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Applied Clinical Trials January/February 2021

Celebrating its 12th successful year, SCOPE Summit 2021 takes place March 2-4,2021 as a fully virtual event. During these difficult times of a global pandemic, the work this clinical research community does is more important than ever and requires collaboration and innovation.

Events

SCOPE 2021 — 3/2-3/4

Medable Inc. has announced a new partnership with Seqster to integrate real-time, real-world data streams into decentralized clinical trials in efforts to improve trial recruitment and participation.

“Patients want clinical trials to fit into their real-world experience, not the other way around,” said Dr. Michelle Longmire, CEO and co-founder of Medable. “Working with Seqster, we can integrate data sources and data streams to provide clinicians with a more holistic view of patient health.”

Medable and Seqster are also partnering with Datavant to integrate and link de-identified data across the entire patient journey, including electronic health records, claims, and diagnostics, as well as emerging sources such as genomics, wearable devices, socioeconomic and behavioral data and more.

Articles

Medable Partners with Seqster to Integrate RWD into Decentralized Trials

Despite shortages in critical components and experienced staff, vaccine manufacturers anticipate significant boosts in output in the coming weeks for these innovative products. The companies with the first Emergency Use Authorizations (EUAs) for vaccines to combat the pandemic produced only 63.7 million doses as of January 31, 2021, far less than the initial goal of 300 million doses, raising skepticism of even meeting the 200 million-dose goal for the end of March 2021. But in recent weeks, the prospects for greater vaccine output have brightened, and the entry of Johnson & Johnson into the market should help. To prevent future production delays of critical products, the Biden administration is examining supply chain vulnerabilities for pharmaceutical ingredients as part of a longer-range consideration of products important to public health.

Efforts to expand production of vaccines to combat COVID-19 have had to overcome a wide range of shortages in materials, qualified facilities, and experienced workers such as engineers and quality control managers. A particular problem is scarce supplies of the ionized lipid nanoparticles needed for the Pfizer-BioNTech and Moderna mRNA vaccines. Only a handful of companies previously produced very small amounts of lipids, most for clinical trials involving rare disease treatments. More contract manufacturers now are licensing the lipid technology, but production scale-up has been a slow process. In addition, finish-fill operations have emerged as serious bottlenecks due to shortages affecting key components for new and revised operating lines plus requirements for high levels of sterility.

At a recent hearing before the House Energy & Commerce subcommittee on Oversight & Investigations, leading vaccine makers outlined efforts to enhance production and packaging processes. Pfizer chief business officer John Young summarized company plans for boosting vaccine shipments from 5 million to 13 million doses per week by the middle of March. Similarly, Moderna president Stephen Hoge outlined efforts to deliver millions of doses by the end of March and other increases leading to a total of 700 million doses this year.

Johnson & Johnson now expects to provide 100 million doses of its single-dose adenovirus vaccine by the end of June 2021, starting with 20 million doses by late March, following FDA granting Emergency Use Authorization (EUA) for the product. Janssen vice president Richard Nettles described for the House committee how the company had to assess nearly 100 potential production sites to find eight able to support its accelerated development timeline. Drug substance production takes about two months and is being done at Emergent BioSolutions in Maryland and at Janssen’s Netherlands plant and another facility in India, Nettles explained. And another five to six weeks are needed to produce, test and release the drug product, which is occurring at U.S. sites in Indiana, Michigan and Pennsylvania, plus operations in Spain, Italy, India and Africa.

Pfizer/BioNTech now projects 2021 global production to reach 2 billion doses, almost double early estimates. Some of that increase is due to FDA approval for extracting 6 doses per vial, as opposed to 5 doses originally approved. Pfizer CEO Albert Bourla provided further details on company production scale-up in conjunction with President Joe Biden’s visit to Pfizer’s Kalamazoo, MI manufacturing facility on February 19, 2021.

 Bourla cited plans to add new formulation suites and lipid production in Kalamazoo and at its research site in Groton, CT. Additional finish/fill lines have been established at its McPherson, KS site. This expansion, together with contracts with two additional U.S. contract manufacturers and improved processes, will enable Pfizer to reduce the time needed to produce vial-ready product from 110 days to 60 days. Innovations involve doubling batch size to increase yield and utilizing more efficient lab test methods to reduce release times.

In addition, Pfizer’s vaccine will be easier to ship and store with FDA approval of higher temperatures—that is sub-zero (-15 to -25C), as opposed to the ultra-cold level initially authorized. That change is based on stability studies conducted over the past nine months and should facilitate distribution to pharmacies and smaller health facilities.

Moderna’s production gains arise from added efficiencies in creating batches of the drug substance at its facility in Norwood, MA and at the Portsmouth, NH plant operated by contract manufacturing partner, Lonza, Ltd. Moderna also is expanding its fill-finish process agreement with Catalent and looking to contract with another partner. And the company expects to speed up manufacturing runs with FDA approval of providing 15 doses per vial, filling up the empty space in vials that currently hold 10 doses.

The difficulties for manufacturers in securing critical ingredients for vaccine production, packaging and delivery has prompted the Biden administration to assess the situation as part of a larger review of shortages related to components of critical industrial products. In an Executive Order issued Feb. 24, 2021, President Biden initiated a comprehensive review of supply chain risks for active pharmaceutical ingredients (APIs), critical minerals, semi-conductors and large-capacity batteries.

 The aim is to identify factors underlying shortages and supply interruptions of these products and steps the government can take to address relevant problems in the short term. Pharmaceutical products are considered particularly vulnerable in a pandemic or other global crisis due to the high proportion of offshore production of APIs.

To reduce such problems in the future, the White House plans to examine more broadly U.S. supply chain issues related to products important for public health and biological preparedness, as well as for national defense, communications technology, food production and the industrial base for energy, transportation and communications sectors. Federal agencies will review goods and materials vulnerable to supply chain disruptions, locations of key manufacturing and production assets, the availability of alternative sources for critical goods, and issues arising from a failure to develop needed domestic capabilities. This initial review of supply chain vulnerabilities leaves off the more strident “Buy American” rhetoricof the Trump administration, but it opens the door to further initiatives to support more “on-shoring” of biopharmaceutical production.

https://energycommerce.house.gov/committee-activity/hearings/hearing-on-pathway-to-protection-expanding-availability-of-covid-19

https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2021-02/Biden%20Visit%20Press%20Statement%20-02.19.21.pdf?0_.cWRfs1JDNo1JfJR9EQHDmb7.Okaa2

https://www.whitehouse.gov/briefing-room/statements-releases/2021/02/24/fact-sheet-securing-americas-critical-supply-chains/

Vaccine manufacturers anticipate significant boosts in output in the coming weeks.

COVID-19 Vaccine Makers Overcome Challenges to Ramp Up Production

CISCRP 3rd Annual Medical Hero Appreci-a-thon — 3/1-3/31

CISCRP is hosting the 3rd annual Medical Hero Appreci-a-thon virtual fitness challenge, March 1st-31st. This team building challenge celebrates all “Medical Heroes”—medical, health care, research professionals, and study volunteers. Invite your friends, family, co-workers to join you in this virtual fitness challenge across the beautiful route through the U.S. National Parks. You can log any type of intentional activity to advance along the route. You’ll visit parks such as Yosemite, Rocky Mountains, Grand Canyon, Acadia, Yellowstone, and more!

https://www.ciscrp.org/events/med-hero-virtual-appreci-a-thon-2021/

Otsuka Pharmaceutical Development & Commercialization, Inc. (Otsuka) and Click Therapeutics, Inc. have announced the initiation of the Mirai study, a fully remote clinical trial to investigate the effectiveness of digital therapeutics in reducing depressive symptoms in adults diagnosed with major depressive disorder (MDD) who are on antidepressant monotherapy.

The randomized, controlled trial will enroll up to 540 patients nationwide. Trial participation will be 10 weeks and efficacy will be evaluated as a change from baseline in the Montgomery–Åsberg Depression Rating Scale (MADRS) total score.

Otsuka and Click will collaborate with Verily, a subsidiary of Alphabet, to execute the trial as a fully remote trial. The collaboration with Verily provides tools and technology to engage patients and clinicians.

Otsuka and Click Therapeutics Initiate Fully Remote Trial in Adults With MDD

Calyx has announced a scientific consulting program aimed at optimizing imaging processes and outcomes to accelerate the clinical development of new medical treatments.

Calyx Scientific Consulting delivers a range of services to meet the needs of new product development, including:

Evaluating whether imaging is required based on specific endpoints

Selecting imaging biomarkers to best demonstrate safety and efficacy at each trial phase

Choosing the ideal image acquisition strategy to best support biomarker requirements

Calyx Offers Scientific Consulting

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

The European Union is still beating itself up for its failings in countering COVID, and the latest initiative to emerge in its bid to remedy the deficiencies is destined to make some early changes to the rules on medicines marketing, and to bring in some longer-term changes to clinical development too. The project, known as HERA—a classic EU non-abbreviation, this time for the European Health Emergency Preparedness and Response Authority—is now taking shape, with multiple objectives that will overall, according to the European Commission proposal, be a systematic response to "revealed vulnerabilities in global supply chains, and insufficient oversight of manufacturing capacities and research priorities in the EU."

EU leaders have been calling for urgent action, ranging from better epidemiological data to mobilizing research funds, and for regulatory flexibilities to accelerate the development of vaccines and therapies, as well as more joint procurement programs for critical supplies. They have openly acknowledged their admiration for the example shown by the US Biomedical Advanced Research and Development Authority in accelerating the development of countermeasures and boosting manufacturing capacities when needed.

So, HERA is going to come into being, as a complement to the European Center for Disease Prevention and Control and the European Medicines Agency. And in the meantime, a series of immediate actions "will test a number of solutions that could serve as a blueprint"—looking particularly at emerging biological threats to human health and antimicrobial resistance. One of these is the 'HERA incubator', presented as a concept in mid-February. This will provide new money for genomic testing, more agile approval procedures, and pressure for industry to boost production capacity. Sourcing vaccines from beyond the EU and support for transfer of technology are also entertained as options.

One of the first changes likely to take effect will be faster regulatory processing of vaccines adapted to tackle COVID variants. Based on current EU procedures for approving annual influenza vaccines, it will permit release on a smaller set of additional data submitted to the European Medicines Agency on a rolling basis, with early guidance for developers on data requirements. Central to this approach is a "new category of emergency authorization of vaccines at EU level with shared liability among member states". The real novelty is the sharing of liability. At present, member states can give deliver national-level emergency approvals on the basis of only limited data—as Hungary has done for the Russian Sputnik vaccine—but each country that chooses this route must cover any liabilities that arise from the product's use. By giving such approvals formal EU status, the liability would be borne by all member states—which would, it is calculated, allow more rapid EU-wide response. To further ease supply, certification of new or repurposed manufacturing sites for vaccines will be pushed through faster, with early involvement of regulatory authorities.

Early responses to the EU thinking have been broadly favorable from stakeholders directly involved in drug development or regulation. The European affairs department of the French government has lent its support to the project, and the Danish government gave its backing, although with a warning against uncertainties arising from overlapping tasks—a view echoed by the German Medicines Manufacturers‘ Association, BAH.

Johnson & Johnson rapidly welcomed the proposal, urging large-scale investments in research and development for new vaccines, therapeutics, diagnostics and devices. "HERA should be equipped to collaborate throughout the entire process for the discovery, development, production, and deployment of effective countermeasures for future health crises, including pre-clinical and clinical development, manufacturing scale-up and validation, regulatory interactions and submissions, procurement and potential stockpiling," it said. GSK said it was ready to cooperate, via its network of 14 manufacturing and four R&D facilities across the EU and applauded the concept of a streamlined approach to development. It recommended funding HERA to carry out R&D and clinical development projects with appropriate research, industry and regulatory experts on its staff. EUCOPE, the lobby for Europe's smaller research-based drug firms, threw its weight behind closer coordination and cooperation, particularly for greater regulatory flexibility, and for the development and manufacturing of specialized medicines and vaccines for that are not viable without financial securities and regulatory collaboration.

In a detailed response, the main European drug industry association, EFPIA—together with its specialist Vaccines Europe section–endorsed the need for "a robust, resilient and agile ecosystem to anticipate and effectively manage pandemics and their consequences," and welcomed the ambition to create HERA. "What is needed most for effective emergency preparedness and response is a system that is connected, responsive and collaborative, as innovation and opportunities to address health threats may come from unexpected areas," it said. HERA could be both a central actor and a systems designer, working with health authorities and the private sector, it suggested. That will need "clear structures to address the existing gaps in supporting late-stage development and manufacturing." But it warns of the risk that such a complex structure "implies hurdles, which might reduce the speed of decision-making," so tools will be required "to eliminate redundant bureaucratic procedures and guarantee the necessary flexibility and speed to act." At the same time, the new authority should have strong ties with international agencies such as WHO or BARDA, to avoiding unnecessary competition and overlaps.

The process of creating this new agency is not going to run rapidly, since the EU has its own lengthy consultative and legislative machinery that must be satisfied. But just at the end of February, EU leaders gave a renewed jolt to the reflections, devoting an entire day of one of their summit meetings to beefing up Europe's response to COVID. EU Council President Charles Michel's invitation letter to the heads of state and government of the 27 member countries was unambiguous about the urgency: the situation "remains challenging due to the emergence of new variants," but "our priority continues to be to speed up vaccinations across the EU." Central to the discussions, he insisted, would be the issues around "accelerating the authorization process of vaccines, as well as their production and delivery," and "solutions to bring manufacturers across supply chains together in order to scale-up production in the EU."

It won't be the first time that EU leaders have been asked to act rapidly on an issue of crucial importance for Europe and its citizens—and their record has not always been perfect in coming up with the required responses. But this is the first time they have been asked to move fast against the background of a mounting toll of death and disease that their actions could prove to be literally vital in arresting.

The latest initiative against COVID, the European Health Emergency Preparedness and Response Authority, is taking shape with intentions of revealing the vulnerabilities in global supply chains and more.

Europe's Leaders Still Discussing How to Respond to the COVID Pandemic

There is arguably not one industry that has not been touched by COVID-19 in some way, with clinical trials—and the professionals responsible for their success—faced with constantly changing operations and patient enrollment. When not managed correctly, these rapid changes can have an adverse effect on the timeline of a trial, which can be critical for those who may rely on the not-yet-released drug for life-saving care.

These conditions will continue to be uncertain for the foreseeable future, so sponsors have little option other than to take an agile approach. Likewise, the work of talented and skilled clinical research associates (CRAs) is perhaps more vital than ever, as they are on the front lines navigating how the evolving clinical landscape impacts them and patients alike—including how to safely travel to and from study sites.

This article will present a top-down analysis of the decentralized trial model’s benefits and impact on the industry, as well as its narrow impact on the CRAs responsible for monitoring clinical sites to ensure testing and data integrity.

The first step in successfully adjusting clinical trial operations during COVID-19, or any pandemic event, is to think differently across all aspects of trial operations, including site visits and data collection, among others. Most importantly, these considerations should place patient safety and centricity, as well as employee safety, among its top priorities.

 arguably provide the most value in addressing the questions at the center of sponsors’ minds during this time. From improving patient experience to increasing patient retention and data quality, the different levels of decentralization offered allows for a personalized and streamlined solution based on the specific needs of trials and programs.

It is important to note that a Risk-based Quality Management (RBQM)

 foundation is required, as it focuses on identifying the critical data, processes, and potential risks unique to each trial. Once identified, sponsors can then determine the appropriate monitoring strategy, choosing virtual or hybrid model for their trial, as well as implementing strategic plans for remote and central monitoring, technology, integration, IP management, and site and patient engagement.

Clinical study staff and the decentralized model

Patient centricity and study logistics are essential components of a clinical trial, neither of which could be operated successfully without the expertise and time offered by dedicated CRAs and other study staff. From project initiation through site selection and activation, clinical operations teams ensure first patient first visit (FPFV) goals are met by conducting a thorough feasibility process and onsite qualification visits. Likewise, they keep a close eye on recruitment and retention, data quality, protocol deviations, and more to make sure that database lock happens promptly following last patient last visit (LPLV).

When COVID-19 hit, the traditional clinical trial site was turned on its head, both for study staff and patients alike. Perhaps the most significant roadblock staff have faced thus far in the pandemic is the lack of resources available. Due to the confidential nature of clinical information and the need for procedures, these resources were not available for sites that had closed and transitioned to remote work. For these trials, the lack of resources would bring about slight delays in getting certain tasks completed, such as IP accountability which must be captured on site. 

Whether sponsors choose a hybrid or virtual model, CRAs and other management staff take the brunt of following through on these operational changes, especially as they relate to clinical monitoring. In a quality-driven, risk-based approach, the schedule of visits relies on the judgement of the study team and access to the risk control measurements. This streamlined approach to the clinical trial monitoring process can reduce the burden of on-site visits for the sites, as well as the overall monitoring budget, while not sacrificing the quality of the data.

Likewise, each site will have its own set of procedures that must be followed. For example, a CRA may have to request an on-site visit two weeks in advance and can only proceed after receiving approval. On the other end of the spectrum, the clinical monitoring process may more heavily rely on remote/electronic approaches, such as the use of an electronic data capture system (EDC).

Regardless of which COVID-19-related procedures are implemented, study management staff must also make sure they document these changes by updating study plans and protocols throughout the trial or program (i.e., project management plan, clinical monitoring plan, etc.). This is crucial for ensuring compliance and generating reliable data to support study endpoints.

From sponsors to study staff and patients, every stakeholder in a clinical trial has been and will continue to be impacted by the operational changes brought about by COVID-19. It is important to note that the possibility of more on-site visits will likely be delayed as we continue to adapt and recover over time. However, even before the pandemic, the clinical research industry was constantly evolving and innovating to meet the needs of—so it is well-equipped to master the management of any roadblocks they may encounter now and into the future. Perhaps the greatest lesson we can learn from these changes is the importance of communication and cohesion among sponsors and study management staff to ensure success and confidence amidst pandemic-era operations.

is the Associate Director of Clinical Monitoring at Rho

https://www.rhoworld.com/considerations-for-implementing-decentralized-clinical-trials/

https://www.rhoworld.com/services/risk-based-quality-management/

A top-down analysis of the decentralized trial model’s benefits and impact on the industry

Navigating a Decentralized Trial Model and the Changing Clinical Landscape During COVID-19

ICON PLC has agreed to acquire PRA Health Sciences Inc. PRAH, 18.41% in a cash and stock deal valued at about $12 billion. Under the terms of the deal. Icon will pay $80 per share in cash plus 0.4125 shares of Icon stock for a roughly 30% premium over PRA's closing price Tuesday.

The deal is expected to close in the third quarter. The combined company will be headquartered in Dublin and continue to be led by CEO Steve Cutler, and CFO Brendan Brennan.

ICON to Acquire PRA Health Sciences

AiCure and OncoBay Clinical have announced a partnership to provide oncology sponsors with scalable, AI-powered insights. A subsidiary of the Moffitt Cancer Center, OncoBay will make AiCure's proprietary AI platform available for oncology trials, aiming to provide sponsors and sites with a more holistic understanding of patient health and site optimization.

The oncology drug pipeline has grown by 63% since 2013, but the average success rate of oncology drugs is only 3.4%. To address this discrepancy and the unique challenges of oncology trials, particularly given the complex treatment regimens, AiCure and OncoBay aim to improve patient support and trial retention, while also providing sponsors and sites with greater visibility into patient behavior. Through AiCure's patient engagement solution, Patient Connect, oncology sites can remotely monitor patients and use real-time communication tools to guide them through treatment protocols, including which medication to take and when, as well as allow direct access to a clinician.

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Applied Clinical Trials January/February 2021