by Jane Nicholson

Luigi Martini, Chief Scientist at the Royal Pharmaceutical Society chaired an EIPG Symposium on the lessons learned from the pandemic and how pharmacists can shape the future in a post-COVID era.

To coordinate the development, authorisation and safety monitoring of therapeutics and vaccines intended for the treatment or prevention of COVID -19, a Task Force was established in April 2020 commented the first speaker, Fergus Sweeney, European Medicines Agency. The EMA is providing guidance for medicine developers and pharma companies to help speed up medicine and vaccine development and how regulatory challenges arising from the pandemic should be addressed. In addition, the Agency is acting as the central coordinator to support Member States in preventing and reducing possible disruptions to the supply of medicines during the pandemic. The EMA is a leading member of the International Coalition of Medicines Regulatory Authorities (ICMRA) involving more than 30m countries and WHO. It is holding bi-weekly policy teleconferences, regular working group meetings and workshops. Regulatory agility, work on vaccine confidence, virus variants, inclusion of pregnant and lactating women in trials and pharmacovigilance collaboration are all under discussion as well as digital transformation of GCP and GMP inspections and clinical trials.

The EMA has opened its procedures to non-EU Authorities (OPEN Initiative) and are sharing scientific expertise, tackling common challenges and enhancing transparency on regulatory decisions. A pilot was launched in December 2020 for Covid-19 vaccines and therapeutics. Authorities in Australia, Canada, Japan, Switzerland and the WHO are participating in the assessments of the Committee for Medicinal Products for Human Use (CHMP) with experts keeping full scientific and regulatory independence, existing confidentiality arrangements and with no role in final Committee decisions.

The Good Manufacturing and Distribution Practices Inspectors Working Group (GMDP IWG) have agreed some regulatory flexibility until the end of the COVID-19 restrictions. These are published in Q and A guidance on the ec.europa website and include automatic extension of validity date for GMP certificates, product specific GMP flexibilities for crucial medicines and non- product specific GMP,GDP and PMF ( plasma master file) specificities. Dr Sweeney discussed distant assessment, cooperation between regulators on post authorisation changes and the challenges of rapid building of manufacturing capacity and the global nature of development and manufacturing.
Looking to the future, he considered a, leaner post-approval change management, harmonisation of data standards, descriptive information assessment and inspection and realisation of the benefits foreseen in ICH Q10 and Q 12. However, he considered that extensive future work with all stakeholders will be needed to bring this about.

For international coordination needed to encourage conduct of large, decision-relevant COVID-19 clinical trials, guidance on the management, methodological aspects and GCP renovation has been proposed and a reflection paper is available for comment. This will modernise ICH E8, clinical trial design principles and ICH E6, GCP clinical trial conduct principles. It is about doing things differently and not just adding more to the status quo and should link to and emphasise ICH E8 focus on achieving quality by good design. Change management is the greatest challenge and adjusting behaviours and attitudism away from preconceived ideas and interests and on to a new better way of working is needed. An evolving regulatory landscape, the accelerated use of digital tools and increased dialogue along the development pathway needs reflection and selection of what works concluded Dr Sweeney.

Speaking from Cambridge, Massachusetts, Derek O’Hagan, Global Head of Vaccine Chemistry and Formulation GSK discussed advances in formulation development strategies for vaccines and what is next. He explained that technological advances continue to expand the range of possible vaccine targets from the old empirical approach (diphtheria, rabies and polio ) to glycol-conjugates (Guillain-Barre, pneumococcal) reverse vaccinology (meningitis B , C.difficile) to new technologies with adjuvants and RNA vaccines.

He noted that adjuvants have been used safely for 100 years and can enhance and extend immune response. GSKs adjuvant systems have been formulated for vaccine delivery but they also contain immune potentiators. An example is an AS01 adjuvant vaccine against Herpes Zoster (shingles). Another such adjuvanted vaccine is AS03, H5N1 influenza vaccine which is much more potent than the same vaccine unadjuvanted. AS03 fulfills several criteria required to be an adjuvant of choice for pandemic vaccines as it enhances immune responses, broadens the response, is antigen sparing and has an acceptable safety profile. GSK is collaborating with several companies on Covid and AS03.

An alternative approach is mRNA vaccines which involve chemically modified nucleotides (e.g. Moderna vaccine). An improvement is self-amplifying mRNA (SAM) vaccines. Self -amplifying mRNA makes many copies of itself intracellularly with the advantage that it produces multiple copies of RNA and an enhanced immune response. SAM drives early and persistent antigen expression versus conventional mRNA in vivo. However, SAM represents a unique delivery challenge including protection against degradation in vivo, facilitating uptake into target cells and enabling endosomal escape. RNA vaccines can simplify product development and enable the rapid production of safe and effective vaccines. They eliminate biologicals in production and have no cell lines to cause problems. There is a generic platform approach to manufacturing and they have a rapid response to newly emerging pathogens. Pre-clinical proof of principle has been achieved for many SAM vaccines. The next steps are to establish robust GMP production and test SAM in human clinical trials.

Mahendra Patel, pharmacy and ethnic minority communities research lead and co-investigator, PRINCIPLE trial at the University of Oxford discussed innovation in trial delivery with COVID -19. This UK study can be joined by patients online, at home from anywhere in the country, regardless of the patient’s background or with which surgery they are registered. PRINCIPLE is the largest platform trial in the world testing treatments in the community setting. This is critical as one of the biggest problems with COVID -19 has been its ability to overwhelm health care systems. Treatments that can be used in the community setting to lessen the severity of the illness and reduce hospitalisations are essential. The aim is to find the most promising treatments and to ensure resources are not wasted on ineffective treatments. As it is a platform trial it can constantly evaluate multiple treatments simultaneously. This provides answers and clinical evidence much quicker, allowing clinicians to stay at the forefront of evidence based knowledge. 2642 general practices have recruited at least one patient and approximately 8000 community pharmacists are promoting engagement with PRINCIPLE.

The PRINCIPLE trial confirmed that two commonly used antibiotics, Azithromycin and Doxycycline are not effective treatment for reducing time to recovery or to reduce the risk of hospitalisation and the recommendation was to cease these treatments unless there are additional indications for which their use remains appropriate. The trial has shown that inhaled budesonide is useful for patients during the early stages of the illness so that general practitioners can prescribe. The product has been included in the clinical guidelines of India and Canada.

There have been new ways of working with virtual trial delivery and innovative recruitment routes. PRINCIPLE has a hybrid recruiting model with both general practices and non-general practice sites. Invitations to participate have been sent to patients using social media. There has been direct National Health Service digital feed of positive cases. Online patient consent has been used with web and telephone follow up. There has been central distribution of medications and study materials and ethnic minorities community engagement. There have been action plans for COVID-19 “hot spots”. There has been UK wide collaboration and support involving pharmacy networks, universities and their communities, pharmacy organisations, research groups and media messaging. PRINCIPLE will continue to evaluate promising drugs and new treatment arms will be opened as potential products are discovered, reviewed and approved.

The last speaker Oksana Pyzik from the School of Pharmacy, University of London discussed future preparedness. She showed this week’s WHO graphs and tables of the current new and total cases and deaths from COVID-19 and the percentage change in weekly cases. Today, 20.9% of the world population has received at least one dose of a COVID -19 vaccine but only 0.8% of people in low income countries have received at least one dose. There should be an elevation of leadership for global health, strengthening of the authority and financing of WHO, investment in preparedness and a new global system of surveillance established said Dr Pyzik. There should be effective national coordination, international financing for global public goods and a platform for tools and supplies.

A high-level Global Health Threats Council should be set up and led by heads of state and governments and IMF should routinely include a pandemic preparedness assessment, including an evaluation of economic policy response plan. Strengthening the supply chain resilience is essential to deal with the fake vaccines, fake chloroquine, fake and unauthorised testing kits for COVID-19, fake surgical masks and fake Covid vaccine certificates. Dr Pyzik commented that Cybercrime has increased and suspicious web domains appeared just a month after the availability of vaccines was announced.