These days we see a lot of critical coverage of the approval of new vaccines in numerous markets. The reporting of data in the respective countries differs from each other. For the layman, it is hardly possible to determine what is due to shortcomings in the studies and what is more attributable to harsh economic interests. Ordinary people exchange their views on the efficacy of the different preparations, and in the media citizens express clear preferences for vaccine A and why they would turn down vaccine B. Specifically the products from AstraZeneca and Russian Sputnik meet an increasingly sceptical public in some countries, therefore, it might be a good idea to take a look behind the scenes with an expert. Andreas Weber is CEO of the EvidentIQ group, a company that builds software to run, monitor and analyze clinical studies. Fifteen of the Top 20 pharma firms rely on their products and services. Andreas should be knowledgable.
Mark: Andreas, to better understand how extraordinary the current procedure of approving new vaccines in most western countries are, can you tell us how this process looks like in normal times?
Andreas Weber: Happy to do so, Mark. Approving a new drug, such as a vaccine, happens in a structured and strongly regulated process that usually can take from 12 to 15 years for the full cycle of research, development and approval. It starts with the Pre-Clinical phase where a new drug is developed, tested on animals and then an Investigational New Drug Application (IND) is submitted to the authorities.The IND will receive approval to commence the Clinical phases once it has been proven that the new drug is safe and does not put human subjects at an unreasonable risk of harm.This process is followed by the Clinical testing where the drug safety and efficacy is reviewed on humans in 3 phases. Commonly, the 3 Clinical phases take at least 3 years from start to completion.
"Approving a new drug, such as a vaccine, usually can take from 12 to 15 years"
If phase 1 has been successful, the drug is tested in phase 2 on a few hundred subjects to assess the efficacy on patients that suffer from the respective disease. It includes a comparison of results from those given the actual drug, a non-active placebo, or a different drug. After the successful completion of phase 2, the drug is tested in phase 3 on a larger patient population, usually in the thousands. Different populations and dosages, and combinations with other drugs are assessed. With the successful completion of phase 3, the New Drug Application (NDA) Review process starts, where the data of the 3 Clinical phases is reviewed in regard to the drug’s safety and efficacy. Approval will be given once it has been determined to provide benefits that outweigh its known and potential risks for the intended population.
After the Clinical phases, there is also a Post Marketing and Post Approval Risk Assessment phase – phase 4. In this phase, the safety of the drug is measured after it has been released to the market. Any serious, unexpected adverse events that were not possible to predict during the clinical trials are captured. The study sponsor submits regular updates to the health authorities.
Mark: A few weeks ago a group of medical experts in the US charged with monitoring the company’s clinical trial made a highly unusual accusation: AstraZeneca had cherry-picked data to make its vaccine look better. Isn’t that both unusual and also potentially fatal at a time when governments around the world need to allay the concerns of populations about rapidly developed vaccines?
Andreas Weber: As mentioned above, the drug approval process is lengthy – but necessary. It has been designed in order to address safety, not speed. However, in order to make it possible to bring critical drugs such as the COVID-19 vaccines faster to the market, the regulatory authorities do offer an Accelerated Approval Program and a Fast Track Program.
Mark: Interesting. So this Fast Track program is not totally new, it had been introduced well before the Covid pandemic?
Andreas Weber: Yes. According to the FDA, the Accelerated Approval Program facilitates rapid development and expedites the review of drugs that treat serious conditions or fill an unmet medical need. The Fast Track Program can be used for drugs that address serious conditions and fill an unmet medical need, using a surrogate endpoint enables the FDA to approve these drugs faster.
Both programs have been applied to the latest COVID-19 vaccine of AstraZeneca, Biontech/Pfizer and Moderna. Obviously there has been a lot of pressure from the various government organisations and the public on the pharmaceutical industry to reduce their development times for the vaccines significantly and on the regulatory authorities to speed up their approval processes.
Obviously there has been a lot of pressure from the various government organisations [...] to reduce their development times for the vaccines significantly
With the Acceleration/Fast Track programs as a basis, they have introduced a novel approach to both development and approval. The 3 Clinical testing phases, for instance, have been conducted in parallel, not sequentially as standard practice. Also the data review activities have been run in parallel. The FDA had to look beyond safety and efficacy and also consider need and standard of care. With COVID, we have a very high need, and there is no standard of care and no treatments. That has significantly lowered the bar and resulted in emergency approvals that were based on much less data compared to the normal process.
However, I still do not believe in the accusations that AstraZeneca has cherry-picked data to make their vaccine look better. I rather believe that the regulatory authorities have lowered their standards significantly – which is one aspect of the FDA’s Fast Track Program – so that AstraZeneca could obtain approval with the submission of very small subset of data compared to what is normally required.
I still do not believe that AstraZeneca has cherry-picked data to make their vaccine look better
Mark: What tools and procedures are available so that pharmaceutical companies cannot influence study results in their favor?
Andreas Weber: Well, it is all about digitalization. During the last years the regulatory authorities such as EMA, FDA and PMDA have introduced many new procedures and processes to avoid any situation where a pharmaceutical company could manipulate study data in their favor. They also have issued new standards for the electronic capture, transformation and analysis of data. However, the important question is how these regulations and standards can be enforced. I think that is only possible if the pharmaceutical companies use an end-to-end digital platform for their entire drug development process – fully integrated and compliant with all regulations, eliminating all error-prone manual interference. This platform should also be integrated with the software tools the authorities are using to review the study data, so that data transmission errors can be avoided. Only when all data collection, transformation, analysis and submission follows a stringent electronic workflow that is compliant with the mandated processes by the authorities, any harmful data manipulation can be avoided.
Mark: Let me guess, this is what EvidentIQ does, right?
Andreas: You are right. In fact I believe we are one of the few vendors to deliver both the end-to-end platform and the scientific services to support the clinical trial process in its entirety. Look at the benefits of a digital approach for the pharmaceutical industry itself: The development timelines can be reduced, potential adverse events can be discovered faster and errors that come with human interference can be eliminated, resulting in a significant reduction of drug development cost. It also makes it easier for the patients with a fully digital virtual trial platform, their data can be easily collected in a compliant way without them having to spend a lot of time with site visits.
Mark: When looking at the latest AstraZeneca scandal, particularly what’s been reported by government offices, how do you see that? Is this vaccine potentially more harmful than others?
Andreas Weber: I believe it is too early to come to that conclusion. The MHRA has reported in the UK 30 cases of cerebral venous sinus thrombosis (CVST), which is a type of blood clot in the brain, out of a total population of 18 million that have been vaccinated till March 24. 7 out of those 30 have died. Investigations are under way to determine if the AstraZeneca vaccine can cause CVST. The EMA has commented that it was “not proven, but is possible” and also said that the benefits continue to outweigh any risk.
The fact that this adverse event has not been discovered during the Clinical development and approval process can of course raise some concerns but then again: The vaccine has been approved based on limited data and 30 adverse event cases in 18 million represent with 0.0002% a very low number.
The AstraZeneca vaccince has been approved [...], 30 adverse event cases in 18 million represent with 0.0002% a very low number
As we are in an unusual situation, now is the time to collect larger volumes of data in ongoing post-marketing studies before dismissing AstraZeneca’s vaccine as being more harmful than others. Also, there is too much controversial and quite often misleading information published in the media, resulting in confusion and fear in the public to the extent that many people refuse to get vaccinated. We have to be careful not to create a general anti-vaccination attitude that could put the objective of achieving public herd-immunity at risk.
There is too much controversial and quite often misleading information published in the media [...]. We have to be careful not to create a general anti-vaccination attitude that could put the objective of achieving public herd-immunity at risk.
Mark: Andreas, allow me a personal question – have you been vaccinated yet and would you accept any vaccine?
Andreas: Not yet Mark. When it’s my turn though I will accept any vaccine that has been approved through EMA or FDA as I have great confidence in the scientific approach and reliability of both organizations.
Mark: Thank you Andreas.