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There is growing concern that the Food and Drug Administration, under political pressure, could approve a Covid-19 vaccine before it has robust safety and efficacy data.

The consequences of such a decision could be significant, particularly if the vaccine is ultimately shown to be less effective than early data suggest. But an approval before the completion of large, Phase 3 trials does not have to be problematic. Experts aren’t ruling out the possibility that a vaccine could be cleared this fall if it is very effective.

“There are mechanisms by which products that have a good amount of data can be made available in a controlled way,” said Natalie Dean, an assistant professor of biostatistics at the University of Florida who specializes in vaccine study design.

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But Dean also sees risks. 

“If you make a decision based on promising but not convincing data, and then you discontinue your randomization,” she said, “you discontinue your evidence-generating process. You can never go backward. You can never go back and generate your evidence.”

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Here is how a fast approval might play out, if all goes well — and some warning signs that a science-based process is not being followed.

The FDA has laid out clear criteria for the full approval of a vaccine: It should reduce the rate of symptomatic Covid-19 disease by 50%. Equally important is that the data should suggest it’s highly unlikely that the vaccine could possibly be less than 30% effective. Any vaccine less  effective than that would be useless.

The agency also said that there should be safety data of a year or more for at least 3,000 patients. There’s no way to shorten that timeframe, and it is one of the reasons experts believe the FDA could grant a Covid-19 vaccine an emergency use authorization, rather than full approval. 

It’s also possible that the studies could be ended early based on an interim analysis of data. 

These early looks are handled by a data and safety monitoring board, or DSMB, that reviews the data from a study regularly to make sure that patients are not being endangered by side effects from the vaccine and that it’s still ethical to give a placebo. 

“At the end of the day, if things are done according to the tradition, the DSMB looks at the data intermittently and makes one of four determinations,” explained Anthony Fauci, the director of the National Institute for Allergy and Infectious Diseases, which is working with Moderna and AstraZeneca on vaccine trials.

A study can be stopped because a vaccine is clearly effective; it can be stopped because  clinicians are seeing troubling side effects. The DSMB can recommend changes to a study. Or, as usually happens, it can do nothing.

“It’s up to the DSMB, in their judgment, to balance the safety issue, the efficacy issue, and the duration of the trial issue,” Fauci said. “And that’s the reason why they’re an independent group. They are not the company because obviously the company is going to want to get their product approved as quickly as possible.”

But there are also pre-set rules as to when a trial can be stopped. “The earlier you stop it, the higher the bar,” Fauci said.

Technically, the final decision about what to do rests with the companies that are developing the vaccines, Fauci said. But, he added, “it would be unusual for the company to do something completely dissociated from or at odds with the DSMB.”

How could these interim analyses play out? Each of the Phase 3 trials is enrolling at least 30,000 volunteers. It’s expected that the trials could need about 150 cases of Covid-19 to tell whether or not the vaccine is preventing disease. 

But the more effective a vaccine is, the more likely it is that the trial could be stopped at an interim analysis based on fewer cases. Because the studies are so big, this could happen very fast. Pfizer, which is conducting its study with partner BioNTech but not with NIAID, has said its first interim analysis will occur when 32 patients have developed Covid-19. That could happen as early as this month.

Is it likely the trial will be stopped that early? Probably only if the vaccine is extremely effective, with only a handful of patients in the vaccine group getting sick. 

Steven Nissen, a cardiologist at the Cleveland Clinic, thinks the trial shouldn’t be stopped so quickly, even if the DSMB has that option based on the efficacy data. He once ran a study of an obesity drug that was stopped — yielding unclear results — because the company funding the study improperly released an interim analysis.

“If I were designing this trial, and I knew you had to have full safety information, what is the value of the interim, exactly?” Nissen asked. “How do you help society with an interim if you can’t stop because you don’t know about safety?”

And if the DSMB thinks that it is ethical to keep patients on placebo, experts are firm that the results of these analyses should not be made public. 

“If you release an interim analysis that didn’t cross the threshold but the groups have started to diverge, chaos can [ensue],” said Dean. “People don’t know what to do with that information. And I don’t think people can use that information responsibly.” 

Side effects, she said, might be more apparent early on than many people expect, because with vaccines they usually occur within weeks of the administration of the shot. But she, too, hopes the DSMBs on these studies have the wherewithal not to rush.

“This is not a disease where you have to wait a decade to accrue the information you need,” Dean said. “You’d have to wait another month, or another week, and when you think about how long the rollout is going to take, that’s not going to be long.”

Luciana Borio, a former acting chief scientist at the FDA, said that in a public health emergency, “it may be reasonable” to deploy vaccines before all requirements for licensure have been met. She added:  “It would be completely unreasonable and wrong to prematurely deploy them before you have randomized controlled clinical trials and clear data that the vaccine is safe and effective.”

And, she said, the decisions must be based on science, and made by staff at the FDA, with input from its advisory committees. The design of the studies, she said, should be made public before results are released.

“I hope we see these decisions driven by the appropriate group of experts in a transparent fashion in our advisory committees, and not from the podium at the White House or in a phone call from the White House to the commissioner,” Borio said.

  • Folks,
    The risks of side effects of a vaccine are possible but thousands are dying daily of the virus. Others who get the virus are at risk for lifetime cardiac and pulmonary issues. The discussion is a great intellectual exercise but there is daily morbidity and mortality going on worldwide.
    So every day without a vaccine means thousands are dying or suffering a lifetime of complications.
    Think of that.
    Every month of delay means over 100,000 die worldwide.
    Given these statistics we need it ASAP.

    • I agree 100 % with Joseph Jameson. Already we know high antibody levels are being achieved in the 3 major studies ( including Oxford). We should know by mid-October if any significant complications are likely. I hope release occurs in November to avoid charges that it is all politics.

    • Every month of delay means over 100,000 die worldwide.

      That’s a good thing, imho. Our obese, scientifically illiterate, hedonistic society needs to change its ways and get used to doing without. We don’t need to be hanging out together in bars or shops. the people who can’t do without constant amusements have tv to keep them tranquilized, passively waiting for their turn to be processed through the hospital system and be disposed of. Make tose DNR arrangements in advance and save your relatives lots of time.

    • Political pressure to be released… HA!
      The only political pressure is to SLOW the release of a vaccine.
      The dems would rather see more people DIE than have a vaccine available before the election.

  • What worries me is the politicization of FDA’s Covid-19 treatment approval process starting with the premature and subsequently withdrawn Emergency Use Authorization (EUA) for hydroxychloroquine. Then over the last two weeks with Dr Stephen Hahn’s misstatements supporting the use of convalescent plasma and his insufficient attempts to correct them later.
    I suspect that FDA’s recommendation of a minimum 3000 subjects in the safety population was based on the number of subjects who they believe will have available data for one of the safety endpoints – local and systemic adverse reactions from a week after the first dose to a week after the second dose or a period of about 5 weeks – by mid-October. Both the Moderna and Pfizer/BioNTech had enrolled about 3000 subjects per arm (vaccination vs placebo) by early August when FDA issued their criteria for approval. Working forward, this will give both companies time to analyze data in early October and then submit applications for Early Use Authorization before the election. Predetermining the size of the safety population for a very short period of time is not the best way to determine whether a vaccine is safe.
    Let’s wait to see what the data tell us.

  • All the people complaining about Trump here, if it were Biden doing the exact same thing, would be gushing with praise at how quickly his administration was able to put forth a vaccine. Sad.

    • It is the person, not the party. I do not trust anyone who lies constantly to undermine others and promote only themselves. What’s sad to watch Is an American President lie every day and actively work to undermine not only his political opponents but the voting process. Trump has earned the distrust. Furthermore it is sad to read comments on this site defending the lies and gaslighting that undermine trust not only in the election but in public health. Sad times indeed.

    • Seriously? I don’t think I’m alone in having lost trust in both the FDA and CDC, most especially over the past few months. It has everything to do with their vulnerability to senior leadership (ie Trump) ( unless it’s the working of the “deep state”). For the CDC, it’s been the numbers. But for the FDA, this year, it’s Emergency Use Authorizations. I would hate for this vaccine to follow the memorable emergency medication, Hydroxychloroquine , followed by the excitement over Blood Plasma which was released before studies were completed, and highlighted by the FDA Commissioner’s exaggerated results. Hydroxychloroquine was found by repeated studies to be ineffective. The emergency use authorization for Blood Plasma continues to manifest damage. The NIH just found there was insufficient data to support its use. Most hospitals refuse to use it but, given the President’s recommendations, patients may have different expectations.
      The EAU bar is so low as in “it is reasonable to believe that the product may be effective “.
      I’m no conspiracy theorist but, there’s a few reasons for everyone to be apprehensive about a vaccine approved just before the election this year.
      Another baffling aspect to the EAU process is that once the product is approved, the study ends, so any real questions or assurances you might have or desire, disappear.

    • @ Linda D
      I don’t drink kool-aid. It is disingenuous of you to call anyone brainwashed. And since there is no true Republican party left, there is certainly no truth there. When you condescend to label and attack people vs. ideas, it reflects far more on you.

    • Suzanne, I thought Linda D’s comments about drinking the Kool Ade were satire, given away by her last sentence. Am I wrong? If I am not, why is she commenting on a story about getting the science and statistics straight?

    • You are correct, sir!
      As I mentioned elsewhere, the dems will do everything that can to PREVENT the release of a vaccine before the election. To hades with peoples health, wealth and well being.

  • I am sorry to say that the behavior of the Trump administration with respect to covid-19 has seriously damaged its credibility. It’s clear that decision-making at both the FDA and the CDC has been seriously compromised for perceived political gains. Consequently, I would place very little trust in a covid vaccine that was developed without a complete, stage three clinical trial!

  • The thalidomide issue came to mind when hearing of a blunted phase 3 due to no political pressure under the Trump Administration. That was boosted when the one FDA doc said it was like Hydrochloriquin and an ER where Doc’s try anything with a patient trying to save them. After working in an ER I’ve never seen an ER doc attempt something non-normative with any patient. They know what they’re doing.

  • The problem with the vaccine is not political but practical.

    If the disease is highly contagious and is putting the entire population at high risk of death, then the imposition of an untested vaccine on a population is justifiable.

    But this is not the case with COVID-19. At least 40% to 50%, and may be as many as 90% of COVID-19 infection are asymptomatic or minimally symptomatic. We don’t know. Widespread testing shows widespread dissemination of the virus; a huge number of asymptomatic or minimally symptomatic cases; and implied widespread immunity in the population.

    The vaccine, if given to a person with an active infection, may make things worse (so called antibody dependent enhancement). What viral load is clinically significant? Many current tests detect too low of a viral load. Will everyone be tested for the virus prior to getting the vaccine? and which test?

    The immunological response of the population is a continuous curve and not a binary response. Side effects of the vaccine will only be detected once it is given to hundreds of millions of patients. This problem only became evident with the swine flu vaccine and increased number of patients with Guillain-Barre.

    Which people will take the vaccine? If I am less than 50, otherwise healthy without obesity, diabetes type 2, hypertension, will I take the vaccine? We use age and medical criteria for pneumococcal and shingles vaccines. If my chance of being asymptomatic is 90%, and probably close to 100% if I don’t have these associated criteria why would I take an untested vaccine? If vaccination is mandatory for work and travel, and I develop Guilain-Barre, MS, or other aberrant immunological response, who is responsible?

    If I am over 50 and I have these associated conditions my immune response is less likely to be optimal, will I be protected? It is very difficult to know, without extensive population testing and long-term follow up.

    The problems are practical, not political. The solution may be political as it gives cover to politicians to lift the imposed lock downs.

    • I don’t get Joan Smith’s reply. Pathcoin1’s observations seem sensible and helpful and I don’t see how anyone can claim that they have a pro-Trump bias.

    • This is my primary concern as well. When altering the immune system there are multiple questions that need to be addressed. I believe that efficacy of the vaccine is going to be established with acceptable certainty – enough to justify it’s release as a prophylactic.

      What I do not see being asked are side effects – what risks do the new antibody & T-cell repitoires confer? As a healthy 25-35y.o., I would prefer to continue to socially distance, wash my hands, and wear a mask in public until more data is collected on adverse effects in the coming months. Perhaps elderly and other at-risk populations may have different considerations to make.

      It should be said that existing vaccines are extremely safe and extremely effective. But that’s because safety and efficacy data is collected over years, not months, before being made publicly available.

  • In the past few weeks the CDC and FDA, government agencies that are meant to protect our health, have made some clearly wrong and unethical proclamations resulting from undue influence by politicians. I would point to for recent examples: convalescent plasma and the “no need to test” guidance for exposed individuals who are non-symptomatic (those who MOST NEED to be tested. I have always supported vaccination. But now I do not believe I can trust that a vaccine (approved before Election Day) can be trusted. I am assuming when a vaccine is approved the rigorous clinical trials cease. Where can we turn for trustworthy information about safety and efficacy? Should we look to trials run by government agencies say in Canada or Europe? I would like a knowledgeable person to answer this question about a source we can trust.

    • I suspect that DSMB decisions will follow the point in late September when the trials are fully enrolled. And I believe no responsible expert on a DSMB will recommend approval with such a limited safety database. Personally, I would like to see at least 3-6 months of safety data for the full population before any decision is made, because many of the autoimmune related serious adverse events don’t develop for several weeks after vaccination. The trials are being run both within the US and in other countries, so if FDA and other health authorities don’t agree, we will know. But perhaps you’re right – don’t get the vaccination until other HA’s approve as well.

  • DSMBs & other experts in US, must recommend EUA, if vaccine is found effective and safe from partial trial-3 data. Thousands are dying everyday
    and many more are suffering from the sickness.

    • “… if vaccine is found effective and safe from partial trial-3 data …”

      That’s a big “if”, whether results can be trusted in trump world. That’s how damaging his “leadership” is – it is hard to know what to trust these days, especially if timing of an announcement is just before elections. Propaganda or truth? Bet my life on it? Hard to say. Probably not.

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