Domenica Sardone,
Regulatory Program Associate Director, Roche Ltd.
The COVID-19 pandemic has demanded a new global approach to vaccine development. There has been unprecedented international attention, cooperation and especially use of resources, enabling pharmaceutical companies and governmental bodies to act at speed in the interest of public health.
During this challenging times and considering the digital era which we live in, media have played a fundamental role, sometimes sharing information in the interest of the public, and sometimes in their own interest and at the expense of the public. How many times have we read: ‘Are these vaccines developed too fast?’ To respond to this question, we should take a step back and briefly explain how usually a drug is developed and which are the main steps leading to regulatory approval.
It is well-known that the development of drugs can take up to 10 years from their early discovery to approval worldwide and commercialisation. There are 4 stages we have to consider for a standard drug development:
- Discovery research, that usually takes between 2 and 5 years and involves lab-based research;
- Pre-clinical stage, that usually takes up to 2 years and involves testing in animals to assess the safety of potential drugs and vaccines in humans;
- Clinical development, involving testing potential vaccines in humans and consisting of phase I, II and III, that can take up to 6/8 years;
- Regulatory approval, that can take up to 2 years.
This is true for the majority of the drugs and vaccines. At the same time, it is a very general statement to make. Three are the main factors that lead a company to the choice of investing billions of dollars to investigate a new compound in the non-clinical and in the clinical setting:
- The unmet medical need.
- The state of art in that particular field (the scientific knowledge from the non-clinical and clinical perspective).
- Consideration around benefit/risk
The combination of the above three factors can determine the urgency and the prioritization of development of some drugs versus others and of course, the investment of the capital of a company in one drug development program versus a different one. It comes without saying that investments affect timelines. In this particular situation, where the percentage of fatal cases considering the total number of infections is surprisingly high (2.1 %)1, the urgency of finding a solution better than a lockdown impacting the economy worldwide is extremely high. Companies with a strong expertise in respiratory viruses are called to contribute to this cause and find a treatment as fast as possible, in collaboration with big pharma that can provide expertise from a drug development point of view on a large scale and ensure the supply in high volumes.
The investment needed for COVID-19 vaccine development is significant: billions compared to standard millions spent for a traditional vaccine, in order to ensure a rapid development and the supply in a very high quantity as fast as possible2.
This need shifted the allocation of resources of companies owing this expertise towards finding in record timelines the best alternative to the risk of contracting Covid-19, reducing investigation timelines that otherwise would have been longer due to allocation of the same resources, for example, to investigate other diseases with higher priorities.
From the EU regulatory perspective, the adoption of specific regulatory procedures (already in place for other types of drugs within the existing legislative system) in combination with a very close collaboration among the European Medicine Agency (EMA), European Commission and other governmental bodies and institutions, with the aim to reach a global harmonisation, and the implementation of new procedures tailored to manage this specific situation, allowed regulatory approvals in record timelines in the interest of public health.
A brief overview of the two main EU regulatory procedures is provided below.
Conditional Marketing Authorisation (CMA)3
This authorisation requires demonstration of a positive benefit–risk balance, allowing for additional post-marketing data to be provided on the condition that the company supplies these data as specific obligations within defined timelines. A conditional marketing authorisation is granted by the EMA if the following criteria are met:
- The benefit-risk balance of a medicine is positive.
- The likelihood of the applicant to be able to provide comprehensive data post-authorisation.
- The medicine fulfils an unmet medical need.
- The benefit of the medicine’s immediate availability to patients is greater than the risk.
Once the above criteria are satisfied (such as for the COVID-19 vaccines of Pfizer, AstraZeneca and Moderna and related partnerships), the company must fulfil specific obligations within defined timelines.
Specific obligations generally include completion of ongoing or new clinical studies and exceptionally, in the context of emergencies, studies to provide further assurance on the pharmaceutical quality of the vaccines.
The CMA provides a controlled and robust framework to ensure that all pharmacovigilance, manufacturing controls, including batch controls for vaccines, and other post-approval obligations apply in a legally binding way and are evaluated by the EMA’s scientific committees on a continuous basis. These elements ensure a high level of protection to the population during a mass vaccination campaign. EU member states could have opted for emergency use in their own territory but have chosen a more robust, unified EU approach, with a joint assessment benefiting all member states and prioritizing citizens’ safety across Europe equally.
Rolling review3
A fast-track regulatory process was also guaranteed thanks to the flexibility the EMA and the European Parliament demonstrated in this particular situation. With a standard marketing authorisation application of a vaccine or a drug, the company shares with the EMA the entire package of data (non-clinical, clinical and quality) at the same time and in one-step. The EMA reviews the entire package of data and takes up to 210 days from submission to provide final recommendation (positive or negative opinion, based purely on scientific data and evaluation of risk-benefit). Following the EMA recommendation, the EU parliament has usually 67 days to review the scientific discussion and endorse or not the EMA positive opinion (final regulatory approval). In this particular instance, also these timelines have been shortened: the EMA’s evaluation was expedited by making use of rolling reviews, specifically designed by the EMA that allowed assessment of datasets as soon as they became available. The EMA, therefore, managed to share a positive recommendation for the use of these vaccines earlier in the process and, using the same approach, the European Commission was able to approve the marketing authorisation within an average of 3 days following the positive recommendation by the EMA.
In addition to the above regulatory procedures, it is also important to mention that the EMA published a new set of guidelines for clinical trials involving COVID-19 vaccines that facilitated the exchange of data between the agency and the companies. A COVID-19 task force was also put together: the main purpose of the COVID-19 task force is to draw on the expertise of the European medicines regulatory network and ensure a fast and coordinated response to the COVID-19 pandemic. Strict rules are in place to assure the independence of all members.4
1 Mortality Risk of COVID-19, Our World in Data.
2 COVAX Announces additional deals to access promising COVID-19 vaccine candidates; plans global rollout starting Q1 2021, WHO.
3 EMA guidelines on Conditional Marketing Authorisation and rolling review.
4 EMA COVID-19 Task force guidelines.
I graduated in Chemistry and Pharmaceutical Technology at University of Pavia, Italy and, following professional qualification I started an internship in Regulatory Affairs in L’Oreal Italy, within the Technical and Scientific Department. Following the first 6 months of internship I decided I wanted to switch to a global role, within regulatory affairs and in a Pharmaceutical Company. I moved to Pfizer, UK, where I worked as support to the Regulatory Strategist in the Oncology department. After 7 months, I accepted a Regulatory Associate role in Cambridge, in Gilead Sciences, within the HIV and emerging viruses department, where I stayed 4 years. In these 4 years I gained experience with the centralised regulatory procedure, for the registration and the maintenance of European drug licences. I also gained experience in managing, from the regulatory point of view, clinical trials in adult and paediatric population, in Europe and in rest of the world countries (mainly Thailand, Latin America, Canada, Australia, Africa, New Zealand).
What I mostly like about regulatory affairs is the diversity of the activities, the involvement of the function in all the different steps of drug development and the everyday challenge to switch from a very detailed scientific consideration of the drug (efficacy, safety, mechanism of action) to the bigger picture of how the drug fits in a complex socio-economic system of each country based on the medical need.
Currently I cover the role of EU Lead in drug development for two small molecules within Roche Oncology and I am training to become Global Regulatory Lead.