RECAP with the RBDCOV Community Advisory Panel | Vaccines 101: How do they make it into the European market? (part 1)

PART 1

ReCAP is a series of interviews with the members of the RBDCOV Community Advisory Panel that will explore the world of community engagement in EU projects and the importance of including people living with immunocompromising conditions in clinical trials. Our guests for this second interview are Christopher Mann, Regulatory Director at Asphalion, and Brian West, EATG member and member of the Community Advisory Panel for the RBDCOV project.

Let’s read this interesting conversation about vaccine regulations and how they make it into the European market from two different stakeholders: the patient community and the legal and regulatory sector.

Thanks to Brian and Christopher for having accepted this interview invitation and for sharing their expertise and knowledge with us. Let’s get started!

Brian West

Hello, my name is Brian West. I live in Edinburgh, Scotland. I have been a member of the European AIDS Treatment Group (EATG) for nearly 20 years, and I am the Chair of the Partners and Science Programme at EATG. I have been involved in the EATG’s input into the RBDCOV vaccine trial with HIPRA from the very beginning. Speaking today with Christopher Mann, who will introduce himself in a second, but I will just ask a question to him right at the beginning. Could you give us a brief overview of the key regulatory steps before a vaccine is allowed into the European market?

Christopher Mann

Hi, Brian. Thanks for the time today and the interview. I have been working in a company called Asphalion here in Spain for about eleven years, doing regulatory consulting for biologic products. We have been working with HIPRA on the vaccine for many years and we have been part of their process to get it approved by the European Medicines Agency (EMA) and onto the market since the very beginning days of the RBDCOV project.

In terms of getting a vaccine onto the market, there are four major steps that you need to think about. The first one is identifying the pathogen and the antigen to design a suitable vaccine technology. In this case, the SARS-CoV-2 spike protein is used as an immunogen. The next step is manufacturing, ensuring the right quality levels, and for this there are a lot of regulations and guidelines on how to manufacture a vaccine. After, when you have your manufacturing process up and running, you can do the safety testing, or non-clinical testing, usually involving animal studies. Finally, clinical studies are performed to demonstrate safety, determine the correct dose, and show efficacy in a large number of people. After these 4 steps, you can use that data for the market authorisation application. Moreover, the regulations for all this process are usually defined in the European legislation, but there are also guidelines from institutions like the World Health Organization (WHO), because obviously many vaccines are intended for an international use, not just a specific local market.

Brian West

Thank you for your answer. In this project, one of the things that struck me is how things were sped along with the development of the HIPRA vaccine, and not just this vaccine, but all of them. I think if you have been involved in the regulatory process for a long time, some things that used to go on serially, one after the other after the other, went along in parallel. And that was, for me, quite an interesting development. Although it was understandable because of the urgency, were you surprised by how fast vaccines were approved?

Christopher Mann

There is a misconception that testing was not done properly on these vaccines because it was done too quickly, but that is not the case. The testing was done, but in parallel. Usually, you would do a systematic and stepwise approach, but in this case, because of the urgency, all the testing was done simultaneously. The regulatory authorities also put more resources than usual into reviewing and assessing the vaccines to expedite the process, which is obviously not something you can do on a routine basis.

Brian West

You mentioned briefly the regulatory agencies adapting fast to the process. Can you give us some specific examples with the HIPRA vaccine being used in the RBDCOV project trials?

Christopher Mann

One of the key aspects for any product or development, including vaccines, is the ability to talk to regulators, which is called ‘scientific advice’, where you make proposals about what you plan to do and if that would be acceptable to them, to show that the vaccine is safe or effective. Normally, those procedures can take a certain amount of time because there is lots of data to review. These procedures were expedited during the pandemic by allocating more resources. The regulators reviewed and interacted with the companies more quickly, providing feedback faster. This allowed for the possibility of data sharing between companies about the experience of all the different vaccines that were under development, for example. And this also included public availability of information. Obviously, all the scientific journals made all the data from COVID studies free to use, which meant everyone could access it quickly in real time.

With the HIPRA vaccine, multiple scientific advisory procedures were conducted in collaboration with the EMA and these were fast-tracked processes. Furthermore, other interactions, including a review procedure known as a ‘rolling review’[1], played a crucial role. In a rolling review, data is assessed in real-time, avoiding the need to wait for the complete accumulation of information. This dynamic process allows for continuous questioning, acquiring additional data, and implementing improvements along the way, eliminating the delays associated with waiting until the end of the process for data collection, which, of course, would take a considerably longer time.

Brian West

One specific question in relation to this vaccine is that it is being used as a booster dose for people who have already had a first vaccination, in contrast with other COVID vaccines that we have in the market. Did that make it more challenging or easier for Asphalion?

Christopher Mann

More challenging in a certain way, and easier in another way. The HIPRA vaccine can, in principle, be used as a primary vaccine. However, by the time it was under full clinical development, other vaccines had already been extensively used. This made it much more difficult to conduct studies in a primary vaccination setting because demonstrating effectiveness would have required showing a reduction in the number of serious cases. However, as widespread primary vaccination had already taken place, it would have been statistically very difficult, if not nearly impossible, at least in Europe, to demonstrate this at the time. Nevertheless, these studies were carried out in other countries where vaccination was less prominent. Another complication was the need for what is called immunobridging, demonstrating that the booster effect is similar to that of the already approved vaccines.  This involved defining that response and implementing proper controls. This was crucial because the HIPRA vaccine was one of the first booster vaccines to enter the market.

But on the other hand, being a booster makes it easier because you have less vaccinations required to achieve the study objectives which are to show immunobridging instead of showing a full clinical efficacy and safety assessment. This means that the clinical assessments are focused on an immune response that is adequate to give the vaccination effect instead of all clinical aspects of COVID, for example.

Christopher Mann

Now, I would like to hear your thoughts on community representation, Brian. What do you think about different stakeholders getting involved with the decision-making process regarding drugs and vaccines? How can they do that more easily, or how can they participate more in this process?

Brian West

I believe, from my experience, it all depends on where the starting point is. At EATG, we have engaged in collaborations with the pharmaceutical industry regarding drug development. This marks only our second venture into vaccine development. The problem arises when we join the process too late, and we find ourselves with limited capacity to contribute. We lack substantial input, especially in areas such as determining the language used in informational materials and outlining specific strategies to target particular populations, if applicable.

This was not the case with RBDCOV. When they applied for the EU Commission grant from the Horizon 2020 funding programme, they involved us right from the very beginning. Although the onset was slightly skewed due to the constraints imposed by COVID, preventing face-to-face meetings as promptly as desired, we were engaged right from the outset. This early involvement means that certain common mistakes, such as overlooking the need to be very public about how data is regularly presented to the community, were avoided. Some scientists may default to presenting at conferences, assuming it is sufficient, but most community members neither attend conferences nor read conference materials.

Our early involvement aimed to ensure collaboration on elements of the trial we deemed vital to comment on and also in shaping how information is quantified on leaflets and when results are released. Another key issue, in my view, is the tendency for people to work in silos, and this is a pervasive problem. Trials sponsored through the EU often suffer from siloed structures, with different work packages operating independently. However, because we had key personnel involved across multiple work packages, we could easily call for meetings with specific teams to address any information that needed sharing. This approach eliminated the need to rely on secondhand information, making the entire process much more manageable for me.

Christopher Mann

And did you have any direct interactions with regulatory agencies as well in the RBDCOV project, or have you had any other experience with that as well, through EATG?

Brian West

Yes, at the EATG, we have had direct interactions with regulatory agencies, including the EMA, on other projects but not this one. For instance, in terms of HIV, we have engaged directly to push for PrEP through the system when we felt it was being held up considerably. There was not as much interaction in this project, but in the past, we have had significant engagements.

Christopher Mann

Yeah, it was challenging, given that the regulators were heavily occupied during the pandemic. I am curious if you could talk more about the role of Health Technology Assessment agencies on a national level and how the pandemic affected that role, particularly in terms of vaccine approval and commercialisation.

Brian West

I think one of the things that struck me the most was the relatively small role played by Health Technology Assessment (HTA) agencies in the rollout of these vaccines, and this is quite understandable. Let me give the example of where I live, using the Scottish Medicines Consortium. Normally, after a drug goes through the regulatory process, the HTA agencies would have three months to evaluate it, decide, and coordinate with health providers on its market introduction. However, all of this was bypassed during the pandemic. We had entities like the Joint Council on Vaccine Initiatives, which made quick decisions. The rationale behind this was twofold: firstly, the urgency to get these vaccines to market as swiftly as possible, and secondly, while cost was not entirely disregarded, it was not the overriding factor. HTAs usually spend a considerable amount of time and resources assessing the cost implications of drugs over different periods. In this case, for the COVID pandemic, the focus was on delivering a couple of vaccine doses.

And yes, some vaccines were more expensive than others. However, at the end of the day, cost was not the defining issue, so they were not excluded from the equation. We need to be acutely aware that in the future, this may not be the case. While the COVID vaccination regime is not yet normalised, there might come a time when HTA agencies will raise questions about the costs and effectiveness of these vaccines. Especially if boosters become a regular occurrence, such as annually (or even every six months for individuals living with HIV—I have had seven vaccines already). If COVID vaccination turns into a routine like the annual flu shot, HTAs will likely need to be involved in the conversation. We are not there yet, but it is crucial for us at the EATG and probably for HIPRA to have a roadmap for potential engagement with HTAs if the need arises. It has not been the case so far, but I do not see them staying out of it forever.

Christopher Mann

Yeah, I think that is a valid point. As you mentioned, when boosting becomes more regular and predefined, the cost will become a significant issue for countries implementing such schemes.

CONTINUE TO PART 2

Disclaimer: This activity was developed under the RBDCOV Project, which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101046118.