During the nine grueling months of 2020, we had to make hundreds of difficult decisions. Many decisions fell on me, and the pressure was greater than I imagined.
Billions of people, millions of companies, and hundreds of governments have high expectations for the pharmaceutical industry, and meeting these expectations is not easy. Pfizer is the leading company in this industry, and I happened to be the CEO of this company, and I just took office at the time. I can feel the weight on my shoulders.
Looking back, the decision that stands out in my mind the most is the use of mRNA technology to develop a COVID-19 vaccine. This decision was the most counterintuitive, requiring bold forward thinking and tremendous courage.
With this choice, Pfizer finally succeeded in developing a new coronavirus vaccine.
I’m a big fan of mRNA technology, and I firmly believe that Pfizer could make a leap forward in the development of a flu vaccine. I thought it would take Pfizer a few years to make progress.
When Mikael Doslten, the head of the R&D department, told me about trying to use the mRNA solution, my first reaction was surprise.
All vaccines have the same function: to train the body’s immune system to recognize and defend against infectious disease-causing agents, so-called pathogens. Vaccines often contain attenuated, killed, or non-infectious parts of these pathogens.
The new mRNA vaccines are different. It is not made up of the actual pathogen and does not contain inactivated, inactivated or non-infectious parts of the virus or bacteria, but it does contain instructions on how the body produces proteins that are part of the pathogen’s makeup. Simply put, mRNA teaches the body to make its own vaccine.
After Novartis withdrew from the vaccine business, Philip Dormitzer left in 2015 to join Pfizer as president and chief scientist of viral vaccines. Philippe led the team to develop a synthetic method for updating influenza vaccine strains and responding to epidemics.
Pfizer has always had a strong interest in RNA, and we prefer the flexibility of this technology. If the emerging virus strain is not fully covered by the current vaccine, the new technology can flexibly change the RNA sequence in the vaccine, which may be effective against the new virus strain.
This is a huge bet.
In 2018, Pfizer turned to its head of vaccine development, Kathrin Jansen, and her team to recommend a partner to advance the development of mRNA and create a game-changing seasonal flu vaccine. .
In the process of looking for a partner, Catherine became close friends with Ur Sahin. Pfizer had cooperated with the German biotech company Dr. Ur Sahin and Dr. Özlem Turesi. Founded in 2008 by a husband and wife team.
Pfizer and his team immediately reached an agreement and signed a three-year research cooperation agreement. During this period, the team from the German biotech company will provide expertise and licenses to Pfizer for the development of a new influenza vaccine.
I was the chief operating officer of Pfizer at the time, and when a subordinate brought the contract to me for approval, I approved it immediately. When COVID-19 hit, our work on the mRNA flu vaccine helped Pfizer get a head start.
Place a bet
In January 2020, Pfizer’s partner German Biotech joined the first team to fight the virus. This virus spreads in an incredible way, and it is impossible to control it.
Work on a vaccine was imminent, and the German biotech company needed a partner. Ur thought of us and he called Catherine. Before Catherine got the call, I had asked her and the team to make recommendations on which technology platform Pfizer should use to develop a vaccine. Her suggestion was to use mRNA.
When Mikael broke the news to me via video call, I was stunned. “Mikael, to be honest, I really didn’t expect this answer,” I said to him. “This bet is very risky and difficult.” First of all, the technology is promising, but it has not been proven yet
. , Pfizer is more familiar with adenovirus and protein technology platforms for vaccine production; secondly, Pfizer must reach an agreement with a German biotech company, which usually takes several months to complete; finally, the German biotech company is smaller, and Pfizer may have to bear All R&D and production costs.
Mikael was very sure. With Pfizer’s experience developing flu vaccines, he was convinced it was the right choice. Having a vaccine that can be boosted at any time if necessary without fear of losing efficacy is crucial, and I came to understand where he was coming from.
”Okay, Mikael,” I said, “let’s get the team together and see what they have to propose.” Mikael breathed a sigh of relief.
At that meeting, they explained that using this technology, Pfizer researchers can quickly design and adjust mRNA, which is a more precise and direct product.
This allows our team to administer the vaccine as many times as needed. We can do this not only during the COVID-19 pandemic, but also in the future when the virus mutates and vaccines need to be boosted. While traditional vaccines can take months to design, this mRNA vaccine takes just a few weeks.
”That’s right, with mRNA, we can indeed advance research and development work quickly, but the vaccine must be frozen during distribution to remain stable.” When talking about the challenges, Philip spoke.
This is something I hadn’t thought of before, and it might be a huge disadvantage. Catherine said Wuerl had already called to express his interest in working with Pfizer.
Clearly, the mRNA technology platform is far more dangerous and complex than all other options available. It was also the quickest solution, and my entire team fully supported this option.
My intuition told me that this was the right choice, so I responded: “Okay, let’s choose mRNA. I’ll call their CEO tomorrow.
We’re all in the same boat
During the past two years of cooperating on the development of influenza vaccines, Ur and I had never found an opportunity to talk. I took the initiative to call him and expressed my willingness to do my best to ensure the success of the project. I immediately felt that he was a trustworthy person.
”Ul, it could take months to finalize all the necessary agreements, as well as research, production and commercial contracts.” I told him time was of the essence and asked if he would be willing to start work before signing the contract.
”Albert, your commitment is enough,” Uhl said. “We can start research work immediately. The lawyer will confirm the research agreement first, and we will sign it as soon as the agreement is ready.” I agreed immediately
. Pfizer’s team held a conference call with its team in Germany. The meeting discussed a wide range of topics, including candidate antigens, toxicology study plans, first-in-human clinical trial plans, regulatory communications and production timelines.
On April 9, 2020, the two parties signed a cooperation agreement to jointly develop a world-class COVID-19 vaccine using mRNA technology to prevent COVID-19 infection.
The German biotech company received an upfront payment of US$72 million from Pfizer and will receive an additional US$563 million in milestone payments in the future, for a total consideration of approximately US$636 million. Pfizer will also purchase equity from a German biotech company, paying $113 million in cash to the other party (owning approximately 2.3% of the company’s equity).
According to the cooperation agreement, both parties agreed to share all development costs equally and all commercialization profits equally, with Pfizer agreeing to bear all costs up front. If the project fails, Pfizer will bear all losses alone; if the project succeeds, the German biotech company will pay Pfizer development costs through the commercialization profits of the product.
challenge the limit
Under normal circumstances, the development of a vaccine takes several years. In the process, many attempts will end in failure. I asked the research team to hand over a plan to ensure the development of a safe and effective vaccine in an unprecedentedly short time frame.
At the beginning of 2020, as the number of COVID-19 infections and deaths increased, the world was involved in this unprecedented crisis, and we must respond bravely.
A few weeks later, during a video conference call in April, Katherine and her team proposed a bold plan that may lead to complete results of the most critical phase 3 clinical trial by the second half of 2021.
At that meeting, Mike McDermott, head of the production department, also proposed a plan to develop a production process within 18 months, including finding matching raw material suppliers and starting from Design specialized equipment that may be used to produce mRNA from scratch.
“Once Pfizer’s vaccine is developed, it will only take me a few months to produce tens of millions of doses,” Mike said. His plan is on the verge of breaking records for the speed of drug development and large-scale production.
The epidemic situation has taken a turn for the worse. Hospitals are overcrowded, intensive care units do not have enough ventilators for patients, and infection and death rates are increasing.
“This is not enough,” I told the team. “We have to have a COVID-19 vaccine by the end of October this year. By next year, we have to produce hundreds of millions of doses, not tens of millions.” I asked them to think from scratch. , how to make the impossible possible. They don’t have to worry about costs at all, and they shouldn’t think about return on investment.
A week later, the team came to me with a brilliant solution.
The process of Phase 1 clinical trials and Phase 2 clinical trials is very cleverly designed. The team will not wait until all relevant experiments on vaccine candidates are completed before starting research, but will start research as soon as the first vaccine candidate is developed.
The team will use multiple combinations of different doses, regimens and age groups to test to better understand how the vaccine candidate interacts with the immune system; when a second vaccine candidate is developed, the team will follow a precise set of targeted sexual testing process to compare this vaccine candidate to the first.
We then apply the same approach to the third and fourth vaccine candidates, quickly eliminating those that don’t work as expected, focusing on testing the two that work best, and then selecting those through some additional testing. to develop a final vaccine candidate and enter the third phase of research.
The team reminded me during this part of the presentation that this design would provide useful information to help them select the best vaccine candidate, but the risk was that a selection error would result in a suboptimal candidate entering Phase 3 clinical trials. very big.
Looking back afterwards, during that period, we felt like we were making life-or-death decisions every day.
”You’ll see right away that the cost of a phase III clinical trial is going to exceed the cost of any previous study,” Catherine told me. I silently noted this sentence in my mind and listened to the team continue to speak.
The purpose of Phase III clinical trials is to produce conclusive results as quickly as possible. The chosen trial format was a placebo-controlled double-blind trial. The FDA stipulates that a vaccine must be 50% effective before it can be approved. The trial designed by the team can make the vaccine effective up to 60%. Our internal standards are higher than official standards.
For emergency use authorization applications, the FDA usually requires 2 months of safety data, and full approval requires 6 months of safety data.
Statistical analysis by Pfizer’s experts in mathematics showed that to demonstrate statistical significance at this level of effectiveness (60%), they would need at least 164 COVID-19 infection events (i.e., participants infected with COVID-19).
A study with 10,000 to 15,000 participants may take less than a year to obtain these results. The team decided to expand the scale of the study and recruit 30,000 participants in order to accumulate new coronavirus infection events faster (later increased to more than 46,000).
A study of this scale usually requires 40 to 60 scientific research sites. They decided to set up 120 scientific research sites to recruit these participants more quickly, and later increased the number of sites to 153.
The most critical factor is to locate research sites in areas with a higher disease burden from COVID-19 infection in order to obtain a higher attack rate (the percentage of participants who naturally contract the disease during the study period). If the attack rate is low and the number of patients is small, it cannot be verified whether the vaccine can prevent it.
Our clinical trials need to be conducted in places with severe epidemics to show that participants who receive the vaccine are less likely to contract the virus than those who receive a placebo.
The problem is that attack rates vary over time in different locations. A city or town with a large number of infections will usually take policy measures, and after a period of time, the attack rate will decrease. In cities or towns with fewer infections, people will begin to relax their vigilance, and over time, the infection rate of the new coronavirus will increase.
For Pfizer researchers, if they want to achieve a high attack rate within a certain period of time (at least within 7 days of the second injection), where should they choose to set up a scientific research site?
Epidemiologists at Pfizer have developed an algorithm that can predict as accurately as possible where the incidence of COVID-19 infection is likely to increase over a given period of time. The research team then attempts to set up survey sites in those locations.
That way, there will be a greater chance of a high disease burden in that location by the time participants get their second dose. As the team continued to explain the plan, I let out an inward gasp.
After the vaccine team’s presentation, Mike McDermott, the head of the production department, expressed his views.
While the laboratory is developing vaccine candidates for Phase I and Phase II clinical trials, and the final candidate vaccine has not yet been determined, the production team will still start to scale up the production process. They need to order raw materials for all vaccine candidates so they are fully prepared.
The challenge we face is that no institution in the world has yet put mRNA products (whether drugs or vaccines) into industrial-scale production.
That is, Pfizer’s manufacturing operations had to invent, design, and order entirely new industrial-grade drug dispensing equipment that did not yet exist. “What about the challenges of ultra-low temperature storage?” I asked, “How are you going to store millions of doses of vaccine in an environment of minus 70 degrees Celsius?” “We are going to move the raw materials for existing products from existing warehouses
to temporary sites and then convert existing warehouses into multiple football field-sized freezer farms,” Mikael said.
”Put 500 large freezers there and use each freezer to store 300,000 doses of vaccine. Calculated, we can store more than 100 million doses of vaccine in total. For Europe, we will also take the same measures for the production plant in Belgium.
” How can millions of vaccine doses be delivered to thousands of locations around the world in ultra-cold conditions?
”The solution is actually easy to think of. Can we make a relatively low-cost container that can maintain the temperature of minus 70 degrees Celsius for 1 to 2 weeks? We can fill the box with dry ice.” We use cars, trains
or Planes carry these boxes around the world. After arriving at the destination, they can store the box in a commercially available special freezer, or they can extend the use time of the box by adding dry ice to the box.
We also placed an electronic device in the box to implement GPS positioning, temperature display and light detection functions. The device can transmit location and temperature information to Pfizer’s control center in real time. “If someone opens the box, the light detector also passes the information to the staff,” Mikael told me.
The plan could cost up to $2 billion. I understand that this stake is very high. If the project fails, I will cause heavy losses of US$2 billion to the company in my second year as CEO.
I called Shantanu Narayen, Pfizer’s lead independent director, to discuss the matter with him. Shantanu is the chairman and CEO of Adobe. He listened carefully to my words and agreed with me that this was the right choice. I got on the phone with several other board members to get their approval.
The critical situation requires everyone to spare no effort to deal with it.
A few days later, I announced to the world that Pfizer planned to have a vaccine capable of preventing this global pandemic by the end of October 2020.