Science Pool

COVID-19 related delay of clinical research - a shortage in novel drugs?

Among the many fallouts of the COVID-19 pandemic is a disruption of clinical research. Laboratories are closed, conferences have been cancelled, travel is restricted, supply chains for equipment have been interrupted, and resources have been lost. In particular smaller biotechs have or will incur losses as they have to considerably stretch their financial resources and can’t meet milestones.

The biggest effect has been on planned and already ongoing clinical trials of new drug candidates. Thousands of trials have been stopped or called off altogether (an unprecedented event with long-lasting effects on medicine). According to Michael Lauer, Deputy Director for Extramural Research at the US National Institutes of Health, about 80% of non-COVID trials in the U.S. have been interrupted or stopped. A recent world-wide research report by Informa Pharma Intelligence and Oracle Health Sciences revealed that the COVID-19 pandemic has led to longer enrolment timelines (49%), amended protocols (45%), and paused protocols (41%). Also, clinical trials have become more decentralised, i.e. the investigational medical product was shipped directly to the trial participant. 46% of respondents are planning or implementing such decentralised trials, 44% are considering new vendors, and 36% are considering new geographies for trial locations. However, this move is facing challenges such as patient monitoring and engagement, ensuring data reliability, quality, and data collection.

Most people are not aware how many participants and sites are involved in a clinical trial. Apart from the researchers and clinical doctors overseeing the trial and the patients, it’s caregivers and nurses, postgraduate researchers, postdocs, data scientists and people involved in funding and paperwork. Particular problems have been caused by the stress put on hospitals by the admission of so many critically ill patients and the necessity to avoid an infection of trial participants (or vice versa, as well as the staff at the trial sites).

Decentralising clinical trials

Regulators have been quick to react by changing their guidance so that physical distancing has been possible without compromising the safety of patients in testing and treatment. As an example, if possible, trial participants were provided with the test medication for a longer period of time, or the drug was distributed to their homes by a distributor so that they don’t need to visit the trial site – something that is called decentralisation of trials.

Decentralised trials, however, create problems in terms of compliance, medical control and data assessment. Solutions such as telemedicine have been known for a long time, but have not yet been implemented in clinical trials due to administrative and bureaucratic hurdles, cost and reimbursement.

Nevertheless, at least U.S. regulators have accepted patient evaluation and data sampling via remote solutions, either via email, phone calls or videoconferences or by tele-medical monitoring. The same approach has been applied to many COVID-related trials. Even completely decentralised trials have been conducted – from recruiting via social media to medication distribution to data collection. However, researchers have warned that several of these clinical trials lack control groups, have poorly defined endpoints, lack generalisability to those of a lower socioeconomic status or were designed too early in the pathophysiological course of the disease to result in substantive recommendations.

Creating a roadmap for the future of clinical research

The developments described above raise a lot of questions:

• Are design and data of trials conducted during the pandemic solid?
• Can self-reported outcome be equalled to an independent assessment by a specialist?
• Do online recruiting and telemedical assessment increase or decrease patient heterogeneity?
• What impact do concomitant COVID infections and stress caused by social distancing have on side effects and outcome?
• Can telemedicine be implemented in the clinical trial routine in the post-pandemic era to save costs?
• What else can be copied for the future?

At the same time, it is clear to researchers in academia as well as in industry that the way clinical trials are conducted is outdated in many aspects and overly burdened by red tape. Conducting trials can and should be improved and modernised to benefit patients, clinicians, and researchers. Therefore, the pandemic may act as a catalyst for positive changes in terms of recruitment, monitoring and innovation to create a more efficient, integrated research platform for the future.

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Given the arrival of SARS-CoV-2 vaccines, why do we still need therapeutics?

After more than a year into the COVID-19 pandemic, vaccines against the new coronavirus are all over the news. However, there is still a long way to go until people have been vaccinated worldwide, and as yet it is not clear how long the protection will last and whether the different vaccines will protect against re-infection and/or infection against mutated viruses.

Therefore, it is clear that even in 2021 and beyond millions of people will get infected by the virus and many thousands will become critically ill and require medical treatment.

Strategies for making SARS-CoV-2 therapeutics broadly available

Similar to vaccines, biopharmaceutical companies all over the world are trying to develop medications to combat Sars-CoV-2 infections: some are trying to repurpose existing drugs, others are developing small molecules or biologicals such as antibodies against a variety of targets – viral as well as cellular.

Evotec is also participating in this worldwide effort – but with a twist. The goal is to develop a monoclonal antibody that is not only effective, but can also be produced at low cost so that it is ideally suited to be administered even in the world’s poorest countries. And if all goes well, Evotec will also provide small, efficient manufacturing sites that can be operated all over the world.

Already in April last year, Evotec´s U.S. subsidiary Just - Evotec Biologics, Inc. entered into a partnership with Ology Bioservices, Inc. to evaluate and characterize antibodies against SARS-CoV-2. A few months later, in July, Just – Evotec Biologics was awarded up to $ 18.2 m by the U.S. Department of Defense for the development and manufacturing of monoclonal antibodies that might be able to prevent or treat COVID-19. And in September last year, the Bill & Melinda Gates Foundation joined in by granting another $1.9 million to develop and manufacture monoclonal antibodies at lowest possible cost of goods for the prevention of severe COVID-19 in vulnerable populations in low- and middle-income countries.

The concept of decentralised, affordable drug manufacturing

Just – acquired by Evotec in 2019 – was founded in 2015 in Seattle by former Amgen employees with the goal to make the entire manufacturing process of biotherapeutic drugs more efficient and affordable – not only by lowering development costs, but also by establishing smaller, more efficient manufacturing sites. The initial therapeutic focus was on anti-infectives, as infections constitute the biggest problems in poor countries that often don’t have enough money to purchase lifesaving drugs or to support their manufacturing, so lowering the costs of developing and producing anti-infectives are of great importance.

To accomplish this goal, Just is using artificial intelligence and an entirely data-driven drug discovery and development process. Its J.DESIGN technology platform integrates the discovery and optimization of drug candidates, process and product development, and manufacturing with the goal of providing a product that can be manufactured at low cost of goods. Using large, diverse data libraries and machine learning, the platform from the outset screens and designs biologics that can be developed and manufactured under the most favourable development conditions.

The know-how of the company comprises cell line development, upstream bioreactor design (fed-batch or continuous), and the development of downstream purification, analytical methods, final drug product, formulation, and long-term storage.

Just – Evotec Biologics also has developed a small, flexible, low-cost facility solution to biotherapeutics manufacturing called J.POD. This facility can be installed easily wherever production is needed.

As infectious diseases are on the rise across the globe and SARS-CoV-2 will unlikely be the last pandemic affecting the human population, the approach developed by Just - Evotec Biologics will become even more important in the future.

Interested in learning more?

Just- Evotec Biologics´ technologies and services are being offered to clients and partners interested in the fast and cost-effective development of biologics.

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The current Sars-CoV-2 pandemic has shown what a powerful threat pathogens can be to human civilisation. However, not only viruses threaten the human population. Every year, at least 700,000 people worldwide die of drug-resistant diseases, including 230,000 people who die from multidrug-resistant tuberculosis. An increasing number of diseases, including respiratory tract infections, sexually transmitted infections and urinary tract infections, has become untreatable, while lifesaving medical procedures are becoming much riskier. Last year, the U.S. CDC listed 18 antibiotic-resistant bacteria and fungi that are a threat to humans. Novel anti-infectives are urgently required to address this unmet medical need.

Evotec is dedicated to the fight against resistant pathogens and the development of novel anti-infectives. In 2018, the Company acquired Sanofi´s infectious disease unit and thereby laid the foundation for accelerating an comprehensive R&D portfolio to combat infectious diseases. Moreover, the Company entered into a five-year partnership with the Bill & Melinda Gates Foundation in June 2019 to discover new treatment regimens that better address tuberculosis (“TB”), a severe global health burden and one of the leading lethal infectious diseases worldwide. Also in 2019, Evotec and Lygature announced their cooperation in a new initiative for the development of novel antibacterial agents against Gram-negative bacteria called “GNA NOW”.

In August 2020, Evotec entered into a new partnership with Resolute Therapeutics to combat infectious diseases and antimicrobial resistance. 

Evotec has established a leading-edge platform enabling the discovery and development of new therapies and therapeutic approaches to treat and prevent serious and life-threatening infections. The Company´s anti-infectives platform includes

• EvostrAIn™ – An extensive range of geographically diverse human pathogenic bacteria and fungi including isolates that are susceptible and resistant to current antimicrobial drugs.
• In vitro and in vivo microbiology encompassing Gram positive and Gram negative pathogens (including anaerobes) in a wide range of animal models with a broad range of endpoints.
• Translational in vitro and in vivo PK/PD and mathematical modelling with emphasis on in vitro Hollow Fibre Systems to mimic defined drug exposure profiles.
• In vitro and in vivo virology, focusing on respiratory viruses such as RSV, HRV, influenza virus and human coronavirus (enabling COVID-19 work).
• In vitro and in vivo mycology: human pathogens including Candida spp. Aspergillus spp. and parasitology

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PK/PD modelling is an important aspect of dose prediction of antibiotics for both preclinical and clinical development and is a requirement of both the European Medicines Agency (EMA) and US Food and Drug Administration (FDA). This technique facilitates efficient dose-response study designs and assists in identifying optimal dosing regimens to ensure clinical efficacy and to suppress drug resistance.

Cyprotex is increasingly supporting its parent company, Evotec, in the modelling and simulation area. For example, mathematical modelling techniques have been applied in the rational design of antibiotic efficacy studies to reduce the number of animals required to determine the magnitude of efficacy and pharmacodynamic driver and promote acceptance of such data by regulatory authorities.

Our research poster, titled Pharmacokinetic/Pharmacodynamic Modelling of Antibiotic Efficacy, was presented at the Alderley Park 3R’s Poster Event on 17th October 2018. The event was jointly hosted by AstraZeneca, Cancer Research UK and Agenda Life Sciences. The poster was awarded 1st prize in the event for its contribution to the 3R’s concept of Replacement, Reduction and Refinement.

The contemporary definitions of the 3Rs are:
• Replacement: accelerating the development and use of models and tools, based on the latest science and technologies, to address important scientific questions without the use of animals.
• Reduction: appropriately designed and analysed animal experiments that are robust and reproducible, and truly add to the knowledge base.
• Refinement: advancing animal welfare by exploiting the latest in vivo technologies and by improving the understanding of the impact of welfare on scientific outcomes.

In silico modelling and simulations can be used to improve study designs leading to a significant reduction in the number of animals required to achieve experimental objectives.

You can read more in our poster.

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