Back before the world of the COVID-19 pandemic, the vaccine development process took a long time. Despite the nonsensical claims of the anti-vaccine zealots, the vaccine development process was robust and thorough. The safety and effectiveness of all of the pre-pandemic vaccines are settled science (read the article before you jump up and down screaming about “settled science”).
However, the world of the coronavirus pandemic means that if we can save a few months or even years off the development timeline on a new COVID-19 vaccine, it could save hundreds of thousands of lives. This does not mean those political agendas like we’ve seen Trump do with hydroxychloroquine and other things should take precedence over good science.
So, this article is going to lay out how, in a world without a pandemic, the coronavirus vaccine development process should proceed while ignoring how the politically-driven FDA may subvert the process.
Although I am very uncomfortable with the coronavirus vaccine development process over the past few months, it looks like, for better or worse, we’ll probably have one or two different vaccines in unknown quantities by early 2021.
Of course, much of the optimism comes from experts like Dr. Anthony Fauci, one of the few rational public health experts who are willing to speak up in Washington DC. Maybe he has seen some secret data only available only to him and Bill Gates that supports this optimism. Maybe he just is trying to be the national cheerleader for healthcare.
I don’t know the real answer, but a lot of vaccine experts who have spent their lifetime studying vaccines, like Dr. Peter Hotez, MD Ph.D., has expressed dismay at how politics may “trump” good science.
So, this article will try to lay out the development process, along with the independent controls that make sure that all vaccines are safe and effective.
The typical vaccine development process
This is the normal timeline for vaccine development:
Month 0-24, Preclinical. This is the period of time where scientists attempt to determine if they can identify a part of the virus which stimulates the immune memory so that the immune system can quickly destroy the pathogen before it can do harm. They also need to isolate and culture a lot of viruses to be used in preclinical studies.
For example, these steps will help scientists understand SARS-CoV-2 characteristics and pathophysiology in humans. Since it would be unethical to do these studies in actual humans, researchers need to develop an animal model that mimics a human. Also, researchers need to determine if the vaccine is safe and triggers an adaptive immune response in that animal model. For the SARS vaccine, ferrets were used, because their physiology and immune responses are similar to humans, so it might be used for a COVID-19 vaccine.
Since we’re only about 10 months past the initial identification of the virus, it is obvious that this process was vastly sped up.
Month 24, IND application. The sponsoring organization (probably a Big Pharma company) must make an Investigational New Drug (IND) application to the FDA’s Center for Biologics Evaluation and Research (CBER) to begin clinical trials. CBER reviews the IND, which will include preclinical data, and the sponsor can proceed with the clinical trial within 30 days if the FDA does not find cause to stop it from moving forward. This is the process in the USA, but it’s much the same in most developed countries.
Month 24-60 (or more), clinical trials. Then the sponsoring organization must get Institutional Review Board (IRB) approval to proceed with clinical trials (see this article for more information about the process).
These clinical studies must go through three phases like all drugs, although the process could be shortened if the data is very clear and there is a public need (like the COVID-19 pandemic) using an Emergency Use Authorization (EUA).
The proposed clinical trials will be posted to a US government website that tracks all clinical trials worldwide (and must be posted there before a drug can get US FDA approval).
Phase 1 clinical trials usually include around 100 healthy patients (that is, they have no comorbidities and generally lack any chronic health conditions). This study is not randomized or blinded, as there is only one group, those that receive the vaccine. Phase 1 clinical trials rarely give any information about the safety and effectiveness of the vaccine – it really only tells the researchers if there are some significant safety signals.
Phase 2 clinical trials usually include around 200-300 patients. This study is a randomized, double-blind trial that is too small to observe small differences in effectiveness and safety. However, it helps researchers to determine if there is sufficient data to move forward.
Phase 3 clinical trials, sometimes called pivotal studies, include around 2-3 thousand patients, although many vaccines have included tens of thousands of participants. These studies must be randomized, double-blinded, placebo-controlled (or versus a standard of care control).
Phase 2 and 3 clinical trials are often published in peer-reviewed journals (unless they’ve failed to show anything, then the vaccine is shelved or reworked). Sometimes, the two phases are combined, but that’s rare.
Despite the really weird claims of the anti-vaccine crowd, phase 3 clinical trials are thorough and are statistically powerful. They truly allow us to know if a vaccine is safe and effective.
Month 60-78, regulatory review, and approval. After all of the preclinical and clinical is completed, the sponsoring organization must make a Biologics License Application (BLA) to CBER. Although this process is what is done in the USA, it’s similar in most other countries (and some countries accept FDA review for their own country.
Part of the review usually requires a thorough review by the Vaccines and Related Biological Products Advisory Committee (VRBPAC), which is made up of leading scientists. They have frequently required further testing, or they could even reject an application for a vaccine.
In addition, every clinical trial employs a Data Safety and Monitoring Board (DSMB) which is made up of an independent group of medical ethics experts, statisticians, patient advocates, and, in the case of vaccines, vaccine experts. They monitor patient safety and drug effectiveness, and they have the power to proceed with or stop a clinical trial.
In other words, in a normal vaccine development process, there are several independent agencies and groups that make certain that only safe and effective vaccines are available to the public.
At the same time, and outside of the clinical trial process, a manufacturing plan has to be developed. People seem to think that a vaccine is simple to manufacture, but it really isn’t. There might be some excess capacity to make 200 million coronavirus vaccines across the world, but that’s not much. One choice would be to convert manufacturing from producing other important vaccines like MMR or Tdap, but that seems like a bad choice as it might impinge on the supply of those critical vaccines.
So, new manufacturing facilities will need to be built so we have more capacity. Of course, these facilities also need to be reviewed and approved by regulatory authorities.
The timeline I provided above is generally one that I would think is fairly optimistic. If someone asked me a year ago, before we knew anything about COVID-19, to tell them how long it would take to get a vaccine to market from scratch, I would have answered, “5-10 years.”
Why are we stuck with this timeline?
There are several answers to this, but I’ll list just a few.
- Setting up the clinical trials takes time. I know everyone thinks it is easy to find patients to volunteer, but they generally have to fit into certain demographic groups across the world. You just can’t recruit American patients who live in one small part of California, you need to have patients from numerous centers. You need patients that represent broad income, ethnic, and other groups. Then, the sponsor has to find investigators, has to get IRB approval (see above), has to get the vaccines and placebos to the sites, and so many other steps that I’d bore you silly writing about them. Then the data has to be analyzed in various ways to see if it is safe and effective.
- Getting results takes time. Since it would be unethical to intentionally expose the patients (both vaccinated and placebo groups) to the virus, we have to wait. If the virus is not circulating widely at the time of the year that the trial starts, then there will probably be no difference between the vaccinated and placebo groups, so the data will be worthless. What if the vaccine only works for six months? What if an adverse event only happens six months later (though this is mostly an anti-vaccine myth, it can happen)? There is no way to rush these steps, that’s why it takes four or five years.
- Sometimes vaccines need to be reworked. Frequently, after phase 2 or 3 clinical trials, the sponsor realizes that the vaccine is not very useful because they did something wrong. Maybe they need an adjuvant or a new adjuvant. Maybe the vaccine goes bad after a few weeks and needs different storage recommendations. Maybe the vaccine needs a higher concentration of antigens. Everyone seems to think that once a vaccine enters clinical trials, it must work, but clinical trials are a scientific experiment. We are asking whether the vaccine is safe and effective, and the clinical trial provides evidence to reject or support that hypothesis. And in real science, you gather data and then go back to the beginning. Again, if the vaccine doesn’t work very well, what can be done to improve it?
- Clinical trials fail the vast majority of the time. This is something that few people understand – clinical trials rarely work out for the drug companies. And it happens all of the time with vaccines. That’s why I keep writing this over and over – if everything goes perfectly, maybe we can have a coronavirus vaccine within 3-5 years. But it never goes perfectly, it’s science.
- The regulatory review is thorough. If we are going to demand safe and effective drugs, where the benefits far exceed the risks, then we want independent agencies and boards to take their time to review the data. I think there’s a belief that we post the data on Twitter, and voila, we know the facts. It doesn’t work that way.
One more thing – ignore any words that come out of the mouths of anyone that is associated with any company that is developing a vaccine. Period. Just don’t do it. I’m not saying they’re lying, but what I am saying is that they have precisely one audience – their investors and shareholders.
They can boost their stock prices by over-exaggerating results or compacting timelines. For example, Moderna, who is developing an mRNA COVID-19 vaccine, has recently claimed that they will have their vaccine available for healthcare workers by the end of 2020. That may be so (I doubt it), but they aren’t the final arbiters as to when their vaccine will be on the market.
The biotechs are being very aggressive in their press statements. What they’re doing is talking to their investors. I think you have to filter that away from what the FDA is thinking. A wishlist from the CEO of a biotech or a pharma company means nothing to me. It’s what the clinical trialists are finding in collaboration with the FDA that matters.
Moreover, Moderna’s mRNA vaccines have never shown to be effective (or safe for that matter) in humans. Again, Dr. Hotez says:
Without having the efficacy and safety data, I think you have to be really careful about bold statements like that. As I often like to say, these nucleic acid vaccines have been around for 30 years and they offer great promise, they work in laboratory animals, but, historically, they have not worked well in people. Maybe now there’s been modifications to improve that. Let’s wait and see.
The point is that pharmaceutical companies try to make their investors giddy, but they aren’t responsibly reporting scientific evidence of their claims. And if you were a healthcare worker, would you take a vaccine that has no known effectiveness and unknown safety issues? I wouldn’t.
To be clear, 99.9% of the scientists and physicians who are working on these vaccines are dedicated to saving human lives. They want to work quickly to try to arrest this pandemic. They do not want to take ridiculous shortcuts or subvert the process that has given us nothing but extremely safe and effective vaccines. Just don’t trust what executives are saying.
Speeding up the vaccine development process
There are ways to speed up the process to get us a new vaccine, including a COVID-19 vaccine. We shouldn’t do this with a regular vaccine (although since all vaccines save lives, I’m not sure why we wouldn’t), but here are a few suggestions:
- Speeding up clinical trials. There is no way to speed it up without sacrificing knowledge about its safety or effectiveness. We cannot reduce the number of patients, the methodology, or statistical analyses of clinical trials just to get a vaccine out to the world. However, with money, you can employ more statisticians and increase the speed of enrolling patients.
- Speeding up regulatory review. This is a slippery slope that right-wing governments would like to implement. Generally, FDA reviewers are not political appointments but are scientists themselves. They probably cannot be forced to overlook issues just to get a vaccine approved, but it’s possible they’ll move a coronavirus vaccine application to the top of the pile. Also, it’s possible to add more regulators to review the data, although they’re probably still waiting for clinical trial results. But this should not default to an Emergency Use Authorization to subvert the process.
- Speeding up manufacturing. Like the amateur vision of how vaccines are developed, there is also a belief that you can push some magical button and billions of doses of vaccines can be made. A vaccine manufacturing plant takes years of planning to build plus billions of dollars. Many vaccine manufacturers could easily convert their plant to a new vaccine, though that might sacrifice the capacity for other important vaccines. And this will not happen quickly.
- Release the vaccine to anyone who wants it regardless of clinical trials. I hate this one. Even some pro-vaccine people are pushing this because they have this odd belief that ALL vaccines that enter clinical trials are safe and effective. This seems to be the mirror image beliefs of anti-vaxxers who think ALL vaccines are unsafe and ineffective. Furthermore, that whole “right to try” nonsense needs to stop.
One more thing that Dr. Hotez said about the FDA:
But the branch of the FDA called the Center for Biologics Evaluation and Research has been around for a while and has some of the smartest vaccine scientists that I’ve ever worked with. I’m fairly confident they would not do anything that would jeopardize the health and safety of Americans.
And that’s why I doubt that this process can or will be rushed
It should be absolutely clear that the vaccine development process in the USA (which is similar in most developed countries) is a robust, careful undertaking that has given us extremely safe and incredibly effective vaccines. it is not a system that can be easily subverted by pharmaceutical companies, scientists, or the government.
This system has so many different checks that, despite the ridiculous claims of our favorite anti-vaxxers, it is nearly impossible to “sneak” a bad vaccine on the market.
Sadly, in the world of coronavirus, there has been and will continue to be incredible pressure to cut corners to get a vaccine to market. It’s not just the USA, but almost every other country that has an elected government that wants to appear to be successful in the fight against the pandemic, that will try to cut these corners.
Look at what AstraZeneca did with its vaccine (the so-called Oxford vaccine) – they announced a serious adverse event to a private meeting of stock analysts rather than to regulatory authorities across the world where this vaccine is undergoing clinical trials. And scientists are troubled by the lack of transparency, something that rarely happens in other drug trials.
Dr. Paul Offit, MD, recently expressed his concerns about subverting the process, point his comments not only against the government but also the pharmaceutical companies:
So you have this difficult-to-characterize, elusive virus that you are now about to meet with a handful of vaccine strategies for which you have no commercial experience. I think you can assume that there may be a learning curve here.
I wish there was a little more humility from some of these companies. They’re always sort of pounding their chests as to how they’re going to have this vaccine. I think, just in the past day, the CEO of Pfizer said, “I think we can have a vaccine by the end of October.” I’m sorry; are you on the Data Safety Monitoring Board (DSMB)?
No, the Pfizer CEO is most certainly not on the DSMB.
This is not only an issue with the coronavirus vaccine but also with future vaccines. Of all the drugs on the market, vaccines have been one class that has been the model of good science. Unlike many drugs in development, that often have few benefits over a generic version of that same drug, the vaccine development process has been transparent and nearly always aimed at the greater good of humans.
Once we allow governments and pharmaceutical companies to change that paradigm, even I, as a pro-vaccine advocate, will worry about any new vaccine.
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