of the safest places in the world to be treated using regenerative medicine technology.

The second extreme is in other countries of the world such as India and China where regulation, if it exists, is poor – and the result is that many patients in such countries receive untested and potentially unsafe ‘treatments’. This means that in these countries, ‘treatments’ can be offered which place patients in potential danger and this has been illustrated only too well by reports of patients suffering life18 Journal for Clinical Studies

changing damage following poorly regulated ‘treatments’. There has also been a considerable rise in ‘medical tourism’ where patients travel to a country and as part of their visit receive ‘treatment’ using stem cells. This is a dangerous practice which all patients are well advised to avoid, but the problem is that false information and false promises lure vulnerable patients to have treatment. One of the ways in which we can try to reduce this problem is by patient education, so that patients know what to expect, to ask the right questions and to turn away when things look questionable or even dangerous. We must try to address the problem of patient education by providing clear, understandable advice written with no jargon for the general reader.

This will be extremely helpful for anyone considering undergoing a regenerative medicine treatment.

There is, unfortunately, another extreme when considering the regulation of regenerative medicine and this is sadly in places in the world such as South America and many small islands, where there is no regulation of regenerative medicine at all. This total lack of regulation means that anyone can set up a ‘clinic’ and offer ‘treatments’ and when doing this, they need not pay any attention at all to the safety and efficacy of the ‘treatments’ being offered. This is an extremely dangerous situation for patients and we must all try to discourage patients from attending any form of unregulated regenerative medicine ‘clinic’.

Regenerative medicine is no different from other medical specialities in that it can raise ethical and social concerns. Ethical issues in regenerative medicine come in many forms; for example, if it is proposed to use human embryonic stem cells as a treatment, then this raises issues about the use of a human embryo to create stem cells. This example not only raises ethical concerns but also, for many people, religious concerns. Embryonic stem cell technology has in fact developed extremely slowly since it was first proposed, and this is largely because of technical problems, but the underlying ethical and religious objections have also contributed to the slow uptake of the technology. There is also the fact that there are not many human embryos available to use to create embryonic stem cells and the technology could therefore never be available on a mass scale. The ethical aspects of regenerative medicine technology also arise in the use of donor stem cells of all types (to ensure the wellbeing of donors) and also in the use of gene insertion technology to produce induced pluripotent stem cells from somatic cells. We all must keep ethical implications in mind when either carrying out or recommending regenerative medicine in the same way as we do in all clinical practice.

The social implications of regenerative medicine are more complex. There is, first, the very obvious fact that most regenerative medicine procedures in most countries can only be obtained by payment and are therefore largely limited to the rich. Payment-only regenerative medicine procedures immediately exclude many people, which may be seen as social injustice, but this is in fact no different to the existing global social injustice in healthcare which we all seem happy to accept. This does not mean that this social injustice is either fair or correct, it just means that regenerative medicine seems to follow the same path as the rest of clinical medicine. Whether this is a good or bad thing needs further debate. This social injustice may Volume 15 Issue 4

Research & Development

also increase the health status of the wealthy, making the difference between the wealthy and the poor even more extreme than it is today.

This is clearly a bad state of affairs, but once again this is a generic problem and not one specifically related to regenerative medicine. It will require a global effort to correct these inequalities.

There are other more subtle social implications associated with specific areas of regenerative medicine and arguably the most important of these is ‘anti-ageing’. Ageing is a natural process, based around the ageing of stem cells, which is essential for the ongoing survival of the human race. If we do not have ageing and death, or make significant reductions using regenerative medicine, then planet earth would very quickly become totally overloaded and we would all die. The use of regenerative medicine technology in ‘anti-ageing’ procedures needs careful consideration and, in my opinion, should not be used. If ‘anti-ageing’ was successful it could be the beginning of the end for the human race.

The unregulated commercialisation of the stem cell technology used in regenerative medicine is a considerable and increasing problem to us all. There is an analogy within the pharmaceutical industry which is heavily commercialised but equally heavily regulated. This is not the case for Regenerative Medicine which is becoming increasingly commercialised but has little or no regulation on a global scale. The problem is accentuated by business workers who see stem cell technology and regenerative medicine as an easy way to make very big profits in countries where there is little or no regulation. They prey on vulnerable patients who are willing to pay large amounts for untested and unproven ‘treatments’. This activity threatens the viability of regenerative medicine as a safe and trusted procedure, but at present there is little which can be done to reduce this unethical and unsafe practice. Our only hope at the moment is to provide clear advice about regenerative medicine to potential patients and to increase the amount of stem cell education provided in schools and colleges.

Finally, we must all be aware of, and guided by, the stem cell science which underpins regenerative medicine. It is absolutely essential that any stem cell-based therapy must have a very clear evidence base composed of peer-reviewed publications and completed clinical trials. Such treatments can then be offered to patients with optimised safety and efficacy. Patients who wish to explore possible regenerative medicine procedures which have yet to go through clinical trials are well advised to enrol as volunteers in clinical trials. This will not ensure their absolute safety because all clinical trials carry risk, but those risks are mitigated to minimise any www.journalforclinicalstudies.com

potential harm to volunteers. This is much better than paying profitmotivated businesspeople to receive untested and unsafe ‘treatments’ which could result in life-changing damage.

Regenerative medicine holds considerable hope for the future but there are many hurdles to be cleared before the technology becomes commonplace in clinics and hospitals. These are scientific, medical, business and ethical hurdles and they cannot be rushed if we are going to provide a safe, effective and trusted regenerative medicine service in the future.

Peter Hollands Peter trained at Cambridge University under the supervision of the co-inventor of IVF and Nobel Laureate Professor Sir Bob Edwards FRS. His PhD was in stem cell technology with a focus on the transplantation of stem cells from the developing fetus. His post-doctoral position was as a Senior Embryologist at Bourn Hall Clinic which was the first IVF clinic in the world. Peter has been the Scientific Director of Cells for Life in Toronto and Smart Cells in the UK and was HTA Designated Individual for Smart Cells. He has carried out research in stem cell technology and has written numerous papers and book chapters on stem cell technology. He has been an invited speaker to many international conferences including personal invitations to speak twice at the Vatican, the UK House of Lords and The Canadian Parliament. Peter also has experience in creating new stem cell technology laboratories and the related accreditation and regulatory aspects of stem cell laboratories.

Peter has been the Group Chief Scientific Officer of the worldwide stem cell services company WideCells Group PLC and a Quality Manager for the Fertility and Gynaecology Academy in London.

He now works as a freelance Consultant Clinical Scientist. Peter has written a book on stem cell technology for the general public called ‘The Regeneration Promise’ which will be published in November 2020. This is the first of a series of books on medical science. Peter was awarded a Visiting Chair in Regenerative Medicine from Kolkata School of Tropical Medicine in November 2017. This was in recognition of his collaborative work in stem cell technology in Kolkata, India.

Email: peterh63@hotmail.com

Journal for Clinical Studies 19

Technology

Revolutionising Hypertension Management Through Personalised, Data-driven Dose Optimisation In the late 1990s, Pfizer’s revenue stream was predominantly fuelled from the sales of antihypertensive drugs. The climax, so to speak, of its rigorous anti-hypertensive research efforts was the discovery of Viagra's unanticipated vascular system consequences. When the team at the Pfizer European Research centre, where the cardiovascular work was undertaken, proposed closing it all down, to move on to the next big thing, it was met with surprise and resistance from the commercial teams. The argument was, we've found the drugs to treat hypertension, our job is done. This poses the pivotal question: how has hypertension, despite decades of medical leaps, persisted as one of the world’s biggest healthcare challenges?

Indeed in 2020, the first year of the COVID-19 global pandemic and before vaccine rollout, SARS-CoV-2 was only the third biggest killer in the Western world’s leading causes of death; behind cancer and hypertension at number one. And it is not just the deaths from heart disease and strokes, for which hypertension is responsible for over half, but also the disease’s core role in accelerating dementia.1 There would be far more impact from rigorous control of blood pressure at a population level on dementia rates and outcomes than any of the anti-amyloid forerunners.

The scope of this challenge becomes apparent when considering approximately 1.28 billion adults between the ages of 30 and 79 are grappling with hypertension worldwide.2 Notably, two-thirds of these individuals reside in low- and middle-income countries, highlighting the complex interplay between health and socio-economic factors.

Adding to the complexity is the fact that an estimated 46% of affected adults are unaware of their condition. Moreover, less than half (42%) of those diagnosed receive appropriate treatment, and only around 1 in 5 (21%) maintain disease control. In response, a global target has been set by the World Health Organisation to reduce the prevalence of hypertension by 33% between 2010 and 2030, calling for innovative strategies to enhance personalised treatment and comprehensive management approaches.

Decoding the Complexities of Precise Dosing What then has gone wrong in the effective management of hypertension, globally? There are two key issues, dose and process failure.

The words of Paracelsus, the father of pharmacology, resonate profoundly to this day: the only thing separating a drug from a poison is dose. Or in modern day parlance, concentration of drug at its effector site critically determines both benefit and side effects. Yet, amidst the pressures of clinical practice, this is not always at the forefront of clinicians’ minds when reviewing a disease management plan.

Partly this is due to the time and resource constraints in the modern healthcare system, but most critically, because of how clinical trials have historically been conducted to determine drug dose, based on 20 Journal for Clinical Studies

average populations, paired with the simplified marketing narratives that pharmaceutical companies would ideally promote.

It is surprising that in today’s consumer-driven societies, healthcare systems impose, and patients accept, a ‘one size fits all’ mentality.

Patients now display an increasing array of critical pharmacokinetic and pharmacodynamic variables, influenced by factors ranging from obesity to numerous co-morbidities associated with an everincreasing older population. Clothing retailers accommodate diversity by offering multiple sizes; should the pharmaceutical and healthcare industry not follow suit? Encouragingly, it is beginning to happen in some areas, most notably with continuous insulin infusions and glucose monitoring, with sophisticated software linking the two. This transformative approach begs the question: can the same philosophy be taken to other drugs, particularly solid dosage forms or injectables, and can this approach be used to manage other chronic diseases such as hypertension?

Blood pressure varies naturally during the day, as part of diurnal rhythms, as well as in response to current or anticipated bodily need.

One-off readings at the clinic can be misleading as they often present a distorted image, contributing to clinician inertia and delay in treatment initiation or dose adjustments until there is a more convincing data set. Home measurements have emerged as a promising alternative, although there are challenges with the validity of measurements and data transmission. Nevertheless, these can be mitigated by undertaking a thorough assessment of an individual’s response to medication through real-time feedback and using this information to dose optimise.

Drug + Software Solutions Disruptive innovations in technology and data acquisition have led to the development of novel platforms set to address this challenge of effective patient monitoring, increase the effectiveness of existing medicines and transform how chronic diseases are managed. The effectiveness of any treatment relies on both its efficacy, safety / tolerability and patient adherence. Integrating traditional therapeutics and medical devices that enable real-time monitoring of patients can support tailored dose optimisation and improve outcomes for patients.

An illustrative example of the technology’s potential is the PERSONAL COVID-BP trial, conducted in the UK, which was designed to evaluate a single-label combination product linking a medical device software product with a first-line anti-hypertensive, amlodipine, one of Pfizer’s old blockbusters.4 Nearly 20% of patients prescribed amlodipine discontinue its use after only the first prescription due to unwanted side effects, such as peripheral oedema, resulting in overall poor medication adherence and undermining the disease management plan.4,5 Taking place during the COVID-19 pandemic, the aim of the PERSONAL COVID-BP trial was to evaluate the ability of the integrated precision care solution to optimise patient care, whilst also monitoring COVID-19 symptoms to allow better understanding of the links between the disease and high blood pressure.

Volume 15 Issue 4

Technology Specifically, 205 participants aged 18 years and over with known hypertension and poor blood pressure control were enrolled in a community-based 14-week trial with remote monitoring and medical management, including patients shielding from COVID-19. Here, the technology closed the loop on blood pressure management by using processed data on both desired and undesired effects to precisely adjust the dose of amlodipine and deliver a personalised dosing regimen, without the patient ever needing to attend clinic. The study has shown promising preliminary results; demonstrating even low (novel) doses of 1 mg or 2 mg amlodipine reduced blood pressure, as did small 1 mg increments between 1mg–10 mg, allowing an individualised dosing sweet spot to be reached for each patient. Importantly, patient adherence to medication was found to be over 90%, perhaps in part because of the patient’s active role in establishing their personal optimal dosage and seeing their personalised dose response curve.

Encouragingly, the adherence rate of older participants was actually higher than their younger peers, which is fortunate as the cardiovascular events in outcome trials using amlodipine are dominated by those over 65 years of age.3 Final findings are anticipated to be published shortly. (in press; Journal of the American Heart Association) These preliminary findings have huge significance when considering the possibilities of software integration in disease management; suggesting that remote monitoring of blood pressure and side effects could revolutionise hypertension management. Tailoring dosages to the individual holds the potential to minimise side effects and significantly improve patient adherence for crucial cardiovascular medications, maximising overall effectiveness. Using this technology, the data also demonstrates how care can be maintained in unprecedented situations where face-to-face contact is not possible or desirable.

The Path to Process Refinement The initial discussion highlighted two primary reasons behind the persistent poor control of blood pressure: dose selection and process failure. These process failures often stem from issues such as clinician availability, time constraints and lack of reimbursement incentives. The optimal system, akin to what we currently have for insulin, involves prescriptions of drugs coupled with software that automatically adjusts and optimises dose, based on collected data. This is paired with direct feedback communication to the patient. In regulatory terms, this marks a transition from clinician-in-theloop, to clinician-on-the-loop, where the product operates automatically, but allows clinicians to intervene if necessary, ultimately aiming for a fully autonomous, clinician-out-of-the-loop system.

A key question then becomes how to conduct trials and evaluations to reach this nirvana. These evaluations should also incorporate health economics outcomes to facilitate uptake by payers. With blood pressure control being tightly linked to long term health outcomes, there is a compelling case. Furthermore, applying such a platform to other drugs can help achieve the outcomes-based reimbursement health care model so long called for by payers and governments.

Similar to insulin and diabetes, the algorithm’s performance improves as more patients are treated and outcomes data assimilated. However, there’s a need to generate evidence and assure regulators as the dose optimisation process becomes automated; in reality, policy-makers cannot simply follow the science. There are also the broader challenges seen with any Softwareas-a-Medical-Device (SaMD) interacting with other components, in terms of maintaining integrity and safety when other components are upgraded.

Incorporating safety features into the software platform from the beginning and understanding the ultimate goals are critical considerations, including the inevitable integration of AI. Acquiring data on effects as part of the product helps provide the regulatory assurance, along with approaches such as regulatory sandboxed deployments and conditional approvals of certain aspects of software. www.journalforclinicalstudies.com

The UK's Medicines and Healthcare products Regulatory Agency (MHRA) is at the forefront of these innovative ideas with the Innovation Access Pathways – involving collaboration between MHRA, The National Institute for Health and Care Excellence (NICE) and their Health Technology Assessments who lead on health economics for the UK government, as well as the NHS itself, the principal payor and healthcare provider in the UK. The aim of these collaborative pathways is to think about how innovative technologies can be deployed. There are also multiagency collaborative support efforts for AI, which can then be fed into the Innovative Access Pathways, as well as multi-national discussions, with the MHRA co-chairing an International Medical Device Regulators Forum (IMDRF) group looking at AI SaMD group looking at AI SaMD. Precision medicine has tended to equate to cancer genomics and an individual’s chemotherapy selection, for which care has been revolutionised. But there’s a growing recognition of its potential impact on the broader population with common diseases and in the not-toodistant future we will see similar impact on many other conditions.

By minimising the need for clinician involvement in the optimisation and monitoring process as much as possible, we have the opportunity to address one of the biggest challenges in modern healthcare, besides funding – the lack of availability of health care professionals. This presents a future where better patient outcomes are delivered by the synergy of pharmaceuticals and technology, whilst reducing process costs for the payers.

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Blood Pressure and Alzheimer's Risk: What's the Connection? [Online] https://www.hopkinsmedicine.org/health/conditions-and-diseases/ alzheimers-disease/blood-pressure-and-alzheimers-risk-whats-theconnection.

Hypertension - World Health Organisation [Online] https://www.who.int/ news-room/fact-sheets/detail/hypertension Taylor M, Godec T, Shiel J, et al. Whose Dose Is It Anyway? Individual Patient Dose-Response Curves From The Remote-Care Personal-Covidbp Trial. J Am Coll Cardiol. 2022 Mar, 79 (9_Supplement) 1997.

Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003 Jun 28;326(7404):1427. doi: 10.1136/bmj.326.7404.1427.

Leonetti G. Tolerability of long-term treatment with lercanidipine versus amlodipine and lacidipine in elderly hypertensives. American Journal of Hypertension 2002; 15: 932–940.

Dr. Paul Goldsmith Dr. Paul Goldsmith, Chief Medical and Innovation Officer, Co-Founder and President of Closed Loop Medicine, a TechBio company developing combination prescription drugplus-software products that enable personalised dosing. Paul has extensive NHS operational and strategic experience, is a NED for MHRA, MDU Ltd and MDU Investments Ltd, a trustee of the Radix Big Tent Foundation, and a visiting Professor at Imperial College.

Dr. Mike Taylor Dr. Mike Taylor is the Senior Vice President, Clinical Development, Medical & Scientific Affairs of Closed Loop Medicine. Mike has broad and deep experience of strategic and operational clinical development in global pharma and biotech including drug development Phase 1 – IV and medical device clinical evidence generation.

Journal for Clinical Studies 21

Technology

Diabesity: Implications for Treatment and Drug Development The term “diabesity” has been used to refer to the twin pandemics of type 2 diabetes (T2D) and obesity.1 It was originally used after experiments showed that overfeeding healthy subjects to an overweight, but not obese, average body mass index (BMI) of 28 kg/m2 led to deterioration in fasting and postprandial (after meal) glucose tolerance. We now know that this glucose intolerance is related to insulin resistance, and it can be reversed by subsequent weight loss.2 The latest data indicate nearly 42 percent of the U.S. population is considered obese; 49 percent has either prediabetes or T2D; and more than 90 percent of patients diagnosed with T2D are overweight or obese.3,4 Here, we discuss the overlap in pathophysiology and treatment of diabetes and obesity, along with considerations for streamlining clinical development of treatments that have therapeutic promise for both conditions.

Insulin Resistance, Adipocytokines and Inflammation Obesity is a condition of energy surfeit, or too much energy, and is associated with expanded and ectopic adipose tissue stores.

Excess fat, particularly visceral adiposity stored in abdominal tissue surrounding the intestines and ectopic fat in the liver, is associated with elevated adipose-derived metabolites that cause local and systemic low-grade inflammation. This is reflected in elevated levels of specific cytokines that are clearly associated with decreases in insulin action – specifically, insulin resistance, a hallmark phenomenon of diabesity that leads to a complex cascade of metabolic adjustments to physiologic stress, which in many individuals leads to eventual T2D.5 T2D occurs when insulin resistance (initially with compensatory insulin hypersecretion) and impaired insulin secretion (initially from pancreatic lipotoxicity, later from beta-cell loss due to inflammation, and other mechanisms) lead to loss of glucose homeostasis and frank hyperglycemia. Many people still think of T2D as a problem of “too much sugar,” but it has been established that T2D is more accurately thought of as a lipid disorder.6,7 The risk of lipotoxicity is increased in obese individuals where excess triglyceride handling – due to over-ingestion (eating) or production (de novo lipogenesis) – results in accumulation of toxic lipid metabolic by-products. Lipotoxicity in the liver is a proximate cause of both fatty liver and hepatic insulin resistance, which together contribute to the risk of T2D.

For example, leptin is an adipocytokine that is a master controller of energy balance. As an adipose-derived hormone, leptin sends signals to the brain about the adequacy of energy (adipose) stores, but it also affects immune function and inflammation through a type 1 cytokine receptor.8 Obesity is associated with leptin resistance, and elevated leptin concentrations may support dysfunctional adipogenesis and inflammation in the setting of obesity.9 Leptin analogs have shown dramatic therapeutic potential, but only in rare and extreme forms of obesity and hyperinsulinemic diabetes associated with lipodystrophy.10 Gut-derived, so-called “incretin” hormones, such as glucagonlike peptide-1 (GLP-1), play an important role in modulating normal glucose-stimulated insulin responses. In T2D, a reduction in secretion or sensitivity to incretin hormones contributes to hyperglycemia.

Treatment with exogenous GLP-1 analogs can normalise hyperglycemia in T2D. The use of GLP-1 has also proven effective in obesity treatment, due to central effects on appetite and ingestion regulation. Large outcomes trials in T2D and obesity have shown that GLP-1 agonists can improve overall mortality and specific outcomes related to atherosclerosis, and cardiac and kidney failure.

Weight loss through diet and lifestyle alone can improve or resolve insulin resistance and decrease inflammatory markers.

However, one of the most effective types of insulin sensitiser agent, PPAR-gamma agonists, led to significant improvements in glycemia in people with T2D, but actually caused weight gain due to additional adiposity.

Newer “diabesity” agents in early in clinical development, for example agents that modulate abnormal lipid availability or function, and/or directly affect the various mechanisms of insulin resistance, including anti-inflammation, should be considered for both potential obesity and T2D indications. Developers should pay careful attention to mechanisms of action and potential effects in early translational clinical development to best plan for sequential, parallel or milestonebased integrated full clinical development plans.

Notably, not all patients treated for obesity may develop diabetes, and not all patients with T2D or pre-diabetes are obese. For example, there are significant portions of south-east Asian populations with insulin resistance, fatty liver and pre-diabetes who do not meet western obesity BMI criteria.

Clinical Trial Design Considerations for Diabesity Therapies Traditional clinical development challenges are of increased importance for therapies for chronic use in widespread conditions of public-health magnitude, such as diabesity. One such challenge is recruitment and retention. Broader participation can be achieved by approaches such as using active comparators in weight loss trials, reducing study burden using hybrid decentralisation for randomisation and limiting the number of in-clinic visits. Additionally, new regulatory guidelines mandate broader inclusion and diversity, and safety data for at least two years. So sponsors must avoid, for example, overrepresentation of middle aged women in obesity trials or white males in T2D studies.

Treating Diabesity The complex interdependent metabolic and immune changes associated with both obesity and T2D – including those leading to insulin resistance and inflammation, such as adipocytokine and endocrine activity – contribute to the pathophysiology of diabesity.

However, they have also shown relevant treatment efficacy.

Engagement and retention are particular challenges for longterm clinical trials. To mitigate these challenges, sponsors can utilize proactive measures, such as patient education on the investigational product, proactive provisions for investigational product restart after temporary discontinuation, and a dedicated retention team. With these and other methods, ICON was able to support a successful large

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Technology 3.

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cardiac outcomes trial for GLP-1 receptor agonists, with over 9900 subjects with T2D followed for up to seven years, attaining greater than 97 percent completion rate.

Based on the recent approvals for GLP-1 receptor agonists for obesity in addition to T2D, integrated approaches to early and late clinical development for new “diabesity” agents can now be considered. There is growing interest in the simultaneous development of assets not just for diabetes and obesity, but also for pre-morbid conditions — such as prediabetes and steatosis (fatty liver) — with potentially more public health impact but currently without approved regulatory registrational pathways. Given the broader range of potential patients suitable to study and the currently separate indications to be treated, ICON is exploring potential advantages to innovative uses of master protocols, which are constructed to test multiple hypotheses with an overarching set of procedures intended to improve efficiency. This maximises the ability to identify relevant populations at screening and to direct them to appropriate substudies.

The Future of Diabesity Treatment The emerging understanding of shared pathophysiology, morbidity and mortality of obesity and T2D, as well as the demonstration of beneficial efficacy and outcomes of GLP-1 agonists, is stimulating research for more therapies to address diabesity-related indications.

These include obesity and diabetes and their shared complications, but also the possibility to pursue new indications for pre-morbid conditions such as pre-diabetes and fatty liver. Therefore, pipeline programs that target lipotoxicity and inflammation, or leverage adipose or intestinal hormones to modulate energy intake and expenditure, or use other approaches, including microbiome modification, will all increasingly benefit from early clinical development planning that considers how best to learn – and to demonstrate data supporting – the role of newer potential assets across multiple indications.

REFERENCES 1.

2.

Kaufman, Francine Ratner. Diabesity: A Doctor and Her Patients on the Front Lines of the Obesity-Diabetes Epidemic. Bantam trade pbk. ed., Bantam Books, 2006.

Haslam, D. Diabesity – a historical perspective: Part I. Diabesity in Practice 1: 141–5

www.journalforclinicalstudies.com

National Diabetes Statistics Report | Diabetes | CDC. Published June 29, 2022. Accessed September 25, 2023. https://www.cdc.gov/diabetes/data/ statistics-report/index.html Bryan S, Afful J, Carroll M, et al. NHSR 158. National Health and Nutrition Examination Survey 2017–March 2020 Pre-Pandemic Data Files. National Center for Health Statistics (U.S.); 2021. doi:10.15620/cdc:106273 Ruze R, Liu T, Zou X, et al. Obesity and type 2 diabetes mellitus: connections in epidemiology, pathogenesis, and treatments. Front Endocrinol.

2023;14. Accessed September 22, 2023. https://www.frontiersin.org/ articles/10.3389/fendo.2023.1161521 DeFronzo, R. A. “Insulin Resistance, Lipotoxicity, Type 2 Diabetes and Atherosclerosis: The Missing Links. The Claude Bernard Lecture 2009.”

Diabetologia, vol. 53, no. 7, July 2010, pp. 1270–87, https://doi.org/10.1007/ s00125-010-1684-1.

Dahik VD, Frisdal E, Le Goff W. Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes. Int J Mol Sci. 2020 Jul 31;21(15):5505. doi: 10.3390/ijms21155505.

Friedman JM. Leptin and the endocrine control of energy balance. Nat Metab. 2019 Aug;1(8):754-764. doi: 10.1038/s42255-019-0095-y Pinheiro-Machado E, Gurgul-Convey E, Marzec MT. Immunometabolism in type 2 diabetes mellitus: tissue-specific interactions. Arch Med Sci. 2020 Jan 31;19(4):895-911. doi: 10.5114/aoms.2020.92674 .

Oral EA, Simha V, Ruiz E, et al. Leptin-replacement therapy for lipodystrophy. N Engl J Med 2002;346:570–8

Dr. Simon Bruce Dr. Bruce, MD joined ICON in May 2021. He has over 22 years of experience working in clinical research or pharmaceutical industry with broad experience across all phases of clinical development and responsible for clinical development strategy and execution from pre-IND to firstin-human and Phase I/II proof-of-concept trials through Phase III planning, execution and filing and Phase IV support. His focus is in Diabetes/Metabolism and Cardiovascular therapies. He has a long history of leading clinical development teams and functions, providing oversight of transition from translational Proof-ofConcept to full development, and shepherding programs through internal portfolio review in large pharma and medium sized biotech.

Dr. Jack L. Martin Dr. Martin, MD, FACC is board certified in Cardiovascular Diseases and Interventional Cardiology. He has over 35 years of clinical practice and investigational experience. Jack is an experienced consultant for pharmaceutical and medical device companies. This includes all phases of product development including device design, trial design, FDA pre-sub and panel meetings. Dr. Martin has served as study chairman or the coordinating investigator for multiple multicenter international pharmaceutical and device trials. His previous roles included Assistant Professor of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Chief, Division of Cardiovascular Diseases and Chief of Interventional Cardiology, Health System.

He has served as President and a Board Member of several research foundations and is a respected educator having served as an Interventional Cardiology Fellowship Program Director. He has numerous peer-reviewed publications, is an active journal reviewer and has been a frequent invited speaker at national and international professional conferences. While at ICON, Jack has provided medical oversight for numerous cardiometabolic studies and has focused on cross functional team building to provide novel solutions for the effective delivery of drug and device trials.

Journal for Clinical Studies 23

Therapeutics

Emerging Treatments for Spinal Cord Damage Injuries to the spinal cord can cause permanent paralysis and even lead to death, with little or no hope of regaining lost functions once the trauma has occurred. News of my spinal cord research first came to prominent public awareness in the 1980s with a front-page story in The New York Times entitled, “Rat Nerves Repaired and Rejoined with Spine” which chronicles our presentation at the annual Society for Neuroscience meeting, the first time crushed peripheral nerves were successfully regenerated back into the spinal cord.

Regeneration of the nerves inside the spinal cord itself after injury, a far more complex challenge, is coming closer to fruition as a Canadian company I have partnered with is tasked with developing my discoveries with the goal of conducting human clinical trials.

My team at Case Western Reserve University medical school and I are working to understand why nerves that are damaged through spinal injury don’t regenerate and to identify non-invasive, easy-toadminister strategies that can promote robust functional recovery.

Can Damaged Nerves Regrow?

My research began by investigating whether it was even possible for an adult nerve cell to regrow within the environment of the damaged adult spinal cord. It had long been thought that this was impossible.

Nerve cells consist of elaborate long extensions (axons) that grow out from the main cell body. It is these axons that make the connections called synapses with other nerve cells, and it is the axons within the spinal cord that are severed when the bony spine is impelled into the cord when it is violently broken. Axons can be incredibly lengthy, some reaching almost the entire span of our bodies. One challenge for researchers working in the field of spinal injury was to determine whether damaged axons have the intrinsic capacity (i.e., a strong enough growth motor) so that, in principle, they had at least the potential to replace the damaged ones.

My team and I found that this was possible, even long after the damage had occurred. To demonstrate this, we conducted a simple experiment. First, we purified in cell culture, fully adult nerve nells that were genetically prelabelled with a fluorescent protein so that the cells could be easily visualised. The first step served not only to harvest the nerve cells but also to cut all the axons away from the cell bodies that, nevertheless, remain alive. Next, we collected the axon-less nerve cell bodies and very gently re-implanted them into the pre-lesioned spinal cord of an unlabelled adult host animal so as not to create any damage or scarring at the implant site.

It was a huge surprise to the scientific community when we found that axons could, indeed, grow robustly in the spinal cord and reach out quickly over long distances. However, we also found that when the new axons reached the area of severe lesion damage and scarring, they stopped growing abruptly and started to deteriorate. We 24 Journal for Clinical Studies

suspected that there was some sort of chemical produced by the scar tissue around the break itself that was hostile to axons and stops even exuberantly growing new ones from extending further.

Understanding Scar Tissue Inflammatory damage to the spinal cord after the initial injury can continue to spread outward from the lesion epicentre into surviving tissue to cause further loss of function. The development of scar tissue encases the lesion core and plays an important role in the protection of the healthy nerve cells from further harm. However, it is now clear that once the important task of protection is complete, the same structure that offered protection soon after the injury then develops into a barrier to the regrowth of the cut axons.

My team and I set out to identify the culprit in the scar that was stopping axon regrowth, and then see what we could do to reduce or overcome the growth inhibitory effect of the scar, once it had mitigated the danger of the initial injury. As we had already shown that axons can regrow once past or through the scar, we understood that this could be the key to returning or improving function to the injured area.

We found a particular family of potently inhibitory molecules that were being produced in the scar tissue, and that when newly regenerating axons encountered them, it caused the growing tips of the axons to become so tightly stuck (similar to a fly on flypaper) that they could no longer move forward. These sticky molecules are known as chondroitin sulphate proteoglycans (CSPGs).

Bridging the Scar Tissue and Repairing the Nerve Damage Having identified the culprit that stops the growth of axons near the scar tissue, our next step was to find a way to selectively eliminate CSPGs. My team and I investigated the use of a special enzyme (chondroitinase) that consumes the CSPGs once injected into the cord, stopping them from having such detrimental effects.

Using these enzymes, we found success in re-growing axons and improving function in animals that had problems with their limbs, bladder and diaphragm (which was hampering them from breathing). As these are common and potentially fatal conditions in humans following paralysis, the improvements in these areas were especially promising.

The use of enzymes to break down CSPGs has been widely investigated, with researchers attempting to optimise various factors, including the timing of administration and appropriate amount of targeted physical therapy. Benefits have been shown in many different animal models, including non-human primates and at long chronic timepoints post-injury. However, problems still exist as the enzyme is of bacterial origin, must be injected directly into the spinal cord, and acts only over a very short distance. Supplementary treatments may also be required to ensure optimal spread of the enzyme and that the regrown axons go on to make the right connections. Studies are Volume 15 Issue 4

Therapeutics

ongoing by a variety of research teams around the world to overcome these challenges.

To overcome the need to directly inject a molecule into the spinal cord, my colleagues and I tested a novel systemic approach to see what effect it would have on axon regrowth. We identified a receptor molecule called protein tyrosine phosphatase sigma (PTPσ) on the axons that acted as a ‘helper’ to cause CSPGs to be overly adhesive.

This newly discovered PTPσ receptor provided a way for the axons to detect CSPGs, signalling them to stop and become entrapped.

We developed a molecule that negates this signal, allowing the regenerating axons to ignore and bypass CSPGs. When the molecule, known as intracellular sigma peptide (ISP), was administered non-invasively via injections under the skin, it interfered with the CSPG/receptor signalling within the spinal cord, allowing for robust axon regrowth, resulting in greatly improved bladder function and improved locomotion in animal models of spinal cord injury.

Beyond Spinal Cord Injuries In working to understand what controls the regrowth of axons after spinal cord injury, we also discovered several medical conditions involving nerve injury where scarring also occurs and CSPGs impact axon regrowth.

Axons that are severed in the peripheral nerves, such as those found in the arms and legs, do have a limited capacity to regrow.

However, when the lesion is severe and closer to the body, a CSPGladen scar also hinders recovery because damaged peripheral axons also upregulate the same PTPσ receptor. My team and I were able to show that ISP can help heal injuries to peripheral nerves by speeding up the growth of injured nerves across and beyond the scar to the muscles they control.

Multiple sclerosis (MS) is an inflammatory mediated nervous system disease that affects both the brain and the spinal cord. It damages the myelin, the material that wraps and insulates the nerve cells. The loss of myelin slows down or blocks the electrical message that travels between the brain and the body, leading to MS. www.journalforclinicalstudies.com

Again, CSPG-filled scar-like plaques that form in the damaged areas play a critical role in preventing recovery by blocking migration of immature, potential myelin-forming stem cells that exist in huge numbers within the central nervous system. In animal models, we recently found that ISP promotes the migration of the stem cells into the lesion with return of the myelin sheath leading to functional recovery.

We also teamed up with investigators who study scars that form after heart attack. When a heart attack occurs, sympathetic axons that control the heart rate are damaged in the vicinity of the forming scar. Just like in the spinal cord, these cut axons die back away from the lesion core and their regenerating tips become entrapped within the outer edges of the scar, causing irregular heartbeats known as arrhythmias, which can be lethal. In animal models of heart attack, systemic treatment with ISP promoted new growth of the damaged axons back into the scar, stopping the arrhythmias.

My team and I are creating innovative solutions for the treatment of nerve damage. Together, we have identified an ISP analogue known as NVG-291 to treat human patients. It is our hope that this technology can improve the lives of the many people living with debilitating nerve damage.

Dr. Jerry Silver Dr. Jerry Silver is the co-inventor and scientific advisor to NervGen Pharma, a company that is creating innovative solutions for the treatment of nerve damage. Dr. Silver is the Professor of Neurosciences at Case Western Reserve University’s School of Medicine and adjunct Professor in the Department of Neurosurgery at the Cleveland Clinic Foundation.

Email: jx10@case.edu

Journal for Clinical Studies 25

Therapeutics

Precision Medicine: Targeted Therapy in Paediatric Oncology Patients For several decades, cancer has been one most of the devastating diseases affecting paediatric patients. A huge number of clinical trials and research papers are aimed at solving the puzzle of cancer; however, most scientists and healthcare providers are often shocked by the unpredictable attitude and response of this disease.

Nevertheless, huge progress has been made in this field as about 50 years ago, the 10-year survival rate didn’t exceed 20% (patients < 20 years old); but nowadays, it has reached 83%. This has been made possible by the efforts of the cooperative group protocols and multidisciplinary treatment.1 However, the toxicities and adverse effects exhibited by chemotherapeutic agents remain a barrier while treating paediatric oncology patients. In such circumstances, precision medicine can help us deal with the above issues.2 In 2015, Mr Barack Obama, the president of the United States, launched the “Precision Medicine Initiative”.3 Furthermore, he described it as being equivalent to the first moon landing as it aimed at providing individualised care to cancer patients.1 What is Targeted Therapy? And What are its Advantages?

Targeted therapy depends on targeting unique receptors or proteins in the malignant cells, thus leading to fewer chemotherapy-induced adverse effects.

In this regard, a study published in the Oncology Times aimed at evaluating the efficacy of targeted therapy in paediatric oncology patients with poor prognosis.4 The trial included 149 children with relapsed, refractory, and progressive high-risk malignancies (survival rate: less than 20%; median survival: 9.5 months). By using a particular algorithm, the paediatric oncologists could identify twenty patients with very high priority targets who could benefit from targeted therapy. After receiving the appropriate targeted therapies, these children showed longer progression-free survival than other children (204.5 days versus 114 days).

Thus, to achieve the highest benefit from the targeted therapy, we would have to focus on developing the diagnostic tools to facilitate identifying the highest priority targets in each patient.

But although targeted therapy can achieve better results, there are only a few approved targeted therapies available for paediatric oncology patients. Thus, the American Society of Clinical Oncology (ASCO) urges the scientific community to undertake precision medicine research and treatment approaches as a critical research priority. But even as it does so, we must be aware of the various challenges faced while developing and using targeted therapy in the paediatric population.5 Challenges of Including Paediatric Population in Clinical Trials To include paediatric patients in clinical trials is not an easy task.

According to the European Society for Medical Oncology (ESMO), the legal age in Europe for participation in clinical trials is above 18 years. However, it’s lowered to 12 years in the USA.6 26 Journal for Clinical Studies

Moreover, cancer in paediatric patients has a different histology3 with a few numbers of mutations and genetic alterations in contrast to adults, and this hinders the development of new targeted therapies.1 However, the MATCH-style trials (paediatric cancer clinical trials) are extending its purview to include participants from various countries as Europe (ESMART), Canada (PROFYLE), and United States (NCI Pediatric MATCH).2 And now, let us focus on particular types of targeted therapies for paediatric oncology patients.

I. Anti-angiogenic Therapy For nutrient supply to cancerous tissue, new blood vessels originate from the pre-existing ones. This process is known as angiogenesis and is crucial for the growth of the malignant cells.

The VEGF (vascular endothelial growth factor) pathway is pivotal for the process of angiogenesis, so most anti-angiogenic drugs, like Bevacizumzb, Sunitinib, and Cediranib, target the VEGF pathway and receptors.5 These drugs decrease the tumour’s interstitial pressure and increase the oxygen delivery to the tumour while decreasing vascular oedema and enhancing the delivery of chemotherapy at the target site.7 In alveolar soft part sarcoma, a rare type of cancer with a prominent capillary vascular pattern, the tumour cells have a poor response to chemotherapeutic agents. But by adding Cediranib and Sunitinib, the tumour cells have shown a good response.

Cilengitide, Pazopanib, and Sorafenib are examples of the other anti-angiogenic agents, which are being examined for various malignancies in paediatrics.

II. Immunotherapy Although the immune system can defend our bodies from viruses and bacteria, its protective mechanism is weak against cancer cells. Immunotherapy aims at boosting the immune system to target the malignant cells. It is now considered the fifth pillar in cancer treatment, and over 40 ongoing clinical trials are examining the effect of different immunotherapies to treat paediatric cancer patients.1 Vaccination In various paediatric solid tumours (neuroblastoma, hepatoblastoma, high and low-grade glioma, atypical teratoid rhabdoid tumour), the result of vaccination was promising as it increased the survival rates even with high-risk sarcoma.

Monoclonal Antibodies In 1997, the FDA approved the first monoclonal antibody Rituximab (targets the CD20 antibody) to treat malignant lymphoma.

Nowadays, Blinatumomab (targets CD19 and CD3) is approved to treat B-cell acute lymphoblastic leukaemia (ALL) in adults and is used off-label in relapsed B-cell ALL in paediatric oncology patients.

Chimeric Antigen Receptor Transgenic T-cells (CAR T-cells) The T-cells are extracted from the patient’s blood; then, it undergoes Volume 15 Issue 4

Therapeutics genetic engineering to add the chimeric antigen receptors on its surface (CARs). In this way, T-cells can target particular antigens on the tumour cells’ surface once it is injected back into the patient.

The CAR T-cell therapies targeting CD19 in B-cell ALL were commonly used in several clinical trials, and they showed encouraging results. An early clinical trial included 30 patients with ALL (children and young adults), and twenty-seven patients showed complete remission without recurrence signs. Then, largescale clinical trials were conducted to ensure the efficacy and safety of CAR T-cells.

In August 2017, the FDA approved the release of Tisagenlecleucel for children and adolescents with ALL. However, as some leukaemic cells may become CD19 negative due to antigen loss, several clinical trials were directed to investigate the results of CAR T-cells when targeting CD22. The outcomes of these trials showed promising results as there were complete remissions with no signs of relapse.8 III. Tyrosine Kinase Inhibitors A hallmark event in cancer is the uncontrolled proliferation of cells during suppression of differentiation and cell death. Such an event is facilitated by dysregulated activation of tyrosine kinases (responsible for transmitting signals). Thus identification of dysregulated kinase can form a potential therapeutic target for the treatment of cancer.

In this, the identification of tyrosine kinase inhibitors (TKIs) in adults has paved the way for its use in paediatric oncology patients.9 The various TKIs available today include Imatinib, Lestaurtinib (FLT3 TK family), Neratinib, and Brigatinib.10,11 However, most of these drugs are effective only for a short time (except in CML) when used as monotherapy.9,12 IV. BRAF and MEK Inhibitors Genetic mutation is the basis for the pathogenesis of cancer.

BRAFV600E is one such genetic mutation that induces activation of the mitogen-activated protein kinase (MAPK) signalling pathway that affects cell proliferation, differentiation, and survival.13 Trials with BRAF-mutant xenograft models have shown that suppression of MAPK signalling by BRAF inhibitors results in tumour regression and may prove to be an effective therapeutic option in patients with BRAFV600-mutant cancer types. Therefore the USFDA and EMA had recently approved Vemurafenib and Dabrafenib for the treatment of unresectable or metastatic melanoma with mutant BRAFV600.13 BRAF mutations are also known to be responsible for paediatric cancer; these genetic aberrations have been identified in the paediatric population with malignant melanoma (50%), gangliogliomas (50%–60%), and highgrade astrocytomas (10%-20%).14,17 Thus, BRAF inhibitors form the cornerstone for BRAF mutated malignancies. However, one must also take into account the incidences of drug resistance (BRAF inhibitors), which result in reactivation of the MAPK 18,19 pathway. Here, the use of combined therapy (BRAF and MEK inhibitors) has demonstrated its ability to overcome resistance in a metastatic melanoma cell.13 V. Proton Beam Therapy Precision radiotherapy has been known to deliver the dose on the tumour. It includes intensity-modulated photon radiotherapy (IMRT) and proton beam therapy (PBT). Both of these treatment modalities developed in the late 1990s; however, as time passed, it was proved that PBT had the upper hand over IMRT in terms of dose distribution and dosimetric control. Initially, the use of PBT www.journalforclinicalstudies.com

was limited to tumours near the critical structure, or those that responded poorly to IMRT. Nevertheless, in recent years, PBT has been applied to treat other neoplasms as well.18 Furthermore, due to the improved sparing characteristic of normal tissue, PBT nowadays is also being used in the paediatric population.19 Yet, there are at least three limitations18 in published data that hinder the large-scale use of PBT. These include: • • •

Studies are retrospective in nature The small sample size of prospective studies The lack of head-to-head comparison between the PBT and conventional radiotherapy

Targeted Therapy: The Other Side of the Story While targeted therapy is traditionally believed to have lesser sideeffects than its non-specific counterparts, it has some side-effects: • • •

•

TKIs as Imatinib lead to significant growth retardation in children receiving them on a chronic basis for the treatment of CML20 Second- and third-generation BCR/ABL TKIs are linked to vascular adverse events, like pulmonary hypertension and occlusive events21 CD19 CAR T-cell therapy has been evidenced to result in disruption of the blood-brain barrier, leading to neurotoxicity and an increase in the risk of infection (due to depletion of B cells)22,23 Almost 85% of melanoma patients treated with Ipilimumab suffer from autoimmune adverse effects24

Moreover, targeted therapies also pose a financial burden on the patient. As of 2018, the costs for Dinutuximab beta was around 173,000€ in the treatment of a paediatric neuroblastoma patient.

1 Similarly, treatment with Tisagenlecleucel (CD19 CAR T-cell therapy) would almost add 330,000$ more to a patient's medical expenditure as compared to traditional chemotherapy for B cell acute leukaemia.25 Conclusion In recent years, the field of precision medicine has experienced some of the most spectacular breakthroughs. However, an increase in the number of prospective trials would facilitate the large-scale use of PBT in paediatric oncology patients. Finally, a continued venture for newer drug development and improved sequencing technique is sure to further expand the scope of precision medicine in paediatric oncology.

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Burdach SEG, Westhoff MA, Steinhauser MF, Debatin KM. Precision medicine in pediatric oncology. Molecular and Cellular Pediatrics. 2018; 5:6.

Evans WE, Pui CH, Yang JJ. The promise and the reality of genomics to guide precision medicine in pediatric oncology: The decade ahead.

Clinical Pharmacology and Therapeutics. 2019.

Precision medicine initiative [Internet]: Privacy and trust principles.

Obama White House. 9 November 2015. [Cited: 17 October 2020].

Available at: https://obamawhitehouse.archives.gov/sites/default/files/ microsites/finalpmiprivacyandtrustprinciples.pdf Mark LF. Matching high risk pediatric cancer patients to targeted therapies. Oncology Times. 2020;14.

Pediatric match trial finds more frequent targetable genetic alterations in pediatric cancers than predicted [Internet]. ASCO. 15 May 2019. [Cited: 17 October 2020]. Available at: https://www.asco.org/about-asco/presscenter/news-releases/pediatric-match-trial-finds-more-frequentargetable-genetic Journal for Clinical Studies 27

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Barrier to early clinical trial access for adolescents and young adults still exist, study shows [Internet]. ESMO. 21 October 20. [Cited: 17 October 2020]. Available at: https://www.esmo.org/newsroom/press-office/ adolescents-paediatric-cancer-clinical-trials-vozy Bernstein ML. Targeted therapy in pediatric and adolescent oncology.

Cancer. 2011;117.

CAR T cells: Engineering patients’ immune cells to treat their cancers [Internet]. Cancer. 30 July 2019. [Cited: 17 October 2020]. Available at: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells Forrest SJ, Geoerger B, and Janeway KA. Precision medicine in pediatric oncology. Curr Opin Pediatr. 2018;30(1):17-24.

Skolnik JM and Adamson PC. Tyrosine kinase inhibitors in pediatric malignancies. Cancer Invest. 2007;25(7):606-612.

Jiao Q, Bi L, Ren Y, et al. Advances in studies of tyrosine kinase inhibitors and their acquired resistance. Mol Cancer. 2018;17(1):36.

Batson S, Mitchell SA, Windisch R, et al. Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis. Onco Targets Ther.

2017;10:2473-2482.

Rizzo D, Ruggiero A, Amato M, et al. BRAF, and MEK inhibitors in pediatric glioma: new therapeutic strategies, new toxicities. Expert Opin Drug Metab Toxicol. 2016;12(12):1397-1405.

Daniotti M, Ferrari A, Frigerio S, et al. Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT. J Invest Dermatol. 2009;129(7):1759–1768.

Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol.

2010;12(7):621–630.

MacConaill LE, Campbell CD, Kehoe SM, et al. Profiling critical cancer gene mutations in clinical tumor samples. PLoS One. 2009;4(11):e7887.

Dasgupta T, Olow AK, Yang X, et al. Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma. J Neurooncol. 2016;126(3):385–393.

Hu M, Jiang L, Cui X, Zhang J, Yu J. Proton beam therapy for cancer in the era of precision medicine. J Hematol Oncol. 2018;11(1):136.

Thomas H, Timmermann B. Paediatric proton therapy. Br J Radiol.

2020;93(1107):3-9.

Bansal D, Shava U, Varma N, Trehan A, Marwaha RK. Imatinib has adverse effect on growth in children with chronic myeloid leukemia.

Pediatr Blood Cancer. 2012;59(3):481-484.

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Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125(6):901-906.

Mackall CL, Miklos DB. CNS Endothelial Cell Activation Emerges as a Driver of CAR T Cell-Associated Neurotoxicity. Cancer Discov.

2017;7(12):1371-1373.

Hill JA, Li D, Hay KA, et al. Infectious complications of CD19-targeted chimeric antigen receptor-modified T-cell immunotherapy. Blood.

2018;131(1):121-130.

Horvat TZ, Adel NG, Dang TO, et al. Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol.

2015;33(28):3193-3198.

Silverman E. Kymriah: A Sign of More Difficult Decisions To Come.

Manag Care. 2018;27(5):17.

Subhajit Hazra Subhajit Hazra, M.Pharma (Pharmacology), is an experienced medical writer specializing in the creation of medical/scientific content for the medical communication industry in India.

Email: subhajithazra.freelancer@gmail.com LinkedIn: www.linkedin.com/in/subhajithazra93

Sara Ahmed Zaki Sara Ahmed Zaki is a Freelance Medical Writer with a previous history of working as a Clinical Oncology Pharmacist in an Oncology Center in Egypt.

Email: sarazaki091@gmail.com LinkedIn: www.linkedin.com/in/sara-ahmed-zaki-313a7816b

Volume 15 Issue 4

www.journalforclinicalstudies.com

Journal for Clinical Studies 29

Market Report

Global Outsourcing and Vendor Management: Key Influence Factors and Strategies Few would argue that global outsourcing is accelerating at an increasingly rapid pace. But what does outsourcing really mean to business, and what is it worth?

By far the fastest growing area of R&D spending is outsourcing.

Exceeding $60 billion in 2016, sponsor company spending on contract R&D services is growing at six times the annual rate of spending on internal staff, infrastructure, and technology support. Clearly, pharmaceutical and biotechnology reliance on outsourcing is high and increasing. Sponsor companies have continued their push to lower their operating costs while leveraging expertise to help manage growth in drug development pipelines.

In the pharmaceutical industry, about one-third of all drugs in the pipeline of the top ten pharmaceutical companies were initially developed elsewhere. Astra Zeneca, for instance, has been in the process of moving its global headquarters to Cambridge to harness the university’s scientific knowledge. Pfizer has undertaken a similar strategy in the United Sates, having positioned many of its research and development facilities close to major bioscience hubs. Bristol-Myers-Squibb has collaborated with Allied Minds, a Boston-based group on commercialisation of academic research to scour American universities for innovative drug discovery ideas, and GlaxoSmithKline has recently teamed up with the University of Leicester to develop novel drugs against blood cancer, showing that the outsourcing trend is an international phenomenon.

for pharmaceutical companies is how best to organise the R&D activities to improve productivity and flexibility: which activities to keep in-house and which to outsource to CROs? Processes that are usually outsourced include medical writing, submission planning and publishing, regulatory data and information management, local regulatory affairs, pharmaceutical-chemical writing, labelling, agency liaison, regulatory strategy, translation, administrative documents, dossier conversion, and literature searches, etc. The regulatory affairs functions most likely to be outsourced include labelling, electronic core technical document (eCTD) assembly, training and submission tracking, indexing, and archival.

Why do companies outsource?

•

•

•

Pharmaceutical companies are increasingly outsourcing different activities to vendors as a strategy to stay competitive and flexible in a world of exponentially growing knowledge, new technologies and an unstable economic environment.

Globally, the pharmaceutical industry is facing strong pressure to contain costs and therefore the expense is largely being directed towards outsourcing.

Because of frequent interaction between sponsor and vendors, the topic of vendor oversight is in the centre of attention.

Because of the outsourcing strategies employed, the question arises if vendors are doing what they were hired to do and if they are adhering to the quality necessary. With the growing use of contract research organisations (CROs) and other vendors, leaders in the field raise their concerns about increasing speed on pharmaceutical matters, like the increasing complexity of clinical trials, rapid recruitment of patients, or finding the best vendors or investigators for one’s own trial, and quality, while trying to adapt the vendor oversight processes per International Council for Harmonisation (ICH) Good Clinical Practice (GCP) E6 (R2) guidelines.

Companies use outsourcing to enter the market to avoid delays in hiring and infrastructure development, as well as to prevent internal resistance to new ideas. A pressing question

30 Journal for Clinical Studies

•

In practice, this means that a CRO can provide quick assistance in a task that is urgent and can be outsourced, or that would otherwise burden the company’s personnel. Anyway, getting ideas and expertise from external sources is a well-established practice.

There is always the possibility that the cooperation does not work. Even so, switching CROs is also expensive. The outsourcing policy may change in a way that the company back-sources the regulatory affairs tasks in-house. To obtain the most success out of the vendor management process, a strategic approach is required – to build and maintain the relationships with the best and preferred vendors. Good suppliers, with which a trustworthy and thriving collaboration is possible, are hard to get. Therefore, it is important to nurture the relationship between sponsor, and vendors the sponsor does not want to lose.

The following practices help maintain a strong sponsor-vendor relationship: •

Share information and priorities: To support the vendors to effectively meet the sponsor’s need, it is crucial to share the Volume 15 Issue 4

Market Report •

•

•

•

sponsor’s information and priorities. This means providing the necessary information in a timely manner, including launch dates, changes in the trial design, forecast information, and other relevant information that might affect the quality or service of the outsourced activity.

Allow strategy and innovation: The sponsor and vendor should work together on a strategy. By following this, the sponsor will receive the best value for the invested money, as this kind of collaboration is for sure the most effective one. The vendor is an expert in the outsourced area and can therefore provide valuable insight or innovative suggestions that could improve the service or would even provide cost savings, resulting in a competitive advantage. Hence, the vendor should be invited to meetings that involve the service the vendor is working for.

It is a double-sided collaboration and not a oneway business relationship.

Focus on the long-term plans: Short-term relationships with vendors are not recommended as they will only lead to shortterm gains and hence to minor cost savings. The real value will result from long-term partnership, which will enable trust and engagement from the contracted vendors. Consequently, this will result in discounts, preferable treatment and access to expert knowledge.

Focus on win-win agreements: Appreciative and trustworthy business relationships cannot be established through overruling negotiation strategies. Quite the contrary, this will cause resentment that could lead to further problems, and unproductive discussions. Instead, negotiations of agreements should be focused, and allow both parties to experience a good feeling about the agreement.

Recent revisions outlined in ICH E6 (R2) have provided an impetus for sponsors to reevaluate their oversight and quality management processes throughout the clinical development process. Specifically, ICH recommends that a sponsor maintain oversight of “any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).”

Identifying, qualifying, and selecting clinical providers are early and critical steps in the clinical outsourcing process that require attention.

Among the different non-clinical activities, logistics and procurement are of great importance as they represent a large portion of healthcare organisations’ expenditure and are essential for their operational performance. Procurement and logistics outsourcing have been considered useful to simplify the procedures for finalising contracts, to encourage competition between supplying firms through transparent selection practices, and to improve the efficiency and effectiveness of the entire healthcare system by increasing economies of scale and scope.

Studying the clinical trials outsourced within each therapeutic area globally, oncology was the area that topped the list across all geographies. The other areas were ranked in order of their importance in those relevant regions. Other diseases such as ophthalmology, speciality disorders, orphan diseases and neurology also received substantial interest, but did not find their spot within the top five areas.

As the COVID-19 pandemic continues to unfold, the capabilities of supply chains are coming into sharp focus, not so much in terms of cost-efficiency, but on their ability to be resilient and effective in delivery. This is why understanding the potential implications of complex outsourcing in the healthcare sector is of paramount importance. www.journalforclinicalstudies.com

Additionally, pharmaceuticals face increasingly stringent regulatory scrutiny around third-party relationship management and seek to bolster their vendor management capabilities to ensure compliance with industry standards.

The outsourcing processes consist of a sequence of stages, summarised as follows: • •

•

The early build-up stage, in which potential providers are selected to negotiate and develop a (formal or informal) contract for the provision of logistics and procurement services.

The execution stage, in which the commitments and rules of action agreed upon by the parties in the previous stage are carried into effect; in this phase, operations are organised, executed, coordinated and monitored, entailing adaptations and increased experience between the companies of the respective activities.

A long-term stage, in which routine approaches are institutionalised and several kinds of bonds between the parties arise or strengthen because of extensive formal and informal adaptations. These bonds have an important function in favouring the creation of longterm relationships and can relate to the technologies used and shared by the parties, personal knowledge and trust, administrative routines, procedures and legal contracts.

A Glance at the Preclinical Outsourcing Market: Frost & Sullivan valued the global CRO market at $28.75 billion in 2014. Approximately 13.1% of the total share arises from the preclinical segment. Globally, in recent years, preclinical outsourcing had experienced a surge in growth rate, leading to capacity constraints. Companies have made large investments in expanding capacities. Capacity issues are likely to result in declining growth over the longterm forecast period. One of the leading areas within the preclinical outsourcing market is preclinical toxicology.

Earlier, preclinical outsourcing was predominantly conducted inhouse by pharma companies, but it has been observed that sponsors are becoming more open to the idea of outsourcing more of these services to CROs to reduce the price burden. The majority of the revenues for this segment arise from North America, followed by Europe, Asia-Pacific, and the rest of the world.

Defining the Required Benefits The first step to realising the desired benefits is a clear definition of end objectives and expectations. The main challenge is to operate efficiently while balancing priorities to innovate and stay relevant in the market. These challenges can be managed through proactive and transparent service level agreements (SLAs), performance metrics, and continuous operational improvements.

Journal for Clinical Studies 31

Market Report A quality vendor performance assesses how the vendor is performing against key performance indicators (KPIs) established in the vendor’s contract. Performance reviews aim to monitor compliance of contractually agreed upon KPIs, identify areas where the vendor is not performing to expectations, partner with the vendor to resolve low vendor performance, benchmark the vendor’s performance against similar vendors, and assess performance trends. Each performance review should have a scoring model that quantifies the performance level. Once the internal review is complete, the vendor management office (VMO – a business unit within the enterprise that is responsible for evaluating suppliers of goods and services, and overseeing regular interaction and longterm relationships with vendors) should work with the vendor to work through any low scores. The best way to resolve low scores is to have the vendor create an action plan and collaborate with the vendor to track the vendor's progress to resolution with SMART goals, to ensure both parties obtain the desired results. SMART goals are specific, measurable, attainable, relevant, and time-bound objectives.

In some cases, it makes sense for a third party to perform select functions that are non-core to the organisation so that the sponsor can adapt a more flexible operating model.

Tracking the Realised Benefits: Post-contract signature issues, along with lack of innovation and leading practices, are two of the top five challenges companies face with their outsourced vendors. With a lack of clear definition on how to track innovation benefits, it is challenging to differentiate the value derived due to innovation. The industry still struggles when it comes to measuring quality; therefore, it becomes increasingly more important to investigate how the performance of the contracted vendors can be measured. Effective clinical trial management and improvement can only happen if there are valid and reliable quality metrics. Metrics should have standard definitions of key terms and study milestones to ensure that the metrics are measuring the right factors in the right way. Driven by competitive and regulatory pressures, the purpose is to be proactive on understanding the level of risk, so that it is possible to measure and monitor risks over the course of the trial.

Vendor Management Skill Sets Not all projects are the same, not all companies are the same, and not all vendor relationships are the same. There is not one universal skill-set to be an effective vendor manager. Many factors determine what competencies (or capabilities) are needed. These are ten typical factors more influential in determining what competencies are needed, in what priority, and to what depth.

Motivating the Vendor to Perform: Motivation is key to forward momentum. The vendor’s employees play a key role in effective delivery and keeping them motivated is a decisive success factor of a well-functioning service delivery model.

Vendor Management Operating Model To better harness and manage innovation, companies likely need flexible vendor management operating models that act as strategic enablers of innovation. This means that the processes, while welldefined, should be well-differentiated and able to change quickly to adapt to evolving business needs. It also means having the appropriate governance in place.

32 Journal for Clinical Studies

Vendor Management Tools Identifying tools that can help automate operations, especially while performing such repetitive tasks as performance reporting and contract analytics, is important. Tool adoption surely helps to streamline processes. Close collaboration with service providers to develop and customise tools is an effective way to meet the innovation needs of the organisation.

• Identifying competency sets from model and list, with development options.

• Strategic reviews of capabilities required and weighting of priorities.

• Tailored training workshops on vendor management to build individual competencies.

• Facilitated events to develop collective team capabilities.

• Webinars and videoconferences on selected competency areas.

1.

Lifecycle responsibility – whole process or one phase (mostly delivery).

2. Relationship with vendor – transactional or partnering (collaborative).

3. Project or programme – deliverables and milestones, or service levels and quality.

4. Extent of integration into client business.

5. Balance of expertise – client or vendor side.

6. New or ongoing project/programme – kick-off vs. maintain.

7. Project complexity, size, budget, depth.

8. Location of vendor.

9. Governance requirements, structure and process.

10. Level of responsibility, discretion and accountability of vendor manager.

Contractual Constructs: Although cost savings and service quality improvement appear to be the overriding motivations for outsourcing from public to private sector, the success of outsourcing also depends on a number of different factors. In fact, hidden costs of outsourcing

Volume 15 Issue 4

Market Report occur in selection, managing the relationship between supplier and outsourcer, and making changes to the service contract, all of which can offset any cost savings and quality improvements identified at the start of the outsourcing contract.

The development of clear risk assessment guidelines and SLA review guidelines can minimise contract renegotiation and associated changes during contract execution. Custom, valuedriven, and gain-share pricing models are appropriate for select initiatives and service providers. A move toward these custom models can help facilitate innovation, but they also require an increased focus on financial management.

A Look Ahead Through working with many different vendors, where different processes are outsourced, vendor management of third parties should not just be essential to gain an oversight over the contracted vendors but should also maintain a mutually beneficial relationship.

Beyond the lowered cost, the main value added is the achievement of benefits provided by a vendor that would normally not be delivered by other customers.

A great challenge for vendor managers is to compete with other sponsors or companies to attract and maintain the best vendors and their performances. Today, vendors indeed still compete with other vendors, but sponsors do also have to compete with other sponsors for the best vendors in their fields. In these times, it is highly important for the sponsor to be aware that a positive sponsorvendor relationship and providing critical feedback is essential for the daily business with the contracted vendors. If there is a good relationship between the sponsor and the vendor, it is more likely for sponsors to rely on vendors, as the motivation to support one another in a good relationship.

Since the scale, complexity and costs of clinical trials have increased during the years, the requirement for risk-based quality systems have emerged. As risk management is essential to identify and avoid potential costs and performances or technical risks to a process or a system, it is mandatory to understand how to introduce, implement and apply risk management principles to clinical trials.

For risk management in the GCP environment, no detailed guidelines or regulations are applicable that define how the processes of risk management should be incorporated. Here the risk process is divided into risk identification and assessment, risk treatment, review of risks and the risk communication and documentation which has to be performed for the whole process. About quality methods, it is necessary to define the key methods for proper quality management, as well as the risk management tools for maintaining a well-functioning quality system, which is needed for ongoing management of vendors. Finding ways to manage quality efficiently is one of the central issues faced by clinical development teams. The quality methods consist of quality control and quality assurance. Quality control is defined by monitoring the sites, which can be on-site monitoring or centralised monitoring.

With recent regulatory guidance, risk-based monitoring with a mix of both types is becoming the industry’s actual approach to clinical monitoring. An audit belongs to the quality assurance activity and is a systematic and independent examination of trial-related activities. For risk management tools, the ICH Q9 guideline mentions many useful tools, but the base for the quality risk management tools is covered through the root cause analysis and the risk analysis, as these are the two easiest handling tools.

Early-stage clinical trial services such as bioanalytics will witness a major boost in coming years, due to their increasing role in eliminating unpromising drug candidates at an early stage, www.journalforclinicalstudies.com

thereby saving R&D cost. Demand for functional services, such as data management, consulting, logistics, translation, regulatory and consulting, is also experiencing strong growth. The co-drug development model will be the future of the drugdevelopment industry, wherein CRO companies will join hands with pharmaceutical companies to develop a drug. As personalised medicine emerges, the co-development of a drug and the diagnostic marker will go hand in hand. This will compel the CROs to collaborate with pharmaceutical and diagnostic companies in the future.

The eClinical trial solution is gaining popularity. It helps in reducing the time and cost of clinical trials, and in streamlining the regulatory process and audit trials for faster approval. Additionally, since there is also an immense need for real-time, evidence-based data, this has paved the way for eClinical technologies that will play a vital role in the way data is being managed in these CROs. Market Watch The current focus strategy has centred on the concept of bigger equals better; companies are gearing up to broaden the breadth of services offered. With personalised medicine becoming a focus, central laboratory testing will also add value to a CRO. One of the recent M&A deals is the acquisition of Covance by LabCorp for $5.6 billion. Covance is a CRO with annual revenue of $2.5 billion, with about 12500 employees in over 60 countries, and stands second after Quintiles, which had annual revenue of $3.8 billion in 2013.

LabCorp is a diagnostic reference laboratory with annual revenue of $5.8 billion in 2013, with over 34,000 employees worldwide. The combined revenue of both LabCorp and Covance is aligned to make LabCorp a market leader and number one in the clinical laboratory market. Global expansion continues to remain the area of priority for many CROs today.

In terms of annual revenue and market share, this strategic longterm alliance is aligned to beat the market leaders. The combination of safety and efficacy data for drug approval from Covance and diagnostic data from 75 million patients from LabCorp will be an effective way to a more costeffective approach toward improving patient diagnostics and also advancing personalised medicine.

Clients will be able to see more value for their products.

Covance generates more safety and efficacy data for the approval of innovative medicines than any other company in the world, and LabCorp has longitudinal diagnostic data from more than 75 million patients. This combination leads the way to more costeffective healthcare by improving the safety and efficacy of drug therapies, enabling accurate patient diagnostics and advancing evidence-based medicines, which will enable their clients to demonstrate the value of their products and services to patients and payers. As a result, there will be greater opportunities for both companies because they will now have a broader universe to compete.

Tahseen Khan Tahseen is a senior regulatory writer at Covance in Mumbai. He did M.Sc. in Biotechnology, and has over 9 years’ experience in drug development. In his current role, Tahseen act as a lead writer authoring clinical study reports, investigator’s brochures, protocols, and other regulatory documents prepared for drug approval primarily for FDA submission.

Email: tahseen.khan@covance.com

Journal for Clinical Studies 33

Market Report

Paving the Way for a Robust Research Ethics Review Structure in Malaysia Introduction The foundation of good research is built on sound ethical principles, which require a good rationale, a solid methodology and proper consideration of the important ethical issues that may arise from the research. The main task of research ethics committees is to ensure the above principles, so all research involving human subjects will have an adequate protection of their dignity, rights and safety.

With over 30 years’ experience in clinical research, Malaysia has a well-established and experienced ethics and regulatory infrastructure.

There are 13 recognised research ethics committees/institutional review boards (RECs/IRBs) in Malaysia, each responsible for the ethical review of research proposals involving human participants conducted at their respective institutions. The Medical Research Ethics Committee (MREC) within the National Institutes of Health (NIH), which is part of the Ministry of Health (MOH) Malaysia, reviews all clinical research protocols involving any of MOH facility.

The majority of public universities and a few private institutions have their own REC/IRB and for institutions that do not have their own REC/IRB, the ethics application is sent to any of the recognised RECs/IRBs. In the case of multicentre research proposals, making use of facilities of different institutions, ethical approval is obtained from each of the institutions involved in the research.

In an attempt to increase the capacity and quality of ethical review of research proposals involving humans, and to streamline and harmonise the processes of the various IRBs/IECs in Malaysia, the Network of Ethical Review Committees in Malaysia (NERCIM) was established in 2015. This article aims to lay out the current challenges faced by various research ethics committees in the region, detailing the current Malaysian ethical and review landscape, and present NERCIM as a proposed way forward to address these issues.

Challenges Faced with Research Ethics Committees in the AsiaPacific Region While ethics review and all processes involved in it seem to be quite uniformed and harmonised for many of the high-income countries, it is just not feasible to adopt all of their processes especially, when factoring in the protection of populations in many low- and middleincome countries in our region. Basic differences in accessibility to healthcare facilities and drugs are quite notable between countries, and even between provinces within many countries. There are also significant gaps in the education, let alone health awareness and commitment to a healthy lifestyle.

On top of the difference in needs between the low- and middleincome countries versus the high-income countries, many of the countries in the region still experience a certain lack of capacity to conduct high-quality ethical review of complex research proposals, often causing unnecessary delays in the start of international projects and sometimes depriving their institutions of good research opportunities.

Studies of existing research ethics committees (RECs) within different countries across the region pointed out some pertinent 34 Journal for Clinical Studies

issues which are listed in Table 1.1–5 A selection of these issues will be discussed for the Malaysian REC landscape in the next section.

Challenges within research ethics committee frameworks from various countries in the Asia-Pacific region1-5 • Inappropriate composition of committee o Primarily consisting of medical and scientific reviewers o Experts that may not cover all necessary specialties o Under representation from the public (lay persons), legal profession, younger members and/or female population o Inclusion of administrators in institutional and private hospital committees and, directors/heads of related departments • Lack or insufficient expertise on ethical issues • Lack of importance placed in capacity building exercises • Insufficient resources to operate the RECs • Inactive/inconsistent participation of members • Not completely independent especially private and institutional RECs that are funded by their own institution • Lack of standardised standard of operating procedures (SOPs) among the different RECs within a country that leads to variations in practice between institutions • Infrequent meetings leading to delays in the overall timelines of clinical trials Table 1: Various challenges faced by countries within the Asia Pacific involving the structure and the Table 1: Various challenges faced by countries within theregion Asia-Pacific region involving operations of researchstructure ethics committees. and operations of research ethics committees.

The Current Malaysian REC Landscape Malaysia developed its first Good Clinical Practice (GCP) guidelines in 19996 based on the ICH-GCP, as the country prepared to launch itself into the international clinical trial environment. Since then, the country has continuously built up its capabilities, resources and experiences, ensuring that Malaysia has a firm footing in the international clinical trial sphere.5,7,8 In 2007, MOH issued a directive that requires all RECs/IRBs approving drug-related clinical trials to be registered with the National Pharmaceutical Regulatory Agency (NPRA), which is the secretariat of the local drug control authority (DCA).1 The aim was to allow the NPRA to audit and monitor these RECs, ensuring that it complied with the Malaysian GCP, regulatory requirements and other established guidelines. The NPRA practices a three-yearly visit to all recognised RECs/IRBs, including those who applied for first-time recognition. They give feedback and demand proper actions before recognition is given and, as such, they contribute in a major way to the capacity and quality of the ethical review processes in Malaysia.

While most RECs/IRBs in Malaysia tend to have quite a balanced composition in terms of representation of the speciality, gender representation as well as medical, scientific and layperson reviewers, the variety of research projects presented to individual committees is large and not all committees may have enough experts to cover some of the specialised areas and research methods.

While it is not bad to have a decentralised structure of different committees making important decisions for their own institutions and subsequently ensure the post-approval processes for their own researchers, harmonisation of the review process among the different committees is a desirable aim. A study by See in 2018 showed that even though all recognised RECs/IRBs in Malaysia were compliant to the Malaysian GCP, there was a large variation in referral to other documents in operational procedures, especially with regard to the review process.

Volume 15 Issue 4

Market Report Network of Ethical Review Committees in Malaysia (NERCIM): The Way Forward In 2013 and 2014, respectively, two Malaysian RECs/IRBs, MREC and the REC of University of Science Malaysia (JEPeM) obtained recognition from FERCAP (Forum for the Ethical Review Committees in the Asian and Western Pacific Region), a voluntary, paid membership organisation that was established in 2000.

FERCAP is a regional forum within the SIDCER (Strategic Initiative for Developing Capacity in Ethical Review) programme and aims to assist and assess the regional RECs’ compliance to international ethics guidelines and local regulatory requirements. In the process, they build up the capacity of their member RECs to deliver goodquality ethical reviews.

Existing (2010–2020) strategic objectives of FERCAP include creating a network between different RECs at national, regional and international levels to promote and facilitate training, sharing of common values and goals and, to offer accreditation to RECs by continuous monitoring and evaluation processes.9 In 2015, MREC and JEPeM decided to initiate the formation of a Malaysian national network of ethics committees, named NERCIM (Network of Ethics Review Committees in Malaysia), following the examples set by established national networks from the Philippines (Philippine Health Research Ethics Board) and

www.journalforclinicalstudies.com

India (Forum for Ethics Review Committees in India ), which had achieved successes in harmonisation and organisation of their own local RECs/IRBs. It was the aim of NERCIM to share the beneficial experiences of getting FERCAP recognition with other committees and to harmonise the review processes (including the post-approval processes) among all RECs/IRBs in Malaysia.

As an informal network, NERCIM operated with biannual meetings jointly organised by MREC and JEPeM. The meetings consisted of an educational event regarding ethics review of various topics, followed by closed-door meetings where common issues and the opportunities for joint educational events and the potential to come up with common guidelines were discussed. Clinical Research Malaysia (CRM), a government body created with the objective of supporting the creation of a robust clinical trial ecosystem in Malaysia, has supported the efforts of NERCIM and has contributed to NERCIM in the planning of the content of the educational meetings and logistics arrangement.

NERCIM’s main objective still focuses on capacity-building exercises such as providing training and sharing of experiences with an aim for individual local RECs to evolve in their processes to harmonise processes amongst them. While individual RECs can maintain some form of autonomy in their review processes, SOPs according to the format and guidelines of FERCAP have been

Journal for Clinical Studies 35

Market Report recommended and the newer RECs have been encouraged to attend training sessions for FERCAP recognition. One of the achievements of the discussion was an informal agreement to expedite reviews of proposals that already got approval from other committees.

NERCIM offers a platform for local FERCAP members to share their experiences and knowledge gained being part of the organisation, as not all RECs in the country have the available resources to become members of the FERCAP. Following the establishment of NERCIM, two additional RECs in Malaysia were recognised by FERCAP, joining the likes of MREC and JEPeM. In the beginning of 2019, the process to formalise NERCIM as an association was undertaken. The concept in forming a registered association comprising RECs across the country, through voluntary application, is to provide an official platform for Malaysian RECs to increase capabilities and facilitate opportunities to overcome current shortcomings. Other than providing training and experience sharing among more established RECs, the platform could guide newer RECs, as more hospitals and universities with medical schools begin to participate in clinical research.

NERCIM members are also discussing the possibility of enhancing collaboration between RECs/IRBs. A first step, a work in progress at the time of writing this article, is a collaboration between MREC and a university-based IRB. A very good thing would be the establishment of a joint review board with representation of most stakeholders involved for protocols of studies being conducted in MOH and this university’s facilities. This would effectively cut short unnecessary time and resources as experienced with current practice.

All drug-related trials conducted in Malaysia require ethics approval from each investigation site involved before a Clinical Trial Import Licence (CTIL) and Clinical Trial Exemption (CTX) is released by the NPRA. If a joint review board could be established, that meets at least once per month, most of the large industrysponsored trials that make use of the facilities of several institutions may be granted approval within a period of 30 to 45 working days, without the need to get approvals from each and every individual REC/IRB. This may make the review process of higher quality, more efficient and more timely.

4.

5.

6.

7.

8.

9.

future. Perspect Clin Res. 2017;8(1):22-30.

Gao C-Q, Wang M-M, Liu Y-B. Rapid response to: Researcher who edited babies’ genome retreats from view as criticism mounts. BMJ 2018;363:k5113. DOI: 10.1136/bmj.k5113.

Maisarah AS, Nurul Ajilah MK, Siti Amalina MR, Norazuroh MN. Short review: implementation of biomedical ethics in Malaysia. Health and the Environment Journal 2016;7(2):54-76.

Ministry of Health Malaysia. Malaysian Guideline for Good Clinical Practice. 4th edition, 2018.

Ooi AJA, Khalid KF. A unique model to accelerate industry sponsored research in Malaysia. Journal for Clinical Studies 2018;11(1):24-27.

Ooi AJA, Khalid KF. Malaysia’s clinical research ecosystem. Applied Clinical Trials 2017. Available at http://www.appliedclinicaltrialsonline. com/malaysia-s-clinical-research-ecosystem. Accessed June 2020.

Torres CE. Reflections on the FERCAP Experience: Moving forawar with partnerships and networks. In: FERCAP@10: In commemoration of a decade of capacity building in ethical health research in the Asia-Pacific Region. 2011. Available at http://www.fercap-sidcer.org/publications.php.

Accessed June 2020.

Conclusion Through the initial steps initiated by RECs across Malaysia with the formalisation of NERCIM, Malaysia takes another step in its effort to firmly entrench its standing within the international clinical trials environment. Continued efforts to streamline and ensure the adherence to international standards will facilitate and speed up the ethical approval process by all IRBs/RECs of the research active institutions. Setting up of a national committee for industry-sponsored RCTs seems to be achievable in the long run.

It will require a lot of discussion and flexibility on the part of all institutions involved.

Asha Thanabalan

REFERENCES

Head of Psychiatric and Mental Health Department, Hospital Kuala Lumpur & Chairman of Medical Research & Ethics Committee, Ministry of Health Malaysia

1.

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See HY, Mohamed MS, Mohd Noor SN, Low WY. Addressing procedural challenges of ethical review system: Towards a better ethical quality of clinical trials review in Malaysia. Accountability in Research.

2019;26(1):49-64.

Panichkul S, Mahaisavariya P, Morakote N, Condo S, Caengow S, Ketunpanya A. Current status of the research ethics committees in Thailand. J Med Assoc Thai. 2011;94(8):1013-1018.

Thatte UM, Marathe PA. Ethics Committees in India: Past, present and

36 Journal for Clinical Studies

Business Development Manager, Clinical Research Malaysia

Professor Hans Van Rostenberghe Department of Paediatrics, Hospital Universiti Sains Malaysia & Chairman of Human Research Ethics Committee of USM, Universiti Sains Malaysia

Dr. Salina Aziz

Dr. Lee Keng Yee Secretary of Medical Research & Ethics Committee, Ministry of Health Malaysia

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Journal for Clinical Studies 37

Market Report

Developing Effective Supply Chain Strategies Utilising Forecasting Technology Drug development has evolved considerably over recent decades, along with the clinical supply chains that underpin the continued advancement of human health.

In the 1980s, single-country clinical trials – where a single patient kit was provided to each study participant for the duration of their treatment period – was the standard. The introduction of Interactive Voice Response systems in the 90s ushered in a new era in patient randomisation and created more flexibility over supplies. This was followed by the increase of globalisation and emergence of biologics in the ‘00s, which gave rise to today’s more complex clinical trials’ landscape.

While this evolution has made the objective of providing the right drug to the right patient at the right time and temperature more challenging, forecasting technology is playing an increasingly important role in supporting sponsors to mitigate the additional complexity and risk and deliver future leaps forward in drug discovery.

Effective forecasting is the ability to align supply and demand for a trial or program of trials. Failure to meet this objective can quickly result in inefficient supply chain operations that heighten risk of stock outs, product waste, negative patient impact and, ultimately, compromise a study’s commercial performance.

Leveraging supply forecasting and demand planning technology can support sponsors to develop optimised and effective supply chain strategies.

Understanding Supply Harnessing forecasting technology to develop effective supply chain strategy requires a solid understanding of core supply-based factors, so that the supply chain can align with the clinical requirements, as defined in the protocol.

The first factor relates to patient need. This is dictated by the quantity of drug needed to support each patient anticipated to enrol in the study through their whole treatment period. The protocol synopsis provides crucial data to support effective forecasting of patient need, covering cohort, weight-based dosing criteria, visit schedules, and other study design factors.

Production strategy is the second port of call when establishing supply requirements. The timing of when drug is required informs production schedules, packaging design and expiry dating. Again, the protocol synopsis will inform production strategy and resupply events for expiry, along with providing visibility over bulk availability of products and lead times.

on the demand factors. This begins with the clinical enrolment projections that allow sponsors to understand when patients are expected to enrol in a study. Understanding site activation and seeding events will also help align requirements within the forecast.

For instance, establishing whether drug is needed on site prior to screening events or if supply should be conserved until the first patient visit. Another demand factor is patient dispensation events that will make up the visit schedule and dictate the timing of when drug is needed.

The depot and site inventory – resupply strategies and countryspecific study approvals – also warrant scrutiny. Sponsors should work closely with IRT vendors to understand how the drug management section of the IRT has been developed, as this will play a key role in understanding the overall demand and associated implications. Order algorithms will inform look ahead windows for site shipments, how they will be raised and how the available inventory at site is considered against projected need for patients due for site visits.

Thoroughly understanding demand to effectively deliver it requires in-depth knowledge of expiry planning. The timing and quantity of new manufactured lots and expiry extensions will impact on timelines for sites to be reseeded. This is especially important as, in the early days of a study drug may only have six months shelf life so pre-seeded sites may be approaching expiry and need resupply. Exploring how to approach an expiry event – by pulling material into a traditional production run and relabelling it with an updated expiry date or harnessing Just in Time Manufacturing methods utilising an updated expiry date – will help develop the best course of action.

Treatment variations form the last piece of the demand puzzle. If dispensation and dose for patients remain unchanged through the total disease progression, then calculating overall patient demand is more straightforward. However, different titration, dose finding and studies with different cohorts or high dropout rates will require continuous examination to ensure demand is met and drugs are appropriately allocated.

Navigating the Ever-evolving Landscape Evolution is a constant of drug development. When supply and demand factors are appropriately considered, forecasting solutions can be harnessed to build more robust and agile supply chain strategies that empower sponsors to better navigate and respond to change, while avoiding negative impact.

A final supply-based factor relates to distribution strategy and helps sponsors to understand the frequency of depot and site shipments, country-specific supply requirements and temperature management considerations.

For instance, scenario planning tools empower sponsors to conduct ‘what if’ analysis that projects the impact to supply should a study experience accelerated or reduced enrolment or if there is an instance of bulk manufacturing failure. This insight helps to bridge the unknowns with calculated solutions; informing effective decision making and supporting sponsors to develop contingency plans that work to mitigate risk.

Delivering Demand Once supply requirements are understood, sponsors can focus

Likewise, forecasting technology also supports more effective program level planning, as the demand feeds into bulk forecasting

38 Journal for Clinical Studies

Volume 15 Issue 4

Market Report tools – to support different aspects of the supply chain. Considering the data housed in each of these systems is interconnected, creating a closed loop, comprehensive linkage is necessary to streamline efficiencies.

To develop effective supply chain strategies utilising forecasting technology integration between systems must be prioritised to enable data flows that promote automated and optimised processes, while lowering overall supply chain risk.

With integration, study ‘actuals’ can be incorporated into forecast management to drive continued supply chain accuracy as studies progress. For instance, inventory oversight, provided by an ERP, enables a proactive approach to drug supply management and fosters the ability to adjust production plans and distribution strategies for a study or program of work with precision and ease. The risks associated with a reliance on manually updating forecasting tools, such as Excel and manual patient dispensation trackers, with study ‘actuals’ is also removed when data flows seamlessly between core systems.

and highlights the impact of any additional scope of work on the overall drug supply. This means sponsors have visibility over how much additional product needs to be allocated to Phase IV, while Phase III is ongoing. The same is true for production planning and distribution strategy.

It is important to remember that leveraging supply and demand factors and harnessing forecasting technology will only create an effective supply strategy if good data is made a priority. This requires sponsors to ensure full and accurate data is used to create a supply forecast and places an onus on continuous evaluation throughout the life of study.

The Benefits of System Integration As clinical trials become more complex – and IMP more expensive – the margin for error decreases, while the need to promote data integrity, reduce risk and streamline processes increases.

Resultingly, system integration is quickly becoming a prerequisite for successful clinical supply management and forecasting technology has a critical role to play.

This is because dedicated clinical supply forecasting technology provides visibility of bulk product and finished goods and generates projections (or several for comparison) detailing material needs within specific periods of time based on factors, including enrolment rates, site and country ramp up, safety stock requirements, dropout rates, medication type and visit schedules.

Another key benefit of forecasting technology is its ability to receive patient and drug order data, such as enrolment, discontinuation, and drug usage information, directly from an IRT so that forecasts can be automatically adjusted based on drug usage data and reports produced to compare what was initially forecast vs actual usage.

However, this optimised forecasting capability would not be possible without integration within the wider supply chain technology eco-system. Sponsors rely on multiple systems – from ERP and Temperature Management software to IRT and forecasting www.journalforclinicalstudies.com

Other examples of how data flows between these core systems can optimise processes and lower risk can be found in the inventory release process, drug order process and patient and medication event data exchanges. When the inventory release process is aligned with QP processes, sponsors can be assured that drug released to the IRT is matched within the ERP system for allowable countries product can be shipped to. Similarly, when drug orders are raised in an IRT and sent to the distribution team, when picked and dispatched, this information is shared through to the IRT before the order is dispatched to site and order details (complete with temperature monitor information) shared to the Temperature Management System. Finally, when patient and/or medication events take place, IRT systems can automatically pass vital information to the forecasting software, which can in turn harness it to inform updated and relevant forecasting adjustments.

Drug supply forecasting encompasses many moving parts. The key to successful clinical supply forecasting – and the successful delivery of modern clinical trials – can be found in timely and accurate data that is achieved via system integration, dedicated resources to support the development of the clinical supply strategy, and continuous evaluation and oversight of that strategy. Expert application of forecasting systems, that are integrated effectively within the wider supply chain technology eco-system, are critical components in successfully bringing an investigational product to market in what is an increasingly complex and competitive drug development landscape.

Caitlyn Clauss Caitlyn Clauss is Supply Chain Solutions Manager at Almac Clinical Services where she is responsible for enhancing and supporting the Almac Supply Chain Management consultation service. Her main responsibilities include ensuring cohesive delivery of new services and products, maintaining positive and collaborative partnerships among supply chain stakeholders, and leading improvement efforts to ensure optimal service quality and client experience.

Caitlyn graduated from Bloomsburg University of Pennsylvania with a Bachelor of Science focused in Business Management and Supply Chain Operations.

Journal for Clinical Studies 39

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