The effect of Covid-19 solutions on the clinical trials process

Shelley McLendon, VP of Project Management, Vaccines and Infectious Diseases at ICON, outlines best practices that can keep trials running at optimal speed and efficiency, and the benefits of adopting a strategic partnership. The world responded to the Covid-19 crisis at unprecedented speed — including vaccine development. During a pandemic, timing is critical as the virus claims lives, overwhelms healthcare systems, and destabilises the global economy. In response to the urgent need, researchers are running more than 1,300 clinical trials on a number of antivirals, antibodies and vaccines for SARS-CoV 2, since March 2020. Even in the best circumstances, vaccine trials for respiratory viruses present operational challenges. These hurdles are exacerbated by a pandemic created by a novel virus, such as SARS-CoV 2. For example, due to restrictions on movement and stay-at-home orders, trials will need to have fewer on-site visits for participants. As a result, during study design and planning, thought should be given to procedures required (physical exams, vital signs, etc.), the number and frequency of blood sample collections and conducting wellness/safety visits by phone versus on-site. Adding to the operational challenges is the fact that respiratory and seasonal vaccine studies are already moving more quickly and have a narrower timeframe for study execution than regular studies. Moving at lightning speed, the scope and timelines of pandemic studies require stringent quality levels, as well as expertise, as there are steep training curves with limited ability to learn on the job. Moreover, unlike other clinical trials, vaccine studies often don’t have “wiggle room” in a timeline for site activation, volunteer recruitment, vaccination and following up with hundreds to thousands of subjects. Therefore, special considerations need to be made when designing and executing vaccine trials, especially under tight deadlines and regulatory scrutiny. Conducting these trials takes a collaborative effort among stakeholders — regulatory, pharma and biotech, patients and sites — to get these trials on track and moving forward, and products approved as quickly and as safely as possible. Understanding best practices for vaccine studies Respiratory pandemic vaccine studies have extraordinarily compressed timelines, with potentially serious consequences for any delay or lack of attention to detail. Efficient study start-up is critical to success, and, therefore, sponsors should work to stabilise protocols quickly and determine in which countries a trial will run. These decisions will impact the selection of a contract research organisation (CRO), labelling, shipping, importation and distribution requirements and timelines. One of the most important aspects when planning a pandemic study is addressing possible contingencies. For instance, trial support staff must prioritise the study and think “outside of the box” for how best to expedite tasks such as protocol writing, regulatory and IRB submissions, site contracting, Interactive Web Response (IWR), electronic data capture (EDC) and other systems set-up. While ensuring Good Clinical Practices (GCPs), researchers and sponsors must also consider new approaches for routine activities, documenting these carefully in study plans. Specifically for a vaccine efficacy study, it is important that the last subject be enrolled and vaccinated about four weeks before the anticipated start of the infection’s spread and well in advance of the disease peak. Vaccine trials require a coordinated approach that accounts for contingencies, properly manages risk, holds to a tight schedule and applies best practices developed through years of experience, including: Designing robust monitoring plans to adapt to various and changing sites’ needs Agility and creativity in problem-solving to ensure rapid execution, while maintaining high-quality performance and documentation Careful planning, strong communications and close collaboration between the sponsor, CRO, sites and other vendors Quick decision-making and resolution skills. Short response times to inquiries, ideally within the same day Prioritising the study within the organisation with internal advocates and leadership support Selecting sites that are experienced in vaccine studies and have proven capabilities Taking extraordinary steps to ensure the availability of the study vaccine and any comparator Aggressively addressing any unanticipated delays Using a robust system for tracking progress and gathering data Addressing a high volume of data and documents. (Developing a statistical analysis plan should be set prior to the first subject randomised) Success factors for Covid-19 studies In addition to the best practices outlined above, Covid-19 vaccine studies warrant further considerations. Because of social distancing measures, standard on-site visits may not be possible. As such, sponsors should consider incorporating risk-based monitoring (RBM) and alternative site solutions, such as remote visits and telemedicine. Additionally, sponsors should address contingencies in the manufacturing plan. The leading reason for enrolment challenges and failure to meet first subject in (FSI) dates are delays in supplying sites with the test and/or comparator vaccine. When developing new vaccines in a pandemic situation, manufacturing might be difficult as the first batches don’t always pass the quality control/quality assurance processes, often delaying study start-up. Transparent communication is critical so all parties can make needed adjustments and prepare for the study to start as soon as the vaccine is shipped. Typically, studies take six to 12 weeks to set up and test systems, including eDiaries, electronic data capture (EDC), interactive response technology (IRT) and electronic trial master files (eTMF) so these systems are live prior to the first subject randomised. With the compressed timelines of a Covid-19 vaccine study, careful and thorough user acceptance tests (UATs) will be of the utmost importance. In addition, all support systems, such as a help desk, need to be fully prepared for the volume of activity that will be required upon study start. Lastly, during a pandemic situation, RBM is well suited to reduce costs and assist study teams in focusing on subject safety and the integrity of endpoint data. Easing the regulatory burden During uncertain times, regulatory guidelines are constantly evolving. Various regulatory agencies, including the European Commission, the European Medicines Agency, the Head of Medicines Agencies and the U.S. Food and Drug Administration (FDA) have all published new recommendations on how to manage clinical trials amid Covid-19. To accelerate the development of Covid-19 treatments and vaccines in general, institutional review boards (IRBs), ethics committees and regulatory authorities are expediting timelines. Understanding that patient safety is a priority and that all changes and risks will be documented and assessed, regulators aim to allow: Accelerated clinical trial start-up Compassionate use Accelerated agency and ethics approval timelines Less stringent reporting requirements, product import rules and patient supply measures Managing sites Sites will need to quickly prepare for the vaccine (and/or the comparator vaccine) and any ancillary study supplies, with the understanding that they may be in short supply. Most vaccines must be distributed via a cold chain, and provisions need to be in place to replace any product quickly that might be affected by a temperature change, so as to prevent recruitment delays. Sites will also need to consider delivery planning and storage capabilities to ensure no interruption of study recruitment. When handling vaccines and lab specimens, sites must have centrifuges and refrigerators/freezers. Due to risk of infection to site staff or other volunteers, sponsors should ensure sites will have necessary personal protection equipment within the clinic. Understanding a site’s capability for alternative approaches to monitoring is integral to qualify sites, conduct investigator meetings, and perform site initiation visits and routine monitoring visits. Sites must receive thorough and consistent training, which can be augmented with systems such as FIRECREST, ICON’s digital solution for providing online training. The large quantity of subjects and the use of patient reported outcomes for reactogenicity — either with paper diaries or eDiaries — produce large volumes of data that must be entered and cleaned quickly. Sites must be prepared to enter the data in real time, and the data management team must perform in-stream data cleaning to review data as backlogs can escalate quickly. Optimising enrolment Typically, with enrolment, a country-level cap is established to ensure that enrolment goals are met and slower enrolling sites do not compromise the completion of on-time enrolments. Yet, with a Covid-19 study, eliminating caps should be considered. Depending on disease spread, site capabilities and changing needs, some sites may suddenly be unable to participate, such as a site suddenly having to close due to an outbreak among its staff. Monitoring and study documentation Covid-19 studies require new approaches to monitoring beyond the standard RBM and on-site visits. New strategies, such as leveraging remote monitoring and technology to conduct visits to verify facilities, as well as selecting sites that are flexible and open to different approaches to monitoring, will ease burdens. Due to volume, failure to keep reporting and filing up to date and reviewed for quality can snowball, prolonging study close and compromising study integrity. Therefore, selecting sites with an FDA-compliant eReg system in place is optimal. Managing data complexity Data will need to be cleaned continuously as it comes in, rather than waiting until a study closes out. Data reviews and laboratory data transfers should also be ongoing with the database lock plan created in advance of the last subject, last visit. Lastly, cybersecurity measures should be taken in order to ensure patient safety and privacy. Preparing for global HTA / reimbursement requirements With the ongoing impacts of the Covid-19 pandemic, we expect a current and immediate term shift towards evidence assessment of antibiotics, antivirals and vaccines by HTA bodies. For drug developers with programmes and products in those drug classes, it would be pertinent to shore up their research and focus on demonstrating value within both mainstream and unusual scenarios. For those with development programs that are currently de-prioritised, we propose using this time to fill data gaps with real world data, expert opinion and indirect treatment comparisons that will strengthen their case when the time comes; particularly as health systems will have been depleted of financial resources and potentially need to apply more stringent assessment to counter these constraints. Adopting a partnership Over the past decade, researchers have accelerated vaccine research with gene sequencing, furthering the development of mRNA and DNA vaccine platforms, along with novel adjuvants for more traditional antigen-based products. These advancements have enabled biopharmaceutical companies, regulatory agencies, CROs and other stakeholders to respond to infectious disease outbreaks by fast tracking the development of vaccines and treatments at ground-breaking speed. Regardless of the phase, a vaccine clinical trial designed to address a pandemic must contend with an aggressive calendar, rapid influx of data, competitive recruitment for sites and participants, complex supply logistic, a demand for active surveillance and monitoring, and regulatory challenges. Successful pandemic studies require collaboration, transparency and agility, along with a deep understanding of clinical research. With the right knowledge and experience, leveraging strategic partnerships can help to manage and execute clinical operations, even amid the most uncertain times. About the author Shelley McLendon, Vice President, Project Management, Vaccines and Infectious Disease. McLendon has more than 25 years of clinical research experience, 19 of which are tenured at ICON. Shelley provides executive leadership and oversight for ICON’s clinical and project management teams in the implementation and execution of vaccine and infectious disease clinical development programs. She also consults with small to mid-size biotechnology clients and large pharmaceutical companies providing strategic operational guidance and driving partnership development. Shelley is a key leader of ICON’s COVID-19 Taskforce which is cross-functional team of ICON executive leaders whose mission is to make a difference by advancing research in the fight against COVID-19.