What happened? A timeline on the development and approval of Moderna, Pfizer, and AstraZeneca's vaccines
Why didn’t we get Pfizer’s vaccine before the election? Why wasn’t the AstraZeneca vaccine approved in the US shortly after being approved in the UK? Why were there not any COVID-19 human challenge trials until 7 March 2021?
To shed some light on these questions, I constructed this timeline. However, much further autopsy is needed on the decision making processes that occurred at the FDA to prevent the FDA’s devastation this past year from happening again. Unfortunately, the decision making in the FDA hasn’t been very transparent. The FDA has not produced even rough cost benefit analyses to explain the following critical decisions, for instance:
Their October decision to issue new guidance requiring a longer follow-up period in Phase III trials, which pushed out Pfizer’s EUA until after the election.
Their decision to not push for human challenge trials.
Their decision to require AstraZeneca essentially redo their Phase III trial, pushing approval of AstraZeneca’s vaccine out until April at the earliest.
Constructing this timeline has helped me infer why these disastrous decisions were made, but much more work is needed to get to the bottom of how these decisions were arrived at, and I suspect FOIA requests will likely be required.
Note that to keep things simple I only focus on the vaccine development and approval process and I only cover the Moderna, Pfizer, and AstraZeneca vaccines. Early on the focus is more on Moderna & Pfizer, and I omitted some parts of the early AstraZeneca story. Obviously there are many other things one could timeline, such as case/death counts, non pharmaceutical interventions, and manufacturing.
💗 Human challenge trails
📜 Scientific paper reporting vaccine trial data
💉 Vaccine approval
3 January 2020 SARS-CoV-2 samples arrive at Prof. Zhang Yongzhen’s lab at the Shanghai Public Health Clinical Center.
5 January 2020 Prof. Zhang Yongzhen’s lab finishes sequencing the genome of SARS-CoV-2. The sequence is uploaded to a public research database at the U.S. National Center for Biotechnology Information, a laboratory at the National Institutes of Health’s campus in Bethesda, Maryland. The upload is not announced though, and it seems nobody noticed.
10 January 2020 Prof. Youngzhen’s lab is shut down by the CCP. The reasons for this are unclear.
13 January 2020 🇲 NIH/NIAID immunologist Barney Graham sends Moderna an optimized version of the spike protein gene that becomes the backbone of Moderna’s vaccine. This date is sometimes cited as the date of the invention of the Moderna vaccine.
15 January 2020 🇲 Manufacturing work begins on mRNA and lipid nanoparticles for Moderna’s Phase I trial, the animal part of which will take place at Barney Graham’s lab at NIH/NIAD. To quote their paper: “Good Manufacturing Practice (cGMP) production of mRNA/LNP expressing the SARS-CoV-2 S-2P as a transmembrane-anchored protein with the native furin cleavage site (mRNA-1273) was initiated in parallel with preclinical evaluation”.
31 January 2020 💗 A paper published in The Journal of Infectious Diseases argues for human challenge trials as an alternative to Phase III trials in order to make efficacious and safe vaccines available more quickly and save lives.
14 February 2020 💗 Economist Robin Hanson publishes the first in a series of articles on exploring deliberate infection. Among other things, he argues that challenge trials should be used to discover what the effect of viral load is and if (as for other viruses) variolation may be an effective strategy in the absence of a vaccine. (See his March 30th summary).
24 February 2020 🇲 Moderna ships mRNA vaccine to NIH/NIAD for a Phase I challenge trial in mice.
11 March 2020 The WHO declares that a pandemic has started.
16 March 2020 🇲 Moderna’s Phase I/II trial starts. Jennifer Haller becomes the first person to receive the Moderna mRNA vaccine.
21 April 2020 💗 a letter signed by 35 members of Congress urges the FDA to accelerate the deployment of vaccines. They say, in part: “In the case of accelerated human trials, justifiable risks may be taken by parallel testing of multiple dose levels, advancing more rapidly from phase to phase and potentially by challenge trials that involve deliberately infecting volunteers who have received candidate vaccines or placebos to confirm the efficacy of those vaccines and are at very low risk of serious disease from the infection.”
27 April 2020 💗 Peter Singer and Richard Yetter Chappell make the case for human challenge trials in The Washington Post.
29 April 2020 🇵 Pfizer’s Phase combined phase I/II/III trial starts.
6 May 2020 🇲 The FDA approves Moderna’s s Investigational New Drug application allowing them to proceed to phase II study.
6 May 2020 💗 The World Health Organization publishes a white paper on criteria for the acceptability of human challenge trials. The report suggests the trials could be useful for speeding vaccine development.
7 May 2020 💗 The number of human challenge trial volunteers recruited by 1DaySooner reaches 14,000 from 102 countries.
12 May 2020 🇲 The FDA gives Moderna a “Fast Track Designation” for their mRNA vaccine.
15 May 2020 Operation Warp Speed is announced.
18 May 2020 🇲 Moderna announces positive interim Phase I data showing robust immune response in humans and blocking of the vaccine in mouse challenge trials.
15 May 2020 The FDA halts the Seattle Flu study, which had pivoted to study the spread of COVID-19, prompting outcry from many experts.
11 June 2020🇲 📜 Barney Graham’s group at NIH publishes a preprint on their studies of mRNA with a lipid nanoparticle in N=47 mice. They find “mRNA-1273 induces both potent neutralizing antibody and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of mice without evidence of immunopathology.”
15 June 2020 the FDA revokes their EUA for hydroxychloroquine.
29 June 2020 💉 China approves CanSino’s vaccine for military use.
8 July 2020 🇲 Moderna completes enrollment for their Phase II study.
20 July 2020 🇦📜 Safety and immunogenicity results from the Phase I/II trials for the AstraZeneca vaccine are published in The Lancet.
28 July 2020 🇲 📜 Positive results from a primate challenge trial of Moderna’s vaccine are published in The New England Journal of Medicine (NEJM).
29 June 2020 🇵 Pfizer submits their paper with Phase I/II data to Nature for review.
14 July 2020 🇲📜Preliminary Phase I data on Moderna’s vaccine (mRNA-1273) is published in The New England Journal of Medicine. The study showed a strong immune response from the vaccine in 45 healthy adults, 18 to 55 years of age.
27 July 2020 🇲 Moderna’s Phase III trial starts.
30 July 2020 White House Chief of Staff Mark Meadows and Treasury Secretary Steven Mnuchin meets with Nancy Pelosi and Chuck Schumer as part of a series of meetings regarding COVID-19 relief. According to one source, he tells them there could be an EUA of the AstraZeneca vaccine in October. In response, Nancy Pelosi warns there should be no “cutting corners”. [ref]
12 August 2020 🇵 Pfizer’s paper with Phase I/II safety and immunogencity data is published in Nature.
22 August 2020 Trump tweets: “The deep state, or whoever, over at the FDA is making it very difficult for drug companies to get people in order to test the vaccines and therapeutics. Obviously, they are hoping to delay the answer until after November 3rd. Must focus on speed, and saving lives! @SteveFDA”
23 August 2020 The FDA issues an EUA for convalescent plasma. The FDA’s triumphant headline “Another Achievement in Administration’s Fight Against Pandemic” and Secretary Azar’s jubilant press conference receive much pushback. In that press conference, FDA Commissioner Stephen Hahn makes a grave error, stating that the trial showed “35% mortality reduction”. The overly laudatory press conference, which was out of step with the science on convalescent plasma, undermines faith in the FDA and leads to a wave of stories about the FDA rushing through treatments under pressure from the Trump administration. Eric Topol says this was the day he became “an activist” to make sure the FDA did not rush the vaccines.
24 August 2020 FDA Commissioner Stephen Hahn admits he made a mistake when discussing the trial results on the effectiveness of convalescent plasma.
27 August 2020 The CDC sends documents to public health officials in 50 states and 5 large cities advising them to prepare for a vaccine approval in late October or early November. One document suggests a total of 3 M doses will be available by the end of October and 20-30 M doses by the end of November, split between “vaccine A” and “vaccine B”. The document is a fascinating window into what might have been.
2 September 2020 The NY Times breaks the news about the notices the CDC sent on August 27th. The story, which cites scientists skeptical about whether such an aggressive timeline is possible, sets off a long-lasting firestorm of objections. A new narrative emerges that the vaccine EUA is being “rushed” to give Trump a win before the election.
3 September 2020 Senate Democratic Leader Chuck Schumer issues a statement which is widely reported in major news outlets. The short statement reads in full: “Too much of the evidence points to the Trump administration pressuring the FDA to approve a vaccine by Election Day to boost the President’s re-election campaign. This raises serious safety concerns about politics, not science and public health, driving the decision making process. All Americans want a safe and effective vaccine as soon as possible, but if these important life and death decisions appear political, it will only undermine Americans’ confidence in a vaccine and prolong the pandemic.”
3 September 2020 Rachel Levine, president of the Association of State and Territorial Health Officials, says Phase III trials must be completed before any EUA. Levine now serves as Assistant Secretary for Health at HHS under the Biden administration.
3 September 2020 Former FDA commissioner and Pfizer board member Scott Gottlieb is quoted in the Washington Post as saying “it is highly likely” the first vaccine cleared through an emergency use authorization would only be approved for a select population, such as the elderly.
4 September 2020 💉 Russia approves their Sputnik V vaccine on basis of Phase I/II data.
5 September 2020 In a CNN interview vice presidential nominee Kalama Harris is asked if she would trust a vaccine that was approved for emergency use before the election. She punts on directly answering the question and casts a lot of doubt on the integrity of the FDA’s process and whether it is shielded from political influence.
8 September 2020 The CEOs of 9 pharma companies sign a pledge to not seek EUA from the FDA until after they have conducted their Phase III trials. Some Trump administration officials had pushed for EUAs for most at-risk groups based on Phase I/II data.
6-9 September 2020 🇦 AstraZeneca has to halt their trial due to a participant showing neurological symptoms. At first they said it was halted due to one participant, but they later revealed there were actually two. The company is slow to release data publicly, causing some backlashes. However, both cases are later found to be false alarms, since both patients were in the control group. AstraZeneca also made a mistake where they forgot to report the trial halt to the FDA. By all accounts this was unintentional and it was described by one reporter as a “clerical error”. According to the NY Times, FDA Commissioner Hahn was “stunned” by the mistake, and employees at the FDA felt “blindsided”. As part of the fallout from the halt AstraZeneca’s enrollment of US patients into their Phase III trial is delayed for 47 days, much longer than in other countries (in Britain, Brazil, India and South Africa, regulators allowed the trial to resume within a week) . The NY Times reports “AstraZeneca was in part to blame for the delay, said the people with knowledge of the F.D.A. talks.”
10 September 2020 8 high ranking career FDA officials pen an op-ed in USA Today. The article lacks substance and specifics regarding the EUA process but attempts to console the public that decisions are made on the basis of science, not politics.
13 September 2020 🇵 Pfizer CEO Albert Bourla tells CBS’s Margaret Brennan on Face The Nation that they are on track to know if their vaccine works by “the end of October”. Anthony Fauci and Mocef Slaoui later opine that the October date is unlikely. Bourla also announced Pfizer has almost 30,000 people enrolled in their Phase III trial and that Pfizer plans to expand the trial to more diverse population of 44,000 people. Unlike other companies, Pfizer did not take any taxpayer money to fund their vaccine development (estimated cost 1.25 - 1.75 billion) (correction: actually they benefit from a 2 billion dollar Operation Warp Speed contract, but they misled the public by claiming they were not part of OWS. Still, they invested substantial private funds and did all research in-house which allowed them to move faster than Moderna). Since they were more free to spend money as they saw fit, Bourla says this “liberated” Pfizer’s researchers and allowed them to spend money more quickly and liberally.
23 September 2020 White House Chief of Staff Mark Meadows calls FDA commissioner Stephen Hahn and asks the agency to provide a detailed justification for new guidance being drafted that will require a longer Phase III follow up period before EUA.
25 September 2020 The campaign to slow down the Pfizer EUA picks up steam. 60 “leading researchers and bioethicists” send a letter to Pfizer CEO Albert Bourla advocating that Phase III trial participants be monitored for a 2 month follow up period after the 2nd dose before the EUA application is submitted.
29 September 2020 🇲 Final results from Moderna’s Phase I study are published in the NEJM.
6 October 2020 The FDA issues new guidance requiring a two month median follow up period in phase III trials. This extends the follow-up period by ~4 weeks and ensures the Pfizer vaccine cannot be approved before the election.
6 October 2020 Reuters reports that Moderna has slowed its vaccine trial to adjust diversity among subjects. Black Americans made up only about 7% of the trial.
9 October 2020 🇦 Nancy Pelosi tells reporters the FDA should not approve the AstraZeneca vaccine based on their Phase III trial in the UK/Brazil/South Africa. She says, in part “My concern is that the UK’s system for that kind of judgment is not on a par with ours in the United States. So if Boris Johnson decides he is going to approve a drug and this president embraces that, that is a concern that I have.”
13 October 2020 🇲 Health Canada starts a rolling review of Moderna’s vaccine trial data.
14 October 2020 💗 An open letter signed by 33 Nobel Laureates and 145 experts urges the UK to start human challenge trials.
14 October 2020 🇵 📜 Phase I safety and immunogenicity data for Pfizer’s vaccine is published in NEJM.
16 October 2020 🇵 Pfizer CEO Albert Bourla writes an open letter explaining that based on their current Phase III enrollment pace, they will reach the FDA’s new follow-up requirements “in the third week of November”.
20 October 2020 💗 The first ever COVID-19 human challenge trial is announced in the UK.
22 October 2020 🇲 Moderna finishes enrolling ~30,000 people into their Phase III trial.
22 October 2020 The FDA convenes their VRBPAC committee to discuss the progress on vaccines so far. Many concerns are raised about the pace of progress, especially from Pfizer. Committee member Stanley Perlman pushes for requiring a 4 month Phase III follow-up period before EUA.
8 November 2020 🇵 Pfizer executives are briefed on the Phase III trial so far. Of 94 people who had gotten sick, they were told, 90 were in the placebo group and only 4 were in the vaccine group.
8 November 2020 President-elect Biden is notified by Pfizer of the vaccine results, before any HHS officials are notified.
9 November 2020 🇵 Pfizer announces interim Phase III efficacy of 90+%. HHS Secretary Alex Azar learns of the results from early morning media reports.
16 November 2020 🇲 Moderna announces interim Phase III efficacy of 94.5%
17 November 2020 🇲 The European Medicine Agency starts a rolling review of Moderna’s vaccine.
18 November 2020 🇦 📜 Safety and immunogencity Data from AstraZeneca’s Phase II/III trial is published in The Lancet.
20 November 2020 🇵 Pfizer submits EUA paperwork to FDA.
26 November 2020 💗 A preprint by Manheim et al. is published that performs a Bayesian analysis to estimate risks to young, healthy, participants in a COVID-19 human challenge trial. With some assumptions they estimate the risk that someone will die in a trial to be 3.1 per 100,000, with a 99.85% (95% CI: 99.7% to 99.9%) chance of no fatalities in an N=50 trial.
27 November 2020 🇵 UAL starts distributing Pfizer vaccine in lieu of EUA. Note, however, they are banned from distributing to health care providers by FDA.
30 November 2020 🇲 Moderna submits EUA paperwork to FDA.
2 December 2020 🇵 💉 The UK approves Pfizer’s vaccine.
8 December 2020 🇦 📜 Efficacy data from AstraZeneca’s Phase III trial is published in The Lancet. It causes controversy due to the lack of COVID-19 events in those aged 65+ in the control arm and a mistake where some participants got a half dose. The mistake happens to be a blessing though as it is discovered that a half dose followed by a full dose is more effective (~90% with the right dosing schedule), something which is not uncommon for vaccines.
9 December 2020 🇵 💉 Health Canada approves Pfizer’s vaccine.
10 December 2020 🇵 The FDA VRBPAC committee votes 17-4 in support of EUA for Pfizer.
10 December 2020 🇵 📜 Pfizer’s Interim Phase III efficacy data is published in the NEJM.
11 December 2020 🇵 💉 The FDA issues an EUA for Pfizer’s vaccine .
17 December 2020 The FDA VRBPAC committee votes 20-0 in support of EUA for Moderna. One committee member abstains from voting.
18 December 2020 🇲 💉 The FDA issues an EUA for Moderna’s vaccine (19 days from submission).
21 December 2020 The EMA authorizes the Pfizer vaccine.
23 December 2020 🇲 💉 Health Canada authorizes Moderna’s vaccine.
30 December 2020 🇲 📜 Phase III efficacy data for Moderna’s vaccine, which had been announced earlier, is published in NEJM.
30 December 2020 🇦 💉 AstraZeneca’s vaccine is approved in the UK.
6 January 2021 🇲 💉 The EMA authorizes Moderna’s vaccine.
8 January 2021 🇲 💉 The UK approves Moderna’s vaccine.
2 February 2021 🇦 France restricts AstraZeneca vaccine to those aged less than 65 years of age.
2 March 2021 🇦 France recommends the AstraZeneca vaccine for those aged 50-75.
19 March 2021 🇦 France recommends AstraZeneca vaccine only to those aged more than 55 years.
7 March 2021 💗 The first COVID-19 challenge trial volunteer is infected in the UK.
I plan to write up a more detailed post with my conclusions from this research, but here are a few high level observations:
The FDA started off using the EUA process along the lines it was intended to be used, issuing EUAs for hydroxychloroquine (HCQ) and convalescent plasma (CP) relatively quickly and then allowing doctors to make individualized decisions on whether to use these treatments for their patients at risk of dying from severe COVID-19. I believe both of these were great decisions, given they are relatively low risk treatments for patients at high risk of dying (note, I am aware HCQ carries cardiovascular risk and CP carries clotting risk!). However, while there were some Chinese RCTs and observational data suggesting efficacy of HCQ at the time, the scientific consensus now is that HCQ is not effective. To their credit, the FDA revoked their HCQ EUA, but the optics on this were very bad, especially with Trump touting HCQ as a “miracle” treatment.
Critical event #1 happened on August 23rd when the FDA announced their EUA for convalescent plasma. Hahn made a terrible mistake in exaggerating how effective the data showed it was. That was the moment Topol says he became an activist. The influence of Eric Topol in this saga should not be underestimated. Many other scientists also started speaking out, rightly calling out the FDA for unscientifically hyping a treatment in an apparent attempt to appease Trump.
Critical event #2 happened on 2 September when The New York Times reported that the CDC told health officials to prepare for vaccine distribution in “late October” or “early November”. This kicked off a huge backlash from people who perceived that the FDA was rushing the vaccines to give Trump a win before the election. Hundreds of editorials and “open letters” were written opposing the idea. From what I can tell, in an alternative world where this backlash had not occurred, millions of Pfizer doses would have been made available to the elderly and other high-risk people in early November and tens of thousands of lives would have been saved.